Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women.

BACKGROUND: There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women. METHODS: We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF. RESULTS: Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions. CONCLUSIONS: No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant.

BACKGROUND: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1-2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission. METHODS: In this phase 2a-b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)-negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 µg of recombinant spike protein with 50 µg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection. RESULTS: Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, -0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups. CONCLUSIONS: The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399.).

Sexually transmitted infections and bacterial vaginosis among adolescent girls and young women in the early postpartum period: a cross-sectional study.

BACKGROUND: Universal antiretroviral treatment (ART) for pregnant women has reduced mother-to-child transmission risk significantly. However, not all women on ART are virally suppressed during pregnancy and lactation. In addition to poor adherence to ART, co-infections particularly other sexually transmitted infections (STIs) are known to increase the risk of HIV acquisition and HIV transmission. While the prevalence of STIs during pregnancy has been well studied, the prevalence of STIs in the postpartum period and its association with HIV viral suppression are underreported. METHODS: In this cross-sectional study, we determined the prevalence of STIs among adolescent girls and young women (AGYW) living with HIV (WLHIV) and without HIV (WNLHIV) at their 6-14 week postnatal clinic visit in a high HIV prevalence district in South Africa. All women were examined for STI-related symptoms and had vaginal swabs collected and stored for later STI testing. Vaginal swabs were tested for Trichomonas vaginalis (T.vaginalis), Chlamydia trachomatis (C. trachomatis), Neisseria gonorrhoeae (N. gonorrhoea) and herpes simplex virus-2 (HSV-2) using PCR. All women were tested for bacterial vaginosis (BV) using the Nugent scoring criteria. WLHIV had a blood sample collected for HIV viral load, Hepatitis B and syphilis. RESULTS: Included in this analysis were 82 WLHIV and 102 WNLHIV. Between 6 and 14 weeks postpartum, 40 (21.7%) AGYW tested positive for any STI and among these 15 (37.5%) were symptomatic and received empirical treatment. C. trachomatis was most commonly detected (10.9%), followed by HSV-2 (7.7%), T. vaginalis (3.8%) and N. gonorrhoea (1.6%). WLHIV were more likely to test positive for an STI (OR 2.0; 0.96-3.96) and BV (OR 4.2; 95%CI 2.1-8.1) compared to WNLHIV. Among WLHIV on ART, 70.5% had an undetectable plasma viral load (PVL) and 20.5% had a PVL > 1000 copies/ml. Testing positive for any STI or BV at the postpartum visit was not associated with PVL > 1000 copies/ml (OR 1.33; 95%CI 0.38-4.64). CONCLUSION: We report a high prevalence of largely asymptomatic STIs and BV in the early postpartum period and STIs in WLHIV were not associated with unsuppressed PVL.The high STI positivity rate among WNLHIV has implications for HIV risk during the postpartum period, and subsequently breastfeeding transmission.

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.

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.

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.

Eliminating postnatal HIV transmission in high incidence areas: need for complementary biomedical interventions.

The rate of mother-to-child transmission (MTCT) of HIV from breastfeeding is increasing relative to other causes of MTCT. Early effective preconception and antenatal antiretroviral therapy (ART) reduces intrauterine and intrapartum MTCT, whereas maternal post-partum HIV acquisition, untreated maternal HIV, and suboptimal postnatal maternal ART adherence increase the risk of MTCT through breastfeeding. Although the absolute number of cases of MTCT acquired through breastfeeding is decreasing, the rate of decrease is less than the decrease in intrauterine and intrapartum MTCT. Unless current strategies are universally applied, they might not be sufficient to eliminate MTCT due to breastfeeding. Urgent action is needed to evaluate and implement additional preventive biomedical strategies in high HIV prevalence and incidence settings to eliminate MTCT from breastfeeding. Preventive strategies include: pre-exposure prophylaxis in breastfeeding women who have an increased risk of acquiring HIV; postnatal reinforcement strategies, such as maternal retesting for HIV, maternal care reinforcement, and prophylaxis in infants exposed to HIV via breastmilk; and active (vaccine) or passive immunoprophylaxis with long-acting broadly neutralising antibodies.

