Combined oral contraception has less effect on nevirapine than efavirenz levels

HIV therapy based on efavirenz may less suitable for women taking combined oral contraception due to greater reductions in efavirenz levels and a higher frequency of hormonal contraception side effects, according to research conducted in Thailand and published in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

Results of the small study showed that only one-fifth of women taking efavirenz and oral contraception had progesterone levels above the target level and that 19% had efavirenz concentrations below the therapeutic threshold. In contrast, women taking nevirapine were protected against pregnancy and maintained therapeutic levels of the antiretroviral.

“Our results suggest that co-administration of COC [combined oral contraception]…with efavirenz is associated with risks for contraceptive and efavirenz failures,” comment the investigators. “On the other hand, the study results suggest that the use of such COC with nevirapine resulted in more favorable ARV [antiretroviral] and progesterone levels.”

Contraception, including hormonal methods, is widely promoted to women with HIV. However, little is known about pharmacokinetic interactions between combined hormonal contraceptives and common classes of antiretrovirals, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs). An interaction is theoretically possible because both combined contraceptives and NNRTIs are metabolished by the body in the same way.

Investigators in Thailand therefore designed a prospective open-label study involving 34 women taking a combined oral contraceptive formula of 0.150 mg desogestrel/0.030 mg ethinyl estradiol (Marvelon 150/30 tablets) and antiretroviral therapy based on the NNRTIs efavirenz (Sustiva, also in Atripla) or nevirapine (Viramune).

Recruitment occurred between August 2011 and April 2012 and participation in the study lasted for two months.

Between the first and third day of their regular menstrual cycle, participants started to take one Marvelon tablet per day for 21 days, followed by seven days without contraception; on day 29 day participants re-started Marvelon  for another treatment cycle.

All the women were taking stable antiretroviral therapy.

The target level for contraceptive effectiveness was a progesterone level below 3.0ng/ml. Antiretroviral concentrations were measured twelve hours after administration with and without combined oral contraception. Target drug concentrations were above 3.1mg/l for nevirapine and between 1.0-4.0mg/l for efavirenz.

Participants had a median age of 36 years. All had normal blood pressure and body mass index. In most respects, the 18 women taking nevirapine and the 16 women taking efavirenz were well matched in terms of baseline characteristics. However, those taking nevirapine had higher systolic blood pressure, whereas those taking efavirenz had higher ALT levels.

All the women maintained an undetectable viral load throughout the study and reported 100% adherence to both their contraceptive treatment and antiretroviral therapy.

Progesterone levels were below 1.0ng/ml for all the women taking nevirapine. In the efavirenz group, twelve individuals (75%) also had a progesterone level below 1.0ng/ml; four had progesterone above 1.0ng/ml. including three individuals (19%) who had a level above 3.0ng/ml.

“We caution the use of combined hormonal contraceptives in HIV-positive women on efavirenz for pregnancy protection,” write the authors.

Median nevirapine concentrations twelve hours after administration without the combined oral contraception were 6.8mg/l, and these increased by an insignificant 17% to 7.2mg/l when taken with Marvelon. However, six women experienced a fall in their nevirapine levels, including one woman where it fell to 2.96mg/l, below the therapeutic threshold of 3.1mg/l.

The median concentration of efavirenz without the contraceptive was 3.3mg/l. It fell by a significant 22% to 2.7mg/ml with Marvelon. In three women (19%) concentrations of the drug dropped below the target 1.0mg/l threshold.

“Efavirenz levels below the therapeutic threshold of 1mg/l might be insufficient for effective viral suppression possibly leading to therapeutic failure,” comment the researchers.

Significantly more women in the efavirenz group reported side-effects attributed to the combined oral contraceptive than women in the nevirapine group (56 vs 22%; p = 0.04).

“As efavirenz-based ARV is becoming the preferred first-line option worldwide it is crucial to study in detail the pharmacokinetic interaction between COC and NNRTI as well as its clinical impact on contraceptive and HIV treatment effects in larger and more diverse population,” conclude the investigators.

Landolt NK et al. Efavirenz, in contrast to nevirapine, is associated with unfavorable progesterone and antiretroviral levels when co-administered with combined oral contraceptives. J Acquir Immune Defic Syndr, online edition. DOI: 10.1097/QAI.0b013e31827e8f98, 2012.