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CLINICAL SCIENCE

Drug interactions between hormonal contraceptives and antiretrovirals

Nanda, Kavita; Stuart, Gretchen S.; Robinson, Jennifer; Gray, Andrew L.; Tepper, Naomi K.; Gaffield, Mary E.

Author Information
doi: 10.1097/QAD.0000000000001392

Abstract

Introduction

Women living with HIV will likely take combination antiretroviral therapy (cART) for much of their lives [1]. Those at high risk for HIV may also use antiretrovirals for preexposure prophylaxis (PrEP). Contraceptive use among women living with HIV or using antiretrovirals for PrEP is critical, as unintended pregnancy and short interpregnancy intervals can be associated with negative health consequences for both mother and infant [2–4]. Decreasing unintended pregnancies also reduces vertical HIV transmission [5]. Hormonal contraceptives are highly used worldwide, including in areas of high HIV prevalence; they are also among the most effective contraceptive methods [6,7]. Evidence-based guidance for hormonal contraceptives use among women using cART or PrEP is needed to ensure access to a full range of the best contraceptive methods, and therefore increase the likelihood of achieving their reproductive life planning goals.

Concurrent use of hormonal contraceptives and antiretrovirals can lead to drug interactions, predominantly due to effects on liver metabolism (Tables 1 and 2). In the liver, cytochrome P450 (CYP) enzymes catalyze many important reactions, with the most significant for contraceptive metabolism being CYP3A4, which is also expressed in the intestines [8,9]. Antiretrovirals include different classes of drug (Table 2), including nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside analogue reverse transcriptase inhibitors or nucleotide analogue reverse transcriptase inhibitor (NRTIs), protease inhibitors, fusion inhibitors, and integrase inhibitors. The NNRTIs and integrase inhibitors are generally not substrates, inhibitors, nor inducers of cytochrome P450 enzymes [10]. In contrast, both protease inhibitors and NNRTIs are metabolized by CYP3A4 and also inhibit or induce this enzyme, resulting in increases or decreases in the concentration of concomitantly administered drugs [10].

Table 1
Table 1:
Steroids used in currently available contraceptive methods, their liver metabolism, and effects on liver enzymes.
Table 2
Table 2:
Antiretrovirals included in the review, their liver metabolism, and effects on liver enzymes.

Such interactions could lead to decreased contraceptive effectiveness (increasing risk of unintended pregnancy), decreased cART effectiveness (associated with resistance and/or HIV disease progression), decreased efficacy of PrEP (increasing risk of HIV acquisition), or increased antiretroviral or contraceptive toxicity. Based on theoretical concerns and limited data, women using cART are sometimes offered fewer contraceptive choices than their HIV-negative peers [11]. The objective of this review was to systematically examine published evidence on drug interactions between hormonal contraceptives and antiretrovirals, in order to contribute to improved clinical and policy decision-making.

Methods

We followed the PRISMA and MOOSE guidelines for conducting the review and reporting the results [12,13].

We searched PubMed, POPLINE, and EMBASE from database inception to 21 September 2015 for studies of hormonal contraceptive and antiretroviral drug interactions (Supplement 1, http://links.lww.com/QAD/B36). We also hand-searched reference lists of published studies, and contacted topic experts.

Study selection

We included published studies of women using hormonal contraceptives (Table 1), including combined oral contraceptives (COCs), progestin-only pills (POPs), emergency contraceptive pills (ECPs), injectables, vaginal rings, patches, or implants. Studies included women who were either HIV-positive, HIV-negative but at risk of HIV, or healthy, who concurrently used cART, PrEP, or single antiretrovirals and hormonal contraceptives. We included studies reporting on women taking oral contraceptives where the type of oral contraceptive was not specified. We excluded studies evaluating women on cART without comparisons by contraceptive use, those evaluating only genital HIV viral load, and those evaluating only hormonal intrauterine devices (IUDs). We also excluded case or case-series reports, cross-sectional studies, reviews, editorials, and letters.

Outcomes of interest were clinical and pharmacokinetic measures of the contraceptive and the antiretroviral. Clinical outcomes included measures of contraceptive, cART, or PrEP effectiveness, and combined toxicity. Contraceptive effectiveness measures of interest were pregnancy or surrogate measures of pregnancy risk, including ovulation, ovarian activity, or cervical mucus. Because no studies reported on true ovulation as documented by ultrasound, we included studies using serum progesterone alone as a marker of presumed ovulation. For cART effectiveness, we included studies that reported markers of HIV disease progression such as CD4+ cell count or HIV viral load, need for change in cART regimen, or death; for PrEP effectiveness, the relevant outcome was HIV prevention. Pharmacokinetic endpoints were plasma drug concentrations over time, as well as the area under the concentration–time curve (AUC), half-life (t1/2), minimum (Cmin; trough) and maximum (Cmax; peak) concentrations, for both contraceptive steroids and antiretrovirals.

Data abstraction and management

After screening and removal of duplicates, we abstracted relevant data from each included report using a predesigned form. Two authors independently reviewed selected manuscripts, with differences resolved by consensus.

We described strengths, weaknesses, and funding source for each included study (Tables 3 and 4) [14–65], but did not do formal quality assessment because no formal evidence grading system exists for pharmacokinetic studies.

