Antiretroviral treatment that consistently suppresses HIV is highly effective at preventing sexual transmission of the virus in heterosexual couples where one person is HIV-infected and the other is not, investigators report today at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment & Prevention (IAS 2015) in Vancouver, Canada. The finding comes from the decade-long HPTN 052 clinical trial funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted by the NIH-funded HIV Prevention Trials Network (HPTN).
In 2011, the HPTN 052 study investigators reported a breakthrough: Starting HIV treatment early, when the immune system is relatively healthy, reduced the risk of sexually transmitting the virus to an uninfected partner by 96 percent over 18 months. Based on additional data gathered since 2011, today's finding unequivocally demonstrates the enduring power of HIV-controlling antiretroviral therapy to greatly reduce sexual transmission of the virus.
The study now makes crystal clear that when an HIV-infected person takes antiretroviral therapy that keeps the virus suppressed, the treatment is highly effective at preventing sexual transmission of HIV to an uninfected heterosexual partner," said NIAID Director Anthony S. Fauci, M.D. "For heterosexuals who can achieve and maintain viral suppression, the risk to their partners is exceedingly low."
The HPTN 052 trial was designed to evaluate whether antiretroviral therapy reduces sexual transmission of HIV. Beginning in April 2005, the study enrolled 1,763 heterosexual couples ages 18 or older in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the United States and Zimbabwe. Each couple included one partner with HIV infection and one without. Infected participants were assigned at random either to start antiretroviral therapy right away, while their immune system was relatively healthy, or to delay starting treatment until their immune system weakened or they developed an AIDS-defining illness, consistent with World Health Organization guidelines at the time. All participants received condoms and counseling on how to protect their partners from sexual transmission of HIV.
Once the investigators reported their landmark data in 2011, all infected study participants were offered the opportunity to begin antiretroviral therapy right away, and the trial continued for another four years, concluding this spring. At the end of the study, 1,171 couples remained in the trial.
Investigators report today that starting antiretroviral therapy early reduced HIV transmission by 93 percent over the course of the study. Only eight cases of HIV transmission occurred in uninfected partners of HIV-infected participants who received antiretroviral therapy. Four of these infections were diagnosed shortly after the start of treatment. In these cases, the virus most likely was transmitted just before antiretroviral therapy began or right after it commenced, before treatment had fully suppressed HIV replication. The other four infections occurred in study participants for whom treatment no longer was working and the virus was replicating. Treatment failure may have occurred because HIV-infected participants did not take their antiretroviral drugs as prescribed or had an HIV strain that was resistant to one or more of the drugs in their treatment regimen.
The lack of sexual transmission of HIV by virally suppressed individuals in this large study provides robust evidence that antiretroviral therapy started at any time in the course of infection can prevent heterosexual HIV transmission if viral suppression is achieved and maintained, the investigators note.
"Throughout our decade-long study with more than 1,600 heterosexual couples, we did not observe HIV transmission when the HIV-infected partner's virus was stably suppressed by antiretroviral therapy," said Myron Cohen, M.D., the study's principal investigator. Dr. Cohen is Associate Vice Chancellor for Global Health at the University of North Carolina at Chapel Hill and director of the university's Institute for Global Health and Infectious Diseases. "These findings illustrate that treatment is an incredibly powerful tool for HIV prevention."
HPTN 052 investigators also are reporting findings today about relationships between viral load, viral suppression, treatment failure and drug resistance. The researchers found that having a relatively high level of HIV in the blood at the start of therapy was associated with a longer time to viral suppression, which, in turn, was associated with both the occurrence of treatment failure and a shorter time to treatment failure. Thus, having a relatively high viral load at the start of treatment could increase the risk for HIV transmission, the scientists suggest.
In addition, the investigators found that among the HPTN 052 participants who started antiretroviral therapy early but failed treatment before May 2011, those who had a higher viral load when they joined the study were likely to develop resistance to their antiretroviral drugs. Additional analysis is needed to clarify this association, according to the investigators.
The HPTN conducted the trial with funding from NIAID, the National Institute on Drug Abuse and the National Institute of Mental Health, all part of NIH, through grant number 5-UM1-AI068619. Additional support was provided by the NIH-funded AIDS Clinical Trials Group.