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.

Pregnancy Outcomes of Women Conceiving on Antiretroviral Therapy (ART) Compared to Those Commenced on ART During Pregnancy.

BACKGROUND: Globally, the number of infected women of childbearing age living with human immunodeficiency virus (HIV) and conceiving on antiretroviral therapy (ART) is increasing. Evidence of ART safety at conception and during pregnancy and adverse pregnancy outcomes remains conflicting. The Promoting Maternal and Infant Survival Everywhere (PROMISE) 1077 breastfeeding (BF) and formula feeding (FF) international multisite trials provide an opportunity to examine the impact of ART at conception on pregnancy outcomes with subsequent pregnancies. METHODS: The PROMISE 1077BF/1077FF trials were designed to address key questions in the management of HIV-infected women who did not meet clinical guidelines for ART treatment during the time of the trials. After the period of risk of mother-to-child transmission was over, women were randomized to either continue or discontinue ART. We compared subsequent pregnancy outcomes of nonbreastfeeding women randomized to continue ART following delivery, or breastfeeding women randomized to continue ART following breastfeeding cessation who conceived while on ART to women randomized to discontinue ART, who restarted ART after pregnancy was diagnosed. RESULTS: Pregnancy outcomes of 939 subsequent pregnancies of 826 mothers were recorded. The intention-to-treat analyses showed increased incidence of low birth weight (<2500 g) for women who conceived while on ART (relative risk, 2.65 [95% confidence interval {CI}, 1.20-5.81]), and also a higher risk of spontaneous abortion, stillbirth, or neonatal death (hazard ratio, 1.40 [95% CI, .99-1.98]) compared to women who restarted ART after they were found to be pregnant during trial follow-up. CONCLUSIONS: We found an increased risk for adverse pregnancy outcomes in women conceiving on ART, emphasizing the need for improved obstetric and neonatal care for this group. CLINICAL TRIALS REGISTRATION: NCT01061151.

Comparison of dried blood spot and plasma sampling for untargeted metabolomics.

INTRODUCTION: Untargeted metabolomics holds significant promise for biomarker detection and development. In resource-limited settings, a dried blood spot (DBS)-based platform would offer significant advantages over plasma-based approaches that require a cold supply chain. OBJECTIVES: The primary goal of this study was to compare the ability of DBS- and plasma-based assays to characterize maternal metabolites. Utility of the two assays was also assessed in the context of a case-control predictive model in pregnant women living with HIV. METHODS: Untargeted metabolomics was performed on archived paired maternal plasma and DBS from n = 79 women enrolled in a large clinical trial. RESULTS: A total of 984 named biochemicals were detected across both plasma and DBS samples, of which 627 (63.7%), 260 (26.4%), and 97 (9.9%) were detected in both plasma and DBS, plasma alone, and DBS alone, respectively. Variation attributable to study individual (R2 = 0.54, p < 0.001) exceeded that of the sample type (R2 = 0.21, p < 0.001), suggesting that both plasma and DBS were capable of differentiating individual metabolomic profiles. Log-transformed metabolite abundances were strongly correlated (mean Spearman rho = 0.51) but showed low agreement (mean intraclass correlation of 0.15). However, following standardization, DBS and plasma metabolite profiles were strongly concordant (mean intraclass correlation of 0.52). Random forests classification models for cases versus controls identified distinct feature sets with comparable performance in plasma and DBS (86.5% versus 91.2% mean accuracy, respectively). CONCLUSION: Maternal plasma and DBS samples yield distinct metabolite profiles highly predictive of the individual subject. In our case study, classification models showed similar performance albeit with distinct feature sets. Appropriate normalization and standardization methods are critical to leverage data from both sample types. Ultimately, the choice of sample type will likely depend on the compounds of interest as well as logistical demands.

