27 MAY 2011, VOLUME 12, ISSUE 21

A new non-nucleoside reverse transcriptase inhibitor, rilpivirine, has been approved for first-line antiretroviral treatment by the United States Food and Drug Administration. Rilpvirine (brand name Edurant) is licensed for use in combination with other antiretroviral drugs, and manufacturer Johnson & Johnson/Tibotec is partnering with Gilead to develop a three-drug combination pill that will allow rilpivirine to be taken in one tablet with tenofovir and FTC. Rilpivirine, previously known as TMC-278, was licensed on the basis of clinical trials that compared the drug with efavirenz, the most commonly prescribed first-line NNRTI... In a press release announcing the approval of rilpivirine, the US Food and Drug Administration noted that the clinical trials that led to the licensing of rilpivirine had demonstrated a similar rate of viral load suppression after 48 weeks of treatment. However, patients with viral load above 100,000 copies/ml at the beginning of treatment were less likely to achieve undetectable viral load than those with lower viral load when treated with rilpivirine. As a consequence a higher rate of viral failure was observed in patients who received rilpivirine (13% vs 9%). Patients who experienced viral failure were also much more likely to develop drug resistance, both to NNRTIs and to 3TC or FTC.In patients receiving efavirenz there was no difference in viral load response according to the level of viral load at the beginning of treatment. These studies also showed that patients taking rilpivirine were less likely to stop treatment due to central nervous system side-effects such as insomnia, depression, dizziness, or due to rash, when compared to patients taking efavirenz. Rilpivirine is taken once daily with food. European marketing authorisation is likely to be granted in the second half of 2011.

Late treatment initiation in HIV clinics in sub-Saharan Africa is being influenced by numerous factors, and there is no single 'quick fix' that will improve the situation, researchers from the International Center for AIDS Care and Treatment Programs report in the journal AIDS. They found that factors relating both to the service design and to the population of the district in which a clinic provided care played important parts in determining the risk of late treatment initiation... The authors looked at quarterly aggregate monitoring and evaluation indicator data from ICAP/Columbia University-supported HIV care clinics in eight sub-Saharan African countries: Ethiopia, Kenya, Lesotho, ozambique, Nigeria, Rwanda, South Africa and Tanzania. Cohort information from the 267 sites was combined with updated programme level data from site surveys in accordance with the date the cohort started ART and with national contextual-level information from Demographic and Health Surveys (DHS).... The data were analysed using three multivariate models: only programme-level factors, only contextual-level factors and a combination of programme and contextual factors significant in the first two models...

Reference:
Nash D et al. Program and contextual-level determinants of low median CD4+ cell count in cohorts of persons initiating ART in 8 sub-Saharan African countries. AIDS 25: advance online publication, doi:10.1097/QAD.0b013e32834811b2, 2011.

There is now, for the first time, hard clinical evidence of an effect that AIDS doctors have suspected for years: If you are H.I.V.-positive, being on antiretroviral drugs will probably save not only your life, but also the lives of your sexual partners. This month, a randomized clinical trial - the gold standard in medical research - showed that the drugs lowered the chances of infecting a partner by 96 percent. This is good news for the infected and their lovers. But it is a moral dilemma for doctors whose infected patients do not want to start taking drugs immediately, usually because they do not yet feel sick and have heard exaggerated rumors about side effects.

What does a responsible doctor do with a patient who is sexually active and teeming with a fatal and incurable virus? Advise him to use condoms and trust him to act decently? Beg? Behind each doctor - whose primary duty is to one patient - there is a government public health bureaucracy, whose duty is to protect the whole country. The epidemic has been killing Americans for 30 years now. Whose rights should be paramount? Those of the patient? Or those of his healthy spouse - or boyfriend, or date, or hookup, or client, or rape victim, or incest target? This debate has been going on since AIDS began, and has always been inextricably mixed with the circumstances of its birth: it was a sexually transmitted disease that emerged among gay men in the middle of the sexual revolution and the new gay rights movement. AIDS still carries a huge stigma and provokes hatred wildly out of proportion with the fact that it is simply a new virus. (Neither SARS nor H1N1 were called "God's wrath.") But the fact that there is a new form of prophylaxis reopens old questions.

Seventy of the world's poorest nations will be able to access modern antiretrovirals for their HIV patients at lower prices, thanks to a new deal. Eight Indian pharmaceutical companies will supply the drugs under the arrangement, which was negotiated by the Clinton Health Access Initiative with the support of British foreign aid and the Bill & Melinda Gates Foundation. To expand their manufacturing capabilities, the drugmakers needed a guarantee of initial payments; that came courtesy of the UN's independent Unitaid agency. The deal includes first-line treatments containing tenofovir and efavirenz as well as second-line treatments containing atazanavir and ritonavir. Many developing-nation HIV patients continue to be treated with older drugs like AZT and nevirapine, which can have harsh side effects. The World Health Organization now recommends combination therapies containing tenofovir; these have fewer side effects and are less likely to lead to the development of drug-resistant virus.

Human papillomavirus vaccine should be given to boys before adolescence to prevent onward transmission, according to a study presented at the recent annual American Urological Association meeting in Washington. The Gardasil HPV vaccine was approved for boys in 2009 to prevent genital warts, but it has not been marketed as aggressively to them as it has been to young females. The vaccine also prevents infection by two HPV types linked to 70 percent of cervical cancer cases. Austrian researchers at the meeting presented the case for using the vaccine among boys to wipe out a potential HPV reservoir, thus protecting future sexual partners. The study involved 133 males ages seven months to 82 years who underwent circumcision to relieve a foreskin retraction problem... "Our study revealed the occurrence of subclinical genital low- and high-risk HPV infections in boys and men, which could be a reservoir for HPV-associated diseases," noted Dr. Michael Ladurner Rennau, of Innsbruck Medical University in Austria, and colleagues. "Since it is proven that viral transfer results from sexual contact, it is advisable to vaccinate not only girls but also boys before adolescence," the authors wrote. To view the abstract, visit http://www.aua2011.org/abstracts/printpdf.cfm?ID=1423.

