15 OCTOBER 2010, VOLUME 11, ISSUE 38

As the economic downturn depresses global investment in AIDS prevention, scientists and those who fund them are struggling to set priorities among several competing research methods that could slow the spread of the disease, which causes about 2.7 million new infections worldwide a year.

The federal contribution has not dropped, thanks to additional funds for the National Institutes of Health that were in the 2009 economic stimulus law (PL 111-5). But resources from other countries and some philanthropic groups have declined. Researchers fear that trend will continue even as U.S. officials are ramping up diplomatic efforts to encourage other nations to give more.

The tight financial situation has the potential to exacerbate the historic competition between scientists who focus on prevention and those on a mission to treat people who are already infected. Even within the prevention-research community there is tension among those searching for effective vaccines and those who are concentrating on other prophylactic methods. With more and more lines of inquiry showing promise, scientists may be victims of their own success.

"The issue there is a limitation of resources," said Margaret I. Johnston, director of the Vaccine Research Program in the Division of AIDS at the National Institute of Health's National Institute of Allergy and Infectious Diseases (NIAID). "As the budget is level for us, there is only a certain limited number of those grants we can give. We do what we can with the funding we have, but there are always more bright ideas than we have funding to support."

Unlike their counterparts elsewhere, US scientists have been sitting pretty in the wake of the global economic downturn. The 2009 American Recovery and Reinvestment Act, or stimulus bill, pumped an extra US$31 billion into science, and President Barack Obama's budget request for fiscal year 2011 included generous increases for several science-funding agencies.

But going into the midterm elections, a different narrative is emerging. Republicans are running on a platform to reduce the $1.4-trillion US deficit, which seems likely to entail freezes or effective cuts for at least some science programmes. If the Democrats retain control of Congress by a thin margin, policy experts say that they are likely to interpret the loss of seats as a call to rein in spending too. "Science is pretty well supported by both sides, but it's a matter of balancing investment with the deficit," says Patrick Clemins, director of the research and development budget and policy programme at the American Association for the Advancement of Science in Washington DC.

Approaching the end of her first year as commissioner of the Food and Drug Administration (FDA), Dr. Margaret Hamburg remarked that, despite past experience with government bureaucracies, she is struck by how hard it is to make her agency act quickly. "You feel it differently at the FDA -- how long it takes to move things through the system," she told an audience at the Institute of Medicine (IOM) in February. "The process of regulation does not allow you to respond in a timely way to emerging science or to other important emerging concerns." The FDA's principal deputy commissioner, Dr. Joshua Sharfstein, put it more bluntly in a recent interview: "I keep a list of things that I wish were moving faster and a list of things moving at just the right speed, and there's nothing on the second list."

Finding ways to make the FDA more nimble and proactive, restoring its credibility and refocusing staff on its public health mission, persuading Congress to boost funding for its expanding portfolio of responsibilities, sharpening its ability to deal with new science and globalization -- these priorities have occupied Hamburg and Sharfstein during their first year. Their agency regulates products accounting for some 25% of U.S. consumer spending, and its recent concerns have included major recalls of over-the-counter pediatric medications and salmonella-contaminated eggs, debates over direct-to-consumer genetic testing and the safety of the one-time blockbuster diabetes drug rosiglitazone, the implementation of a 2009 law making the agency responsible for tobacco regulation, and efforts to make food-package labeling more evidence based. While responding to such issues, they have also launched initiatives to clarify and standardize processes for evaluating drugs and medical devices and to make more information public -- efforts that could lead to lasting changes at the agency.

One hundred publicly traded biotechnology companies in the U.S. have been acquired or ceased operations since the end of 2007, a 25 percent drop in the number of active companies, a report said. Companies have struggled to raise funds from public offerings and acquisitions haven't filled the void, said John Craighead, managing director for investor relations and business development of the Biotechnology Industry Organization, a Washington-based trade group. While acquisitions of biotech companies grew to 55 in 2008 from 40 in 2007, the number fell to 38 last year and to 21 so far this year, Craighead said.

The estimated 294 public companies that remain in the biotechnology industry are in a better cash position than they were at the end of 2008, when 45 percent of companies had less than a year's worth of funds available. Today, only 25 percent of companies have such limited resources, according to data released today by BIO.

The development of a vaccine to prevent HIV infection is one of the most daunting scientific challenges of our time. Yet, for all its complexity, this field of research seeks to answer a relatively simple question: how do you get the immune system to detect and disable HIV before it has a chance to insert itself into the human genome and establish an intractable infection? Most vaccines against viruses, such as those that prevent measles and polio, do so by teaching the immune system's B cells to generate neutralizing antibodies - exquisitely targeted protein missiles that bind to invading pathogens and tag them for destruction. HIV, however, is no ordinary adversary. It has evolved multiple strategies to flummox the immune response. Not least among these is a nearly unparalleled mutability that has vexed vaccine designers for the better part of three decades.

