I’m Not Ready to Give Up on PrEP for Women!

In 2010-2011, the world of pre-exposure prophylaxis (PrEP) was opened up as a possible strategy for women to protect themselves from HIV when the results of three important studies; Caprisa 004, TDF 2 and Partners PrEP; were announced.

The first study, Caprisa 004, showed that a 1% tenofovir microbicide gel used vaginally 12 hours before and after sex resulted in a 39% reduction in HIV infections when compared to placebo, and as much as a 54% reduction in women who used the gel consistently. The gel was also found to reduce genital herpes infections by 51% (Abdool Karim et al., 2010).

The second study, TDF2, tested daily dosage of a combination pill of emtricitabine and tenofovir (TDF), also known as Truvada, in heterosexual couples in Botswana. This study showed an overall reduction in HIV acquisition of 63% (Thigpen, IAS 2011).

Evidence from the third study, Partners PrEP, that also tested Truvada as well as tenofovir alone, appeared to confirm the TDF2 results by showing a similar efficacy rate among both male and female HIV negative partners in a sero-discordant relationship (where the partner is HIV positive) (Baeten CROI 2012).

Upon hearing these results my heart soared for all the women of the world that could use PrEP as a strategy to protect themselves against HIV en lieu of not being able to negotiate monogamy or condom usage with their partners because of social and cultural factors. That’s why it was so disappointing when two additional studies released results suggesting that PrEP was not effective for the women in these studies.

The first of these seemingly contradictory results came from the FemPrEP study, which was stopped in April 2011 due to the fact that there was no difference in HIV infections between the group taking Truvada and the placebo group; also known in research terms as “futility.” Additional analysis of study data, including testing of blood samples for detection of Truvada in the blood, suggest that pill use was too low in this study for it to show a protective benefit of PrEP (Van Damme, CROI 2012).

In September 2011, more contradictory results came from the VOICE (Vaginal and Oral Interventions to Control the Epidemic) study, which declared that they were stopping the oral tenofovir arm because it also did not show any preventive effect as compared to placebo. Two months later, in another routine data review, the tenofovir gel arm of VOICE was stopped as well, again due to futility. As a ray of hope, the oral combination emtricitabine and tenfovir study arm is continuing (MTN, VOICE press release, Nov. 2011). Data analysis for VOICE has yet to be released and will hopefully shed some light on why tenofovir appeared to be ineffective for women in this study.

In a recent literature review entitled How well does PrEP work? Unraveling the divergent results of PrEP trials for HIV prevention, the authors propose that adherence (taking the study product as directed) is a key factor in explaining these discrepant results. The most personally compelling point on adherence comes from their summary of the Partners PrEP study adherence methods. Partners PrEP was the only PrEP study to enroll couples and provide adherence counseling to both partners. Early Partners PrEP study findings suggest that including influential people such as a partner, in adherence counseling could increase the rate of adherence, especially for women. This could be a very promising adherence strategy that should be studied in future clinical trials involving women in general, not exclusively in PrEP studies.

However, the authors also assert that adherence is not the only factor explaining the mixed results. Other important considerations include the levels of drug in the vaginal lining, and the role of inflammation in the genital tract and sexually transmitted infections, which may decrease the effectiveness of PrEP. It was also noted that the rate of new HIV infections was higher in both the VOICE and FEM-PrEP study populations as compared to the Partners PrEP study. Women in VOICE and FEM-PREP were likely exposed to higher levels of HIV, particularly if partners were recently infected, a condition associated with very high HIV viral load. Despite these divergent findings, the Partners PrEP and TDF2 studies demonstrate that significant protection can be achieved in men and women taking PrEP.

As usual in research, divergent findings create more research questions that can and should be answered. I have come to the conclusion that the preliminary FemPrEP and VOICE findings that at first saddened me deeply, have proven to be exceedingly important in the field of PrEP research. In particular, these results have pushed the boundaries of our knowledge and raised important questions on the impact of behavioral and biologic factors that may influence the protection from PrEP in women.

Written by: Saoirse Folsom & David Nalos

References:

Abdool Karim, Q., Abdool Karim, S.S., Frohlich, J.A., Grrobier, A.C., Baxter, C., Mansoor, L.E.,… Douglas Taylor on behalf of theCAPRISA 004 Trial Group. (2010, September). Effectiveness and safety of tenofovir gel, an antitretroviral microbicide, for the prevention of HIV infection in women. Science, 329(5996), 1168-1174.

Baeten J., Donnell D., Ndase P., et al. (2012, March). ARV PrEP for HIV-1 prevention among heterosexual men and women. Presentation at the 19th conference on retroviruses and opportunistic infections, Seattle, WA. http://www.natap.org/2012/CROI/croi_57.htm.

Microbicide Trial Network. (Nov. 2011). MTN statement on decision to discontinue use of tenofovir gel in VOICE, a major HIV prevention study in women [Press release]. Retrieved from http://www.mtnstopshiv.org/node/3909

Thigpen, M.C., P.M. Kebaabetswe, D.K. Smith, T.M. Segolodi, F.A. Soud, K. Chillag, … L.A. Paxton1, for the TDF2 Study Group IAS 2011. (2011, July). Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. Presentation at the 6th IAS conference on HIV pathogenesis, treatment and prevention, Rome, Italy.

Van Damme L., Corneli A., Ahmed K., et al. (2012, March). The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. Presentation at the 19th conference on retroviruses and opportunistic infections, Seattle, WA. http://www.natap.org/2012/CROI/croi_19.htm.