Table 3
Table 3:
Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 3
Table 3:
(Continued) Studies reporting clinical measures of contraceptive and/or antiretroviral effectiveness with co-administration of hormonal contraceptives and antiretrovirals.
Table 4
Table 4:
Studies reporting pharmacokinetic outcomes with co-administration of hormonal contraceptives and antiretrovirals.
Table 4
Table 4:
(Continued) Studies reporting pharmacokinetic outcomes with co-administration of hormonal contraceptives and antiretrovirals.
Table 4
Table 4:
(Continued) Studies reporting pharmacokinetic outcomes with co-administration of hormonal contraceptives and antiretrovirals.
Table 4
Table 4:
(Continued) Studies reporting pharmacokinetic outcomes with co-administration of hormonal contraceptives and antiretrovirals.
Table 4
Table 4:
(Continued) Studies reporting pharmacokinetic outcomes with co-administration of hormonal contraceptives and antiretrovirals.
Table 4
Table 4:
(Continued) Studies reporting pharmacokinetic outcomes with co-administration of hormonal contraceptives and antiretrovirals.
Table 4
Table 4:
(Continued) Studies reporting pharmacokinetic outcomes with co-administration of hormonal contraceptives and antiretrovirals.
Table 4
Table 4:
(Continued) Studies reporting pharmacokinetic outcomes with co-administration of hormonal contraceptives and antiretrovirals.

Results

Our search identified 1570 records. Fifty published reports from 46 individual studies met the inclusion criteria (Fig. 1, Tables 3 and 4). Four reports were secondary analyses or subsets of the primary studies and are included with the primary study in the tables [14–17]. The results are presented by outcome assessed, focusing first on the most important clinical outcomes (contraceptive effectiveness, antiretroviral effectiveness, toxicity associated with combined administration), then the pharmacokinetic data (for contraceptives and antiretrovirals), in each case by antiretroviral class and by contraceptive method.

Fig. 1
Fig. 1:
Flow diagram of publication selection for inclusion into the review.

Contraceptive effectiveness

Although pregnancy is the most relevant outcome, few large studies were designed to investigate contraceptive effectiveness. Several secondary analyses helped fill this gap, particularly for women using nevirapine-containing or efavirenz-containing cART. Although some small pharmacokinetic studies of healthy women report on pregnancy, women were generally required to use additional contraception; these studies are included in Table 3 but not summarized here.

Nonnucleoside reverse transcriptase inhibitors

Fourteen reports from clinical trials and six secondary analyses described contraceptive effectiveness measures among women using NNRTIs and hormonal contraceptives (Table 3).

Oral contraceptives

Two clinical trials of women using cART and oral contraceptives [18,19], six secondary analyses [20–25] and five pharmacokinetic trials (mostly in healthy women using single antiretrovirals with COCs) [26–30], evaluated pregnancy or ovulation. No pregnancies were found to be associated with nevirapine or efavirenz in the prospective clinical trials.

Pregnancy rates and ovulation rates did not differ between HIV-positive women taking COCs and nevirapine-containing cART and those not yet taking cART [18]. In a small trial of women using COCs with efavirenz-containing cART, three women ovulated (out of 25) but no pregnancies were reported [19]. Five small pharmacokinetic trials of NNRTIs and COCs also demonstrated no ovulation among study participants [26–30].

In large cohort studies, pregnancy rates were slightly higher among women taking efavirenz-containing cART (11–15/100 woman-years) compared with women taking oral contraceptive and nevirapine-containing cART or no cART (pregnancy rates 6–11/100 woman-years) [24,25]. Notably the reported pregnancy rates in the large cohort studies are still lower than an expected pregnancy rate of 40 per 100 woman-years among women not using any modern contraceptive and trying to prevent pregnancy.

Other retrospective cohort studies reported pregnancy rates among oral contraceptive users ranging from 2.6 to 5.8 per 100 woman-years (most, but not all, women were using nevirapine) [20,21].

Depot medroxyprogesterone acetate

In two pharmacokinetic studies, women using depot medroxyprogesterone acetate (DMPA) remained anovulatory when using cART containing either efavirenz or nevirapine [14,31,32]. Five cohort studies also presented pregnancy rates with injectables among cART users. In the largest, pregnancy rates ranged from 8 to 10 per 100 woman-years for injectable users, with higher rates in efavirenz users and those not on cART compared with pregnancy rates in those using nevirapine [24]. Another found women using DMPA had pregnancy rates from 3 to 5 per 100 woman-years, with lower rates among users of nevirapine and efavirenz compared with no cART [25]. Two additional studies reported pregnancy rates from 1.8 to 4.2 per 100 woman-years among DMPA users taking various antiretrovirals (primarily nevirapine) [20,21].

Implants

Pregnancy rates among users of cART and contraceptive implants differed by whether the implant contained levonorgestrel or etonogestrel, and whether women were taking efavirenz or nevirapine. Pregnancy rates were higher among women using the levonorgestrel implant concomitantly with efavirenz. Two prospective studies (N = 79 and N = 45) reported no pregnancies through 3 years and 6 months, respectively, among women using etonogestrel implants and NNRTI-containing cART [33,34], although the second study found that women taking efavirenz-containing cART had a 2.8% presumed ovulation rate over 6 months. In a small pharmacokinetic study of women using levonorgestrel implants and cART containing efavirenz or nevirapine, three pregnancies (3/20; 15%) occurred within 48 weeks, all in women taking efavirenz [35]. Similar findings were seen in a large retrospective study, where 15 of 121 (12.4%) women using levonorgestrel implants and efavirenz-containing cART became pregnant, at a mean duration of 16.4 months; no pregnancies occurred among women taking nevirapine-containing cART [36].

Two secondary analyses described pregnancy rates with implant use in women using efavirenz-containing or nevirapine-containing cART [24,25]. In the first, pregnancy rates for users of efavirenz, nevirapine, and no cART were 5.5, 2.3, and 3.4 per 100 woman-years for etonogestrel implant users, and 7.1, 1.9, and 3.3 per 100 woman-years for levonorgestrel implant users, respectively [24]. In the second, pregnancy rates per 100 woman-years were 1.4 for unspecified implant users not taking cART, 0 for nevirapine users, and 6 for women taking efavirenz [25].

Protease inhibitors

Seven small pharmacokinetic trials described contraceptive effectiveness measures among women using protease inhibitors and hormonal contraceptives (Table 3) [14,16,31,34,37–39].

Combined oral contraceptives/patches

Co-administration of darunavir/ritonavir with COCs resulted in no ovulation [38]. Similarly, coadministration of lopinavir/ritonavir containing cART in women using a contraceptive patch also found no ovulations [37].

Progestin-only pills

One report showed that oral norethindrone thickened cervical mucus and led to similar mucus scores in women using protease inhibitor-containing cART compared with those taking NRTIs alone [16].

Depot medroxyprogesterone acetate

Reports of women using lopinavir/ritonavir-containing or nelfinavir-containing cART with DMPA found that no women ovulated [14,31,39].

Implants

No ovulations nor pregnancies were reported in a pharmacokinetic study of etonogestrel implant users taking lopinavir/ritonavir-containing cART [34].

Nucleoside/nucleotide reverse transcriptase inhibitors

Analyses of two large trials of hormonal contraceptives and NRTIs used for PrEP found that use of tenofovir/emtricitabine did not affect pregnancy rates among users of COCs, injectables, or implants [40,41].

Integrase inhibitors

A small pharmacokinetic study of dolutegravir with COCs resulted in no ovulations [42].

Antiretroviral effectiveness

Eight reports evaluated the effects of hormonal contraceptive use on the effectiveness of NNRTI-containing or protease inhibitor-containing cART, and found no effects on death, CD4+ cell count, or plasma viral load with concurrent use of DMPA, levonorgestrel implants, or oral contraceptives [14,43–49]. Use of DMPA also did not affect the efficacy of PrEP [50].

Toxicity of combined administration

Studies among healthy women using hormonal contraceptives concurrently with single antiretrovirals, or HIV-positive women using cART, generally reported no difference in adverse events of concurrent treatment compared with use of either hormonal contraceptives or antiretrovirals alone (Table 3). One HIV prevention trial evaluated pharmacodynamic interactions between tenofovir-containing PrEP with oral contraceptives or DMPA, and found that bone mineral density was not significantly decreased [51].

Contraceptive pharmacokinetics

Thirty-two reports include contraceptive pharmacokinetic measures among women using antiretrovirals and hormonal contraceptives (Table 4).

Nonnucleoside reverse transcriptase inhibitors

Contraceptive pharmacokinetics among women using NNRTIs and hormonal contraceptives were described in 11 studies (Table 4) [15,26–32,34,52,53].

Combined oral contraceptives

Two studies evaluated efavirenz with COCs: one in women taking only efavirenz, and one in women taking efavirenz-containing cART [15,26]. Ethinyl estradiol concentrations were not significantly changed, but progestin levels decreased by approximately 60%.

Three studies reported the effect of nevirapine on COC pharmacokinetics. Ethinyl estradiol levels varied from being unchanged to being approximately 30–60% lower [15,30,53]. Progestin levels were not significantly affected.

Studies of etravirine and rilpivirine in women taking COCs found minimal effects [27,28]. Similarly, a study of fosdevirine (the development of which was discontinued due to toxicity) found no effect on hormone levels in COC users [29].

Depot medroxyprogesterone acetate

Two studies evaluated the effect of NNRTIs on DMPA, and found no difference in medroxyprogesterone acetate pharmacokinetics through 12 weeks with concurrent use of either efavirenz-containing or nevirapine-containing cART [31,32].

Implants

A study of women using etonogestrel implants found 54–70% lower etonogestrel levels among women taking efavirenz-containing cART compared with women taking no cART [34].

Emergency contraceptive pills

One study in healthy women showed that levonorgestrel levels were 56% lower in ECP users after use of efavirenz [52].

Protease Inhibitors

Ten reports described contraceptive pharmacokinetics among women using protease inhibitors and hormonal contraceptives (Table 3) [17,31,34,37–39,54–57].

Combined oral contraceptives/Patch

Two studies examining concurrent use of ritonavir and COCs found decreased ethinyl estradiol levels, whereas progestin levels were unaffected [54,57]. Another study showed decreased ethinyl estradiol levels, but increased progestin levels, when COCs were used with atazanavir/ritonavir [55]. Similar findings were reported with lopinavir/ritonavir-containing cART and the contraceptive patch [37]. This study also reported lower ethinyl estradiol levels with concurrent use of a single COC pill, but progestin levels were not evaluated. Only darunavir/ritonavir was associated with significantly lower ethinyl estradiol levels as well as slightly lower norethindrone levels [38].

Progestin-only pills

In women receiving protease inhibitor-containing cART, norethindrone levels were higher compared with controls [56]. A subanalysis restricted to women using ritonavir-boosted atazanavir confirmed this finding [17].

Depot medroxyprogesterone acetate

One study showed significantly increased medroxyprogesterone acetate concentrations, compared with historical controls, in women using DMPA and lopinavir/ritonavir-containing cART [39].

Implants

A study evaluating the effect of cART on the pharmacokinetics of the etonogestrel implant found women using lopinavir/ritonavir-containing cART had etonogestrel levels approximately 50% higher than women not taking cART [34].