Any vaccine devised to seriously curb the AIDS pandemic will, at a minimum, have to protect against those HIV subtypes that predominate in developing countries, where some 90 percent of new infections occur. It should also thwart multiple variants of those viruses. This poses extraordinary scientific and logistical challenges. But it also has significant implications for the policies that guide and shape AIDS vaccine research and development. First, it requires that candidate HIV vaccines be tested in developing countries, which entails the establishment of the requisite human resources and technical capacity in such places.

Only 0.028% of India's population is HIV positive, but the sheer size in absolute numbers makes them the world's largest national contingent of those infected by the AIDS virus. Considerable progress has been made in providing first-line treatment. However, for pretty much the same reasons that have led to the development of antibiotics-resistant superbugs in India, many patients require second-line treatment, the drugs for which are very expensive. India has to give maximum emphasis to prevention, not cure.

Within prevention, awareness and appropriate prophylactic behaviour have received the most attention, with basic research that could lead to an AIDS vaccine relatively neglected, both in terms of money and effort. The India chapter of the International AIDS Vaccine Initiative has been trying to drum up policy support for a greater role for India in the global effort to develop a vaccine. Given the extremely complex nature of the virus and a couple of spectacular failures by commercial ventures to find a vaccine, it would be a mistake to expect pharma companies to discover a vaccine on their own.

Is India right up there among the major contenders doing pathbreaking research to develop an AIDS vaccine? If the results of the Phase I trials currently underway for an AIDS vaccine at the city-based National Aids Research Institute (NARI) are any indication, then it could be true.

Preliminary results of Phase I of the AIDS vaccine trials conducted by NARI and Chennai-based Tuberculosis Research Centre have found it to be safe. This is the first research of its kind in India for the development of a vaccine that would check the spread of the HIV/AIDS epidemic. Speaking to Mid Day, Dr Sanjay Mehendale, acting director of NARI, cautioned that while the results were encouraging, the study was an ongoing one and would take many years for completion.

Not so long ago, the media was awash with news of Judith Koriang, a woman who had been sentenced to death by the Court Martial after she killed her husband following a domestic dispute. Apparently this young mother shot dead her husband after he tormented her for being HIV-positive, yet he was negative. This was a discordant couple, where partners have different HIV test results. As testing together (as a couple) for HIV becomes more common in Uganda, more and more couples are finding that one partner is positive while the other is negative. Koriang's story is a clear indicator of our need to better understand what HIV discordance is, and how couples can deal with it in their relationship.

Discordant results are often the hardest to accept among couples. It is also difficult for health workers to explain, yet it is common in Uganda. The 2004/05 Uganda HIV/AIDS Sero-Behavioural Survey showed that of all couples where at least one partner was infected with HIV, about half were HIV discordant. Couples may have different HIV test results even after being together for many years. This is because HIV is not transmitted every time an HIV-positive person has sex with an HIV-negative person. Just like when you may or may not get sick after being around someone with flu. Other factors that facilitate transmission of HIV may include presence of sexually transmitted infections, amount of virus in the body and not using condoms.

Merely controlling HIV and Aids will cost between $397bn and $733bn over the next 20 years -- and unless more money is spent the pandemic will continue to spread, experts warned today. If funding is not increased from 2009, infections could rise from 2.3 million a year to 3.2 million by 2031, claimed a report by the aids2031 financing group, headed by the Results for Development Institute in Washington DC.

In the Lancet medical journal, the group warns it is "increasingly improbable" in tough economic times that donors and governments will find enough money to fund a rapid increase in universal access to prevention and treatment services by 2015. It is estimated that would prevent about 7 million more deaths and 14.2 million infections than if efforts continued on the present scale.

To read the abstract of the Lancet article, see "Financing of HIV/AIDS programme scale-up in low-income and middle-income countries, 2009-31" in the "Published Research" section of this issue of the NewsDigest.

AIDS vaccine researchers, meeting in Atlanta, expressed renewed optimism that they might finally be on a path to creating a product that can prevent the deadly HIV virus. "A few years ago I was not even sure that it was possible," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. Then last year, the RV144 trial in Thailand - a trial that many researchers thought would fail and tried to stop - showed a surprising 31 percent protection. Fauci called it a significant "proof of concept" that such a vaccine is possible. "But we still do not know what the correlates of protection are." Correlates are those components of the innate and adaptive immune systems that provide protection.

