Adverse perinatal outcomes associated with different classes of antiretroviral drugs in pregnant women living with HIV: a systematic review and meta-analysis.

OBJECTIVE: Women living with HIV (WLHIV) are at increased risk of adverse perinatal outcomes compared to HIV-negative women, despite antiretroviral therapy (ART). There is evidence that the risk of adverse perinatal outcomes may differ according to ART regimen. We aimed to assess the risk of adverse perinatal outcomes among WLHIV receiving different classes of ART, compared to HIV-negative women. DESIGN: Systematic review and meta-analysis. METHODS: We searched Medline, CINAHL, Global Health and EMBASE for studies published between 1 January 1980 and 14 July 2023. We included studies which assessed the risk of 11 predefined adverse perinatal outcomes among WLHIV receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART, protease inhibitor (PI)-based ART or integrase strand transfer inhibitor (INSTI)-based ART, compared to HIV-negative women. The perinatal outcomes assessed were preterm birth (PTB), very PTB (VPTB), spontaneous PTB (sPTB), low birthweight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth and neonatal death (NND). Random effects meta-analyses examined the risk of each adverse outcome in WLHIV receiving either NNRTI-based, PI-based or INSTI-based ART, compared with HIV-negative women. Subgroup and sensitivity analyses were conducted based on country income status, study quality, and timing of ART initiation. The protocol is registered with PROSPERO, CRD42021248987. RESULTS: Of 108,720 identified citations, 22 cohort studies including 191,857 women were eligible for analysis. We found that WLHIV receiving NNRTI-based ART (mainly efavirenz or nevirapine) are at increased risk of PTB (risk ratio (RR) 1.40, 95% confidence interval 1.27-1.56), VPTB (1.94, 1.25-3.01), LBW (1.63, 1.30-2.04), SGA (1.53, 1.17-1.99) and VSGA (1.48, 1.16-1.87), compared with HIV-negative women. WLHIV receiving PI-based ART (mainly lopinavir/ritonavir or unspecified) are at increased risk of PTB (1.88, 1.55-2.28), VPTB (2.06, 1.01-4.18), sPTB (16.96, 1.01-284.08), LBW (2.90, 2.41-3.50), VLBW (4.35, 2.67-7.09) and VSGA (2.37, 1.84-3.05), compared with HIV-negative women. WLHIV receiving INSTI-based ART (mainly dolutegravir) are at increased risk of PTB (1.17, 1.06-1.30) and SGA (1.20, 1.08-1.33), compared with HIV-negative women. CONCLUSIONS: The risks of adverse perinatal outcomes are higher among WLHIV receiving ART compared with HIV-negative women, irrespective of the class of ART drugs. This underlines the need to further optimise ART in pregnancy and improve perinatal outcomes of WLHIV.

Global and regional genetic diversity of HIV-1 in 2010-21: systematic review and analysis of prevalence.

