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Antiretroviral Therapy To Reduce HIV Transmission

Antiretrovirals (ARVs) first changed the course of the HIV epidemic when in 1996, as part of potent combination therapy (often referred to as highly active antiretroviral therapy or HAART), they were able to extend significantly the life span of those living with HIV. Much of NIAID clinical HIV prevention research is conducted by the HIV Prevention Trials Network (HPTN), a worldwide collaborative network funded by NIAID, as well as the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA).

ARVs have been shown to be an effective tool for HIV prevention. Two strategies utilizing ARVs for HIV prevention are now in use: Treatment as Prevention and Pre-Exposure Prophylaxis.

Treatment as Prevention (TasP)

In one approach, known as Treatment as Prevention (TasP), ARVs are used as primary treatment for HIV-infected individuals and reduce the possibility that they transmit HIV to others. One HPTN study found that early use of antiretroviral therapy (ART) reduced HIV transmission in serodiscordant couples (where one partner is HIV-infected and the other is not) by 96 percent. Data from the study further demonstrated the long-term durability of ART in preventing HIV transmission among the heterosexual serodiscordant couples. The investigators reported that starting ART early reduced HIV transmission by at least 93 percent over the course of the study. There was no sexual transmission of HIV among those in the study who maintained viral suppression.

Read more about HPTN 052:

The World Health Organization recommends the initiation of ART for HIV-infected people regardless of their CD4 cell count. While this is based on a number of clinical trials that have demonstrated better clinical outcomes for those who started treatment early compared to those who delayed treatment, it can also have a highly beneficial prevention effect by reducing the risk of HIV transmission.

Read Guideline on when to start ART and on pre-exposure prophylaxis for HIV.

Ongoing research is examining a number of “test and treat” strategies, including new approaches to increase HIV testing because testing is the initial step required to identify HIV-infected individuals and link them to care. Research is also examining the impact of early treatment in other groups of high risk individuals, such as injecting drug users and the potential impact of early ART on HIV transmission at a population level.

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Pre-Exposure Prophylaxis

In another approach, HIV-uninfected individuals are prescribed ARV medication to prevent HIV acquisition; this is known as Pre-Exposure Prophylaxis (PrEP). NIAID has supported and continues to support research on PrEP through grant-funded studies and demonstration projects, and the HPTN.

PrEP is an approach to HIV prevention in which ARVs or other agents are given to HIV-uninfected individuals to reduce their risk of becoming infected. Truvada (a combination of tenofovir disoproxil fumarate [TDF] and emtricitabine [FTC]) was approved for use as PrEP by the FDA in 2012 based on the results of the National Institutes of Health (NIH)-supported iPrEx study and the Partners PrEP study funded by the Bill and Melinda Gates Foundation. The Centers for Disease Control and Prevention’s (CDC) Bangkok Tenofovir Study and TDF2 Study also demonstrated effectiveness. Truvada remains the only drug approved for PrEP in the United States.

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  • iPrEx, which demonstrated that Truvada when taken as PrEP reduced the risk of HIV infection in uninfected men who have sex with men (MSM) and transgender women by 43.8 percent and up to 73 percent with high treatment adherence to the daily regimen. A combined analysis of data from iPrEX and the STRAND study (pharmacokinetics of tenofovir during directly observed dosing) estimated that 100 percent adherence to daily dosing was associated with a 99 percent reduction in the risk of HIV acquisition.
  • Partners PrEP Study, which found that among heterosexual discordant couples (where one person is infected and one is not), those who received PrEP (tenofovir alone or Truvada) were 75 percent less likely to become infected than those on placebo. Among those with detectable levels of drug in their blood, PrEP reduced the risk of HIV infection by up to 90 percent.
  • Bangkok Tenofovir Study (daily oral tenofovir among injection drug users) and the TDF2 trial (daily oral Truvada among heterosexual men and women in Botswana), both of which found daily PrEP to be effective when taken regularly.

While the use of PrEP has been shown to be effective, uptake has been slow. This has been attributed to a lack of awareness, a perceived low risk of HIV acquisition, concerns about potential side effects, cost, the requirement of repeated and frequent HIV testing, provider attitudes and lack of awareness, and social stigma. To address these issues efforts are underway to increase awareness and understanding of PrEP, which would also help reduce stigma surrounding its use. Research is also ongoing to optimize existing interventions and develop novel approaches that could improve acceptability, adherence and access to PrEP.

