About HIV/AIDS

New targets for HIV vaccine

2007-07-20T10:23:00.000-07:00

Duke University Medical Center has claimed that genomic analysis has uncoverved new targets for HIV vaccine

An international team of researchers has identified three gene variants in the DNA of 486 people infected with HIV that appear to have helped some of the patients fight off the virus and delay the onset of full-blown AIDS, according to the Science Daily report.

The researchers expect the new findings to aid the search for an HIV vaccine that would work by boosting the protective effects of one or more of these genes, and help the body's own immune system overcome an infection. One of the genes looks particularly attractive as a vaccine target.

The study, published by the journal Science July 19, was directed by David Goldstein at Duke University and is the first large cooperative study with major findings arising from the Center for HIV/AIDS Vaccine Immunology, (CHAVI) a seven-year project funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, in 2005, led by Duke's Barton Haynes, M.D.

It took the international genetics team, called EuroCHAVI, pooling their cohorts of carefully selected patients and using the latest in genome-wide screening technology, 18 months to discover the three genes, that together greatly increase our knowledge of why patients differ in how well they can control the virus that causes AIDS.

These findings represent only the first of what investigators said will be a series of future genome-wide studies to pinpoint additional targets for HIV vaccines. In the new analysis, patients with specific gene variants in key immune system cells appear to be much better at controlling the proliferation of the virus after infection. These gene variants are known as polymorphisms.

"These results not only approximately double our understanding of the factors that influence variation amongst individuals in how they control HIV-1, but also point torward new mechanisms of control," said David Goldstein, Ph.D., director of the Center for Population Genomics and Pharmacogenetics at Duke's Institute for Genome Sciences & Policy. Goldstein is the senior author of the paper.

"As we expand the number of patients in future studies conducted by CHAVI researchers, we aim to discover even more polymorphisms that could provide additional clues how some patients are better able to control the virus than others," Goldstein. "This should ultimately lead to novel targets for vaccines, the primary goal of CHAVI."

Two of the polymorphisms found were in genes controlling the human leukocyte antigen (HLA) system, which plays a major role in the immune system by identifying foreign invaders and "tagging" them for destruction.

Two of the HLA genes, known as HLA-A and B, are turned off by HIV when it enters the body, which keeps the immune system from recognizing the virus as foreign. HLA-C however is not thought to be turned off by HIV-1. The new results suggest that for some individuals at least HLA-C is involved in controlling HIV-1. Since HIV-1 appears unable to shut off HLA-C, unlike A and B, HLA-C may represent an Achilles heel of HIV, according to Goldstein, who said that a vaccine could be designed to elicit an HLA-C mediated response which HIV-1 might be unable to defuse.

"This study was the first time a genome-wide approach has been used for an infectious disease," Goldstein said. "Past studies have looked at individual candidate genes. Since different people respond differently to infections, a better understanding of how immune system genes control responses to infections should help us to design better treatments and more effective vaccines."

Added Haynes: "CHAVI was designed to do big science, and the results of this analysis represent just the first of what should be many advances. The technology used and collaborative efforts involved were truly remarkable: together as a group we were able to do something that none of us individually could accomplish. The results of this and future CHAVI studies should help individual laboratories across the world perform research to better understand the virus."

When someone becomes infected with HIV, the amount of virus in the blood spikes as the virus multiplies. After this peak, the amount of virus in the blood, known as the viral load, gradually decreases and then levels off, a period during which patients do not exhibit symptoms of their disease. The viral load during this leveling out is an indication of how well the patients' own immune system is battling the virus, and this is the point in the infection's natural history that the researchers studied.

The CHAVI investigators wanted to study those patients who had many sequential blood samples taken during this plateau in viral load. Before their analyses began collaborators in the EuroChavi consortium, coordinated by Amalio Telenti at the University of Lausanne, sifted through data collected from more than 30,000 patients who had blood samples taken as a part of nine studies in Europe and Australia. They arrived at 486 patients who had had multiple blood tests documenting viral loads after infection and before they started receiving antiretroviral treatment.

The three polymorphisms were identified after all the blood samples of the selected patients were screened for more than 555,000.

Additionally, the researchers discovered many other genetic variants that may confer protection for patients but whose effects did not reach statistical significance in the study. However, some of these polymorphisms could ultimately be shown to play a major role when future analyses involving more patients are performed, the researchers said.

Source: Duke University Medical Center and
Science Daily

Control of HIV virus

2007-07-20T09:54:00.000-07:00

According to the Science Daily based on United Press International reports, researchers from North Carolina's Duke University discovered a series of genetic variations that could help HIV-infected people avoid developing AIDS.

The study, which was led by scientists at Duke's Center for HIV/AIDS Vaccine Immunology, used Human Genome Project research to find specific variations in a trio of genes that offer hope for a better understanding of how to control the HIV virus, the San Francisco Chronicle said Friday.

By focusing on the individual stability of the virus within a patient's bloodstream, the researchers were able to discover two genes that appeared to help control the virus.

Through analyzing the genetic makeup of 486 patients in relation to virus control, the scientific team came up with the HLA-B*5701 and HLA-C genes.

The team, that also included several other scientists worldwide, found that each gene was able to control the HIV virus in its own unique way.

A third gene, ZNRD1, was recognized by the group for its apparent ability to limit HIV replication, the Chronicle reported.

3D Animation of HIV Replication

2007-03-07T11:51:00.000-08:00

Here is a link of an outstanding 3D animation of HIV replication cycle. Hope you will find it informative.

Click here to see the ANIMATION
>>>>>

It is about six minutes log. So be patient.

The animation is fairly accurate representation of what we know about the this viruses life cycle today, except the part on entry of viral DNA into nucleus. Based on our current knowledge, import of viral DNA into nucleus is not dependent on integrase but other viral and host proteins that are still elusive. Integrase is however necessary for the integration of virus DNA into host genome.

HIV AIDS in Nepal from UNDP's eyes

2006-12-30T09:16:00.000-08:00

Regarding HIV/AIDS in Nepal, the UNDPsays:

Nepal has developed a "National Strategy on HIV/AIDS, 2002 - 2006", a costed 5-year Operational Plan with annual National Programme on HIV/AIDS (2004-2005). The National Programme is the overarching framework to guide, monitor and coordinate an expanded response to the epidemic in Nepal. Included in the National Programme, are the activities supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM), and DFID (in a "programme" approach). It has also received parallel funding from AusAID and USAID (through their respective partners), and the UN system.

His Majesty's Government of Nepal (HMG/N), Ministry of Health (MoH), has requested the United Nations System in Nepal (the UN system) to support the implementation of the National Programme in assisting with the management of GFATM funded activities of the programme.

The project is directly executed by UNDP, as the administrative and management agent on behalf of the UN System in Nepal. HMG/ MoH/ National Center for AIDS and STD Control (NCASC) and one representative of the MoH in the expanded UN Theme Group on HIV/AIDS in Nepal, as the guiding and coordinating body for the UN System for the implementation of activities. In this regard, a Third-Party Cost-Sharing Agreement between His Majesty's Government of Nepal, Ministry of Health and the United Nations Development Programme (on behalf of the UN System Nepal), a project document was signed on 27 Feb 2005.

The HMG/N National Center for AIDS and STD Control (NCASC), as the principle-monitoring agent, will monitor the implementation through the agreed indicators with added responsibility in epidemiological surveillance, care, and support.

As Management Support Agency (MSA), the UN system will assist HMG/N, MoH, in managing specific activities funded by the GFATM which form part of the National Strategy on HIV/AIDS, for the period February 2005 to March 2006.

The total budget for the project amounts to US$ 3,181,380 for the period of Feb 2005 to March 2006.

The project is inspired by the principles of the Greater Involvement of People Living with HIV/AIDS (PLWHA).

HIV/AIDS in Five Development Regions
Facts
Focus Area HIV/AIDS
No of Program(s) 1
No of Districts covered 21

Programme
Regions Districts MSNP
Far Western Development Region Achham
Baitadi
Bajhang
Bajura
Dadeldhura
Darchula
Doti
Kailali
Kanchanpur

Mid Western Development Region Banke
Bardiya
Dailekh
Dang
Dolpa
Humla
Jajarkot
Jumla
Kalikot
Mugu
Pyuthan
Rolpa
Rukum
Salyan
Surkhet

Western Development Region Arghakhanchi
Baglung
Gorkha
Gulmi
Kapilbastu
Kaski
Lamjung
Manang
Mustang
Myagdi
Nawalparasi
Palpa
Parbat
Rupandehi
Syangja
Tanahu

Central Development Region Bara
Bhaktapur
Chitwan
Dhading
Dhanusha
Dolkha
Kabhrepalanchowk
Kathmandu
Lalitpur
Mahottari
Makwanpur
Nuwakot
Parsa
Ramechhap
Rasuwa
Rautahat
Sarlahi
Sindhuli
Sindhupalchok

Eastern Development Region Bhojpur
Dhankuta
Ilam
Jhapa
Khotang
Morang
Okhaldhunga
Panchthar
Sankhuwasava
Saptari
Siraha
Solokhumbu
Sunsari
Taplejung
Terathum
Udayapur

Management Support to the National Programme on HIV/AIDS - MSNP

Background

Nepal is facing rapid increase in HIV/AIDS prevalence among high risk groups. The first case of AIDS in Nepal was reported in 1988. By April 2006, more than 1025 cases of full-blown AIDS and over 6443 cases of HIV infection were reported officially. However, due to the limitations of the surveillance system, the actual number of infected people in Nepal is expected to be much higher. According to the Global AIDS Epidemic report 2006, it is estimated around 75000 people living with HIV/AIDS in Nepal.

The government of Nepal requested the UN system to serve as a Management Support Agency (MSA) for executing the Global Fund to Fight against AIDS, Tuberculosis and Malaria (GFATM) grant for HIV/AIDS for which the government is the Principal Recipient. Within the UN system, the responsibility of implementing the grant was given to the UNDP. A Programme Management Unit (PMU) was established at UNDP to manage the grant. Australian Aid for International Development (AusAID) also used the same modality for implementing the harm reduction activities which were being implemented by UNDP since 2004. The Department For International Development (DFID) also gave UNDP the responsibility of managing its funds for responding to the national HIV/AIDS action plan. DFID agreement with UNDP spans from 2005 – 2008. However, DFID has opted to have UNDP directly implement its 2006 - 2008 programmes outside of the UN MSA at UNDP arrangement.

Within the UN system, an MSA coordinating body was been formed to coordinate and monitor the activities conducted by UNDP on behalf of the UN System. Its membership includes UNICEF, UNDP, UNAIDS, UNFPA, NCASC and the Programme Manager of the HIV/AIDS PMU. Moreover, the UN HIV/AIDS theme group and the UN Technical Working Group, chaired by UNICEF and UNAIDS respectively, provide overall policy guidance and technical support to the MSA.

The UNDP HIV/AIDS Programme Management Unit is implementing the following activities from the National HIV/AIDS Plan 2005 -2006 and is directly contributing to the achievement of the national goals. In total 119 projects are implemented in 27 districts through 77 Non Governmental Organisations.

Mobile Population and Families Awareness Raising
Comprehensive Package for Mobile Population
Comprehensive Package for MSW
Comprehensive Package for IDUs
Drug Treatment
Comprehensive Package for MSM
Comprehensive Package for PLWHA
Safe Blood Supply
Adult and Paediatric Care and Support
Behavioural and Contextual Research
Awareness raising for Uniformed Forces
Behaviour Change Intervention among Uniformed Forces
Awareness Raising for Young People
Life Skill Intervention for Young People
Youth Friendly Information Services

Description of Key Activities:

Harm reduction activities for Injecting Drug Users

HIV/AIDS Harm Reduction Program among Injecting Drug Users in Nepal (IDUs) succeeds and builds on the lessons learnt from the multi-donor project “Nepal Initiative”. There are eight harm reduction partners in different location in Nepal providing essential advice and services for IDUs. This project aims to a) maintain and expand harm reduction activities, b) establish and expand oral substitution treatment, and c) design and implement social support services to support harm reduction activities linked to rehabilitation and Antiretroviral Therapy (ARVT).

Prevention and Care & Support activities among labour migrants and young people

The present political situation in Nepal has encouraged the outflow of migrants, many of whom are youth, to migrate towards major Indian cities. They remain out of country for a long period of time only visiting during major festivals. The HIV/AIDS prevention and care activity has targeted migrants and youth due to their increased vulnerability in engaging in high risk activities which are peer pressure, solitude and other underlying factors. The overall goal of HIV/AIDS programme is “To prevent HIV infection in labour migrants and young people in Nepal and provide care and support to the affected people".

The programme is implemented in six districts with high migration pattern, especially to India. The strategies to prevent HIV/AIDS/STI transmission executed by the programme are Advocacy; BCC; Peer Education; Establishment of Information Counselling Centres; Establishment of Youth Friendly Service Centre and Establishment of STI/VCT centres.

Comprehensive Package for IDUs

Injecting Drug Users (IDUs) constitute the population sub-group in which HIV threatens to rise most rapidly. Behavioural research among IDU in Nepal clearly indicates that needle sharing, the major risk factor for HIV, is common. Studies have shown that HIV prevalence among IDUs is high. Rapid assessment in 1999 showed HIV prevalence among IDUs nationwide of 40% and 50% in Kathmandu. Furthermore in 2002 a survey revealed that the prevalence rate has risen to 68% among IDUs in Kathmandu.

With the objective of reducing the HIV/AIDS incidence among the IDUs, comprehensive service package including primary health care services; IEC/BCC; community sensitisation; availability of clean needle and syringes; peer education; condom distribution; establishment of sti/vct service or referral links and counselling and psychosocial support has been planned.

Drug Treatment

The drug treatment activities for IDUs include procurement of methadone; oral substitution programme; rehabilitation and reintegration programme; development of guidelines for harm reduction and linkage to ART programme.

Comprehensive Package for Mobile Population and families

The National HIV/AIDS Action plan has identified the need to target mobile population and their families due to their increased vulnerability towards HIV/AIDS infection. The comprehensive package for mobile population and families includes the following activities: Community orientation and sensitisation; district planning; establishment of district information centres integrated with VCT/STI services or referrals; BCC and community media; development and distribution of destination package; cultural dramas and events.

Comprehensive Package for PLWHA

The comprehensive package for people living with HIV/AIDS includes community sensitization; peer education and psychosocial support, crisis care, home based care and strengthening of PLWHA network.

Comprehensive Package for MSM and MSW

The comprehensive package for MSM and MSW includes behaviour change communication; community sensitisation; peer education; condom distribution and social marketing; and establishment of VCT and STI service or referral links.

Adult and Paediatric Care and Support

The services under Adult and Paediatric Care and Support are procurement of ARVs for adults and paediatrics; procurement and training for CD4 and viral load; support to the establishment of grass root networks for home based care; support to hospice for palliative care and support patient follow up and outreach for ART.

Safe Blood Supply:

The support to the scale-up of blood transfusion services in Nepal is focussed on building capacity of blood banks in order to ensure the adequate , safe and timely supply of blood and blood products to meet the transfusion requirement of the people of Nepal in an equitable and affordable manner. The support incorporates the strengthening of institutional capacity of blood banks to collect and distribute safe blood and blood products. The support is also focused on standardizing the methodologies for grouping and HIV, HBsAG, HCV, Syphilis screening by development of Standard Operating Procedure (SOP) manual and capacity building thereof.

Donor Partner District
The Global Fund to Fight AIDS, Tuberculosis and Malaria Britain Nepal Medical Trust
Save the Children U.S.
Youth Power Nepal
Women Acting Together for Change
Himalayan Association Against STI-AIDS
Community Awareness Against HIV/AIDS and Drug Addiction
Association of Medical Doctors of Asia– Nepal
Innovative Forum for Community Development
Nepal Fertility Care Center
Federation of Nepalese Chamber of Commerce and Industries
Sakriya Sewa Samaj
Nepal Red Cross Society
Care Nepal
B.P. Memorial Health Foundation
Himalayan Social Welfare Organization
Institute of Cultural Affairs
Pro-Public
MRMG
GWP
ABC
CWC
Accham, Doti, Banke, Rupandehi, Chitwan, Jhapa, Dang and Kathmandu
AusAID Knight Chess Club
Help Group for Creative Development
Kirat Yakthum Chumlung Punar Jiwan Kendra
Bidhyarthi Jagaran Manch
Naulo Ghumti
Life giving and Life saving Society
Siddhi Memorial Foundation
Association of Helping the Helpless
Youth Power Nepal
Jhapa Sunsari, Morang, Kaski, Bara,Lalitpur,Kathmandu,Parsa, Kailali, Kanchanpur, Bhaktapur
DFID Addiction Recovery Centre
Association for Rural Social Welfare
Bidyarthi Jagaran Manch (BIJAM)
Blue Diamond
Community Support Group
Community Welfare Centre
General Welfare Pratisthan
Geruwa Rural Awareness Association
Help- Nepal Network
Happy Nepal Wisdom Foundation
Himalayan Social Welfare Organisation
Knight Chess Club
Kirat Yakthung Chumlung Punarjivan Kendra
Lifesaving and Lifegiving Society
Life line Help Group
Lumbini Drug Treatment and Rehab Center
Mountain Resource Management Group
Multipurpose Development Society
Nagarjun Development Community
Namuna Integrated Development Council
National Association of People Living with HIV/AIDS- Nepal
Nava Kiran Rehabilitation Centre
Nava Kiran Plus - Biratnagar
Nava Kiran Plus - Surkhet
Nava Kiran Plus - Chitwan
Nava Kiran Plus - Rupandehi
Nava Kiran Plus - Makwanpur
Naulo Ghumti-Kaski
Naya Goreto
Nepal Aradhana Samaj (Karuna Bhawan)
Nepal Plus
New Hope Foundation
Nepal Red Cross Society including Blood Transfusion Services
Oppressed Class and Women Awareness Center
PRERANA
Punarjiwan Sarokar Kendra
Recovering Nepal
Richmond Fellowship Male
Richmond Fellowship Female
Samjhauta Nepal
Sneha Samaj
Society Support Group
Sparsha Nepal
St. Xavier's Social Services
Support and Care Rehab centre
Women Acting Together for Change
Youth Power Nepal
Youth Vision
Safe Concern
Sustainable Development Facility
STEP Nepal
Jhapa, Morang, Sunsari, Dhanusha, Bara, Parsa, Makwanpur, Chitwan, Syangja, Kaski, Kathmandu, Lalitpur, Bhaktapur, Rupandehi, Bardiya, Surkhet, Kailali, Kanchanpur, Accham, Sarlahi, Mahottari, Dadeldhura, Kavre

› MSNP Programme Districts

Contact

UNDP Focal Point
Ms. Sara Nyanti
HIV/AIDS Unit
UN House, Pulchowk, P.O.Box 107 Kathmandu, Nepal
Tel: 977-1- 552 3200
Fax: 977-1-552 3991
Email: sara.nyanti@undp.org

HIV AIDS SOUTH ASIA NEPAL

2006-12-30T09:13:00.000-08:00

According to the World Bank:

Nepal is facing increases in HIV prevalence among high risk groups such as sex workers, injecting drug users (IDUs), men who have sex with men (MSM), and migrants. There is an urgent need to scale up effective interventions, especially among IDUs. Nepal's poverty, political instability and gender inequality, combined with low levels of education and literacy make the task all the more challenging, as do the denial, stigma, and discrimination that surround HIV/AIDS.

State of the Epidemic

The first case of AIDS in Nepal was reported in 1988. Since then, the numbers have risen among the country’s 27 million people. By the end of 2005, more than 950 cases of AIDS and over 5,800 cases of HIV infection were officially reported, with three times as many men reported to be infected as women. However, given the limitations of Nepal’s public health surveillance system, the actual number of infections is expected to be much higher. UNAIDS estimates that 75,000 people were living with HIV at the end of 2005.

Nepal’s HIV epidemic is largely concentrated in high-risk groups, especially female sex workers (FSW), IDUs, MSM and migrants. Injection drug use appears to be extensive in Nepal and to overlap with commercial sex. Another important factor is the high number of sex workers who migrate or are trafficked to Mumbai, India to work, thereby increasing HIV prevalence in the sex workers’ network in Nepal more rapidly.

Risk Factors

Nepal’s epidemic will continue to grow if immediate and vigorous action is not taken and will be largely driven by injection drug use and sex work. Major risk factors are as follows:

Continued Spread among Injecting Drug Users: In most Asian countries, IDUs are the first community to be affected by HIV. Nepal was the first developing country to establish a harm reduction program with needle exchange for IDUs. However, due to the program’s limited coverage, the impact on HIV transmission has been limited. HIV prevalence among Nepal’s estimated 19,850 IDUs varies by location. 22% of IDUs are HIV positive in Pokhara, whereas 52%, 33% and 8% are HIV positive in Morang, Sunsari, and Jhapa districts respectively (FHI 2005). HIV prevalence among Kathmandu’s 5-6,500 IDUs has decreased from 68% to 52%.
Trafficking of Female Sex Workers: Due to their highly marginalized status in society, female sex workers in Nepal have limited access to information about reproductive health and safe sex practices. Cultural, social, and economic constraints bar them from negotiating condom use with their clients or obtaining legal protection and medical services. Almost 60% of their clients, who are mainly transport workers, members of the police or military, wage earners, and migrant workers, do not use condoms. While nationally, HIV prevalence among FSWs is 4%, infection rates among street-based sex workers in the Kathmandu valley are between 15-17%. Nationally, clients of FSWs have an estimated HIV prevalence rate of 2%. A major challenge to HIV control in the country is the trafficking of Nepalese girls and women into commercial sex work in India, and their return to Nepal. About 50% of Nepal's FSWs previously worked in Mumbai, India, and some 100,000 Nepalese women continue to engage in the practice there. It is estimated that 50% of Nepalese sex workers in Mumbai brothels are HIV positive (FHI 2004).
Changing Values among Young People: Young people are increasingly vulnerable to HIV due to changing values, group norms, and independence. Girls, even if they have knowledge about HIV/AIDS and other Sexually Transmitted Infections (STIs), do not have the means of protecting themselves due to their traditionally lower social status. Teenagers, although apparently highly aware of the HIV risk (based on behavioral surveys), do not necessarily translate this awareness into safe sex practices. A high prevalence of premarital sex exists, with 20% of teenagers considering it acceptable among young people.
High Rates of Migration and Mobility: Estimates of internal and external migration for seasonal and long-term labor range from 1.5 to 2 million people. It is necessary for the economic survival of many households in both rural and urban areas. Removal from traditional social structures, such as family, has been shown to promote unsafe sexual practices, such as having multiple sexual partners and engaging in commercial sex. A 2002 study suggests that HIV prevalence is nearly 8% in migrants returning from Mumbai.
Low Awareness among Men Who Have Sex with Men (MSM): Although accurate data on sex between men are not available, a recent report suggests that MSM activity in Nepal is not different from the MSM activities of the rest of the South Asia region. Current HIV prevalence among urban-based MSM is 4%. The knowledge of safe sex and condom use is low in this community. Furthermore, many men who have sex with men are also married, which puts their spouses at risk of becoming infected with HIV. The Blue Diamond Society is a Non-governmental Organization (NGO) founded in 2001 to address the needs of Nepal’s sexual minorities. It provides community-based sexual health, HIV/AIDS, and advocacy services for local networks of sexual minorities.

