*The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand
†The Thai Red Cross AIDS Research Centre, Bangkok, Thailand
‡SEARCH, Bangkok, Thailand
§The Kirby Institute, The University of New South Wales, Sydney, Australia
‖Irving Institute for Clinical and Translation, Research Biomarkers Core Laboratory, Columbia University Medical Center, New York, NY
¶Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
#Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
Supported by Ratchadapiseksompotch Endowment Fund, Faculty of Medicine, Chulalongkorn University Grant Number RA53/54 (1); RA 55/53, and The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT). The conducting of laboratory tests at the Irving Institute for Clinical and Translation, Research Biomarkers Core Laboratory was also supported by the National Center for Advancing Translational Sciences, the National Institutes of Health, through Grant Number UL1 TR000040.
The authors have no conflicts of interest to disclose.
To the Editors:
According to the World Health Organization, there are “no restrictions on the use of any hormonal contraceptive method for women living with HIV or at high risk of HIV.”1 Nevertheless, there are many unanswered questions in this field.
Sex steroid hormones and certain antiretrovirals (ARVs), such as nonnucleoside reverse transcriptase inhibitors, have common metabolic pathways, mainly through the cytochrome P450 enzyme system, especially Cyp3A4.2,3 As a result, pharmacokinetic (PK) interactions lead to changes in their blood levels and possible changes in their therapeutic activity. Comparison between the few existing studies is limited by the differences in study population and contraceptive products used.4–8
In an earlier study, we assessed the contraceptive effectiveness and safety of combined oral contraceptive (COC) pills in HIV-positive women taking nevirapine (NVP)-based or efavirenz (EFV)-based therapy.9 We found that the co-administration of desogestrel (DSG)/ethinyl estradiol (EE2) contraceptive pills in the NVP group did not affect the effectiveness of the contraceptive pills, based on the measurement of endogenous progesterone. In contrast, in the EFV group, the co-administration of DSG/EE2 contraceptive pills led to a possible compromise in both the contraceptive effectiveness of DSG/EE2 and the ARV activity of EFV. In this article, we report etonogestrel (ENG), the active metabolite of DSG,10 and EE2 levels from this cohort, thus substantiating our initial findings and contributing to the scarce literature on this subject.
This was a prospective, open-label, nonrandomized steady-state clinical trial. We administered Marvelon (0.150 mg of DSG/0.030 mg of EE2), manufactured by Organon (Oss, the Netherlands), in a standard dose of 1 pill per day for 2 consecutive cycles (56 study days: 21 days with pills, 7 days without pills, 21 days with pills, and 7 days without pills) to HIV-positive women on either NVP- or EFV-based regimens with 2 nucleoside reverse transcriptase inhibitors. The details of the original study are described elsewhere.9 In addition, we had a control group of 14 HIV-negative women to whom we administered Marvelon in the same way as to the HIV-positive women. All stages of the study were approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University in Bangkok, Thailand.
We collected blood at study day 44 ± 2 days (second half of the second hormonal cycle, allowing sufficient time to reach steady state concentrations for both hormones11) to measure EE2 and ENG levels 24 hours after pill intake (C24). Studies show that when only single samples can be compared, sampling in the last third of the cycle, just before the ingestion of the following pill, is optimal.12 We compared the plasma levels of EE2 and ENG in HIV-positive women on either NVP- or EFV-based therapy with those of HIV-negative women without any ARV therapy.
Collected blood in EDTA tubes was centrifuged and stored at −80 °C in cryovials; each subject had 2 cryovials of 1 mL each. Laboratory tests for quantitative analysis for EE2 and ENG in plasma were performed at the Biomarkers Core Laboratory of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center, New York, NY. EE2 and ENG were measured in plasma by ultra performance liquid chromatography-tandem mass spectometry (UPLC-MS/MS) as described earlier.13,14 In short, ENG and EE2 were measured in plasma by UPLC-MS/MS after liquid/liquid extraction using D8-Progesterone or D4-EE2 as the internal standard for ENG and EE2, respectively. EE2 was derivatized with dansyl chloride before analysis. The steroids were quantified by positive electrospray ionization in multiple reaction monitoring mode using the Waters Xevo TQ-S system (Waters, Milford, MA). The method was linear between 50 and 2000 pg/mL and 2.5 and 100 pg/mL for ENG and EE2, respectively [limit of quantification (LOQ): 50 and 2.5 pg/mL]. The intraassay and interassay coefficients of variation (CVs) were <6% and <13%, respectively, for ENG; <3.9% and <4.4%, respectively, for EE2.
We calculated median (interquartile range), geometric mean (GM), coefficient of variation as a percentage (%CV) of the EE2 and ENG C24 at day 44. Differences in steroid metabolite concentrations in study groups (NVP or EFV) versus the HIV-negative control women were quantitated by calculating the geometric mean ratio (GMR) and 95% confidence intervals (95% CIs) for the NVP and EFV groups versus the HIV-negative controls. Values for EE2 lower than the LOQ were imputed as the LOQ (ie, <2.5 was made equal to 2.5).
Forty-eight subjects in 3 groups (NVP group, n = 18; EFV group, n = 16; HIV-negative group, n = 14) completed the study between August 2011 and April 2012. All subjects were of Thai ethnicity, and detailed baseline characteristics are presented elsewhere.9 Subjects had been on their current regimens for a median of 5.5 years in the NVP group (200 mg of NVP twice daily) and for 3 years in the EFV group (600 mg of EFV once daily). Subjects reported complete adherence to ARVs and COC pills.
The median (interquartile range) and GM (%CV) C24 of EE2 and ENG in each study group are shown in Table 1. In women taking NVP, the GMR of EE2 versus the control group was 0.42 (95% CI: 0.30 to 0.57), representing a significant 58% reduction in the EE2 C24 (P < 0.0001). The C24 of ENG was not significantly different in women taking NVP compared with the control group (GMR = 0.78, 95% CI: 0.53 to 1.15, P = 0.2). In contrast, in women taking EFV, there was no significant reduction in the C24 GMR of EE2 versus the control group (GMR = 0.91, 95% CI: 0.74 to 1.11, P = 0.33). However, the GMR of ENG in the EFV group versus the controls was 0.39 (95% CI: 0.30 to 0.51, P < 0.0001), representing a significant 61% reduction in ENG C24. These results were consistent when a nonparametric Mann–Whitney U test was used to compare whether the distributions from which the samples were drawn were the same (data not shown).
Plasma ENG levels in the EFV group could be measured in only 8 of 16 subjects. The remaining 8 subjects had an interfering peak with the same retention time as ENG, during initial and repeated laboratory analysis.
We found that the expected GM C24 of EE2 in HIV-positive women taking NVP co-administered with DSG/EE2 was significantly lower by 58% versus healthy controls, but the reduction in ENG C24 was not statistically significant. These results corroborate an earlier report of PK interactions between NVP and sex steroid hormones,4 and differ from the other, which found increased levels of sex steroid hormones when COC was co-administered with NVP.5 In addition to the different study design, the difference in the results can be explained by the large interindividual and intergroup variability in the bioavailability of sex steroid hormones,15 determined by genetic polymorphism.16,17 Nevertheless, as we earlier reported, the contraceptive effect of the pill seems to have been preserved in our NVP group, based on the measurement of endogenous progesterone—in all subjects in the NVP group, serum progesterone remained <3 ng/mL,9 values consistent with anovulation.18 This is not surprising, as the progestin component of the COC pill contributes more to the suppression of ovulation by suppressing luteinizing hormone secretion and thus preventing the luteinizing hormone surge that triggers ovulation.19 In our study group, ENG levels were only insignificantly reduced in comparison with the control. The reduced levels of EE2 could explain the significantly less common side effects, reported earlier, such as headache, breast tenderness, and nausea, in the NVP group in comparison with the EFV group.9 These side effects are considered to be dose related to the estrogen component of the pill.20
In the EFV group, the co-administration of DSG/EE2 with EFV led to a 61% reduction in the expected GM C24 of ENG and no significant changes in the EE2 C24 compared with healthy controls. These findings are consistent with earlier studies.7,8 The PK profile of ENG is generally comparable with that of levonorgestrel and norethindrone.10 Not surprisingly, and in contrast to the earlier study,8 we found possible signs of ovulation in 19% of the subjects based on single endogenous progesterone measurement.9 Our findings of PK interactions between DSG and EFV provide an explanation of case reports in the literature describing contraceptive failure of implantable contraceptive containing ENG in women on EFV-based therapy.21,22
As reported, we could not measure ENG levels in 8 subjects, due to an interfering peak with the same retention time as ENG. There were no differences in the variables under study between the women in whom ENG could be measured and those in whom we found an interfering peak. It is unclear why this occurred but could be due to pharmacogenomic differences, particularly in CYP3A enzyme system, and CYP2B6, ABCB1 among others.23
This analysis has certain limitations—the sample size was relatively small, and hormonal levels were measured in a single sampling. Furthermore, our findings cannot be attributed to all progestins used for hormonal contraception.24 However, the study was conducted under steady-state conditions of hormones and ARVs and in an ethnically homogenous population.