At a May 19 press conference in Paris, the executive director of the Global Fund to Fight AIDS, TB and Malaria warned that current pledges do not cover the minimum funding needed in 2011-13. Michel Kazatchkine said donor nations and private sources so far have promised $11.7 billion for the three-year period, while the fund needs at least $13 billion. Maximum needs could top $20 billion, he noted. "We need more if we are going to have a world in 2015 where nearly no one dies of malaria, no more children are born infected with HIV and at least 70 percent to 80 percent of patients who need treatment for AIDS get it," said Kazatchkine. A funding shortfall will especially hamper efforts to provide universal coverage of insecticide-treated anti-malaria nets and treatment to prevent mother-to-child HIV transmission, he said. The call comes ahead of a May 26-27 meeting of the G-20 nations in Deauville, France. Kazatchkine urged emerging nations to do their part. "The world is changing, the G-8 has become the G-20. It is clear that emerging nations - Brazil, China, India, South Africa, and Mexico - should become actors in this collective, international effort," he said. From its founding in 2002 through last year, the Global Fund has helped save 6.5 million lives, according to a new report. By the end of 2010, fund-supported programs were providing HIV treatment to some 3 million people, of whom 1 million were pregnant women with the virus; last year's figures represent a 20 percent increase over 2009. In addition, fund-sponsored TB detection and treatment efforts in 2010 increased by 29 percent, with an even larger increase, 50 percent, for multidrug-resistant TB.

Pharma needs to learn from other sectors and abandon the multistage development paradigm in favour of a two-stage design and manufacturing model to cut attrition rates. This is the view of Biotech PharmaFlow's Hedley Rees who told in-Pharmatechnologist.com the pharmaceutical industry's separation of research and development functions is part of the problem. "We have a group of people who find, discover and patent candidate molecules who hand it over to another group of scientists responsible for developing it, who have a need to prove safety and efficacy as quickly as they possible can. This need means the drug industry often takes less time at the development-stage than other sectors, the result of which, Rees said, can be seen in recent US GAO data which show that only one in 250 preclinical candidates reach the market. Instead Rees proposes a broad two-stage model where research and development are combined into a single unit that properly tests drug prototypes and a manufacturing-step which tests these prototypes.

Asha (not her real name) is in a polygamous marriage, and while she would like to protect herself from HIV and other sexually transmitted infections, the message from the preachers at her local mosque in the Burundian capital, Bujumbura, is that condoms promote adultery. "We can't use condoms as a way of preventing AIDS in our community; only abstinence is preached in our mosques," she said. "We [Muslims] are so exposed to the AIDS pandemic, especially because we believe in polygamy..." The scholars at her mosque, in the predominantly Muslim suburb of Buyenzi, are keen to participate in the fight against HIV, caring for HIV-positive people and orphans in their communities and even encouraging HIV testing before marriage, but according to Asha, this advice is flawed. "I can take HIV tests but the problem is that I can't know that the other wife of my husband has done it or will do it; I have no right to tell her to do so," she said. "How do you [protect yourself from HIV] when... subjected to the constraints of religion?"...

Muslim scholars are not the only religious leaders firmly against condom use. Father Emmanuel Gihutu, a professor of philosophy at a seminary in Gitega, east of the capital, said: "It is unthinkable that people insist on condom use in schools and even among young children, rather than teaching them to [wait] before any sexual temptation..."We're so concerned about the AIDS pandemic, but we cannot teach Christians to engage in debauchery; that's not our mission," said Father Evode Bigirimana, rector of the Marian shrine at Mount Zion in Bujumbura... Members of the Seventh Day Adventist Church have similarly strong views on the subject... However, according to INERELA+, a network of religious leaders living with or personally affected by HIV/AIDS, condoms must be an integral part of any realistic HIV prevention strategy. "The implication that the use of a condom automatically marks a person as unable to be faithful fuels stigma and acts as a disincentive to evidence-based prevention," the organization says in its prevention model, which involves safer practices such as abstinence and condom use, counselling and testing, and empowerment and education. Local NGOs are urging religious leaders to rethink their stance on condom use. "We ask them to change their language because it can prevent people from using condoms to protect themselves against AIDS, and I am sure among them [religious leaders] there are those in need of condoms," said Baselissa Ndayisaba, coordinator of the NGO, Society for Women Against AIDS in Africa.

The WHO must regain the trust of donors and the scientific community by becoming more transparent and transforming itself into the main source of global health knowledge, argues Barry R. Bloom. Despite some great achievements in the 63 years since it was created, the organisation is increasingly "underfunded and marginalised", Bloom says. And it has failed to lead on science or public health priorities - the organisation's response to the recent outbreak of cholera in Haiti was slow, and, although chronic diseases are the main contributors to disease burden, its 2008-2009 funding still focuses on infectious diseases. The proliferation of public health organisations - 196 agencies garnered funds for the cholera epidemic in Haiti, for example - also means that the WHO now operates in a more complex, fragmented and inefficient global health system that developing countries find cumbersome. But this has created a demand for an authoritative provider of technical, scientific and practical information about public health, says Bloom, and the WHO could fill this gap with a few simple steps. To succeed, it must engage more effectively with the pharmaceutical industry and civil-society organisations; become more transparent about its decisions and funding priorities, particularly for regional spending; and adopt a peer-review system to evaluate its plans and performance. Bloom argues that the agency must focus on what it does well, such as "provide forums for experts, scientists and health officials worldwide to interact and agree on best practices". And it must make the results of these exchanges available online. In this new leading role the WHO could also influence research and innovation priorities to ensure that they address developing countries' concerns, he says. And it must strengthen its advisory role, securing funding for experts to evaluate future needs such as antibiotic resistance.

