The clinical trial, known as HPTN 052, was slated to end in 2015, but the findings were released earlier this month, after a scheduled interim review of the study data by an independent data and safety monitoring board (DSMB) concluded it was overwhelmingly clear that such use of antiretrovirals substantially reduced virus transmission.
The results are the first from a major randomized clinical trial to indicate that treating HIV-infected individuals can reduce the risk of sexual transmission of the virus to an uninfected partner.
The study was conducted by the HIV Prevention Trials Network, which is largely funded by NIAID, with additional funding from the National Institute on Drug Abuse and the National Institute of Mental Health, both part of the NIH. Additional support was provided by the NIAID-funded AIDS Clinical Trials Group.
“The results of HPTN 052 are extraordinary news for HIV prevention efforts worldwide,” said study co-chair Dr. Karin Nielsen, a professor of pediatric infectious diseases at the David Geffen School of Medicine at UCLA
and a member of the UCLA AIDS Institute
. “Most new HIV infections worldwide tend to happen to individuals in stable relationships. A 96 percent reduction in the risk of HIV transmission is one of the most dramatic successes in HIV prevention reported to date.
Previous data about the potential value of antiretrovirals in making HIV-infected individuals less infectious to their sexual partners came largely from observational and epidemiological studies, according to NIAID director Dr. Anthony S. Fauci.
“This new finding convincingly demonstrates that treating the infected individual — and doing so sooner rather than later — can have a major impact on reducing HIV transmission,” he said.
Led by study chair Dr. Myron Cohen, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina–Chapel Hill, HPTN 052 began in April 2005 and enrolled 1,763 couples, all at least 18 years of age. The vast majority of the couples (97 percent) were heterosexual, which precludes any definitive conclusions about effectiveness in men who have sex with men.
The study was conducted at 13 sites in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the United States and Zimbabwe. While the U.S. site collected only limited data because of difficulties enrolling participants into the study, data from one serodiscordant couple at the site was included in the DSMB’s analysis.
At the time of enrollment, the HIV-infected partners (890 men, 873 women) had CD4+ T cell levels — a key measure of immune system health — between 350 and 550 cells per cubic millimeter within 60 days of entering the study. The uninfected partners had tested negative for the virus within 14 days of entering the study.
The investigators randomly assigned the couples to one of two study groups. In the first group, the HIV-infected partner immediately began taking a combination of three antiretroviral drugs. In the second group — the deferred group — the HIV-infected partners began antiretroviral therapy when their CD4 counts fell below 250 cells per cubic millimeter or an AIDS-related event such as pneumocystis pneumonia occurred.
Throughout the study, both groups received HIV-related care that included counseling on safe-sex practices, free condoms, treatment for sexually transmitted infections, regular HIV testing, and frequent evaluation and treatment for any complications related to HIV infection. Each group received the same amount of care and counseling.
In addition, the researchers explained all risks to the study participants and listed those risks in the informed consents the subjects signed.
In its review, the DSMB found a total of 39 cases of HIV infection among the previously uninfected partners. Of those, 28 were linked through genetic analysis to the HIV-infected partner as the source of infection. Seven infections were not linked to the HIV-infected partner. Four infections are still undergoing analysis. Of the 28 linked infections, 27 occurred among the 877 couples in which the HIV-infected partner did not begin antiretroviral therapy immediately.
Only one case of HIV infection occurred among those couples in which the HIV-infected partner began immediate antiretroviral therapy. This finding was statistically significant and means that earlier initiation of antiretrovirals led to a 96 percent reduction in HIV transmission to the uninfected partner. Infections were confirmed by genetic analyses of viruses from both partners.
Additionally, 17 cases of extrapulmonary tuberculosis occurred in the HIV-infected partners in the deferred treatment arm, compared with three cases in the immediate treatment arm, a statistically significant difference. There were also 23 deaths during the study. Ten occurred in the immediate treatment group and 13 in the deferred treatment group, a difference that did not reach statistical significance.
UCLA’s Nielsen joined the project in 2002, when the protocol for the trial was under development and site selection was beginning. She was responsible for inclusion of the Brazilian sites — three in Rio de Janeiro and one in Porto Alegre. The UCLA–Brazil team developed the clinical trials infrastructure, trained staff and assisted in data management, laboratory capacity-building, protocol development and implementation.
“This was an extremely well-thought-out and detailed study, coordinated by Family Health International and supported by the NIAID,” Nielsen said. “More than 500 subjects were enrolled in Brazil, and the sites did a fantastic job in retaining the study population with excellent study follow-up.”
The study was designed to evaluate the effect of antiretroviral treatment on virus transmission, as well as how such treatent potentially benefited the HIV-infected individual. Additionally, the study sought to evaluate the optimal time for a person infected with HIV to initiate antiretrovirals in order to reduce HIV-related sickness and death. Based on their analysis, the DSMB recommended that the deferred study arm be discontinued and that the study participants be informed of the trial’s outcome.
“We want to thank the study participants for making such an important contribution in the fight against HIV/AIDS,” Cohen, the study chair, said. “We think that these results will be important to help improve both HIV treatment and prevention.”
Study participants are being informed of the results. Individuals who became HIV-infected during the course of the study were referred to local services for appropriate medical care and treatment. HIV-infected participants in the deferred treatment group will be offered antiretroviral therapy. The study investigators will continue following the study participants for at least one year.
The antiretroviral drugs used in the study were made available by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals Inc., Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/Viiv Healthcare and Merck & Co. Inc.
The 11 HIV drugs that were used in various combinations and dosages included the following:
- emtricitabine/tenofovir disoproxil fumarate
- tenofovir disoproxil fumarate
In an ongoing international clinical study called Strategic Timing of Antiretroviral Therapy, NIAID is examining the optimal time for asymptomatic HIV-infected individuals to begin antiretrovirals.
The NIAID conducts and supports research — at the NIH, throughout the U.S. 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 website at www.niaid.nih.gov
The UCLA AIDS Institute
, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social sciences, public health, nursing and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer.