Attitudes and perceptions towards developing a health educational video to enhance optimal uptake of malaria preventive therapy among pregnant women in Uganda: a qualitative study involving pregnant women, health workers, and Ministry of health officials.

BACKGROUND: Malaria in pregnancy remains a major global public health problem. Intermittent prophylaxis treatment of malaria in pregnancy with Sulphadoxine-pyrimethamine and co-trimoxazole is efficacious for prevention of malaria in pregnancy HIV negative and positive women, respectively. However, uptake of the recommended doses of therapies has remained suboptimal in Uganda, majorly due to inadequate knowledge among pregnant women. Therefore, this study aimed to explore attitudes and perceptions towards developing an educational video for malaria preventive therapy. METHODS: We conducted an exploratory study with qualitative methods among pregnant women attending antenatal care at Kisenyi Health Center IV (KHCIV), health workers from KHCIV, and officials from the Ministry of Health. The study was conducted at KHCIV from October 2022 to March 2023. Focus group discussions (FGD) were conducted among purposively selected pregnant women and key informant interviews (KII) among health workers and Ministry of Health officials. Data were analyzed using inductive and deductive thematic methods in atlas ti.8. RESULTS: A total of five FGDs comprising of 7-10 pregnant women were conducted; and KIIs were conducted among four mid-wives, two obstetricians, and two Ministry of Health officials. Generally, all respondents mentioned a need for interventions to improve malaria preventive knowledge among pregnant women; were positive about developing an educative video for malaria preventive therapy in pregnancy; and suggested a short, concise, and edutaining video focusing both the benefits of taking and risks of not taking malaria preventive therapy. They proposed that women may be encouraged to view the video as soon as they conceive and throughout the pregnancy. It also was suggested that the video may be viewed on television sets in maternal and reproductive health clinics and homes, and on smart phones. CONCLUSION: Pregnant women, health workers, and Ministry of Health officials were positive about the development of a short edutaining video on malaria preventive therapy that focuses on both benefits of taking and risks of not taking the malaria preventive therapy in pregnancy. This information guided the video development and therefore, in the development of health educative videos, client and stakeholder inputs may always be solicited.

Prevalence of overweight and obesity among adolescents living with HIV after dolutegravir - based antiretroviral therapy start in Kampala, Uganda.

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is currently the preferred first-line treatment for persons living with HIV (PLHIV) including children and adolescents in many low- and middle-income countries including Uganda. However, there are concerns about excessive weight gain associated with DTG especially in adults. There remains paucity of current information on weight-related outcomes among adolescents on DTG. We determined the prevalence of excessive weight gain and associated factors among adolescents living with HIV (ALHIV) receiving DTG-based ART in Kampala, Uganda. METHODS: Cross-sectional study involving ALHIV aged 10-19 years on DTG-based ART for at least one year were recruited from public health facilities in Kampala between February and May 2022. Excessive weight gain was defined as becoming overweight or obese per body mass index (BMI) norms while on DTG-based ART for at least one year. Demographic, clinical and laboratory data were collected using interviewer-administered questionnaires and data extracted from medical records. At enrolment, blood pressure and anthropometry were measured and blood was drawn for blood glucose and lipid profile. Data was summarised using descriptive statistics and logistic regression was performed to determine the associated factors. RESULTS: We enrolled 165 ALHIV with a median age of 14 years (IQR 12-16). Eighty (48.5%) were female. The median duration on ART and DTG was 8 years (IQR 7-11) and 2 years (IQR 1-3) respectively. At DTG initiation, the majority of participants (152/165, 92.1%) were ART-experienced, and had normal BMI (160/165, 97%). Overall, 12/165 (7.3%) adolescents (95% CI: 4.2-12.4) had excessive weight gain. No factors were significantly associated with excessive weight gain after DTG start in ALHIV. However, all ALHIV with excessive weight gain were females. CONCLUSION: Our study found a prevalence of 7.3% of overweight and obesity in ALHIV after initiating DTG. We did not find any factor significantly associated with excessive weight gain in ALHIV on DTG. Nonetheless, we recommend ongoing routine monitoring of anthropometry and metabolic markers in ALHIV as DTG use increases globally, to determine the exact magnitude of excessive weight gain and to identify those at risk of becoming overweight or obese while taking the medication.

Enhanced peer-group strategies to support the prevention of mother-to-child HIV transmission leads to increased retention in care in Uganda: A randomized controlled trial.