BACKGROUND: The extensive global genetic diversity of HIV-1 poses a major challenge to HIV vaccine development. We aimed to determine recent estimates of and changes in the global and regional distributions of HIV-1 genetic variants. METHODS: We conducted a systematic literature review by searching PubMed, Embase, Global Health, and CINAHL for studies containing country-specific HIV-1 subtyping data, published between Jan 1, 2010 and Sep 16, 2022. The proportions of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in each country were weighted by UNAIDS estimates of the numbers of people living with HIV (PLHIV) in each country to obtain regional and global prevalence estimates of HIV-1 subtypes, CRFs, and URFs with 95% CIs for the time periods 2010-15 and 2016-21. The protocol is registered with PROSPERO, CRD42017067164. FINDINGS: We obtained 1044 datasets, containing HIV-1 subtyping data from 653 013 PLHIV from 122 countries in 2010-2021. In 2016-2021, subtype C accounted for 50·4% (95% CI 50·2-50·7; n=18 570 462 of 36 823 798) of global HIV infections, subtype A for 12·4% (12·2-12·6; n=4 571 250), subtype B for 11·3% (11·1-11·5; n=4 157 686), subtype G for 2·9% (2·9-3·0; n=1 083 568), subtype D for 2·6% (2·5-2·7; n=945 815), subtype F for 0·9% (0·8-0·9; n=316 724), CRFs for 15·1% (14·9-15·3; n=5 564 566), and URFs for 2·0% (1·9-2·1; n=733 374). Subtypes H, J, and K each accounted for 0·1% or less of infections. Compared with 2010-15, we observed significant (p<0·0001) increases in global proportions of subtype A (0·9%, 95% CI 0·7 to 1·1) and subtype C (3·4%, 3·0 to 3·7) and decreases in subtype D (-0·5%, -0·6 to -0·4), subtype G (-0·8%, -1·0 to -0·7), CRFs (-1·0%, -1·3 to -0·8), and URFs (-1·8%, -1·9 to -1·7), with no changes for subtypes B and F. The global proportion of infections attributed to recombinants decreased from 21·6% (95% CI 21·4 to 21·7; n=7 099 252 of 32 622 808) in 2010-15 to 19·3% (19·1 to 19·5; n=7 094 694 of 36 823 798) in 2016-21 (-2·3%, 95% CI -2·6 to -2·0; p<0·0001). Regional distributions of HIV-1 variants were complex and evolving, with global trends in the prevalence of HIV-1 variants supported by trends across the regions. INTERPRETATION: Global and regional HIV-1 genetic diversity are complex and continue to evolve. Continued and improved surveillance of HIV-1 variants remains vital for HIV vaccine development and implementation. FUNDING: None.

Perinatal outcomes associated with pre-exposure prophylaxis for HIV prevention during pregnancy: a systematic review and meta-analysis.

Background: The World Health Organization (WHO) recommends tenofovir disoproxil fumarate (TDF)-based oral pre-exposure prophylaxis (PrEP), the dapivirine vaginal ring, and long-acting intramuscular injectable cabotegravir (CAB-LA) for HIV prevention in populations at substantial risk of HIV infection. Pregnancy is a period of elevated risk of maternal HIV infection and transmission to the infant. This systematic review and meta-analysis assessed the risk of adverse perinatal outcomes among HIV-negative pregnant women with exposure to any PrEP modality. Methods: We conducted a systematic review by searching Medline, EMBASE, CINAHL, Global Health, the Cochrane Library, WHO ICTR, ISRCTN, PACTR, and ClinicalTrials.gov for studies published between 1 January 2000 and 29 August 2023. We included studies reporting on the association of antenatal exposure to any PrEP modality with 13 perinatal outcomes: preterm birth (PTB), very PTB, spontaneous PTB, spontaneous very PTB, low birthweight (LBW), very LBW, term LBW, preterm LBW, small for gestational age (SGA), very SGA, miscarriage, stillbirth, or neonatal death (NND). Quality assessments of included studies were performed. Fixed-effect meta-analyses were conducted to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). The protocol is registered with PROSPERO, CRD42022339825. Findings: Of 18,598 citations identified, 13 studies (eight randomised controlled trials (RCTs) and five cohort studies), assessing 8712 pregnant women in Africa, were included. Oral PrEP, compared to no PrEP, was not associated with PTB in meta-analyses of six RCTs (OR 0.73, 95% CI 0.43-1.26; I2 = 0.0%) or five unadjusted cohort studies (OR 0.84, 95% CI 0.69-1.03; I2 = 0.0%), but was associated with a reduced risk of PTB in three adjusted cohort studies (aOR 0.67; 95% CI 0.52-0.88, I2 = 0.0%). There was no association of oral PrEP with LBW, vLBW, SGA, or NND, compared to no PrEP. There was no association with PTB when oral TDF/emtricitabine (FTC) PrEP, oral TDF PrEP, and tenofovir vaginal gel were compared to each other. There was no association of the dapivirine vaginal ring with PTB or NND, compared to placebo or oral TDF/FTC PrEP. We found no data on CAB-LA. Interpretation: We found no evidence of adverse perinatal outcomes associated with PrEP exposure during pregnancy. Our findings support the WHO recommendation to provide oral PrEP to women of reproductive age and pregnant women. More data is needed to assess the safety of all PrEP modalities in pregnancy. Funding: None.

Predicting risk of preterm birth in singleton pregnancies using machine learning algorithms.

