The Weekly NewsDigest is a compilation of HIV prevention research media coverage and relevant science in peer-reviewed journals; material on
other reproductive health issues; and matters of policy and politics relevant to HIV prevention research, development and advocacy.
Its purpose is to raise awareness around the range of opinions and information about HIV prevention research disseminated in the press and
scientific journals and provide a neutral, objective basis for decision-making and evidence-based advocacy.
New Delhi, Feb. 22: India plans to set up its first laboratory exclusively tasked with designing vaccines against the human immunodeficiency virus (HIV) and plunge deeper into a back-to-biology movement hatched after disappointing results worldwide with 30 candidate vaccines. India's biotechnology department and the International AIDS Vaccine Initiative, a public-private partnership, will establish the vaccine design laboratory at the Translational Health Science and Technology Institute, a government-funded biotechnology centre near Delhi. Research at the THSTI-IAVI laboratory is expected to focus on designing and testing molecules that show potential in generating antibodies that can effectively neutralise HIV, scientists familiar with the proposal told The Telegraph....
The proposed activities at the THSTI-IAVI laboratory will be part of a renewed back-to-biology effort to decipher the molecular details of HIV infection and the immune system's response to it. Over the past two years, vaccine researchers at IAVI's New York laboratory and elsewhere have turned their attention on a set of molecules called the broadly neutralising antibodies that can neutralise the virus and appear to actually protect a small proportion of HIV-infected people from becoming ill. One of the tasks of the THSTI-IAVI laboratory may be to screen a large number of small fragments of proteins that, scientists hope, will generate these neutralising antibodies and protect humans from HIV, scientists familiar with the project said. "Nothing else seems to be working," said Virander Chauhan, the director of the International Centre for Genetic Engineering and Biotechnology in New Delhi, who leads an independent team of scientists seeking molecules that will generate two neutralising antibodies codenamed 4E10 and 2F5.
Better-known for its battles against global disease, the Gates Foundation has also become a force in journalism. The foundation's contributions to nonprofit and for-profit media have helped spur coverage of global health, development and education issues. But some people worry that its growing support of media organizations blurs the line between journalism and advocacy.
Perhaps you saw Ray Suarez's three-part series on poverty and AIDS in Mozambique on the PBS NewsHour. Or listened to Public Radio International's piece on the rationing of kidney dialysis in South Africa. Beyond their subject matter, these reports have something else in common: They were all bankrolled by the Bill & Melinda Gates Foundation. Better-known for its battles against global disease, the giant philanthropy has also become a force in journalism. The foundation's grants to media organizations such as ABC and The Guardian, one of Britain's leading newspapers, raise obvious conflict-of-interest questions: How can reporting be unbiased when a major player holds the purse strings?
Infants who are spared HIV from their infected mothers have a four-fold risk of dying from other infectious diseases during their first year, a new study finds. In a group of 109 HIV-infected and uninfected mothers and their babies in Khayelitsha, South Africa, researchers compared the antibody levels of HIV-exposed but uninfected infants to those who were unexposed to HIV. The uninfected, HIV-exposed babies were shown to have lower levels of antibodies to whooping cough, tetanus, and pneumococcus infections - all of which can be preventable through vaccination. However, these vaccines are not always available in developing countries.
"These infants and children represent a vulnerable group with increased rates of lower respiratory tract infection and meningitis and up to four-fold higher mortality in the first year of life," the study authors said. "Altered immune responses might contribute to the high morbidity and mortality observed in HIV-exposed uninfected infants."
New research has questioned the widely accepted $1.3bn average cost of R&D per new drug, claiming that it is an overestimate and an obstacle to the development of better medicines. Study author Donald Light argues the figure is an update of a 2003 paper by Joseph DiMasi et al at the Tufts Center for Drug Development, whose original $802m estimate was based on "inflationary data and assumptions."
The main criticism is that the average is based on data voluntarily provided by 10 pharma firm's which, according to Light, was not a random sample and may have been skewed towards those with highest R&D costs. Light also says that DiMasi et al failed to verify the reported costs and points out that: "Methods of identifying and counting R&D costs may changes with changes in company administrations after mergers and acquisitions."
