Adverse perinatal outcomes associated with timing of initiation of antiretroviral therapy: Systematic review and meta-analysis.

BACKGROUND: The World Health Organization (WHO) recommends immediate initiation of lifelong antiretroviral therapy (ART) for all people living with HIV, including pregnant women. As a result, an increasing number of women living with HIV conceive while taking ART, the vast majority of whom reside in low- and middle-income countries (LMICs). We aimed to assess the association between timing of ART initiation and perinatal outcomes. METHODS: We conducted a systematic literature review by searching PubMed, CINAHL (EBSCOhost), Global Health (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials and four clinical trial databases (WHO International Clinical Trials Registry Platform, the Pan African Clinical Trials Registry, the ClinicalTrials.gov database, and the ISRCTN Registry) from 1 January 1980 to 28 April 2018. We identified studies reporting specific perinatal outcomes among pregnant women living with HIV according to timing of ART initiation and extracted data. Perinatal outcomes assessed were preterm birth (<37 weeks), very preterm birth (<32 weeks), low birthweight (<2500 g), very low birthweight (<1500 g), small for gestational age (<10th centile), very small for gestational age (<3rd centile) and neonatal death (<29 days). Random-effects meta-analyses examined perinatal outcomes associated with preconception and antenatal ART initiation as well as according to trimesters of antenatal initiation. We performed quality assessments and subgroup and sensitivity analyses, and assessed the effect of adjustment for confounders. This systematic review and meta-analyses is registered with PROSPERO, number CRD42021248987. RESULTS: Of 51 874 unique citations, 25 studies (eight prospective and 17 retrospective cohort studies) were eligible for analysis, including 40 920 women living with HIV. Preconception ART initiation was associated with a significantly increased risk of preterm birth (relative risk 1.16; 95% confidence interval [CI] 1.03-1.31) compared with antenatal ART initiation. Preconception ART initiation was not significantly associated with very preterm birth, low birthweight, very low birthweight, small for gestational age, very small for gestational age, or neonatal death. First trimester exposure (i.e. preconception or first trimester initiation) was not significantly associated with any increased risk of adverse perinatal outcomes. No significant association between timing of ART initiation and adverse perinatal outcomes was found in the studies of higher quality and those conducted in LMICs. CONCLUSION: Preconception ART initiation is associated with preterm birth but no other adverse perinatal outcomes. In LMICs, where most pregnant women living with HIV reside, the timing of ART initiation was not associated with any adverse perinatal outcomes.

Medical student support for vulnerable patients during COVID-19 - a convergent mixed-methods study.

BACKGROUND: The coronavirus pandemic has exerted significant impacts on primary care, causing rapid digital transformation, exacerbating social isolation, and disrupting medical student and General Practice [GP] trainee education. Here we report on a medical student telephone initiative set-up by a final year GP trainee (the equivalent of a family medicine resident), which aimed to support patients at high risk and vulnerable to the Coronavirus Disease of 2019 [Covid-19]. In addition, it was hoped the project would mitigate a digital divide, enable proactive anticipatory planning, and provide an active learning environment to compensate for the pandemic's impact on medical education. METHODS: Thirty-three medical students conducted daily telephone conversations with high risk and vulnerable patients as specified by the initial NHSE published lists. They confirmed public health messages, offered details for voluntary support groups, established need for medication delivery, explored levels of digital connectivity, and prompted discussions around end-of-life choices. Students had access to online reflective resources and daily remote debriefing sessions with the GP trainee. A convergent mixed-methods evaluation was subsequently undertaken, using quantitative process and descriptive data and individual qualitative interviews were conducted according to a maximal variation sampling strategy with students, General Practitioners [GPs], and the GP trainee. Inductive thematic analysis was then applied with cross-validation, respondent validation, and rich evidential illustration aiding integrity. RESULTS: Ninety-seven 'high risk' and 781 'vulnerable' calls were made. Individuals were generally aware of public heath information, but some struggled to interpret and apply it within their own lives. Therefore respondents felt students provided additional practical and psychological benefits, particularly with regard to strengthening the links with the community voluntary groups. The project was widely liked by students who reported high levels of skill development and widened awareness, particularly valuing the active learning environment and reflective feedback sessions. CONCLUSION: This study demonstrates utilization of medical students as wider assets within the primary health care team, with an initiative that enables support for vulnerable patients whilst promoting active medical education. Ongoing integration of students within 'normal' primary health care roles, such as chronic disease or mental health reviews, could provide similar opportunities for supported active and reflective learning.

Comparative risk of adverse perinatal outcomes associated with classes of antiretroviral therapy in pregnant women living with HIV: systematic review and meta-analysis.

