Vaginal ring reduces efavirenz but not atazanavir exposures 

Polly Clayden, HIV i-Base

The contraceptive vaginal ring (NuvaRing) reduces efavirenz and ritonavir exposures while atazanavir exposure was not significantly different. [1]

Antiretrovirals are known to alter the exposure of hormonal contraceptives. Hormones might also induce or inhibit drug-metabolising enzymes, with potential to affect antiretroviral exposure. Lower exposure has been observed for efavirenz (EFV), ritonavir (RTV, r) and nelfinavir (NFV) when combined with various hormonal contraceptives in some studies – others find no difference in antiretroviral exposure.

ACTG A5316 was designed to characterise plasma hormone exposure when combined with EFV- or ATV/r-based ART. These results were presented at CROI 2018. [2,3]

Compared to the control group, participants in the EFV group had 76–79% lower ENG and 53–57% lower EE over 21 days (all comparisons p<0.001). Participants in the ATV/r group had 71–79% higher ENG (all p<0.001), but 29– 35% lower EE (p=0.066, 0.032 and 0.004 at days 7, 14 and 21, respectively) over 21 days compared to the control group.

A secondary objective of the study was to estimate the effect of etonogestral (ENG) ethinyl estradiol (EE) – 15/120 mcg/day in the combined contraceptive vaginal ring – on the pharmacokinetics (PK) of ATV, RTV and EFV.

Kim Scarsi from the University of Nebraska presented these data at 19th International Workshop on Clinical Pharmacology.

A5316 was an international, multicentre, parallel group, PK evaluation of HIV positive women at least 16 years old. A vaginal ring was inserted at study entry (Day 0) in two groups of participants receiving ART containing EFV 600mg daily or ATV/r 300/100mg daily, both + 2 NRTIs. Participants were on stable ART and had viral load 400 copies/mL or less at screening.

PK sampling for EFV or ATV/r on Day 0 took place pre-ART dose (0h), then 1, 3, 4, 5, and 8 hours post-ART dose, and before vaginal ring placement.

ART PK sampling was repeated on Day 21 before the vaginal ring was removed. EFV, ATV, and RTV were assessed by validated LC/MS/MS methods. Antiretroviral exposure was compared between Day 21 and Day 0 within each group by geometric mean ratio (GMR) with 90% CI.

For the antiretroviral PK analysis, there were 24 evaluable participants in the EFV group and 23 in the ATV/r group.

In the EFV group, Cmin 2.1 (range 0.90 to 13.62) mcg/mL on Day 0 and 1.77 (range BLQ to 12.93) mcg/mL on Day 21: GMR 0.64 (90% CI 0.42 to 0.97); AUC0-24h GMR was 0.87 (90% CI 0.77 to 0.99), both p<0.05.

In the ATV/r group, ATV Cmin 797 (range BLQ to 2731) ng/mL on Day 0 and 599 (range BLQ to 3599) ng/mL on Day 21: GMR 0.70 (90% CI 0.41 to 1.21); AUC0-24h GMR was 0.77 (90% CI 0.57 to 1.03).

Also in the ATV/r group, RTV Cmin 70 (range BLQ to 1042) ng/mL on Day 0 and 51.9 (range BLQ to 917) ng/mL on Day 21: GMR 0.67 (90% CI 0.38 to 1.19); AUC0-24h GMR 0.63 (90% CI 0.45 to 0.89), p<0.05.

The investigators observed moderately lower EFV (13–36%) and RTV (34–41%) concentrations after 21 days of vaginal ring use.

Despite lower RTV exposure, ATV exposure was not statistically different. Median Cmin values remained within the expected range for each antiretroviral on Day 21.

The investigators noted that four participants in each ART group had at least one EFV or ATV measurement below a conservative concentration threshold.

Viral load remained undetectable in 7 of 8 participants; the other increased from <40 copies/mL at entry to 54 copies/mL on Day 21.

Despite lower antiretroviral concentrations, there was still a significant drug-drug interaction with the combined hormonal contraceptive.  


  1. Scarsi K et al. Intraindividual comparison of efavirenz, atazanavir, or ritonavir plasma pharmacokinetics before and during 21-days of vaginally administered hormone contraception. 19th International Workshop on Clinical Pharmacology, 22– 24 May 2018, Baltimore. Oral abstract 10. (PDF)
  2. Scarsi K et al. Vaginal contraceptive hormone exposure profoundly altered by EFV- and ATV/r-based ART. 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018), 4–7 March 2018, Boston. Oral abstract 141.


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