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Background: Severe hepatotoxicity in people with human immunodeficiency virus (HIV) receiving efavirenz (EFV) has been reported. We assessed the incidence and risk factors of hepatotoxicity in women of childbearing age initiating EFV-containing regimens. Methods: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, ART-naive pregnant women with HIV and CD4 count ≥ 350 cells/μL and alanine aminotransferase ≤ 2.5 the upper limit of normal were randomized during the antepartum and postpartum periods to antiretroviral therapy (ART) strategies to assess HIV vertical transmission, safety, and maternal disease progression. Hepatotoxicity was defined per the Division of AIDS Toxicity Tables. Cox proportional hazards models were constructed with covariates including participant characteristics, ART regimens, and timing of EFV initiation. Results: Among 3576 women, 2435 (68%) initiated EFV at a median 121.1 weeks post delivery. After EFV initiation, 2.5% (61/2435) had severe (grade 3 or higher) hepatotoxicity with an incidence of 2.3 (95% confidence interval [CI], 2.0-2.6) per 100 person-years. Events occurred between 1 and 132 weeks postpartum. Of those with severe hepatotoxicity, 8.2% (5/61) were symptomatic, and 3.3% (2/61) of those with severe hepatotoxicity died from EFV-related hepatotoxicity, 1 of whom was symptomatic. The incidence of liver-related mortality was 0.07 (95% CI,. 06-.08) per 100 person-years. In multivariable analysis, older age was associated with severe hepatotoxicity (adjusted hazard ratio per 5 years, 1.35 [95% CI, 1.06-1.70]). Conclusions: Severe hepatotoxicity after EFV initiation occurred in 2.5% of women and liver-related mortality occurred in 3% of those with severe hepatotoxicity. The occurrence of fatal events underscores the need for safer treatments for women of childbearing age.
The PROMISE multicountry randomized trial [19] compared antepartum and postpartum HIV PMTCT strategies in pregnant women with high CD4 cell counts through sequential antepartum and postpartum randomizations. The full methodology has been presented previously [19, 20]. In brief, antepartum women were randomized to 1 of 3 regimens: (1) zidovudine (ZDV) plus intrapartum single-dose nevirapine (sd-NVP) followed by 6–14 days of tenofovir disproxil fumarate (TDF) and emtricitabine (FTC) “tail” postpartum (ZDV alone); (2) ZDV, lamivudine, and ritonavir-boosted lopinavir (LPV/r) (ZDV-based ART); or (3) TDF, FTC, and LPV/r (TDF-based ART). After delivery, women were randomized again to postpartum ART or no ART. In the last randomization (maternal health component), mothers on ART were randomized to either continue or stop ART. Mothers who did not want to be randomized or meet criteria for randomization were followed in observational follow-up. The first randomization occurred in 2011 with follow-up ending in September 2016. Supplementary Figure 1 outlines the PROMISE randomizations. On 7 July 2015, PROMISE sites were notified of the results of the Strategic Timing of Antiretroviral Therapy (START) study, which demonstrated a lower risk of developing AIDS or other serious illnesses with ART initiation in early asymptomatic HIV infection [21], and sites were instructed to recommend that all women enrolled in PROMISE initiate ART regardless of prior randomization or CD4 cell count. Sites offered either local standard of care ART (generally EFV-ART) or, if access was unavailable, study-supplied ART. Consequently, EFV-ART became more common in the last 15 months of the study. This analysis focuses on women enrolled in PROMISE who received EFV-ART, the majority of who first received EFV-ART after delivery. Figure 1A demonstrates the uptake of EFV-ART and other ART regimens during the study period from the first randomization. Antiretroviral therapy (ART) distribution and median alanine aminotransferase (ALT) over Promoting Maternal and Infant Survival Everywhere (PROMISE) study period. A, Proportion of women in major antiretroviral regimen groups as percentage in each ART group across time (week) since the first PROMISE randomization. B, Median ALT/upper limit of normal in each ART group across time (week) since the first PROMISE randomization (1-week time window for sample sizes > 10). Abbreviations: 3TC, lamivudine; ALT, alanine aminotransferase; ARV, antiretroviral; EFV, efavirenz; FTC, emtricitabine; LPV/r, ritonavir-boosted lopinavir; sd-NVP, single-dose nevirapine; START, Strategic Timing of Antiretroviral Therapy; TDF, tenofovir disoproxil fumarate; TDF-FTC tail, 1 week of tenofovir disoproxil fumarate–emtricitabine administered postpartum in the women who were randomized to ZDV alone in the antepartum period; ULN, upper limit of normal; ZDV, zidovudine. Toxicity management included drug discontinuation for any symptomatic alanine aminotransferase (ALT) elevation deemed possibly, probably, or definitely related to EFV-ART and study treatment hold for asymptomatic grade 3 or higher ALT elevation. Permanent discontinuation of individual ART regimens was performed with guidance from a clinical monitoring committee. The PROMISE1077BF/1077FF study inclusion criteria included pretreatment CD4 count ≥ 350 cells/μL, or greater than or equal to the country-specific threshold of treatment initiation if the threshold was > 350 cells/μL; gestation ≥ 14 weeks; no previous use of triple ART except for PMTCT in previous pregnancies; a hemoglobin level of at least 7.5 g/dL; an absolute neutrophil count of ≥ 750 cells/μL; an ALT ≤ 2.5 times the upper limit of normal (ULN); a calculated creatinine clearance of at least 60 mL/minute; and no serious pregnancy complications. After delivery, ALT was assessed at weeks 1, 6, 14, 26, and 50 and every 24 weeks until the end of follow-up. In the maternal health component, ALT was assessed at screening, entry, and at weeks 4, 12, 24, and every 24 weeks until the end of follow-up. Additional ALT measurements occurred at early ART discontinuation and when women met criteria for ART initiation; ALT was then repeated 4 weeks afterward. ALT was also assessed at an event-driven visit, defined as confirmation of immunologic or virologic failure, discontinuation of ART for toxicity reasons, or a clinically significant event suggestive of acute exacerbation of hepatitis B. Women who were hepatitis B surface antigen (HBsAg) positive at enrollment had an additional ALT assessment at postpartum week 38. Severe hepatotoxicity was defined as grade 3 (5.1–10.0) or grade 4 (> 10.0) × ULN ALT elevation using the Division of AIDS toxicity tables (2004/2009) [22]; grade 2 ALT elevation was defined as 1.25–2.5 times the ULN. Symptomatic events were defined as scleral icterus or jaundice, abdominal, or lower extremity swelling, or otherwise unexplained petechiae or abdominal pain. We defined a medication to be hepatotoxic if it was 1 of 72 medications identified as a cause of drug-induced liver injury (DILI) in 5 or more adjudicated DILI cases in 3 DILI registries [23]. We also included albendazole and antimalarial medications. Cox proportional hazards models were run for each covariate and entered in a multivariable model. Covariates included age, body mass index, ALT, prior ALT elevation, HBsAg status, ART regimen prior to EFV-ART and duration, CD4 cell count, country, EFV-ART initiation date, time from delivery to EFV-ART initiation, receipt of EFV-ART prior to delivery, nucleos(t)ide reverse transcriptase inhibitor (NRTI) in EFV-ART, and antepartum and postpartum randomizations. Two-sided 95% confidence intervals (CIs) are presented and associations were assessed at a .05 significance level. Analyses were carried out in SAS software version 9.4.