INTRODUCTION: Despite the scale-up of Option B+, long-term retention of women in HIV care during pregnancy and the postpartum period remains an important challenge. We compared adherence to clinic appointments and antiretroviral therapy (ART) at 6 weeks, 6, and and 24 months postpartum among pregnant women living with HIV and initiating Option B+. Women were randomized to a peer group support, community-based drug distribution and income-generating intervention called "Friends for Life Circles" (FLCs) versus the standard of care (SOC). Our secondary outcome was infant HIV status and HIV-free survival at 6 weeks and 18 months postpartum. METHODS: Between 16 May 2016 and 12 September 2017, 540 ART-naïve pregnant women living with HIV at urban and rural health facilities in Uganda were enrolled in the study at any gestational age. Participants were randomized 1:1 to the unblinded FLC intervention or SOC at enrolment and assessed for adherence to the prevention of mother-to-child HIV transmission (PMTCT) clinic appointments at 6 weeks, 12, and 24 months postpartum, self-reported adherence to ART at 6 weeks, 6 and 24 months postpartum and supported by plasma HIV-1 RNA viral load (VL) measured at the same time points, retention in care through the end of study, and HIV status and HIV-free survival of infants at 18 months postpartum. The FLC groups were formed during pregnancy within 4 months of enrollment and held monthly meetings in their communites, and were followed up until the last group participant reached 24 months post delivery. We used Log-rank and Chi-Square p-values to test the equality of Kaplan-Meier survival probabilities and hazard rates (HR) for failure to retain in care for any reason by study arm. RESULTS: There was no significant difference in adherence to PMTCT clinic visits or to ART or in median viral loads between FLC and SOC arms at any follow-up time points. Retention in care through the end of study was high in both arms but significantly higher among participants randomized to FLC (86.7%) compared to SOC (79.3%), p = 0.022. The adjusted HR of visit dropout was 2.4 times greater among participants randomized to SOC compared to FLC (aHR = 2.363, 95% CI: 1.199-4.656, p = 0.013). Median VL remained < 400 copies/ml in both arms at 6 weeks, 6, and 24 months postpartum. Eight of the 431 infants tested at 18 months were HIV positive (1.9%), however, this was not statistically different among mothers enrolled in the FLC arm compared to those in the SOC arm. At 18 months, HIV-free survival of children born to mothers in the FLC arm was significantly higher than that of children born to mothers in the SOC arm. CONCLUSIONS: Our findings suggest that programmatic interventions that provide group support, community-based ART distribution, and income-generation activities may contribute to retention in PMTCT care, HIV-free survival of children born to women living with HIV, and ultimately, to the elimination of mother-to-child HIV transmission (EMTCT). TRIAL REGISTRATION: NCT02515370 (04/08/2015) on ClinicalTrials.gov.

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.

Unintended pregnancy and contraception use among African women living with HIV: Baseline analysis of the multi-country US PEPFAR PROMOTE cohort.

BACKGROUND: About 90% of unintended pregnancies are attributed to non-use of effective contraception-tubal ligation, or reversible effective contraception (REC) including injectables, oral pills, intra-uterine contraceptive device (IUCD), and implant. We assessed the prevalence of unintended pregnancy and factors associated with using RECs, and Long-Acting-Reversible-Contraceptives (LARCs)-implants and IUCDs, among women living with HIV (WLHIV) receiving antiretroviral therapy (ART). METHODS: We conducted cross-sectional analyses of the US-PEPFAR PROMOTE study WLHIV on ART at enrollment. Separate outcome (REC and LARC) modified-Poisson regression models were used to estimate prevalence risk ratio (PRR) and corresponding 95% confidence interval (CI). RESULTS: Of 1,987 enrolled WLHIV, 990 (49.8%) reported their last/current pregnancy was unintended; 1,027/1,254 (81.9%) non-pregnant women with a potential to become pregnant reported current use of effective contraception including 215/1,254 (17.1%) LARC users. Compared to Zimbabwe, REC rates were similar in South Africa, aPRR = 0.97 (95% CI: 0.90-1.04), p = 0.355, lower in Malawi, aPRR = 0.84 (95% CI: 0.78-0.91), p<0.001, and Uganda, 0.82 (95% CI: 0.73-0.91), p<0.001. Additionally, REC use was independently associated with education attained, primary versus higher education, aPRR = 1.10 (95% CI: 1.02-1.18), p = 0.013; marriage/stable union, aPRR = 1.10 (95% CI: 1.01-1.21), p = 0.039; no desire for another child, PRR = 1.10 (95% CI: 1.02-1.16), p = 0.016; infrequent sex (none in the last 3 months), aPRR = 1.24 (95% CI: 1.15-1.33), p<0001; and controlled HIV load (≤ 1000 copies/ml), PRR = 1.10 (95% CI: 1.02-1.19), p = 0.014. LARC use was independently associated with country (Zimbabwe ref: South Africa, PRR = 0.39 (95% CI: 0.26-0.57), p<0.001; Uganda, PRR = 0.65 (95% CI: 0.42-1.01), p = 0.054; and Malawi, aPRR = 0.87 (95% CI: 0.64-1.19), p = 0.386; HIV load (≤ 1000 copies/ml copies/ml), aPRR=1.73 (95% CI: 1.26-2.37), p<0.001; and formal/self-employment, aPRR = 1.37 (95% CI: 1.02-1.91), p = 0.027. CONCLUSIONS: Unintended pregnancy was common while use of effective contraception methods particularly LARCs was low among these African WLHIV. HIV viral load, education, sexual-activity, fertility desires, and economic independence are pertinent individual-level factors integral to the multi-level barriers to utilization of effective contraception among African WLHIV. National programs should prioritize strategies for effective integration of HIV and reproductive health care in the respective African countries.