Nucleoside/nucleotide reverse transcriptase inhibitors

Two studies evaluating NRTIs used for PrEP with COCs or levonorgestrel implants showed no change in hormone levels [58,59].

Chemokine receptor 5 antagonists

Two studies showed that neither maraviroc nor vicriviroc impacted hormone levels when used concurrently with COCs [57,60].

Integrase inhibitors

In two studies, concurrent use of COCs and raltegravir led to small increases in progestin exposure [61], but dolutegravir had no impact on hormone levels [42].

Antiretroviral pharmacokinetics

Fifteen studies described antiretroviral pharmacokinetics among women using antiretrovirals and hormonal contraceptives; most were among healthy women and compared drug concentrations to historical controls (Table 4) [19,26,27,31,37–39,53–55,60,62–65].

Nonnucleoside reverse transcriptase inhibitors

Three studies evaluated the impact of COCs on the pharmacokinetics of efavirenz [19,26,62]. Among women using COCs and efavirenz alone, concentrations were similar to historical controls [26]. However, in a trial of women on efavirenz-containing cART, use of COCs led to efavirenz concentrations lower than historical controls [19]. Another analysis of women taking efavirenz-containing cART found no difference in efavirenz concentrations between hormonal contraceptive users and nonusers [62].

Three studies evaluated the impact of COCs on nevirapine levels. In two reports of women using nevirapine-containing cART, nevirapine levels were not significantly different in women using COCs [19,53]. Time to undetectable nevirapine levels was longer in women receiving single-dose nevirapine and using COCs [63]. Another study found rilpivirine levels in COC users to be similar to historical controls [27].

Among women on various cART regimens, nevirapine levels were slightly higher after administration of DMPA, but no changes in efavirenz levels were noted [31].

Protease inhibitors

Four studies investigated the effects of COCs on the pharmacokinetics of protease inhibitors [38,54,55,64]. Levels of saquinavir were not affected by COC use, but atazanavir levels were slightly increased [55,64]. Co-administration with COCs resulted in darunavir and ritonavir levels comparable to those in historical controls [38,54].

Co-administration of the contraceptive patch with lopinavir/ritonavir-containing cART resulted in slightly decreased levels of both protease inhibitors compared with historical controls [37], whereas DMPA had no effect on protease inhibitor levels in women taking such regimens [39].

Nucleoside/nucleotide reverse transcriptase inhibitors

One study found no effect of hormonal contraceptives (COCs and DMPA) on zidovudine plasma or intracellular pharmacokinetics [65].

Chemokine receptor 5 antagonists

When maraviroc was taken with COCs, levels were similar to those seen in historical controls [60].

Discussion

Few of the 50 reports included in this review provided relevant data that can be applied to clinical practice with certainty (Table 5). The most significant interactions with hormonal contraceptives occurred in women using cART-containing NNRTIs, particularly efavirenz. However, even in these studies, the outcomes reported were often pharmacokinetic rather than clinical, involved small populations, which limited study power, or were derived retrospectively from secondary analyses of existing cohorts.

Table 5
Table 5:
Summary of included clinical and pharmacokinetic data on HC-antiretroviral drug interactions; PK differences <30% considered no change (↔), blank cells indicate absence of data.
Table 5
Table 5:
(Continued) Summary of included clinical and pharmacokinetic data on HC-antiretroviral drug interactions; PK differences <30% considered no change (↔), blank cells indicate absence of data.
Table 5
Table 5:
(Continued) Summary of included clinical and pharmacokinetic data on HC-antiretroviral drug interactions; PK differences <30% considered no change (↔), blank cells indicate absence of data.

The most important outcome for contraceptive drug interactions is method failure resulting in pregnancy, but few studies reported this outcome (Table 5). Changes in contraceptive hormone levels do not necessarily translate into reduced efficacy or increased toxicity, as levels vary greatly within and between individuals and populations [66,67]. Further, the contraceptive threshold, or minimum steroid hormone level required to maintain contraceptive effectiveness, is difficult to determine [68,69]. However, when pharmacokinetic data show no or minimal changes, clinical effects are unlikely. Ovulation is used in many drug–drug interaction studies to indicate risk of pregnancy, but ovulation is also a surrogate marker. The occurrence of ovulation does not always result in pregnancy. For example, many women ovulate during levonorgestrel implant use, yet contraceptive effectiveness remains high [70]. Additionally, no included studies evaluated true ovulation; rather, ovulation was presumed based on serum progesterone measurements alone, which can be inaccurate [70].

The most clinically significant drug–drug interactions identified in our systematic review were reported in women using efavirenz-containing cART and COCs or progestin-containing subdermal implants. Although studies show DMPA is not impacted by efavirenz use, studies of women using efavirenz and contraceptive implants reported pregnancy rates ranging from 5 to 15 per 100 woman-years, and COC users taking efavirenz had pregnancy rates ranging from 13 to 15 per 100 woman-years [24,25,35]. For COCs, because contraceptive effectiveness relies on user adherence, potential additional reductions in effectiveness from a drug interaction, if confirmed, are concerning. Conversely, studies that reported on women using contraceptives with nevirapine-containing cART were generally reassuring. None of the studies that enrolled women using a number of different hormonal contraceptives with nevirapine reported increases in pregnancy or ovulation rates [18,19,21,24,25,30,35,36,45].