Gilead Sciences Inc.'s Truvada topped Time magazine's list of medical breakthroughs for 2010 after a study showed it may achieve a goal pursued by scientists for a quarter-century: a pill to prevent HIV infection. Three months later, the advance has hit a wall. While study findings show the drug prevents HIV in non-infected, sexually active gay men, doctors say they're wary about giving healthy people a $12,000-a-year medicine that has side effects including nausea and kidney damage, and may not be used as regularly as needed. They also say they're not often asked to make the drug available for that use. "We're not seeing people beating down the doors," said Kenneth Mayer, medical research director and co-chair of The Fenway Institute, a clinic that serves 15,000 people in Boston, including several thousand gay men. While a few patients have asked about using Truvada for prevention, perhaps for their healthy partners, Mayer says he doesn't know any clinic doctor who has prescribed it that way. The issue is central this week at the Conference on Retroviruses and Opportunistic Infections, or CROI, a meeting for AIDS doctors that began yesterday in Boston. A dozen presentations are scheduled that will examine Truvada's long- term use in uninfected people, its' side effects and safety, the best candidates for it and the potential risk of developing drug-resistance with inconsistent use.
The medicine was Gilead's second-best selling product last year with $2.6 billion in revenue. The company plans to file for U.S. approval as a preventative in the first half of 2011, said Chief Executive Officer John C. Martin in the company's Jan. 25 earnings call. In November, soon after the study was reported, Robyn Karnauskas, a Deutsche Bank Securities analyst in New York, said the finding may add $1 billion to Truvada's sales. The shares in 2011 have risen 7.6 percent before today, compared with the S&P 500 Pharmaceutical Index, which has been little changed. Use of the drug, though, has increased only slightly, according to data compiled by Bloomberg.
The recommended two-stage HIV testing may be creating a gap that means some patients don't get timely treatment, a researcher said here. But a program of two rapid tests -- rather than a rapid test, followed by an outside confirmatory lab test -- closes the gap, according to Kevin Delaney, MPH, of the CDC. Currently, many patients don't return for the results of the confirmatory test and, although some go into care on their own, others do not, Delaney said at the Conference on Retroviruses and Opportunistic Infections. The standard testing practice, Delaney told reporters, "leaves an opportunity for people to be lost to follow-up." On the other hand, if two sequential rapid tests, which can usually be completed within an hour or so, are positive for HIV, patients can be immediately linked to care, he said, with no loss to follow-up. The two-stage testing regimen is the current CDC recommendation for practice in the U.S., Delaney told MedPage Today, but in light of a demonstration project in Los Angeles and San Francisco, the guideline is being re-examined....
... The study suggests changes that might markedly improve the chances of getting people into care, according to Susan Buchbinder, MD, of the San Francisco Department of Public Health, who moderated a press conference at which some study details were presented. "The linkage is really critical," Buchbinder told MedPage Today. "For years people had to wait two weeks to see if they were HIV infected," she said, but many would forget to return or simply be too nervous to come back. "You'd have all this testing done, but people weren't getting their results," she said, but the advent of rapid testing has the potential to change that. "In many parts of the world they do use rapid tests, and it's really time for us to move in that direction," she added.
With drug pipelines running dry and a slew of blockbuster medicines about to lose patent protection, the voices arguing that the traditional drug-development process is too expensive and inefficient to survive are getting louder. Employing thousands of in-house scientists to develop drug candidates from scratch has turned into a billion-dollar gamble that simply isn't delivering enough profitable products to market. Bernard Munos, founder of the InnoThink pharmaceutical policy research group in Indianapolis, Indiana, is not alone in believing that the next three years "will probably see an implosion of the old model" of drug discovery.
So what comes next? Cutbacks, certainly: witness Pfizer's dramatic announcement early last month that it will soon close its research site at Sandwich, UK, and slice roughly US$1.5 billion from its proposed 2012 research and development spend (see Nature 470, 154; 2011). But beyond that, perhaps, a rethink of the old divisions of labour is needed. Canny drug-makers are listening to those who propose that they should increasingly outsource early-stage drug development, including phase I safety trials, to academia or to small, specialist companies. This would leave pharmaceutical companies to focus on their strengths: running large clinical trials and marketing medicines.
A gene-therapy method that specifically disrupts a single gene may have had its first success in the clinic, potentially boosting immune-cell counts in a small number of patients with HIV. The results, presented on 28 February at the Conference on Retroviruses and Opportunistic Infections in Boston, Massachusetts, mark an important therapeutic test for enzymes known as zinc finger nucleases -- small proteins that can be designed to bind to and edit specific DNA sequences by virtue of their zinc-bearing structures. The study, a phase I safety trial, tested a zinc finger enzyme developed by Sangamo BioSciences in Richmond, California. It included six men with HIV who were already taking the standard regimen of antiretroviral drugs. The drugs had kept the virus at bay, but their immune-cell counts remained abnormally low. Researchers removed a sample of CD4+ T cells, the type of immune cells affected by HIV, from each man and used Sangamo's enzyme to disrupt the CCR5 gene, which encodes a protein that HIV uses to enter CD4+ cells. The engineered cells were then infused back into the patients. Immune-cell counts subsequently rose for five of the six patients who received the therapy. "It's very exciting," says John Rossi, a molecular biologist at the City of Hope's Beckman Research Institute in Duarte, California. "If they did this several times in a given patient, you could establish a high percentage of resistant cells."
