Daily Dose of HIV Drug Reduces Risk of HIV Infection

A daily dose of an oral antiretroviral drug, currently approved to treat HIV infection, reduced the risk of acquiring HIV infection by 43.8 percent among men who have sex with men. The findings, a major advance in HIV prevention research, come from a large international clinical trial published online Nov. 23 by the New England Journal of Medicine. The study, titled “Chemoprophylaxis for HIV Prevention in Men,” found even higher rates of effectiveness, up to 72.8 percent, among those participants who adhered most closely to the daily drug regimen.

“We now have strong evidence that pre-exposure prophylaxis with an antiretroviral drug, a strategy widely referred to as PrEP, can reduce the risk of HIV acquisition among men who have sex with men, a segment of the population disproportionately affected by HIV/AIDS,” says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. “Additional research is needed, but certainly this is an important finding that provides the basis for further investigating, developing and employing this prevention strategy, which has the potential to make a significant impact in the fight against HIV/AIDS.”

“No single HIV prevention strategy is going to be effective for everyone,” adds Dr. Fauci, “and it is important to note that the new findings pertain only to the effectiveness of PrEP among men who have sex with men and cannot at this point be extrapolated to other populations. Therefore, we must continue to conduct PrEP research among other study populations, such as women and heterosexual men, to provide a comprehensive picture of its potential utility as an HIV prevention tool.”

NIAID sponsored the study, also known as iPrEx, through a grant to the J. David Gladstone Institutes, a non-profit independent research organization affiliated with the University of California at San Francisco. Additional study funding was provided by the Bill & Melinda Gates Foundation. Gilead Sciences, based in Foster City, Calif., donated the study drug.

Led by study chair Robert M. Grant, M.D., of the Gladstone Institute of Virology and Immunology, and study co-chair Javier R. Lama, M.D., of Investigaciones Medicas en Salud, a Peruvian-based research organization, the iPrEx study enrolled a total of 2,499 men who have sex with men and transgendered women who have sex with men. All participants were at least 18 years old and HIV-negative at time of enrollment. The study, which began in June 2007, was conducted at 11 sites in Brazil, Ecuador, Peru, South Africa, Thailand and the United States.

The study participants were randomly assigned to receive either a daily antiretroviral tablet containing combination emtricitabine (FTC 200 milligrams) and tenofovir (TDF 300 milligrams), known by the brand name Truvada, or a placebo pill. Before enrollment, all participants received detailed information about the possible risks and benefits of participating in the trial. Once enrolled, they were evaluated for HIV infection monthly for the duration of their participation in the study. The average enrollment was 1.2 years. In addition, all participants were routinely counseled about safe sex practices and provided condoms and treatment for other sexually transmitted infections.

In the final analysis, 100 cases of HIV infection occurred among participants in the iPrEx study. Of those, 36 HIV infections occurred among the 1,251 participants who received the antiretroviral therapy compared with 64 HIV infections among the 1,248 participants who received the placebo. This level of effectiveness in reducing the risk of HIV infection, 43.8 percent, is statistically significant. Furthermore, the drug’s ability to reduce the risk of HIV acquisition was greater among those volunteers who were more adherent to the daily drug regimen. Participants who took the drug on 50 percent or more days as measured by pill count, bottle count and self reporting experienced 50.2 percent fewer HIV infections. Those who took the drug on 90 percent or more days had 72.8 percent fewer HIV infections.

The researchers concluded that consistent with earlier, smaller studies leading up to this trial, Truvada appeared to be safe and well-tolerated for its use in the iPrEx study. Side effects were mild and infrequent and included a small number of participants with transient nausea and mild elevations in creatinine, a naturally occurring molecule filtered by the kidneys. These elevations resolved spontaneously or with discontinuation of the drug. Additionally, very little drug resistance occurred with no instances of tenofovir resistance and three cases of emtricitabine resistance (one participant in the placebo group; two participants in the active drug group). The two cases of emtricitabine in the active drug group occurred among individuals who were in the stages of acute HIV infection at the time of enrollment, but who tested negative for HIV. Both groups of study participants reported a decrease in the number of sexual partners and increased condom use.