Col. Nelson Michael, the U.S. Army researcher who led the Thai study, said collaborators at 20 academic centers are submitting the remaining blood samples from the trial to different analyses, trying to tease out exactly what was going on among those protected from infection. The army, with the support of NIAID, is planning to start two mid-sized follow-up studies in populations with high rates of infection in 2013. The study in Thailand will focus on men who have sex with men and female sex workers; the other, in southern Africa, will be among high-risk heterosexual couples.

The following letters were published on pages 174-178 of the 8 October 2010 issue of Science. Access to the full text of these letters requires a subscription.

AIDS funds: promised
Donna Barry and Megan Townsend
 
AIDS funds: undervalued
Nicoli Nattrass and Gregg Gonsalves

AIDS funds: benefits
Anand Reddi and Sarah C. Leeper

AIDS funds: Rwanda
Anita Asiimwe, Angelique K. Rwiyereka, Joan A. Kaufman, and Donald S. Shepard

AIDS funds: prevention
Charles B. Holmes, Harsha Thirumurthy, Nancy S. Padian, and Eric P. Goosby

Response: AIDS funds
John Bongaarts and Mead Over

Health officials in South Africa said Wednesday they recommend screening all HIV patients for tuberculosis and want automatic TB tests for HIV patients to become normal procedure within five years. UNAIDS official Paul De Lay said that by 2015, all TB patients in South Africa should be automatically screened for HIV. Officials gathered in Johannesburg on Wednesday appealed for international donations to help them develop a new drug regimen to treat TB patients who have developed drug resistance. They said they are also testing four vaccines that they hope to released by 2015.

HIV patients are much more likely to contract tuberculosis because of weakened immune systems. South Africa has one of the world's highest TB rates because of its AIDS epidemic. South Africa has more people living with HIV than anywhere else in the world. "There's a terrible link between HIV and TB," De Lay said. "The epidemic here is much more severe than it would've been because of the HIV epidemic." De Lay said the new screening procedure could sooner identify TB in HIV-positive patients, but warned that linking TB to HIV could make people reluctant to voluntarily seek TB treatment because of the social stigma against HIV.

They have sex with friends, acquaintances and people they're casually dating. Many have never been tested for H.I.V. or any other sexually transmitted disease, but they rarely use condoms. Who are they?

The irresponsible scoundrels are not teenagers but 50-something singles, according to the National Survey of Sexual Health and Behavior, one of the most comprehensive national sex studies in almost 20 years, carried out at the Center for Sexual Health Promotion at Indiana University.

It turns out that "friends with benefits" -- a sexual partner who is "just a friend," and neither a soulmate nor a romantic interest -- isn't just for teenagers and college students anymore, and maybe it never was. Young adults may have given the practice a new name, but it probably started during the '60s sexual revolution, when the middle-aged Americans of today were young themselves.

To view the study results, see: Findings from the National Survey of Sexual Health and Behavior (NSSHB), Center for Sexual Health Promotion, Indiana University. Journal of Sexual Medicine. October 2010; 7(s5): 243-373.

Treatment with antiretroviral drugs did not reduce the rate of HIV transmission in serodiscordant heterosexual couples in the Henan province of China, investigators report in the October edition of the Journal of Acquired Immune Deficiency Syndromes. The transmission rate in couples where the HIV-infected partner was taking antiretroviral treatment was 5% compared to a rate of 3% in other couples.

In an accompanying editorial, Dr Myron Cohen says that the results "demand a giant pause" and show that the ability of HIV treatment to reduce the risk of transmission outside the setting of clinical studies is uncertain.

However, the investigators note that the high transmission rate seen in couples where HIV treatment was used could be due to poor adherence. A separate study showed that 66% of patients in Henan province had sub-optimal adherence to their HIV treatment six months after starting HIV treatment. Henan province has a high number of HIV infections due to unsanitary procedures for collecting commercial blood donations. Thousands became infected with HIV after selling blood at clinics with poor infection control methods.

See “Published Research” section of this issue of the NewsDigest for abstracts of the source articles: Wany L et al. HIV transmission among serodiscordant couples: a retrospective study of former plasma donors in Henan, China. J Acquir Immune Defic Syndr. 7 October 2010; 55:232-38. Cohen MS HIV treatment as prevention: to be or not to be? J Acquir Immune Defic Syndr. 7 October 2010; 55:137-8.

Civil society is preparing to challenge a recent government decision in Bangladesh to exclude "prostitution" as a profession on new voter cards on the grounds it effectively blocks sex workers' access to HIV prevention and life-saving health care. On 17 August the Bangladesh Election Commission (BEC) announced "prostitution" would be recognized for the first time as a profession on new voter ID cards. But pressure from conservative religious groups led the BEC to reverse its decision, according to Shahnaz Begum, president of Sex Workers Network (SWN), a local NGO that works in half of the nation's 64 districts.