Adherence

In all PrEP studies, adherence to the daily regimen was critical to achieving a reduction of HIV infection; higher levels of adherence led to a greater reductions in risk of HIV acquisition. Because PrEP adherence within a clinical trial, where testing and counseling services are emphasized and readily available, may not accurately represent “real world” circumstances, the results of the open-label extension of Truvda (iPrEX OLE [PDF]) as well as other open-label studies and demonstration projects have been important in understanding patterns of use among different populations.

  • iPrEX-OLE found that PrEP uptake and adherence to the daily regimen was highest among MSM who had a greater risk of HIV infection.
  • A sub-analysis of iPrEX-OLE, however, found that transgender women in the study who reported sexual practices that would put them at higher risk of HIV were less likely to have PrEP drug detected in their blood, indicating that they did not adhere to the regimen as instructed.
  • The NIH-funded HPTN 067 study and the PrEP Demonstration Project, as well as the PROUD Study (conducted by the Medical Research Council Clinical Trials Unit and Public Health England) showed that people at high-risk for HIV infection can regularly take their medications for PrEP as prescribed.
  • HPTN 067 included a diverse group of study participants (South African women, MSM, and transgender women in New York and Thailand). Participants in this open-label study knew they were taking active drugs rather than placebo and were randomized to either take Truvada daily or to one of two different non-daily regimens. At all three study sites, adherence to the daily regimen was higher than adherence to the two non-daily regimens.
  • In the NIH-funded PrEP Demonstration Project, participants provided blood samples so that researchers could measure the level of the metabolized form of tenofovir in their blood and then estimate the frequency with which they were taking Truvada. Overall, 63 percent of participants whose blood samples were tested had blood levels consistent with four or more doses of Truvada per week at every study visit. As was seen in iPrEX OLE, PrEP adherence was highest among those who reported sexual behaviors that placed them at higher risk for HIV infection.
  • The French IPERGAY trial showed that the use of Truvada by MSM before and after sexual exposure reduced HIV incidence by 86 percent. Most IPERGAY participants took four or more doses per week, however, so it is not yet known if this dosing regimen is effective for protecting against HIV among MSM during less frequent sexual exposure.

PrEP Guidelines

Daily PrEP for HIV prevention is recommended by the Centers for Disease Control and Prevention (CDC), and the newest WHO guidance recommends daily oral PrEP as an additional prevention choice for those at substantial risk of contracting HIV as part of a combination prevention approach. WHO implementation guidance, including how “substantial risk” is defined, is forthcoming and likely take HIV incidence levels and individual risk factors into consideration.

Read guidelines at

Women and PrEP

While women in the Partners PrEP study who took Truvada or tenofovir alone had a reduced risk of HIV infection, those who received Truvada in two other studies, the Fem-PrEP trial (sponsored by the United States Agency for International Development [USAID]) and the NIH-sponsored Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, had similar rates of HIV acquisition to those who received placebo. In both of the latter studies, there was very low use of the study agents, despite very high rates of self-reported use during the study. This emphasizes the importance of adherence and the need to develop products that are desirable to women. In contrast, HPTN 067 found that the majority of the young, single, black South African women in this open-label study who were assigned to take PrEP on a daily basis (76 percent) adhered to the prescribed regimen and had better coverage of sexual acts, when compared to those assigned to non-daily dosing regimens (CROI 2015). The importance of adherence for women is emphasized by research done by NIH grantees that, based on mathematical modeling, predicts that women must take Truvada daily to prevent HIV infection via vaginal sex, whereas just two doses per week can protect men from HIV infection via anal sex.

Future Candidates

To guide the selection of candidates for clinical evaluation as PrEP, NIAID has developed a list of ideal properties. While the most important property is safety since PrEP is used by healthy, HIV-uninfected individuals, other properties will be important for a PrEP strategy to have a significant impact.

Ideal Properties for PrEP Candidates

  • Safe for episodic and chronic use in diverse HIV-uninfected populations
  • Penetrates target tissues
  • Protects against HIV infection in tissue
  • Long-lasting activity for convenient dosing
  • Displays a unique resistance profile and/or a high genetic barrier to resistance
  • No clinically important interactions with other medications
  • Not part of current treatment regimens
  • Relative affordability, easy to use and implement
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Last Updated January 19, 2016