BOSTON (FRONTLINE MEDICAL NEWS) – Efavirenz-based antiretroviral therapy may significantly impair the effectiveness of vaginal ring contraceptives, investigators reported.

Over a 21-day period, levels of estrogen among women who used a vaginal ring (NuvaRing) while on efavirenz-based antiretroviral therapy (ART) were up to 79% lower, and levels of progestin were up to 57% lower, than in women with HIV infection who used the vaginal ring before starting ART, reported Kimberly K. Scarsi, PharmD , of the University of Nebraska, Omaha.

In contrast, women on an atazanavir-based ART regimen had lower estrogen levels than untreated controls who used a vaginal ring, but higher levels of progestin – the primary antiovulatory component of the ring – suggesting that it would retain contraceptive effectiveness, she said at the annual Conference on Retroviruses and Opportunistic Infections.

“In a broader context, these data can be applied to other drugs that behave similarly. So for example, erythromycins are also known to interfere with hormones in this way, as well as some anticonvulsant agents that may also impair the effectiveness of vaginal ring contraceptives,” she said at a brief, following her presentation of the data in an oral abstract session.

She noted that the findings have important implications for developers of vaginal rings designed to prevent HIV transmission as well as provide hormone-based contraception.

Dr. Scarsi and colleagues conducted a phase 2, international, nonrandomized, parallel pharmacokinetic study comparing levels of estrogen in the form of ethinyl estradiol (EE) and progestin in the form of etonogestrel among women with HIV infection who had not yet begun ART, as well as women on efavirenz- or atazanavir-based regimens.

Participants 16 years and older from centers in Africa, Asia, and North and South America were enrolled. The patients had to be willing to use a second, nonhormonal form of effective contraceptive, and if they were not on ART had to have CD4 cell counts of 350 cells/m3 or higher at screening. Participants on ART had to be on stable therapy for at least 30 days, and have HIV-1 RNA of 400 copies/mL or less.

A total of 25 control subjects, 25 women on efavirenz, and 24 on atazanavir were available for the primary pharmacokinetic analysis.

Over 21 days, EE levels among the efavirenz groups were 53%-57% lower than those of controls. Levels among the atazanavir groups were 29%-59% lower.

On days 7, 14, and 21, the EE geometric means ratios in efavirenz-treated patients versus controls were 0.47, 0.45, and 0.43, respectively (P less than .05 for each comparison).

In the atazanavir group, the EE geometric mean ratios versus controls at the same time points were 0.68 (P nonsignificant), 0.71 (P less than .05), and 0.65 (P less than .05).

For those in the efavirenz group, etonogestrel levels over 21 days were 76%-79% lower than in controls. In contrast, levels in the atazanavir group were 71%-79% higher than in controls.

The geometric mean ratios for the efavirenz group at 7, 14, and 21 days versus controls were 0.21, 0.22, and 0.24 (P less than .05 for all comparisons). In the atazanavir group, the respective geometric mean ratios were 1.71, 1.79, and 1.74 (P less than .05 for all comparisons).

Safety and tolerability of the ring, a secondary endpoint, was similar among the groups, with slightly more than one-fourth of participants in each arm having a mild adverse event, most commonly associated with abnormal vaginal discharge or menstrual irregularities such as spotting.

The investigators also looked at endogenous progesterone levels as a surrogate for ovulation. Although the ring’s package insert recommends to start using it within the first 5 days after the start of menses, the median enrollment time was 9 days after menses in all groups. Nonetheless, all participants in the control and atazanavir groups had undetectable progesterone values (less than 5 ng/mL) by day 14.

In contrast, among women in the efavirenz group, all women had undetectable progesterone values only at day 21.

The findings suggest that, when considering contraception and ART in HIV-infected women, developers of intravaginally administered drugs should consider systemic drug-drug interactions, because hormones released from a vaginal ring are extensively absorbed and act systemically. It is also important to consider local drug-drug interactions with the microbiome, because although it is known that dapivirine released from a vaginal ring can concentrate in the vaginal tract, possible interactions with the local microbiome, local drug transporters, and local drug-metabolizing enzymes are not known, Dr. Scarsi cautioned.

The study was supported by the National Institutes of Health. Merck provided the vaginal ring used in the study. Dr. Scarsi reported having no conflicts of interest to disclose.

SOURCE: Scarsi KK et al. CROI 2018, Abstract 141.


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