Development of normal reference intervals for renal function in pregnancy: a secondary analysis of clinical trial data.

BACKGROUND: Due to its potential nephrotoxicity, screening for pre-existing renal function disorders has become a routine clinical assessment for initiating Tenofovir diphosphate fumarate (TDF)-containing antiretroviral treatment (ART) or pre-exposure prophylaxis (PrEP) in pregnant and non-pregnant adults. We aimed to establish reference values for commonly used markers of renal function in healthy pregnant women of African origin. METHODS: Pregnant women ≥18 years, not living with HIV, and at 14-28 weeks gestation were enrolled in a PrEP clinical trial in Durban, South Africa between September 2017 and December 2019. Women were monitored 4-weekly during pregnancy until six months postpartum. We measured maternal weight and serum creatinine (sCr) at each visit and calculated creatinine clearance (CrCl) rates using the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae. Reference ranges for sCr and CrCl by CG and MDRD calculations were derived from the mean ± 2SD of values for pregnancy and postdelivery. RESULTS: Between 14--and 40 weeks gestation, 249 African women not exposed to TDF-PrEP contributed a total of 1193 renal function values. Postdelivery, 207 of these women contributed to 800 renal function values. The normal reference range for sCr was 30-57 and 32-60 umol/l in the 2nd and 3rd trimesters of pregnancy. Normal reference ranges for CrCl using the MDRD calculation were 129-282 and 119-267 ml/min/1.73m2 for the 2nd and 3rd trimesters, respectively. Using the CG method of calculation, normal reference ranges for CrCl were 120-304 and 123-309 ml/min/1.73m2 for the 2nd and 3rd trimesters respectively. In comparison, the normal reference range for sCr, CrCl by MDRD and CG calculations postpartum was 40-77 umol/l, 92-201, and 90-238 ml/min/1.73m2, respectively. CONCLUSIONS: In African women, the Upper Limit of Normal (ULN) for sCr in pregnancy is approximately 20% lower than 6 months postnatally. Inversely, the Lower Limit of Normal (LLN) for CrCl using either MDRD or CG equation is approximately 35% higher than 6 months postnatally. We provide normal reference ranges for sCr and CrCl for both methods of calculation and appropriate for the 2nd and 3rd trimesters of pregnancy in African women.

Screening for pre-existing renal function disorders has become a routine clinical assessment for initiating TDF-containing antiretroviral treatment or pre-exposure prophylaxis in adults including pregnant women. Pregnancy inherently increases renal function, hence normal reference standards for non-pregnant adults cannot be used for pregnant women. In a secondary analysis of data from a healthy pregnant population not living with HIV who participated in a PrEP clinical trial, we established reference intervals for serum creatinine (sCr) concentration and creatinine clearance (CrCl) during pregnancy and postpartum in an African population. Using sCr and CrCl values for 249 healthy pregnant African women, we can confirm that the upper limit of normal for sCr in pregnancy is 20% lower than that for the 6-month postnatal period and recommend an upper limit of 57 umol/l and 60 umol/l in the second and third trimesters respectively to determine normal renal function in pregnant African women.We further determined the lower limit of normal for creatinine clearance using two methods of calculation, which was 35% higher than that of the postnatal period. Using the modification of diet in renal disease calculation, we recommend a lower limit of 129 and 119 ml/min/1.73m² for the second and third trimesters respectively. Using the Cockcroft­Gault calculation, we recommend a lower limit of 120 and 123 ml/min/1.73m² for the second and third trimesters respectively. Using current standard cut-off values estimated for adults may lead to underreporting of abnormal renal function in African pregnant women.

Sexually transmitted infections in pregnancy and adverse pregnancy outcomes: A retrospective cohort study.

OBJECTIVE: There is a high prevalence and incidence rate of asymptomatic sexually transmitted infections (STIs) during pregnancy in adolescent girls and young women in Africa. The association between STIs and pregnancy outcomes in a hyperepidemic HIV setting has not been well described. METHODS: Pregnant women, HIV-1 negative and <28 weeks' gestation at three primary health clinics in KwaZulu-Natal, South Africa were enrolled from February 2017 to March 2018. Vaginal swabs collected at the first and later antenatal visits were stored and retrospectively tested for HSV-2, Trichomonas vaginalis, Chlamydia trachomatis and Neisseria gonorrhoeae at the end of the study. The association between STIs detected at first and later antenatal visits and pregnancy outcome was assessed using multivariable logistic regression models adjusted for maternal age and treatment received for symptomatic STIs. RESULTS: Testing positive Mycoplasma genitalium at the first antenatal visit was significantly associated with low birth weight (odds ratio [OR] 5.22; 95% confidence interval [CI]: 1.10-15.98). Testing positive for T. vaginalis at the repeat visit was significantly associated with preterm births (OR 2.37; 95% CI: 1.11-5.03), low birth weight (OR 2.56; 1.16-5.63) and a composite adverse pregnancy outcome (OR 2.11; 95% CI: 1.09-4.08). Testing positive for HSV-2 at the repeat visit was also likely associated with experiencing a preterm birth or any adverse pregnancy outcome (OR 3.39; 95% CI: 0.86-13.3) (P = 0.096). CONCLUSIONS: Among predominantly asymptomatic STIs, M. genitalium detected at baseline visit was significantly associated with low birth weight, while T. vaginalis detected at the repeat visit in later pregnancy was significantly associated with preterm birth. Further research is warranted to study the impact of etiological testing of STIs at more than one antenatal visit and empirical treatment on pregnancy outcomes.