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 multi-country 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 to zidovudine alone, the difference in biomarker concentration between week 0 and week 4 was significantly higher (p < 0.05) for both PI-based regimens. However, the estimated proportion of the ART effect on increased PTD mediated by persistently high biomarker levels was ≤5% for all biomarkers. CONCLUSIONS: : Persistently high IL-6 during pregnancy was associated with PTD. While PI-based ART was associated with increases in inflammation, factors other than inflammation likely explain the increased PTD in ART-based regimens compared to zidovudine alone.

Breastfeeding Among Women Living With HIV in the Era of Lifelong ART: An Observational Multicountry Study in Eastern and Southern Africa.

BACKGROUND: Lifelong antiretroviral treatment (ART) use is recommended for pregnant and breastfeeding (BF) women living with HIV (WLWH) to prevent perinatal HIV transmission and improve maternal health. We address 2 objectives in this analysis: (1) determine timing and factors associated with BF cessation and (2) assess the impact of BF on health of WLWH on ART. SETTING: This multicountry study included 8 sites in Uganda, Malawi, Zimbabwe, and South Africa. METHODS: This was a prospective study of WLWH on lifelong ART. These women initially participated from 2011 to 2016 in a randomized clinical trial (PROMISE) to prevent perinatal HIV transmission and subsequently reenrolled in an observational study (PROMOTE, 2016-2021) to assess ART adherence, safety, and impact. RESULTS: The PROMOTE cohort included 1987 women on ART. Of them, 752 breastfed and were included in analyses of objective 1; all women were included in analyses of objective 2. The median time to BF cessation varied by country (11.2-19.7 months). Country of residence, age, and health status of women were significantly associated with time to BF cessation (compared with Zimbabwe: Malawi, adjusted hazard ratio [aHR] 0.50, 95% confidence interval [95% CI]: 0.40 to 0.62, P < 0.001; South Africa, aHR 1.49, 95% CI: 1.11 to 2.00, P = 0.008; and Uganda, aHR 1.77, 95% CI: 1.37 to 2.29, P < 0.001). Women who breastfed had lower risk of being "unwell" compared with women who never breastfed (adjusted rate ratio 0.87, 95% CI: 0.81 to 0.95 P = 0.030). CONCLUSION: Women on lifelong ART should be encouraged to continue BF with no concern for their health. Time to BF cessation should be monitored for proper counseling in each country.

'When I receive ARVs through my group, my heart settles': Participants' perceptions and experiences of Friends for Life Circles for Option B+ in Kampala and Mityana Districts, Uganda.

