PrEP in Heterosexual Adults: Mixed Results

Summary and Comment |
July 11, 2012

PrEP in Heterosexual Adults: Mixed Results

  1. Raphael J. Landovitz, MD, MSc

A trio of studies on pre-exposure prophylaxis demonstrates proof-of-principle in heterosexual populations but highlights the need for more data from women.

  1. Raphael J. Landovitz, MD, MSc

Pre-exposure prophylaxis (PrEP) has been shown to be efficacious among men who have sex with men (MSM; JW AIDS Clin Care Nov 23 2010). This week, the New England Journal of Medicine published the results of three trials of PrEP among heterosexual populations in Africa:

  • Partners-PrEP, in which researchers tested oral tenofovir alone and oral tenofovir/FTC among 4747 heterosexual, HIV-serodiscordant couples

  • TDF2, in which researchers tested oral tenofovir/FTC among 1219 heterosexual men and women

  • FEM-PrEP, in which researchers tested oral tenofovir/FTC among 2120 heterosexual women

In all three trials, HIV-negative individuals were randomized to receive daily oral PrEP or placebo, along with comprehensive HIV prevention services, and were assessed monthly for HIV infection and clinical events. The primary endpoint was HIV prevention efficacy (the proportion of individuals who acquired HIV infection in the PrEP group compared with the placebo group).

The efficacy results were decidedly mixed (see table). In the Partners PrEP trial, PrEP was efficacious both in the overall population and among both men and women; the efficacy and safety of tenofovir alone and tenofovir/FTC were not significantly different. In the TDF2 trial, PrEP was efficacious in the overall population, but the study did not have sufficient power to demonstrate a statistically significant effect among women. Finally, in the FEM-PrEP trial, which involved only women, PrEP completely lacked efficacy.

In all three trials, adherence was relatively high (>80%) when measured by pill count and returned pill bottles. However, all these studies, as well as the iPrEx study among MSM, demonstrated low rates of detectable drug in plasma samples taken from seroconverters.

Treatment-emergent resistance was rare in the trials, occurring in only four participants (all in the FEM-PrEP study). The TDF2 study demonstrated a statistically significant but clinically ambiguous decline in bone-mineral density among those receiving tenofovir/FTC. In all three studies, researchers noted a decrease in sexual-risk behavior during follow-up.


These large, well-conducted trials demonstrate proof-of-principle that oral PrEP can be effective in both men and women, but they highlight the need for further research on how to optimize protective efficacy, particularly among women. Pharmacokinetic data hint that after ingestion of oral tenofovir, vaginal tenofovir levels are relatively low compared with rectal levels and may thus render women more susceptible to other parameters influencing transmission, such as hormonal contraception, concomitant sexually transmitted infections, and partner viral burden. However, adherence issues will likely trump these more-subtle biologic and exposure differences between men and women. The finding of treatment-emergent resistance among four FEM-PrEP participants (out of 108 active treatment seroconversions across all four published PrEP efficacy studies) is a cautionary reminder that PrEP nonadherence could potentially compromise first-line treatment options in those who seroconvert. Furthermore, the true effect of PrEP administration on sexual-risk behavior (e.g., condom use and number of sexual partners) remains to be clarified in open-label operational research, which is now beginning. As we move forward with PrEP, the largest challenge to widespread implementation is to optimize adherence, minimize short and long-term toxicity, and simultaneously provide equitable access.

Dr. Landovitz is Assistant Professor, Division of Infectious Diseases, Center for Clinical AIDS Research and Education, University of California, Los Angeles. He reports no conflicts of interest.


Reader Comments (2)

WL Greaves

Helpful and concise review but disconcerting for women. Your thoughts about the role of vaginal microbicides would be of interest.

Competing interests: None declared

Jonathan Peng

Great review Dr. Landovitz! Hope all is well.

Competing interests: None declared

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