Norway, Sweden, Finland and several UN agencies including the World Food Programme, the UN Population Fund, and the UN Development Programme (UNDP) rank among the lowest out of 42 bilateral and multilateral donors measured for aid transparency, according to just-published research by New York University Economics Professors William Easterly and Claudia Williamson. The US Agency for International Development (USAID) and the UK Department for International Development (DFID) scored highest. Researchers measured transparency by analysing donor reporting data to the Organisation for Economic Co-operation and Development, Development Assistance Committee (OECD-DAC); publicly available information; how fully donors responded to direct requests for information concerning how many people they employed; their administrative costs; salaries and benefits; and total development assistance disbursed. Finland, Norway and Sweden were found to be poor on data sharing. UNDP fared worst partly because it published no information online, nor would it respond to any requests for information. Williamson recognized it is hard to accurately measure transparency of all donors, but stressed that nevertheless their findings show progress on donor transparency is moving too slowly. Sweden fares far better - coming third top after Denmark and the UK - in a separate assessment of aid effectiveness of European donors, undertaken by Aidwatch. In this case, Aidwatch assessed the availability of 35 types of information at organizational, partner country, and project level. In the Aidwatch analysis, France, the EU's second largest aid donor, came bottom alongside Hungary, Greece and Poland. Four European donors - Denmark, the European Commission, Finland and the Netherlands - have agreed to join the UK in meeting the aid transparency standard set by the International Aid Transparency Initiative, by the end of 2011. The goal entails making aid spend information easier to access, use and understand. The World Bank just became the first multilateral to attain this goal. Donors will discuss aid transparency challenges when they meet in Busan, South Korea, at the fourth annual aid effectiveness forum at the end of 2011. As part of an accountability drive in 2005, donors promised to open up their financial flows and policies for greater scrutiny, by signing the Paris Declaration on aid effectiveness.

Adcock Ingram (AIPJ, South Africa's second-biggest drugmaker, would consider an acquisition in Nigeria as part of its plan to enter Africa's most populous nation, its chief executive said. Adcock, which scrapped a bid for rival Cipla Medpro (CMPJ) in 2009, has been looking for new revenue streams and hopes to generate 30 percent of its earnings from outside South Africa in two to three years. It finalised the acquisition of Ghana's Ayrton last year and increased its pipeline of drugs by teaming up with U.S. firm Merck & Co to co-promote drugs in sub-Saharan Africa. Adcock, which on Tuesday posted a flat first-half profit, is now looking at Nigeria, sub-Saharan Africa's largest economy after South Africa. The company also said it was working on new partnerships with two global pharmaceuticals companies, deals that could increase the amount of drugs available for distribution. Adcock declined to name the companies. Adcock reported half-year headline earnings per share almost unchanged at 221 cents, hurt by the suspension of some of its key drugs and a sharp drop in its share of the lucrative government HIV/AIDS drug supply contract. The company is supplying 166.5 million rand of drugs under South Africa's two-year HIV/AIDS drugs supply contract, just 4 percent of the total, compared with 21 percent under the previous deal.

Just about every big pharma or biotech company that has earned an unwelcome reputation for building huge and unproductive R&D empires is taking a page from the household products behemoth Procter & Gamble and joining the shift to "open innovation." A new article in Mass High Tech explores how that trend is affecting several big research organizations in the Boston area, home to some of the best minds in drug development. Pfizer's Global Centers for Therapeutic Innovation in Cambridge has been setting up a farm system, relying on teams matching investigators from the pharma giant and academia to advance important new therapies through the pipeline... AstraZeneca has already taken an axe to its R&D ops, preferring to recruit new leaders for research and often going outside the company to find fresh talent, says John Hennessy, executive director, AstraZeneca R&D Boston. Now it plans to get up to 40 percent of its new programs from outside the walls of its R&D silos. Even Biogen Idec is signaling its interest in finding new programs outside the company. "In parts of our R&D we saw radical ideas squashed too quickly," Hennessy recently told a conference... For MIT professor Michael Cima, who's founded multiple biotechs and did a stint as a consultant for Johnson & Johnson, big companies are paying for their past R&D sins. "I saw hundreds of good ideas squashed at Johnson & Johnson in those five years," he told Mass High Tech.

The discovery of a near-perfect way to halt sexual transmission of the AIDS virus has the potential to change the way international agencies and nations cope with the epidemic. But that can only happen if troubling issues of cost and practicality can be surmounted. The study involved more than 1,700 couples in nine countries, the vast majority of them heterosexuals. One member had the virus that causes AIDS; the other did not. It demonstrated conclusively that if infected partners are treated with a cocktail of drugs immediately -- instead of waiting for their immune systems to deteriorate -- the risk of transmitting the virus to the uninfected partner drops by 96 percent. The only reported health benefit of early treatment for the infected partner was a reduced risk of tuberculosis spreading beyond the lungs. Infected partners would have to start early on a lifetime of taking drugs mostly for altruistic reasons -- to avoid infecting their partners. Further research may document greater health benefits. It seems likely that earlier treatment that keeps immune systems strong should further slow the progression of the virus to full-fledged AIDS and ward off other devastating co-infections.

International organizations don't have enough money to treat all those who qualify for drug therapy under current guidelines. They will be hard-pressed to find additional money to treat millions more people to slow the spread of the virus. With most industrialized economies still lagging, there is little appetite for increasing aid. A strong moral case can be made for protecting millions more people from infection, but there may be an economic case as well. We need valid, well-documented estimates as to whether a big investment in prevention now might pay for itself in the long run by greatly reducing the number of sick people who have to be cared for.

In advance of a major United Nations meeting on the global AIDS epidemic, public-health leaders face a paradox: New evidence suggests the epidemic can finally be controlled, but that would demand increased spending at a time of severe global budget restraints. Preliminary estimates show that funding from donor nations to fight AIDS in developing nations actually fell in 2010, the first decline ever in the battle against HIV, which currently afflicts 33 million people world-wide. The U.N. High Level Meeting on HIV/AIDS, to be held June 8-10 in New York, is designed to chart how to fight the disease through 2015. A key point of contention: Whether to set specific targets for how many people to put on AIDS treatment. Any such targets will not be met unless new money is found to buy medicine for more people after the 2010 funding drop. Last year was "a real decrease," said Jennifer Kates, director of Global Health and HIV Policy at the Kaiser Family Foundation, which tracks global HIV spending with the Joint U.N. Programme on HIV/AIDS, or UNAIDS. Ms. Kates declined to provide specific figures, saying they were still under analysis. But she said "a major factor" in the decrease appeared to be the global economic crisis.