The Friends for Life Circles (FLC) was a parallel randomized controlled trial testing the efficacy of a group peer support intervention to support long-term adherence to Option B+ in Kampala and Mityana districts in Uganda. We explored FLC participants' experiences and perceptions of the intervention on adherence to Option B+ for PMTCT and potential implications for strengthening the PMTCT program. We collected data from six focus group discussions with lactating women enrolled in the FLC intervention, and from 14 key informant interviews with health workers, district and national level stakeholders, as well as male partners of FLC participants. Data were analysed using a content thematic approach in a continuous and iterative process. Women described the FLC intervention as acceptable and beneficial in enhancing their understanding of HIV and the need for ART. The FLC helped women, especially those newly diagnosed with HIV infection to come to terms with their diagnosis and overcome the fear of death linked to testing HIV positive, and provided opportunities to enhance ART initiation, resumption and adherence. The FLC provided safe spaces for women, to learn about ART, and to receive support from peers including adherence reminders through home visits and 'coded' reminder messages. Receiving ART from support groups protected members from stigma and long lines at health facilities. Fear of stigma, health system challenges, the high cost of caring for animals and lack of money to save in groups were key challenges noted. The FLC support groups were crucial in providing needed support for women to initiate, resume and adhere to lifelong ART for Option B+. It is important that women who test HIV positive and start ART for life receive psychosocial support from peers and health workers to improve chances of preventing HIV transmission from mothers to children.

Metabolomic profiling of preterm birth in pregnant women living with HIV.

BACKGROUND: Preterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive. OBJECTIVES: Metabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens. METHODS: This pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23-35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth. RESULTS: Classification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context. CONCLUSION: This study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation.

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.

Biochemical Markers of Calcium and Bone Metabolism during and after Lactation in Ugandan Women with HIV on Universal Maternal Antiretroviral Therapy.

We reported accentuated lactational decreases in areal bone mineral density and only partial skeletal recovery after lactation in Ugandan women with HIV (WWH) initiated on tenofovir disoproxil fumarate-based antiretroviral therapy (TDF-based ART) during pregnancy compared to women without HIV (REF). WWH also had higher breast milk calcium in the first months of lactation. To investigate the mechanisms, we measured bone turnover markers (bone resorption: C-terminal telopeptide [CTX]; bone formation: procollagen type 1 N-terminal propeptide [P1NP], bone-specific and total alkaline phosphatase [BALP, TALP]), hormones (parathyroid hormone [PTH], intact fibroblast growth factor 23 [FGF23], 1,25-dihydroxyvitamin D [1,25(OH)2 D]), vitamin D status (25-hydroxyvitamin D [25OHD]), and indices of mineral metabolism and renal function. Blood and urine samples collected at 36 weeks of gestation, 14 and 26 weeks of lactation, and 3-6 months after lactation were analyzed. Mean 25OHD was >50 nmol/L throughout. Both groups experienced similar biochemical changes during pregnancy and lactation to women in other settings, but within these patterns, the two groups differed significantly. Notably, WWH had higher PTH (+31%) and lower 1,25(OH)2 D (-9%) and TmP/GFR (-9%) throughout, lower P1NP (-27%) and plasma phosphate (-10%) in pregnancy, higher CTX (+15%) and BALP (+19%), and lower eGFR (-4%) during and after lactation. P1NP/CTX ratio was lower in WWH than REF in pregnancy (-21%), less so in lactation (-15%), and similar after lactation. Additionally, WWH had lower plasma calcium (-5%), lower FGF23 (-16%) and fasting urinary calcium (-34%) at one or both lactation timepoints, and higher fasting urinary phosphate (+22%) at 26 weeks of lactation and after lactation. These differences resemble reported TDF effects, especially raised PTH, increased bone resorption, decreased bone formation, and decreased renal function, and may explain the observed differences in bone mineral density and breast milk calcium. Further studies are needed to determine whether HIV and TDF-based ART have long-term consequences for maternal bone health and offspring growth. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Enhanced Peer-Group strategies to support prevention of Mother-to-Child HIV transmission leads to increased retention in care in Uganda: A Randomized controlled trial.