We aimed to develop, train, and validate machine learning models for predicting preterm birth (<37 weeks' gestation) in singleton pregnancies at different gestational intervals. Models were developed based on complete data from 22,603 singleton pregnancies from a prospective population-based cohort study that was conducted in 51 midwifery clinics and hospitals in Wenzhou City of China between 2014 and 2016. We applied Catboost, Random Forest, Stacked Model, Deep Neural Networks (DNN), and Support Vector Machine (SVM) algorithms, as well as logistic regression, to conduct feature selection and predictive modeling. Feature selection was implemented based on permutation-based feature importance lists derived from the machine learning models including all features, using a balanced training data set. To develop prediction models, the top 10%, 25%, and 50% most important predictive features were selected. Prediction models were developed with the training data set with 5-fold cross-validation for internal validation. Model performance was assessed using area under the receiver operating curve (AUC) values. The CatBoost-based prediction model after 26 weeks' gestation performed best with an AUC value of 0.70 (0.67, 0.73), accuracy of 0.81, sensitivity of 0.47, and specificity of 0.83. Number of antenatal care visits before 24 weeks' gestation, aspartate aminotransferase level at registration, symphysis fundal height, maternal weight, abdominal circumference, and blood pressure emerged as strong predictors after 26 completed weeks. The application of machine learning on pregnancy surveillance data is a promising approach to predict preterm birth and we identified several modifiable antenatal predictors.

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.

Global associations of key populations with HIV-1 recombinants: a systematic review, global survey, and individual participant data meta-analysis.

Introduction: Global HIV infections due to HIV-1 recombinants are increasing and impede prevention and treatment efforts. Key populations suffer most new HIV infections, but their role in the spread of HIV-1 recombinants is unknown. We conducted a global analysis of the associations between key populations and HIV-1 recombinants. Methods: We searched PubMed, EMBASE, CINAHL, and Global Health for HIV-1 subtyping studies published from 1/1/1990 to 31/12/2015. Unpublished data was collected through a global survey. We included studies with HIV-1 subtyping data of key populations collected during 1990-2015. Key populations assessed were heterosexual people (HET), men who have sex with men (MSM), people who inject drugs (PWID), vertical transmissions (VERT), commercial sex workers (CSW), and transfusion-associated infections (BLOOD). Logistic regression was used to determine associations of key populations with HIV-1 recombinants. Subgroup analyses were performed for circulating recombinant forms (CRFs), unique recombinant forms (URFs), regions, and time periods. Results: Eight hundred and eighty five datasets including 77,284 participants from 83 countries were included. Globally, PWID were associated with the greatest odds of recombinants and CRFs (OR 2.6 [95% CI 2.46-2.74] and 2.99 [2.83-3.16]), compared to HET. CSW were associated with increased odds of recombinants and URFs (1.59 [1.44-1.75] and 3.61 [3.15-4.13]). VERT and BLOOD were associated with decreased odds of recombinants (0.58 [0.54-0.63] and 0.43 [0.33-0.56]). MSM were associated with increased odds of recombinants in 2010-2015 (1.43 [1.35-1.51]). Subgroup analyses supported our main findings. Discussion: As PWID, CSW, and MSM are associated with HIV-1 recombinants, increased preventative measures and HIV-1 molecular surveillance are crucial within these key populations. Systematic review registration: PROSPERO [CRD42017067164].

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.

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 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.

Trends in management and outcomes of pregnant women living with HIV between 2008-2013 and 2014-2019: A retrospective cohort study.