Election commissioner Sohul Hossain told IRIN the term "sex worker" was omitted in order to prevent commercial sex work, in line with Article 18(2) of Bangladesh's constitution, which states that "gambling and prostitution" should be "discouraged". But activists are seizing upon Article 40 of the constitution, which gives citizens the right to "enter upon any lawful profession or occupation", arguing that women, therefore, can choose sex work as a profession. This decision is "ripe for a public interest challenge", said Khaled Chowdhury, a lawyer at the Supreme Court. "Sex work is not illegal, but as moral and social issues are involved, it is not encouraged. The decision of the EC [Electoral Commission] may have an impact [on the acceptance of sex workers], as voter ID cards are now essential in many aspects of a citizen's life."

Objective The UNAIDS Estimation and Projection Package (EPP) is a tool for country-level estimation and short-term projection of HIV/AIDS epidemics based on fitting observed HIV surveillance data on prevalence. This paper describes the adaptations made in EPP 2009, the latest version of this tool, as new issues have arisen in the global response, in particular the global expansion of antiretroviral therapy (ART).

Results By December 2008 over 4 million people globally were receiving ART, substantially improving their survival. EPP 2009 required modifications to correctly adjust for the effects of ART on incidence and the resulting increases in HIV prevalence in populations with high ART coverage. Because changing incidence is a better indicator of program impact, the 2009 series of UNAIDS tools also focuses on calculating incidence alongside prevalence. Other changes made in EPP 2009 include: an improved procedure, incremental mixture importance sampling, for efficiently generating more accurate uncertainty estimates; provisions to vary the urban/rural population ratios in generalised epidemics over time; introduction of a modified epidemic model that accommodates behaviour change in low incidence settings; and improved procedures for calibrating models. This paper describes these changes in detail, and discusses anticipated future changes in the next version of EPP.

Background Analyzing pooled data from 4 recent microbicide trials, we aimed to determine characteristics of participants at higher risk of HIV and sexually transmitted infections (STIs), to inform targeted recruitment, preserved study power, and potentially smaller study sizes in future trials.

Methods We evaluated the relationships between participants' characteristics and the incidence of HIV, STIs, and reproductive tract infections (RTIs). We calculated incidence rates as the number of infection events divided by the person-years of observation. We applied Cox regression models to assess the relationships between baseline demographic, reproductive and behavioral factors and incident HIV, STIs and RTIs.

Results The pooled incidence rates for HIV, chlamydia, and gonorrhea were 2.1, 6.4 and 9.9 per 100 person-years, respectively. Proportions of participants with trichomoniasis, bacterial vaginosis (BV), and candidiasis were 0.06, 0.40, and 0.40, respectively. In final multivariable models, age and education were significantly (and inversely) associated with incident HIV; baseline chlamydia, baseline trichomoniasis, and younger age were associated with incident Chlamydia; and baseline gonorrhea infection, younger age, less education, nulliparous status, baseline chlamydia, and condom use for contraception were associated with incident gonorrhea. Three factors were associated with trichomoniasis: baseline trichomoniasis infection, baseline chlamydia, and baseline BV.

Conclusions Only younger age was robustly associated with multiple STI outcomes in our multivariable analyses. Although there was little evidence of associations between baseline STIs and incident HIV, they were strongly associated with incident STIs. We found no evidence that measured baseline sexual behavior factors were associated with incident HIV or STIs.

Context This article describes results of a process evaluation of a cooperative agreement between the Centers for Disease Control and Prevention's Division of Reproductive Health and 10 regional training centers to increase the number of reproductive health (RH) settings that integrate human immunodeficiency virus (HIV) prevention services at an appropriate level intoroutine care.

Objective Our goal was to learn about the process of integrating HIV prevention into RH settings.

Design We conducted a retrospective evaluation, using qualitative methods.

Setting The clinics were from 10 US Department of Health and Human Services regions.

Participants We interviewed 16 key informants from 10 selected model clinics.

Main Outcome Measures The main outcome was organization change.

Results The most common obstacles to integration were staff issues, logistics barriers, inadequate clinic structure to support integration, and staff training barriers. Using the transtheoretical model (TTM) applied to organizations, we documented organizational change as informants described their clinics' progression to integration and overcoming obstacles. All model clinics began in the contemplation stage of transtheoretical model. Every clinic exhibited at least 1 process of change for every stage. In the contemplation stage, most informants discussed fears about not changing, stated that the integration was consistent with the agency's mission, and described thinking about commitment to the change. In the preparation stage, all informants described building teams that supported integration of HIV prevention. During the action stage, informants talked about assessments of facilities, staff and protocols, commitments through grantsor agreements, and then using training to support new behaviors and adopting new cognitions. In the maintenance stage, all reported changing policies, procedures, or protocols, most promoted helping relationships among the staff, and nearly all reported rewards forthe new ways of working.