National Response to HIV/AIDS

Government and Institutional Framework: In 1988, the Government of Nepal launched the first National AIDS Prevention and Control Program. In 1995, a national policy was formulated, emphasizing the importance of multi-sectoral involvement, decentralized implementation, and partnership between the public, and the private sectors (including NGOs). It also called for coordinated monitoring and evaluation, promoting actions for safe practices, counseling, and services to people living with HIV and AIDS. Provisions were made for reducing stigma and discriminatory practices against people living with HIV/AIDS, confidentiality of blood testing, and safe blood transfusion.

Toward this effort, Nepal established a multi-sector National AIDS Coordinating Committee (NACC) chaired by the Minister of Health in 1992. More recently, a National AIDS Council (NAC) chaired by the Prime Minister was established to raise the profile of HIV/AIDS. The NACC reports to the NAC. The NAC was meant to set overall policy, lead national level advocacy, and provide overall guidance and direction to the program. The NACC, on the other hand, was expected to lead the multi-sector response, and to coordinate active participation of all sectors in the fight against HIV/AIDS. However, both the NAC and the NACC have essentially been non-functional. Each has met only once or twice and activating these entities is a great challenge. At the district level, District Development Committees are charged with implementing and monitoring HIV projects according to national strategies and guidelines.

The main governmental agency responsible for HIV/AIDS and STD is the National Center for AIDS and STD Control (NACSC) under the Ministry of Health and Population. The NCASC has developed a National Strategy on HIV/AIDS, which has subsequently been translated into a five year HIV/AIDS Operational Plan for 2003-07. Each year, an Annual Work Plan is developed; the Annual Work Plan and Budget for 2005-06 was developed in a participatory manner, involving a wide array of key stakeholders and thus it currently provides a common reference point for the national response. The strategy and operational plan seek to address management needs and define the resource requirements for an expanded response to HIV/AIDS in the country.

The government estimates a requirement of US$88 million for the National Operational Plan for 2003-07; the current Annual Plan indicates a budget of about $20 million, of which a financing gap of US$5.5 million has been identified. While available funds may not be sufficient, the lack of implementation capacity has hampered the utilization of the existing resources. USAID funds are, however, an exception as they are spent directly through non-governmental channels. Reorganizing the management mechanism to improve implementation is under discussion. One idea under consideration is the establishment of a semi-autonomous entity to oversee and coordinate the overall program. The currently weak capacity in NCASC, bureaucratic constraints inherent in the government system, and its inability to involve non-health sectors as well as NGOs effectively, would argue for such an entity. An institutional reform task-force that was

established in May 2005 has produced an options paper and the Government is actively considering its recommendations.

An antiretroviral treatment protocol has been endorsed by the Ministry of Health and Population, and treatment has been has been started on a limited basis. Initial focus, being undertaken with assistance from UNICEF, is on preventing mother-to-child transmission.

Non-Governmental and Community Based Organizations (NGOs & CBOs): Numerous private and voluntary organizations implement HIV/AIDS activities funded by donors. There are currently almost 100 NGOs working in the area of HIV/AIDS. NANGAN, a consortium of NGOs in Nepal, is working to coordinate and share information, education, and communication materials, experiences, and lessons learned. The National Network Against Girls’ Trafficking, a coalition of approximately 40 NGOs initially established to tackle the problem of girl trafficking, has also begun to address the issue of HIV.

The relationship and communications between the government and the NGO community, as well as among NGOs themselves, however, are not coherent. A private business collaborative group, called FNCCI, has signed a declaration of commitment and has designed an initial HIV/AIDS-at-workplace initiative with UNAIDS and the ILO.

Donors: A number of multi-lateral and bilateral organizations support HIV/AIDS prevention and control initiatives in Nepal, including interventions for vulnerable groups; behavioral change communications; condom promotion; STD control; testing and counseling; surveillance; and operational research.

USAID provides through its cooperating agencies the largest funding for HIV/AIDS interventions in Nepal, including surveillance activities, condom social marketing, as well as communication and advocacy programs.

The Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) has approved a grant to implement the National Strategy over a period of four years. The focus is to be on young people and migrants, as well as on providing care and support to people living with HIV/AIDS. However, there was an implementation delay of more than two years after the funds were approved. This was mainly been due to the lack of a Management Support Agency (MSA). This problem was solved when UNDP was contracted to serve as the MSA, and the GFATM resources began to flow about a year back. More recently, UNDP is being proposed as a second Principal Recipient for the GFATM funds, thus making the fund-flow direct.

DFID committed a 5-year grant to support the HIV/AIDS program, based on gaps identified in the Annual Work Plan. This grant is also implemented through the same MSA which supports the GFATM-financed program, and includes a fast-track mechanism to contract NGOs rapidly, and a Challenge Fund mechanism to promote innovative ideas as well as a traditional procurement mechanism.

UNAIDS coordinates a theme group based in Kathmandu, and, between 1990 and 1999, the UN system supported the national response in Nepal with approximately US$5 million to build capacity, integrate HIV/AIDS into reproductive health services, and initiate a decentralized response. WHO has provided funds and technical support. Other donors include the European Union, Germany, and Switzerland.

A consortium of multilateral and bilateral donors (UNAIDS, UNDP, USAID, DFID, AusAid) collaborated with the government to address the issue of reducing the risk for female sex workers, their clients, and IDUs. Family Health International was the executing partner of the US$2.6 million project. Harm and risk reduction components included behavior-change communication; social marketing of condoms; harm-reduction equipment, such as clean needles and syringes; STI treatment; and drug substitution therapy. Support services, such as drug counseling, HIV care and support, voluntary HIV testing, and counseling, have been established. The project has ended and the various donor agencies involved are currently implementing separate programs, with significant room for improving their coordination mechanism. While the UN Theme group does meet fairly regularly, it does not include the major bilateral donors and the “Expanded Theme Group” has not been meeting regularly. More recently, an informal monthly lunch meeting has been started to supplement the formal mechanisms.

Issues and Challenges: Priority Areas

Addressing the HIV/AIDS epidemic in Nepal requires immediate action and long-term continuity and sustainability. The following actions are essential:
Emphasize HIV/AIDS as a development issue with continued high-level leadership. The epidemic cannot be tackled through medical/clinical interventions alone. HIV/AIDS prevention and control requires a multi-sectoral approach, involving sectors other than health, such as education, women’s affairs, information, law and order, defense, agriculture, labor and transport.
Demonstrate the need for an expanded and coherent response. Also strengthen management for effective collaboration and coordination between public and private sectors, and improve implementation.
Mobilize resources for scaling up responses for high risk groups. These include migrants, female sex workers, injecting drug users, and men who have sex with men.
Scale up advocacy, behavioral change activities, and health promotion interventions for young people, mobile populations, female sex workers, IDUs, and men who have sex with men.
Implement harm-reduction initiatives for IDUs and promote condom use in casual and commercial sex. Address opposition to scaling up harm-reduction measures such as the distribution of clean needles and syringes to IDUs.
Strengthen biological and behavioral surveillance to enhance understanding of the extent and nature of HIV and STIs, sexual behaviors, and healthcare-seeking behaviors related to HIV and STIs.
Encourage openness in addressing risky behaviors and to protect vulnerable populations. Denial and stigma of HIV and groups that are at high risk only hamper prevention efforts. Efforts to increase knowledge, reduce stigmatization, and promote positive attitudes and norms about safe sexual behaviors are critical.
Provide comprehensive care for people living with HIV and AIDS, including widely available voluntary counseling and testing facilities, provisions for treating opportunistic infections, rolling out of quality structured treatment, and adherence to monitoring.

World Bank Response

The World Bank has provided the Government of Nepal with technical assistance in a variety of areas pertaining to HIV/AIDS. This includes updating the National Strategy, and integrating HIV/AIDS prevention into the country’s National Health Sector Program. It also covers issues related to STI treatment, blood safety, HIV surveillance, voluntary counseling and testing for HIV, and care and support of people living with HIV and AIDS.

The lack of a suitable institutional mechanism with adequate capacity and an appropriate mandate, effective multi-sectoral involvement, and strong public-private partnership, has been a key impediment to mounting an effective response to the epidemic so far. The Bank has enhanced its technical support to include specific assistance in removing this hurdle.

HIV/AIDS | UNICEF, Baylor Partner To Increase Access to Treatment Among HIV-Positive Children in 120 Countries

2006-12-30T09:10:00.000-08:00

GlobalHealthReporting.org

UNICEF and the Baylor International Pediatric AIDS Initiative on Thursday in New York City are scheduled to sign a partnership agreement aimed at expanding access to antiretroviral drugs and other treatments among HIV-positive children to 120 countries, the Houston Chronicle reports (Leigh, Houston Chronicle, 11/16). Currently, BIPAI and UNICEF are working together to expand antiretroviral drugs access to children in 20 countries in Eastern and Southern Africa. BIPAI has clinics in Botswana, Lesotho, Malawi and Romania that aim to treat 80,000 HIV-positive children in five years (Kaiser Daily HIV/AIDS Report, 3/3). BIPAI currently provides HIV/AIDS care to about 10,000 children and treatment to about 4,700 children. The expanded partnership will increase Baylor's operations to 120 countries -- including India, Pakistan and Nepal -- the Chronicle reports. Under the partnership, UNICEF and BIPAI aim to build more pediatric HIV/AIDS clinics, provide four-wheel drive vehicles for health workers to reach remote locations, expand existing clinics, train local health workers in pediatric HIV/AIDS care and support programs to prevent mother-to-child HIV transmission. UNICEF and BIPAI "complement each other so beautifully," BIPAI President Mark Kline said, adding that the new partnership has no limit in terms of funding or time frames. According to the Chronicle, BIPAI will help UNICEF meet its goal of providing about 700,000 HIV-positive children with access to antiretroviral treatment by 2010 (Houston Chronicle, 11/16).
Immediate SOurce: http://www.kaisernetwork.org/

HIV/AIDS | Link Between Antiretrovirals, Leprosy Probable, According to Researchers

2006-12-30T09:05:00.000-08:00

GlobalHealthReporting.org

Increased access to antiretroviral drugs in developing countries has revealed a "startling and worrisome side effect" by exposing "hidden leprosy infection" in some HIV-positive people receiving antiretrovirals, the New York Times reports. According to experts, antiretrovirals help rebuild the immune system, which then produces new white blood cells that carry bacteria from dormant leprosy infections to the skin of the face, hands and feet. Experts say that in Brazil and India, as well as in African and Caribbean countries and elsewhere, some HIV-positive people taking antiretrovirals have developed facial ulcers and have lost feeling in their fingers and toes. Roughly 12 such cases have been reported in medical literature since 2003, according to the Times. Experts say such cases are likely to increase in the developing world, where 300,000 new leprosy cases were reported last year and 38 million people are living with HIV. Gilla Kaplan, a professor at the University of Medicine and Dentistry of New Jersey, said antiretroviral therapy is "going to flush out the silent leprosy by making it symptomatic." According to Pierre Couppie -- chief of dermatology at the Central Hospital in Cayenne, French Guiana -- roughly one in 500 people living with AIDS in the country will develop leprosy lesions after beginning antiretroviral treatment. Experts are most concerned about India, which has recorded 5.2 million HIV cases and at one point was home to 70% of the world's leprosy cases, according to the Times. Other countries with high leprosy prevalence include Madagascar, Mozambique, Myanmar and Nepal. According to experts, a leprosy pandemic or high numbers of leprosy-related deaths likely will not occur because the disease can be treated with antibiotics that are provided at no cost by Novartis. Denis Daumerie, who heads the World Health Organization's efforts to combat leprosy, said, "It's not a matter of concern for public health. It's a matter of concern for the individual patients." Treatment for the disease involves taking several pills for six months to two years, which can be "an added burden" for people living with HIV/AIDS who typically take three pills daily, according to the Times. In addition, because little is known about HIV and leprosy coinfection, it might take weeks for doctors to diagnose leprosy in HIV-positive people (McNeil, New York Times, 10/24).
Immediate SOurce: http://www.kaisernetwork.org/

About HIV/AIDS

2006-12-30T09:01:00.000-08:00

Overview:

In the twenty-five years since the beginning of the HIV/AIDS pandemic, approximately 65 million people worldwide have become infected with HIV, including more than 25 million who already have died. If more is not done to fight the HIV/AIDS pandemic, it is on course to be one of the worst in history, with millions more people estimated to become infected by the end of this decade. The HIV/AIDS pandemic presents political, economic, public health, social and scientific challenges to nations worldwide.

State of the Pandemic
As of the end of 2006, 39.5 million people were estimated to be living with HIV/AIDS worldwide. An estimated 4.3 million people became newly infected with HIV in 2006 and nearly three million people died of AIDS-related causes in 2006. Women represent a growing proportion of people living with HIV/AIDS and now comprise nearly half (48%) of adults estimated to be living with HIV/AIDS worldwide. Young people under the age of 25 are estimated to account for half of all new HIV infections worldwide.

According to UNAIDS, there is no single AIDS epidemic worldwide. Instead, many regions and countries are experiencing diverse epidemics, some of which remain in their early stages. Sub-Saharan Africa is the most-affected region in the world as measured by HIV/AIDS prevalence rates, followed by the Caribbean. There also is growing concern about the "next wave" of the epidemic emerging in parts of Eastern Europe and Asia.

Access to needed services remains low overall and uneven around the world. Although access to antiretroviral (ARV) treatment has more than quadrupled since December 2003 in low- and middle-income countries, only 24% of people living with HIV/AIDS in need of ARVs were estimated to be receiving treatment as of June 2006. This represents 1.65 million of the estimated 6.8 million people in need of antiretroviral treatment in these countries. Access to prevention services also is low, with fewer than one in five people at risk of HIV infection estimated to have access in low and middle-income countries.

Worldwide, financial resources for addressing HIV/AIDS in low- and middle-income countries have increased notably over time, but a significant resource gap remains. UNAIDS estimates that spending on HIV/AIDS rose from US$300 million in 1996 to US$8.3 billion in 2005, and is projected to reach US$8.9 billion in 2006 and US$10 billion in 2007. However, current spending falls far short of what is needed to respond to the epidemic –- resource needs are projected to be $15 billion in 2006, rising to $22 billion by 2008. Sustaining and increasing current efforts to meet the need remain significant challenges in the fight against HIV/AIDS.

Source

UNAIDS 2006 AIDS Epidemic Update, December 2006

UNAIDS Global Facts and Figures, Fact Sheet, December 2006

Source

UNAIDS 2006 AIDS Epidemic Update, December 2006
UNAIDS Global Facts and Figures, Fact Sheet, December 2006 (.pdf)
UNAIDS 2006 Report on the Global AIDS Epidemic, May 2006
WHO Progress in Scaling Up Access to HIV Treatment in Low- and Middle-Income Countries, June 2006 (.pdf)

UNAIDS 2006 Report on the Global AIDS Epidemic, May 2006
WHO Progress in Scaling Up Access to HIV Treatment in Low- and Middle-Income Countries, June 2006 (.pdf)

(From: http://www.globalhealthreporting.org)

HIV/AIDS in Nepal

2006-12-30T08:59:00.000-08:00

28,287,147: population of Nepal (July 2006 est.)

75,000: Estimated number of people living with HIV/AIDS by the end of 2005

0.5%: Estimated percentage of adults (ages 15-49) living with HIV/AIDS by the end of 2005

16,000: Estimated number of women (ages 15-49) living with HIV/AIDS by the end of 2005.

5,100: Estimated number of deaths due to AIDS during 2005

Sources

UNAIDS 2006 Report on the Global AIDS Epidemic. May 2006.

CIA World Factbook 2006

(From http://www.globalhealthreporting.org)

USAID/NEPAL SUPPORTS THE FIGHT AGAINST HIV/AIDS

2006-12-30T08:53:00.000-08:00

Source:Embassy of the United States, Nepal

On the eve of World AIDS Day (December 1), and continuing its commitment to the health sector and the issue of HIV/AIDS in Nepal, USAID/Nepal, on has recently awarded up to $25 million to two new health programs for use over the next three years. USAID/Nepal, on behalf of the American people and government, has been providing support for HIV/AIDS interventions in Nepal since 1993; total funding in this period has reached more than $50 million, not including this new funding.

Nepal has a "concentrated epidemic," driven by injecting drug use, high risk sexual activity and labor migration, all of which are risk factors that lead to substantial rates of HIV infection among female sex workers, their clients, men who have sex with men, injecting drug users and labor migrants. Most of the estimated 70,000 people living with HIV/AIDS do not know they are infected, and HIV/AIDS related stigma and discrimination prevent them and others from seeking HIV counseling and testing, prevention, care and treatment services.

USAID/Nepal, part of the U.S. Mission to Nepal, has developed and supported partnerships with the Government of Nepal and more than 50 international and local non-governmental organizations, community based organizations, groups and networks of people living with and affected by HIV/AIDS, research organizations, private companies, management agencies and faith-based organizations. The current program provides prevention to care services.

Advancing Surveillance, Policies, Prevention, Care and Support to Fight HIV/AIDS (ASHA): This program, implemented under the President’s Emergency Plan, directly contributes to Nepal’s National HIV/AIDS Strategy and National HIV/AIDS Operating Plan. In this phase of the HIV/AIDS program in Nepal, USAID/Nepal plans to sustain the successes of the program to date including: promoting strong local ownership and building capacity in the public sector to oversee HIV/AIDS services; implementing targeted behavior change activities in close collaboration with all partners; encouraging and supporting more public-private partnerships; and optimizing coordination of all activities including surveillance, and monitoring and evaluation to track progress and monitor trends.

Nepal Social Marketing and Franchise Project (N-MARC): Achieving adequate coverage of vital health products and services requires both public and private sector involvement in Nepal. Building on past successes and learning, USAID/Nepal is supporting social marketing/franchising of key family planning, maternal and child health and HIV commodities through the N-MARC project. The goal is to increase access to key health products for a large segment of the population by providing an affordable and accessible alternative to free government products and services. This project will continue to target HIV/AIDS prevention, reproductive health and child survival. Products marketed through the program include clean delivery kits, disinfectant, oral rehydration salts, condoms and a full range of contraceptives for family planning.

Some Results to Date

Recent studies of HIV rates in high risk populations such as female sex workers and injecting drug users show that the HIV rates have stabilized at a low prevalence in female sex workers (1.5%) and have significantly decreased among injecting drug users in Kathmandu from 68% in 2003 to 51.6% in 2005. Rates in other high risk populations have also decreased.
USAID/Nepal has been helping the Government of Nepal to enhance its leadership and management capacity for HIV/AIDS programming. Technical assistance from USAID/Nepal has helped to develop national strategies, guidelines and training curricula on HIV/AIDS prevention-to-care services including Nepal’s national HIV/AIDS supply chain management system.
USAID/Nepal support has strengthened Nepal’s surveillance system to monitor HIV, STI and risk behaviors with most-at-risk population groups. Data from these surveys have helped not only in planning and modifying HIV/AIDS programs but also to generate political commitment and resources for program activities.
USAID/Nepal support for targeted and high quality sexually-transmitted infections (STI) services has resulted in increased access to and demand for these services among most-at-risk groups. The prevalence of syphilis has decreased significantly in USAID-supported program areas. A 2003 study in 16 districts along the highways similar to one conducted in 1999, showed that syphilis prevalence was halved among female sex workers and dropped by 20% among truckers. A 2006 study demonstrates that syphilis infection rates have remained low with small pockets of outbreaks.
To develop local capacity to establish and expand Voluntary Counseling and Testing programs, USAID/Nepal has provided ongoing technical assistance to develop national policies, guidelines, training curricula and quality control mechanisms as well as trained human resources. In addition, these services are linked with other prevention and care programs.
USAID/Nepal has helped community programs to provide care and support for those affected by HIV/AIDS. Nepal now has an essential package of care services to prevent and manage infections as well as the capacity to provide community and home based care for people with HIV/AIDS.

The U.S. Government, through USAID, extends assistance from the American people to peoples of other countries struggling to build better lives. This support ranges from helping to recover from a natural disaster to working to create a free and democratic nation. For 55 years, USAID/Nepal has provided assistance to the people of Nepal in the areas of conflict mitigation and peace building, democracy and governance, health and family planning, economic growth, and disaster and humanitarian aid.