“The iPrEx study provides important evidence that PrEP works to reduce HIV infection risk among gay and bisexual men,” says Dr. Grant. “The need for new HIV prevention methods is critical. PrEP, in combination with other prevention methods, such as HIV testing, counseling and consistent condom use, could represent a major step forward for efforts to control the global epidemic.”

Correct and consistent condom use and a reduced number of sexual partners remain the most effective ways for gay and bisexual men to protect against HIV infection.

“A variety of expert and community advisory groups at the federal, state and local levels are looking closely at the study data and will move forward in a deliberative and measured way over the coming months to determine whether and how these findings should be incorporated into ongoing HIV prevention programs,” says Howard K. Koh, M.D., assistant secretary for health at the U.S. Department of Health and Human Services.

Participants in the iPrEx study are being informed of the results and counseled on the need to continue safe sex practices. Individuals who acquired HIV infection during the study were referred to appropriate medical care. Investigators will conduct a follow-on study in which all HIV-negative iPrEx participants will be offered the combination drug for 18 months. That study, which will begin in 2011, is designed to provide additional information about the drug’s long-term effectiveness and safety as well as participant risk behavior and pill-taking practices.

The NIAID-sponsored VOICE study, which launched in Sept. 2009, is examining three different, once-daily HIV prevention strategies in women: a combination pill, a pill containing only tenofovir, and a tenofovir-based vaginal gel. The study is expected to enroll as many as 5,000 women in three African countries, and results are expected in 2013.

For additional information about the iPrEx study, see the Questions and Answers and and visit the iPrEx News Web site. Visit theNIAID HIV/AIDS portal for more information about NIAID’s HIV/AIDS research.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of  preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH)—The Nation’s Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov

Photo: Natalie Bailey/IRIN

Thailand has the highest HIV prevalence in Southeast Asia

The first locally acquired case of dengue fever in Miami-Dade County in more than 50 years was confirmed Thursday by health officials. They warned people countywide to take precautions against the human-loving mosquitoes that carry it.

“This is a big deal,” said Lillian Rivera, administrator of the Miami-Dade Health Department.

“We have not had a locally acquired case of dengue fever since the 1950s,” said Dr. Fermin Leguen, the department’s chief epidemiologist.

The victim, identified only as a man who had not traveled outside Miami-Dade County for more than two weeks, was briefly hospitalized but has fully recovered, Rivera said. His case was confirmed by laboratory tests. Health officials said they don’t know where the man acquired the painful but seldom fatal disease. Dengue fever has been on the rise in Florida for two years. Key West has reported 57 locally acquired cases in 2009 and 2010. One locally acquired case was reported in Broward in August.

The new Miami-Dade case was a different strain from those in Key West and Broward, so was not acquired there, Leguen said.

The fact that the new case was contracted locally means it apparently was the result of a bite of a mosquito that had bitten another Dade resident who was infected, health officials said. The disease does not pass from mosquito to mosquito.

It raises questions about whether the disease might become endemic — occurring widely in a local area and feeding upon itself. Miami-Dade health officials also reminded the public that the Florida-wide alert issued in July about Eastern Equine Encephalitis — spread by a different mosquito — has not been lifted, with four nonfatal human cases reported over the summer in Hillsborough, Wakulla and Leon counties.

Leguen also repeated the warning to local doctors and hospitals to be on the lookout for cholera cases that might be spread by travelers returning from Haiti, where a cholera epidemic has killed more than 600 people.

And Rivera said there is a growing efforts to handle an outbreak of hookworm spreading in the sand along the Atlantic Ocean between 40th Street and 60th street in Miami Beach. Six human cases have been reported of the disease, which Leguen said is spread primarily by the feces of dogs and cats.

She said county crews are cleaning the beaches, and a multicity task force is studying ways to keep cats and dogs under better control.