In conclusion, we caution against the use of DSG/ENG-containing hormonal contraception in HIV-positive women on EFV-based therapy due to possible contraceptive failure based on high progesterone levels, explained by low ENG level. The changes in ENG/EE2 levels in the NVP group seem not to affect the contraceptive efficacy of the pill based on progesterone levels.
The authors are grateful to the research and clinical staff and clients at the HIV-NAT Clinic and at The Thai Red Cross Anonymous Clinic for their contribution to this study. The team appreciated the support of Rosalin Kriengsinyot for assisting with patient enrollment, Theeradej Boonmangum for helping with the data entry, and June Ohata and Chatsuda Auchieng for dealing with administrative issues.
2. Wang B, Sanchez RI, Franklin RB, et al.. The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol. Drug Metab Dispos. 2004;32:1209–1212.
3. Korhonen T, Tolonen A, Uusitalo J, et al.. The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel. Br J Clin Pharmacol. 2005;60:69–75.
4. Mildvan D, Yarrish R, Marshak A, et al.. Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when administered concurrently to HIV-Infected women. J Acquir Immune Defic Syndr. 2002;29:471–477.
5. Stuart GS, Moses A, Corbett A, et al.. Combined oral contraceptives and antiretroviral PK/PD in Malawian women: pharmacokinetics and pharmacodynamics of a combined oral contraceptive and a generic combined formulation antiretroviral in Malawi. J Acquir Immune Defic Syndr. 2011;58:e40–e43.
6. Joshi AS, Fiske WD, Benedek IH, et al.. Lack of a pharmacokinetic interaction between efavirenz (DMP 266) and ethinyl estradiol in healthy female volunteers. Conf Retrovir Oppor Infect. 1998. Abstract no. 348. Available at: http://www.aegis.org/DisplayContent/?SectionID=327474
. Accessed March 14, 2014.
7. Carten ML, Kiser JJ, Kwara A, et al.. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. Infect Dis Obstet Gynecol. 2012;2012:137192.
8. Sevinsky H, Eley T, Persson A, et al.. The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women. Antivir Ther. 2011;16:149–156.
9. Landolt NK, Phanuphak N, Ubolyam S, et al.. Efavirenz, in contrast to nevirapine, is associated with unfavorable progesterone and antiretroviral levels when coadministered with combined oral contraceptives. J Acquir Immune Defic Syndr. 2013;62:534–539.
10. McClamrock HD, Adashi EY. Pharmacokinetics of desogestrel. Am J Obstet Gynecol. 1993;168:1021–1028.
12. Kaufman JM, Thiery M, Vermeulen A. Plasma levels of ethinylestradiol (EE2) during cyclic treatment with combined oral contraceptives. Contraception. 1981;24:589–602.
13. Westhoff CL, Torgal AH, Mayeda ER, et al.. Pharmacokinetics and ovarian suppression during use of a contraceptive vaginal ring in normal-weight and obese women. Am J Obstet Gynecol. 2012;207:39.e1–e6.
14. Thomas T, Petrie K, Shim J, et al.. A UPLC-MS/MS method for therapeutic drug monitoring of etonogestrel. Ther Drug Monit. 2013;35:844–848.
15. Fotherby K, Akpoviroro J, Abdel-Rahman HA, et al.. Pharmacokinetics of ethynyloestradiol in women for different populations. Contraception. 1981;23:487–496.
16. Lamba JK, Lin YS, Schuetz EG, et al.. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2002;54:1271–1294.
17. Yamaori S, Yamazaki H, Iwano S, et al.. Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of co-regulation of the expression of CYP3A in Japanese livers. Xenobiotica. 2005;35:69–83.
18. Israel R, Mishell DR Jr, Stone SC, et al.. Single luteal phase serum progesterone assay as an indicator of ovulation. Am J Obstet Gynecol. 1972;112:1043–1046.
19. Wright KP, Johnson JV. Evaluation of extended and continuous use oral contraceptives. Ther Clin Risk Manag. 2008;4:905–911.
20. Rosenberg MJ, Meyers A, Roy V, et al.. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception. 1999;60:321–329.
21. Leticee N, Viard JP, Yamgnane A, et al.. Contraceptive failure of etonogestrel implant in patients treated with antiretrovirals including efavirenz. Contraception. 2012;85:425–427.
22. Matiluko AA, Soundararjan L, Hogston P. Early contraceptive failure of Implanon in an HIV-seropositive patient on triple antiretroviral therapy with zidovudine, lamivudine and efavirenz. J Fam Plann Reprod Health Care. 2007;33:277–278.
23. Lakhman SS, Ma Q, Morse GD. Pharmacogenomics of CYP3A: considerations for HIV treatment. Pharmacogenomics. 2009;10:1323–1339.
24. Sitruk-Ware R. Pharmacological profile of progestins. Maturitas. 2004;47:277–283.