Earlier this month, a landmark study proved that AIDS drugs, known as antiretrovirals, not only restore health to people with HIV but also make them strikingly less infectious. Compared with people not yet taking drugs, those on treatment were found to be more than 96% less likely to transmit the virus to their sexual partners... AIDS experts call treating patients to slow the spread of the epidemic "treatment as prevention." Combined with other new prevention tools, many scientists believe it could turn the tide on an epidemic that currently infects more than 2.5 million people each year. At the end of 2009, about 5.2 million people were on treatment, and the world spent about $15.9 billion that year, with a little less than half coming from donor nations, according to UNAIDS and Kaiser estimates. But another 10 million patients needed treatment, and the funding gap exceeded $7.5 billion. Newer estimates, based on more efficient delivery of care, suggest the gap might be as narrow as $6 billion, according to estimates prepared by a group of prominent HIV experts. But the global economic slowdown has taken a toll. For the first time, the multinational Global Fund to Fight AIDS, Tuberculosis and Malaria has seen some nations fail to meet their pledges...

An expert committee set up to investigate the conduct of studies using human papillomavirus (HPV) vaccines in India has reported large-scale ethical violations. Members of the committee said since the project proposal involved research on human participants it should have followed "all the guidelines and statutory requirements applicable to research on human participants", the daily The Hindu reported. Concern was expressed by members at unacceptable and prolonged delays in the reporting of adverse events and deaths, and a lack of independent monitoring systems. "There has been direct contact with the human participants, they have administered an intervention which is not part of a prescribed prevention and have expected adverse events," members reported. The committee comprised S.S. Aggarwal, former director of the Sanjay Gandhi Post-graduate Institute of Medical Sciences, S.P. Agarwal, former director-general of health services, and Suneeta Mittal, head of obstetrics and gynaecology at the All-India Institute of Medical Sciences (AIIMS) in New Delhi. They were assisted by a three-member sub-committee. Members said there was a need for specific and separate legislation covering all aspects of biomedical and health research involving human participants and that statutory status should be given to the guidelines of the Indian Council of Medical Research.

When former NIH head Elias Zerhouni ran the $30 billion federal research institute, he pushed for so-called translational research in which findings from basic lab research would be used to develop medicines and other applications that would help patients directly. Now the head of R&D at French drug maker Sanofi, Zerhouni says that such "bench to bedside" research is more difficult than he thought. When he arrived at Sanofi, "I thought the solution would be simple," Zerhouni said at a recent R&D press event attended by the Health Blog. He thought the answer to the company's R&D woes was to make it more creative and more nimble, like a small biotech. But he realized that small biotechs are no more successful than large drug makers at coming up with new drugs. "At the end of the day, there's a gap in translation," he said. While at the NIH, Zerhouni witnessed a lot of progress in basic science that had implications for human health. But those findings weren't being translated because clinician-scientists weren't receiving the right training, he said. At pharma companies, most R&D scientists are too isolated -- they talk primarily to those within their own company -- and the experimental therapies that companies are developing are created without enough communication with the doctors who actually treat patients. There needs to be a "re-do" in pharma R&D, Zerhouni said. At Sanofi, the goal now is to strive for "open innovation," which involves looking for new research and ideas both internally and externally -- for example, at universities and hospitals. In addition, the company is focusing on first understanding a disease and then figuring out what tools might be effective in treating it, rather than identifying a potential tool first and then looking for a disease area in which it could be helpful. In addition, last year the company cut the number of projects in its portfolio by about half, to around 60, so it could focus on those that have the greatest potential to meet medical objectives, commercial return and are clinically feasible, according to Paul Chew, U.S. Sanofi's chief medical and scientific officer.

The Centre for Infectious Disease Research in Zambia (CIDRZ), funded by the United States government and other organisations, recently organised a sensitisation meeting that drew the participation of the media, and other stakeholders, to enlighten them on the importance of clinical trials and research. Dr Margaret Kasaro, an investigator - Microbicide Trials Network, explains that in the case of sub-Saharan Africa, the major driver was the heterosexual mode of transmission, and that the prevalence of people living with HIV was higher among the women. Dr Kasaro is of the view that research strategies should be tried in the locality where the identified problem is, and that before statistics can be drawn, results should be based on extensive research... Dr Kasaro says that it is important for researchers to disseminate the research results to the volunteers, local authorities, scientific peers and the public. One such way of disseminating these research findings and results is through the media. "This is where the partnership between researchers and the media comes into play. We have realised that the media are critical partners in clinical research," she says. This is because the media are better-placed to assist in the sensitisation of the public on the importance of the research and in the dissemination of research findings. CIDRZ director Jeff Stringer explains that the media are essential and a powerful tool in educating and mobilising communities and are particularly valuable in promoting participation in HIV clinical trials. "From the trials in Tanzania on HIV prevention interventions research on microbicides and discordant couples, our approach showed to be very useful as both participants and their communities are now better informed about trials, through the media," he explained... "However, sometimes the media could erode gains made through HIV clinical trials, especially by reporting about efforts inaccurately and superficially. Eventually, this leads to wrong decisions among trial participants, the public and policy makers thereby discouraging volunteers to continue participating in trials. This could lead to policy makers halting trials," Dr Stringer said. However, most journalists lack background knowledge in science, which leads to inability to comprehend the clinical trials procedures. One way of bridging the gap between scientists and the media is through the involvement of the media at all stages of the trials, covering basic knowledge on HIV clinical trials, with emphasis on research, ethics and the drug development process. Media institutions can also participate by promoting in-house training to build capacity in their staff on reporting on health matters. In stressing the importance of media participation in clinical trials, Dr Kasaro says that "the media in clinical trials should not come as an after thought, and each trial should have a communication plan which includes the media."

The Navajo Area Indian Health Service (NAIHS) is calling for increased HIV/AIDS awareness in the region, following a dramatic rise in new cases over the past decade. "In 2000, approximately 15 cases were diagnosed per year at Navajo area facilities," said Dr. Jonathan Iralu, an NAIHS infectious-disease consultant. "In 2009, there were 40 new cases and in 2010, there were 35 new HIV cases. These figures are very alarming." Melvin Harrison, executive director of the nonprofit Navajo AIDS Network, said the groups most at risk are men who have sex with men and people with substance abuse problems. "People lose inhibitions when they are drinking and drugging and don't take any precautions," he said. "People have to realize that HIV does exist on the Navajo Nation." IHS spokesperson Jenny Notah said HIV testing is now offered to all IHS patients ages 13-64 who seek health care services. "Patients admitted to the hospital are routinely offered a voluntary HIV test upon admission," said Notah. "Patients presenting to the obstetrics clinic for prenatal care are given the same opportunity for testing." Furthermore, funding from the Minority AIDS Initiative has allowed IHS to significantly expand HIV care. "HIV primary care is available at all IHS service units on the Navajo Nation and specialty care is available at [Gallup Indian Medical Center]. An HIV nurse specialist was hired at GIMC to improve HIV care and coordinate care of people who are HIV-positive," said Notah. "It is hoped that these improvements in outreach and care will result in increased awareness of HIV on and near the Navajo Nation, and improved quality of life for HIV patients as well as a reduction in the spread of HIV," Iralu said.