Effects of preterm birth, maternal ART and breastfeeding on 24-month infant HIV-free survival in a randomized trial.

BACKGROUND: IMPAACT 1077BF/FF compared the safety/efficacy of two HIV antiretroviral therapy (ART) regimens to zidovudine (ZDV) alone during pregnancy for HIV prevention. PROMISE found an increased risk of preterm delivery (<37 weeks) with antepartum triple ART (TDF/FTC/LPV+r or ZDV/3TC/LPV+r) compared to ZDV alone. We assessed the impact of preterm birth, breastfeeding and antepartum ART regimen on 24-month infant survival. METHODS: We compared HIV-free and overall survival at 24-months for liveborn infants by gestational age, time-varying breastfeeding status, and antepartum ART arm at 14 sites in Africa and India. Kaplan-Meier survival probabilities and Cox proportional hazards ratios (HR) were estimated. RESULTS: 3,482 live-born infants (568 [16 3%] preterm and 2,914 [83 7%] term) were included. Preterm birth was significantly associated with lower HIV-free survival (0·85; 95% CI: 0·82-0·88) and lower overall survival (0·89; 95% CI: 0·86-0·91) versus term birth (0·96; 95% CI: 0·95-0·96). Very preterm birth (<34 weeks) was associated with low HIV-free survival (0·65; 95% CI: 0·54-0·73) and low overall survival (0·66; 95% CI: 0·56-0·74). Risk of HIV infection or death at 24-months was higher with TDF-ART than ZDV-ART (adjusted HR 2·37; 95% CI: 1·21-4·64). Breastfeeding initiated near birth decreased risk of infection or death at 24 months (adjusted HR 0·05; 95% CI: 0·03-0·08) compared to not breastfeeding. CONCLUSION: Preterm birth and antepartum TDF-ART were associated with lower 24-month HIV-free survival compared to term birth and ZDV-ART. Any breastfeeding strongly promoted HIV-free survival, especially if initiated close to birth. Reducing preterm birth and promoting infant feeding with breastmilk among HIV/ARV-exposed infants remain global health priorities.

Performance of Softcup® menstrual cup and vulvovaginal swab samples for detection and quantification of genital cytokines.

Cytokines are important mediators of immunity in the female genital tract, and their levels may be associated with various reproductive health outcomes. However, the measurement of cytokines and chemokines in vaginal fluid samples may be influenced by a variety of factors, each with the potential to affect the sensitivity and accuracy of the assay, including the interpretation and comparison of data. We measured and compared cytokine milieu in samples collected via Softcup® menstrual cup versus vulvovaginal swabs. One hundred and eighty vulvovaginal swabs from CAPRISA 088 and 42 Softcup supernatants from CAPRISA 016 cohorts of pregnant women were used to measure the concentrations of 28 cytokines through multiplexing. Cytokines measured in this study were detectable in each of the methods however, SoftCup supernatants showed consistently, higher detectability, expression ratios, and mean concentration of cytokines than vulvovaginal swabs. While mean concentrations differed, the majority of cytokines correlated between SoftCup supernatants and vulvovaginal swabs. Additionally, there were no significant differences in a number of participants between the two sampling methods for the classification of genital inflammation. Our findings suggest that SoftCup supernatants and vulvovaginal swab samples are suitable for the collection of genital specimens to study biological markers of genital inflammatory response. However, the Softcup menstrual cup performs better for the detection and quantification of soluble biomarkers that are found in low concentrations in cervicovaginal fluid.

The Impact of Regular Screening and Lifestyle Modification on Cardiovascular Disease Risk Factors in South African Women Living With HIV.

BACKGROUND: The Integration of cardiovascular disease SCreening and prevention in the HIV MAnagement plan for women of reproductive age study set out to determine the effectiveness of screening and lifestyle modification in modifying cardiovascular disease (CVD) risk factors in women living with HIV (WLHIV). METHODS: In this prospective, quasiexperimental, intervention study, WLHIV aged 18-<50 years were enrolled from 2 clinics (intervention [I-arm]) and (control arms [C-arm]) in Umlazi, South Africa, between November 2018 and May 2019. Women in the I-arm received lifestyle modification advice on diet, physical activity, alcohol use, and smoking cessation and underwent annual screening for CVD risk. The CVD risk factors were assessed through standardized questionnaires and clinical and laboratory procedures at baseline and at end of 3 years of follow-up. Prevalence of metabolic syndrome and other CVD indices were compared between arms at end-of-study (EOS). RESULTS: Total of 269 WLHIV (149 I-arm and 120 C-arm) with a mean ± SD age of 36 ± 1 years were included in the EOS analyses after 32 ± 2 months of follow-up. The metabolic syndrome prevalence at EOS was 16.8% (25/149) in the I-arm and 24% (24/120) in the C-arm (risk ratio 0.9; 95% CI: 0.5 to 1.1; P 0.86). Proportion of women with fasting blood glucose >5.6 mmol/L in the I-arm and C-arm were 2.7% (4/149) and 13.3% (16/120) respectively (risk ratio 0.2; 95% CI: 0.069 to 0.646; P < 0.01). High-density lipoprotein improved with the intervention arm from baseline to EOS (95% CI: -0.157 to -0.034; P < 0.05). CONCLUSIONS: Although there was no significant difference in the prevalence of metabolic syndrome between study arms, we observed decreased blood glucose levels in the I-arm compared with the C-arm and improved high-density lipoprotein within the I-arm, following lifestyle modification and regular screening for CVD risk factors in WLHIV.