The many other studies included in this review that evaluated hormonal contraceptives and antiretrovirals other than efavirenz reported no results that should change clinical practice. Antiretrovirals used in PrEP do not affect hormonal contraceptive effectiveness. Concurrent use of protease inhibitors with COCs does not alter contraceptive effectiveness despite the observed decreased ethinyl estradiol plasma levels found, as the progestin component is primarily responsible for contraceptive effectiveness. Minimal to no changes in progestin levels were reported in multiple studies of concurrent protease inhibitor and hormonal contraceptive use. Although concomitant use of a few protease inhibitors led to increased progestin levels in some studies, these changes are unlikely to impact safety given the variable doses and wide safety margin of contraceptive progestins.

Despite the small number of reports in our review, studies were also reassuring with regard to the effect of hormonal contraceptives on cART or PrEP effectiveness, or antiretroviral pharmacokinetics. Pharmacokinetic studies were limited because they either only reported antiretroviral pharmacokinetics compared with historical controls or presented data from healthy women taking single antiretrovirals.

Concurrent antiretroviral and hormonal contraceptive use also does not appear to lead to increased toxicity, though most studies were of short duration (1–28 days). Short-term pharmacokinetic studies may not accurately reflect adverse effects that may occur during use of long-term cART or PrEP with hormonal contraceptives. The only study to evaluate long-term toxicity showed little impact of concurrent use of DMPA and tenofovir on bone mineral density over 1 year [51]. Pharmacokinetic effects may also be time-dependent, further limiting the utility of short-term evaluations.

Strengths of our review included a comprehensive search strategy, systematic review of study inclusion by all authors, and dual data abstraction. Limitations are generally due to lack of studies evaluating relevant clinical outcomes. In addition, few studies are available regarding whether implants containing levonorgestrel or etonogestrel have different contraceptive effectiveness when used with efavirenz. Furthermore, with both implants, it is possible that interactions with enzyme inducers such as efavirenz are time-dependent, because hormone levels decrease over time after implantation [71]. Other data gaps are whether injectable contraceptives other than intramuscular DMPA, such as the lower-dose subcutaneous DMPA or injectable norethisterone enanthate, might be susceptible to drug interactions. Questions also remain regarding any impact of lower-dose efavirenz regimens [72] on hormonal contraceptive effectiveness, which cannot be predicted. Another limitation is that intracellular antiretroviral concentrations are likely a better predictor of clinical effectiveness than plasma levels, but pharmacokinetic studies only reported the latter. Finally, women on cART may also take other drugs that can alter liver metabolism, such as rifampin, and the combined effect of multiple enzyme-inducing medications on contraceptive hormone levels remains poorly characterized.

Our review highlights the dearth of studies designed to provide meaningful clinical data to guide contraceptive choices for HIV-positive women taking cART. Studies should be designed to report clinical outcomes such as pregnancy and HIV disease progression during long-term administration. Currently, incomplete data are being used to limit contraceptive choices for HIV-positive women. In the absence of well conducted prospective clinical trials, data from pharmacokinetic studies and secondary analyses have been used to make clinical judgments on medication effectiveness and inform contraceptive policy. For example, in October 2014 the South African authorities recommended that women using efavirenz or other enzyme-inducing drugs should not use etonogestrel implants [11]. In May 2016, the European Medicines Agency recommended that women taking hepatic enzyme inducing drugs, including efavirenz, be offered double doses of oral levonorgestrel for postcoital emergency contraception [73]. When such guidance is developed, the absolute risk of pregnancy should be considered and addressed in the guidance publications, as well as other considerations such as availability and contraceptive effectiveness of the alternatives proposed. Even if a particular contraceptive method is potentially less effective than usual in a woman using a concomitant antiretroviral, it may still be more effective than many alternative contraceptive methods [74]. Although nonhormonal methods such as copper IUDs are not affected by drug interactions, their use remains very low in many settings worldwide, and efforts to increase IUD use have had limited success [7]. If access to implants is restricted, in many settings DMPA would be the primary option available to women, virtually eliminating woman-centered decision making.

In summary, current published data do not support limiting women's access to any hormonal contraceptives. Women taking antiretrovirals for HIV treatment (in the form of cART) or prevention (in the form of PrEP) should have access to the full range of hormonal contraceptive options, and be enabled to make informed decisions about their options. Contraceptive efficacy is only one of many factors that an individual may consider when choosing a contraceptive method, and some women who are motivated to use the etonogestrel implant may wish to do so even if there is concern for decreased efficacy when used with efavirenz. National or regional restrictions on contraceptive method access, while well intentioned, supersede women's personal decisions, which may actually increase risk of unintended pregnancy if remaining contraceptive options are unacceptable or inaccessible. More well designed prospective studies are needed to examine potential drug interactions between antiretrovirals and all contraceptive methods, to better inform guidelines and counseling for the more than 16 million women living with HIV.

Acknowledgements

This manuscript is made possible by the generous support of the American people through the United States Agency for International Development (USAID), provided to FHI 360 through cooperative agreement number AID-OAA-A-15-00045 and consolidated grant number GHA-G-00-09-00003 provided to the WHO. We also thank Drs Margaret Doherty, Marco De Avila Vitoria, and Shaffiq Essajee for their expert advice.

Roles of the authors: The WHO (MLG) initiated the idea to update this systematic review. K.N. led the conduct of the systematic review, conducted the literature searches, and coordinated review procedures and drafting of the manuscript. All authors participated in framing the study questions, developing eligibility criteria, reviewing identified studies for eligibility, abstracting study information, interpreting the data, and contributing to the writing, and editing of the manuscript. All authors reviewed and approved the final manuscript before submission.

Source of funding: K.N. has led previous systematic reviews on this topic, and authored a few of the studies included in the review. G.S.S. authored one of the studies included in the review. The WHO and USAID provided support for the writing of this systematic review and for the writing group to attend a working meeting in Geneva, Switzerland, in 2015.

