Abacavir hydroxyacetate

The WHO recommends antiretroviral therapy (ART) containing two nucleoside reverse transcriptase inhibitors (NRTIs) as backbone. WHO recommends tenofovir disoproxil fumarate combined with lamivudine or emtricitabine as first line in pregnancy, and zidovudine, abacavir or tenofovir alafenamide, combined with lamivudine or emtricitabine, as alternatives.

This study aims to evaluate the risk of adverse perinatal outcomes in pregnant women living with HIV (WLHIV) receiving different NRTIs.

Data sources included Medline, CINAHL, Global Health, and Embase.

Cohort studies.

Pregnant WLHIV.

ART regimens containing different NRTI drugs.

Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development and Evaluation.

Random-effects meta-analysis.

In total, 22 cohort studies including 124,478 pregnant WLHIV met the eligibility criteria. ART containing tenofovir disoproxil fumarate was associated with lower risk of preterm birth (risk ratio, 0.89; 95% CI, 0.81-0.97), very preterm birth (0.58; 0.40-0.86), small for gestational age (0.76; 0.59-0.98), very small for gestational age (0.60; 0.48-0.73), stillbirth (0.49; 0.31-0.78), and neonatal death (0.61; 0.40-0.93), compared with ART not containing tenofovir disoproxil fumarate. ART containing zidovudine was associated with an increased risk of very preterm birth (1.59; 1.01-2.49), small for gestational age (1.33; 1.03-1.70), very small for gestational age (1.63; 1.25-2.13), stillbirth (2.23; 1.10-4.55), and neonatal death (1.65; 1.08-2.52), compared with ART not containing zidovudine. For ART regimens also containing either lamivudine or emtricitabine, zidovudine was associated with an increased risk of very preterm birth (1.62; 1.04-2.52), small for gestational age (1.52; 1.28-1.82), very small for gestational age (1.68; 1.36-2.06), stillbirth (2.19; 1.03-4.67), and neonatal death (1.65; 1.08-2.52), compared with ART containing tenofovir disoproxil fumarate. Abacavir was not associated with adverse perinatal outcomes. Tenofovir alafenamide was not associated with low birthweight compared with tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate is associated with a lower risk of adverse perinatal outcomes, whereas zidovudine is associated with an increased risk of perinatal outcomes. Abacavir is not associated with adverse perinatal outcomes. Our findings support current WHO guidelines.

Abacavir (ABC), Dolutegravir (DTG), and Lamivudine (3TC) are part of a fixed-dose combination medication for the treatment of HIV. The three drugs offer different but complementary mechanisms of action by inhibiting reverse transcriptase and integrase, and ultimately inhibiting HIV replication. Due to the lack of information regarding long-term safety following in utero exposure, we are evaluating potential toxicity to offspring following in utero exposure to this combination therapy in Hsd:Sprague Dawley®SD® (HSD) rats, including cardiovascular toxicity and neurotoxicity. Generating internal exposure data are integral to putting toxicological findings into context. The objective of this work was to develop and validate a method to simultaneously quantitate ABC, DTG, and 3TC in rat matrices following exposure to this combination. The method used protein precipitation of plasma, fetal, placental, brain, or heart homogenate, followed by ultra-performance liquid chromatography-tandem mass spectrometry. In adult Sprague Dawley rat plasma, the method was linear (r ≥ 0.99) over the range 10/15/5 to 10,000/15,000/5000 ng/mL for ABC/DTG/3TC and recovery was ≥92% for all three analytes at all concentration levels. The limits of detection were 2.22, 3.69, and 0.978 ng/mL for ABC, DTG, and 3TC, respectively. Intra- and inter-day precision was ≤8.7% relative standard deviation (RSD), and relative error (RE) ≤±12.0% for standards prepared at 20/30/10, 400/600/200, and 5000/7500/2500 ng/mL. Matrix standards as high as 40/60/20 µg/mL could be diluted into the calibration range (RE≤±3.5% and RSD ≤2.4%). The method was evaluated for HSD rat maternal plasma and fetal, placental, brain, and heart homogenates (mean RE ≤±15.0% and RSD ≤8.6%). Analyte stability was demonstrated in extracted plasma for 2 days at different temperatures, and in various matrices stored at −80°C for at least 32 days (80–113% of Day 0 concentrations). These data demonstrate that this simple and efficient method is suitable for quantitation of ABC, DTG, and 3TC in rat matrices generated from toxicology studies. The method can easily be adapted to other biological matrices and species (e.g. human).