Systemic inflammation in pregnant women with HIV: relationship with HIV treatment regimen and preterm delivery.

OBJECTIVE: HIV treatment regimen during pregnancy was associated with preterm delivery (PTD) in the PROMISE 1077 BF trial. Systemic inflammation among pregnant women with HIV could help explain differences in PTD by treatment regimen. We assessed associations between inflammation, treatment regimen, and PTD. DESIGN/METHODS: A nested 1 : 1 case-control study ( N  = 362) was conducted within a multicountry randomized trial comparing three HIV regimens in pregnant women: zidovudine alone, or combination antiretroviral therapy (ART) with lopinavir/ritonavir and either zidovudine or tenofovir. Cases were women with PTD (<37 weeks of gestational age). The following inflammatory biomarkers were measured in plasma samples using immunoassays: soluble CD14 (sCD14) and sCD163, intestinal fatty acid-binding protein, interleukin (IL)-6, interferon γ, and tumor necrosis factor α. We fit regression models to assess associations between second trimester biomarkers (measured before ART initiation at 13-23 weeks of gestational age and 4 weeks later), treatment regimen, and PTD. We also assessed whether inflammation was a mediator in the relationship between ART regimen and PTD. RESULTS: Persistently high interleukin-6 was associated with increased PTD. Compared with zidovudine alone, the difference in biomarker concentration between week 0 and week 4 was significantly higher ( P  < 0.05) for both protease inhibitor-based regimens. However, the estimated proportion of the ART effect on increased PTD mediated by persistently high biomarker levels was 5% or less for all biomarkers. CONCLUSION: Persistently high IL-6 during pregnancy was associated with PTD. Although protease inhibitor-based ART was associated with increases in inflammation, factors other than inflammation likely explain the increased PTD in ART-based regimens compared with zidovudine alone.

Hepatitis B virus clinical and virologic characteristics in an HIV perinatal transmission study in sub-Saharan Africa.

OBJECTIVES: To describe the clinical and virologic characteristics of HIV-HBV coinfection, including the predictors of high maternal HBV viral load in pregnant women with HIV in sub-Saharan Africa (SSA). METHODS: HPTN 046 was a HIV perinatal transmission clinical trial evaluating infant nevirapine vs. placebo. Women-infant pairs ( n  = 2016) were enrolled in SSA from 2007 to 2010; 1579 (78%) received antiretrovirals (ARV). Maternal delivery samples were retrospectively tested for hepatitis B surface antigen (HBsAg), and if positive, were tested for hepatitis B e antigen (HBeAg) and HBV viral load (VL). High HBV VL was defined as ≥10 6  IU/ml. RESULTS: Overall, 4.4% (88/2016) had HBV co-infection, with geographic variability ranging from 2.4% to 8.7% ( P  < 0.0001); 25% (22/88) were HBeAg positive with prevalence in countries ranging from 10.5% to 39%. Fifty-two percentage (40/77) of those with HBV received ARV, the majority (97%) received 3TC as the only HBV active agent. HBeAg positivity was associated with high maternal HBV VL, odds ratio (OR) 37.0, 95% confidence interval (CI) 5.4-252.4. Of those with high HBV VL, 40% (4/10) were receiving HBV active drugs (HBV-ARV). HBV drug resistance occurred in 7.5% (3/40) receiving HBV-ARV. CONCLUSIONS: In SSA, HBV co-infection is common in pregnant women with HIV. HBsAg and HBeAg prevalence vary widely by country in this clinical trial cohort. HBeAg is a surrogate for high HBV viral load. HBV drug resistance occurred in 7.5% receiving HBV-ARV with lamivudine as the only HBV active agent. These findings reinforce the importance of HBsAg screening and early treatment with two active agents for HBV.

Safety surveillance for PrEP in pregnant and breastfeeding women.

