Pre-exposure Prophylaxis for HIV-1 Prevention Does Not Diminish the Pregnancy Prevention Effectiveness of Hormonal Contraception

Pamela M. Murnane; Renee Heffron; Allan Ronald; Elizabeth A. Bukusi; Deborah Donnell; Nelly R. Mugob; Edwin Were; Andrew Mujugira; James Kiarie; Connie Celum; Jared M. Baeten

Disclosures

AIDS. 2014;28(12):1825-1830. 

In This Article

Discussion

In this randomized, placebo-controlled trial of FTC/TDF and TDF PrEP among 1785 HIV-1-uninfected women, we found no evidence that PrEP reduced the effectiveness of hormonal contraception for pregnancy prevention. Our study population provided a unique opportunity to evaluate the question of a potential adverse interaction between PrEP and contraception for several reasons: contraception was not required for participation, allowing a comparison group of women not using hormonal contraception to estimate contraceptive effectiveness; PrEP was randomly assigned, providing a placebo comparison; and PrEP was used with high adherence,[8] thus permitting a robust assessment of whether PrEP modified contraceptive effectiveness.

In FEM-PrEP,[3] another clinical trial of FTC/TDF PrEP among African women, more pregnancies occurred among those assigned PrEP (incidence 11.2% per year) versus placebo (7.5% per year). Because contraception was required for participation in that trial and over 95% of women selected a hormonal method, this difference in pregnancy incidence raised concern that PrEP might negatively affect hormonal contraception effectiveness. Both biologic and behavioral hypotheses were offered to potentially explain this observed difference. Little evidence supports an adverse biologic interaction between TDF and contraception, as tenofovir is not a substrate, inducer, or inhibitor of human cytochrome P450 enzymes, does not interact with selected drugs that are metabolized similarly to hormonal contraceptives, and was not found to affect plasma concentrations of oral contraceptives.[5] Instead, behavioral factors could explain the FEM-PrEP findings: adherence to PrEP was low overall in FEM-PrEP (~30%), and pregnancy incidence was 29% per year among women reporting oral contraceptive use, suggesting poor adherence to oral contraception as well. In addition, the proportion using oral contraception was slightly higher among women assigned PrEP (32%) compared to placebo (28%), and thus the difference in pregnancy incidence between arms was likely confounded by this imbalance. In our study, we found no adverse effect of PrEP on contraceptive effectiveness, although, as in FEM-PrEP, we found high pregnancy incidence in women reporting oral contraceptive use.

Hormonal contraception in the form of implants was nearly perfectly efficacious in our study; notably this method requires minimal user dependence as implants remain effective up to 5 years. Adherence is likely the primary reason for the lack of oral contraceptive effectiveness we observed. Other prospective studies among women at risk for HIV-1 have reported high pregnancy incidence in oral contraceptive users, suggesting low real-world effectiveness in this important population.[12,13] In our study, family planning counseling was provided at study sites by trained counselors and at family planning clinics for those who sought contraception elsewhere. It is notable that PrEP adherence in our population was high, in contrast to the suggestion that oral contraceptive adherence was not. Women at risk of HIV-1 require increased access to long-acting reversible contraception, and development of long-acting HIV-1 prevention methods is needed. Preclinical studies of longer-acting PrEP report promising results[14,15] and further study is underway in humans.[16] Ongoing PrEP trials are not limited to TDF-based PrEP; therefore, continued study of potential interactions between hormonal contraceptives and new PrEP formulations is necessary. Further examination of whether hormonal contraception diminishes PrEP efficacy is also needed.[6] Co-formulated PrEP and hormonal contraceptives in development are of particular interest, including intravaginal rings and injectables; these products promise further reduction in user dependence while offering dual protection.[17]

A potential limitation of our study is that contraceptive use was self-reported which could result in misclassification, though monthly reporting minimizes the likelihood of recall bias. Also, unmeasured or imperfectly measured confounders of contraceptive effectiveness are possible. Nonetheless, we do not expect these potential limitations to be differential by randomization arm and therefore they would not bias our primary analysis, which was to evaluate the effect of PrEP on contraceptive effectiveness.

In conclusion, our results suggest that TDF-based PrEP can be used together with hormonal contraception as a dual prevention strategy with no reduction in protection from unintended pregnancy. Future development of co-formulated long-acting PrEP and contraception is an important public health goal.

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