The inspiration for targeting the CCR5 gene comes from the small percentage of people who, thanks to a natural mutation in the gene, are resistant to most types of HIV infection. At the meeting on Monday, Jacob Lalezari of Quest Clinical Research in San Francisco, California, reported that the engineered cells migrated throughout the body and thrived in the gut mucosa -- a key reservoir of HIV. No serious side effects were seen. The zinc finger nuclease technique is promising for the treatment of many diseases beyond HIV, says Patrick Aubourg, who studies gene therapy at France's national biomedical agency INSERM in Paris. The method could replace the more common technique of inserting modified genes into the genome, in which researchers have less control over the gene in question. But he cautions that the technique still has a relatively low efficiency and might have off-target effects.
A meta-analysis of five clinical trials suggests that African-American patients infected with HIV are more likely to experience virologic failure than whites after initiating antiretroviral therapy (ART), researchers said. The analysis, encompassing data from more than 2,400 ART-naive non-Hispanic white and black patients, found that the risk of having detectable HIV viremia was 40% higher among blacks than whites, said Heather Ribaudo, PhD, senior research scientist at the Harvard School of Public Health in Boston.
After 192 weeks of therapy, virologic failure emerged among 45% of black patients and 32% of the white patients, a difference that achieved statistical significance (P<0.001), Ribaudo reported here at the annual Conference on Retroviruses and Opportunistic Infections. Aside from race, other factors associated with an increased hazard of virologic failure included younger age, lower baseline CD4+ cell counts, higher baseline HIV-1 RNA levels, less education, infection with hepatitis C, and recent nonadherence. In their meta-analysis, the research team also observed that black race was associated with a modest increase of about 33 CD4+ cells/mm3 (P=0.18), a larger increase over 96 weeks than seen in whites after adjusting for pretreatment factors (including baseline CD4), although Ribaudo said that it was unlikely this would have been associated with clinically meaningful differences.
Extended follow-up of a landmark HIV prevention study is "reassuring," the lead researcher said here. The prevention tool -- a single two-drug anti-HIV pill once a day -- had a durable effect, was safe, and did not lead to drug resistance, according to Robert Grant, MD, of the University of California San Francisco. On the other hand, a small substudy suggested that the medication significantly reduced bone mineral density, although the clinical importance of the decline remains unclear, Grant and colleagues reported at the Conference on Retroviruses and Opportunistic Infections here.
The results are "mainly reassuring" for doctors and patients who are considering the approach, Grant told MedPage Today after his presentation.
Outside experts here concurred that the results support so-called pre-exposure prophylaxis -- at least in the trial population, men who have sex with men. But they cautioned that there are differences between the controlled environs of a clinical trial and the real world of clinical practice that will need to be taken into account.
The female condom, once the contraceptive that got little respect, seems to be making a comeback in U.S. cities, thanks to a new and improved design. On Valentine's Day, San Francisco's health department passed out free FC2s - short for second-generation female condom - in several neighborhoods.
That same week, Walgreens stocked about 10% of its 7,600 stores - many in cities with higher HIV rates - with three-packs.
And in Washington, where all 55 CVS stores carry it, 25,000 people used it in the past year, says Mary Ann Leeper, founder of its maker, the Female Health Co. In fact, she says, the number of FC2s distributed in the USA tripled in the past year. It's the only female condom on the U.S. market, but it's sold in more than 100 other countries and even has a Facebook fan page.
Project Ubuzima will spend the next three years conducting a research on an Anti-HIV gel for women following the approval by the Medical Ethics Committee. The vaginal gel is part of the microbicide medical products and is believed to reduce the risk of HIV infection among women.
"The proposal was approved by the Ministry of Health and the Ethics Committee. The approval was based on the evaluation of the content and methodology of the research," said Dr. Justin Wane, the Chairperson of the committee. The research is based on microbicide products that contain an ARV compound, Dapirivine that is being developed as vaginal gels, films and rings to help protect women from HIV infection during sexual intercourse.
The benefit of male circumcision for HIV prevention persists, even long after the procedure, a researcher reported here. The finding comes from surveillance after the end of one of the major trials -- in the Ugandan district of Rakai -- that first established the benefit of the procedure, according to Xiangrong Kong, PhD, of Johns Hopkins University.
Moreover, the procedure did not induce men who were circumcised to change their sexual behavior in risky ways, Kong reported at the annual Conference on Retroviruses and Opportunistic Infections. The post-trial period -- now almost five years -- "approximates" normal life and allowed researchers to see how circumcision affects both the risk of HIV and human behavior, Kong told reporters.