LInk

Dangerous Parasite Gains New Attention In Battles Against AIDS, Bioterrorism

2006-12-26T11:03:00.000-08:00

Montana State University researchers and their collaborators are gaining widespread attention for discoveries involving a common parasite that can threaten everyone from babies to AIDS patients.

Toxoplasma gondii parasites invade a mouse cell. The parasites are green and the nucleus is blue. (Photo by Jim Ajioka, University of Cambridge)

Their findings about Toxoplasma gondii and toxoplasmosis were published recently in three major scientific journals. Nature published a paper Dec. 20 in its advanced online version. Science published a paper on Dec. 15 and PLoS Pathogens on Oct. 27.

"It's not often you get such a cluster of papers coming out," said Michael White, one of the authors and an MSU professor of veterinary molecular biology. He added that MSU researchers will have another opportunity to explain the studies when they host an international conference on toxoplasmosis from June 29-July 2 at Chico Hot Springs.

Toxoplasmosis is normally associated with medical advice that pregnant women avoid changing cat litter, but it's gaining new attention because of the AIDS epidemic and bioterrorism, the researchers said. Severe toxoplasmosis can cause AIDS patients to go into a deep dementia and become unconscious of their surroundings.

"It's one of the worst syndromes an AIDS patient can die from," said Jay Radke, another of the MSU authors.

Toxoplasmosis is a disease caused by the parasite Toxoplasma gondii. Symptoms usually appear only in people with weakened immune systems, but on rare occasions, healthy people suffer serious eye and central nervous system problems from toxoplasmosis. Their babies can have birth defects. White said toxoplasmosis also may be linked to some cases of schizophrenia and bipolar disease. It can kill livestock and has devastated efforts to restore sea otters near Monterey, Calif. Because it's common, yet complex, toxoplasmosis is a potential weapon for bioterrorists.

People usually acquire toxoplasmosis by eating commercial meat or drinking water that's contaminated with Toxoplasma gondii, White said. They can also pick it up by handling soil or anything that has come in contact with cat feces.

"It's a complex cell just likes ours in terms of metabolism and biochemistry, which makes it a tough nut to crack," White said.

The recently-published studies show that molecular interactions between the parasite and host directly regulate the disease's severity, White said. Genes from the parasite also disrupt signals in the host's immune system and control the establishment of life-long chronic disease.

Genetic crosses produced at MSU were critical in the study that discovered that the parasite dumps a protein into the host to dramatically regulate its immune response, White said. Labs in MSU's Department of Veterinary Molecular Biology and MSU's microarray facility helped establish the role of a second pathogen protein that makes one strain of Toxoplasma especially dangerous.

"Type I strains are extremely important to human medicine as they are disproportionately responsible for inflammation of the brain in AIDS patients and for severe congenital disease that is passed from mother to baby," White said.

MSU led the study that was published in PloS, White said. MSU made major contributions to the Nature and Science papers which were collaborations with Stanford University and Washington University in St. Louis.

The studies give other scientists a model for studying toxoplasmosis or related diseases like malaria and Eimeria, which causes coccidiosis, White added. Eimeria parasites kill chickens and other commercially-raised animals like cattle.

A press release from Washington University said researchers in the future will try to develop more effective treatments against toxoplasmosis by blocking ROP18, the gene largely responsible for making toxoplasmosis so dangerous to humans. The Toxoplasma gondii parasite has approximately 6,000 genes in all. Scientists will also look for other genes that work together with ROP18.

Note: This story has been adapted from a news release issued by Montana State University. via ScienceDaily

HIV and antiretroviral therapy in the brain: neuronal injury and repair

2006-12-25T08:40:00.000-08:00

Ronald Ellis, Dianne Langford, Eliezer Masliah

via Nature

SUMMARY: With combination antiretroviral therapy, HIV becomes a chronic, manageable condition. Ellis and colleagues explore how this has altered the time course of cognitive impairment associated with inf

CONTEXT: ...with human immunodeficiency virus (HIV) often involve severe and disabling dementia. Less well known, however, is that combination antiretroviral therapy (cART) (Box 1), by transforming HIV from a fatal illness into a chronic, ...Full text...

Nature Reviews Neuroscience 8, 33 - 44 (01 Jan 2007)

Tuberculosis Bacillus Hides From Immune System In Host's Fat Cells

2006-12-24T08:35:00.000-08:00

A team from the Institut Pasteur has recently shown that the tuberculosis bacillus hides from the immune system in its host's fat cells. This formidable pathogen is protected against even the most powerful antibiotics in these cells, in which it may remain dormant for years. This discovery, published in PLoS ONE, sheds new light on possible strategies for fighting tuberculosis. Attempts to eradicate the bacillus entirely from infected individuals should take these newly identified reservoir cells into account.

Mycobacterium tuberculosis, the bacillus responsible for tuberculosis can hide, in a dormant state, in adipose cells throughout the body. The bacterium is protected in this cellular environment, to which the natural immune defences have little access, and is inaccessible to isoniazid, one of the main antibiotics used to treat tuberculosis worldwide. These results were obtained by Olivier Neyrolles* and his colleagues from the Mycobacterial Genetics Unit directed by Brigitte Gicquel at the Institut Pasteur, in collaboration with Paul Fornès, a pathologist from Hôpital Européen Georges Pompidou. They raise questions of considerable importance in the fight against tuberculosis.

Tuberculosis kills almost two million people worldwide every year and is considered by the World Health Organisation to represent a global health emergency. However, the bacillus is much more prevalent in the world's population than the statistics would lead us to believe, because only 5 to 10% of those infected actually develop tuberculosis. The bacillus may be present in a significant proportion of the population, remaining in a "dormant" state in the body, sometimes for years, and may be "reactivated" at any time. The risk of rea ctivation is particularly high in immunocompromised individuals, such as those infected with AIDS: the HIV virus and the tuberculosis bacillus make a formidable team, with each infectious agent facilitating the progression of the other.

Neyrolles' team first demonstrated, in cell and tissue cultures, that adipose cells served as a reservoir for Mycobacterium tuberculosis, and that this protected the bacillus against isoniazid. They then investigated whether the pathogen was present in adipose cells in humans. They did this by testing for traces of the genetic structure of the bacillus in samples from people considered not to be infected. Analyses were carried out on samples from deceased subjects from Mexico, where tuberculosis is endemic, and from Parisian districts reporting very few cases of tuberculosis.

The bacterium was detected in the adipose tissue of about a quarter of these people, all of whom were unaware they were infected, in both Mexico and France. These results suggest that the bacillus responsible for tuberculosis can remain protected in the adipose tissue of the body in the absence of any sign of disease.

This work has important implications for the prevention of this disease. It helps to explain how, many years after first testing positive for tuberculosis, people with no trace of the microbe in the lungs may develop some form of tuberculosis attacking the lungs, bones or genitals. It also suggests that isoniazid treatment, prescribed to the close friends and family of patients as a preventative measure, may in some cases not provide sufficient protection against the disease. This is particularly important for immunocompromised patients and for people with AIDS, for whom a secondary infection with tuberculosis bacillus may have very serious consequences.

This work highlights the importance of the search for new targeted therapeutic weapons, such as new antibiotics, which must be able to reach the dormant bacillus that has been hiding in adipose cells without our knowing it.

Citation: Neyrolles O, Hernández-Pando R, Pietri-Rouxel F, Fornès P, Tailleux L, et al. (2006) Is Adipose Tissue a Place for Mycobacterium tuberculosis Persistence? PLoS ONE 1(1): e43. doi:10.1371/journal.pone.0000043 (http://dx.doi.org/10.1371/journal.pone.0000043)

Note: This story has been adapted from a news release issued by Public Library of Science.

via Science Daily

HIV Patients Have Increased Risk Of Pneumonia, Death Following Surgery

2006-12-24T08:20:00.001-08:00

HIV-infected patients undergoing surgical procedures may be more likely to develop pneumonia after surgery and to die within 12 months than those without HIV, according to a report in the December issue of Archives of Surgery, one of the JAMA/Archives journals. In addition, HIV patients with a preoperative viral load (number of copies of the virus in the blood) greater than 30,000 per milliliter appear to have increased risk of surgical complications.

Since the development of medication regimens known as highly active antiretroviral therapy (HAART), HIV has become a chronic, manageable condition, according to background information in the article. "Consequently, many HIV-infected patients elect to undergo surgical procedures to correct physical ailments that would not have been treated previously, and undergo operative interventions in lieu of medical therapies for certain conditions," the authors write.

Michael A. Horberg, M.D., M.A.S., and colleagues at Kaiser Permanente Medical Care Program--Northern California, Oakland, studied surgical outcomes in 332 HIV-infected patients who underwent a variety of procedures (including abdominal, orthopedic and heart surgeries) between 1997 and 2002. For comparison, the researchers selected a group of 332 patients who did not have HIV but were the same age and sex and had a similar procedure at around the same time and at the same location as one of the HIV-infected patients. The investigators then used health plan databases to obtain clinical information about the HIV patients' disease and to track whether any of the patients had complications after surgery or died within 12 months.

The surgical procedures analyzed included abdominal or pelvic procedures (80.8 percent), cardiac or breast procedures (8.4 percent) and orthopedic procedures (10.8 percent). Most complications--including infections and delayed wound healing--occurred equally frequently in patients with and without HIV. No difference between the two groups was found in the length of hospital stay, number of complications or need for additional procedures to treat complications. However, more HIV patients developed pneumonia (eight or 2.4 percent vs. one or .3 percent) and more died within 12 months (10 or 3 percent vs. two or .6 percent). "The causes of death varied" in HIV patients, the authors write. "While none of the causes appeared to be a direct consequence of the operation, two deaths were within 30 days of the operation."

The researchers also examined risk factors for complications and death among HIV patients, including CD4 cell count response, a measure of the state of the immune system. The lower the CD4 count, the more likely a patient with HIV/AIDS is to develop secondary infections or illnesses. Those with a CD4 count of less than 50 cells per cubic millimeter of blood had more complications than those with higher CD4 counts. In addition, viral loads--measured as the number of copies of the virus in a milliliter of blood--of more than 30,000 were associated with a higher complication rate. Whether the patients were taking antiretroviral therapy did not appear to be related to their risk of developing complications. "Our results indicate that a higher HIV viral load seems to be a greater predictor of surgically related complications than either the CD4 cell count or the presence or absence of HAART use," the authors write.

"Patients with HIV are living longer and regaining a substantial amount of immune function," they conclude. "Many HIV-infected patients will require surgical attention because of a variety of disorders. In many cases, HIV serostatus [whether a person is infected with HIV or not] should not be a criterion when determining the need for surgery if patients have adequate viral control."

Note: This story has been adapted from a news release issued by JAMA and Archives Journals.

via Science Daily

Quality Not Quantity Important For Immune Response To HIV

2006-12-24T08:20:00.000-08:00

Science Daily — When it comes to an immune response against HIV, research funded by the Wellcome Trust in the UK and the National Institutes of Health in the US has found that bigger is not necessarily better, contrary to conventional medical wisdom. The research may have a profound impact on the development of a vaccine against the disease.

"Conventional medical wisdom tells us that the bigger the immune response, the more effective it will be in controlling HIV," says Professor Philip Goulder, a Wellcome Trust Senior Research Fellow in Clinical Science at the University of Oxford. "However, our study suggests that this might not be the case. While most of the immune responses generated against HIV appear to be ineffective, responses targeting one particular HIV protein can bring about control of the virus."

About 40 million people are thought to be living with HIV worldwide. The virus, which causes AIDS, is thought to kill 3 million people each year. Despite being first identified in 1981, a vaccine to prevent infection has so far proved elusive.

When HIV infects the body, it hides out in so-called "helper T-cells". T cells play an important role in the immune response generated by the body to fight infection. There are a number of different types of T cells, each playing a different role in this battle. Helper T-cells (HTCs) regulate the body's immune response and it is the loss of these cells that leads to the development of AIDS.

Another type of T cell, the cytotoxic T cell (CTC), recognises and attacks infected HTCs. It was previously thought that the bigger the CTC response, the more effective it would be. It is this dogma that has influenced development of HIV vaccines, with the vaccines attempting to stimulate a large response.

However, Professor Goulder and colleagues found that the type of CTC response is crucial and that some types of response may have a negative effect and could actually hinder the immune response. The research, a population-based study involving investigators at the University of Oxford in the UK, Partners AIDS Research Center at Massachusetts General Hospital in the US and the University of KwaZulu-Natal, South Africa, investigated the immune responses against HIV in nearly 580 HIV-infected people in KwaZulu-Natal. It is published online today in the journal Nature Medicine.

"Some of the CTCs attack so-called 'Gag' proteins within the HIV virus, whilst others attack proteins such as the 'Env' protein on its surface," explains Professor Goulder. "In our study group, it seems that the higher the response to the Gag proteins, the more effective the immune system was at fighting infection. However, for reasons that are unclear, the opposite was true for responses to the Env proteins, where a stronger response was associated with a higher viral load -- in other words, worse control of HIV."

Professor Goulder believes these findings may have implications for the development of a HIV vaccine.

"There seems to be clear evidence that 'Gag is good'," says Professor Goulder. "This means that rather than developing a vaccine with a spectrum of CTC responses, we may need to look at a more targeted vaccine."

Note: This story has been adapted from a news release issued by Wellcome Trust.

What is HIV AIDS?

2006-12-22T08:53:00.000-08:00

Giving due credit to Wikipedia, the free encyclopedia, we have reproduced here this article.

Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS or Aids) is a collection of symptoms and infections resulting from the specific damage to the immune system caused by the human immunodeficiency virus (HIV).[1] The late stage of the condition leaves individuals prone to opportunistic infections and tumors. Although treatments for AIDS and HIV exist to slow the virus's progression, there is no known cure. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.[2][3] This transmission can come in the form of anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, or breastfeeding, or other exposure to one of the above bodily fluids.

Most researchers believe that HIV originated in sub-Saharan Africa during the twentieth century;[4] it is now a pandemic, with an estimated 38.6 million people now living with the disease worldwide.[5] As of January 2006, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognized on June 5, 1981, making it one of the most destructive epidemics in recorded history. In 2005 alone, AIDS claimed an estimated 2.4–3.3 million lives, of which more than 570,000 were children.[5] A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth and destroying human capital. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries.[6] HIV/AIDS stigma is more severe than that associated with other life-threatening conditions and extends beyond the disease itself to providers and even volunteers involved with the care of people living with HIV.

Infection by HIV
AIDS is the most severe manifestation of infection with HIV. HIV is a retrovirus that primarily infects vital components of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and dendritic cells. It directly and indirectly destroys CD4+ T cells. CD4+ T cells are required for the proper functioning of the immune system. When HIV kills CD4+ T cells so that there are fewer than 200 CD4+ T cells per microliter (µL) of blood, cellular immunity is lost, leading to the condition known as AIDS. Acute HIV infection progresses over time to clinical latent HIV infection and then to early symptomatic HIV infection and later to AIDS, which is identified on the basis of the amount of CD4+ T cells in the blood and the presence of certain infections.

In the absence of antiretroviral therapy, the median time of progression from HIV infection to AIDS is nine to ten years, and the median survival time after developing AIDS is only 9.2 months.[7] However, the rate of clinical disease progression varies widely between individuals, from two weeks up to 20 years. Many factors affect the rate of progression. These include factors that influence the body's ability to defend against HIV such as the infected person's general immune function.[8][9] Older people have weaker immune systems, and therefore have a greater risk of rapid disease progression than younger people. Poor access to health care and the existence of coexisting infections such as tuberculosis also may predispose people to faster disease progression.[7][10][11] The infected person's genetic inheritance plays an important role and some people are resistant to certain strains of HIV.[12] An example of this is people with the CCR5-?32 mutation are resistant to infection with certain strains of HIV. HIV is genetically variable and exists as different strains, which cause different rates of clinical disease progression.[13][14][15] The use of highly active antiretroviral therapy prolongs both the median time of progression to AIDS and the median survival time.

Diagnosis
Since June 5, 1981, many definitions have been developed for epidemiological surveillance such as the Bangui definition and the 1994 expanded World Health Organization AIDS case definition. However, clinical staging of patients was not an intended use for these systems as they are neither sensitive, nor specific. In developing countries, the World Health Organization staging system for HIV infection and disease, using clinical and laboratory data, is used and in developed countries, the Centers for Disease Control (CDC) Classification System is used.

WHO disease staging system for HIV infection and disease
Main article: WHO Disease Staging System for HIV Infection and Disease
In 1990, the World Health Organization (WHO) grouped these infections and conditions together by introducing a staging system for patients infected with HIV-1.[16] An update took place in September 2005. Most of these conditions are opportunistic infections that are easily treatable in healthy people.

Stage I: HIV disease is asymptomatic and not categorized as AIDS
Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections
Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis
Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS.
CDC classification system for HIV infection
Main article: CDC Classification System for HIV Infection
The Centers for Disease Control and Prevention (CDC) originally classified AIDS as GRID which stood for Gay Related Immune Disease.[citation needed] However, after determining that AIDS is not isolated to homosexual people the name was changed to the neutral AIDS. In 1993, the CDC expanded their definition of AIDS to include all HIV positive people with a CD4+ T cell count below 200 per µL of blood or 14% of all lymphocytes.[17] The majority of new AIDS cases in developed countries use either this definition or the pre-1993 CDC definition. The AIDS diagnosis still stands even if, after treatment, the CD4+ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.

HIV test
Main article: HIV test
Many people are unaware that they are infected with HIV.[18] Less than 1% of the sexually active urban population in Africa has been tested, and this proportion is even lower in rural populations. Furthermore, only 0.5% of pregnant women attending urban health facilities are counseled, tested or receive their test results. Again, this proportion is even lower in rural health facilities.[18] Therefore, donor blood and blood products used in medicine and medical research are screened for HIV. Typical HIV tests, including the HIV enzyme immunoassay and the Western blot assay, detect HIV antibodies in serum, plasma, oral fluid, dried blood spot or urine of patients. However, the window period (the time between initial infection and the development of detectable antibodies against the infection) can vary. This is why it can take 3-6 months to seroconvert and test positive. Commercially available tests to detect other HIV antigens, HIV-RNA, and HIV-DNA in order to detect HIV infection prior to the development of detectable antibodies are available. For the diagnosis of HIV infection these assays are not specifically approved, but are nonetheless routinely used in developed countries.

Symptoms and complications
The symptoms of AIDS are primarily the result of conditions that do not normally develop in individuals with healthy immune systems. Most of these conditions are infections caused by bacteria, viruses, fungi and parasites that are normally controlled by the elements of the immune system that HIV damages. Opportunistic infections are common in people with AIDS.[19] HIV affects nearly every organ system. People with AIDS also have an increased risk of developing various cancers such as Kaposi's sarcoma, cervical cancer and cancers of the immune system known as lymphomas.

Additionally, people with AIDS often have systemic symptoms of infection like fevers, sweats (particularly at night), swollen glands, chills, weakness, and weight loss.[20][21] After the diagnosis of AIDS is made, the current average survival time with antiretroviral therapy (as of 2005) is estimated to be more than 5 years,[22] but because new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year.[7] Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.[23]

The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function[8][9][12] health care and co-infections,[7][23] as well as factors relating to the viral strain.[14][24][25] The specific opportunistic infections that AIDS patients develop depend in part on the prevalence of these infections in the geographic area in which the patient lives.

Major pulmonary illnesses
Pneumocystis jiroveci pneumonia (originally known as Pneumocystis carinii pneumonia, often-abbreviated PCP) is relatively rare in healthy, immunocompetent people, but common among HIV-infected individuals. Before the advent of effective diagnosis, treatment and routine prophylaxis in Western countries, it was a common immediate cause of death. In developing countries, it is still one of the first indications of AIDS in untested individuals, although it does not generally occur unless the CD4 count is less than 200 per µL.[26]
Tuberculosis (TB) is unique among infections associated with HIV because it is transmissible to immunocompetent people via the respiratory route, is easily treatable once identified, may occur in early-stage HIV disease, and is preventable with drug therapy. However, multidrug resistance is a potentially serious problem. Even though its incidence has declined because of the use of directly observed therapy and other improved practices in Western countries, this is not the case in developing countries where HIV is most prevalent. In early-stage HIV infection (CD4 count >300 cells per µL), TB typically presents as a pulmonary disease. In advanced HIV infection, TB often presents atypically with extrapulmonary (systemic) disease a common feature. Symptoms are usually constitutional and are not localized to one particular site, often affecting bone marrow, bone, urinary and gastrointestinal tracts, liver, regional lymph nodes, and the central nervous system.[27] Alternatively, symptoms may relate more to the site of extrapulmonary involvement.

Major gastro-intestinal illnesses
Esophagitis is an inflammation of the lining of the lower end of the esophagus (gullet or swallowing tube leading to the stomach). In HIV infected individuals, this is normally due to fungal (candidiasis) or viral (herpes simplex-1 or cytomegalovirus) infections. In rare cases, it could be due to mycobacteria.[28]
Unexplained chronic diarrhea in HIV infection is due to many possible causes, including common bacterial (Salmonella, Shigella, Listeria, Campylobacter, or Escherichia coli) and parasitic infections, and uncommon opportunistic infections such as cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and cytomegalovirus (CMV) colitis. In some cases, diarrhea may be a side effect of several drugs used to treat HIV, or it may simply accompany HIV infection, particularly during primary HIV infection. It may also be a side effect of antibiotics used to treat bacterial causes of diarrhea (common for Clostridium difficile). In the later stages of HIV infection, diarrhea is thought to be a reflection of changes in the way the intestinal tract absorbs nutrients, and may be an important component of HIV-related wasting.[29]

Major neurological illnesses

Toxoplasmosis is a disease caused by the single-celled parasite called Toxoplasma gondii; it usually infects the brain causing toxoplasma encephalitis but it can infect and cause disease in the eyes and lungs.[30]
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease, in which the gradual destruction of the myelin sheath covering the axons of nerve cells impairs the transmission of nerve impulses. It is caused by a virus called JC virus which occurs in 70% of the population in latent form, causing disease only when the immune system has been severely weakened, as is the case for AIDS patients. It progresses rapidly, usually causing death within months of diagnosis.[31]
AIDS dementia complex (ADC) is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of HIV infected brain macrophages and microglia which secrete neurotoxins of both host and viral origin.[32] Specific neurological impairments are manifested by cognitive, behavioral, and motor abnormalities that occur after years of HIV infection and is associated with low CD4+ T cell levels and high plasma viral loads. Prevalence is 10-20% in Western countries[33] but only 1-2% of HIV infections in India.[34][35] This difference is possibly due to the HIV subtype in India.
Cryptococcal meningitis is an infection of the meninx (the membrane covering the brain and spinal cord) by the fungus Cryptococcus neoformans. It can cause fevers, headache, fatigue, nausea, and vomiting. Patients may also develop seizures and confusion; left untreated, it can be lethal.