For more information about the HPTN 052 trial, please see Questions and Answers: The HPTN 052 Study: Preventing Sexual Transmission of HIV with Anti-HIV Drugs below. Information is also available in ClinicalTrials.gov under study identifier NCT00074581.
Question & Answer:
The HPTN 052 Study: Preventing Sexual Transmission of HIV with Anti-HIV Drugs
The HPTN 052 study is a Phase III randomized clinical trial with the primary objective of evaluating whether antiretroviral drugs, which are mainly licensed to treat HIV infection, can prevent the sexual transmission of HIV among couples in which one partner is HIV-infected and the other is not (serodiscordant couples). Additionally, the study was designed to evaluate the optimal time to begin antiretroviral therapy in order to reduce illness and death among people infected with HIV.
The study was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The trial was led by protocol chair Myron Cohen, M.D., Associate Vice Chancellor for Global Health at the University of North Carolina at Chapel Hill and director of the university’s Institute for Global Health and Infectious Diseases. The study was conducted by the HIV Prevention Trials Network (HPTN), 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 NIH. Additional support was provided by the NIH-funded AIDS Clinical Trials Group.
A total of 1,763 serodiscordant couples participated in the study. Each participant was at least 18 years of age; the median age of the study population was 33. The vast majority of the couples (97 percent) were heterosexual. At the time of enrollment, the HIV-infected participants (890 men, 873 women) had CD4+ T-cell counts, a key measure of immune system health, between 350 and 550 cells per cubic millimeter (mm3) within 60 days of entering the study. The median CD4 count at study entry was 436 cells/mm3. The HIV-uninfected partners tested negative for the virus within 14 days of entering the study.
The study took place at 13 sites in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the United States and Zimbabwe. The trial began in April 2005. Enrollment ended in May 2010, and the study concluded in May 2015.
Participating couples were randomly assigned to one of two treatment groups. In the first group, the HIV-infected participants immediately began taking a combination of three antiretroviral drugs. In the second group, the HIV-infected participants delayed taking antiretroviral drugs until either their CD4 counts fell below 250 cells/mm3 or they were diagnosed with an AIDS-related illness, as defined by World Health Organization guidelines. All participants in both groups received counseling on safe sex practices, free condoms, treatment for sexually transmitted infections, frequent HIV testing, and evaluation and treatment for any complications related to HIV infection.
HPTN 052 participants were given a combination three- or four-drug regimen using the following 11 HIV drugs:
- Atazanavir (300 mg once daily)
- Didanosine (400 mg once daily)
- Efavirenz (600 mg once daily)
- Emtricitabine/tenofovir disoproxil fumarate (200 mg emtricitabine/300 mg tenofovir disoproxil fumarate once daily)
- Lamivudine (300 mg once daily)
- Lopinavir/ritonavir 800/200 mg daily (Qday) or lopinavir/ritonavir 400/100 mg twice daily (BID)
- Nevirapine (200 mg taken once daily for 14 days followed by 200 mg taken twice daily)
- Ritonavir (100 mg once daily, used only to boost atazanavir)
- Stavudine (weight-dependent dosage)
- Tenofovir disoproxil fumarate (300 mg once daily)
- Zidovudine/lamivudine (150 mg lamivudine/300 mg zidovudine taken orally twice daily)
In April 2011, the HPTN 052 investigators discovered that starting HIV treatment early, when the immune system is relatively healthy, reduced the risk of sexually transmitting the virus to an uninfected partner by 96 percent over 18 months.
The study participants were informed of the findings in May 2011, and all HIV-infected participants were offered the opportunity to begin antiretroviral therapy immediately, regardless of CD4 count. The trial continued for another four years, concluding in May 2015. By the end of the study, 98 percent of HIV-infected participants had started antiretroviral therapy and 1,171 couples remained in the trial.
The investigators observed a total of 78 new HIV infections among the originally uninfected partners. Cases where the HIV-infected study participant was the likely source of his or her partner’s infection, as determined by specialized laboratory testing, were classified as linked. Overall, 46 of the 78 partner infections were linked.