This is the story of how my husband's circumcision saved my life. It's a personal story, but let it also serve as a public health rebuttal to the proposed ban on male circumcision that will be on the San Francisco ballot this November. San Francisco's ballot initiative would prohibit circumcision on all males under the age of 18. It would allow no religious exemptions, and it apparently gives no regard to the numerous studies demonstrating that male circumcision can substantially reduce--by more than 50%--the transmission of the HIV virus during sex.

Peter, my husband, was born with hemophilia... As a result of one such clotting factor transfusion prior to 1985, Peter became HIV-positive. Today, the U.S. blood supply has been cleaned up significantly, reducing the chance of such transmission to almost nil. But before the risk was known and blood screening had been introduced, the risk to hemophiliacs was enormous... the very blood products that had helped save and heal and improve the lives of so many hemophiliacs also had the power to infect them with AIDS. As for sex--as they say in Brooklyn, fuggedaboutit. In politer terms, Peter's hematologists advised us to cease and desist getting pregnant again. Our mutual, sad assumption in the months that ensued: Not only had our love not produced a baby, but it may well have doomed me, too. And then our very own HIV test results--his and hers--arrived. Peter was positive. I was negative. How had it happened that I never became HIV-positive myself? It wasn't until recently that we knew: He was circumcised. Actually, I should say, now I know. Peter died in 1999. But here is the reason I am alive today: In the same way that circumcision vastly diminishes the chance of infecting women with the human papillomavirus that causes cervical cancer, studies suggest that circumcision also helps guard against the transmission of the HIV virus. In both cases, cells on the inside of the male foreskin are implicated in spreading the virus. But if the foreskin is removed, a source of infection is also removed. So there you have it: My husband's circumcision saved my life.

Cash-strapped states are scaling back efforts to provide life-saving medicines to HIV patients. The result: more than 8,300 people -- a record number -- are on waiting lists in 13 states to get antiretrovirals and other drugs used to treat HIV and AIDS or the side effects, mental health conditions or opportunistic infections. And that number probably understates the need, say advocates, who note that many states have simply eliminated waiting lists or reduced eligibility. AIDS drug assistance programs, or ADAPs, pay for HIV medications for low-income patients when they cannot afford the drugs and don't have insurance or have limited coverage that fails to include the cost of the drugs. Nearly 174,000 people are covered by the programs... The federal government provides the bulk of the ADAP financing through the Ryan White Care Act. This year the budget is $885 million, $25 million more than last year, according to Brandon Macsata, chief executive of the ADAP Advocacy Association. Many states supplement the funding. But the number of people seeking help is rising after the recession pushed millions of people out of work and cut their insurance coverage. And the downturn in the economy has created budget shortfalls for states and limited their ability to help those patients. ADAP is not an entitlement program, so even applicants who are qualified can be turned away or put on waiting lists if funding is not available. Advocacy groups say the pullback by states is shortsighted: HIV patients who get the antiretroviral drugs are generally able to manage their disease, allowing them to continue working and keeping long-term medical costs down for the state. New research even suggests that people put on medication immediately after being diagnosed are less likely to spread the disease.

Hundreds of males mainly youth in Bushenyi district last week underwent free circumcision by surgeons from the health ministry. This was at the district headquarters during the launch of Safe Male Circumcision, a new internationally recommended strategy for HIV prevention. The district health officer, Celestine Barigye, said about 50,000 males would be circumcised though they were targeting all the 110,000 males in the district. He said over 1,000 people had so far been circumcised... The programme is funded by the Government and Strengthening TB and HIV & AIDS Response in South Western Uganda (STAR-SW), an NGO operating in 13 districts in the south western region. STAR-SW country director Dr. Edward Bitarakwatesaid the project will be carried out in the districts of Kabale, Kisoro, Kanungu, Rukungiri, Ntungamo and Ibanda. Others are Isingiro, Kiruhura, Bushenyi, Sheema, Buhweju, Mitooma and Rubirizi. Bitarakwate noted that if 4.5 million males in Uganda were circumcised in the next five years, about 34,000 infections would be prevented... The outgoing district chairman, Longino Ndyanabo Ishanga, urged local leaders and other stakeholders to sensitise people on the benefits of circumcision.

The Global Fund to Fight AIDS, TB and Malaria is reconsidering its support for China. A quiet decision in November to withhold payments for a major AIDS grant there has been followed in recent weeks with the freezing of funds for other grants. Sources say the Global Fund is concerned over China's management of the grants and its hostility to civil society groups, which the fund considers to be a cornerstone of disease-fighting efforts. Officials from the Global Fund and China met for two days to discuss the concerns. Fund spokesperson Jon Liden said Friday China agreed to a number of stipulations on how money would be used and monitored. "We came to a point where we needed to make clear signals to China," he said. "We seem to share an understanding of the way forward." Sources familiar with the negotiations said China has pledged to repay any funds that have been misspent, though it is not clear whether it has agreed to include nongovernmental organizations in fund-sponsored initiatives. The meetings took place amid growing questions of whether China should receive Global Fund support at all. China spent approximately $46 billion hosting the 2008 Summer Olympics and last year's Shanghai Expo, in addition to financing a $586 billion economic stimulus package. Since 2003, China has received $539 million from the fund, according to the Global Fund's website; another $295 million is in the pipeline. China, the fourth-largest recipient of Global Fund aid after Ethiopia, India, and Tanzania, qualifies for grants as a middle-income country, much like India, Thailand, and the Philippines. These nations are expected to contribute a certain percentage to the cost of fund-financed health programs. China has given the fund just $16 million. The United States, by comparison, has contributed $5.5 billion.