Major HIV-associated malignancies
Patients with HIV infection have substantially increased incidence of several malignant cancers. This is primarily due to co-infection with an oncogenic DNA virus, especially Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV).[36][37] The following confer a diagnosis of AIDS when they occur in an HIV-infected person.

Kaposi's sarcoma (KS) is the most common tumor in HIV-infected patients. The appearance of this tumor in young homosexual men in 1981 was one of the first signals of the AIDS epidemic. Caused by a gammaherpes virus called Kaposi's sarcoma-associated herpes virus (KSHV), it often appears as purplish nodules on the skin, but can affect other organs, especially the mouth, gastrointestinal tract, and lungs.
High-grade B cell lymphomas such as Burkitt's lymphoma, Burkitt's-like lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary central nervous system lymphoma present more often in HIV-infected patients. These particular cancers often foreshadow a poor prognosis. In some cases these lymphomas are AIDS-defining. Epstein-Barr virus (EBV) or KSHV cause many of these lymphomas.
Cervical cancer in HIV-infected women is considered AIDS-defining. It is caused by human papillomavirus (HPV).
In addition to the AIDS-defining tumors listed above, HIV-infected patients are at increased risk of certain other tumors, such as Hodgkin's disease and anal and rectal carcinomas. However, the incidence of many common tumors, such as breast cancer or colon cancer, does not increase in HIV-infected patients. In areas where HAART is extensively used to treat AIDS, the incidence of many AIDS-related malignancies has decreased, but at the same time malignant cancers overall have become the most common cause of death of HIV-infected patients.[38]

Other opportunistic infections
AIDS patients often develop opportunistic infections that present with non-specific symptoms, especially low-grade fevers and weight loss. These include infection with Mycobacterium avium-intracellulare and cytomegalovirus (CMV). CMV can cause colitis, as described above, and CMV retinitis can cause blindness. Penicilliosis due to Penicillium marneffei is now the third most common opportunistic infection (after extrapulmonary tuberculosis and cryptococcosis) in HIV-positive individuals within the endemic area of Southeast Asia.[39]

Transmission and prevention
The three main transmission routes of HIV are sexual contact, exposure to infected body fluids or tissues, and from mother to fetus or child during perinatal period. It is possible to find HIV in the saliva, tears, and urine of infected individuals, but due to the low concentration of virus in these biological liquids, the risk is negligible.

Sexual contact
The majority of HIV infections are acquired through unprotected sexual relations between partners, one of whom has HIV. Sexual transmission occurs with the contact between sexual secretions of one partner with the rectal, genital or oral mucous membranes of another. Unprotected receptive sexual acts are riskier than unprotected insertive sexual acts, with the risk for transmitting HIV from an infected partner to an uninfected partner through unprotected insertive anal intercourse greater than the risk for transmission through vaginal intercourse or oral sex. Oral sex is not without its risks as HIV is transmissible through both insertive and receptive oral sex.[48] The risk of HIV transmission from exposure to saliva is considerably smaller than the risk from exposure to semen; contrary to popular belief, one would have to swallow gallons of saliva from a carrier to run a significant risk of becoming infected.[49]

Worldwide, approximately 30% of women report that their first sexual experience was forced or coerced, making sexual violence a key driver of the HIV/AIDS pandemic.[50] Sexual assault greatly increases the risk of HIV transmission as protection is rarely employed and physical trauma to the vaginal cavity frequently occurs which facilitates the transmission of HIV.[51]

Sexually transmitted infections (STI) increase the risk of HIV transmission and infection because they cause the disruption of the normal epithelial barrier by genital ulceration and/or microulceration; and by accumulation of pools of HIV-susceptible or HIV-infected cells (lymphocytes and macrophages) in semen and vaginal secretions. Epidemiological studies from sub-Saharan Africa, Europe and North America have suggested that there is approximately a four times greater risk of becoming infected with HIV in the presence of a genital ulcer such as those caused by syphilis and/or chancroid. There is also a significant though lesser increased risk in the presence of STIs such as gonorrhea, Chlamydial infection and trichomoniasis which cause local accumulations of lymphocytes and macrophages.[52]

Transmission of HIV depends on the infectiousness of the index case and the susceptibility of the uninfected partner. Infectivity seems to vary during the course of illness and is not constant between individuals. An undetectable plasma viral load does not necessarily indicate a low viral load in the seminal liquid or genital secretions. Each 10-fold increment of blood plasma HIV RNA is associated with an 81% increased rate of HIV transmission.[52][53] Women are more susceptible to HIV-1 infection due to hormonal changes, vaginal microbial ecology and physiology, and a higher prevalence of sexually transmitted diseases.[54][55] People who are infected with HIV can still be infected by other, more virulent strains.

During a sexual act, only male or female condoms can reduce the chances of infection with HIV and other STDs and the chances of becoming pregnant. The best evidence to date indicates that typical condom use reduces the risk of heterosexual HIV transmission by approximately 80% over the long-term, though the benefit is likely to be higher if condoms are used correctly on every occasion.[56] The effective use of condoms and screening of blood transfusion in North America, Western and Central Europe is credited with contributing to the low rates of AIDS in these regions. Promoting condom use, however, has often proved controversial and difficult. Many religious groups, most noticeably the Catholic Church, have opposed the use of condoms on religious grounds, and have sometimes seen condom promotion as an affront to the promotion of marriage, monogamy and sexual morality. Defenders of the Catholic Church's role in AIDS and general STD prevention state that, while they may be against the use of contraception, they are strong advocates of abstinence outside marriage.[57] This attitude is also found among some health care providers and policy makers in sub-Saharan African nations, where HIV and AIDS prevalence is extremely high.[58] They also believe that the distribution and promotion of condoms is tantamount to promoting sex amongst the youth and sending the wrong message to uninfected individuals. However, no evidence has been produced that promotion of condom use increases sexual promiscuity,[59] and abstinence-only programs have been unsuccessful in both changing sexual behavior and in reducing HIV transmission.[60] Evaluations of several abstinence-only programs in the US showed a negative impact on the willingness of youths to use contraceptives, due to the emphasis on contraceptives' failure rates.[61]

The male latex condom, if used correctly without oil-based lubricants, is the single most effective available technology to reduce the sexual transmission of HIV and other sexually transmitted infections. Manufacturers recommend that oil-based lubricants such as petroleum jelly, butter, and lard not be used with latex condoms as they weaken the latex, making the condoms porous. If necessary, manufacturers recommend using water-based lubricants. Oil-based lubricants can however be used with polyurethane condoms.[62] Latex degrades over time, making them porous, which is why condoms have expiration dates. In Europe and the United States, condoms have to conform to European (EC 600) or American (D3492) standards to be considered protective against HIV transmission.

The female condom is an alternative to the male condom and is made from polyurethane, which allows it to be used in the presence of oil-based lubricants. They are larger than male condoms and have a stiffened ring-shaped opening, and are designed to be inserted into the vagina. The female condom contains an inner ring, which keeps the condom in place inside the vagina – inserting the female condom requires squeezing this ring. However, at present availability of female condoms is very low and the price remains prohibitive for many women. Preliminary studies suggest that, where female condoms are available, overall protected sexual acts increase relative to unprotected sexual acts, making them an important HIV prevention strategy that must be scaled-up.[63]

With consistent and correct use of condoms, there is a very low risk of HIV infection. Studies on couples where one partner is infected show that with consistent condom use, HIV infection rates for the uninfected partner are below 1% per year.[64]

The United States government and health organizations both endorse the ABC Approach to lower the risk of acquiring AIDS during sex:

Abstinence or delay of sexual activity, especially for youth,
Being faithful, especially for those in committed relationships,
Condom use, for those who engage in risky behavior.
This approach has been very successful in Uganda, where HIV prevalence has decreased from 15% to 5%. However, more has been done than just this. As Edward Green, a Harvard medical anthropologist, put it, "Uganda has pioneered approaches towards reducing stigma, bringing discussion of sexual behavior out into the open, involving HIV-infected people in public education, persuading individuals and couples to be tested and counseled, improving the status of women, involving religious organizations, enlisting traditional healers, and much more." However, criticism of the ABC approach is widespread because a faithful partner of an unfaithful partner is at risk of contracting HIV and that discrimination against women and girls is so great that they are without voice in almost every area of their lives.[65] Other programs and initiatives promote condom use more heavily. Condom use is an integral part of the CNN Approach.

This is:
Condom use, for those who engage in risky behavior,
Needles, use clean ones,
Negotiating skills; negotiating safer sex with a partner and empowering women to make smart choices.
In December 2006, the last of three large, randomized trials confirmed that male circumcision lowers the risk of HIV infection among heterosexual African men by around 50%. It is expected that this intervention will be actively promoted in many of the countries worst affected by HIV, although doing so will involve confronting a number of practical, cultural and attitudinal issues. Some experts fear that a lower perception of vulnerability among circumcised men may result in more sexual risk-taking behavior, thus negating its preventive effects.[66] Furthermore, South African medical experts are concerned that the repeated use of unsterilized blades in the ritual circumcision of adolescent boys may be spreading HIV.[67]

Exposure to infected body fluids
This transmission route is particularly relevant to intravenous drug users, hemophiliacs and recipients of blood transfusions and blood products. Sharing and reusing syringes contaminated with HIV-infected blood represents a major risk for infection with not only HIV, but also hepatitis B and hepatitis C. Needle sharing is the cause of one third of all new HIV-infections and 50% of hepatitis C infections in Northern America, China, and Eastern Europe. The risk of being infected with HIV from a single prick with a needle that has been used on an HIV infected person is thought to be about 1 in 150 (see table above). Post-exposure prophylaxis with anti-HIV drugs can further reduce that small risk.[68] Health care workers (nurses, laboratory workers, doctors etc) are also concerned, although more rarely. This route can affect people who give and receive tattoos and piercings. Universal precautions are frequently not followed in both sub-Saharan Africa and much of Asia because of both a shortage of supplies and inadequate training. The WHO estimates that approximately 2.5% of all HIV infections in sub-Saharan Africa are transmitted through unsafe healthcare injections.[69] Because of this, the United Nations General Assembly, supported by universal medical opinion on the matter, has urged the nations of the world to implement universal precautions to prevent HIV transmission in health care settings.[70][71]

The risk of transmitting HIV to blood transfusion recipients is extremely low in developed countries where improved donor selection and HIV screening is performed. However, according to the WHO, the overwhelming majority of the world's population does not have access to safe blood and "between 5% and 10% of HIV infections worldwide are transmitted through the transfusion of infected blood and blood products".[72]

Medical workers who follow universal precautions or body substance isolation such as wearing latex gloves when giving injections and washing the hands frequently can help prevent infection of HIV.

All AIDS-prevention organizations advise drug-users not to share needles and other material required to prepare and take drugs (including syringes, cotton balls, the spoons, water for diluting the drug, straws, crack pipes, etc). It is important that people use new or properly sterilized needles for each injection. Information on cleaning needles using bleach is available from health care and addiction professionals and from needle exchanges. In some developed countries, clean needles are available free in some cities, at needle exchanges or safe injection sites. Additionally, many nations have decriminalized needle possession and made it possible to buy injection equipment from pharmacists without a prescription.

Mother-to-child transmission (MTCT)
The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between the mother to the child during pregnancy, labor and delivery is 25%. However, when the mother has access to antiretroviral therapy and gives birth by caesarean section, the rate of transmission is just 1%.[42] A number of factors influence the risk of infection, particularly the viral load of the mother at birth (the higher the load, the higher the risk). Breastfeeding increases the risk of transmission by 10–15%. This risk depends on clinical factors and may vary according to the pattern and duration of breast-feeding.

Studies have shown that antiretroviral drugs, caesarean delivery and formula feeding reduce the chance of transmission of HIV from mother to child.[73] Current recommendations state that when replacement feeding is acceptable, feasible, affordable, sustainable and safe, HIV-infected mothers should avoid breast-feeding their infant. However, if this is not the case, exclusive breast-feeding is recommended during the first months of life and discontinued as soon as possible.[5] In 2005, around 700,000 children under 15 contracted HIV, mainly through MTCT, with 630,000 of these infections occurring in Africa.[74] Of the estimated 2.3 million [1.7-3.5 million] children currently living with HIV, 2 million (almost 90%) live in sub-Saharan Africa.[5]

Prevention strategies are well known in developed countries, however, recent epidemiological and behavioral studies in Europe and North America have suggested that a substantial minority of young people continue to engage in high-risk practices and that despite HIV/AIDS knowledge, young people underestimate their own risk of becoming infected with HIV. [75] However, transmission of HIV between intravenous drug users has clearly decreased, and HIV transmission by blood transfusion has become quite rare in developed countries.

Treatment
There is currently no vaccine or cure for HIV or AIDS. The only known methods of prevention are based on avoiding exposure to the virus or, failing that, an antiretroviral treatment directly after a highly significant exposure, called post-exposure prophylaxis (PEP).[68] PEP has a very demanding four week schedule of dosage. It also has very unpleasant side effects including diarrhea, malaise, nausea and fatigue.[76
Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.[77] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available.[78] Current optimal HAART options consist of combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of anti-retroviral agents. Typical regimens consist of two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations are more aggressive for children than for adults.[79] In developed countries where HAART is available, doctors assess the viral load, rapidity in CD4 decline, and patient readiness while deciding when to recommend initiating treatment.[80]

HAART allows the stabilisation of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped.[81][82] Moreover, it would take more than the lifetime of an individual to be cleared of HIV infection using HAART.[83] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality.[78][84][85] In the absence of HAART, progression from HIV infection to AIDS occurs at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.[7] Still, for some patients - and in many clinical cohorts this may be more than fifty percent of patients - HAART achieves far less than optimal results. This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. However, non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to get any benefit from and develop resistance to HAART.[86] The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues along with side effects that create intentional non-adherence also has a weighty impact.[87][88][89] The side effects include lipodystrophy, dyslipidaemia, insulin resistance, an increase in cardiovascular risks and birth defects.[90][91]

Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.[92] Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Only a vaccine is postulated to be able to halt the pandemic. This is because a vaccine would possibly cost less, thus being affordable for developing countries, and would not require daily treatments.[92] However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.[92]

A number of studies have shown that measures to prevent opportunistic infections can be beneficial when treating patients with HIV infection or AIDS. Vaccination against hepatitis A and B is advised for patients who are not infected with these viruses and are at risk of becoming infected.[93] In addition, AIDS patients should receive vaccination against Streptococcus pneumoniae and should receive yearly vaccination against influenza virus.[citation needed] Patients with substantial immunosuppression are also advised to receive prophylactic therapy for Pneumocystis jiroveci pneumonia (PCP), and many patients may benefit from prophylactic therapy for toxoplasmosis and Cryptococcus meningitis. Daily multivitamin supplements have been found to reduce HIV disease progression among men and women. This could become an important low-cost intervention provided during early HIV disease to prolong the time before antiretroviral therapy is required.[94]

Various forms of alternative medicine have been used to treat symptoms or alter the course of the disease.[93] In the first decade of the epidemic when no useful conventional treatment was available, a large number of people with AIDS experimented with alternative therapies. The definition of "alternative therapies" in AIDS has changed since that time. Then, the phrase often referred to community-driven treatments, untested by government or pharmaceutical company research, that some hoped would directly suppress the virus or stimulate immunity against it. These kinds of approaches have become less common over time as the benefits of AIDS drugs have become more apparent. Examples of alternative medicine that people hoped would improve their symptoms or their quality of life include massage, herbal and flower remedies and acupuncture;[93] when used with conventional treatment, many now refer to these as "complementary" approaches. None of these treatments have been proven in controlled trials to have any effect in treating HIV or AIDS.[95]

Epidemiology
UNAIDS and the WHO estimate that AIDS has killed more than 25 million people since it was first recognized in 1981, making it one of the most destructive epidemics in recorded history. Despite recent, improved access to antiretroviral treatment and care in many regions of the world, the AIDS epidemic claimed an estimated 2.8 million (between 2.4 and 3.3 million) lives in 2005 of which more than half a million (570,000) were children.[5]

Globally, between 33.4 and 46 million people currently live with HIV.[5] In 2005, between 3.4 and 6.2 million people were newly infected and between 2.4 and 3.3 million people with AIDS died, an increase from 2003 and the highest number since 1981.[5]

Sub-Saharan Africa remains by far the worst affected region, with an estimated 21.6 to 27.4 million people currently living with HIV. Two million [1.5–3.0 million] of them are children younger than 15 years of age. More than 64% of all people living with HIV are in sub-Saharan Africa, as are more than three quarters (76%) of all women living with HIV. In 2005, there were 12.0 million [10.6–13.6 million] AIDS orphans living in sub-Saharan Africa 2005.[5] South & South East Asia are second worst affected with 15%. AIDS accounts for the deaths of 500,000 children in this region. Two-thirds of HIV/AIDS infections in Asia occur in India, with an estimated 5.7 million infections (estimated 3.4 - 9.4 million) (0.9% of population), surpassing South Africa's estimated 5.5 million (4.9-6.1 million) (11.9% of population) infections, making it the country with the highest number of HIV infections in the world.[96] In the 35 African nations with the highest prevalence, average life expectancy is 48.3 years— 6.5 years less than it would be without the disease.[97]

The latest evaluation report of the World Bank's Operations Evaluation Department assesses the effectiveness of the World Bank's country-level HIV/AIDS assistance, defined as policy dialogue, analytic work, and lending, with the explicit objective of reducing the scope or impact of the AIDS epidemic.[98] This is the first comprehensive evaluation of the World Bank's HIV/AIDS support to countries, from the beginning of the epidemic through mid-2004. Because the Bank's assistance is for implementation of government programs by government, it provides important insights on how national AIDS programs can be made more effective.

The development of HAART as effective therapy for HIV infection and AIDS has substantially reduced the death rate from this disease in those areas where it is widely available. This has created the misperception that the disease has gone away. In fact, as the life expectancy of persons with AIDS has increased in countries where HAART is widely used, the number of persons living with AIDS has increased substantially. In the United States, the number of persons with AIDS increased from about 35,000 in 1988 to over 220,000 in 1996.[99]

In Africa, the number of MTCT and the prevalence of AIDS is beginning to reverse decades of steady progress in child survival. Countries such as Uganda are attempting to curb the MTCT epidemic by offering VCT (voluntary counseling and testing), PMTCT (prevention of mother-to-child transmission) and ANC (ante-natal care) services, which include the distribution of antiretroviral therapy.

Economic impact
HIV and AIDS retard economic growth by destroying human capital. UNAIDS has predicted outcomes for sub-Saharan Africa to the year 2025. These range from a plateau and eventual decline in deaths beginning around 2012 to a catastrophic continual growth in the death rate with potentially 90 million cases of infection.[5]

Without proper nutrition, health care and medicine that is available in developed countries, large numbers of people in these countries are falling victim to AIDS. They will not only be unable to work, but will also require significant medical care. The forecast is that this will likely cause a collapse of economies and societies in the region. In some heavily infected areas, the epidemic has left behind many orphans cared for by elderly grandparents.

The increased mortality in this region will result in a smaller skilled population and labor force.[100] This smaller labor force will be predominantly young people, with reduced knowledge and work experience leading to reduced productivity. An increase in workers’ time off to look after sick family members or for sick leave will also lower productivity. Increased mortality will also weaken the mechanisms that generate human capital and investment in people, through loss of income and the death of parents.[100] By killing off mainly young adults, AIDS seriously weakens the taxable population, reducing the resources available for public expenditures such as education and health services not related to AIDS resulting in increasing pressure for the state's finances and slower growth of the economy. This results in a slower growth of the tax base, an effect that will be reinforced if there are growing expenditures on treating the sick, training (to replace sick workers), sick pay and caring for AIDS orphans. This is especially true if the sharp increase in adult mortality shifts the responsibility and blame from the family to the government in caring for these orphans.

On the level of the household, AIDS results in both the loss of income and increased spending on healthcare by the household. The income effects of this lead to spending reduction as well as a substitution effect away from education and towards healthcare and funeral spending. A study in Côte d'Ivoire showed that households with an HIV/AIDS patient spent twice as much on medical expenses as other households.[101]

UNAIDS, WHO and the United Nations Development Programme have documented a correlation between the decreasing life expectancies and the lowering of gross national product in many African countries with prevalence rates of 10% or more. Indeed, since 1992 predictions that AIDS would slow economic growth in these countries have been published. The degree of impact depended on assumptions about the extent to which illness would be funded by savings and who would be infected.[102] Conclusions reached from models of the growth trajectories of 30 sub-Saharan economies over the period 1990–2025 were that the economic growth rates of these countries would be between 0.56 and 1.47% lower. The impact on gross domestic product (GDP) per capita was less conclusive. However, in 2000, the rate of growth of Africa's per capita GDP was in fact reduced by 0.7% per year from 1990–1997 with a further 0.3% per year lower in countries also affected by malaria.[103] The forecast now is that the growth of GDP for these countries will undergo a further reduction of between 0.5 and 2.6% per annum.[100] However, these estimates may be an underestimate, as they do not look at the effects on output per capita.[104]

Many governments in sub-Saharan Africa denied that there was a problem for years, and are only now starting to work towards solutions. Underfunding is a problem in all areas of HIV prevention when compared to even conservative estimates of the problems.