Conclusions RH settings were able to integrate HIV prevention services by employing a systematic process.

Misreporting of adherence undermines detection of an association between product use and HIV infection in microbicide trials. This study investigates whether, in a placebo trial, audio computer-assisted self-interviewing (ACASI) produces more accurate reporting of adherence and sexual behavior than a face-to-face interview (FTFI). At three South African clinics, 849 women were enrolled and instructed to use applicators filled with placebo gel; participants were randomly assigned to FTFI or ACASI. Behavioral reports were validated through two biomarkers that detect product usage and unprotected sex. For most behaviors, ACASI generated significantly higher reporting, although differences by interview mode appeared to diminish over time. ACASI participants were more likely to report having had sex without gel, but reported and tested applicators did not indicate greater honesty about gel insertion with ACASI. While comparisons of reported unprotected sex with the validated biomarker revealed more agreement with ACASI than with FTFI, differences were small.

Innovations in antiretroviral (ARV) treatment strategies have resulted in treated HIV-infected patients having life expectancies similar to those of uninfected individuals. Yet the number of individuals capable of HIV transmission is increasing--for every person in whom ARV treatment is initiated, four others are becoming newly infected with HIV. The limited progress with microbicides and vaccines for HIV prevention reinforce the need for a concentrated exploration of the utility of ARVs. Preliminary animal studies with topical and systemic ARVs show promising results. However, current clinical trials were designed without a comprehensive understanding of ARV pharmacokinetic-pharmacodynamic relationships in HIV prevention. This review focuses on current strategies for the prevention of HIV infection and on the ways in which the tools of pharmacology can be a valuable resource for determining pharmacodynamic targets, providing interspecies scaling of exposures, identifying the optimal drugs/drug combinations, doses, and dosing regimens, and designing efficient clinical trials.

Background HIV reservoirs are rapidly established after infection, and the effect of HAART initiated very early during acute infection on HIV reservoirs remains poorly documented, particularly in tissue known to actively replicate the virus. In this context, we used the model of experimental infection of macaques with pathogenic SIV to assess in different tissues: (i) the effect of a short-term HAART initiated at different stages during acute infection on viral dissemination and replication, and (ii) the local concentration of antiviral drugs.

Results Here, we show that early treatment with AZT/3TC/IDV initiated either within 4 hours after intravenous infection of macaques with SIVmac251 (as a post exposure prophylaxis) or before viremia peak (7 days post-infection [pi]), had a strong impact on SIV production and dissemination in all tissues but did not prevent infection. When treatment was initiated after the viremia peak (14 days pi) or during early chronic infection (150 days pi), significant viral replication persists in the peripheral lymph nodes and the spleen of treated macaques despite a strong effect of treatment on viremia and gut associated lymphoid tissues. In these animals, the level of virus persistence in tissues was inversely correlated with local concentrations of 3TC: high concentrations of 3TC were measured in the gut whereas low concentrations were observed in the secondary lymphoid tissues. IDV, like 3TC, showed much higher concentration in the colon than in the spleen. AZT concentration was below the quantification threshold in all tissues studied.

Conclusions Our results suggest that limited antiviral drug diffusion in secondary lymphoid tissues may allow persistent viral replication in these tissues and could represent an obstacle to HIV prevention and eradication.

As the global HIV/AIDS pandemic nears the end of its third decade, the challenges of efficient mobilisation of funds and management of resources are increasingly prominent. The aids2031 project modelled long-term funding needs for HIV/AIDS in developing countries with a range of scenarios and substantial variation in costs: ranging from US$397 to $722 billion globally between 2009 and 2031, depending on policy choices adopted by governments and donors. We examine what these figures mean for individual developing countries, and estimate the proportion of HIV/AIDS funding that they and donors will provide. Scenarios for expanded HIV/AIDS prevention, treatment, and mitigation were analysed for 15 representative countries. We suggest that countries will move in increasingly divergent directions over the next 20 years; middle-income countries with a low burden of HIV/AIDS will gradually be able to take on the modest costs of their HIV/AIDS response, whereas low-income countries with a high burden of disease will remain reliant upon external support for their rapidly expanding costs. A small but important group of middle-income countries with a high prevalence of HIV/AIDS (eg, South Africa) form a third category, in which rapid scale-up in the short term, matched by outside funds, could be phased down within 10 years assuming strategic investments are made for prevention and efficiency gains are made in treatment.