Disclaimer: The contents are the responsibility of the authors and do not necessarily reflect represent the official positions of FHI360, USAID, the Centers for Disease Control and Prevention, the WHO, or other institutions with which the authors are affiliated.

Conflicts of interest

There are no conflicts of interest.

References

1. Gunthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society – USA panel. JAMA 2016; 316:191–210.
2. Obare F, van der Kwaak A, Birungi H. Factors associated with unintended pregnancy, poor birth outcomes and postpartum contraceptive use among HIV-positive female adolescents in Kenya. BMC Womens Health 2012; 12:34.
3. DeFranco EA, Seske LM, Greenberg JM, Muglia LJ. Influence of interpregnancy interval on neonatal morbidity. Am J Obstet Gynecol 2015; 212:386.e381–386.389.
4. Ngo AD, Roberts CL, Figtree G. Association between interpregnancy interval and future risk of maternal cardiovascular disease – a population-based record linkage study. BJOG 2016; 123:1311–1318.
5. Wilcher R, Petruney T, Cates W. The role of family planning in elimination of new pediatric HIV infection. Curr Opin HIV AIDS 2013; 8:490–497.
6. Trussell J. Contraceptive failure in the United States. Contraception 2011; 83:397–404.
7. United Nations Department of Social and Economic Affairs, Population Division. World Contraceptive Use; 2015. http://www.un.org/en/development/desa/population/publications/dataset/contraception/wcu2015.shtml. [Accessed 1 December 2016].
8. Shen DD, Kunze KL, Thummel KE. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev 1997; 27:99–127.
9. Edelman AB, Cherala G, Stanczyk FZ. Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review. Contraception 2010; 82:314–323.
10. Tseng A, Hills-Nieminen C. Drug interactions between antiretrovirals and hormonal contraceptives. Expert Opin Drug Metab Toxicol 2013; 9:559–572.
11. Department of Health, Republic of South Africa. Circular: changes in the prescription of progestin subdermal implants (Implanon) in women who are taking enzyme inducing drugs such as efavirenz for HIV, rifampicin for TB, and certain drugs used for epilepsy (carbamazepine, phenytoin, and phenobarbital); 2014. Available at: http://www.sahivsoc.org/upload/documents/Circular – Changes in the Prescription of Progestin Subdermal Implants.pdf. [Accessed 1 December 2016].
12. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339:b2535.
13. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008–2012.
14. Watts DH, Park JG, Cohn SE, Yu S, Hitti J, Stek A, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception 2008; 77:84–90.
15. Landolt NK, Phanuphak N, Ubolyam S, Pinyakorn S, Kerr S, Ahluwalia J, et al. Significant decrease of ethinylestradiol with nevirapine, and of etonogestrel with efavirenz in HIV-positive women. J Acquir Immune Defic Syndr 2014; 66:e50–e52.
16. Atrio J, Stek A, Vora H, Sanchez-Keeland L, Zannat F, Natavio M. The effect of protease inhibitors on the cervical mucus of HIV-positive women taking norethindrone contraception. Eur J Contracept Reprod Healthcare 2015; 20:149–153.
17. DuBois BN, Atrio J, Stanczyk FZ, Cherala G. Increased exposure of norethindrone in HIV+ women treated with ritonavir-boosted atazanavir therapy. Contraception 2015; 91:71–75.
18. Nanda K, Delany-Moretlwe S, Dube K, Lendvay A, Kwok C, Molife L, et al. Nevirapine-based antiretroviral therapy does not reduce oral contraceptive effectiveness. AIDS 2013; 27 (suppl 1):S17–S25.
19. Landolt NK, Phanuphak N, Ubolyam S, Pinyakorn S, Kriengsinyot R, Ahluwalia J, 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.
20. Myer L, Carter RJ, Katyal M, Toro P, El-Sadr WM, Abrams EJ. Impact of antiretroviral therapy on incidence of pregnancy among HIV-infected women in Sub-Saharan Africa: a cohort study. PLoS Med 2010; 7:e1000229.
21. Schwartz SR, Rees H, Mehta S, Venter WD, Taha TE, Black V. High incidence of unplanned pregnancy after antiretroviral therapy initiation: findings from a prospective cohort study in South Africa. PLoS One 2012; 7:e36039.
22. Danel C, Moh R, Anzian A, Abo Y, Chenal H, Guehi C, et al. Tolerance and acceptability of an efavirenz-based regimen in 740 adults (predominantly women) in West Africa. J Acquir Immune Defic Syndr 2006; 42:29–35.
23. Clark RA, Theall K. Population-based study evaluating association between selected antiretroviral therapies and potential oral contraceptive failure. J Acquir Immune Defic Syndr 2004; 37:1219–1220.
24. Patel RC, Onono M, Gandhi M, Blat C, Hagey J, Shade SB, et al. Pregnancy rates in HIV-positive women using contraceptives and efavirenz-based or nevirapine-based antiretroviral therapy in Kenya: a retrospective cohort study. Lancet HIV 2015; 2:e474–e482.
25. Pyra M, Heffron R, Mugo NR, Nanda K, Thomas KK, Celum C, et al. Effectiveness of hormonal contraception in HIV-infected women using antiretroviral therapy. AIDS 2015; 29:2353–2359.
26. Sevinsky H, Eley T, Persson A, Garner D, Yones C, Nettles R, 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.