The launching of the world's first official HIV/AIDS Toolkit in Zimbabwe on October 3, 2006 is a product of collaborative work between the International Federation of Red Cross and Red Crescent Societies, World Health Organization and the Southern Africa HIV/AIDS Information Dissemination Service. It is for the strengthening of people living with HIV/AIDS and nurses by minimal external support. The package, which is in form of eight modules focusing on basic facts about HIV and AIDS, was pre-tested in Zimbabwe in March 2006 to determine its adaptability. It disposes, among other things, categorized guidelines on clinical management, education and counseling of AIDS victims at community level.[105]

The Copenhagen Consensus is a project that seeks to establish priorities for advancing global welfare using methodologies based on the theory of welfare economics. The participants are all economists, with the focus of the project being a rational prioritization based on economic analysis. The project is based on the contention that, in spite of the billions of dollars spent on global challenges by the United Nations, the governments of wealthy nations, foundations, charities, and non-governmental organizations, the money spent on problems such as malnutrition and climate change is not sufficient to meet many internationally-agreed targets. The highest priority was assigned to implementing new measures to prevent the spread of HIV and AIDS. The economists estimated that an investment of $27 billion could avert nearly 30 million new infections by 2010.

Stigma
AIDS stigma exists around the world in a variety of ways, including ostracism, rejection, discrimination and avoidance of HIV infected people; compulsory HIV testing without prior consent or protection of confidentiality; violence against HIV infected individuals or people who are perceived to be infected with HIV; and the quarantine of HIV infected individuals.[106]

AIDS stigma has been further divided into the following three categories:

Instrumental AIDS stigma—a reflection of the fear and apprehension that are likely to be associated with any deadly and transmissible illness.[107]
Symbolic AIDS stigma—the use of HIV/AIDS to express attitudes toward the social groups or lifestyles perceived to be associated with the disease.[107]
Courtesy AIDS stigma—stigmatization of people connected to the issue of HIV/AIDS or HIV- positive people.[108]
Often, AIDS stigma is expressed in conjunction with one or more other stigmas, particularly those associated with homosexuality, bisexuality, promiscuity, and intravenous drug use.

In many developed countries, there is an association between AIDS and homosexuality or bisexuality, and this association is correlated with higher levels of sexual prejudice such as anti-homosexual attitudes.[109] There is also a perceived association between all male-male sexual behavior and AIDS, even sex between two uninfected men.[107]

For more details on this topic, see Stigma and HIV-AIDS, A review of the literature [110]
Stigma can lead to various forms of violence at the hands of family and community members. Stigma-related violence or the fear of violence prevents many people from seeking HIV testing, returning for their results, or securing treatment. This turns what could be a manageable chronic illness into a death sentence and perpetuates the spread of HIV.[111]

Origin of HIV
AIDS was first reported June 5, 1981, when the U.S. Centers for Disease Control and Prevention recorded a cluster of Pneumocystis carinii pneumonia (now classified as Pneumocystis jiroveci pneumonia) in five homosexual men in Los Angeles.[112] Originally dubbed GRID, or Gay-Related Immune Deficiency, health authorities soon realized that nearly half of the people identified with the syndrome were not homosexual men. In 1982, the CDC introduced the term AIDS to describe the newly recognized syndrome.

Three of the earliest known instances of HIV infection are as follows:

A plasma sample taken in 1959 from an adult male living in what is now the Democratic Republic of the Congo.[113]
HIV found in tissue samples from a 15 year old African-American teenager who died in St. Louis in 1969.[114]
HIV found in tissue samples from a Norwegian sailor who died around 1976.[115]
Two species of HIV infect humans: HIV-1 and HIV-2. HIV-1 is more virulent and more easily transmitted. HIV-1 is the source of the majority of HIV infections throughout the world, while HIV-2 is not as easily transmitted and is largely confined to West Africa.[116] Both HIV-1 and HIV-2 are of primate origin. The origin of HIV-1 is the Central Common Chimpanzee (Pan troglodytes troglodytes) found in southern Cameroon.[117] It is established that HIV-2 originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea Bissau, Gabon, and Cameroon.

Most experts believe that HIV probably transferred to humans as a result of direct contact with primates, for instance during hunting or butchery.[118] A more controversial theory known as the OPV AIDS hypothesis suggests that the AIDS epidemic was inadvertently started in the late 1950s in the Belgian Congo by Hilary Koprowski's research into a polio vaccine.[119] [120] According to scientific consensus, this scenario is not supported by the available evidence.[121] [122] [123]

Alternative hypotheses
A small minority of scientists and activists question the connection between HIV and AIDS,[124] the existence of HIV itself,[125] or the validity of current testing and treatment methods. These claims are considered baseless by the vast majority of the scientific community. The medical community argues that so-called "AIDS dissidents" selectively ignore evidence in favor of HIV's role in AIDS and irresponsibly pose a threat to public health by discouraging HIV testing and proven treatments.[126][127]

AIDS dissidents assert that the current mainstream approach to AIDS, based on HIV causation, has resulted in inaccurate diagnoses, psychological terror, toxic treatments, and a squandering of public funds.[128] Dissident views have been widely rejected,[129][130] and are considered pseudoscience by the mainstream scientific community.

HIV and AIDS misconceptions
A number of misconceptions have arisen surrounding HIV/AIDS. Three of the most common are that AIDS can spread through casual contact, sexual intercourse with a virgin will cure AIDS, and HIV can infect only homosexual men and drug users.

When scientists first recognized the syndrome in 1981 initially they termed it Gay Related Immune Deficiency Syndrome, a possible source for the misconception holding that AIDS infects only homosexual men; scientists soon renamed the disease in recognition of transmission other than by male-male intercourse.

HIV appears to have entered the United States around the late 1960s and seems to have then been unknowingly spread by people throughout the U.S. and Europe. In a survey on AIDS conducted in 1983 in Belgium, Denmark, Finland, France, Germany, Italy, the Netherlands, Norway, Sweden, Switzerland, and the United Kingdom a majority of those infected with HIV were male homosexuals (58% of all cases).[131]

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Coinfection With Both HIV And Hepatitis C Virus A Growing Problem

2006-12-21T10:44:00.002-08:00

Science Daily — Although many individuals infected with the hepatitis C virus (HCV) are naturally able to control levels of the virus with their immune systems, those who also become infected with HIV, the virus that causes AIDS, may lose that ability. In a report in the December issue of PLOS Medicine, a group of researchers from the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH) report one of the first studies of how HIV infection impacts immune system functions involved with HCV control. Their findings suggest that beginning antiretroviral therapy earlier than is generally recommended may help preserve HCV control in patients infected with both viruses.

"The global burden on health of chronic viral infections is immense, and HCV and HIV are chief among culprit viruses," says Arthur Kim, MD, of PARC-MGH, co-first author of the PLOS Medicine report. "Due to shared routes of transmission, infection with both viruses is common. Unfortunately, HCV behaves as an opportunistic infection in the presence of HIV and is becoming a leading cause of illness and death in persons with HIV."

In order to examine immune system factors associated with spontaneous control of HCV and how that control is altered by HIV infection, the researchers enrolled four groups of participants: 60 were infected with both viruses, and half of those had low HCV levels upon entering the study. The other two groups of 17 participants were infected with HCV only, with one group successfully controlling viral levels. Spontaneous HCV control is known to rely on the activity of CD4 helper T cells specifically targeted against the virus, and destruction of CD4 cells by HIV underlies the immune deficiency that characterizes AIDS. Therefore the researchers measured participants' T cell response to HCV at the outset of the study and at two- to six-month intervals during the study period.

The results showed that those individuals able to maintain low HCV levels in spite of HIV coinfection had stronger virus-specific responses for both CD4 T cells and the CD8 "killer" T cells than did those with elevated HCV counts. Not surprisingly, participants infected only with HCV had even more powerful antiviral T cell responses. About a quarter of those infected with both viruses who originally controlled HCV levels lost control during the two-and-a half-year study period, and their increased virus levels corresponded with an overall drop in CD4 T cells. None of the viral controllers who were infected with HCV alone had any increase in viral levels during the study period. Loss of protective responses and susceptibility to recurrent HCV infection may help to explain the higher rates of persistent HCV observed in subjects who are HIV/HCV coinfected, compared to those with HCV alone.

In analyzing factors that might be associated with the loss of HCV control in those infected with both viruses, the researchers made a surprising discovery. The factor most powerfully associated with maintaining HCV control was not the CD4 T cell count upon entering the study but the lowest previously recorded or 'nadir' CD4 count. That finding suggests that, for individuals infected with both viruses, beginning antiretroviral treatment before CD4 levels drop too low to maintain HCV responses may be desirable.

The researchers also found that, among those whose HCV levels rose, individuals who maintained some T cell responses had lower viral levels than did those with little or no T cell response. This suggests that the immune system retains a level of secondary immunity against HCV -- the kind of 'memory' response against a previously encountered pathogen seen in many infections.

"Currently a nationwide trial is recruiting people for a study examining whether earlier treatment of HIV will improve hepatitis C treatment outcomes," Kim says. "Part of this study will investigate how earlier treatment may affect immune responses. It also will be important to follow the impact of loss of HCV control on liver disease, since this will probably have important consequences for patients with HIV." Kim is an instructor in Medicine at Harvard Medical School.

Bruce Walker, MD, director of the Partners AIDS Research Center at MGH and a Howard Hughes Medical Institute (HHMI) investigator is senior author of the PLOS Medicine report, and Julian Schulze zur Wiesch, MD, of PARC-MGH and HHMI is co-first author. The study's co-authors are Thomas Kuntzen, MD, Joerg Timm, Daniel Kaufmann, MD, Jared Duncan, Andrea Jones, Benjamin Davis, MD, Rajesh Gandhi, MD, Gregory Robbins, MD, Todd Allen, PhD, and Georg Lauer, MD, of PARC-MGH, Raymond Chung, MD, MGH Gastroenterology; and Alysse Wurcel, Lemuel Shattuck Hospital, Boston. The study was supported by grants from the National Institutes of Health, the Campbell Foundation, the American Liver Foundation, the German Academic Exchange Service, Doris Duke Charitable Foundation and the Howard Hughes Medical Institute.

Note: This story has been adapted from a news release issued by Massachusetts General Hospital.

Effective HIV Control May Depend On Viral Protein Targeted By Immune Cells

2006-12-21T10:44:00.001-08:00

Science Daily — An effective response of the immune system's 'killer' T cells against infection with HIV may depend on exactly which viral protein is targeted, according to an international group of researchers. A new study finds that HIV-infected individuals in whom virus-specific CD8 T cells are targeted against the Gag protein have lower viral levels than do those with CD8 responses directed against other viral proteins. The report from the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH), the University of Oxford and University of KwaZulu-Natal in South Africa is receiving early online release in Nature Medicine.

"Understanding which immune responses are effective in control of HIV is of critical importance in vaccine development," says Philip Goulder, MD, PhD, of PARC-MGH and Oxford, the senior author of the study. "Previous approaches have focused on a 'more is better' approach, seeking to generate responses against a broad range of viral proteins, but these results challenge that dogma."

While many strategies for developing a vaccine to control HIV focus on the activity of the CD8 T lymphocytes that recognize and destroy virus-infected CD4 T cells, the fact that even patients in the last stages of AIDS can have measurable CD8 responses indicates that those responses are not always effective. To investigate how variations in CD8 response alter the ability to control HIV, the research team enrolled almost 600 South African patients who had not yet been treated for their HIV infections.

The researchers comprehensively mapped the CD8 responses against all viral proteins and also investigated whether the versions of HLA Class I molecules involved in the immune system's recognition of HIV protein fragments made a difference. When new viruses are produced within an infected cell, Class I molecules grab viral fragments and display them at the cell surface, thereby alerting CD8 cells that the cell has been infected and should be destroyed. Earlier studies, including a 2004 Nature report from the same group, showed that the genetically determined version of an individual's HLA Class I molecules could strongly influence immune control of HIV.

The current study found that only CD8 responses against the Gag protein were associated with significantly reduced viral levels and that individuals with responses against several different Gag fragments had even lower viral loads. In contrast, those with stronger responses against other HIV proteins -- including Env, a protein that is the focus of several vaccine studies -- had higher viral levels indicating poorer control of HIV.

In people receiving no antiretroviral treatment, the improved HIV control associated with Gag-specific CD8 response would probably translate into asymptomatic infection for more than a decade, compared with progression to AIDS within two to three years of infection in those with no Gag responses. The reason why patients' particular HLA Class I molecules are linked to different HIV disease outcomes now appears to be related to the number of Gag fragments displayed by different versions of the Class I molecule.

Mechanisms underlying the different effects of the protein-specific immune responses are unknown and require further investigation. The researchers suggest that responses against proteins like Env might be inherently less effective or might only be generated in response to elevated viral loads. Therefore, the findings of this study, which reflect chronic HIV infection, might not apply in situations in which vaccination generates an immune response before infection occurs.

"The possibility that there may be fundamental differences between the impact of Gag and non-Gag CD8 responses on the ability to control HIV has clear relevance to vaccine development," says Goulder, who is an associate professor of Medicine at Harvard Medical School.

Co-authors of the Nature Medicine report from Doris Duke Medical Research Institute at the University of KwaZulu-Natal are first author Photini Kiepiela, Kholiswa Ngumbela, Christina Thobakgale, Dhanwanthie Ramduth, Eshia Moodley, Shabashini Reddy, Chantal de Pierres, Zenele Mncube, Nompumelelo Mkhwanazi, Karen Bishop, Mary van der Stok, Kriebashnie Nair, Nasreen Kahn, and Hoosen Coovadia. Other co-authors are Isobella Honeyborne, Hayley Crawford, Rebecca Payne, Alasdair Leslie, Julia Prado, Andrew Prendergast, John Frater, and Noel McCarthy, University of Oxford; Christian Brander and Bruce Walker, Partners AIDS Research Center at Massachusetts General Hospital; Gerald Learn, David Nickle, Christian Rousseau and James Mullins, University of Washington School of Medicine; and David Heckerman, Microsoft Research.

The study was supported by grants from the U.S. National Institutes of Health, the Wellcome Trust, and the Mark and Lisa Schwartz Foundation. Walker is a Howard Hughes Medical Institute investigator and a Doris Duke Distinguished Clinical Science Professor, and Goulder is an Elizabeth Glaser Pediatric AIDS Foundation Scientist.

Note: This story has been adapted from a news release issued by Massachusetts General Hospital.

Male Circumcision Reduces HIV Risk, Study Stopped Early

2006-12-21T10:44:00.000-08:00

Science Daily — A University of Illinois at Chicago study has been stopped early due to preliminary results indicating that medical circumcision of men reduces their risk of acquiring HIV during heterosexual intercourse by 53 percent.

The study's independent Data Safety and Monitoring Board met Dec. 12 to review the interim data. Based on the board's review, the National Institutes of Health halted the trial and recommended that all men enrolled in the study who remain uncircumcised be offered circumcision.

"Circumcision is now a proven, effective prevention strategy to reduce HIV infections in men," said Robert Bailey, professor of epidemiology in the UIC School of Public Health and principal investigator of the study.

The clinical trial, funded by the National Institute of Allergy and Infectious Diseases and the Canadian Institute of Health Research, enrolled 2,784 HIV negative, uncircumcised men between 18 and 24 years old in Kisumu, Kenya.

Half the men were randomly assigned to circumcision, half remained uncircumcised. All men enrolled in the study received free HIV testing and counseling, medical care, tests and treatment for sexually transmitted infections, condoms and behavioral risk counseling for 24 months.

Study results show that 22 of the 1,393 circumcised men in the study contracted HIV, compared to 47 of the 1,391 uncircumcised men. In other words, circumcised men had 53 percent fewer HIV infections than uncircumcised men.

Until now, public health organizations have not supported circumcision as a method of HIV prevention due to a lack of randomized controlled trials.

"With these findings, the evidence is now available for donor and normative agencies, like WHO and UNAIDS, to actively promote circumcision in a safe context and along with other HIV prevention strategies," Bailey said.

"Circumcision cannot be a stand-alone intervention. It has to be integrated with all the other things that we do to prevent new HIV infections, such as treating sexual transmitted diseases and providing condoms and behavioral counseling," Bailey said. "We can't expect to just cut off a foreskin and have the guy go on his merry way without additional tools to fight against getting infected."

Opponents of circumcision have speculated that circumcised men may feel they are not at risk of contracting HIV and may be more likely to engage in risky behavior. The Kenya study suggests that circumcision did not increase risky behavior among circumcised or uncircumcised men, according to Bailey.

"Both uncircumcised and circumcised men are reducing their sexual risk behavior," he said, "which indicates that our counseling is doing some good."

The study also evaluated the safety of circumcision in a community health clinic with specially trained practitioners. There were no severe or lasting complications from circumcision. However, 1.7 percent of surgeries resulted in mild complications, such as bleeding or infection.

Bailey said that promoting circumcision in Africa must be done in conjunction with proper technical training and medical tools, equipment and supplies necessary to perform large numbers of circumcisions safely.

"Already, there are large numbers of boys and young men who are seeking circumcision in areas of Africa where men are not traditionally circumcised," he said. "The danger is that unqualified practitioners will fill a niche by providing circumcision, but with much higher complication rates."

An estimated 30 million people in Africa are infected with HIV/AIDS and more than 90 percent of HIV infections in adults result from heterosexual intercourse. In Kisumu, the third-largest city in Kenya, an estimated 26 percent of uncircumcised men are HIV infected by age 25.

"This study will likely not have a large impact on the incidence of HIV/AIDS in the United States or Europe where heterosexual transmission of HIV is low compared with areas like sub-Saharan Africa and parts of Asia," Bailey said. "However, there are other proven health benefits of circumcision, including better hygiene, fewer urinary tract infections, and less risk of cervical cancer in the partners of circumcised men."

The armamentarium of HIV prevention strategies is very small, according to Bailey. The only other strategy proven effective is the use of antiretroviral drugs to reduce transmission from mother to child.

If a significant proportion of men in a population get circumcised, it will have an enormous impact on preventing HIV infection in men, as well as reducing infections in women, Bailey said.

Co-investigators of the study include Stephen Moses and Ian Maclean at the University of Manitoba, Jekoniah Ndinya-Achola at the University of Nairobi, Corette Parker at Research Triangle International, Kawango Agot at UNIM Project, John Krieger at University of Washington, and Richard Campbell at UIC.

During the past two decades, more than 40 observational epidemiological studies and one previous clinical trial have reported an association between male circumcision and a reduced risk of HIV infection.

On Dec. 12, the NIH stopped another clinical trial of male circumcision undertaken by investigators in Uganda and at Johns Hopkins University, after the study's Data Safety Monitoring Board reviewed the preliminary results and found a protective effect similar to that found in Bailey's study.

Note: This story has been adapted from a news release issued by University of Illinois at Chicago.

Early HIV Treatment Fails To Restore Memory T Cells

2006-12-21T10:43:00.000-08:00

Science Daily — Most of the body's memory T cells vanish within weeks after a person is infected with the HIV virus. In a study from the Aaron Diamond AIDS Research Center and the Bernard-Nocht Institute appearing in the international open-access journal PLoS Medicine, researchers report that these memory T cells, mostly found in the digestive tract, tend not to return to normal even after years of treatment for HIV.

In recent years, HIV infection has been shown to deplete the body's memory T cells quite rapidly. In particular, the memory cells in the intestinal lining are decimated within days, while the T cells usually measured in the blood fall much more gradually, typically over several years. Although T cells in the blood can return and remain at normal levels when HIV infection is treated with antiviral drugs, it has been unclear whether the intestinal mucosal memory cells return as well. By performing intestinal biopsies on volunteers who started HIV treatment shortly after infection, the researchers found that, unlike in blood, intestinal T cells remained low even after several years of HIV treatment in 70% of volunteers, even though only a tiny fraction of these cells were found to be expressing HIV. Furthermore, they found that the level of immune activation in the gastrointestinal tract remained elevated despite treatment.

The finding that intestinal immune cells do not return to normal in most people with HIV despite years of treatment raises the concern that clinical problems will result over time. Fortunately, this does not appear to be the case in most people currently being treated for HIV, some for as long as 10 years, but the results of this study suggest that vigilance is warranted for infections or other gastrointestinal problems resulting from prolonged impairment of immunity.

These results also suggest that treatments to preserve immune function early after infection should be studied, and in particular that an HIV vaccine may need to stimulate immune responses that can act very quickly following infection, before the bulk of lymphocytes capable of countering the infection are lost.

Citation: Mehandru S, Poles MA, Tenner-Racz K, Jean-Pierre P, Manuelli V, et al. (2006) Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med 3(11): e484. (http://dx.doi.org/10.1371/journal.pmed.0040484)

Note: This story has been adapted from a news release issued by Public Library of Science.

A Molecular Condom Against AIDS

2006-12-21T10:34:00.007-08:00

Science Daily — University of Utah scientists designed a "molecular condom" women could use daily to prevent AIDS by vaginally inserting a liquid that would turn into a gel-like coating and then, when exposed to semen, return to liquid form and release an antiviral drug.We have developed a new vaginal gel that we call a molecular condom because it is composed of molecules that are liquid at room temperature and, when applied in the vagina, will spread and turn into a gel and effectively coat the tissue," says Patrick Kiser, an assistant professor of bioengineering. "It's a smart molecular condom because we designed this gel to release anti-HIV drugs when the gel comes into contact with semen during intercourse."