Background: Despite major advances in the care of pregnant women living with HIV (WLHIV), they remain at increased risk of adverse pregnancy outcomes. This study assesses recent developments in management and outcomes of pregnant WLHIV at a tertiary obstetric unit in the United Kingdom. Methods: We conducted a retrospective cohort study of WLHIV delivering at the John Radcliffe Hospital, Oxford, during 2008-2019. Detailed data was collected for maternal, virological, obstetric, and perinatal characteristics. To determine changes over time, data from the periods 2008-13 and 2014-19 were compared. Results: We identified 116 pregnancies in 94 WLHIV. Between 2008-2013 and 2014-2019, the rate of preconception HIV diagnosis increased from 73 to 90% (p = 0.021) and the proportion of WLHIV on combination ART (cART) at conception increased from 54 to 84% (p = 0.001). The median gestation at which cART was initiated antenatally decreased from 22+1 to 17+1 weeks (p = 0.003). In 2014-2019, 41% of WLHIV received non-nucleoside reverse transcriptase inhibitor-based cART, 37% protease inhibitor-based cART, and 22% of cART regimens contained an integrase inhibitor. The proportion of WLHIV with a viral load <50 copies/mL at delivery rose from 87 to 94% (p = 0.235). Sixty-six percent of WLHIV delivered by Cesarean section, with a significant decrease over time in the rate of both planned (62-39%, p = 0.016) and actual (49-31%, p = 0.044) elective Cesarean. Perinatal outcomes included one case of perinatal HIV transmission (0.86%), 11% preterm birth, 15% small-for-gestational-age, and 2% stillbirth. There was an association between a viral load >50 copies/mL at delivery and preterm delivery (p = 0.0004). Conclusion: Virological, obstetric, and perinatal outcomes of WLHIV improved during the study period. Implementation of national guidance has led to an increase in preconception diagnosis and treatment, earlier initiation of antenatal treatment, a reduction in the number of women with a detectable viral load at delivery, and an increase in vaginal deliveries.

Planned mode of birth after previous cesarean section and risk of undergoing pelvic floor surgery: A Scottish population-based record linkage cohort study.

BACKGROUND: The global rise in cesarean sections has led to increasing numbers of pregnant women with a history of previous cesarean section. Policy in many high-income settings supports offering these women a choice between planned elective repeat cesarean section (ERCS) or planned vaginal birth after previous cesarean (VBAC), in the absence of contraindications to VBAC. Despite the potential for this choice to affect women's subsequent risk of experiencing pelvic floor disorders, evidence on the associated effects to fully counsel women is lacking. This study investigated the association between planned mode of birth after previous cesarean section and the woman's subsequent risk of undergoing pelvic floor surgery. METHODS AND FINDINGS: A population-based cohort study of 47,414 singleton term births in Scotland between 1983 to 1996 to women with 1 or more previous cesarean sections was conducted using linked Scottish national routine datasets. Cox regression was used to investigate the association between planned as well as actual mode of birth and women's subsequent risk of having any pelvic floor surgery and specific types of pelvic floor surgery adjusted for sociodemographic, maternal medical, and obstetric-related factors. Over a median of 22.1 years of follow-up, 1,159 (2.44%) of the study population had pelvic floor surgery. The crude incidence rate of any pelvic floor surgery per 1,000 person-years was 1.35, 95% confidence interval (CI) 1.27 to 1.43 in the overall study population, 1.75, 95% CI 1.64 to 1.86 in the planned VBAC group and 0.66, 95% CI 0.57 to 0.75 in the ERCS group. Planned VBAC compared to ERCS was associated with a greater than 2-fold increased risk of the woman undergoing any pelvic floor surgery (adjusted hazard ratio [aHR] 2.38, 95% CI 2.03 to 2.80, p < 0.001) and a 2- to 3-fold increased risk of the woman having surgery for pelvic organ prolapse or urinary incontinence (aHR 3.17, 95% CI 2.47 to 4.09, p < 0.001 and aHR 2.26, 95% CI 1.79 to 2.84, p < 0.001, respectively). Analysis by actual mode of birth showed these increased risks were only apparent in the women who actually had a VBAC, with the women who needed an in-labor non-elective repeat cesarean section having a comparable risk of pelvic floor surgery to those who had an ERCS. The main limitation of this study is the potential for misclassification bias. CONCLUSIONS: This study suggests that among women with previous cesarean section giving birth to a singleton at term, planned VBAC compared to ERCS is associated with an increased risk of the woman subsequently undergoing pelvic floor surgery including surgery for pelvic organ prolapse and urinary incontinence. However, these risks appear to be only apparent in women who actually give birth vaginally as planned, highlighting the role of vaginal birth rather than labor in pelvic floor dysfunction requiring surgery. The findings provide useful additional information to counsel women with previous cesarean section about the risks and benefits associated with their future birth choices.

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.