Ethically designing research to inform multidimensional, rapidly evolving policy decisions: Lessons learned from the PROMISE HIV Perinatal Prevention Trial.

Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study's standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the "PROMISE" (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study's standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.

Reliability of last menstrual period recall, an early ultrasound and a Smartphone App in predicting date of delivery and classification of preterm and post-term births.

BACKGROUND: A reliable expected date of delivery (EDD) is important for pregnant women in planning for a safe delivery and critical for management of obstetric emergencies. We compared the accuracy of LMP recall, an early ultrasound (EUS) and a Smartphone App in predicting the EDD in South African pregnant women. We further evaluated the rates of preterm and post-term births based on using the different measures. METHODS: This is a retrospective sub-study of pregnant women enrolled in a randomized controlled trial between October 2017-December 2019. EDD and gestational age (GA) at delivery were calculated from EUS, LMP and Smartphone App. Data were analysed using SPSS version 25. A Bland-Altman plot was constructed to determine the limits of agreement between LMP and EUS. RESULTS: Three hundred twenty-five pregnant women who delivered at term (≥ 37 weeks by EUS) and without pregnancy complications were included in this analysis. Women had an EUS at a mean GA of 16 weeks and 3 days). The mean difference between LMP dating and EUS is 0.8 days with the limits of agreement 31.4-30.3 days (Concordance Correlation Co-efficient 0.835; 95%CI 0.802, 0.867). The mean(SD) of the marginal time distribution of the two methods differ significantly (p = 0.00187). EDDs were < 14 days of the actual date of delivery (ADD) for 287 (88.3%;95%CI 84.4-91.4), 279 (85.9%;95%CI 81.6-89.2) and 215 (66.2%;95%CI 60.9-71.1) women for EUS, Smartphone App and LMP respectively but overall agreement between EUS and LMP was only 46.5% using a five category scale for EDD-ADD with a kappa of .22. EUS 14-24 weeks and EUS < 14 weeks predicted EDDs < 14 days of ADD in 88.1% and 79.3% of women respectively. The proportion of births classified as preterm (< 37 weeks) was 9.9% (95%CI 7.1-13.6) by LMP and 0.3% (95%CI 0.1-1.7) by Smartphone App. The proportion of post-term (> 42 weeks gestation) births was 11.4% (95%CI 8.4-15.3), 1.9% (95%CI 0.9-3.9) and 3.4% (95%CI 1.9-5.9) by LMP, EUS and Smartphone respectively. CONCLUSIONS: EUS and Smartphone App were the most accurate to estimate the EDD in pregnant women. LMP-based dating resulted in misclassification of a significantly greater number of preterm and post-term deliveries compared to EUS and the Smartphone App.

Growth patterns and clinical outcomes in association with breastfeeding duration in HIV exposed and unexposed infants: a cohort study in KwaZulu Natal, South Africa.