The risk of HIV acquisition is higher during pregnancy and postpartum than other times. Newly acquired maternal HIV infection associated with high primary viraemia, substantially increases the risk of vertical HIV transmission. Pre-exposure prophylaxis (PrEP) reduces the risk of HIV acquisition. Currently available products include oral tenofovir/emtricitabine (TDF/FTC) and tenofovir alafenamide (TAF)/FTC), long-acting cabotegravir (CAB-LA) and the dapivirine ring (DVR). All except oral TDF/FTC have limited safety data available for use in pregnant and breastfeeding women. The safety of new PrEP agents for pregnant women and the fetus, infant and child, either exposed in utero or during breastfeeding is an ongoing concern for health care workers and pregnant and breastfeeding women, particularly as the safety risk appetite for antiretroviral (ARV) agents used as PrEP is lower in pregnant and breastfeeding women who are HIV-uninfected, compared to women living with HIV taking ARVs as treatment. With the widespread rollout of TDF/FTC among pregnant women in South Africa and other low-middle income countries (LMIC) and the potential introduction of new PrEP agents for pregnant women, there is a need for safety surveillance systems to identify potential signals of risk to either the mother or fetus, measure the burden of such a risk, and where appropriate, provide specific reassurance to PrEP users. Safety data needs to be collected across the continuum of the product life cycle from pre-licensure into the post-marketing period, building a safety profile through both passive and active surveillance systems, recognising the strengths and limitations of each, and the potential for bias and confounding. Pharmacovigilance systems that aim to assess the risk of adverse birth outcomes in pregnant women exposed to PrEP and other agents need to consider the special requirements of pregnancy epidemiology to ensure that the data derived from surveillance are sufficiently robust to inform treatment policies. Here we review the known safety profiles of currently available PrEP candidates in women of child-bearing potential, pregnancy and breastfeeding and discuss pragmatic approaches for such surveillance in HIV-endemic LMICs.

Comparison of Antiretroviral Therapies in Pregnant Women Living With Human Immunodeficiency Virus and Hepatitis B Virus: A Randomized Controlled Trial.

OBJECTIVE: To describe the anti-hepatitis B virus (HBV) efficacy, HBeAg serologic changes, HBV perinatal transmission, and safety in pregnant women who are living with human immunodeficiency virus (HIV) and HBV co-infection who were randomized to various antiretroviral therapy (ART) regimens. METHODS: The PROMISE (Promoting Maternal and Infant Survival Everywhere) trial was a multicenter randomized trial for ART-naive pregnant women with HIV infection. Women with HIV and HBV co-infection at 14 or more weeks of gestation were randomized to one of three ART arms: one without HBV treatment (group 1) and two HBV treatment arms with single (group 2) or dual anti-HBV activity (group 3). The primary HBV outcome was HBV viral load antepartum change from baseline (enrollment) to 8 weeks; safety assessments included alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, and anemia (hemoglobin less than 10 g/dL). Primary comparison was for the HBV-active treatment arms. Pairwise comparisons applied t test and the Fisher exact tests. RESULTS: Of 3,543 women, 3.9% were HBsAg-positive; 42 were randomized to group 1, 48 to group 2, and 48 to group 3. Median gestational age at enrollment was 27 weeks. Among HBV-viremic women, mean antepartum HBV viral load change at week 8 was -0.26 log 10 international units/mL in group 1, -1.86 in group 2, and -1.89 in group 3. In those who were HBeAg-positive, HBeAg loss occurred in 44.4% at delivery. Two perinatal HBV transmissions occurred in group 2. During the antepartum period, one woman (2.4%) in group 1 had grade 3 or 4 ALT or AST elevations, two women (4.2%) in group 2, and three women (6.3%) in group 3. CONCLUSION: Over a short period of time, HBV DNA suppression was not different with one or two HBV-active agents. HbeAg loss occurred in a substantial proportion of participants. Perinatal transmission of HBV infection was low. Hepatitis B virus-active ART was well-tolerated in pregnancy, with few grade 3 or 4 ALT or AST elevations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT01061151.

Intimate partner violence victimization during pregnancy increases risk of postpartum depression among urban adolescent mothers in South Africa.

BACKGROUND: It is estimated that 38.8% of mothers develop postpartum depression (PPD) in South Africa. While empirical evidence documents an association between intimate partner violence (IPV) victimization in pregnancy and PPD among adult women, the association has been underexamined among adolescent mothers (< 19 years). The study's purpose is to examine whether IPV victimization during pregnancy is associated with PPD among adolescent mothers. METHODS: Adolescent mothers (14-19 years) were recruited at a regional hospital's maternity ward in KwaZulu Natal, South Africa between July 2017-April 2018. Participants completed behavioral assessments at two visits (n = 90): baseline (up to 4 weeks postpartum) and follow-up (6-9 weeks postpartum, when PPD is typically assessed). The WHO modified conflict tactics scale was used to create a binary measure of any physical and/or psychological IPV victimization that occurred during pregnancy. Participants with scores ≥ 13 on the Edinburgh Postpartum Depression Scale (EPDS) were classified as having symptoms of PPD. We used a modified Poisson regression with robust standard errors to assess PPD in association with IPV victimization during pregnancy, controlling for relevant covariates. RESULTS: Nearly one-half (47%) of adolescent mothers reported symptoms of PPD by 6-9 weeks post-delivery. Further, IPV victimization during pregnancy was highly prevalent (40%). Adolescent mothers who reported IPV victimization during pregnancy had marginally higher risk of PPD at follow-up (RR: 1.50, 95 CI: 0.97-2.31; p = 0.07). The association was strengthened and significant in covariate-adjusted analysis (RR: 1.62, 95 CI: 1.06-2.49; p = 0.03). CONCLUSIONS: Poor mental health was common among adolescent mothers, and IPV victimization during pregnancy was associated with PPD risk among adolescent mothers. Implementing IPV and PPD routine screenings during the perinatal period may aid in identifying adolescent mothers for IPV and PPD interventions and treatment. With the high prevalence of IPV and PPD in this vulnerable population and the potential negative impact on maternal and infant outcomes, interventions to reduce IPV and PPD are needed to improve adolescent mothers' well-being and their baby's health.