Background: Integrase strand transfer inhibitor (INSTI) dolutegravir (DTG)-based antiretroviral therapy (ART) is recommended by World Health Organisation as preferred first-line regimen in pregnant women living with human immunodeficiency virus (HIV) (WLHIV). Non-nucleoside reverse transfer inhibitor (NNRTI)-based ART and protease inhibitor (PI)-based ART are designated as alternative regimens. The impact of different ART regimens on perinatal outcomes is uncertain. We aimed to assess the comparative risk of adverse perinatal outcomes in WLHIV receiving different classes of ART. Materials and methods: A systematic literature review was conducted by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and July 14, 2023. We included studies reporting on the association of pregnant WLHIV receiving different classes of ART with 11 perinatal outcomes: preterm birth (PTB), very PTB, spontaneous PTB, low birthweight (LBW), very LBW, term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Pairwise random-effects meta-analyses compared the risk of each adverse perinatal outcome among WLHIV receiving INSTI-ART, NNRTI-ART, PI-ART, and nucleoside reverse transfer inhibitor (NRTI)-based ART, and compared specific "third drugs" from different ART classes. Subgroup and sensitivity analyses were conducted based on country income status and study quality. Results: Thirty cohort studies published in 2006-2022, including 222,312 pregnant women, met the eligibility criteria. Random-effects meta-analyses found no evidence that INSTI-ART is associated with adverse perinatal outcomes compared to NNRTI-ART and PI-ART. We found that PI-ART is associated with a significantly increased risk of SGA (RR 1.28, 95% confidence interval (95% CI) [1.09, 1.51], p = 0.003) and VSGA (RR 1.41, 95% CI [1.08, 1.83], p = 0.011), compared to NNRTI-ART. Specifically, lopinavir/ritonavir (LPV/r) was associated with an increased risk of SGA (RR 1.40, 95% CI [1.18, 1.65], p = 0.003) and VSGA (RR 1.84, 95% CI [1.37, 2.45], p = 0.002), compared to efavirenz, but not compared to nevirapine. We found no evidence that any class of ART or specific "third drug" was associated with an increased risk of PTB. Conclusion: Our findings support the recommendation of INSTI-ART as first-line ART regimen for use in pregnant WLHIV. However, the increased risks of SGA and VGSA associated with PI-ART, compared to NNRTI-ART, may impact choice of second- and third-line ART regimens in pregnancy.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021248987.

Perinatal outcomes associated with combination antiretroviral therapy compared with monotherapy.

OBJECTIVES: Increasing numbers of women living with HIV (WLHIV) worldwide receive combination antiretroviral therapy (cART) during pregnancy. We aimed to assess the risk of adverse perinatal outcomes in pregnant WLHIV receiving cART compared with pregnant WLHIV receiving zidovudine monotherapy. DESIGN: Systematic review and meta-analysis. METHODS: We searched four electronic literature databases (PubMed, CINAHL, Global Health, EMBASE) for studies published between 1 January 1980 and 20 April 2020 using a comprehensive search strategy. Studies reporting data on WLHIV receiving cART compared with WLHIV receiving monotherapy for 11 adverse perinatal outcomes were sought: preterm birth (PTB), very PTB, spontaneous PTB, low birthweight (LBW), very LBW, preterm and term LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses were conducted to calculate relative risk (RR) and 95% confidence intervals (95% CI). RESULTS: We included 30 studies reporting on 317 101 pregnant women in 27 countries. WLHIV receiving cART were at increased risk of PTB (RR 1.32, 95% CI 1.18-1.46), LBW (1.35, 1.19-1.53), SGA (1.32, 1.13-1.53), VSGA (1.64, 1.34-2.02), and stillbirth (2.41, 1.83-3.17) compared to WLHIV receiving monotherapy. The significance of these results was maintained in subgroup analyses for studies conducted in low and middle-income countries and average quality studies. Additionally, WLHIV receiving nonnucleoside reverse transcriptase inhibitor-based cART were associated with increased risk of PTB, LBW, and stillbirth, while WLHIV receiving protease inhibitor-based cART were associated with increased risk of PTB, compared with WLHIV receiving monotherapy. CONCLUSION: Pregnant WLHIV receiving cART are associated with increased risk of adverse perinatal outcomes, compared with WLHIV receiving monotherapy.

Adverse perinatal outcomes attributable to HIV in sub-Saharan Africa from 1990 to 2020: Systematic review and meta-analyses.