Approximately half of the 33.4 million persons living with the human immunodeficiency virus (HIV) worldwide are women of reproductive age, and among the 2.1 million HIV-infected children, virtually all were infected during pregnancy, delivery, or breast-feeding. Since 2002, the number of newly infected children has declined, probably owing to increased implementation of interventions for the prevention of mother-to-child transmission of HIV and the global stabilization of HIV prevalence among women. With these advances, new challenges have surfaced.

In 2008, almost half of HIV-infected pregnant women received antiretroviral medications for the prevention of mother-to-child transmission. In most cases, the simplest intervention, single-dose nevirapine, was given to the mother during labor and to the infant after birth. Nevirapine halves the risk of peripartum transmission but persists at clinically significant levels for days, potentially selecting HIV resistance mutations that may negatively affect the efficacy of nevirapine-based therapies when mothers and infected children subsequently require treatment for their own health. This poses an important public health challenge, since nevirapine-based therapies are the most widely available and affordable treatments in resource-limited countries, where more than 95% of infections in infants and children occur.

Because resistance mutations may fade away over time, there has been considerable uncertainty regarding treatment outcomes with regimens based on non-nucleoside reverse-transcriptase inhibitors (NNRTIs) as compared with outcomes with NNRTI-sparing regimens, when therapy is initiated more than 6 months after exposure to single-dose nevirapine. Two articles in this issue of the Journal provide some of the most clear, concrete, and consistent evidence to address this question.

See related articles in the New England Journal of Medicine:
Lockman S, et al. Antiretroviral therapies in women after single-dose nevirapine exposure. N Engl J Med. 14 October 2010; 363:1499-1509.
Palumbo P, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. 14 October 2010;363:1510-1520.

Background Studies have reported young ages at cancer diagnosis in HIV-infected persons and have suggested that HIV accelerates carcinogenesis. However, these comparisons did not account for differences in population age structures.

Objective To compare ages at diagnosis for non-AIDS-defining types of cancer that occur in both the AIDS and general populations, after adjustment for differences in age and other demographic characteristics between these populations.

Design Registry linkage study.

Setting 15 HIV/AIDS and cancer registry databases in the United States.

Participants 212 055 persons with AIDS enrolled in the U.S. HIV/AIDS Cancer Match Study from 1996 to 2007.

Measurements Comparison of age-at-diagnosis distributions for various types of cancer in both the AIDS and general populations, after adjustment for age and other demographic characteristics.

Results The proportion of person-time contributed by older persons (age >=65 years) was far smaller in the AIDS population (1.5%) than in the general population (12.5%). Reflecting this difference, the ages at diagnosis for most types of cancer were approximately 20 years younger among persons with AIDS. However, after adjustment for differences in the populations at risk, the median ages at diagnosis in the AIDS and general populations did not differ for most types of cancer (for example, colon, prostate, or breast cancer; all P > 0.100). In contrast, ages at diagnosis of lung (median, 50 vs. 54 years) and anal cancer (median, 42 vs. 45 years) were significantly younger in persons with AIDS than expected in the general population (P < 0.001), and the age at diagnosis of Hodgkin lymphoma was significantly older (median, 42 vs. 40 years; P < 0.001).

Limitations Information on other cancer risk factors, including cigarette smoking, was not available. Analysis was restricted to non-Hispanic white and black persons who had AIDS, which could limit the generalizability of the findings to other racial and ethnic groups or to persons with HIV but not AIDS.

Conclusion For most types of cancer, the age at diagnosis is similar in the AIDS and general populations, after adjustment for the ages of the populations at risk. Modest age differences remained for a few types of cancer, which may indicate either acceleration of carcinogenesis by HIV or earlier exposure to cancer risk factors.

Background Combination antiretroviral therapy (cART) has improved the survival of patients with HIV/AIDS but its impact remains uncertain on the changing prevalence and incidence of neurologic disorders with ensuing effects on mortality.

Methods The prevalence and incidence of neurologic disorders were examined in patients receiving active care in a regional HIV care program from 1998 to 2008. The mortality hazard ratio (HR) was calculated by Cox proportional hazard models with adjustment for demographic and clinical variables.