BACKGROUND: Exclusive breastfeeding for 6 months and breastfeeding with complementary feeds until 12 months for HIV exposed and uninfected (HEU) infants or 24 months for HIV unexposed (HU) infants is the current World Health Organisation (WHO) recommendation for low and middle income countries (LMICs) to improve clinical outcomes and growth trajectories in infants. In a post-hoc evaluation of HEU and HU cohorts, we examine growth patterns and clinical outcomes in the first 9 months of infancy in association with breastfeeding duration. METHODS: Two cohorts of infants, HEU and HU from a low-socioeconomic township in South Africa, were evaluated from birth until 9 months of age. Clinical, anthropometric and infant feeding data were analysed. Standard descriptive statistics and regression analysis were performed to determine the effect of HIV exposure and breastfeeding duration on growth and clinical outcomes. RESULTS: Included in this secondary analysis were 123 HEU and 157 HU infants breastfed for a median of 26 and 14 weeks respectively. Median WLZ score was significantly (p < 0.001) lower in HEU than HU infants at 3, 6 and 9 months (- 0.19 vs 2.09; - 0.81 vs 0.28; 0.05 vs 0.97 respectively). The median LAZ score was significantly lower among HU infants at 3 and 6 months (- 1.63 vs 0.91, p < 0.001; - 0.37 vs 0.51, p < 0.01) and a significantly higher proportion of HU was classified as stunted (LAZ < -2SD) at 3 and 6 months (3.9% vs 44.9%, p < 0.001; 4.8% vs 20.9%, p < 0.001 respectively) independent of breastfeeding duration. A higher proportion of HEU infants experienced one or more episodes of skin rash (44.5% vs 12.8%) and upper respiratory tract infection (URTI) (30.1% vs 10.9%) (p < 0.0001). In a multivariable analysis, the odds of occurrence of wasting, skin rash, URTI or any clinical adverse event in HEU infants were 2.86, 7.06, 3.01 and 8.89 times higher than HU infants after adjusting for breastfeeding duration. CONCLUSION: Our study has generated additional evidence that HEU infants are at substantial risk of infectious morbidity and decreased growth trajectories however we have further demonstrated that these adverse outcomes were independent of breastfeeding duration.

IPV victimization in pregnancy increases postpartum STI incidence among adolescent mothers in Durban, South Africa.

Women, and specifically, adolescents, are at high risk of HIV and STIs during the postpartum period. Biological and behavioral factors contribute to adolescents' susceptibility. However, the influence of behavioral factors, like intimate partner violence (IPV), on postpartum STI acquisition has been understudied. The study's purpose is to determine whether IPV victimization during pregnancy predicts incident STIs in the first 6 months postpartum. Adolescent mothers (14-19 years) were recruited at a township hospital's maternity ward near Durban. Adolescent mothers who were HIV-negative and had no laboratory-diagnosed STIs at baseline (6 weeks postpartum) were included in the analysis (n = 61). We used a modified Poisson regression with robust standard errors to assess differences in postpartum STI risk by IPV victimization during pregnancy controlling for covariates. At baseline, 25 (41%) adolescent mothers reported IPV victimization during pregnancy. Adolescent mothers who reported IPV during pregnancy were at higher risk of receiving an STI diagnoses at 6 months postpartum (aRR: 4.43; 95% CI: 1.31-14.97). Our findings heighten understanding of HIV risk among a vulnerable subset of adolescent girls: adolescent mothers. Non-combined interventions that help young mothers and their partners navigate partnership dynamics to reduce IPV and STIs are needed to reduce HIV risk.

Preterm prelabour rupture of membranes (PPROM) and pregnancy outcomes in association with HIV-1 infection in KwaZulu-Natal, South Africa.