BACKGROUND: Maternal HIV infection and antiretroviral drugs (ARVs) are associated with increased risks of adverse perinatal outcomes. The vast majority of pregnant women living with HIV (WLHIV) reside in sub-Saharan Africa. We aimed to determine the burden of adverse perinatal outcomes attributable to HIV and ARVs in sub-Saharan Africa between 1990 and 2020. METHODS: We conduct a systematic review of studies on the association of pregnant WLHIV with adverse perinatal outcomes in sub-Saharan Africa. We perform random-effects meta-analyses to determine the risk difference (attributable risk, AR) of perinatal outcomes among WLHIV receiving no ARVs, monotherapy, or combination antiretroviral therapy (cART) initiated antenatally or preconception, compared to HIV-negative women. We estimate numbers of perinatal outcomes attributable to HIV and ARVs by combining the AR values with numbers of WLHIV receiving different ARV regimens in each country in sub-Saharan Africa annually between 1990 and 2020. RESULTS: We find that WLHIV receiving no ARVs or cART initiated antenatally or preconception, but not monotherapy, have an increased risk of preterm birth (PTB), low birthweight (LBW) and small for gestational age (SGA), compared to HIV-negative women. Between 1990 and 2020, 1,921,563 PTBs, 2,119,320 LBWs, and 2,049,434 SGAs are estimated to be attributable to HIV and ARVs in sub-Saharan Africa, mainly among WLHIV receiving no ARVs, while monotherapy and preconception and antenatal cART averted many adverse outcomes. In 2020, 64,585 PTBs, 58,608 LBWs, and 61,112 SGAs were estimated to be attributable to HIV and ARVs, the majority among WLHIV receiving preconception cART. CONCLUSIONS: As the proportion of WLHIV receiving preconception cART increases, the burden of adverse perinatal outcomes among WLHIV in sub-Saharan Africa is likely to remain high. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42021248987.

Pregnant women living with HIV (WLHIV) are at higher risk of adverse birth outcomes, such as babies born too soon (premature birth), babies born too small (low birthweight) or small-for-gestational-age (smaller than expected based on the weeks of pregnancy). It is unknown how many cases of these outcomes are attributable to HIV in sub-Saharan Africa, where most pregnant WLHIV reside. We conduct a search for published studies to determine the risk of adverse birth outcomes among WLHIV. We find that around 2 million premature births, low birthweight babies, and small-for-gestational-age babies are attributable to HIV in sub-Saharan Africa between 1990 and 2020. We conclude that adverse birth outcomes among WLHIV in sub-Saharan Africa are likely to remain high for the foreseeable future. Our findings could guide strategies to improve the health of WLHIV and their children in this region.

Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis.

Background: The World Health Organization recommends protease inhibitor (PI)-based antiretroviral therapy (ART) as second-line and third-line regimens in pregnant women living with HIV (WLHIV). US, European, and UK guidelines include PI-based ART as first-line regimens, but advise against the use of lopinavir/ritonavir (LPV/r)-based ART, citing an increased risk of preterm birth (PTB). We aimed to assess the risk of adverse perinatal outcomes in WLHIV receiving PI-ART and the comparative risks associated with different PI-ART regimens. Methods: We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and April 20, 2020. Two investigators independently selected studies and extracted data from studies reporting on the association of pregnant WLHIV receiving PI-ART with 11 perinatal outcomes: PTB, very PTB (VPTB), spontaneous PTB (sPTB), low birth weight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Pairwise random-effects meta-analyses examined the risk of each adverse perinatal outcome in WLHIV receiving PI-ART compared to non-PI-based ART (non-PI-ART), and comparisons of different PI-ART regimens. Quality assessments of studies were performed, subgroup and sensitivity analyses were conducted based on country income status and study quality, heterogeneity assessed, and the effect of adjustment for confounding factors assessed. The protocol is registered with PROSPERO, CRD42021248987. Findings: Of 94,594 studies identified, 34 cohort studies including 57,546 women met the inclusion criteria. Random-effects meta-analyses showed that PI-ART was associated with a significantly increased risk of SGA (Relative Risk [RR] 1.24, 95% CI 1.08-1.43; I2 =66.7%) and VSGA (RR 1.40, 1.09-1.81; I2 =0.0%), but not PTB (RR 1.09, 0.95-1.24; I2 =68.3%), VPTB (RR 1.30, 0.78-2.18; I2 =43.0%), sPTB (RR 1.91, 0.61-5.99; I2 =95.7%), LBW (RR 1.04, 0.85-1.27; I2 =63.9%), VLBW (RR 0.72, 0.37-1.43; I2 =37.9%), term LBW (RR 0.94, 0.30-3.02; I2 =0.0%), stillbirth (RR 1.04, 0.60-1.79; I2 =0.0%), and neonatal death (RR 1.82, 0.97-3.40; I2 =0.0%), compared to non-PI-ART. We found no significant differences in perinatal outcomes between ART regimens containing LPV/r, atazanavir/ritonavir (ATV/r), and darunavir/ritonavir (DRV/r), which are the most commonly used PIs. Interpretation: PI-ART is associated with an increased risk of SGA and VSGA, but not PTB or other perinatal outcomes. No significant differences in perinatal outcomes were found between LPV/r, ATV/r, and DRV/r. These findings should inform clinical guidelines, and further efforts should be made to improve perinatal outcomes among pregnant WLHIV. Funding: None.

