Liverpool HIV Interactions

Do Not Coadminister

Efavirenz (EFV)

Levonorgestrel (implant)

Quality of Evidence: Moderate

Summary:

Coadministration is expected to reduce the contraceptive efficacy of the levonorgestrel progestogen-only implant and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives. Data from a study in Malawian women showed efavirenz decreased levonorgestrel concentrations by 40% (at 1 month after implant insertion) to 73% (30 months after implant insertion). An analysis of 570 HIV-infected women in Swaziland using a levonorgestrel implant and lopinavir/ritonavir, nevirapine or efavirenz based regimens showed that 15/121 (12.4%) women on efavirenz became pregnant whereas none of the women on nevirapine (n=208) or lopinavir (n=13) became pregnant. In a smaller study in Uganda, levonorgestrel concentrations decreased by ~50% in women using a levonorgestrel implant with efavirenz (n=20) when compared to ART-naive women (n=17). Three pregnancies (3/20, 15%) occurred in the efavirenz group, but none in the ART-naive group. Data from a small number of subjects (n=8) with levonorgestrel implants showed that efavirenz decreased levonorgestrel concentrations by 61% when compared to a control group of subjects (n=14). The use of levonorgestrel implants is not recommended in women on long-term treatment with hepatic enzyme-inducing drugs. Doubling the dose of a levonorgestrel implant from 150 mg to 300 mg does not fully overcome the interaction with efavirenz. When compared to antiretroviral drug naive women on a 150 mg levonorgestrel implant dose, levonorgestrel concentrations in women on efavirenz were 57% lower with a 150 mg levonorgestrel implant dose and 34% lower with a 300 mg levonorgestrel implant dose. A population pharmacokinetic modelling study showed doubling the levonorgestrel implant dose in patients on EFV allowed levonorgestrel concentrations to reach levels above the efficacy threshold in 91% of the simulations, however, the authors did not recommend this approach as women with a slow metabolizer profile were expected to have sub-therapeutic levonorgestrel concentrations. Note, although women using implants and efavirenz-based antiretroviral regimens have a risk of contraceptive failure, the failure rate is still lower in comparison to other contraceptive methods (i.e., depo-medroxyprogesterone or combined oral contraceptives) due to the higher efficacy of implants.

Description:

Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is recommended.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

Females of reproductive potential should use effective contraception during treatment with efavirenz and for 12 weeks after discontinuing efavirenz due to the long half-life of efavirenz. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods that contain progesterone may have decreased effectiveness.

Efavirenz US Prescribing Information, Aurobindo Pharma Limited, October 2021.

A population pharmacokinetic model was developed for the levonorgestrel implant to simulate exposure of the contraceptive in women living with HIV on an efavirenz, nevirapine, darunavir/r or rilpivirine containing regimen. All women received the standard levonorgestrel implant dose (150 mg) except those on efavirenz containing regimens who received a double dose (300 mg) of the contraceptive. Simulations were also done in uninfected women on the levonorgestrel implant without concurrent antiretroviral treatment. The analysis included 166 Ugandan women; 39 (24%) were not taking antiretrovirals; 29 (18%) were on darunavir/r; 48 (29%) were on efavirenz; 20 (12%) on nevirapine and 30 (18%) on rilpivirine-based regimens. Darunavir/r, efavirenz double dose, nevirapine and rilpivirine treatments were shown to impact the elimination constant (KE) of levonorgestrel. KE was 0.56 (0.46-0.67) with the concurrent use of darunavir/r; 1.44 (1.21-1.69) with efavirenz double-dose and 0.88 (0.76-1.03) with nevirapine or rilpivirine treatments. CYP2B6 metabolizer status further impacted levonorgestrel KE; slow, intermediate and normal metabolizers increased KE by 4.1-, 2.5-, and 1.76-fold, respectively. Most simulated participants on efavirenz-based regimens fell below 300 pg/mL (i.e. levonorgestrel concentrations threshold observed prior to unintended pregnancy). Of these, 92% were efavirenz single dose simulated participants compared to 8% simulated participants on efavirenz double-dose. Simulations demonstrated a rate of concentrations falling below the threshold in line with the typical failure rate of the levonorgestrel implant (<1%) for nevirapine-, darunavir/r-, and rilpivirine-based antiretroviral regimens, supporting the effectiveness of the levonorgestrel implant in combination with these antiretroviral regimens. Conversely, only 15 (1%) of efavirenz single dose participants did not fall below the threshold. On the other hand, 91% of efavirenz double dose simulated participants did not fall below the threshold demonstrating improved efficacy with increased levonorgestrel dosage in combination with efavirenz.