Global and Regional Estimates for Subtype-Specific Therapeutic and Prophylactic HIV-1 Vaccines: A Modeling Study.

Global HIV-1 genetic diversity forms a major obstacle to the development of an HIV vaccine. It may be necessary to employ subtype-specific HIV-1 vaccines in individual countries according to their HIV-1 subtype distribution. We estimated the global and regional need for subtype-specific HIV-1 vaccines. We took into account the proportions of different HIV-1 variants circulating in each country, the genetic composition of HIV-1 recombinants, and the different genome segments (gag, pol, env) that may be incorporated into vaccines. We modeled different scenarios according to whether countries would employ subtype-specific HIV-1 vaccines against (1) the most common subtype; (2) subtypes contributing more than 5% of HIV infections; or (3) all circulating subtypes. For therapeutic vaccines targeting the most common HIV-1 subtype in each country, 16.5 million doses of subtype C vaccine were estimated globally, followed by subtypes A (14.3 million) and B (4.2 million). A vaccine based on env required 2.6 million subtype E doses, and a vaccine based on pol required 4.8 million subtype G doses. For prophylactic vaccines targeting the most common HIV-1 subtype in each country, 1.9 billion doses of subtype A vaccine were estimated globally, followed by subtype C (1.1 billion) and subtype B (1.0 billion). A vaccine based on env required 1.2 billion subtype E doses, and a vaccine based on pol required 0.3 billion subtype G doses. If subtype-specific HIV-1 vaccines are also directed against less common subtypes in each country, vaccines targeting subtypes D, F, H, and K are also needed and would require up to five times more vaccine doses in total. We conclude that to provide global coverage, subtype-specific HIV-1 vaccines need to be directed against subtypes A, B, and C. Vaccines targeting env also need to include subtype E and those targeting pol need to include subtype G.

Maternal HIV infection is associated with distinct systemic cytokine profiles throughout pregnancy in South African women.

Maternal HIV infection is associated with adverse pregnancy outcomes, but the mechanisms remain unknown. The course of pregnancy is regulated by immunological processes and HIV infection and antiretroviral therapy (ART) impact key immune mechanisms, which may disrupt the immune programme of pregnancy. We evaluated a broad range of systemic cytokines at each trimester of pregnancy in 56 women living with HIV (WLHIV) and 68 HIV-negative women, who were enrolled in a prospective pregnancy cohort study in Soweto, South Africa. The pro-inflammatory cytokine IP-10 was detected in each trimester in all WLHIV, which was significantly more than in HIV-negative women. The anti-viral cytokine IFNλ1 was detected more frequently in WLHIV, whereas IFNß and IFNλ2/3 were detected more frequently in HIV-negative women. Th1 cytokines IL-12 and IL-12p70, Th2 cytokine IL-5, and Th17 cytokine IL-17A were detected more frequently in WLHIV throughout pregnancy. Il-6, IL-9, and IL-10 were more commonly detected in WLHIV in the first trimester. Trends of increased detection of Th1 (IL-2, IL-12p70), Th2 (IL-4, Il-5, Il-13) and Th17 (IL-17A, Il-17F, IL-21, IL-22) cytokines were associated with small-for-gestational-age babies. Our findings indicate that maternal HIV/ART is associated with distinct systemic cytokine profiles throughout pregnancy.

Country Level Diversity of the HIV-1 Pandemic between 1990 and 2015.