New research enhances the current knowledge of how human immunodeficiency virus type-1 (HIV-1), which causes AIDS, controls the cell cycle of cells that it infects. The new findings may shed light on how the virus reactivates after entering a dormant state, called latency.
"As we better understand the biological events that revive HIV from latency, we hope to devise ways to eventually intervene in this process with better treatments for people with HIV infection," said study leader Terri H. Finkel, M.D., Ph.D., chief of Rheumatology at The Children's Hospital of Philadelphia. Finkel is the senior author of a study published in the Jan. 27 issue of the journal Blood. The first author, also from Children's Hospital, is Jiangfang Wang, M.D., Ph.D. Viral latency is one of the persistent problems in treating HIV infection. Current combinations of anti-HIV drugs can reduce HIV to undetectable levels, but the virus hides in latently infected cells in a sort of hibernation. If a patient stops taking medication, or is weakened by a different infection, HIV can make a resurgence out of its viral reservoirs, often becoming resistant to previously effective drugs.
Will the FDA get an Obama-backed makeover? Before a panel meeting on jobs and competitiveness, the president said the FDA isn't up to speed on current technology, so it's not able and ready to handle current medical advances, the Financial Times reports. The White House is in the midst of a push to bolster the economy, and President Obama has promised to review government regulation as part of that effort. At the panel meeting, Obama emphasized that regulations protecting safety should stick around, but redundant rules and unnecessary red tape should go. The industry lobby PhRMA has complained of "an overdose of regulations that imperils the future growth" of the industry.
MIT engineers have designed a new type of nanoparticle that could safely and effectively deliver vaccines for diseases such as HIV and malaria. The new particles, described in the Feb. 20 issue of Nature Materials, consist of concentric fatty spheres that can carry synthetic versions of proteins normally produced by viruses. These synthetic particles elicit a strong immune response -- comparable to that produced by live virus vaccines -- but should be much safer, says Darrell Irvine, corresponding author of the paper and an associate professor of materials science and engineering and biological engineering. Such particles could help scientists develop vaccines against cancer as well as infectious diseases. In collaboration with scientists at the Walter Reed Army Institute of Research, Irvine and his students are now testing the nanoparticles' ability to deliver an experimental malaria vaccine in mice....
In tests with mice, Irvine and his colleagues used the nanoparticles to deliver a protein called ovalbumin, an egg-white protein commonly used in immunology studies because biochemical tools are available to track the immune response to this molecule. They found that three immunizations of low doses of the vaccine produced a strong T cell response -- after immunization, up to 30 percent of all killer T cells in the mice were specific to the vaccine protein....
Reference: Moon JJ, Suh H, Bershteyn A, Stephan MT, et al. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nature Materials, 2011; 10 (3): 243 DOI: 10.1038/nmat2960
The Medicines Patent Pool Initiative, set up with the aim of persuading pharmaceutical companies to waive intellectual property rights to their HIV/AIDS drugs, has announced its first possible successes. Set up by Unitaid in 2009, the pool has announced that it is in negotiations with F. Hoffman-La Roche, Gilead Sciences, Sequoia Pharmaceuticals and ViiV Healthcare (a joint venture of GlaxoSmithKline (GSK) and Pfizer). The biggest surprise is the discussions with ViiV Healthcare, said Sarah Boseley in her Guardian blog, as GSK had seemed uninterested in the concept. Although committed to improving access to its medicines in poor countries, chief executive Andrew Witty said they were taking other routes. The patent pool has listed on its website all the companies it has approached, along with the replies from those who are "less than enthusiastic", said the article.
Much-hyped tie-ups between Indian and multinational drug companies have not improved domestic research and development (R&D) capabilities, according to a study. But they have raised fears of a steady loss of domestic manufacturing capacity for the cheap drugs needed in the rest of the developing world.
Some Indian drug companies have acquired foreign firms in the past decade or agreed marketing deals to promote the products of foreign companies in India. Meanwhile, foreign companies have bought Indian firms, including Ranbaxy, Nicholas Piramal India and Shantha Biotech.
Mathematical modeling that enabled the examination of various HIV transmission-related behaviors by men who have sex with men (MSM) suggests that the possibility of HIV transmission is low -- but still possible -- even after a 12-month highly active antiretroviral therapy (HAART) regimen. Results of a study based on viral load data from nearly 1100 HIV-positive males after the initiation of HAART were presented here at the 18th Conference on Retroviruses and Opportunistic Infections.