BACKGROUND: SubSaharan Africa has a disproportionate burden of HIV and preterm births (PTB). We hypothesized that PTB in HIV-1 infected women are more likely a result of prelabour rupture of membranes (PROM) and could lead to worse birth outcomes than HIV-uninfected women. We also hypothesized that PPROM increased the risk of mother-to-child transmission (MTCT) of HIV-1. Current clinical management protocols for PPROM do not include a differential treatment plan for HIV-infected women. METHODS: The maternity register at a regional hospital in a high HIV-burden district in South Africa was reviewed to identify all preterm births over a 3 month-period in 2018. We determined the incidence of PPROM using predefined criteria. Maternal age, parity, previous pregnancy complications, antenatal care, body mass index, history of smoking or alcohol, HIV infection and syphilis were computed on chi-square contingency tables to determine risk of PPROM. Overall pregnancy outcomes that included mode of delivery, fetal survival, birth weight, gestational age and newborn apgar scores were compared between HIV-infected and HIV-uninfected women whose pregnancies were complicated by PPROM. HIV-exposed newborns are routinely tested at birth for HIV by PCR. RESULTS: A total of 1758 deliveries were recorded for Jan-Mar, 2018, and 295 (16.8%) were preterm. Maternity charts were retrieved for 236 (80.0%) PTB; 47 of PTB (19.9%; 95%CI 15.0-25.6) were further complicated by PROM which translates to 2.7% (95%CI 1.9-3.4) of all deliveries. None of the risk variables including HIV-positive status (48.9% vs 47.6%) were different between PPROM and non-PPROM groups and the majority of women were receiving cART (94.7 and 92.0%). There were no differences in the proportion of low birth weight (RR 1.2 95%CI 0.6-2.1) or severe preterm birth (RR 1.6; 95%CI 0.9-2.9) between HIV-infected and HIV-uninfected women whose pregnancies were complicated by PPROM. None of the 22 HIV-exposed newborns in the PPROM group were HIV-infected at birth. CONCLUSION: The PPROM incidence is not higher among HIV-infected women and our findings suggest that HIV-infected women who are virally suppressed on cART and presenting with PPROM are less likely to transmit HIV to their infants and do not have worse birth outcomes than HIV-uninfected women.

Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention.

BACKGROUND: Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS: We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS: The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS: Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).

A longitudinal study of the relationship between intimate partner violence and postpartum unsafe sex among newly diagnosed HIV-infected South African women.

HIV-positive women who engage in postpartum unsafe sex are at risk for sexually transmitted infection (STI), unintended pregnancy, and secondary transmission of HIV to uninfected partners. One factor that may increase risk for postpartum unsafe sex among HIV-positive women is intimate partner violence (IPV) victimization; few studies, however, have examined this association. This longitudinal study examined whether patterns of psychological, physical, and sexual IPV, assessed during pregnancy, predicted unsafe sex at 14 weeks postpartum among South African women diagnosed as HIV-positive during pregnancy (n = 561). In a latent class analysis, we identified three distinct patterns of IPV victimization: non-victims (74%), moderate IPV (20%), and multiform severe controlling IPV (5%). Compared to non-victims, victims of multiform severe controlling IPV were significantly more likely to engage in postpartum unsafe sex (p = .01), even after adjusting for potential confounding factors. Moderate IPV was not associated with postpartum unsafe sex. Findings support the need for targeted sexual risk reduction interventions for HIV-positive pregnant women who have experienced severe patterns of IPV.

Association of endogenous progesterone levels in young women using hormonal contraception with recent HIV-1 infection.

BACKGROUND: A high endogenous progesterone luteal state in the menstrual cycle has been independently associated with Human Immunodeficiency Virus (HIV) incidence in epidemiological studies. Hormonal contraception particularly high dose Depot Medroxyprogesterone Acetate (DMPA) is also thought to increase the risk of HIV acquisition. Inconsistent reports of this association have led us to hypothesize that unsuppressed endogenous progesterone level in women who reported hormonal contraception (HC) use may be an explanation for increased vulnerability to HIV. METHODS: This pilot study was a secondary cross-sectional analysis of data and laboratory testing of stored specimens collected from women who participated in the SAMRC HIV prevention MDP 301 trial during 2005-2009 in South Africa. Serum progesterone levels were measured in 39 women at the point of first positive HIV diagnosis during study follow-up and 36 women who remained HIV uninfected at the 52-week study exit visit. RESULTS: Overall, the median (IQR) progesterone level in 49 women using hormonal contraception was 0.39 ng/ml (IQR 0.13-0.45) and 48 (97.9%) women had a progesterone level < 3.0 ng/ml suggestive of adequate progesterone suppression for contraceptive efficacy. After excluding the one woman with a progesterone level of > 3.0 ng/ml, the median progesterone level in women using DMPA remained marginally higher at 0.42 ng/ml (IQR 0.27-0.45) than women using Norethisterone Enanthate (NET-EN) (0.31 ng/ml; IQR 0.13-0.41, p = 0.061). For women using hormonal contraception, the median progesterone level did not differ between women with recent HIV infection or women who remained HIV negative (0.39 vs 0.38 ng/ml, p = 0.959). Similarly, the median progesterone level in women using DMPA or NET-EN did not differ by HIV status (0.43 vs 0.41 ng/ml, p = 0.905; 0.24 vs 0.31 ng/ml, p = 0.889). CONCLUSION: Among women using hormonal contraception, DMPA or NET-EN we did not observe a significant difference in progesterone levels between women with recently acquired HIV infection and women who remained HIV negative. Our findings suggest that endogenous progesterone levels remain suppressed in the presence of hormonal contraception and are not likely to be associated with HIV acquisition.

