Adverse Perinatal Outcomes Associated With Antiretroviral Therapy Regimens

Systematic Review and Network Meta-Analysis

Chrystelle O.O. Tshivuila-Matala; Susan Honeyman; Charlotte Nesbitt; Shona Kirtley; Stephen H. Kennedy; Joris Hemelaar

Disclosures

AIDS. 2020;34(11):1643-1656. 

In This Article

Abstract and Introduction

Abstract

Objective: Assess adverse perinatal outcomes associated with antenatal antiretroviral therapy (ART) regimens.

Design: Systematic review and network meta-analysis of randomized controlled trials (RCTS).

Methods: We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, EMBASE, and the Cochrane Central Register of Controlled Trials and four clinical trial databases from 1 January 1980 to 28 April 2018. We included RCTs of antenatal ART regimens in HIV-positive pregnant women, which assessed preterm birth (PTB), spontaneous preterm birth (sPTB), very preterm birth (VPTB), low birthweight (LBW), very low birthweight (VLBW), small-for-gestational-age (SGA), neonatal death (NND), and mother-to-child-transmission. We used random-effects network meta-analysis models to calculate relative risks for treatment comparisons and the hierarchy of treatments.

Results: Of 83 260 citations identified, 10 manuscripts were included, assessing 6285 women. Compared with zidovudine (ZDV) monotherapy, we found a higher risk of LBW after exposure to zidovudine/lamivudine/efavirenz (ZDV/3TC/EFV; relative risk 1.61; 95% CI 1.03–2.51), tenofovir disoproxil fumarate/emtricitabine/ritonavir-boosted lopinavir (TDF/FTC/LPV/r; 1.64; 1.18–2.29), or zidovudine/lamivudine/ritonavir-boosted lopinavir (ZDV/3TC/LPV/r; 1.87; 1.58–2.20). TDF/FTC/LPV/r carried an increased risk of VLBW, compared with ZDV monotherapy (5.40; 1.08–27.08). ZDV/3TC/LPV/r posed a higher risk of PTB than ZDV monotherapy (1.43; 1.08–1.91) and a higher risk of sPTB than zidovudine/lamivudine/abacavir (ZDV/3TC/ABC) (1.81; 1.21–2.71). LPV/r-containing regimens also carried the highest risks of VPTB, SGA and NND, although the limited data showed no significant differences.

Conclusion: Of the ART regimens assessed in RCTs in pregnancy, LPV/r-containing regimens were associated with the highest risks of adverse perinatal outcomes.

Introduction

The vast majority of the estimated 1.3 million HIV-positive pregnant women who give birth every year reside in sub-Saharan Africa,[1] a region, which also has the highest rates of neonatal and child mortality.[2] We previously conducted a systematic review and meta-analysis, which showed that maternal HIV infection without antiretroviral therapy (ART) is associated with increased risks of preterm birth (PTB; <37 weeks gestation), low birthweight (LBW; <2500 g), small-for-gestational-age (SGA;<10th centile) and stillbirth.[3] PTB is the most important cause of neonatal and child mortality globally.[4] Furthermore, SGA babies account for 21.9% of neonatal deaths in low-and-middle-income countries (LMICs).[5] PTB and SGA are both causes of LBW, which is frequently used as a surrogate outcome in LMICs, as gestational age is often unknown.[6] Sustainable Development Goal 3 (SDG3) target 3.2 aims to reduce preventable deaths of newborns and children under 5 years, a goal that will be impossible to achieve without addressing the perinatal outcomes that are at the basis of many of these deaths.[7]

Since 2013, the WHO recommends that all HIV-infected pregnant women should receive HAART in order to prevent mother-to-child-transmission (MTCT) of HIV.[8] This led to an increase in the global proportion of pregnant women with HIV who received ART during pregnancy from 44% in 2010 to 82% in 2018, resulting in a 41% reduction in mother-to-child HIV transmission in the same period.[1] In 2015, WHO adopted a 'treat all' approach, which recommends that all HIV-infected individuals, including pregnant women, should initiate lifelong ART as soon as possible after diagnosis, regardless of WHO clinical stage or CD4+ cell count.[9]

WHO currently recommends integrase inhibitor dolutegravir (DTG) combined with a backbone of tenofovir disoproxil fumarate and lamivudine (TDF/3TC) as first-line regimen.[10] Nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) with the same backbone is an alternative first-line regimen. Boosted protease inhibitors, preferably ritonavir-boosted lopinavir (LPV/r) or ritonavir-boosted atazanavir (ATV/r), are designated as second-line regimens. Many aspects are taken into account when recommending ART regimens, such as efficacy in viral suppression, tolerability/adherence, drug resistance, side effects such as weight gain, drug availability and cost.[10,11] In pregnancy, additional considerations need to be taken into account, such as effectiveness in prevention of vertical transmission of HIV and potential risk of congenital abnormalities, such as neural tube defects (NTD).[10–12] The impact of different ART regimens on other important perinatal outcomes, such as PTB, SGA, LBW, stillbirth and neonatal death have been controversial, with conflicting findings reported.[13–16]

With the rapid expansion of ART programs in sub-Saharan Africa, it is imperative to determine the optimal ART regimen in pregnancy. We, therefore, conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) of ART in HIV-positive pregnant women to assess the association of ART regimens with specific adverse perinatal outcomes.

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