"The ultimate hope for this technology is to protect women and their unborn or nursing children from the AIDS virus," but the molecular condom is five years away from tests in humans and roughly 10 years until it might be in widespread use, Kiser says.

Kiser and colleagues report development of the molecular condom in a study to be published online Monday, Dec. 11, 2006, in the Journal of Pharmaceutical Sciences.

The molecular condom is part of a worldwide research effort to develop "microbicides" -- drug-delivery systems such as gels, rings, sponges or creams to prevent infection by the human immunodeficiency virus and other sexually transmitted diseases. HIV causes AIDS, which cripples the immune system, leaving patients vulnerable to other infections, cancers and death.

Microbicides are seen as a way for women to gain power by protecting themselves from HIV, particularly in impoverished nations where AIDS is widespread, where rape is rampant or where conventional condoms are taboo, not reliably available or where men resist using them. Worldwide, most AIDS cases are spread heterosexually.

About 16 microbicides are in development and five are undergoing testing in thousands of women, mostly in Africa. They are designed to fight HIV infection by preventing the virus from entering cells or replicating, or by maintaining acidic vaginal conditions. No first-generation microbicide has been approved yet for wide use.

Delivering Anti-HIV Medicine When and Where Needed

Kiser says the University of Utah molecular condom would be a more advanced method of delivering an antiviral drug to prevent infection by the AIDS virus.

"Up until now, most of the microbicide work has focused on the development of the active drug, not on the delivery of the drug," Kiser says. "This study and other work in my lab are directed at developing new technologies for vaginal delivery of antiviral agents, particularly a microbicide that can respond to triggers [body temperature and semen] that are present before, during and after intercourse. This is the first paper that begins to point in that direction."

Kiser says the dosage of anti-HIV drugs in first-generation microbicides lasts only a few hours, so "you have to use them an hour before sex, which is difficult. You only need one failure to get the disease. We're shooting for a microbicide delivery system that would be used once a day or once a month."

In the study, Kiser and colleagues outline how they designed a water-based gel or "hydrogel" sensitive to body temperature and pH (acidity or alkalinity) so that it could serve as a "smart semen-triggered vaginal microbiocidal vehicle."

The researchers have not yet tried incorporating an antiviral drug into the hydrogel, but showed that in laboratory conditions, the substance turns from a liquid to a gel at body temperature, then returns to liquid form and can release test compounds -- stand-ins for antiAIDS drugs -- when exposed to semen, which has a pH of 7.5, more alkaline than the acidic vaginal pH of 4 to 5.

Kiser conducted the research with University of Utah bioengineering graduate students Kavita Gupta and Meredith Roberts, and undergraduates Scott Barnes and Rachel Tangaro. The research is part of Gupta's doctoral thesis, and she did much of the work. Other coauthors of the study were bioengineers David Katz and Derek Owen at Duke University in Durham, N.C. The National Institutes of Health funded the study.

Designing a Microbicide to Empower Women

First-generation microbicides now being tested are expected to be available within four years and be 50 percent to 60 percent effective. That sounds low, but a British study found that even if a microbicide was only 50 percent effective against HIV and used by only 20 percent of the women in 73 developing nations, it would prevent 2.5 million infections during a three-year period. Kiser says he hopes the molecular condom ultimately will prove to be 90 percent effective.

Potential side effects of microbicides include itching, increased vaginal discharge and inflammation. But initial testing of the molecular condom -- in which the hydrogel was tested on basic tissue cells known as mouse fibroblasts -- "indicates these gels are likely to be well tolerated," Kiser says.

What about the comfort of a thin gel lining the vagina" "At the end of the day, women will use a material that protects them," he says. "But there is no reason to think these gels are uncomfortable."

The molecular condom is a polymer -- a molecule with a repeating, chain-like structure -- made from three chemicals in these proportions:

80 parts of N-isopropylacrylamide.
15 parts of butyl methacrylate, which is used in coatings, adhesives, solvents, resins, oil additives and to finish leather and paper.
Five parts acrylic acid, which is used in lubricant and spermicidal gels.

"The three together have the property of liquid at room temperature and vaginal pH, solid at body temperature and vaginal pH, and liquid at body temperature and semen pH," Kiser says.

Other researchers previously discovered this combination of chemicals forms a heat-sensitive gel, but Kiser and colleagues altered the polymer so it would change from liquid to gel and back at the desired temperature and pH. They also designed the gel so it would not dehydrate vaginal cells, which can trigger infections.

The researchers analyzed and optimized the gel's ability to adhere to a surface similar to vaginal tissue without being diluted by other fluids, but to erode rapidly in the presence of seminal fluid. Kiser says first-generation microbicides use gels like those in spermicides and lubricants, and are not optimized to coat and be retained in the vagina.

A Burst of Anti-AIDS Medicine

Kiser, Gupta and colleagues demonstrated how the polymer could change from liquid to gel at body temperature, then return to liquid form when exposed to simulated seminal fluid -- a sticky mixture of sugars and salt--and release large and small molecules used as stand-ins for real medicines in drug-delivery experiments.

In the experiments, when the hydrogel molecular condom was exposed to mock seminal fluid, it released 49 percent of the small-molecule drug within five minutes and 81 percent within an hour. It released 48 percent of the large molecule drug within 30 minutes and 66 percent in 90 minutes.

The lab experiments were designed to make it difficult for the molecular condom to release simulated drugs, Kiser says. Inside a woman, the gel would be much thinner than in the lab tests, so antiviral drugs "would all be released in just a few minutes."

Kiser hopes to incorporate experimental anti-AIDS drugs known as entry inhibitors into the molecular condom.

Note: This story has been adapted from a news release issued by University of Utah.

HIV/AIDS Trial Finds Risks Increase On Episodic Antiretroviral Therapy

2006-12-21T10:34:00.006-08:00

Science Daily — Results from one of the largest HIV/AIDS treatment trials ever conducted show that a specific strategy of interrupting antiretroviral therapy more than doubles the risk of AIDS or death from any cause. In the study, the investigators used two predetermined levels of CD4+ T cells, the primary immune cell targeted by HIV, to guide them in respectively suspending or restarting the study participants on antiretroviral therapy.

A report describing this research--which involved 318 clinical sites in 33 countries--appears in this week's issue of The New England Journal of Medicine. The trial, known as Strategies for Management of Anti-Retroviral Therapies, or SMART, was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

"The SMART trial has provided important new data that will help physicians and their HIV-infected patients make treatment decisions," says NIAID Director Anthony S. Fauci, M.D. "The study reflects an extraordinary global collaboration among hundreds of dedicated AIDS clinicians and thousands of their patients, all of whom should be commended for their contributions to this pivotal HIV/AIDS treatment study."

As HIV/AIDS has evolved into a chronic disease without a cure, lifelong antiretroviral therapy has become the norm. Lifelong therapy, however, can be difficult to adhere to as well as expensive. For these reasons, there has been a concerted research effort to test treatment interruption strategies that may enhance patients' quality of life and limit adverse drug effects. The experimental strategies vary in their approach to when to interrupt therapy. Some, like SMART, use a specific CD4+ count as a guide; others schedule regular time periods during which treatment is stopped (for example, alternating one month off and three months on).

SMART was designed to determine which of two different HIV treatment strategies would result in greater overall clinical benefit. Volunteers with chronic HIV infection--nearly all of whom had taken antiretroviral therapy (ART)--were assigned at random to one of two groups. In the "viral suppression" group, ART was taken on an ongoing basis to suppress HIV viral load; in the "drug conservation" group, participants received episodic ART in an effort to reduce drug side effects and preserve treatment options. In the latter group, ART was suspended whenever CD4+ counts were above 350 cells per cubic millimeter (mm3) and ART was started only when levels of CD4+ cells dropped below 250 cells/mm3. (For more details see http://www.smart-trial.org .) The CD4+ count thresholds for stopping and starting ART were chosen based on previously reported associations between CD4+ counts and risks of opportunistic diseases and death.

Beginning in January 2002, the trial recruited 5,472 volunteers: 2,720 were assigned at random to the drug conservation group and 2,752 to the viral suppression group. The participants were followed for an average of 16 months.

In early 2006, NIAID announced that enrollment into the trial had been halted after review of the interim data by an independent data and safety monitoring board (DSMB) found that those participants receiving episodic therapy had a significantly increased risk of disease progression. "Disease progression" was defined as the development of an opportunistic disease (AIDS) or death from any cause. The Executive Committee of SMART recommended that ART be re-initiated in ART-experienced participants in the drug conservation group. Follow-up is currently scheduled to continue through July 2007.

At the time the trial was stopped, 120 participants in the drug conservation group compared with 47 on continuous antiretroviral therapy had developed disease progression. The difference represents a 2.6-fold increased risk for those receiving episodic treatment. Notably, the drug conservation group had significantly more major adverse events, specifically, cardiovascular, kidney and liver disease, complications previously associated with ART. The study investigators had hoped that these complications would be seen less frequently in those trial volunteers receiving less drug.

"Quite unexpectedly, our results show that interrupting therapy increases the risk of serious non-AIDS-related events," says Wafaa El-Sadr, M.D., M.P.H., M.P.A., of the Harlem Hospital Center and Columbia University in New York City, one of the co-chairs of the trial. "This is a major lesson learned for designing any HIV/AIDS treatment trial: It is important to evaluate all causes of death, not just death from AIDS, and to also evaluate other major non-fatal clinical diseases, not just those considered AIDS-related opportunistic diseases."

The University of Minnesota's James Neaton, Ph.D., the other co-chair and chief biostatistician for the trial, notes, "The SMART study demonstrates the tremendous advantages inherent in conducting large enough trials to precisely assess risks and benefits of any treatment strategy in a diverse population. First, the study ended much earlier than we expected. Second, we could analyze the data according to many variables--age, race, sex, HIV risk behavior, and baseline CD4+ count, among other factors. Importantly, among every subgroup we looked at, the conclusion remained consistent: CD4+ count-guided episodic antiretroviral therapy as implemented in the SMART study carries increased health risks compared with continuous therapy."

The SMART study was coordinated by four international centers: the Medical Research Council Clinical Trials Unit in London; the Copenhagen HIV Program in Denmark; the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales in Sydney, Australia; and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) in Washington, DC. The statistical and data management center was based at the University of Minnesota in Minneapolis.

Fred Gordin, M.D., of the VA Medical Center in Washington, DC, the CPCRA director, says, "The study participants understood that our goal was to test a strategy that we hoped might simplify their treatment and prevent some adverse side effects. SMART has better focused the discussion of what questions we can and should be addressing in this important area of HIV/AIDS treatment research." A workshop held by the NIH Office of AIDS Research in July in London assessed the current state of research on intermittent therapy strategies.

Initial analyses indicate that most but not all of the excess risk in the drug conservation group can be explained by CD4+ count and viral load differences. Jens Lundgren, M.D., Director of the Copenhagen HIV Programme and the Copenhagen international coordinating center, says, "The continued follow-up of patients and planned research on patient specimens will help us better understand the differences between the treatment groups that we observed."

David Cooper, M.D., D.Sc., of the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales, the Sydney international coordinating center director, notes, "The prospect of lifelong treatment is difficult for people with HIV. We are gratified that the SMART study has so clearly delineated the risk and benefits of these two strategies, and we are committed to continuing to try to find ways to improve treatment strategies for those with chronic HIV disease."

Janet Darbyshire, M.Sc., FRCP and Director of the MRC Clinical Trials Unit and the London international coordinating center comments, "This question could not have been answered so quickly without the collaboration and active participation of the 318 clinical sites and thousands of patients worldwide which contributed to SMART. Such collaborations are essential if we are to answer some of the key strategic questions about how to best manage HIV disease."

Note: This story has been adapted from a news release issued by NIH/National Institute of Allergy and Infectious Diseases.

Causes Of Global Death And Disease In The Next 25 Years

2006-12-21T10:34:00.005-08:00

Science Daily — In 1993, the World Bank sponsored the 1990 Global Burden of Disease study carried out by researchers at Harvard University and the World Health Organization (WHO). This study provided the first comprehensive global estimates of death and illness by age, sex, and region. It also provided projections of the global burden of disease and mortality up to 2020. The study and its projections have been crucial in national and international health policy planning. Colin Mathers and Dejan Locar (from the World Health Organization, Geneva) have now updated the projections based on 2002 data on mortality and burden of disease and published their results in the international open-access journal PLoS Medicine.

As for the earlier report, the researchers used projections of socio-economic development to model future patterns of mortality and illness for three different scenarios: a baseline scenario, a pessimistic scenario that assumes a slower rate of socio-economic development, and an optimistic scenario that assumes a faster rate of growth.

They predict that between 2002 and 2030 under all three scenarios life expectancy will increase around the world, fewer children under the age of 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase. Despite this increase, 50% more people are predicted to die of tobacco-related disease than of HIV/AIDS in 2015. By 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischemic heart disease in the baseline and pessimistic scenarios. In the optimistic scenario, road-traffic accidents (which increase with socioeconomic development) will replace heart disease as the number 3 killer.

In an accompanying editorial, the PLoS Medicine editors ask whether they are publishing "the right stuff", i.e. research and commentary whose goal it is to reduce mortality and suffering from the most relevant conditions--and whether research funding and health expenditure are consistent with these results.

Citation: Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11): e442. (http://dx.doi.org/10.1371/journal.pmed.0030442)

Note: This story has been adapted from a news release issued by Public Library of Science.

Human Testis Harbors HIV-1 In Resident Immune Cells

2006-12-21T10:34:00.004-08:00

Science Daily — Researchers have demonstrated HIV replication within resident immune cells of the testis, providing an explanation for the persistence of virus in semen even after effective highly active antiretroviral therapy. The related report by Roulet et al., "Susceptibility of human testis to human immunodeficiency virus-1 infection in situ and in vitro," appears in the December issue of The American Journal of Pathology.

According to the most recent World Health Organization data, 39.5 million people are infected with HIV. Semen remains the main means of spreading the virus, even though highly active antiretroviral therapy (HAART) can successfully suppress virus in the blood. The presence of HIV in the semen despite successful HAART has intrigued scientists.

Researchers led by Dr. Nathalie Dejucq-Rainsford examined testis tissue for the presence of HIV receptors. They found that all of the necessary cellular receptors (CD4, CXCR4, CCR5, and DC-SIGN) were present on cells located within the testis, specifically testicular macrophages.

The point was demonstrated further by using explanted organ cultures in which human testis tissue was grown in culture. This testis culture, which retained the same tissue architecture as in vivo tissue and continued to secrete testosterone, was able to support infection by HIV-1. Virus produced from the testis culture was fully active as collected virus was able to infect permissive cells in culture.

The finding that HIV-1 can replicate within testicular macrophages is significant because the testis represents a pharmacological sanctuary--many anti-retroviral drugs have difficulty penetrating this organ and may be present at sub-therapeutic levels. Thus, although HAART may achieve undetectable virus levels in the blood, virus replication in the testis may permit continued spread of the virus.

Finally, with HIV infection continuing to rise, the development of anti-retroviral therapy that effectively targets all sources of HIV, including the testis, is gravely needed. The use of this testis culture system may allow assessment of new anti-retroviral drugs that target HIV in the testis.

This work was supported by INSERM, ANRS, Sidaction, Région Bretagne, Ministère de l'Enseignement Supérieur et de la Recherche and Faculté de Médecine de Rennes.

Work was directed by Dr. Nathalie Dejucq-Rainsford from INSERM U625-GERHM, Rennes, France.

Roulet V, Satie A-P, Ruffault A, Le Tortorec A, Denis H, Guist'hau O, Patard J-J, Rioux-Leclerq N, Gicquel J, Jégou B, Dejucq-Rainsford N. Susceptibility of human testis to human immunodeficiency virus-1 infection in situ and in vitro. Am J Pathol 2006 169:2094-2103

The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.

Note: This story has been adapted from a news release issued by American Journal of Pathology.

HIV/AIDS Linked To Extensively Drug Resistant TB

2006-12-21T10:34:00.003-08:00

Science Daily — A highly drug-resistant form of tuberculosis (TB) has been linked to HIV/AIDS in a study conducted in rural South Africa by researchers at Yale School of Medicine.

Published in the October 26 issue of The Lancet, the study is the result of a five-year collaboration between a Yale and South African team of researchers who aim to integrate HIV and TB care and treatment.

TB is the most common cause of death and illness in those with HIV infection in sub-Saharan Africa. HIV greatly increases the risk of active TB disease and about 80 percent of patients with active TB in the province of KwaZulu Natal, South Africa, are co-infected with HIV. Death rates of up to 40 percent per year have been reported in patients with both HIV and TB.

Led by senior author Gerald Friedland, M.D., director of the AIDS Program at Yale and Professor in the Departments of Medicine and Epidemiology and Public Health, the study measured the prevalence of multi-drug resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis in a hospital in KwaZulu Natal. Between January 2005 and March 2006, sputum samples from 1,539 patients were screened. MDR TB was found in 221 patients and of those, 53 had XDR TB. Those patients with XDR who were tested for HIV were found to be co-infected. All but one of the 53 patients with both XDR TB and HIV died, with an average survival of 16 days.

"This is an issue of grave worldwide importance," said Friedland. "MDR and XDR carry the danger of blunting or reversing the success of TB programs and the roll-out of anti-retroviral therapies for HIV where they are desperately needed in resource limited settings. Urgent intervention is necessary, especially now that we know that MDR tuberculosis is far more prevalent than previously thought and that XDR tuberculosis has been transmitted to HIV co-infected patients and associated with high mortality."

Future studies will involve defining the extent and consequences of the problem in greater detail, Friedland said, with operational research focused on quickly determining what kind of infection control practices can practically and feasibly be instituted to reduce the transmission of this lethal form of tuberculosis to others.

Friedland said there is a desperate need for new diagnostic tests and treatment for TB. "It is still being diagnosed the same way it was in 1882," he said. "Modern technology for diagnosis and new treatment needs to be developed urgently. The last approved TB drug was 40 years ago."

In addition to Friedland, the study also included first author Neel R. Gandhi, M.D., a former Yale Robert Wood Johnson Clinical Scholar, now at the Albert Einstein College of Medicine; Kimberly Zeller, M.D., a former Yale Robert Wood Johnson Clinical Scholar, now at Brown Medical School; and Yale School of Medicine student Jason Andrews. South African co-investigators included Anthony Moll of the Church of Scotland Hospital and Philanjalo; A. Willem Sturm, M.D., Robert Pawinski and Umesh Lalloo, M.D., of the Nelson R. Mandela School of Medicine; and Thiloshini Govender of the KaZulu Natal Department of Health.

The study was funded by the Irene Diamond Fund, the Doris Duke Charitable Foundation and Yale University.

Citation: The Lancet, Early online edition (October 26, 2006)

Note: This story has been adapted from a news release issued by Yale University.

Fighting HIV With HIV: New Gene Therapy Vector Shows Promise

2006-12-21T10:34:00.002-08:00

Science Daily — Researchers at the University of Pennsylvania School of Medicine report the first clinical test of a new gene therapy based on a disabled AIDS virus carrying genetic material that inhibits HIV replication. For the first application of the new vector five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were given a single infusion of their own immune cells that had been genetically modified for HIV resistance.

The researchers, led by Carl June, MD, and Bruce Levine, PhD, of the Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, along with Rob Roy MacGregor, MD, Professor of Medicine, report their findings in the online edition of the Proceedings of the National Academy of Sciences. Viral loads of the patients remained stable or decreased during the study, and one subject showed a sustained decrease in viral load. T-cell counts remained steady or increased in four patients during the nine-month trial. Additionally, in four patients, immune function specific to HIV improved.

Overall, the study results are significant, say the researchers, because it is the first demonstration of safety in humans for a lentiviral vector (of which HIV is an example) for any disease. Additionally, the vector, called VRX496, produced encouraging results in some patients where other treatments have failed.

"The goal of this phase I trial was safety and feasibility and the results established that," says June. "But the results also hint at something much more."

Each patient received one infusion of his or her own gene-modified T cells. The target dose was 10 billion cells, which is about 2 to 10 percent of the number of T cells in an average person. The T-cell count was unchanged early after the infusions. "We were able to detect the gene-modified cells for months, and in one or two patients, a year or more later," says Levine. "That's significant -- showing that these cells just don't die inside the patient. The really interesting part of the study came when we saw a significant decrease in viral load in two patients, and in one patient, a very dramatic decrease.

But, cautions Levine, "just because this has produced encouraging results in one or two patients doesn't mean it will work for everyone. We have much more work to do." In the current study, each patient will be followed for 15 years.

Trojan Horses

"The new vector is a lab-modified HIV that has been disabled to allow it to function as a Trojan horse, carrying a gene that prevents new infectious HIV from being produced," says Levine. "Essentially, the vector puts a wrench in the HIV replication process." Instead of chemical- or protein-based HIV replication blockers, this approach is genetic and uses a disabled AIDS virus to carry an anti-HIV genetic payload. The modified AIDS virus is added to immune cells that have been removed from the patients' blood by apheresis, purified, genetically modified, and expanded by a process June and Levine developed. The modified immune cells are then returned to the patients' body by simple intravenous infusion.

This approach enables patients' own T cells, which are targets for HIV, to inhibit HIV replication -- via the HIV vector and its anti-viral cargo. The HIV vector delivers an antisense RNA molecule that is the mirror image of an HIV gene called envelope to the T cells. When the modified T cells are given back to the patient, the antisense gene is permanently integrated into the cellular DNA. When the virus starts to replicate inside the host cell, the antisense gene prevents translation of the full-length HIV envelope gene, thereby shutting down HIV replication by preventing it from making essential building blocks for progeny virus. VRX496 was designed and produced by the Gaithersburg, Md. biotech company VIRxSYS Corp.