Results Of 1,651 HIV-infected patients assessed, 404 (24.5%) were identified as having one or more neurologic disorders, while 41% of AIDS-affected persons exhibited neurologic disease. Symptomatic distal sensory polyneuropathy (DSP, 10.0%) and HIV-associated neurocognitive disorder (HAND, 6.2%) represented the most prevalent disorders among 53 recognized neurologic disorders. Patients with at least one neurologic disorder exhibited higher mortality rates (17.6% vs 8.0%, p < 0.0001), particularly AIDS-related deaths (9.7% vs 3.2%, p < 0.0001), compared with those without neurologic disorders. The highest mortality HR was associated with opportunistic infections of CNS (HR 5.3, 95% confidence interval [CI] 2.5-11.2), followed by HAND (HR 3.1, 95% CI 1.8-5.3) and the presence of any neurologic disorder (HR 2.0, 95% CI 1.2-3.2). The risk of AIDS-related death with a neurologic disorder was increased by 13.3% per 100 cells/mm3 decrement in blood CD4+ T-cell levels or by 39% per 10-fold increment in plasma viral load.

Conclusions The burden and type of HIV-related neurologic disease have evolved over the past decade and despite the availability of cART, neurologic disorders occur frequently and predict an increased risk of death.

We have previously developed HIV-1 Pr55gag-based virus-like particles (HIV-VLPs) as presentation and delivery model using a transient Baculovirus expression system. Here we describe the establishment and characterization of stably transfected insect cell line for the constitutive and reproducible production of HIV-VLPs. The persistence of HIV gag coding gene has been verified in clonal resistant insect cells and the protein expression has been confirmed by Western blot analysis. The resulting HIV-VLPs have been evaluated by standard transmission electron microscopy and their immunogenicity has been evaluated in vivo. Our results demonstrate that this strategy is highly efficient for constitutive expression of conformational enveloped VLPs which can be employed as presentation and delivery system for pathogen as well as tumor-associated antigens. This represents, to our knowledge, the first example of stably transfected insect cell line for the constitutive production of VLPs.

Herpes simplex virus-1 (HSV-1), the prototype of the alpha-herpesvirus family, causes life-long infections in humans. Although generally associated with various mucocutaneous diseases, HSV-1 is also involved in lethal encephalitis. HSV-1 entry into host cells requires cellular receptors for both envelope glycoproteins B (gB) and D (gD). However, the gB receptors responsible for its broad host range in vitro and infection of critical targets in vivo remain unknown. Here we show that non-muscle myosin heavy chain IIA (NMHC-IIA), a subunit of non-muscle myosin IIA (NM-IIA), functions as an HSV-1 entry receptor by interacting with gB. A cell line that is relatively resistant to HSV-1 infection became highly susceptible to infection by this virus when NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA in the permissive cells inhibited HSV-1 infection as well as cell-cell fusion when gB, gD, gH and gL were coexpressed. Cell-surface expression of NMHC-IIA was markedly and rapidly induced during the initiation of HSV-1 entry. A specific inhibitor of myosin light chain kinase, which regulates NM-IIA by phosphorylation, reduced the redistribution of NMHC-IIA as well as HSV-1 infection in cell culture and in a murine model for herpes stromal keratitis. NMHC-IIA is ubiquitously expressed in various human tissues and cell types and, therefore, is implicated as a functional gB receptor that mediates broad HSV-1 infectivity both in vitro and in vivo. The identification of NMHC-IIA as an HSV-1 entry receptor and the involvement of NM-IIA regulation in HSV-1 infection provide an insight into HSV-1 entry and identify new targets for antiviral drug development.

Now 30 years after the first case of AIDS was described we have yet to develop reliable methods-either behavioral or biological-to prevent the spread of HIV. The spectacular and life-saving success of antiretroviral therapy has been more than offset by the challenge of treating millions of people world wide for their entire lives, and the sobering observation that for every person we treat several more become newly infected.

Given this sad reality, no prevention stone should go unturned. And it seems more than reasonable to believe that antiretroviral drugs can be used for prevention. Indeed, these drugs have demonstrated the ability to nearly eliminate vertical (mother to baby) transmission of HIV, implementation challenges notwithstanding.

Antiretroviral agents could be used to prevent the sexual transmission of HIV as preexposure prophylaxis, postexposure prophylaxis or to reduce transmission from infected patients. The latter approach has great promise: because personal health can benefit from antiretroviral therapy (ART) why not exploit the public health benefit as well? Indeed, many drugs concentrate in the genital secretions leading to profound and prolonged (albeit incomplete) suppression of HIV in the genital tract.

Objectives To estimate the HIV incidence and assess the behavioral, clinical, and quality-of-life risk factors for HIV transmission among serodiscordant couples from Henan Province, China.

Methods Between January 2006 and December 2008, initially seronegative spouses were tested for HIV at 6-month intervals. Retrospectively identified subjects were interviewed through face-to-face questionnaire. Cox proportional-hazards model was used to assess the relationship between risk factors and HIV seroconversion.