The global diversity of HIV forms a major challenge to the development of an HIV vaccine, as well as diagnostic, drug resistance, and viral load assays, which are essential to reaching the UNAIDS 90:90:90 targets. We sought to determine country level HIV-1 diversity globally between 1990 and 2015. We assembled a global HIV-1 molecular epidemiology database through a systematic literature search and a global survey. We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published from 1 January 1990 to 31 December 2015. We collected additional unpublished data through a global survey of experts. Prevalence studies with original HIV-1 subtyping data collected between 1990 and 2015 were included. This resulted in a database with 383,519 subtyped HIV-1 samples from 116 countries over four time periods (1990 to 1999, 2000 to 2004, 2005 to 2009, and 2010 to 2015). We analyzed country-specific numbers of distinct HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in each time period. We also analyzed country-specific proportions of infections due to HIV-1 recombinants, CRFs, and URFs and calculated the Shannon diversity index for each country. Finally, we analyzed global temporal trends in each of these measures of HIV-1 diversity. We found extremely wide variation in complexity of country level HIV diversity around the world. Central African countries such as Chad, Democratic Republic of the Congo, Angola, and Republic of the Congo have the most diverse HIV epidemics. The number of distinct HIV-1 subtypes and recombinants was greatest in Western Europe (Spain and France) and North America (United States) (up to 39 distinct HIV-1 variants in Spain). The proportion of HIV-1 infections due to recombinants was highest in Southeast Asia (>95% of infections in Viet Nam, Cambodia, and Thailand), China, and West and Central Africa, mainly due to high proportions of CRF01_AE and CRF02_AG. Other CRFs played major roles (>75% of HIV-1 infections) in Estonia (CRF06_cpx), Iran (CRF35_AD), and Algeria (CRF06_cpx). The highest proportions of URFs (>30%) were found in Myanmar, Republic of the Congo, and Argentina. Global temporal analysis showed consistent increases over time in country level numbers of distinct HIV-1 variants and proportions of CRFs and URFs, leading to increases in country level HIV-1 diversity. Our study provides epidemiological evidence that the HIV pandemic is diversifying at country level and highlights the increasing challenge to prevention and treatment efforts. HIV-1 molecular epidemiological surveillance needs to be continued and improved.IMPORTANCE This is the first study to analyze global country level HIV-1 diversity from 1990 to 2015. We found extremely wide variation in complexity of country level HIV diversity around the world. Central African countries have the most diverse HIV epidemics. The number of distinct HIV-1 subtypes and recombinants was greatest in Western Europe and North America. The proportion of HIV-1 infections due to recombinants was highest in South-East Asia, China, and West and Central Africa. The highest proportions of URFs were found in Myanmar, Republic of the Congo, and Argentina. Our study provides epidemiological evidence that the HIV pandemic is diversifying at country level and highlights the increasing challenge to HIV vaccine development and diagnostic, drug resistance, and viral load assays.

Global and regional epidemiology of HIV-1 recombinants in 1990-2015: a systematic review and global survey.

BACKGROUND: Global HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identified worldwide, but their contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015. METHODS: We assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched the PubMed, Embase (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) databases for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data were collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses were done for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, CRD42017067164. FINDINGS: Our global data collection yielded an HIV-1 molecular epidemiology database of 383 519 samples from 116 countries in 1990-2015. We found that the proportion of recombinants increased over time, both globally and in most regions, reaching 22·8% (7 978 517 of 34 921 639) of global HIV-1 infections in 2010-15. Both the proportion and the number of distinct CRFs detected increased over time to 16·7% and 57 CRFs in 2010-15. The global and regional distribution of HIV-1 recombinants was diverse and evolved over time, and we found large regional variation in the numbers (0-44 CRFs), types (58 distinct CRFs), and proportions (0-80·5%) of HIV-1 recombinants. Globally, CRF02_AG was the most prevalent recombinant, accounting for 33·9% (2 701 364 of 7 978 517) of all recombinant infections in 2010-15. URFs accounted for 26·7% (2 131 450 of 7 978 517), CRF01_AE for 23·0% (1 838 433), and other CRFs for 16·4% (1 307 270) of all recombinant infections in 2010-15. Although other CRFs accounted for small proportions of infections globally (<1% each), they were prominent in regional epidemics, including in east and southeast Asia, west and central Africa, Middle East and north Africa, and eastern Europe and central Asia. In addition, in 2010-15, central Africa (21·3% [243 041 of 1 143 531]), west Africa (15·5% [838 476 of 5 419 010]), east Africa (12·6% [591 140 of 4 704 986]), and Latin America (9·6% [153 069 of 1 586 605]) had high proportions of URFs. INTERPRETATION: HIV-1 recombinants are increasingly prominent in global and regional HIV epidemics, which has important implications for the development of an HIV vaccine and the design of diagnostic, resistance, and viral load assays. Continued and improved surveillance of the global molecular epidemiology of HIV is crucial. FUNDING: None.