Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study

Summary Background Drug-drug interactionsbetween orally administered antiretroviral therapy (ART) and hormones released from an intravaginal ring are not known. We hypothesised that ART containing either efavirenzor ritonavir-boosted atazanavirwould alter plasma concentrations of vaginally administered etonogestreland ethinylestradiolbut that ART concentrations would be unchanged during use of an intravaginal ring. Methods We did a parallel, three-group, pharmacokinetic evaluation at HIV clinics in Asia (two sites), South America (five), sub-Saharan Africa (three), and the USA (11) between Dec 30, 2014, and Sept 12, 2016. We enrolled women with HIV who were either ART-naive (control group; n=25), receiving efavirenz-based ART (n=25), or receiving atazanavir–ritonavir-based ART (n=24). Women receiving ART were required to be on the same regimen for at least 30 days, with 400 copies or less per mL of plasma HIV-1 RNA; women not receiving ART had CD4 counts of 350 cells per μL or less. We excluded participants who had a bilateral oophorectomyor conditions that were contraindicated in the intravaginal ring product labelling. An intravaginal ring releasing etonogestreland ethinylestradiolwas inserted at entry (day 0). Single plasma samples for hormone concentrations were collected on days 7, 14, and 21 after intravaginal ring insertion. The primary outcome was the plasma concentration of etonogestreland ethinylestradiolon day 21. Etonogestreland ethinylestradiolconcentrations were compared between each ART group and the control group by geometric mean ratio (GMR) with 90% CIs and Wilcoxon rank-sum test. As secondary outcomes, efavirenzor ritonavir-boosted atazanavirconcentrations were assessed by 8-h intensive pharmacokinetic sampling at entry before intravaginal ring insertion and before intravaginal ring removal on day 21. Antiretroviral areas under the concentration-time curve (AUC0–8 h) were compared before and after intravaginal ring insertion by GMR (90% CI) and Wilcoxon signed-rank test. This study is registered with ClinicalTrials.gov , number NCT01903031 . Findings Between Dec 30, 2014, and Sept 12, 2016, we enrolled 84 participants in the study; ten participants were excluded from the primary hormone analysis. 74 participants met the primary endpoint: 25 in the control group, 25 in the efavirenzgroup, and 24 in the atazanavirgroup. On day 21 of intravaginal ring use, participants receiving efavirenzhad 79% lower etonogestrel(GMR 0·21, 90% CI 0·16–0·28; p Interpretation Hormone exposure was significantly lower when an intravaginal ring contraceptive was combined with efavirenz-based ART. Further studies designed to examine pharmacodynamic endpoints, such as ovulation, when intravaginal ring hormones are combined with efavirenzare warranted. Funding National Institutes of Health, through the AIDS Clinical Trials Group and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.