"To halt the spread of HIV in [MSM], we have to tackle the key players in transmission: the number of susceptible individuals, the mixing patterns between infected and uninfected populations, the duration of infectiousness, the transmission probability of acquiring HIV through unprotected anal intercourse, and the sexual risk behavior in this group. We decided to move one step backward, and try to longitudinally model the relationship of the per-act and per-partnership unintended anal insertion transmission of HIV-1 RNA after HAART initiation, and the impact on HIV transmission," Vivian D. Lima, PhD, a senior statistician at the British Columbia Centre for Excellence in HIV/AIDS in Vancouver, Canada, told Medscape Medical News.
Starting antiretroviral therapy (ART) within 2 weeks of commencing treatment for tuberculosis (TB) is dramatically effective, as opposed to starting ART 8 to 12 weeks after commencing TB therapy, according to the results of a large international trial presented here at the 18th Conference on Retroviruses and Opportunistic Infections.
"In patients with a CD4 count of less than 50 cells/mm3, the proportion of patients who had AIDS-defining conditions decreased from 27% to 16% over 48 weeks [with anti-TB therapy plus immediate ART]. This is really a dramatic reduction. We absolutely need to act on these data," Diane V. Havlir, MD, chief of the HIV/AIDS division at the University of California at San Francisco, told Medscape Medical News.
The call for action is based on findings from a study by the AIDS Clinical Trial Group. The 48-week phase 4 open-label randomized study involved 806 people from 26 sites on 4 continents, and was undertaken to optimally determine when to start ART.
Antiretroviral therapy in combination with pre-exposure prophylaxis may likely have a significant impact on the prevention of HIV when compared with either strategy alone. However, overlapping agents may increase drug resistance from antiretrovirals, according to Ume Abbas, MD. Abbas, of the department of infectious disease at the Cleveland Clinic, and colleagues developed and assessed a detailed mathematical model that imitated the HIV epidemic in South Africa to predict the combined impact of ART and PrEP rollout on the spread of HIV and drug resistance between 2012 and 2022.
The model incorporated heterogeneity in sexual behavior, HIV transmission, disease progression, and emergence of drug resistance. Three different scenarios were simulated in the study: ART alone, PreP alone, and ART and PreP rollout combined. The key model outputs included incidence and prevalence of HIV, cumulative new infections prevented, and HIV drug resistance.
Delaying initiation of antiretroviral therapy would more than halve the incidence for immune reconstitution syndrome in HIV/TB patients who are not severely immuno-suppressed, according to findings from the open-label, randomized, controlled SAPiT trial.
"The current WHO guidelines recommend initiation of ART as early as possible in all TB patients--our data suggest a short delay of about 8 to 12 weeks and may be preferable in patients with higher CD4 counts in some settings," Salim Abdool Karim, MD, PhD, of the University of KwaZulu-Natal and Columbia University, said during a presentation here.
Second, third, or even fourth babies born to HIV-infected women who have access to antiretroviral treatment appear to have no greater risk of being born with HIV infection than the firstborn, researchers said here. In fact, there may even be a reduced risk, said Clare French, PhD, of the Institute of Child Health at University College London. She observed a 1.2% risk of mother-to-child-transmission among HIV-infected pregnant women having their first child, compared with a 0.6% risk among women who already had at least one child (P<0.05, in the univariate analysis; P=NS in multivariate analysis).
A new study presented Monday at the annual Conference on Retroviruses and Opportunistic Infections (CROI) in Boston suggested the potential of an anti-HIV gel in protecting rectal tissue cells from infection with the virus that causes AIDS. The gel made by Gilead Sciences Inc. contains the antiretroviral drug tenofovir, which, when applied in the vagina in previous trials, reduced HIV infection by 34% compared with placebo. Researchers have wanted to know whether the gel could protect against anal transmission of the virus, since the risk of infection from unprotected anal sex may be more than 20 times that of unprotected vaginal sex. In part, that's because the rectal wall is one-cell thick, compared with the multiple layers of vaginal walls.
For the new study, researchers from the Microbicide Trials Network, University of Pittsburgh and Magee-Womens Research Institute recruited 18 sexually abstinent HIV-negative men and women to participate. The volunteers were first asked either to apply the anti-HIV gel to the rectum once or to take an oral tenofovir pill once. Then, the patients followed up by applying either tenofovir gel or placebo gel every day for six days at home; a final, seventh dose was applied in the lab.
In a new study, scientists found that giving breastfeeding infants of HIV-infected mothers a daily dose of the antiretroviral drug nevirapine for six months halved the risk of HIV transmission to the infants at age 6 months compared with giving infants the drug daily for six weeks. The longer nevirapine regimen achieved a 75 percent reduction in HIV transmission risk through breast milk for the infants of HIV-infected mothers with higher T-cell counts who had not yet begun treatment for HIV.
