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Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

ABSTRACT: Background: To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens.

Methods: We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework.

Findings: We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48-2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04-0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48-0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50-0·92).

Interpretation: The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable.

Funding: WHO.

SUBMITTER: Kanters S

PROVIDER: S-EPMC7700905 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

Kanters Steve S Vitoria Marco M Zoratti Michael M Doherty Meg M Penazzato Martina M Rangaraj Ajay A Ford Nathan N Thorlund Kristian K Anis Prof Aslam H PAH Karim Mohammad Ehsanul ME Mofenson Lynne L Zash Rebecca R Calmy Alexandra A Kredo Tamara T Bansback Nick N

EClinicalMedicine 20201016

<h4>Background</h4>To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens.<h4>Methods</h4>We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 ...[more]

PMID: 33294805

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Project description:BACKGROUND:Global rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana. METHODS:In this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [<37 weeks' gestation], small for gestational age [SGA; less than the tenth percentile of birthweight by gestational age], or neonatal death [within 28 days of age]) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks' gestation], and very SGA [less than the third percentile of birthweight by gestational age]). We fitted log-binomial regression models, controlling for maternal age, gravidity, and education, to estimate adjusted risk ratios (aRRs). FINDINGS:Our analysis included 1729 pregnant women who initiated dolutegravir-based ART and 4593 who initiated efavirenz-based ART. The risk for any adverse birth outcome among women on dolutegravir versus efavirenz was similar (33·2% vs 35·0%; aRR 0·95, 95% CI 0·88-1·03), as was the risk of any severe birth outcome (10·7% vs 11·3%; 0·94, 0·81-1·11). We found no significant differences by regimen in the individual outcomes of stillbirth, neonatal death, preterm birth, very preterm birth, SGA, or very SGA. INTERPRETATION:Adverse birth outcomes were similar among pregnant women who initiated dolutegravir-based and efavirenz-based ART. Dolutegravir-based ART can be safely initiated in pregnancy. FUNDING:National Institutes of Health.

Project description:BackgroundTuberculosis (TB) is a significant public health problem that causes substantial morbidity and mortality. Current first-line anti-TB chemotherapy, although very effective, has limitations including long-treatment duration with a possibility of non-adherence, drug interactions, and toxicities. Dose escalation of rifampicin, an important drug within the regimen, has been proposed as a potential route to higher treatment efficacy with shorter duration and some studies have suggested that dose escalation is safe; however, these have almost entirely been conducted among human immunodeficiency (HIV)-negative TB patients. TB-HIV co-infected patients on antiretroviral therapy (ART) are at increased risk of drug-drug interactions and drug-related toxicities. This study aims to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz (EFV) and dolutegravir (DTG) in TB-HIV co-infected patients.MethodsThis study is a randomized, open-label, phase IIb clinical trial among TB-HIV infected adult outpatients attending an HIV clinic in Kampala, Uganda. Patients newly diagnosed with TB will be randomized to either standard-dose or high-dose rifampicin (35 mg/kg) alongside standard TB treatment. ART-naïve patients will be randomly assigned to first-line ART regimens (DTG or EFV). Those who are already on ART (DTG or EFV) at enrollment will be continued on the same ART regimen but with dose adjustment of DTG to twice daily dosing. Participants will be followed every 2 weeks with assessment for toxicities at each visit and measurement of drug concentrations at week 6. At the end of intensive-phase therapy (8 weeks), all participants will be initiated on continuation-phase treatment using standard-dose rifampicin and isoniazid.DiscussionThis study should avail us with evidence about the effect of higher doses of rifampicin on the pharmacokinetics of EFV and DTG among TB-HIV co-infected patients. The trial should also help us to understand safety concerns of high-dose rifampicin among this vulnerable cohort.Trial registrationClinicalTrials.gov, ID: NCT03982277. Registered retrospectively on 11 June 2019.

Project description:IntroductionConcerns about dolutegravir (DTG) tolerability in the real-life setting have recently arisen. We aimed to estimate the risk of treatment discontinuation and virological failure of DTG-based regimens from a large cohort of HIV-infected individuals.MethodsWe performed a multicentre, observational study including all antiretroviral therapy (ART)-naïve and virologically suppressed treatment-experienced (TE) patients from the Icona (Italian Cohort Naïve Antiretrovirals) cohort who started, for the first time, a DTG-based regimen from January 2015 to December 2017. We estimated the cumulative risk of DTG discontinuation regardless of the reason and for toxicity, and of virological failure using Kaplan-Meier curves. We used Cox regression model to investigate predictors of DTG discontinuation.ResultsAbout 1679 individuals (932 ART-naïve, 747 TE) were included. The one- and two-year probabilities (95% CI) of DTG discontinuation were 6.7% (4.9 to 8.4) and 11.5% (8.7 to 14.3) for ART-naïve and 6.6% (4.6 to 8.6) and 7.6% (5.4 to 9.8) for TE subjects. In both ART-naïve and TE patients, discontinuations of DTG were mainly driven by toxicity with an estimated risk (95% CI) of 4.0% (2.6 to 5.4) and 2.5% (1.3 to 3.6) by one year and 5.6% (3.8 to 7.5) and 4.0% (2.4 to 5.6) by two years respectively. Neuropsychiatric events were the main reason for stopping DTG in both ART-naïve (2.1%) and TE (1.7%) patients. In ART-naïve, a concomitant AIDS diagnosis predicted the risk of discontinuing DTG for any reason (adjusted relative hazard (aRH) = 3.38, p = 0.001), whereas starting DTG in combination with abacavir (ABC) was associated with a higher risk of discontinuing because of toxicity (aRH = 3.30, p = 0.009). TE patients starting a DTG-based dual therapy compared to a triple therapy had a lower risk of discontinuation for any reason (adjusted hazard ratio (aHR) = 2.50, p = 0.037 for ABC-based triple-therapies, aHR = 3.56, p = 0.012 for tenofovir-based) and for toxicity (aHR = 5.26, p = 0.030 for ABC-based, aHR = 6.60, p = 0.024 for tenofovir-based). The one- and two-year probabilities (95% CI) of virological failure were 1.2% (0.3 to 2.0) and 4.6% (2.7 to 6.5) in the ART naïve group and 2.2% (1.0 to 3.3) and 2.9% (1.5 to 4.3) in the TE group.ConclusionsIn this large cohort, DTG showed excellent efficacy and optimal tolerability both as first-line and switching ART. The low risk of treatment-limiting toxicities in ART-naïve as well as in treated individuals reassures on the use of DTG in everyday clinical practice.

Dataset Information

Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

Publications

Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

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