BACKGROUND: More than one-third of adult mothers experience postpartum depression (PPD) in South Africa and intimate partner violence (IPV) victimization is a strong risk factor of PPD for adult mothers. However, there are no studies on adolescent mothers that look at the link between IPV victimization and PPD. This paper aims to examine whether IPV victimization during pregnancy is associated with PPD among adolescent South African mothers. METHODS: We had 90 adolescent mothers (aged 14­19 years old) complete an initial survey between delivery and 4 weeks postpartum to collect information on IPV during their pregnancy. Participants completed an additional survey between 6 and 9 week postpartum to collect information on the symptoms of PPD. RESULTS: Nearly one-half (47%) of adolescent mothers reported symptoms of PPD by 6­9 weeks post-delivery. Report of IPV victimization during pregnancy was also very high (40%). Adolescent mothers who experienced IPV victimization during pregnancy were more likely to report symptoms of PPD between 6 and 9 weeks postpartum. CONCLUSIONS: PPD and IPV was very common in our sample, and IPV victimization during pregnancy was linked to PPD among adolescent mothers. Having routine screenings during pregnancy and postpartum period can identify adolescent mothers IPV and PPD interventions and treatment. With the high reports of IPV and PPD in this sample and the potential negative impact on maternal and infant outcomes, interventions to reduce IPV and PPD are needed to improve adolescent mothers' well-being and their baby's health.

High incidence of asymptomatic genital tract infections in pregnancy in adolescent girls and young women: need for repeat aetiological screening.

INTRODUCTION: Sexually transmitted infection (STI) prevalence and incidence estimates for pregnant adolescents are under-reported. We estimated prevalence and incidence of STIs in pregnant adolescents (15-19 years) in comparison with pregnant women 20-24 and >25 years. METHODS: Pregnant women registering at primary care clinics in Umlazi, a periurban subdistrict in KwaZulu-Natal, South Africa, were enrolled in an HIV incidence cohort study during February 2017-March 2018. Women were examined for abnormal vaginal discharge, received empirical treatment, tested for HIV-1 and had vaginal swabs taken at their first and a subsequent visit in the third trimester. Vaginal swabs were stored for STI testing at completion of study and tested for Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium using PCR. RESULTS: A total of 752 HIV-negative pregnant women were enrolled at a median gestational age of 17 weeks: 180 (23.9%), 291 (38.7%) and 281 (37.4%) in the 15-19, 20-24 and >25 years age groups. Pregnant adolescents had an STI prevalence of 26.7% at baseline, not significantly lower than the 20-24 (34.7%, OR 1.4; 95% CI 1.0 to 2.1, p=0.09) and >25 years (33.8%, OR 1.4; 95% CI 0.9 to 2.1, p=0.12) age groups. T. vaginalis (11.1%), C. trachomatis (7.8%) and N. gonorrhoeae (4.4%) were most prevalent in adolescents, a trend similar to the other age groups. Overall, 43.4% were symptomatic and treated at baseline. Overall, 40.7% (118 of 290) of women who tested negative for an STI at baseline tested positive at the repeat visit (incidence 19.5/100 person years). STI incidence in pregnant adolescents was 23.9/100 person years and comparable with older age groups (20.5/100 person years and 16.2/100 person years). At the repeat visit, 19.0% of all women with an STI were symptomatic and treated. Performance of syndromic management was poor at baseline (negative predictive value (NPV) 68.6%, positive predictive value (PPV) 34.0%) and at repeat visit (NPV 58.4%, PPV 34.3%). CONCLUSIONS: Prevalence of asymptomatic curable STIs in pregnant adolescents is high and comparable with women >20 years old. Adolescents remain at substantial risk of asymptomatic incident STIs during pregnancy.

Bone and Renal Health in Infants With or Without Breastmilk Exposure to Tenofovir-Based Maternal Antiretroviral Treatment in the PROMISE Randomized Trial.