A New Field

The new vector is based on a lentivirus, a subgroup of the well-known retroviruses. The study and its safety profile to date have now opened up the field of lentiviral vectors, which have potential advantages over other viral vectors currently being studied because they infect T cells better than adenoviruses, a commonly used viral vector. Lentiviruses also infect non-dividing or slowly dividing cells, which improves delivery to cells such as neurons or stem cells, thus enabling the evaluation of gene therapy in an even wider array of diseases than before. Furthermore, lentiviral vectors insert into cellular DNA in such a way that may be safer than other gene therapy vectors. This is because lentiviruses appear to insert differently from other retroviruses that have caused side effects in other trials involving stem-cell therapy. In addition, gene insertion by lentiviral vectors is attractive for potential therapeutics since it enables long-term gene expression, unlike other viral vectors where expression is lost over time.

Penn researchers are now recruiting for a second trial using the VRX496 vector with HIV patients whose virus is well controlled by existing anti-retroviral drugs, a group of patients who are generally healthier and have more treatment options available. This trial will use six infusions rather than one and is designed to evaluate the safety of multiple infusions and to test the effect of infusions on the patients' ability to control HIV after removal of their anti-retroviral drugs. The hope is that this treatment approach may ultimately allow patients to stay off antiretroviral drugs for an extensive period, which are known to have significant toxicity, especially after long-term use.

The research was supported by the National Institute of Allergy and Infectious Disease; the Abramson Family Cancer Research Institute; and VIRxSYS Corp. In addition to June, Levine, and MacGregor, co-authors on the paper are: Jean Boyer and Frederic Bushman from Penn; Laurent M. Humeau, Tessio Rebello, Xiaobin Lu (now with US Pharmacopeia), Gwendolyn K. Binder (now with Penn), Vladimir Slepushkin, Frank Lemiale, and Boro Dropulic (now with Lentigen Corp, Baltmore) from VIRxSYS; and John R. Mascola from the National Institutes of Health.

Note: This story has been adapted from a news release issued by University of Pennsylvania School of Medicine.

Targeted Irradiation: A New Weapon Against HIV?

2006-12-21T10:34:00.001-08:00

Science Daily — Antiretroviral therapy can keep HIV infection in check and delay and ameliorate the symptoms of HIV/AIDS. However, the drugs do not manage to eradicate the virus completely; individuals have to stay on the drugs permanently. Preclinical studies in mice by Ekatarina Dadachova and colleagues (Albert Einstein College of Medicine) published in the international open-access journal PLoS Medicine now suggest a new strategy to locate and kill many if not all HIV-infected cells in the body.

Radioimmunotherapy refers to an approach pioneered by cancer researchers in which patients are injected with antibodies against specific molecules characteristic of cancer cells (or in this case, HIV-infected cells) which carry a radioactive isotope. The approach takes advantage of the antibody's ability to rapidly hone in on its target cells and deliver the radioactive payload which then selectively kills the target cells and any HIV particles within it.

The study included some test-tube experiments on HIV infected human white blood cells as well as experiments on HIV infected mice that were injected with the radioactive antibodies. The researchers found that HIV infected white blood cells were successfully killed by radioactive antibodies that had been developed against specific proteins in the HIV particle that are routinely displayed at the surface of infected cells.

Two different types of antibodies and two different types of radioactive payload were tried. Both antibodies were very effective in targeting HIV infected cells, but one type of radioactive tag (213-Bismuth) was more efficient in killing the HIV-infected target cells than the other (188-Rhenium).

Then, mice were infected with HIV and treated with the radioactive antibodies (these particular mice had a deficient immune system, which means that they can be infected with the HIV virus that normally does not infect mice). The number of HIV infected cells was reduced in the treated mice compared with control animals, which were treated with antibodies not joined to a radioactive tag. The greater the antibody dose, the greater the proportion of HIV infected cells that were killed.

To assess 'collateral damage' the researchers examined whether the treatment with the radioactive antibodies damaged the red blood cells in the infected mice. They saw a drop in red blood cell numbers only for the mice receiving the highest dose of antibodies, suggesting that there is dose at which the antibodies are efficient and selective at killing their specific target cells.

These results provide initial support for the idea that radioimmunotherapy could work against HIV/AIDS and are encouraging for two reasons: First, because HIV is a formidable opponent and patients and doctors need as many different strategies as possible to help patients control the disease. And second, because they hint at the possibility of eradicating HIV completely, something that Dadachova and colleagues speculate would have the best chance of working at the early stage of infection right after someone is exposed to the virus.

Citation: Dadachova E, Patel MC, Toussi S, Apostolidis C, Morgenstern A, et al. (2006) Targeted killing of virally infected cells by radiolabeled antibodies to viral proteins. PLoS Med 3(11): e427. (http://dx.doi.org/10.1371/journal.pmed.0030427)

Note: This story has been adapted from a news release issued by Public Library of Science.

Researchers Identify Cell Line That Is Resistant To Retroviruses, Including HIV

2006-12-21T10:33:00.001-08:00

Science Daily — Researchers at the University of Minnesota have identified a protein that enables viruses such as HIV to infect cells and spread through the body.

This discovery gives drug developers a target to discover new types of drugs to stop the virus from spreading.

The research, led by Nikunj Somia, Ph.D., assistant professor of Genetics, Cell Biology and Development, will be published online this week in the Proceedings of the National Academy of Sciences, and will appear in a subsequent print edition of the journal.

HIV is a parasite that does not have enough proteins of its own to complete its life cycle. To survive, the virus needs to use proteins in the cells that it infects.

Currently, the drugs that are available to fight HIV act on proteins that the virus itself produces.

"The downfall of existing HIV drugs is that since the virus is constantly changing, the drugs eventually stop working, and the virus becomes drug resistant," Somia said. "We hypothesized that if we could find the proteins within the cells that HIV uses to make more copies of itself, we would find a potential new and more effective way to fight HIV."

To begin their search for these proteins, they first induced mutations in cells through chemical manipulation; this made random mutations in the DNA of the cell lines. Then they altered HIV so it contained a protein that immediately kills cells, and infected the different mutant cell lines.

The Somia laboratory found that some cell lines lived after being infected with HIV. In the cell lines that live, the HIV is able to get into the cell, but it is attacked. The cell's proteasome, a "machine" in the cell that destroys or chews up proteins, attacks the virus, preventing it from making more copies of itself.

Proteasomes are signal dependant machines in the cell, and proteins are typically "tagged" to be destroyed.

"Finding the switch that turns on the proteasome machine in cells to seek and destroy the virus could be a powerful therapeutic agent in the fight against HIV and in controlling AIDS," Somia said.

Note: This story has been adapted from a news release issued by University of Minnesota.

HIV Gets Makeover: Tweaking AIDS Virus Could Alter Course Of Research

2006-12-21T10:16:00.009-08:00

Science Daily — The slow pace of AIDS research can be pinned, in no small part, on something akin to the square-peg-round-hole conundrum. The HIV-1 virus won’t replicate in monkey cells, so researchers use a monkey virus — known as SIVmac, or the macaque version of simian immunodeficiency virus — to test potential therapies and vaccines in animals. But therapies and vaccines that are effective on SIV don’t necessarily translate into human success.

Now, using a combination of genetic engineering and forced adaptation, researchers at Rockefeller and the Aaron Diamond AIDS Research Center have created a version of the AIDS virus that replicates vigorously in both human and monkey cells — an advance that has the potential to revolutionize vaccine research.

In a paper published in today’s issue of Science, Paul Bieniasz, associate professor and head of the Laboratory of Retrovirology, describes how he and his colleagues maneuvered around the intrinsic immunity of primate cells by replacing just a few parts of the human virus — the ones responsible for blocking replication in monkey cells — with components from SIV. “Overall, the virus is a mixture of engineering and forced evolution,” Bieniasz says. “It sounds simple, in theory, but it took us two years to do.”

Bieniasz and Theodora Hatziioannou, a research scientist in the lab and the paper’s first author, had to overcome two major obstacles: the first was a protein called TRIM5 that, in monkeys, recognizes the outer shell or “capsid” of HIV-1 but not that of SIV. By swapping out the capsid region of the HIV-1 genome for that of the monkey virus, and then selectively growing the viruses that replicated most robustly, over several generations Hatziioannou created an HIV-1 mutant that could evade the monkey cells’ TRIM5 recognition.

Another bit of engineering was required to get around the second obstacle: APOBEC proteins produced by a host normally cause invading viruses to mutate so much that they can’t survive, but HIV-1 uses a protein called Vif to destroy APOBEC and prevent the attack. Monkey APOBEC proteins, however, aren’t susceptible to the human virus’s Vif. So Hatziioannou did another swap — the SIV Vif gene for the HIV one — and then another round of forced adaptation to create viruses that would multiply with vigor.

The researchers dubbed their end result simian tropic HIV (stHIV): a form of HIV-1 that only differs from the original by about 10 percent, but can effectively infect primate cells and be used to test potential therapies. “If we can make this virus work in animals the way it works in tissue culture, it will likely change the way that AIDS vaccine and therapeutics research is done,” Bieniasz says.

Note: This story has been adapted from a news release issued by Rockefeller University.

Major Advance In The Fight Against Chronic Virus Infections

2006-12-21T10:16:00.008-08:00

Science Daily — A major finding that could lead to a new approach for treating hepatitis C and other chronic virus infections was announced today by researchers at the La Jolla Institute for Allergy & Immunology (LIAI). The research team, using controlled laboratory studies of mice, was able to eliminate a chronic virus infection in the animals by blocking a key messenger molecule in the immune system. The finding has particular relevance for hepatitis C, a viral illness which can cause liver disease and cancer, but may also be applicable to AIDS, cytomegalovirus and other chronic virus infections.

"This is a significant advance that holds great promise for the treatment of chronic virus infections," said Mitchell Kronenberg, LIAI President & Scientific Director. He noted that the research is particularly exciting because the scientific team was able to completely eradicate the usually chronic infection in the mice, not just tone it down, like many of the current treatment methods for such infections.

The research team, led by Matthias von Herrath, M.D., announced its finding in a paper, "Resolution of a Chronic Viral Infection Following IL-10 Receptor Blockade," published today in the online version of the Journal of Experimental Medicine. A separate study, led by Michael Oldstone from the Scripps Research Institute, produced similar results and was published Sunday in a science journal.

LIAI's research team used a novel method for tackling a chronic viral infection, which involved releasing the disease-fighting power of the immune system by blocking the interleukin-10 (IL-10) messenger molecule receptor with a simple antibody. Normally, this molecule, which is produced at substantial levels during hepatitis C, HIV and cytomegalovirus infections, acts to suppress the immune system's attack on chronic virus infections. "We thought, 'what if we try to correct what the immune system seems to be doing wrong in response to many chronic viral infections?,'" said von Herrath. "So we unleashed the power of the immune system by using an antibody to block the IL-10 receptor. This taught the immune system to take the right action and fight the disease."

The discovery by scientific researchers that mice chronically infected with lymphocytic choriomeningitis virus produce large amounts of IL-10 led to the development of this new intervention. Von Herrath used a version of the virus that causes chronic infections in a study involving 40 infected mice. The mice were treated with the IL-10-blocking antibody for two weeks. "They got better after one week," he said. "After two weeks, the infection was resolved in the majority of the mice and, in the end, all animals were able to cope with the virus. They developed a normal antiviral immune response, gained weight and returned to a healthy state." Von Herrath noted that their studies showed that the treatment worked best when given immediately after infection. "The later you give it after the infection, the lesser the efficacy," he said.

Von Herrath said that future studies in humans should primarily target hepatitis C because it causes the body to produce the most IL-10 of any of the chronic virus infections. Hepatitis C has been compared to a "viral time bomb." The World Health Organization estimates that about 180 million people, some 3% of the world's population, are infected with hepatitis C virus, 130 million of whom are chronic carriers at risk of developing liver cirrhosis and/or liver cancer. The hepatitis C virus is responsible for 50--76% of all liver cancer cases, and two thirds of all liver transplants in the developed world. Current estimates in the U.S. are that 3.9 million Americans are chronically infected with hepatitis C.

Currently, hepatitis C is treated with a variety of drugs, with only modest success. "The problem is you need to strengthen the immune system to fight the (chronic) virus, but in doing so it may destroy too many cells. This cellular damage can eventually become intolerable for the body," Von Herrath explained, a condition known as immunopathology. However, in their studies with IL-10, "we found that by blocking this molecule, you can release the brakes on the immune system at a crucial juncture," he said. "This results in an immune system attack that is intense enough to rid the body of the disease, but not so high as to cause immunopathology."

Von Herrath said the research team will continue to expand on the finding. "One of the next steps will be to test the IL-10 blocking antibody on human cells in the lab to see whether these cells also become normal and functional against the virus and to test combination therapies that add viral vaccines, anti-viral drugs and other antibodies to the IL-10 receptor blockade. Combination therapies bear the promise to minimize potential side effects while achieving synergy in combating the viral disease."

Note: This story has been adapted from a news release issued by La Jolla Institute for Allergy and Immunology.

AIDS Study Challenges Conventional Treatment Guidelines For HIV Patients

2006-12-21T10:16:00.007-08:00

Science Daily — A newly published study by investigators at the Center for AIDS Research at Case Medical Center, led by Benigno Rodríguez, MD, along with a nationwide team of AIDS/HIV experts, strongly challenges conventional thinking about the role of measurements of the amount of HIV particles in the blood as a method of predicting a patient's ability to fight off the disease. The study, published in the current issue of JAMA (Journal of the American Medical Association), indicates that the amount of HIV in a patient's blood (commonly known as the viral load) is much less reliable as a tool for determining the rate at which he or she will lose infection-fighting CD4 cells than previously thought.

HIV targets CD4 cells, a type of white blood cell, and as they decline after HIV infection, the complications that characterize the Acquired Immunodeficiency Syndrome (AIDS) become more common. These study results showed that the viral load explains only about 5% of the variation from person to person in the rate of CD4 cell loss. Thus, CD4 depletion cannot be viewed as a simple consequence of the amount of virus circulating in the blood.

"The results of this nationwide study may have profound implications in our understanding of how HIV causes disease and in our approach to the management of HIV-infected patients," says Dr. Rodriguez, infectious disease specialist at the Case Medical Center, a partnership of University Hospitals and Case Western Reserve University School of Medicine. "We hope that this study will provide impetus for a more thorough understanding of the mechanisms of HIV-induced damage to the immune system and for the design of strategies to block those mechanisms."

In the study, entitled Predictive Value of Plasma HIV RNA Level on Rate of CD4 T Cell Decline in Untreated HIV infection, Dr. Rodríguez and his colleagues report the results of analyses conducted on two large cohorts of HIV-infected patients who were not receiving treatment for HIV, totaling more than 2,800 individuals. The first cohort consisted of patients included in three data sources: a) four sites of the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a database of real-time clinical care and laboratory data; b) the San Francisco Men's Health Study (SFMHS) and the Research in Access to Care for the Homeless Cohort (REACH). This cohort included approximately 12% female and 35% non- Caucasian participants. The second cohort, which the investigators used to validate their findings in the first group, included participants in the Multicenter AIDS Cohort Study, a long-standing federally funded study composed largely of Caucasian men who have sex with men.

The investigators sought to estimate how much of the person-to-person variation in the rate of CD4 cell loss could be accounted for on the basis of each patient's initial viral load, in an attempt to reproduce more closely the situation that a physician would encounter in clinical practice, where a patient presents with an initial set of laboratory results and the clinician must try to predict how quickly that person's CD4 cell count will reach the danger level at which treatment for HIV becomes most critical. Current clinical practice, based on previous work from other groups, is to focus on both the current CD4 count and the viral load to estimate how rapidly a person's CD4 cell count will decrease. This approach is based on comparisons of the average rate of CD4 cell loss among groups of patients with roughly similar viral loads, which indicate that generally speaking, patients with higher viral loads will tend to experience more rapid CD4 cell loss than patients with lower viral loads. Until now, however, there had been no attempt to quantify how well this observation held when considering the estimated rate of CD4 cell loss for each individual patient.

Using sophisticated statistical modeling, the researchers found that only 4-6% of an individual patient's CD4 cell loss rate can be explained by his or her presenting viral load. Moreover, the results were remarkably similar when the analyses were reproduced separately in each of the two cohorts, and changed only minimally when the investigators considered the possible effect of errors in the measurement of the CD4 cell count and the HIV viral load.

These results represent a shift in the paradigm that the rate of CD4 cell loss in a given HIV-infected individual can be accurately predicted by his or her viral load. Predicting disease progression is crucial in the treatment of HIV-positive people, such as in making the decision as to when it is best for starting antiretroviral therapy. Current treatment guidelines, while diminishing its importance, continue to include HIV viral load as one element in making decisions regarding when to begin antiretroviral therapy. Antiretroviral therapy, also known as HAART, is credited with saving millions of lives. However, potent side effects and issues of drug resistance, often cause doctors and patients to defer starting the medications, until it becomes medically necessary.

In addition to the clinical ramifications, the findings suggest that HIV-associated CD4 depletion cannot be thought of as a mere consequence of the amount of virus circulating in the blood. Instead, the findings suggest rather more complex scenarios of disease progression, and hint at indirect processes though which HIV can induce damage to the immune system, which cannot be adequately captured by measuring HIV levels in the blood.

Note: This story has been adapted from a news release issued by University Hospitals of Cleveland.

Researchers Seek To Solve Mystery Of Natural HIV Control

2006-12-21T10:16:00.006-08:00

Science Daily — American and South African scientists working at the epicenter of the AIDS epidemic in South Africa have discovered how the human immunodeficiency virus (HIV) "exhausts" killer T cells that would otherwise attack the virus. The researchers found that HIV can simply “turn off” fully functional T cells by flipping a molecular switch on the cells. In test tube studies, however, the scientists showed that they could reinvigorate the killer T cells by blocking that inhibitory switch, which is called programmed death-1 (PD-1).
The study's senior author, Bruce Walker, a Howard Hughes Medical Institute researcher at Massachusetts General Hospital, said that clinical testing of drugs that block the PD-1 switch could begin very soon, since such drugs exist already. However, he cautioned that these kinds of drugs could cause serious side effects, including autoimmune reactions that trigger the immune system to attack the body. Walker added that the researchers' findings will also likely have application in understanding other chronic viral diseases.

The findings by Walker and his colleagues were published in an advance online publication on August 20, 2006, by the journal Nature. Walker is also at the Partners AIDS Research Center and Harvard Medical School. Other co-authors were from the University of KwaZulu Natal in South Africa, Oxford University, Dana-Farber Cancer Institute of Harvard Medical School, Emory University School of Medicine, and The Wistar Institute.

“It's long been known that people with HIV infection have a lot of HIV-specific immune cells that one would think would be actively combating the virus,” said Walker. “But a major puzzle has been that even in late-stage illness, when one can still measure great numbers of these immune cells, they don't seem to be controlling the virus at all.”

An important clue to why killer T cells stop functioning after infection came from earlier studies in mice, which were published by co-author Rafi Ahmed of Emory. Ahmed found that chronic viral infection actively inhibits T cells by switching on the cells' inhibitory PD-1 pathway. He also found that blocking the PD-1 pathway in the mice restored T cell function and reduced the amount of virus in the animals' blood, which is known as viral load. Ahmed's studies showed that blocking PD-1 rejuvenated killer T cells, which directly attack viruses, but did not investigate helper T cells, which mobilize the immune system against infection.

Ahmed's findings prompted Walker and his colleagues to explore the role of the PD-1 pathway in a large population of HIV-infected patients in the KwaZulu-Natal province of South Africa. The province is at the epicenter of the HIV epidemic in sub-Saharan Africa; a third of pregnant women there are infected with HIV. The researchers conducted much of their work at the Doris Duke Medical Research Institute in Durban. Durban is the largest city in KwaZulu-Natal, and HIV prevalence among pregnant women in the city exceeds 50 percent.

The studies at the lab in South Africa found that PD-1 was significantly activated in 71 HIV-infected patients who had not yet begun antiviral treatment. In a separate study, the researchers demonstrated that PD-1 is also activated in the T cells of people with Epstein-Barr virus, which is a persistent infection, but much lower on T cells of persons immunized with vaccinia virus, a live virus vaccine against smallpox that is effectively cleared by the immune system. According to Walker, those findings indicate that activation of the PD-1 pathway occurs during the immune system's general response to viral infection.

In test tube studies, the researchers showed that higher PD-1 expression was associated with more severe functional “exhaustion” of HIV-specific killer T cells. The studies clearly demonstrated that the greater the PD-1 expression, the higher the patient's viral load and the lower the count of helper T cells, said Walker.

When they compared PD-1 activation in blood samples from four patients before and after antiviral therapy, they found that PD-1 expression dropped when treatment began. “It became very clear from this analysis that the virus was actually driving these high levels of PD-1 expression, and that you could actually change the PD-1 level by getting rid of the viral antigen with drugs,” said Walker. An antigen is a protein on a virus or other infectious agent that triggers an immune reaction.

Walker said one of the team's key findings emerged from their test tube studies showing that blocking the PD-1 pathway could restore the function of exhausted killer T cells. “We wanted to determine whether these T cells had been irreparably damaged or misprogrammed,” he said. “And we found that they are capable of functioning; they've just been turned off.”

Similarly, the researchers also found that blocking PD-1 restored helper T cell function. “This was the most striking finding, because the majority of patients we have studied had no detectable levels of these HIV-specific cells; but as soon as we blocked the PD-1 pathway, they had a ton of them,” said Walker.

The researchers' discoveries could lead to immediate clinical application, although Walker cautioned against over-optimism. “Obviously, the big question is whether you could manipulate this pathway in HIV-infected people to turn these T cells back on and better control the virus,” he said. “And drugs to block this pathway have already been developed for cancer, so that question should be able to be addressed in the very near future.