San Francisco election officials recently confirmed that a citizens' initiative to ban male circumcision in the city will be placed on the November ballot. The initiative garnered more than 7,700 valid signatures from city residents, more than the 7,168 it required. If approved, the ban would prohibit circumcising males under the age of 18 and carry a misdemeanor penalty of up to $1,000 or up to one year in jail. There are no religious exemptions, prompting widespread criticism that it would violate First Amendment freedoms to exercise one's religion. Male circumcision is seen as a sacred rite by Jews and Muslims. Activists behind the city ballot initiative regard the procedure as genital mutilation, similar to that forbidden for girls, as well as a painful, dangerous procedure forced on a child. "Parents are really guardians, and guardians have to do what's in the best interest of the child," said Lloyd Schofield, the proposal's lead advocate. "It's his body. It's his choice." "For a city that's renowned for being progressive and open-minded, to even have to consider such an intolerant proposition... it sets a dangerous precedent for all cities and states," said Rabbi Gil Yosef Leeds of Berkeley, a mohel, or one who performs Jewish ritual circumcisions... US health officials are still developing recommendations regarding male circumcision. CDC does not have a position on the ballot initiative, said agency spokesperson Elizabeth-Ann Chandler.

Abstract
The primate lentivirus auxiliary protein Vpx counteracts an unknown restriction factor that renders human dendritic and myeloid cells largely refractory to HIV-1 infection. Here we identify SAMHD1 as this restriction factor. SAMHD1 is a protein involved in Aicardi-Goutieres syndrome, a genetic encephalopathy with symptoms mimicking congenital viral infection, that has been proposed to act as a negative regulator of the interferon response. We show that Vpx induces proteasomal degradation of SAMHD1. Silencing of SAMHD1 in non-permissive cell lines alleviates HIV-1 restriction and is associated with a significant accumulation of viral DNA in infected cells. Concurrently, overexpression of SAMHD1 in sensitive cells inhibits HIV-1 infection. The putative phosphohydrolase activity of SAMHD1 is probably required for HIV-1 restriction. Vpx-mediated relief of restriction is abolished in SAMHD1-negative cells. Finally, silencing of SAMHD1 markedly increases the susceptibility of monocytic-derived dendritic cells to infection. Our results demonstrate that SAMHD1 is an antiretroviral protein expressed in cells of the myeloid lineage that inhibits an early step of the viral life cycle.

Abstract
Background: Human immunodeficiency virus type 1 (HIV-1) superinfection is infection of an HIV-1 seropositive individual with another HIV-1 strain. The rate at which HIV-1 superinfection occurs might be influenced by sexual behavior. Superinfection might be detected more often by analyzing longitudinal samples collected from time periods of unsafe sexual behavior.

Methods: Envelope C2-C4 and gag sequences were generated from HIV-1 RNA from longitudinal serum samples that were obtained around self-reported sexual risk periods from 15 homosexual therapy-naive men who participated in the Amsterdam Cohort Studies on HIV Infection and AIDS. Maximum likelihood phylogenetic analysis was used to determine whether HIV-1 superinfection had occurred.

Results: We studied a total of 124 serum samples from 15 patients with a median of 8 samples and of 5.8 person-years of follow-up per patient. Phylogenetic analysis on 907 C2-C4 env and 672 gag sequences revealed no case of HIV-1 superinfection, resulting in a superinfection incidence rate of 0 per 100 person-years [95%CI: 0 - -4.2].

Conclusions: We conclude that HIV-1 superinfection incidence is low in this subgroup of homosexual men who reported unsafe sexual behavior. Additional studies are required to estimate the impact of also other factors, which may determine the risk to acquire HIV-1 superinfection.

Collectively, malaria, TB & HIV/AIDS cause more than five million deaths per year -- nearly the entire population of the state of Washington -- and represent one of the world's major public health challenges as we move into the second decade of the 21st century. In the May 26, 2011, edition of the journal Nature, Seattle BioMed Director Alan Aderem, Ph.D., along with Rino Rappuoli, Ph.D., Global Head of Vaccines Research for Novartis Vaccines & Diagnostics, discuss recent advances in vaccine development, along with new tools including systems biology and structure-based antigen design that could lead to a deeper understanding of mechanisms of protection. This, in turn, will illuminate the path to rational vaccine development to lift the burden of the world's most devastating infectious diseases.

According to Aderem, a systems biology pioneer who recently joined Seattle BioMed to incorporate that approach with the Institute's infectious disease research, new conceptual and technological advances indicate that it will be possible to develop vaccines for the "big three" infectious diseases within the next 10 years. "Success will be largely dependent on our ability to use novel approaches such as systems biology to analyze data sets generated during proof-of-concept trials," he explained. "This will lead to new insights such as the identification of correlates of protection or signatures of immunogenicity and the acceleration of large-scale clinical trials." Aderem added that innovative, new clinical and regulatory approaches will also accelerate the pathway to much-needed vaccines. The article discusses the strengths and criticisms of the systems biology approach, with the key strength of the approach lying in its ability to capture and integrate massive amounts of biological data to visualize emergent properties that are not demonstrated by their individual parts and cannot be predicted from the parts alone.

Reference:
Rappuoli R, Aderem R. A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature 2011; 473 (7348): 463-469. doi:10.1038/nature10124

Is medical research a victim of its own success? A surprising economic analysis suggests that each new medical innovation may make the next more difficult to achieve, because patients prefer to stick with proven -- though potentially inferior -- treatments rather than trying something new. Good effectively becomes the enemy of great. The finding confirms the experience of many medical researchers struggling to recruit patients for their next clinical trial. But the solution proposed by the study's authors -- to pay trial participants higher stipends -- makes some clinicians queasy. The analysis, published this month by the National Bureau of Economic Research based in Cambridge, Massachusetts, shows that the percentage of HIV-infected men who enrolled in clinical trials plummeted immediately after a regimen of antiretroviral drugs known as HAART hit the market in 1996. The precipitous decline, seen in data from the Multicenter AIDS Cohort Study of around 7,000 homosexual and bisexual men in four US cities from 1984 to 2005, occurred even as federal funding for HIV research nearly doubled. HAART simply worked so well, says Anup Malani, a law professor at the University of Chicago, Illinois, and an author of the new study, that patients were no longer motivated to sign up for clinical trials as a way to gain access to better treatments. Malani and his co-author Tomas Philipson, also of the University of Chicago, believe similar problems arise whenever a new drug significantly improves the treatment of a particular disease, leading to a decline in pharmaceutical productivity...