"Extended breastfeeding reduces infant mortality in places that lack safe, clean water by protecting babies from common childhood diseases because breast milk contains protective antibodies from the mother that formula feeding does not provide," says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, which funds the trial.
Jay Lalezari, M.D., from the University of California-San Francisco presented first-of-its-kind data on the use of zing finger nucleases (ZFN) to artificially disrupt the CCR5 receptor on the surface of the CD4 cell, which HIV uses to infect its human host. This is an attempt to determine if genetically modifying a patient's own CD4 cells and re-infusing them could result in the population of a patient's immune system with lasting, HIV-resistant cells.
Some HIV-infected patients who have an undetectable viral load while taking HIV medications continue to have low CD4 counts. Lalezari et al decided to perform their proof-of-concept study on six of these patients: Each was on HIV antiretrovirals, had an undetectable HIV viral load, had a CD4+ cell count between 200 and 500, and had been HIV positive for more than 20 years. The patients were enrolled in one of two cohorts: in one, 10 billion total cells were modified; in the other, 20 billion. Autologous (i.e., derived from thepatient) R5-disrupted T cells were then expanded and modified with ZFNs outside the patients' bodies and re-infused. Subjects were followed weekly for one month and then monthly for 11 months post-infusion; blood and rectal mucosa samples were taken.
Immune recovery and T-cell restoration may play a key role in bone loss that occurs very soon after starting antiretroviral therapy, according to a small study presented on Tuesday at the 18th Conference on Retroviruses and Opportunistic Infections (CROI), taking place this week in Boston. A growing body of evidence shows that bone loss commonly occurs after starting HIV treatment. This has been linked to specific drugs, in particular tenofovir (Viread), but also appears to be an effect of antiretroviral therapy (ART) more generally. Most research has looked at bone loss over time, however, and there is little data about changes immediately after starting therapy.
Ighovwerha Ofotokun, from Emory University in Atlanta, and colleagues, performed human and animal studies to evaluate when ART-related bone loss occurs and what might be its underlying cause. In many diseases inflammation and T-cell activation contribute to bone loss by altering production of cytokines, or chemical messengers that affect bone build-up and breakdown. A cytokine known as RANKL stimulates osteoclasts, the cells that break down bone and promote resorption (loss and reassimilation) of its minerals, whilst a protein called osteoprotegerin binds to RANKL and protects against bone loss. As considerable CD4 T-cell recovery occurs during the first 12 weeks on ART, the researchers looked at bone changes during this period. Most prior studies, in contrast, have looked at bone loss after six months or more. Their first analysis included 20 HIV-positive individuals with an average age of 40 who started antiretroviral drugs for the first time. The mean CD4 count at the beginning of treatment was quite low, at 123 cells/mm3.
HIV-positive people who lose muscle mass in their arms and legs whilst gaining abdominal fat have a higher likelihood of death, according to findings from the FRAM study presented on Tuesday at the 18th Conference on Retroviruses and Opportunistic Infections(CROI), taking place this week in Boston. But the common measure of body massindex (BMI) may fail to capture this increased risk. Unintended weight loss and loss of lean muscle due to disease or aging are known risk factors for mortality. While many studies have looked at body fat changes in people with HIV, less is known about changes in muscle mass.
Rebecca Scherzer from the University of California at San Francisco and colleagues looked at muscle loss, subcutaneous fat loss, and central or abdominal fat gain (reflecting visceral fat around the internal organs) as predictors of death among people with HIV. The researchers performed whole-body magnetic resonance imaging (MRI) on nearly 1200 HIV-positive participants in the FRAM (Fat Redistribution and Metabolic Change in HIV Infection) study. About two-thirds were men and the average age was just over 40 years. The mean BMI was about 25, the threshold for classification as "overweight". Looking at all-cause mortality over five years, the investigators found that decreased muscle tissue in the arms and legs, as well as increased belly fat, were strong and consistent predictors of mortality, even after controlling for other risk factors. After adjusting for demographic factors, cardiovascular risk factors, HIV-related factors including CD4 cell count and viral load, kidney disease, and inflammation markers, people with the lowest arm or leg muscle mass had approximately twice the risk of death, as did those with the most visceral fat. The researchers calculated that having the lowest level of arm muscle mass could account for 15% of excess mortality in people with HIV, or about two extra deaths over five years. Having the lowest leg mass could account for one additional death. Contrary to expectations, however, peripheral lipoatrophy, or loss of fat in the arms and legs, was not associated with higher mortality. "Lower muscle mass and central adiposity appear to be important risk factors for mortality in HIV-infected individuals," the FRAM researchers concluded.