Adverse perinatal outcomes associated with HAART and monotherapy.

OBJECTIVES: Assess adverse perinatal outcomes in pregnant women living with HIV (WLHIV) receiving HAART or zidovudine (ZDV) monotherapy, compared with antiretroviral therapy (ART)-naive WLHIV and HIV-negative women. DESIGN: Systematic review and meta-analysis. METHODS: We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between 1 January 1980 and 20 April 2020. We included studies reporting on the association of pregnant WLHIV receiving HAART or ZDV monotherapy with 11 perinatal outcomes: preterm birth (PTB), very PTB, spontaneous PTB (sPTB), low birth weight (LBW), very LBW, term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses were conducted. RESULTS: Sixty-one cohort studies assessing 409 781 pregnant women were included. WLHIV receiving ZDV monotherapy were associated with a decreased risk of PTB [relative risk 0.70, 95% confidence interval (CI) 0.62-0.79] and LBW (0.77, 0.67-0.88), and comparable risk of SGA, compared with ART-naive WLHIV. WLHIV receiving ZDV monotherapy had a comparable risk of PTB and LBW, and an increased risk of SGA (1.16, 1.04-1.30) compared with HIV-negative women. In contrast, WLHIV receiving HAART were associated with a comparable risk of PTB and LBW, and increased risk of SGA (1.38, 1.09-1.75), compared with ART-naive WLHIV. WLHIV receiving HAART were associated with an increased risk of PTB (1.55, 1.38-1.74), sPTB (2.09, 1.48-2.96), LBW (1.79, 1.51-2.13), term LBW (1.88, 1.23-2.85), SGA (1.80,1.34-2.40), and VSGA (1.22, 1.10-1.34) compared with HIV-negative women. CONCLUSION: Pregnant WLHIV receiving HAART have an increased risk of a wide range of perinatal outcomes compared with HIV-negative women.

Adverse perinatal outcomes associated with antiretroviral therapy in women living with HIV: A systematic review and meta-analysis.

Background: Maternal HIV infection is associated with an increased risk of adverse perinatal outcomes. The World Health Organization (WHO) recommends immediate initiation of lifelong antiretroviral therapy (ART) for all people living with HIV, including pregnant women living with HIV (WLHIV). We aimed to assess the risk of adverse perinatal outcomes in WLHIV receiving ART compared to ART-naïve WLHIV and HIV-negative women. Materials and methods: We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and April 20, 2020. Two investigators independently selected relevant studies and extracted data from studies reporting on the association of pregnant WLHIV receiving ART with adverse perinatal outcomes. Perinatal outcomes examined were preterm birth (PTB), very PTB, spontaneous PTB (sPTB), low birth weight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses examined the risk of adverse perinatal outcomes in WLHIV receiving ART compared to ART-naïve WLHIV and HIV-negative women. Subgroup and sensitivity analyses were performed based on country income status and study quality, and adjustment for confounding factors assessed. Results: Of 94,594 studies identified, 73 cohort studies, including 424,277 pregnant women, met the inclusion criteria. We found that WLHIV receiving ART are associated with a significantly decreased risk of PTB (relative risk 0.79, 95% CI 0.67-0.93), sPTB (0.46, 0.32-0.66), LBW (0.86, 0.79-0.93), and VLBW (0.62, 0.39-0.97) compared to ART-naïve WLHIV. However, WLHIV receiving ART are associated with a significantly increased risk of PTB (1.42, 1.28-1.57), sPTB (2.20, 1.32-3.67), LBW (1.58, 1.36-1.84), term LBW (1.88, 1.23-2.85), SGA (1.69, 1.32-2.17), and VSGA (1.22, 1.10-1.34) compared to HIV-negative women. Conclusion: ART reduces the risk of adverse perinatal outcomes in pregnant WLHIV, but the risk remains higher than in HIV-negative women. Our findings support the WHO recommendation of immediate initiation of lifelong ART for all people living with HIV, including pregnant WLHIV. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021248987.