BACKGROUND: We assessed bone and kidney outcomes in infants randomized postdelivery as mother-infant pairs within the IMPAACT PROMISE trial to maternal tenofovir disoproxil fumarate-based antiretroviral treatment (mART) or infant nevirapine prophylaxis (iNVP) to prevent breastfeeding HIV transmission. METHODS: Infants were coenrolled in the P1084s substudy on randomization day and followed through Week 74. Lumbar spine bone mineral content (LS-BMC) was assessed at entry (6-21 age days) and Week 26 by dual-energy x-ray absorptiometry. Creatinine clearance (CrCl) was calculated at entry; Weeks 10, 26, and 74. Student t tests compared mean LS-BMC and CrCl at Week 26 and mean change from entry between arms. RESULTS: Of 400 enrolled infants, the mean (SD; n) for entry LS-BMC was 1.68 g (0.35; n = 363) and CrCl was 64.2 mL/min/1.73 m 2 (24.6; n = 357). At Week 26, 98% of infants were breastfeeding and 96% on their assigned HIV prevention strategy. The mean (SD) Week 26 LS-BMC was 2.64 g (0.48) for mART and 2.77 g (0.44) for iNVP; mean difference (95% confidence interval [CI]) -0.13 g (-0.22 to -0.04), P = 0.007, n = 375/398 (94%). Mean absolute (-0.14 g [-0.23 to -0.06]) and percent (-10.88% [-18.53 to -3.23]) increase in LS-BMC from entry was smaller for mART than iNVP. At Week 26, the mean (SD) CrCl was 130.0 mL/min/1.73 m 2 (34.9) for mART vs. 126.1 mL/min/1.73 m 2 (30.0) for iNVP; mean difference (95% CI) 3.8 (-3.0 to 10.7), P = 0.27, n = 349/398 (88%). CONCLUSION: Week 26 mean LS-BMC was lower in infants in the mART group compared with the iNVP group. However, this difference (∼0.23 g) was less than one-half SD, considered potentially clinically relevant. No infant renal safety concerns were observed.

Pregnancy and neonatal safety outcomes of timing of initiation of daily oral tenofovir disoproxil fumarate and emtricitabine pre-exposure prophylaxis for HIV prevention (CAP016): an open-label, randomised, non-inferiority trial.

BACKGROUND: The safety of tenofovir disoproxil fumarate and emtricitabine as pre-exposure prophylaxis (PrEP) in pregnant women not living with HIV is uncertain. We aimed to compare pregnancy and neonatal outcomes in women exposed and not exposed to PrEP during pregnancy. METHODS: In this single-site, open-label, randomised, non-inferiority trial in Durban, South Africa, we evaluated pregnancy and neonatal outcomes in pregnant women aged 18 years or older, not living with HIV, and at 14-28 weeks' gestation at the time of enrolment. Eligible participants were randomly assigned (1:1) using a computer-generated permuted block (block size of ten) randomisation list to immediate initiation or deferred initiation of PrEP until breastfeeding cessation. Participants in the immediate PrEP group received a monthly supply of once daily oral tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg. Participants in the deferred PrEP group received standard of care for HIV prevention. The primary outcomes were the occurrence of preterm live birth (<37 weeks gestational age) and very preterm birth (<34 weeks gestational age) determined by menstrual dating, low birthweight (<2500 g), very low birthweight (<1500 g), stillbirth (≥20 weeks gestational age), and small for gestational age (birthweight less than the tenth percentile). Post-natal safety outcomes will be reported elsewhere. We used binomial regression models to estimate risk differences and two-sided 90% CIs. Immediate PrEP was non-inferior to deferred PrEP if the upper bound of the 90% CI of the risk difference was less than the upper predefined non-inferiority margin for preterm birth (7·5%), very preterm birth (2·6%), low birthweight (5·5%), very low birthweight (1·2%), stillbirth (1·0%), and small for gestational age (3·7%). All outcomes were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT3227731. FINDINGS: Between Sept 25, 2017, and Dec 6, 2019, we screened 693 women, of whom 540 were randomly assigned to immediate PrEP (n=271) or deferred PrEP (n=269). The median gestational age was 19 weeks (IQR 15-23 for immediate PrEP and 16-23 for deferred PrEP). The risk difference between the immediate PrEP group and the deferred PrEP group for preterm birth was -4·7% (90% CI -10·7 to 1·2; immediate PrEP was non-inferior), for very preterm birth was 0·6% (-3·4 to 4·6; upper limit exceeded the non-inferiority margin), for low birthweight was 2·5% (-1·6 to 6·6; upper limit exceeded the non-inferiority margin), for very low birthweight was 0% (-1·4 to 1·4; upper limit exceeded the non-inferiority margin), for stillbirth was 1·2% (-1·5 to 3·8; upper limit exceeded the non-inferiority margin), and for small for gestational age was 0·9% (-1·2 to 2·9; immediate PrEP was non-inferior). INTERPRETATION: In our study, PrEP was not associated with preterm birth or small for gestational age infants. Our data support the use of tenofovir disoproxil fumarate and emtricitabine in pregnancy and our reassuring findings can be used to allay safety concerns among pregnant women. FUNDING: South African Medical Research Council and Gilead Sciences.

Self-reported Antiretroviral Adherence: Association With Maternal Viral Load Suppression in Postpartum Women Living With HIV-1 From Promoting Maternal and Infant Survival Everywhere, a Randomized Controlled Trial in Sub-Saharan Africa and India.