Merck & Co. Inc., Tuesday announced new findings from the ongoing STARTMRK clinicaltrial in previously untreated adult patients infected with HIV-1. Merck reported that patients maintained undetectable viral loads and increases in CD4 cell counts at three years of treatment with Isentress tablets in combination therapy, comparable to treatment with efavirenz in combination therapy. The new data demonstrated that the antiviral efficacy and safety profile of Isentress seen at weeks 48 and 96 of treatment in this study were sustained through week 156. Additionally, Isentress in combination therapy demonstrated less impact on lipids and triglycerides at week 144. The data was presented by Dr. Juergen Rockstroh, University of Bonn, Bonn-Venusberg, Germany, at the Conference on Retroviruses and Opportunistic Infections in Boston. Rockstroh said, "These three-year results for ISENTRESS reinforce what we saw previously at week 96 with sustained decreases in HIV-1 viral loads and increases in CD4 cell counts."
Prompted by concerns about an unethical U.S.-sponsored study in the 1940s, bioethics advisers to President Barack Obama formed an international panel today that will examine whether current rules adequately protect volunteers in global clinical trials. A historian at Wellesley College shocked the nation last October with the revelation that, from 1946 to 1948, a U.S. Public Health Service researcher deliberately exposed Guatemalan prisoners, soldiers, and others to syphilis and gonorrhea. The experiments drew comparisons with Tuskegee, the notorious 40-year study in Alabama begun in 1932 in which U.S. researchers allowed hundreds of African-American men with syphilis to go untreated.
In response, President Obama asked his Presidential Commission for the Study of Bioethical Issues to examine whether "current rules for research participants protect people from harm or unethical treatment, domestically as well as internationally." Obama also asked the Institute of Medicine (IOM) to investigate the Guatemala study. But that fact-finding job also fell to the bioethics commission after IOM realized that five of its members had been involved in the study. The commission is chaired by University of Pennsylvania President Amy Gutmann and vice-chaired by Emory University President James Wagner.
Elite suppressors (ES) are a rare population of HIV-infected individuals that are capable of naturally controlling the infection without the use of highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods to measure viral burden are needed to elucidate important differences between these two patient populations in order to better understand their mechanisms of control. Viral burden quantification in ES patients has been limited to measurements of total DNA in PBMC, and estimates of Infectious Units per Million cells (IUPM). There appears to be no significant difference in the level of total HIV DNA between cells from ES patients and patients on HAART. However, recovering infectious virus from ES patient samples is much more difficult, suggesting their reservoir size should be much smaller than that in patients on HAART. Here we find that there is a significant difference in the level of integrated HIV DNA in ES patients compared to patients on HAART, providing an explanation for the previous results. When comparing the level of total to integrated HIV DNA in these samples we find ES patients have large excesses of unintegrated HIV DNA. To determine the composition of unintegrated HIV DNA in these samples, we measured circular 2-LTR HIV DNA forms and found ES patients frequently have high levels of 2-LTR circles in PBMC. We further show that these high levels of 2-LTR circles are not the result of inefficient integration in ES cells, since HIV integrates with similar efficiency in ES and normal donor cells. Our findings suggest that measuring integration provides a better surrogate of viral burden than total HIV DNA in ES patients. Moreover, they add significantly to our understanding of the mechanisms that allow viral control and reservoir maintenance in this unique patient population.
We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.
Background: Injection drug use (IDU) and heterosexual virus transmission both contribute to the growing mixed HIV epidemics in Eastern Europe and Central Asia. In Ukraine--chosen in this study as a representative country--IDU-related risk behaviors cause half of new infections, but few injection drug users (IDUs) receive methadone substitution therapy. Only 10% of eligible individuals receive antiretroviral therapy (ART). The appropriate resource allocation between these programs has not been studied. We estimated the effectiveness and cost-effectiveness of strategies for expanding methadone substitution therapy programs and ART in mixed HIV epidemics, using Ukraine as a case study.
Methods and Findings: We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs using opiates, and IDUs on methadone substitution therapy, stratified by HIV status, and populated it with data from the Ukraine. We considered interventions expanding methadone substitution therapy, increasing access to ART, or both. We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost-effectiveness. Without incremental interventions, HIV prevalence reached 67.2% (IDUs) and 0.88% (non-IDUs) after 20 years. Offering methadone substitution therapy to 25% of IDUs reduced prevalence most effectively (to 53.1% IDUs, 0.80% non-IDUs), and was most cost-effective, averting 4,700 infections and adding 76,000 QALYs compared with no intervention at US$530/QALY gained. Expanding both ART (80% coverage of those eligible for ART according to WHO criteria) and methadone substitution therapy (25% coverage) was the next most cost-effective strategy, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy and averting 8,300 infections versus no intervention. Expanding only ART (80% coverage) added 38,000 QALYs at US$2,240/QALY gained versus the methadone substitution therapy-only strategy, and averted 4,080 infections versus no intervention. Offering ART to 80% of non-IDUs eligible for treatment by WHO criteria, but only 10% of IDUs, averted only 1,800 infections versus no intervention and was not cost effective.