“However, one has to proceed with real caution, because if you turn back on an immune regulatory switch that the body has decided to turn off, you could trigger serious immunological problems such as autoimmunity,” Walker noted. And while an ideal clinical strategy would be to seek to switch off PD-1 only in HIV-specific T cells, techniques for such a targeted approach do not exist, he said.

The researchers are also exploring PD-1 measurement as a diagnostic tool, said Walker. “Currently, we just count the number of helper T cells to decide when to treat someone, but we are excited about the possibility that adding PD-1 measurement might tell us more about the likelihood of progression of the disease and need for treatment in infected people,” he said.

Walker said that scientists know little about the evolutionary purpose of a pathway that would deactivate such an important component of the immune system in the face of a viral attack. “It may be that in the heat of a battle that it sees it's not winning, the body makes an adjustment to try to co-exist,” he said. “But we really do not know at this point.”

Walker emphasized that the study could not have been done without his group's ongoing collaboration with the University of KwaZulu Natal. “These are studies that simply could not have been done in the United States,” he said. “Despite the fact that these patients in Africa are living in poverty and in rural areas, it is easier for us to obtain their cooperation in such studies than with patients in the United States.

“It was with the key support of the Doris Duke Charitable Foundation and the Nelson Mandela School of Medicine that we have been able to build a biomedical research institute and develop this rich international collaboration that enables us to study the HIV epidemic at its epicenter, to gain knowledge that we could not obtain anywhere else,” he said.

Note: This story has been adapted from a news release issued by Howard Hughes Medical Institute.

Researchers Seek To Solve Mystery Of Natural HIV Control

2006-12-21T10:16:00.005-08:00

Science Daily — An international, multi-institutional research consortium is seeking to discover how a few HIV-infected individuals are naturally able to suppress replication of the virus. The Elite Controller Collaborative Study, the first large-scale haplotype-mapping study in people infected with HIV, is searching for genetic factors that may explain these individuals' unique ability to control the virus without treatment, sometimes as long as 25 years after infection.

"If we could discover how these individuals can coexist with this virus without damage to their immune system and could find a way to replicate that ability in others, we would have a recipe for halting the HIV epidemic," says Bruce Walker, MD, director of Partners AIDS Research Center (PARC) at Massachusetts General Hospital and an initial organizer of the Elite Controller Collaborative Study. Walker discussed the project in a media briefing today at the 16th International AIDS Conference in Toronto.

Most people infected with HIV cannot control replication of the virus with their immune systems alone. Unless antiviral medications are used, the virus continues to reproduce until it overwhelms the CD4 T helper cells, suppressing the immune response and leading to AIDS. In the early 1990s, it was recognized that a small minority of HIV-positive people remained healthy and did not progress to AIDS despite many years of infection. The term "long-term nonprogressors" was used to refer to this group. With today's more sensitive techniques for measuring viral levels in the bloodstream, individuals who are able to maintain low levels of HIV replication can be identified soon after their infection is diagnosed. Some of these viremic controllers can maintain viral loads below 2,000 copies/ml, while an even smaller group, called elite controllers, have viral loads too low to be detected by currently available assays.

"The primary goal of the Elite Controller Collaborative Study is to identify the mechanism that explains control of viral replication in both of these groups, " says Florencia Pereyra, MD, of PARC, lead coordinator of the research team. "We want to use that knowledge to develop a first-generation HIV vaccine, which may not cure or prevent infection but could successfully suppress viral levels. Since this natural ability is so rare, we need to work with collaborators around the world to recruit the number of participants we will need to determine what is going on.

"We expect to need data from at least 1,000 such individuals in order to define the genetic factors associated with this extraordinary outcome," she adds. "This effort will only be possible with the collaboration of HIV researchers, providers, advocacy groups and most important the HIV-infected individuals that fall in this category."

Those eligible to participate in the Elite Controller Collaborative Study are HIV-positive adults, aged 18 to 75, who have maintained viral loads below 2,000 copies without taking HIV antiviral medications. Participation involves having a single blood sample taken, which can be done by participants' local healthcare providers. Those located near a participating research center may choose to be followed over time and provide additional blood samples.

"So far we have enrolled nearly 200 participants from 25 U.S. states, and we are looking forward to adding participants from other countries," says Pereyra. Potential participants or collaborating providers seeking more information should contact Rachel Rosenberg, Partners AIDS Research Center, (617) 726-5536 or rrosenberg2@partners.org.

In addition to Walker, other organizers of the Elite Controller Collaborative Study are Eric Lander, PhD, director of the Broad Institute of Harvard University and Massachusetts Institute of Technology; Dennis Burton, PhD, of the Scripps Institute; Steven Deeks, MD, University of California at San Francisco; and Mary Carrington, PhD, of the U.S. National Cancer Institute. The project is supported by a philanthropic gift from the Mark and Lisa Schwartz Foundation.

The Partners AIDS Research Center, the project's coordinating center, was established in 1995 in response to the continuing world-wide AIDS pandemic. The center serves both Massachusetts General Hospital and Brigham and Women's Hospital, the founding members of Partners HealthCare, and is a natural progression of the more than 20-year commitment by the clinicians and scientists at those institutions to HIV and AIDS research and care. The center's scope has broadened further with the participation of the Dana Farber/Partners Cancer Center regarding AIDS oncology and close collaborative ties to Fenway Community Health Center and the Lemuel Shattuck Hospital.

Note: This story has been adapted from a news release issued by Massachusetts General Hospital.

HIV's Cellular Kiss Of Death Explains Loss Of Uninfected T Cells In AIDS

2006-12-21T10:16:00.004-08:00

Science Daily — Since the beginning of the AIDS epidemic in the 1980s, even before the HIV virus was identified, physicians and scientists recognized that a cardinal feature of AIDS was the loss of CD4+ T cells. These cells are killed by direct HIV infection but researchers have remained puzzled as to why uninfected CD4+ T cells also die in HIV-infected patients.

Researchers at the Institut de Biologie in France have now shown that an HIV surface glycoprotein expressed by HIV-infected CD4+ T cells interacts with a receptor known as CXCR4 on the surface of uninfected CD4+ T cells, which triggers a cell signaling pathway known as autophagy, resulting in the death of uninfected T cells. The study appears in the August issue of the Journal of Clinical Investigation.

Martine Biard-Piechaczyk and colleagues co-cultured HIV-infected CD4+ T cells that express the HIV envelope glycoprotein with uninfected target cells that express CD4 and the CXC chemokine receptor CXCR4. They found that CXCR4 engagement by the HIV envelope glycoprotein activates the degradation pathway known as autophagy, causing the death of these uninfected "bystander" cells.

The authors go on to show that molecules known as "short interfering RNAs" specific for two different genes involved in the autophagy pathway (beclin1 and atg7) can completely block the cell death process triggered by CXCR4 engagement by the HIV envelope glycoprotein.

In an accompanying commentary, Beth Levine from University of Texas Southwestern Medical Center discusses how this work eloquently establishes a mechanism for how the number of uninfected CD4+ T cells is likely depleted in patients with AIDS.

Note: This story has been adapted from a news release issued by Journal of Clinical Investigation.

Study Shows Promise For Simplified Treatment Of HIV Infection

2006-12-21T10:16:00.003-08:00

Science Daily — A preliminary study indicates that using a single boosted protease inhibitor instead of the standard regimen of 3 drugs for maintenance therapy may be an effective treatment for select patients with HIV infection, according to a study in the August 16 issue of JAMA, a theme issue on HIV/AIDS.

Susan Swindells, M.B.B.S., of the University of Nebraska Medical Center, Omaha, presented the findings of the study today at a JAMA media briefing at the International AIDS Conference in Toronto.

The long-term adverse effects, expense, and difficulty of sustained adherence to multidrug antiretroviral regimens have prompted studies of simpler therapies for human immunodeficiency virus type 1 (HIV-1) infection. Treatment cessation, intermittent therapy, and induction-maintenance (a few months of triple therapy followed by simplified therapy) regimens have been evaluated with mostly inferior results, according to background information in the article.

Dr. Swindells and colleagues conducted a study to determine whether a simplified maintenance therapy with the antiretroviral medication "boosted" atazanavir alone after virologic suppression (cessation of detectable HIV virus replication) would not markedly increase the risk of virologic failure. Protease inhibitors, such as atazanavir, are often combined with a small dose of ritonavir to increase blood levels -- a phenomenon known as "boosting." This regimen was selected because of low pill burden, once-daily dosing, safety, and unique resistance profile. The 24-week pilot study, conducted between Sept. 2004 and April 2006, included 36 HIV-infected adults with virologic suppression for 48 weeks or longer receiving their first protease inhibitor (PI)--based regimen. Participants switched PIs to atazanavir-ritonavir at entry and discontinued nucleoside analog reverse transcriptase inhibitors (NRTIs) after 6 weeks. Virologic failure was defined as two consecutive HIV-1 RNA measurements of 200 copies/mL or more. The final analysis included 34 patients.

Virologic success (absence of failure) through 24 weeks of simplified therapy occurred in 91 percent of patients (31 of 34). Three participants experienced virologic failure at 12, 14, and 20 weeks after simplification. Resistance testing at failure did not identify protease inhibitor resistance mutations. Atazanavir concentrations in the blood at failure were low or below detection in 2 of 3 participants experiencing failure, indicating these patients may not have taken the prescribed doses. There were no treatment discontinuations for adverse events after simplification and no significant changes in CD4 cell counts.

"In this pilot study, the data suggest that simplified maintenance therapy with atazanavir-ritonavir alone in patients who have never experienced treatment failure may be efficacious in maintaining HIV-1 RNA suppression below 200 copies/mL for 24 weeks after discontinuing NRTIs," the authors write. "Maintenance therapy with a single boosted PI offers a treatment strategy with potentially less complexity, pill burden, long-term complications, and cost."

The researchers add that although the findings are encouraging, caution regarding inferences is warranted due to study limitations such as the small number of participants in the study. "Larger, randomized trials comparing this approach with standard antiretroviral therapy are warranted." (JAMA. 2006;296:806-814. Available pre-embargo to the media at www.jamamedia.org)

This work was supported by NIH grants and a Virology Support Laboratory subcontract of the ACTG Central Group Grant. Industry support from Bristol-Myers Squibb and Abbott Laboratories was in the form of supplying study drugs and participation on the protocol team.

Note: This story has been adapted from a news release issued by JAMA and Archives Journals.

Defense Peptide Found In Primates May Block Some Human HIV Transmissions

2006-12-21T10:16:00.002-08:00

Science Daily — As primates evolved 7 million years ago, the more advanced species stopped making a protein that University of Central Florida researchers believe can effectively block the HIV-1 virus from entering and infecting blood cells.

HIV-1 often mutates quickly to overcome antiviral compounds designed to prevent infections. But a research team led by Associate Professor Alexander Cole of UCF's Burnett College of Biomedical Sciences has demonstrated that over 100 days the virus develops only weak resistance to retrocyclin, a defense peptide still found in monkeys and lower primates.

If additional laboratory tests demonstrate only weak resistance, Cole will study how retrocyclin could be developed into a drug designed to prevent the HIV virus from entering human cells.

Cole is also working with Henry Daniell, a UCF professor of molecular biology and microbiology, to develop a way to grow retrocyclin through genetically engineered tobacco plants. The retrocyclin gene would be incorporated into the chloroplast genome of tobacco cells before the plants grow. Daniell has developed a similar approach to growing anthrax vaccine in tobacco plants.

An inexpensive way to produce the drug with only a small amount of tobacco would help to make it accessible in areas such as Southeast Asia, Africa and the Caribbean where the disease spreads most quickly.

"If we could develop retrocyclin in plants and produce enough of the drug cheaply, we could potentially save a lot of lives," Cole said.

Cole was recently awarded about $4 million of National Institutes of Health grants through 2011 for the HIV-1 research and similar studies. The grants were provided through the National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; and the National Heart, Lung and Blood Institute.

Cole started his research into theta-defensins at the University of California, Los Angeles, before he moved to UCF in 2003. Drs. Otto Yang and Robert Lehrer, infectious disease specialists at UCLA, and researchers at the University of Pittsburgh and Emory University are collaborating with Cole.

There are three classes of defensin peptides, and most research around the world has focused on alpha and beta defensins, the two types that humans still make. Cole studies theta-defensins called retrocyclins, which are no longer made by humans or advanced primates such as chimpanzees. However, theta-defensins are more active against HIV-1 than the other two types of defensins and can be developed in laboratories, two features that suggest retrocyclins still could become an effective way to fight the virus.

HIV-1 is the most common form of the human immunodeficiency virus that causes AIDS. The disease is often transmitted sexually, and the drugs produced from Cole's research would be applied to the vagina in the form of a gel or cream. Many of the laboratory tests have shown that retrocyclin can prevent HIV-1 infection of human vaginal tissue.

Retrocyclin was still an effective inhibitor of HIV-1 even after 100 days of continuous exposure to human cells in a laboratory setting. Cole and his team are encouraged that only minimal resistance of the virus occurred during that time. Higher resistance levels make it more difficult to develop drugs to fight the virus because doses must be increased substantially over time.

The exact reason why resistance does not develop quickly with retrocyclin is unclear, but it may be a result of retrocyclin interacting with more than one target on both the cell and virus. Viruses that have to defeat more than one antiviral mechanism often develop resistance at a much slower pace.

The next phase of Cole's research will delve more into the mutations that HIV-1 can take in an effort to minimize them as much as possible. Many series of laboratory tests would need to be completed before clinical trials could begin no earlier than 2009.

Cole's findings were published in the June 1 issue of The Journal of Immunology, a top journal in the fields of immunology, molecular biology and microbiology.

Note: This story has been adapted from a news release issued by University of Central Florida.

Meth Promotes Spread Of Virus In HIV-infected Users

2006-12-21T10:16:00.001-08:00

Science Daily — Researchers at the University at Buffalo have presented the first evidence that the addictive drug methamphetamine, or meth, also commonly known as "speed" or "crystal," increases production of a docking protein that promotes the spread of the HIV-1 virus in infected users.

The investigators found that meth increases expression of a receptor called DC-SIGN, a "virus-attachment factor," allowing more of the virus to invade the immune system.

"This finding shows that using meth is doubly dangerous," said Madhavan P.N. Nair, Ph.D., first author on the study, published in the online version of the Journal of Neuroimmune Pharmacology. The study will appear in print in the September issue of the journal.

"Meth reduces inhibitions, thus increasing the likelihood of risky sexual behavior and the potential to introduce the virus into the body, and at the same time allows more virus to get into the cell," said Nair, professor of medicine and a specialist in immunology in the UB School of Medicine and Biomedical Sciences.

His research centers on dendritic cells, which serve as the first line of defense again pathogens, and two receptors on these cells -- HIV binding/attachment receptors (DC-SIGN) and the meth-specific dopamine receptor. Dendritic cells overloaded with virus due to the action of methamphetamine can overwhelm the T cells, the major target of HIV, and disrupt the immune response, promoting HIV infection.

"Now that we have identified the target receptor, we can develop ways to block that receptor and decrease the viral spread," said Nair. "We have to approach this disease from as many different perspectives as possible.

"If we could prevent the upregulation of the meth-specific dopamine receptor by blocking it, we may be able to prevent the interaction of meth with its specific receptors, thereby inhibiting the virus attachment receptor," said Nair.

"Right now, we don't know how the virus-attachment receptor and meth-specific receptors interact with each other, leading to the progression of HIV disease in meth-using HIV-infected subjects. That is the next question we want to answer.

"Since meth mediates its effects through interacting with dopamine receptors present on the cells, and meth increases DC-SIGN, which are the HIV attachment receptors, use of dopamine receptor blockers during HIV infection in meth users could be beneficial therapeutically to reduce HIV infection in these high-risk populations," Nair said.

Additional researchers on the publication, all from the UB Department of Medicine, are Supriya Mahajan, Ph.D., research assistant professor; Donald Sykes, Ph.D., research associate professor; Meghana V. Bapardekar, Ph.D., postdoctoral associate, and Jessica L. Reynolds, Ph.D., research assistant professor.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center.

Note: This story has been adapted from a news release issued by University at Buffalo.

Research Leads To First Treatment For Drug-resistant HIV

2006-12-21T10:13:00.001-08:00

Science Daily — Doctors have their first FDA-approved tool to treat drug-resistant HIV thanks to a new molecule created by a Purdue University researcher.

"There are many treatments for AIDS on the market, but none are able to combat drug resistance," said Arun Ghosh (pronounced A-rune GO-sh), a professor with a dual appointment in the departments of chemistry and medicinal chemistry and molecular pharmacology. "This is the first treatment that is effective against the growing number of drug-resistant strains of HIV, the virus that causes AIDS. The problem is widespread."

The FDA recently approved the pill-based therapy of Ghosh's molecule, TMC-114, for medical use. The molecule, also known as Darunavir (pronounced DA-rune-a-veer), is the forerunner in a series of molecules under development by Ghosh.

Earlier research shows that almost half of patients with the human immunodeficiency virus (HIV) who initially respond to treatment develop drug-resistant strains and stop responding to treatment within eight to 10 months, he said. An additional 20 percent to 40 percent of patients have drug-resistant strains when they are first diagnosed, suggesting these strains can be transmitted from one person to the next.

This year marks the 25th anniversary of the first reported U.S. cases of AIDS, a disease that claims the lives of more than 15,000 Americans each year, according to the Centers for Disease Control and Prevention. World Health Organization figures estimate more than 40 million people worldwide are infected with HIV.

For years the virus has frustrated drug developers through its ability to "outsmart" therapies. The virus rapidly mutates and, as parts of its structure change, it becomes resistant to treatment. Previously, patients with drug-resistant strains were out of options and had greatly reduced life expectancies.

"My only wish was that my design would help people and alleviate suffering," Ghosh said. "I'm so grateful it has turned into a drug and been approved by the FDA so quickly."

The molecule Ghosh created is expected to be available to physicians this year, he said.

"I think that this drug will have a sizeable impact on the current therapy for AIDS and HIV infection," said Hiroaki Mitsuya (pronounced HE-row-ah-key MIT-sue-ya), chief and principal investigator of the Experimental Retrovirology Section at the National Cancer Institute who collaborated with Ghosh in this research.

Molecules are made up of groups of atoms bonded together. These bonded groups form an oddly shaped structure with sections that branch off and others that form loops. Different sections are responsible for various behaviors of the molecule.

Ghosh's designed compound has selected features of naturally occurring molecules that improve its ability to fight HIV. The result is a variation of one of the most common treatments existing today, a protease inhibitor.

Protease is an enzyme necessary for HIV to reproduce properly. A protease inhibitor binds to protease, making it unusable by the virus. Without the use of protease, HIV is incapable of infecting cells and harming the patient. By reducing the amount of active virus, patients' bodies have an increased ability to fend off opportunistic infections, the leading cause of death for those with AIDS.

Eight protease inhibitors are currently on the market and have greatly improved the quality of life for those suffering from HIV, Ghosh said. These inhibitors, however, lose their effectiveness over time, often cause severe side effects and are ineffective against drug-resistant HIV strains, he said.

Treatment using the molecule designed by Ghosh has fewer associated side effects because the dose required is significantly less than those for existing protease inhibitors. The molecule also is smaller than those that make up current protease inhibitors and is much more easily absorbed and tolerated by the body, according to research results.

"In Phase 3 clinical trials of TMC-114, the majority of patients receiving the drug did very well with relatively few side effects," Mitsuya said. "Those patients showed a significant increase in their CD4 cell counts. Many of those patients have been treated for a year or more and have shown no signs of developing a significant resistance to the drug."

Ghosh is now expanding on his design, making alterations to the original molecule aimed at making even more effective treatments.

"The most recent protease inhibitors we created are exceedingly potent," he said.

Ghosh's work has opened the door to a new path for antiretroviral therapy.

"Earlier, researchers were unsure of how to deal with drug-resistant viruses," he said. "Problems that arose with treatments developed in the 1990s were disheartening. There was no concept on the horizon. We created a conceptually new class of protease inhibitors to combat drug resistance. That has renewed excitement in antiretroviral treatment and provided a direction for the future."

These new protease inhibitors are beneficial for reasons beyond their potency and enduring effectiveness, Ghosh said.

"Because they are synthetic, lab-created materials, they are amenable to cost-effective mass production. Keeping costs down greatly increases the accessibility of the drugs to Third World countries where the epidemic is worst."

The design, synthesis and evaluation of these new protease inhibitors will be detailed in a paper in the Aug. 24 issue of the Journal of Medicinal Chemistry and is currently available on the journal's Web site.

Irene Weber of Georgia State University, Eric Walters of Rosalind Franklin University of Medicine and Mitsuya co-authored the papers with Ghosh. Mitsuya characterized the molecules' effectiveness and Walters and Weber performed the crystallography that provided images of the molecules' structures.

"It is very important to have an image of the structure to see exactly how the inhibitors work," said Weber, Georgia Cancer Coalition Distinguished Cancer Scholar. "We can know a treatment is working without fully understanding its behavior. Visualizing the structure of the inhibitor as it interacts with the virus shows us how and why it works so well and greatly advances our ongoing fight against drug-resistant HIV."

Ghosh began his work at the University of Illinois and set out to design and synthesize a molecule that would interact with a part of the virus that did not change as the rest of it mutated — the backbone of protease.

"We designed this molecule top to bottom to interact with the protease backbone and deactivate the virus," he said. "This allows it to continue to be effective as the virus mutates, when other treatments would fail."

Mitsuya said he is pleased with the effectiveness of this new class of inhibitors and sees it as a possible turning point in HIV therapy.

"This will save many lives of patients suffering from drug-resistant HIV," he said. "This is encouraging."

Ghosh said he hopes this approach could be applied to other viruses, and he is currently involved in research into the SARS virus.

This research is funded by the National Institutes of Health.

Note: This story has been adapted from a news release issued by Purdue University.

Research Leads To First Treatment For Drug-resistant HIV

2006-12-21T10:13:00.000-08:00