INTRODUCTION: Optimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal-infant health. SETTING: Fourteen sites in 7 countries within sub-Saharan Africa and India. METHODS: The multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother-infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm. RESULTS: Two thousand four hundred thirty-one mother-infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553-869), and the median mVL was 322 copies/mL (IQR 40-1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P < 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL ( P < 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99). CONCLUSIONS: Postpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed. CLINICAL TRIAL NUMBER: ClinicalTrials.gov: NCT01061151; closed to follow-up.

Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. TRIAL DESIGN: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. METHODS: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. RESULTS: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). CONCLUSIONS: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. TRIAL REGISTRATION: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Brief Report: Impact of Antiretroviral Regimen on Pregnancy and Infant Outcomes in Women With HIV/ HBV Coinfection.

BACKGROUND: There are limited data on the impact of antenatal antiretroviral regimens (ARV) on pregnancy and infant outcomes in HIV/HBV coinfection. We compared outcomes among 3 antenatal antiretroviral regimens for pregnant women with HIV/HBV. METHODS: The PROMISE study enrolled ARV-naive pregnant women with HIV. Women with HBV were randomized to (no anti-HBV)-zidovudine (ZDV) + intrapartum nevirapine and 1 week of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC); (3TC)-3TC + ZDV + LPV/r; or (FTC-TDF)-FTC + TDF + LPV/r. Pairwise group comparisons were performed with Fisher exact, t , or log rank tests. Adverse pregnancy outcome (APO) was a composite of low birth weight, preterm delivery, spontaneous abortion, stillbirth, or congenital anomaly. RESULTS: Of 138 women with HIV/HBV, 42, 48, and 48 were analyzed in the no anti-HBV, 3TC, and FTC-TDF arms. Median age was 27 years. APOs trended lower in the no anti-HBV (26%) vs 3TC (38%), and FTC-TDF arms (35%), P ≥ 0.25). More infant deaths occurred among the FTC-TDF [6 (13%)] vs no anti-HBV [2 (5%)] and 3TC [3 (7%)] arms. There were no differences in time-to-death, HIV-free survival, birth or one-year WHO Z-score length-for-age, and head circumference. Hepatitis B e antigen (HBeAg) was associated with an increased risk of APO, 48% vs 27% (odds ratio 2.79, 95% confidence interval: 1.19 to 6.67, post hoc ). CONCLUSION: With HBV/HIV coinfection, the risk of an APO was increased with maternal ARV compared with ZDV alone, although the differences were not statistically significant. Maternal HBeAg was associated with a significantly increased risk of APO. Infant mortality was highest with FTC + TDF + LPV/r. Early assessment of HBeAg could assist in identifying high-risk pregnancies for close monitoring.

Immunogenicity and safety of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine in people living with and without HIV-1 infection: a randomised, controlled, phase 2A/2B trial.