Of the 46 linked HIV infections, 43 occurred among couples in which the HIV-infected partner delayed antiretroviral treatment, and three occurred among couples in which the HIV-infected partner began immediate antiretroviral treatment. This means that starting antiretroviral therapy early reduced HIV transmission by 93 percent over the course of the entire study.
A more detailed analysis of linked HIV transmissions that were diagnosed after the infected participant began antiretroviral therapy revealed critical information about the power of antiretroviral treatment to prevent HIV infection.
A total of eight linked cases of HIV transmission occurred in the uninfected partners of HIV-infected participants who received antiretroviral therapy. Four of these infections were diagnosed shortly after the start of treatment. In these cases, the virus most likely was transmitted just before antiretroviral therapy began or right after it commenced, before treatment had fully suppressed HIV replication. The other four infections occurred in study participants for whom treatment no longer was working and the virus was replicating. Treatment failure may have occurred because the HIV-infected participants did not take their antiretroviral drugs as prescribed or had an HIV strain that was resistant to one or more of the drugs in their treatment regimen.
Do the final results mean that antiretroviral therapy is less effective at preventing HIV transmission than previously thought?
The difference between the efficacy reported in the 2011 interim analysis of the trial (96 percent) and the efficacy reported in the final results (93 percent) is small. Moreover, in the final analysis, all eight linked partner infections that were diagnosed after antiretroviral treatment began are likely to have occurred when the virus was not suppressed by the treatment regimen. The investigators did not observe any linked partner infections when the HIV-infected participant’s virus was stably suppressed by antiretroviral therapy. These results indicate that antiretroviral therapy is highly effective at preventing heterosexual transmission of HIV if viral suppression is achieved and maintained..
Participants who became HIV-infected during the study were referred to local services for appropriate medical care and treatment.
Once the study ended, what happened to HIV-infected participants who started antiretroviral therapy during the trial?
All HIV-infected participants who started antiretroviral therapy during the study were connected to local health-care services for ongoing treatment after the trial ended.
A data and safety monitoring board (DSMB) is an independent committee composed of clinical research experts, statisticians, ethicists, and community representatives that provides additional oversight of a clinical study. The DSMB regularly reviews data while a clinical trial is underway to ensure the safety of the participants and that any benefits shown in the study are quickly made available to all participants. A DSMB may recommend that a clinical trial, or part of a trial, be stopped or modified if there are safety concerns or if the trial objectives have been achieved or are unlikely to be achieved. A DSMB looks at analyses that are not available to the investigators. Restricting certain information to the DSMB while the trial is ongoing helps to maintain the integrity of the study.
In the original HPTN 052 study design, antiretroviral treatment was delayed in one of the study groups until CD4 counts reached or fell below 250 cells/mm3....
When the study began enrolling in April 2005, the protocol and the in-country guidelines of the participating sites were consistent with the WHO treatment guidelines (November 2003) that recommended that anyone with advanced clinical HIV disease or with a CD4+ T-cell count less than 200 cells/mm³ begin antiretroviral treatment. However, the WHO guidelines were revised over time, recommending first that antiretroviral treatment be considered between 200 and 350 cells/mm³ and started before 200 cells/mm³ (January 2006), and then to initiate antiretroviral treatment in all patients with a CD4 cell count less than 350 cells/mm³, irrespective of clinical symptoms (November 2009). In response to the first revision, most countries quickly adopted the new guidelines, and the study team changed the protocol such that the criteria for initiating antiretroviral treatment in the delayed group went from less than 200 cells/mm³ to between 200 and 250 cells/mm³ and raised the entry criteria for CD4 cell count from 300 to 500 cells/mm³ to 350 to 550 cells/mm³ to maintain the integrity of the study design. However, the second revision was not readily adopted by all of the countries participating in the study, primarily due to a lack of drug supply.
The study team, NIAID and the DSMB carefully considered the same data that led to the second revision of the WHO guidelines. The DSMB concluded that no change in the study was necessary based on existing HPTN 052 data, taking into consideration the safety of the participants. Nevertheless, the study team and NIAID determined that all participants should be notified of the change in the WHO guidelines and any corresponding changes in country guidelines. In addition, the study team reminded the participants that they were free to leave the study at any time or to start antiretroviral treatment outside of the study, according to the local standard of care. This action was approved by all of the institutional review boards and ethics committees overseeing the study.