Reference:
Malani, A, Philipson T. Can medical progress be sustained? Implications of the link between development and output markets. NBER, 2011; available at http://www.nber.org/papers/w17011.

The persistence of prolonged HIV reservoirs in patients on effective antiretroviral therapy is the main hurdle to HIV eradication. However, major advances have been made over the last few years, both in basic and clinical science of HIV reservoirs. Consequently, the scientific community no longer banishes the term "cure". Despite such renewed hope, there is little investment by both public and private groups in the field. It is therefore imperative to make this a priority and allocate sufficient resources, especially financial support, to aid in finding the cure since there is no effective preventive vaccine. This article discusses the main scientific aspects and strategies to address and build an international task force tackling issues associated with HIV reservoirs.

In order to propagate and persist within the host, HIV-1 subverts a variety of checkpoints of innate and adaptive viral immunosurveillance. Many of these are related to natural killer cells, which bridge innate and adaptive immunity and play a major role in defeating virus infections. HIV-1 affects cytotoxicity of natural killer cells towards infected cells and natural killer cell-mediated priming of effector cells of the adaptive immune system. Moreover, a subpopulation of natural killer cells was found sensitive to infection by HIV-1. Consequently, an efficient immune response against HIV-1 cannot be mounted in most patients. The current review highlights the molecular interplay between HIV-1 and effector cells of the host immune system with a focus on natural killer cells, and summarizes strategies of HIV-1 to escape from natural killer cell immunosurveillance. A detailed knowledge of these immune escape strategies might lead to the identification of access points for intervention in order to block infection and progression to AIDS.

The European HIV Drug Resistance Guidelines Panel, established to make recommendations to clinicians and virologists, felt that sufficient new information has become available to warrant an update of its recommendations, explained in both pocket guidelines and this full paper. The Panel makes the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure, and other drug targets (integrase and envelope) if such drugs were part of the failing regimen; (iii) consider testing for CCR5 tropism at virologic failure or when a change of therapy has to be made in absence of detectable viral load, and in the latter case test DNA or last detectable plasma RNA; (iv) consider testing earliest detectable plasma RNA when a successful nonnucleoside reverse transcriptase inhibitor-containing therapy was inappropriately interrupted; (v) genotype source patient when postexposure prophylaxis is considered; for HIV-2, (vi) consider resistance testing where treatment change is needed after treatment failure. The Panel recommends genotyping in most situations, using updated and clinically evaluated interpretation systems. It is mandatory that laboratories performing HIV resistance tests take part regularly in external quality assurance programs, and that they consider storing samples in situations where resistance testing cannot be performed as recommended. Similarly, it is necessary that HIV clinicians and virologists take part in continuous education and discuss problematic clinical cases. Indeed, resistance test results should be used in the context of all other clinically relevant information for predicting therapy response.

Bruce Walker didn't want to sit next to Terry Ragon on the 24-hour plane ride from Boston to South Africa. He had only recently met the wealthy, Cambridge, Massachusetts-based software executive and was about to spend two full days touring AIDS-ravaged Durban with him in hope of obtaining a donation. Walker, an immunologist and physician at Massachusetts General Hospital (MGH), wanted to give Ragon some space and get some work done, but Ragon insisted they sit together. During the flight, he peppered Walker with questions about his research in South Africa. He also warned him not to get his hopes up. "I go on a lot of these kinds of trips, and I don't give people very much money," Ragon said. Walker was disappointed, but he stuck to the plan. He took Ragon to the crumbling, 100-year-old McCord Hospital, where he followed doctors and visited impoverished, young people with HIV.

"All three of the patients I sat in with were going to die, and one of them was dying right there in front of me," says Ragon. He had been to Africa before but never had he so intimately seen the pain and suffering caused by AIDS. As the trip neared its end, Walker knew that it was time to broach the subject of money again. He had been trained by MGH fundraisers to give potential donors a range of options. For a modest sum, US$5,000-20,000, Ragon could fund lab equipment or nurses -- $1 million might fund a small clinical trial. But on a whim, Walker decided to float a more ambitious idea: creating an institute in which researchers from different fields could focus solely on HIV vaccines under one roof, with the kind of funding that would enable high-risk projects. "I thought the idea was half-baked," says Ragon, "but it intrigued me." That was in March 2007. Talks continued, and about a year later Ragon and his wife, Susan, agreed to give $100 million over 10 years to create the Ragon Institute of MGH, MIT and Harvard. Established in early 2009, with Walker as its director, the institute was a positive note at a challenging time for HIV vaccine development...

Abstract
This paper uses multivariate logistic regressions to explore: (1) potential socio-economic, cultural, psychological and political determinants of AIDS conspiracy beliefs among young adults in Cape Town; and (2) whether these beliefs matter for unsafe sex. Membership of a religious organisation reduced the odds of believing AIDS origin conspiracy theories by more than a third, whereas serious psychological distress more than doubled it and belief in witchcraft tripled the odds among Africans. Political factors mattered, but in ways that differed by gender. Tertiary education and relatively high household income reduced the odds of believing AIDS conspiracies for African women (but not men) and trust in President Mbeki's health minister (relative to her successor) increased the odds sevenfold for African men (but not women). Never having heard of the Treatment Action Campaign (TAC), the pro-science activist group that opposed Mbeki on AIDS, tripled the odds of believing AIDS conspiracies for African women (but not men). Controlling for demographic, attitudinal and relationship variables, the odds of using a condom were halved amongst female African AIDS conspiracy believers, whereas for African men, never having heard of TAC and holding AIDS denialist beliefs were the key determinants of unsafe sex.

Abstract
Background: Overall HIV mortality rates in China have not been reported. In this analysis we assess overall mortality in treatment-eligible adults with HIV and attempt to identify risk factors for HIV-related mortality.

Methods: We used data from the national HIV epidemiology and treatment databases to identify individuals aged 15 years or older with HIV who were eligible for highly active antiretroviral therapy between 1985 and 2009. Mortality rates were calculated in terms of person-years, with risk factors determined by Cox proportional hazard regression. Treatment coverage was calculated as the proportion of time that patients who were eligible for treatment received treatment, with risk factors for not receiving treatment identified by use of logistic regression.