Population pharmacokinetics of the levonorgestrel implant in combination with four antiretroviral therapies. Pham M, Nakalema S, Chappell C, et al. International Workshop on Clinical Pharmacology of HIV, hepatitis and other antiviral drugs, Barcelona, September 2022, abstract 13.

A study evaluated levonorgestrel concentrations in Malawian women on levonorgestrel implant in the presence (n=30) or absence (n=12) of efavirenz during a follow-up of 30 months after initiating the implant. A secondary objective was to evaluate the pregnancy rate among levonorgestrel implant users on efavirenz. The mean geometric concentrations of levonorgestrel were found to be lower in efavirenz users than non-efavirenz users at every time point and ranged from 0.6 (90% confidence interval (CI): 0.46-0.79) at 1 month to 0.27 (90% CI: 0.12-0.61) at 30 months after implant insertion. No pregnancies occurred over 60 women-years of concomitant levonorgestrel implant and efavirenz use, although 11 women had levonorgestrel concentrations <180 pg/mL (i.e. minimum threshold concentration for efficacy).

Effect of efavirenz on levonorgestrel concentrations among Malawian levonorgestrel implant users for up to 30 months of concomitant use: a subanalysis of a randomized clinical trial. Tang JH, Davis NL, Corbett AH et al. Contraception X, 2020; 2:100027.

Coadministration of efavirenz and levonorgestrel (150 mg) implant has been shown to result in a substantial decrease in levonorgestrel concentrations (57%). This study evaluated whether doubling levonorgestrel implant dose (300 mg) would overcome the interaction with efavirenz. Levonorgestrel concentrations (median (IQR)) were 373 (319, 540) pg/mL in women with double levonorgestrel implant dose versus 651 (469, 879) pg/mL in women receiving standard levonorgestrel implant dose (150 mg) (control group) [GMR (90% CI) was 0.66 (0.61, 0.72)]. During the study, 18% in the control group and 46% in the group with double dose of levonorgestrel had any levonorgestrel value < 303 pg/mL (i.e. levonorgestrel concentration threshold previously associated with unintended pregnancy) (p=0.06). Levonorgestrel concentrations were 33-44% lower in women receiving efavirenz based antiretroviral therapy with double levonorgestrel implant dose compared to antiretroviral drug naïve women on levonorgestrel implant dose 150 mg. Relative to efavirenz + levonorgestrel implant dose 150 mg, the magnitude of the interaction with efavirenz was smaller with levonorgestrel implant dose 300 mg (34% lower) versus standard-dose levonorgestrel (57% lower). In addition, fewer women receiving efavirenz based therapy had a levonorgestrel level <303 pg/mL when doubling levonorgestrel dose versus standard dose (46% versus 90%, respectively; p = 0.002). The authors conclude that doubling the dose of levonorgestrel implant does not fully overcome the interaction with efavirenz, and the contraceptive effectiveness of this approach remains uncertain.

Double-dose levonorgestrel implant does not fully overcome interaction with efavirenz. Scarsi KK, Cirrincione L, Nakalema S, et al. CROI 2019, Seattle, March 2019, abstract 51.

CYP2B6 single nucleotide polymorphisms associated with a slow efavirenz metabolism have been associated with lower levonorgestrel exposure when the standard dose of levonorgestrel implant was combined with efavirenz. This study evaluated the association between CYP2B6 metabolizer status and levonorgestrel pharmacokinetics when doubling the implant dose. Levonorgestrel concentrations (median (IQR)) were 537 (529.5-597) pg/mL, 310 (253-344.8) pg/mL and 167 (103-301) pg/mL for normal (n=7), intermediate (n=16) and slow (n=5) metabolizers, respectively. CYP2B6 metabolizer status was correlated with levonorgestrel exposure. Levonorgestrel AUC was 35% lower in intermediate metabolizers and 47% lower in slow metabolizers when compared with normal metabolizers. Efavirenz concentrations were associated with lower levonorgestrel concentrations. This study provides further evidence that CYP2B6 genetic variants influence levonorgestrel pharmacokinetics when combined with efavirenz based antiretroviral therapy. The authors conclude that impaired efavirenz metabolism may make it more difficult to use an increased levonorgestrel dose to overcome the interaction with efavirenz-based treatment.