27. Crauwels HM, Van Heeswijk RPG, Buelens A, Stevens M, Hoetelmans RMW. Lack of an effect of rilpivirine on the pharmacokinetics of ethinylestradiol and norethindrone in healthy volunteers. Int J Clin Pharmacol Ther 2014; 52:118–128.
28. Scholler-Gyure M, Kakuda TN, Woodfall B, Aharchi F, Peeters M, Vandermeulen K, et al. Effect of steady-state etravirine on the pharmacokinetics and pharmacodynamics of ethinylestradiol and norethindrone. Contraception 2009; 80:44–52.
29. Piscitelli S, Kim J, Gould E, Lou Y, White S, de Serres M, et al. Drug interaction profile for GSK2248761, a next generation nonnucleoside reverse transcriptase inhibitor. Br J Clin Pharmacol 2012; 74:336–345.
30. Stuart GS, Moses A, Corbett A, Phiri G, Kumwenda W, Mkandawire N, 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.
31. Cohn SE, Park JG, Watts DH, Stek A, Hitti J, Clax PA, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther 2007; 81:222–227.
32. Nanda K, Amaral E, Hays M, Viscola MA, Mehta N. Pharmacokinetic interactions between depot medroxyprogesterone acetate and combination antiretroviral therapy. Fertil Steril 2008; 90:965–971.
33. Kreitchmann R, Innocente AP, Preussler GM. Safety and efficacy of contraceptive implants for HIV-infected women in Porto Alegre, Brazil. Int J Gynaecol Obstet 2012; 117:81–82.
34. Vieira C, Bahamondes MV, Souza R, Brito M, Prandini T, Amaral E, et al. Effect of antiretroviral therapy including lopinavir/ritonavir or efavirenz on the etonogestrel-releasing implant pharmacokinetics in HIV-infected women. Eur J Contracept Reprod Healthcare 2014; 19:S72–S73.
35. Scarsi KK, Darin KM, Nakalema S, Back DJ, Byakika-Kibwika P, Else LJ, et al. Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks. Clin Infect Dis 2016; 62:675–682.
36. Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. Implementing the Jadelle implant for women living with HIV in a resource-limited setting: concerns for drug interactions leading to unintended pregnancies. AIDS 2014; 28:791–793.
37. Vogler MA, Patterson K, Kamemoto L, Park JG, Watts H, Aweeka F, et al. Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1-infected women: pharmacokinetic results of ACTG trial A5188. J Acquir Immune Defic Syndr 2010; 55:473–482.
38. Sekar VJ, Lefebvre E, Guzman SS, Felicione E, De Pauw M, Vangeneugden T, et al. Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. Antivir Ther 2008; 13:563–569.
39. Luque AE, Cohn SE, Park JG, Cramer Y, Weinberg A, Livingston E, et al. Depot medroxyprogesterone acetate in combination with a twice-daily lopinavir-ritonavir-based regimen in HIV-infected women showed effective contraception and a lack of clinically significant interactions, with good safety and tolerability: results of the ACTG 5283 study. Antimicrob Agents Chemother 2015; 59:2094–2101.
40. Murnane PM, Heffron R, Ronald A, Bukusi EA, Donnell D, Mugo NR, et al. Preexposure prophylaxis for HIV-1 prevention does not diminish the pregnancy prevention effectiveness of hormonal contraception. AIDS 2014; 28:1825–1830.
41. Callahan R, Nanda K, Kapiga S, Malahleha M, Mandala J, Ogada T, et al. Pregnancy and contraceptive use among women participating in the FEM-PrEP trial. J Acquir Immune Defic Syndr 2015; 68:196–203.
42. Song IH, Borland J, Chen S, Wajima T, Peppercorn AF, Piscitelli SC. Dolutegravir has no effect on the pharmacokinetics of oral contraceptives with norgestimate and ethinyl estradiol. Ann Pharmacother 2015; 49:784–789.
43. Whiteman MK, Jeng G, Samarina A, Akatova N, Martirosyan M, Kissin DM, et al. Associations of hormonal contraceptive use with measures of HIV disease progression and antiretroviral therapy effectiveness. Contraception 2015; 93:17–24.
44. Day S, Graham SM, Masese LN, Richardson BA, Kiarie JN, Jaoko W, et al. A prospective cohort study of the effect of depot medroxyprogesterone acetate on detection of plasma and cervical HIV-1 in women initiating and continuing antiretroviral therapy. J Acquir Immune Defic Syndr 2014; 66:452–456.
45. Hubacher D, Liku J, Kiarie J, Rakwar J, Muiruri P, Omwenga J, et al. Effect of concurrent use of antiretroviral therapy and levonorgestrel sub-dermal implant for contraception on CD4 counts: a prospective cohort study in Kenya. J Int AIDS Soc 2013; 16:18448.
46. Polis CB, Nakigozi G, Ssempijja V, Makumbi FE, Boaz I, Reynolds SJ, et al. Effect of injectable contraceptive use on response to antiretroviral therapy among women in Rakai, Uganda. Contraception 2012; 86:725–730.
47. Johnson D, Kempf MC, Wilson CM, Shrestha S. Hormonal contraceptive use and response to antiretroviral therapy among adolescent females. HIV AIDS Rev 2011; 10:65–69.
48. Chu JH, Gange SJ, Anastos K, Minkoff H, Cejtin H, Bacon M, et al. Hormonal contraceptive use and the effectiveness of highly active antiretroviral therapy. Am J Epidemiol 2005; 161:881–890.
49. Cejtin HE, Jacobson L, Springer G, Watts DH, Levine A, Greenblatt R, et al. Effect of hormonal contraceptive use on plasma HIV-1-RNA levels among HIV-infected women. AIDS 2003; 17:1702–1704.
50. Heffron R, Mugo N, Were E, Kiarie J, Bukusi E, Mujugira A, et al. PrEP is efficacious for HIV prevention among women using DMPA for contraception. Topics Antivir Med 2014; 22:498.