Asked if her department feels it’s under siege, Rivera said, “It’s just part of living. We’re ready 24/7 to deal with all that Mother Nature has thrown at us.”

The new dengue fever case occurred in a densely populated area of 77 properties somewhere in Miami-Dade County, said county Mosquito Control Director Sandra Fisher.

County crews have gone house to house with handheld sprayers and have emptied bird baths, rain-filled tires, stagnant pools and even bottle caps filled with water, she said.

Removing stagnant water is more effective than spraying from trucks, she said, because the Aedes aegypti mosquito that carries the dengue virus from one human to others seeks close contact with humans.

She urged residents to remove stagnant water sources in their own yards.

“This mosquito lives and breathes around people,” she said. “It actually flies into houses looking for a blood meal so it can lay eggs. So checking yards is our first line of prevention.

Said Rivera: “This is everywhere in Dade County. Everyone should consider themselves at risk no matter where they live.”

http://www.iavi.org/research-development/IAVI-RD-Programs/Pages/NewAntibodiesFoundthatCrippleHIV.aspx

IAVI and affiliated researchers have discovered two powerful new antibodies to HIV that reveal what may be an Achilles heel on the virus. The findings are the result of a worldwide effort launched by IAVI in 2006 to find new antibodies that neutralize a wide variety of strains of HIV circulating in the world. The study was published in the journal Science.

HIV, the virus that causes AIDS, is the most mutable pathogen ever encountered by modern science. It changes at a furious rate, which helps it evade the body’s immune system. Today, countless variations of the virus infect people around the world. To be effective an AIDS vaccine would have to work against many versions of HIV.

The two new broadly neutralizing antibodies are the first to be discovered in more than a decade, and the first to be isolated from donors in developing countries where the pandemic is raging. Now researchers will try to exploit the newfound vulnerability on the virus to craft new approaches to designing an AIDS vaccine.

 “The findings are an exciting advance because now we’ve got a new, potentially better target on HIV to focus our efforts for vaccine design,” said Wayne Koff, senior vice president of research and development at IAVI. “And having identified this one, we’re set up to find more.”

What are broadly neutralizing antibodies?

Antibodies are infection-fighting protein molecules that tag, neutralize and help destroy toxins and invading pathogens. They are secreted by immune cells known as B lymphocytes (a kind of white blood cell) in response to stimulation by antigens, which are molecules found on the invading pathogen. Each antibody binds only to the specific antigen that stimulated its production. HIV attacks and quickly overwhelms the body’s immune system, but a minority of people naturally produce broadly neutralizing antibodies—ones that target multiple strains of HIV and prevent the virus from infecting cells. Isolating these antibodies gives vaccine researchers valuable insight into fighting the virus.

Why is this discovery important?

Before this discovery, researchers had found just four antibodies widely considered to be broadly neutralizing, and those four were associated with a strain of the virus circulating primarily in the Americas, Europe and Australia. The new antibodies came from a donor in the developing world, where 95% of new infections occur.

They also reveal a new vulnerable spot on HIV, binding to a potentially easier-to-reach patch on the virus that no previously known antibodies targeted. This is extremely important—it provides a new target for vaccine designers to exploit. And the antibodies appear to be highly potent as well, which means they bind to the virus tightly.  This is important because—if they can be elicited by vaccination—the body might not have to produce large amounts of the antibodies to gain protection from HIV.

What’s the next step?

The new antibodies will now be closely studied by researchers in IAVI’s Neutralizing Antibody Consortium, who will work out the molecular structure and the precise mechanism by which the antibodies bind to HIV. With this information in hand, they will begin working to design novel immunogens—the active ingredient in vaccines—to elicit these antibodies in all people. If they succeed, the immunogens will be put through the preclinical process to produce an industrially viable vaccine candidate for further development.

 How were the antibodies found?

The discovery of the new antibodies is the result of a global collaboration among IAVI, the Scripps Research Institute, private biotech firms and more than a dozen clinical research centers around the world.  Learn more