Results Of 1927 couples, 84 (4.3%) seroconversions occurred, representing a seroconversion rate of 1.71 per 100 person-years. Seroconversion rates increased over time. Not always using condoms [relative ratio (RR) = 8.42; 95% confidence interval (CI): 4.83 to 14.67], sexual activity >=4 times per month (RR = 5.24; 95% CI: 2.55 to 10.77), not switching antiretroviral treatment regimen (RR = 1.99; 95% CI: 0.85 to 4.65), and a quality-of-life score <12 on the psychological domain (RR = 2.33; 95% CI: 1.21 to 4.48) were associated with increased risk of seroconversion. Seventy-one percent of index spouses were on antiretroviral therapy. There was no association between rate of HIV seroconversion and last recorded CD4 cell count level of the index spouse.

Conclusions Effective HIV prevention interventions targeting discordant couples should focus on sustaining health education, increasing psychosocial support services, and increasing medication adherence monitoring.

Tenofovir gel, a vaginal microbicide that has shown promise for preventing HIV through vaginal sex, is being tested in a new trial looking at its safety and acceptability when used rectally. The results of the study, being led by the U.S. National Institutes of Health (NIH)-funded Microbicide Trials Network (MTN), will help determine if the gel should be evaluated further for its potential to prevent HIV among both men and women who engage in receptive anal intercourse.

While condoms are generally effective for protecting against HIV and other sexually transmitted infections, most acts of anal sex go unprotected. Moreover, the risk of acquiring HIV through unprotected anal sex is at least 20 times greater than unprotected vaginal sex and increases if other infections are already present in the rectal lining. Microbicides -- substances applied topically on the inside of the rectum or vagina -- could potentially help prevent the rectal transmission of HIV, although considerably more research has been conducted looking at microbicides for preventing transmission of HIV through vaginal sex. Tenofovir gel, for example, is a candidate microbicide specifically developed to prevent vaginal transmission of HIV.

The new study, known as MTN-007, is the second early phase trial evaluating the rectal safety of the vaginal product. It also comes on the heels of CAPRISA 004, a Phase IIb study conducted in South Africa that found tenofovir gel significantly reduced the risk of HIV among at-risk women who were instructed to use the gel before and after vaginal sex. In an ongoing, large-scale effectiveness trial called VOICE -- Vaginal and Oral Interventions to Control the Epidemic, the MTN is testing daily use of tenofovir gel in African women, with results expected in 2013.

amfAR's MSM Initiative is pleased to inaugurate a new blog charting the lives and work of grassroots MSM activists fighting HIV/AIDS around the world. Beginning with posts from China and continuing in the coming weeks with reports from Belize, Russia, and South Africa, Grassroots: The MSM Initiative Blog will introduce us to the hopes, the achievements, and the ordeals of organizations and individuals who struggle every day to make the world safer and healthier for MSM and transgenders. In the first posting on Grassroots, MSM Initiative Director Kent Klindera writes from Beijing about the impact of fear and homophobia among Chinese MSM, and notes that things may be getting better for younger men.

The Food and Drug Administration (FDA) is tasked with regulating drugs to ensure that Americans have access to medicines that are both safe and effective. FDA's science base must be strong enough to make certain that regulatory decisions are based on the best scientific evidence and keep pace with innovation, so that research is translated into treatments for patients. FDA Commissioner Margaret Hamburg describes "regulatory science" as "the critical bridge between basic scientific research discoveries and new marketed medical products," including drugs. Regulatory science, therefore, touches upon a range of disciplines--not only biomedical science, but also law, public health, and statistics. In 2010, FDA established a Regulatory Science Initiative that will work to develop new scientific tools, technologies, and approaches to strengthen the scientific decision making of the agency and accelerate the development of quality medical products.

The IOM held a public workshop on February 26, 2010, to examine the state of regulatory science and to consider approaches for enhancing it. The workshop provided an opportunity for stakeholders to clarify and explore the concept of regulatory science, examine how it can be used to improve regulatory decision making, consider its funding needs, and contemplate alternative mechanisms and institutional frameworks for its development and application. This document summarizes the workshop.

The next National Institutes of Health (NIH) OARAC meeting will be held on Tuesday, November 9, 2010 from 8:30 a.m. to 5:00 p.m. at the Fishers Lane Conference Center, Terrace Level, 5635 Fishers Lane, Rockville, Maryland, 20852.

The meeting topic is "HIV/AIDS and Adolescents." The meeting will focus on research to address:  the epidemiology of HIV infection among adolescents; HIV prevention, treatment and care for adolescents; biological and cognitive development of HIV-infected adolescents; and ethical and regulatory issues for involving youth in AIDS clinical research.  An update also will be provided on the OARAC Working Groups for HIV Treatment and Prevention Guidelines.