51. Kasonde M, Niska RW, Rose C, Henderson FL, Segolodi TM, Turner K, et al. Bone mineral density changes among HIV-uninfected young adults in a randomised trial of preexposure prophylaxis with tenofovir-emtricitabine or placebo in Botswana. PLoS One 2014; 9:e90111.
52. Carten ML, Kiser JJ, Kwara A, Mawhinney S, Cu-Uvin S. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. Infect Dis Obstet Gynecol 2012; 2012:137192.
53. Mildvan D, Yarrish R, Marshak A, Hutman HW, McDonough M, Lamson M, 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.
54. Ouellet D, Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, et al. Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin Pharmacol 1998; 46:111–116.
55. Zhang J, Chung E, Yones C, Persson A, Mahnke L, Eley T, et al. The effect of atazanavir/ritonavir on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy women. Antivir Ther 2011; 16:157–164.
56. Atrio J, Stanczyk FZ, Neely M, Cherala G, Kovacs A, Mishell DR Jr. Effect of protease inhibitors on steady state pharmacokinetics of oral norethindrone contraception in HIV infected women. J Acquir Immune Defic Syndr 2014; 65:72–77.
57. Kasserra C, Li J, March B, O’Mara E. Effect of vicriviroc with or without ritonavir on oral contraceptive pharmacokinetics: a randomized, open-label, parallel-group, fixed-sequence crossover trial in healthy women. Clin Ther 2011; 33:1503–1514.
58. Kearney BP, Mathias A. Lack of effect of tenofovir disoproxil fumarate on pharmacokinetics of hormonal contraceptives. Pharmacotherapy 2009; 29:924–929.
59. Todd CS, Deese J, Wang M, Hubacher D, Steiner MJ, Otunga S, et al. Sino-implant (II)(R) continuation and effect of concomitant tenofovir disoproxil fumarate-emtricitabine use on plasma levonorgestrel concentrations among women in Bondo, Kenya. Contraception 2015; 91:248–252.
60. Abel S, Russell D, Whitlock LA, Ridgway CE, Muirhead GJ. Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers. Br J Clin Pharmacol 2008; 65 (suppl 1):19–26.
61. Anderson MS, Hanley WD, Moreau AR, Jin B, Bieberdorf FA, Kost JT, et al. Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women. Br J Clin Pharmacol 2011; 71:616–620.
62. Burger D, van der Heiden I, la Porte C, van der Ende M, Groeneveld P, Richter C, et al. Interpatient variability in the pharmacokinetics of the HIV nonnucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 2006; 61:148–154.
63. Muro E, Droste JA, Hofstede HT, Bosch M, Dolmans W, Burger DM. Nevirapine plasma concentrations are still detectable after more than 2 weeks in the majority of women receiving single-dose nevirapine: implications for intervention studies. J Acquir Immune Defic Syndr 2005; 39:419–421.
64. Frohlich M, Burhenne J, Martin-Facklam M, Weiss J, von Wolff M, Strowitzki T, et al. Oral contraception does not alter single dose saquinavir pharmacokinetics in women. Br J Clin Pharmacol 2004; 57:244–252.
65. Aweeka FT, Rosenkranz SL, Segal Y, Coombs RW, Bardeguez A, Thevanayagam L, et al. The impact of sex and contraceptive therapy on the plasma and intracellular pharmacokinetics of zidovudine. Aids 2006; 20:1833–1841.
66. Fotherby K, Akpoviroro J, Abdel-Rahman HA, Toppozada HK, de Souza JC, Coutinho EM, et al. Pharmacokinetics of ethynyloestradiol in women for different populations. Contraception 1981; 23:487–496.
67. Fotherby K. Variability of pharmacokinetic parameters for contraceptive steroids. J Steroid Biochem 1983; 19:817–820.
68. Lobo RA, Stanczyk FZ. New knowledge in the physiology of hormonal contraceptives. Am J Obstet Gynecol 1994; 170:1499–1507.
69. Cherala G, Edelman A, Dorflinger L, Stanczyk FZ. The elusive minimum threshold concentration of levonorgestrel for contraceptive efficacy. Contraception 2016; 94:104–108.
70. Alvarez F, Brache V, Faundes A, Tejada AS, Thevenin F. Ultrasonographic and endocrine evaluation of ovarian function among Norplant implants users with regular menses. Contraception 1996; 54:275–279.
71. Sivin I, Wan L, Ranta S, Alvarez F, Brache V, Mishell DR Jr, et al. Levonorgestrel concentrations during 7 years of continuous use of Jadelle contraceptive implants. Contraception 2001; 64:43–49.
72. Carey D, Puls R, Amin J, Losso M, Phanupak P, Foulkes S, et al. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, noninferiority ENCORE1 study. Lancet Infect Dis 2015; 15:793–802.
73. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). CHMP assessment report: Levonelle 1500 mcg tablets and associated names; 26 May 2016. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Levonelle_13/WC500211776.pdf. [Accessed 1 December 2016].
74. Steiner MJ, Kwok C, Dominik R, Byamugisha JK, Chipato T, Magwali T, et al. Pregnancy risk among oral contraceptive pill, injectable contraceptive, and condom users in Uganda, zimbabwe, and Thailand. Obstet Gynecol 2007; 110:1003–1009.
Keywords:

antiretroviral therapy; contraceptive implant; depot medroxyprogesterone acetate; HIV; hormonal contraception; systematic review

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