BACKGROUND: There is a paucity of data on COVID-19 vaccines in people living with HIV-1, who could be at increased risk of severe illness and death from COVID-19. We evaluated the safety and immunogenicity of a Matrix-M adjuvanted recombinant spike protein nanoparticle COVID-19 vaccine (NVX-CoV2373; Novavax) in HIV-negative people and people living with HIV-1. METHODS: In this randomised, observer-blinded, multicentre, placebo-controlled phase 2A/B trial in South Africa, participants aged 18-84 years, with and without underlying HIV-1, were enrolled from 16 sites and randomly assigned (1:1) to receive two intramuscular injections of NVX-CoV2373 or placebo, 21 days apart. People living with HIV-1 were on stable antiretroviral therapy and had an HIV-1 viral load of less than 1000 copies per mL. Vaccine dosage was 5 µg SARS-CoV-2 recombinant spike protein with 50 µg Matrix-M adjuvant, whereas 0·9% saline was used as placebo injection (volume 0·5 mL each). All study staff and participants remained masked to study group assignment. We previously reported an interim analysis on the efficacy and safety of the NVX-CoV2373 vaccine (coprimary endpoints). In this Article, we present an expanded safety analysis for the full cohort of participants and report on the secondary objective of vaccine immunogenicity in the full cohort of people living with HIV-1 and in HIV-negative individuals overall and stratified by baseline SARS-CoV-2 serostatus. This trial is registered with ClinicalTrials.gov, NCT04533399, and the Pan-African Clinical Trials Registry, PACTR202009726132275. FINDINGS: Participants were enrolled between Aug 17 and Nov 25, 2020. The safety analysis set included 4164 HIV-negative participants (2089 in the intervention group and 2075 in the placebo group) and 244 people living with HIV-1 (122 in the intervention group and 122 in the placebo group). 1422 (34·1%) of 4164 HIV-negative people and 83 (34·0%) of 244 people living with HIV-1 were categorised as baseline SARS-CoV-2-positive (ie, anti-spike IgG reactive at enrolment or had a reactive SARS-CoV-2 nucleic acid amplification test by 14 days after the second study vaccination). In the NVX-CoV2373 group, solicited local and systemic adverse events were more common in HIV-negative participants (427 [30·6%] local and 401 [28·7%] systemic) than in people living with HIV-1 (20 [25·3%] local and 20 [25·3%] systemic) among those who were baseline SARS-CoV-2-seronegative (naive). Of the serious adverse events that occurred among HIV-negative people (of whom, two [0·1%] were baseline SARS-CoV-2-negative and four [0·6%] were baseline SARS-CoV-2-positive) and people living with HIV-1 (for whom there were no serious adverse events) in the NVX-CoV2373 group, none were assessed as related to the vaccine. Among participants who were baseline SARS-CoV-2-negative in the NVX-CoV2373 group, the anti-spike IgG geometric mean titres (GMTs) and seroconversion rates (SCRs) were lower in people living with HIV-1 (n=62) than in HIV-negative people (n=1234) following the first vaccination (GMT: 508·6 vs 1195·3 ELISA units [EU]/mL; SCR: 51·6% vs 81·3%); and similarly so 14 days after the second vaccination for GMTs (14 420·5 vs 31 631·8 EU/mL), whereas the SCR was similar at this point (100·0% vs 99·3%). In the NVX-CoV2373 group, anti-spike IgG GMTs 14 days after the second vaccination were substantially higher in those who were baseline SARS-CoV-2-positive than in those who were baseline SARS-CoV-2-seronegative for HIV-negative participants (100 666·1 vs 31 631·8 EU/mL) and for people living with HIV-1 (98 399·5 vs 14 420·5 EU/mL). This was also the case for angiotensin-converting enzyme 2 receptor-binding antibody and neutralising antibody titres. INTERPRETATION: The safety of the NVX-CoV2373 vaccine in people living with HIV-1 was similar to that in HIV-negative participants. However, people living with HIV-1 not previously exposed to SARS-CoV-2 had attenuated humoral immune responses to NVX-CoV2373 compared with their HIV-negative vaccine counterparts, but not so if they were baseline SARS-CoV-2-positive. FUNDING: Novavax and the Bill & Melinda Gates Foundation; investigational vaccine manufacturing support was provided by the Coalition for Epidemic Preparedness Innovations.

Examining Why Age-Disparate Relationships Influence Unsafe Sex Postpartum Among South African Women: Relationship Control and Physical Partner Violence as Explanatory Mechanisms.

HIV incidence rates in South Africa are extremely high, particularly postpartum. However, there is limited knowledge of women's HIV risk behavior postpartum. Women in age-disparate relationships may be less able to negotiate safe sex postpartum than women whose partners are similar ages because they have less relationship power. The study's purpose is to test whether being in an age-disparate relationship predicts postpartum unsafe sex and to explore relationship control and intimate partner violence (IPV) as explanatory mechanisms. Data are obtained from 516 HIV-negative participants who completed a survey during pregnancy and at 14 weeks postpartum as part of a longitudinal study in Durban. Age variables, relationship control, and IPV during pregnancy were included in a multivariate model predicting unsafe sex postpartum. We also assessed whether the hypothesized mediators explained the association between being in an age-disparate relationship and unsafe sex postpartum by using indirect effect analysis with bootstrapping. Women's mean age was 24.34 years (range = 18.03-45.36); the mean difference in ages in relationships was 3.19 years (range = -6.1 to 30.1). More than a quarter reported unsafe sex postpartum (27%). Age-disparate relationship, lower relationship control, and higher IPV were each longitudinally associated with unsafe sex. Relationship control, but not IPV, mediated the association between age-disparate relationship and unsafe sex (indirect effect [B] = 0.01, 95% confidence interval [CI] = [0.0002, 0.0283]). Age disparity, relationship control, and IPV all contributed to unsafe sex postpartum. Interventions that reduce the formation of age-disparate relationships and increase women's relationship power in pregnancy are needed to reduce women's HIV risk in the postpartum period.

A mixed-methods study of resilience and return to school among adolescent mothers in South Africa.

ABSTRACTUp to two-thirds of South African adolescent mothers drop out of school, which increases their HIV risk and other poor health outcomes. Despite variability in adolescent mothers' schooling trajectories, we have a limited understanding of their re-enrollment in school following the life-changing circumstance of childbirth. In this paper, we draw on qualitative interviews (n = 16) and quantitative surveys (n = 109) with adolescent mothers (aged 14-19) who had recently given birth to describe how access to individual and social resources contributes to their resilience following childbirth and thus affects their ability to re-enroll in school. Nearly all the adolescent mothers in our study expressed a desire to return to school, and most of their families also emotionally supported adolescent mothers in these goals. Despite mothers' high hopes and familial emotional support, only half of the adolescent mothers re-enrolled in the first six months following childbirth. Adolescent mothers' re-entry trajectories were strongly affected by institutional support and by family members' provision of instrumental support. To a lesser extent, support from partners and peers also played a role in re-enrollment. Multilevel interventions to maximise resilience following the onset of early motherhood may facilitate return to school and positively influence adolescent mothers' health and well-being.