March 21, 2013
Pre-exposure prophylaxis, or PrEP, is a new tool that an HIV-negative person may be able to use to reduce their risk of becoming infected with HIV. It involves taking anti-HIV medications on a regular basis.
Recently, several types of PrEP have been investigated, including the daily use of pills taken orally (oral PrEP) and the insertion of a gel into the vagina either daily or before and after sex (topical PrEP). These types of PrEP contain the antiretroviral drug tenofovir (called Viread when used in pill form) or combinations of tenofovir and emtricitabine (sold as a fixed-dose co-formulation pill called Truvada).
While some PrEP clinical trials have had promising results, others have not.
Some research studies, such as iPrEX, PartnersPrEP, TDF2 and CAPRISA 004, have shown that certain types of oral and topical PrEP are effective at reducing the risk of HIV transmission in specific populations. The extent to which PrEP reduced the overall risk of HIV transmission in these studies has ranged widely, from 39% in CAPRISA 004 to 75% in PartnersPrEP, likely due to varying levels of adherence among study participants.
In another study, known as FEM-PrEP, oral Truvada did not appear to reduce the risk of HIV infection among high-risk heterosexual women. This was surprising because daily Truvada was found effective for women in the PartnersPrEP and TDF2 studies.
More recently, a study known as VOICE announced similar disappointing results. A preliminary analysis of this study was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta, Georgia, in March.
The VOICE (Vaginal and Oral Interventions to Control the Epidemic) study was designed so that researchers could compare the effectiveness and safety of different types of PrEP in preventing HIV infection in women.
More than 5,000 HIV-negative women from Eastern and Southern Africa were enrolled in the study. The majority of these women were from South Africa (81%), while a smaller proportion was from Uganda (6%) and Zimbabwe (13%). Almost half of the participants were under 25 and most were not married (79%).
Researchers randomly assigned the women to one of five study arms. Each arm included approximately 1,000 women and they were asked to use or take one of the following on a daily basis:
All study participants were blinded, meaning they did not know which study arm they were assigned to. They were also all provided with ongoing adherence and risk-reduction counselling, testing and treatment for sexually transmitted infections (STIs), and free condoms.
The study began enrolling participants in September 2009 and was scheduled to end in August 2012. However, only the daily Truvada and placebo pill arms continued until the expected end date of the study. The tenofovir vaginal gel arm and the tenofovir pill arm were stopped early because interim data suggested they were not effective.
The results presented at CROI showed that the rates of HIV infection were very similar in each of the five groups. Since there was no significant difference in the rate of HIV infection between the PrEP and placebo groups, the researchers concluded that none of the interventions were effective at reducing the risk of HIV infection.
These results were surprising, as daily Viread and Truvada pills had previously been found effective for women in the PartnersPrEP and TDF2 studies. Also, a tenofovir vaginal gel had been found effective in the CAPRISA 004 study (when used before and after sex, not daily).
Similar to the FEM-PrEP study, poor adherence has been suggested as the most likely explanation for the lack of PrEP effectiveness in the VOICE study.
Although self-reported adherence was high among VOICE participants, blood analysis of 773 participants assigned to daily PrEP showed that only 23% to 29% on average had detectable drug in their blood. This suggests that the majority of study participants were not using or taking PrEP consistently. Adherence was lower (and the rate of HIV infection higher) among young, unmarried women compared to participants who were older and married.
Further analysis is being done to understand why adherence was low among women in the VOICE study. These analyses are investigating individual and community-based factors, such as attitudes and beliefs, which may have influenced adherence.
It is concerning that -- within the context of controlled clinical trials -- the effectiveness of PrEP cannot be replicated and has ranged widely (from 0% to 75%). As a result, it is unclear what impact PrEP may have on the HIV epidemic outside of a clinical trial, particularly among populations that may have trouble adhering to consistent PrEP use.
However, at the individual level, research shows that PrEP can be effective at preventing HIV transmission when used consistently and when STIs are managed through regular testing and treatment. Like all other HIV prevention strategies, such as condoms and the effective use of treatment by people living with HIV, this level of protection drops dramatically with inconsistent and incorrect use.
In the United States, the Food and Drug Administration (FDA) has approved daily Truvada for the prevention of HIV infection and the Centers for Disease Control and Prevention (CDC) has developed interim guidelines for healthcare providers. Also, the World Health Organization (WHO) has developed guidance on oral PrEP for use in the context of demonstration projects.
Demonstration projects are currently underway in several parts of the U.S. and will provide a better understanding of the effectiveness of PrEP and adherence to daily pill-taking outside of a clinical trial. These projects are also evaluating different strategies to improve adherence among PrEP users.
Daily Truvada has not been approved for use as PrEP by Health Canada. However, Truvada is available for the treatment of HIV and therefore some doctors may be willing to prescribe it "off-label" for the prevention of HIV infection.
Vaginal gels for use as PrEP have not been approved by any regulatory agencies and cannot be obtained "off-label" from healthcare providers. There is currently an ongoing study, known as FACTS 001, that is investigating the use of a tenofovir vaginal gel used before and after sex. It is likely that results from this study will be needed before regulatory approval can be considered. Smaller studies are also investigating the use of gels in the rectum.
VOICE Factsheet -- Microbicide Trials Network
Pre-Exposure Prophylaxis (PrEP) -- CATIE Fact Sheet
Is Taking PrEP the Right Choice for You? -- Project Inform
Marrazzo J, Ramjee G, Nair G et al. Pre-exposure Prophylaxis for HIV in Women: Daily Oral Tenofovir, Oral Tenofovir/Emtricitabine, or Vaginal Tenofovir Gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, Paper#26LB, 2013.