Effect of CYP2B6 metabolizer status on levonorgestrel pharmacokinetics when combined with efavirenz-based antiretroviral therapy. Pham M, Mbabazi O, Neary M, et al. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs, May 2019, abstract 7

Plasma concentrations of contraceptive implant progestins were determined in HIV-positive women already on contraceptive implants who started efavirenz-containing (n=11) or nevirapine-containing (n=13) antiretroviral therapy or who remained ART-naïve (levonorgestrel n=14; etonogestrel n=22). In the efavirenz group, levonorgestrel concentrations decreased by 61% (n=8) and etonogestrel concentrations decreased by 49% (n=3) when compared to the control group. No difference was observed in the nevirapine group compared with controls (levonorgestrel concentrations decreased by 7% (n=6); etonogestrel concentrations increased by 7%(n=7)).

A pharmacokinetic and pharmacogenetic evaluation of contraceptive implants and antiretroviral therapy among women in Kenya and Uganda. Patel RC, Stalter RM, Thomas KK, et al. AIDS. 2019;33(13):1995-2004.

The effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics was studied in three groups of HIV-infected Ugandan women: ART-naive (n=17), efavirenz-based ART (n=20), and nevirapine-based ART (n=20). Levonorgestrel implants were inserted at baseline in all women. In one year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy. At week 24, levonorgestrel concentration were 47% lower in the efavirenz group, and 35% higher in the nevirapine group when compared to the ART-naive group (geometric mean levonorgestrel concentrations 528, 280, and 710 pg/ml in the ART-naive, efavirenz, and nevirapine groups, respectively). At week 48, levonorgestrel concentration were 57% lower in the efavirenz group, and 14% higher in the nevirapine group when compared to the ART-naive group (levonorgestrel concentrations 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups.

Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks. Scarsi KK, Darin KM, Nakalema S, et al. Clin Infect Dis, 2016, 62(6): 675-82.

A retrospective analysis including data from 24,560 Kenyan HIV-positive women aimed to determine whether pregnancy rates differ between women who use various contraceptive methods and either efavirenz-based or nevirapine-based antiretroviral therapy regimens. The primary outcome was incident pregnancy diagnosed clinically. In women using etonogestrel or levonorgestrel implants, adjusted pregnancy incidence 1.1 per 100 person-years (95% CI 0.72-1.5) for nevirapine-based regimens users and 3.3 per 100 person-years (1.8-4.8) for efavirenz-based ART users. In women using depot medroxyprogesterone acetate, adjusted pregnancy incidence was 4.5 per 100 person-years (3.7-5.2) for nevirapine-based ART users and 5.4 per 100 person-years (4-6.8) for efavirenz-based ART users. Women using other contraceptive methods, except for intrauterine devices, had 3.1-4.1 higher rates of pregnancy than those using implants with 1.6-2.8 higher rates in women using efavirenz-based ART. The authors conclude that although HIV-positive women using implants and efavirenz-based ART had a three-times higher risk of contraceptive failure than those using nevirapine-based ART, the contraceptive failure rates were still lower than in women receiving all other contraceptive methods except for intrauterine devices and permanent methods.

Pregnancy rates in HIV-positive women using contraceptives and efavirenz-based or nevirapine-based antiretroviral therapy in Kenya: a retrospective cohort study. Patel RC, Onono M, Gandhi M, et al. Lancet HIV 2015; 2(11): e474-82.

An analysis of 570 HIV-infected women in Swaziland using levonorgestrel implant and lopinavir/ritonavir, nevirapine or efavirenz based regimens showed that none of the women on nevirapine (n=208) or lopinavir (n=13) became pregnant whereas 15/121 (12.4%) women on efavirenz became pregnant.

Implementing the Jadelle implant for women living with HIV in a resource-limited setting: concerns for drug interactions leading to unintended pregnancies. Perry SH, Swamy P, Preidis GA, et al. AIDS, 2014, 28(5): 791-793.

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