Conclusions: Methadone substitution therapy is a highly cost-effective option for the growing mixed HIV epidemic in Ukraine. A strategy that expands both methadone substitution therapy and ART to high levels is the most effective intervention, and is very cost effective by WHO criteria. When expanding ART, access to methadone substitution therapy provides additional benefit in infections averted. Our findings are potentially relevant to other settings with mixed HIV epidemics.
Background: Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting.
Methods and Findings: A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naive individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49-1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA greater than or equal to 5,000 copies/ml) (HR 0.41; 95% CI 0.21-0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65-1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53-1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution.
Conclusions: Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.
GS-8374 is a novel bis-tetrahydrofuran HIV-1 protease inhibitor (PI) with a unique diethylphosphonate moiety. It was selected from a series of analogs containing various di(alkyl)phosphonate substitutions connected via a linker to the para-position of a P1 phenyl ring. GS-8374 inhibits HIV-1 protease (PR) with high potency (Ki = 8.1 pM) with no known effect on host proteases. Kinetic and thermodynamic analysis of GS-8374 binding to PR demonstrated an extremely slow off-rate for the inhibitor and favorable contributions of both the enthalpic and entropic components to the total free binding energy. GS-8374 showed potent antiretroviral activity in T-cell lines, primary CD4(+) T-cells (EC50 = 3.4 to 11.5 nM), and macrophages (EC50 = 25.5 nM), and exhibited low cytotoxicity in multiple human cell types. Antiviral potency of GS-8374 was only moderately affected by human serum protein binding and its combination with multiple approved antiretrovirals showed synergistic effects. When tested in a PhenoSense(TM) assay against a panel of 24 patient-derived viruses with high-level PI resistance, GS-8374 showed lower mean EC50 values and lower fold resistance than any of the clinically approved PIs. Similar to other PIs, in vitro hepatic microsomal metabolism of GS-8374 was efficiently blocked by ritonavir, suggesting a potential for effective pharmacokinetic boosting in vivo. In summary, results from this broad in vitro pharmacological profiling indicate that GS-8374 is a promising candidate to be further assessed as a new antiretroviral agent with potential for clinical efficacy in both treatment-naive and -experienced patients.
Background: Bacteria and yeasts isolated from respiratory tracts of 39 Cambodian and 28 Kenyan HIV-positive children were tested for the presence of HIV-1 sequences.
Material/Methods: Bacteria and yeasts from the respiratory tract (nose, pharyngeal swabs) were isolated from 39 Cambodian and 28 Kenyan HIV-positive children. Bacterial chromosomal DNA was prepared by standard protocol and by Qiagen kit. The PCR specific for HIV sequences was carried out using HIV-1-specific primers.The analysis was performed by colony and dot-blot hybridization using HIV-1-specific primers which represent gag, pol and env genes of the virus. The sequencing of some PCR products was performed on the ABI 373 DNA Sequencer.
Results: The majority of microbes were characterized as Staphylococcus aureus, Klebsiella pneumoniae, and resp. Candida albicans. In some cases E. coli, Streptococcus pyogenes, Proteus mirabilis and Candida tropicalis were identified. Bacteria of 16 Cambodian (41%) and 8 Kenyan (31%) children were found to be positive in colony and dot-blot DNA hybridization. By the sequencing of PCR products synthesized on the template of patients' bacterial DNA using primers 68;69 for env HIV-1 gene, homology of greater than 90% with HIV-1 isolate HXB2 (HIVHXB2CG) was revealed.
Conclusions: Bacteria and yeasts from the respiratory tract of 41% of Cambodian and 31% of Kenyan HIV-positive children bear HIV-like sequences. The role of bacteria in the HIV disease process is discussed.
If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B*27, B*57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.
The European Medicines Authority (EMA) has issued a concept paper on matters to be taken into account when considering European licensing/change of indication for microbicides and for drugs used as PrEP. The paper was prompted in part by community pressure from advocates.
The SLDF addresses contemporary sexuality issues and emerging best practice in policy and programming for sexual well-being in Africa. The curriculum will focus on sexuality, sexual health and rights, sexual diversity, pleasure, HIV/AIDS and vulnerabilities, gender and violence against women.