Asymptomatic Bacterial Vaginosis in Pregnancy and Missed Opportunities for Treatment: A Cross-Sectional Observational Study.

Background: High rates of bacterial vaginosis (BV) have been described in nonpregnant South African women. Studies of BV in South African pregnant women are sparse. Diagnosis and prompt treatment of BV in pregnancy are expected to have a positive impact on pregnancy outcomes and HIV prevention. This study was undertaken to determine the prevalence of BV in pregnant women in a high HIV burden periurban setting in KwaZulu-Natal and explore how to enhance BV diagnosis in this setting where syndromic management of sexually transmitted diseases is the standard of care. Methods: In this cross-sectional study, consenting HIV uninfected pregnant women were examined for abnormal vaginal discharge; nurses determined the vaginal pH and collected a vaginal swab for Gram-stain and Nugent scoring. Findings: Among 750 HIV uninfected pregnant women, 280 (37.3%; 95%CI 33.9-40.9) tested positive for BV. Using a vaginal pH > 4.4, 65% of women with BV were correctly identified, while an abnormal vaginal discharge correctly identified a significantly lower proportion (52.9%) of women with BV (p=0.005). The sensitivity, specificity, and positive and negative predictive values of vaginal pH testing were 65.9% (95%CI 60.0 - 71.5%), 61.4% (95%CI 56.8 - 65.9%), and 50.1% and 75.4%, respectively. The 20-24 year-old pregnant women were twice more likely to test positive for BV than the adolescent pregnant women (43.6% vs 21.1%) (p = 0.037) and BV was not associated with the duration of a sexual relationship, frequency of unprotected sex during pregnancy, number of lifetime sex partners, or the partner's age. Conclusion: There is a high burden of primarily asymptomatic BV in HIV uninfected pregnant women in this periurban setting. Both the sensitivity and specificity of vaginal pH testing are superior to the symptomatic diagnosis of BV but not good enough to be used as a screening tool.

HIV Positive Diagnosis During Pregnancy Increases Risk of IPV Postpartum Among Women with No History of IPV in Their Relationship.

There has been limited study of whether and for whom physical intimate partner violence (IPV) is a consequence of an HIV-positive diagnosis. Per the diathesis stress model, the consequences of HIV infection may be worse for women with a history of IPV. We hypothesize that the positive association between HIV diagnosis in pregnancy and postpartum IPV will be exacerbated for women with a history of IPV. Data come from a prospective cohort study with 1015 participants who completed a baseline antenatal and 9-month postpartum visit. Using logistic regression analyses, we found a statistically significant interaction between HIV diagnosis, history of IPV and postpartum IPV (AOR: 0.40, 95% CI 0.17-0.96). The findings were in the opposite direction as expected: HIV-diagnosis was not associated with IPV for women with a history of IPV (AOR: 2.17, 95% CI 1.06, 4.42). However, HIV-positive women without a history of IPV faced more than two times the risk of incident postpartum IPV than HIV-negative women (AOR: 2.17, 95% CI 1.06, 4.42). Interventions to reduce incident and ongoing IPV during the perinatal period are needed.