Findings: Of 323 252 people reported as having HIV in China by the end of 2009, 145 484 (45%) were identified as treatment-eligible and included in this analysis. Median CD4 count was 201 cells per uL (IQR 71-315) at HIV diagnosis and 194 cells per uL (73-293) when first declared eligible for treatment. Overall mortality decreased from 39.3 per 100 person-years in 2002 to 14.2 per 100 person-years in 2009, with treatment coverage concomitantly increasing from almost zero to 63.4%. By 2009, mortality was higher and treatment coverage lower in injecting drug users (15.9 deaths per 100 person-years; 42.7% coverage) and those infected sexually (17.5 deaths per 100 person-years; 61.7% coverage), compared with those infected through plasma donation or blood transfusion (6.7 deaths per 100 person-years; 80.2% coverage). The two strongest risk factors for HIV-related mortality were not receiving highly active antiretroviral therapy (adjusted hazard ratio 4.35, 95% CI 4.10-4.62) and having a CD4 count of less than 50 cells per uL when first declared eligible for treatment (7.92, 7.33-8.57).

Interpretation: An urgent need exists for earlier HIV diagnosis and better access to treatment for injecting drug users and patients infected with HIV sexually, especially before they become severely immunosuppressed.

Abstract
Background: Because of limited work opportunities in Nepal and the open-border provision between Nepal and India, a seasonal labor migration of males from Far-Western Nepal to India is common. Unsafe sexual activities of these migrants in India, such as frequent visits to brothels, lead to a high HIV prevalence among them and to a potential transmission upon their return home to Nepal. The present study aims to evaluate the role of such seasonal labor-migration to India on HIV transmission in Far-Western Nepal and to assess prevention programs.

Methods: An HIV epidemic model was developed for a population in Far-Western Nepal. The model was fitted to the data to estimate the back and forth mobility rates of labor-migrants to India, the HIV prevalence among migrants and the HIV transmission rate in Far-Western Nepal. HIV prevalence, new infections, disease deaths and HIV infections recruited from India were calculated. Prevention programs targeting the general population and the migrants were evaluated.

Results: Without any intervention programs, Far-Western Nepal will have about 7,000 HIV infected individuals returning from India by 2015, and 12,000 labor-migrants living with HIV in India. An increase of condom use among the general population from 39% to 80% will reduce new HIV infections due to sexual activity in Far-Western Nepal from 239 to 77. However, such a program loses its effectiveness due to the recruitment of HIV infections via returning migrants from India. The reduction of prevalence among migrants from 2.2% to 1.1% can bring general prevalence down to 0.4% with only 3,500 recruitments of HIV infections from India.

Conclusion: Recruitment of HIV infections from India via seasonal labor-migrants is the key factor contributing to the HIV epidemic in Far-Western Nepal. Prevention programs focused on the general population are ineffective. Our finding highlights the urgency of developing prevention programs which reduce the prevalence of HIV among migrants for a successful control of the HIV epidemic in Far-Western Nepal.

Abstract
Background: Female sex workers (FSWs) are a population sub-group most affected by the HIV epidemic in India and elsewhere. Despite research and programmatic attention to FSWs, little is known regarding sex workers' reproductive health and HIV risk in relation to their experiences of violence. This paper therefore aims to understand the linkages between violence and the reproductive health and HIV risks among a group of mobile FSWs in India.

Methods: Data are drawn from a cross-sectional behavioural survey conducted in 22 districts from four high HIV prevalence states (Andhra Pradesh, Karnataka, Maharashtra, Tamil Nadu) in India between September 2007 and July 2008. The survey sample included 5,498 FSWs who had moved to at least two different places for sex work in the past two years, and are classified as mobile FSWs in the current study. Analyses calculated the prevalence of past year experiences of violence; and adjusted logistic regression models examined the association between violence and reproductive health and HIV risks after controlling for background characteristics and program exposure.

Results: Approximately one-third of the total mobile FSWs (30.5%, n=1,676) reported experiencing violence at least once in the past year; 11% reported experiencing physical violence, and 19.5% reported experiencing sexual violence. Results indicate that FSWs who had experienced any violence (physical or sexual) were significantly more likely to be vulnerable to both reproductive health and HIV risks. For example, FSWs who experienced violence were more likely than those who did not experience violence to have experienced a higher number of pregnancies (adjusted odds ratio [OR] = 1.2, 95% confidence interval [CI]=1.0-1.6), ever experienced pregnancy loss (adjusted OR = 1.4, 95% CI=1.2-1.6), ever experienced forced termination of pregnancy (adjusted OR = 2.4, 95% CI=2.0-2.7), experienced multiple forced termination of pregnancies (adjusted OR = 2.2, 95% CI=1.7-2.8), and practice inconsistent condom use currently (adjusted OR=1.97, 95% CI: 1.4-2.0). Among FSWs who experienced violence, those who experienced sexual violence were more likely than those who had experienced physical violence to report inconsistent condom use (adjusted OR = 1.8, 95% CI: 1.4-2.3), and experience STI symptoms (adjusted OR=1.3, 95% CI: 1.1-1.7).

Conclusion: The pervasiveness of violence and its association with reproductive health and HIV risk highlights that the abuse in general is an important determinant for reproductive health risks; and sexual violence is significantly associated with HIV risks among those who experienced violence. Existing community mobilization programs that have primarily focused on empowering FSWs should broaden their efforts to promote reproductive health in addition to the prevention of HIV among all FSWs, with particular emphasis on FSWs who experienced violence.

AVAC is pleased to announce that it is currently accepting applications for its 2011-12 PxROAR program. The PxROAR program offers training for US advocates in biomedical HIV prevention research education and advocacy through mentorship, peer support, networking opportunities, and technical and financial support.

PxROAR (Prevention Research, Outreach, Advocacy and Representation) is an AVAC program that supports HIV prevention research advocates based in the United States. You do not have to be a US citizen to apply, but you must reside in the US and be engaged in work related to HIV/AIDS and affected communities in the US. PxROAR members represent the communities in the US that are most highly affected by the HIV epidemic. Current PxROAR members are engaged in activities to help further engage people of color, gay men, and women to collaborate in addressing long-standing barriers to community input in HIV prevention research.

Complete applications are due by Friday, June 17, 2011.