Introduction: Despite scale up of Option B+, long-term retention of women in HIV care during pregnancy and the postpartum period remains an important challenge. We compared adherence to clinic appointments and antiretroviral therapy (ART) at different follow-up time points between enrolment and 24 months postpartum among pregnant women living with HIV and initiating Option B+ randomized to a peer group support, community-based drug distribution and income-generating intervention called "Friends for Life Circles" (FLCs) versus the standard of care (SOC). Methods: Between 16 May 2016 and 12 September 2017, 540 ART-naïve pregnant women living with HIV at urban and rural health facilities in Uganda were enrolled in the study. Participants were randomized 1:1 to the FLC intervention or SOC and assessed for adherence to prevention of mother to child HIV transmission (PMTCT) clinic appointments at 6 weeks, 12 and 24 months postpartum, self-reported adherence to ART at 6 weeks, 6 and 24 months postpartum validated by plasma HIV-1 RNA viral load (VL) measured at the same time points, and HIV status and HIV-free survival of infants at 18 months postpartum. We used Log-rank and Chi-Square p-values to test the equality of Kaplan-Meier survival probabilities and hazard rates (HR) for failure to retain in care for any reason by study arm. Results: There was no significant difference in adherence to PMTCT clinic visits or to ART or in median viral loads between FLC and SOC arms at any follow-up time points. Retention in care through the end of study was high in both arms but significantly higher among participants randomized to FLC (86.7%) compared to SOC (79.3%), p=0.022. The adjusted HR of visit dropout was 2.5 times greater among participants randomized to SOC compared to FLC (aHR=2.498, 95% CI: 1.417 - 4.406, p=0.002). Median VL remained < 400 copies/ml in both arms at 6 weeks, 6 and 24 months postpartum. Conclusions: Our findings suggest that programmatic interventions that provide group support, community based ART distribution and income-generation activities may contribute to retention in PMTCT care, HIV-free survival of children born to women living with HIV, and to the elimination of mother to child HIV transmission (MTCT).

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.

SARS-CoV-2 seroprevalence among blood donors in Uganda: 2019-2022.

BACKGROUND: The true burden of COVID-19 in low- and middle-income countries remains poorly characterized, especially in Africa. Even prior to the availability of SARS-CoV-2 vaccines, countries in Africa had lower numbers of reported COVID-19 related hospitalizations and deaths than other regions globally. METHODS: Ugandan blood donors were evaluated between October 2019 and April 2022 for IgG antibodies to SARS-CoV-2 nucleocapsid (N), spike (S), and five variants of the S protein using multiplexed electrochemiluminescence immunoassays (MesoScale Diagnostics, Rockville, MD). Seropositivity for N and S was assigned using manufacturer-provided cutoffs and trends in seroprevalence were estimated by quarter. Statistically significant associations between N and S antibody seropositivity and donor characteristics in November-December 2021 were assessed by chi-square tests. RESULTS: A total of 5393 blood unit samples from donors were evaluated. N and S seropositivity increased throughout the pandemic to 82.6% in January-April 2022. Among seropositive individuals, N and S antibody levels increased ≥9-fold over the study period. In November-December 2021, seropositivity to N and S antibody was higher among repeat donors (61.3%) compared with new donors (55.1%; p = .043) and among donors from Kampala (capital city of Uganda) compared with rural regions (p = .007). Seropositivity to S antibody was significantly lower among HIV-seropositive individuals (58.8% vs. 84.9%; p = .009). CONCLUSIONS: Despite previously reported low numbers of COVID-19 cases and related deaths in Uganda, high SARS-CoV-2 seroprevalence and increasing antibody levels among blood donors indicated that the country experienced high levels of infection over the course of the pandemic.

Progesterone and prolactin levels in pregnant women living with HIV who delivered preterm and low birthweight infants: A nested case-control study.

BACKGROUND: Antiretroviral therapy (ART) is associated with high rates of adverse birth outcomes, including preterm birth and low birthweight. Studies suggest that progesterone and prolactin may play important intermediary roles. METHODS: We analyzed data from the Antenatal Component of the PROMISE trial, a multi-center study of pregnant women taking antiretroviral regimens (lopinavir/ritonavir-containing ART or zidovudine alone) to prevent mother-to-child HIV transmission. In a nested case-control study, we compared data from women who gave birth to preterm (<37 weeks gestation) and/or low birthweight (<2500 g) infants to matched individuals who did not. We measured serum progesterone and prolactin at 24-34 weeks gestation. We used conditional logistic regression to describe relationships between hormone levels, birth outcomes, and antiretroviral regimens. RESULTS: 299 women and their newborns were included (146 cases, 153 controls). When compared to women receiving zidovudine alone, those on ART had higher odds of progesterone levels under the 10th percentile (adjusted odds ratio [AOR]:2.34, 95%CI:1.41-3.89) and 25th percentile (AOR:2.07, 95%CI:1.46-2.94). However, higher levels of progesterone-rather than lower levels-were associated with our composite case outcome at the 10th percentile (AOR:1.88, 95%CI:0.77-4.59) and 25th percentile (AOR:1.96, 95%CI:1.06-3.61). Associations were not observed between prolactin, antiretroviral regimen, and birth outcomes. CONCLUSION: We observed lower progesterone levels among women allocated to ART regimens; however, higher progesterone levels were associated with preterm birth and/or low birthweight. While features of the study design may have contributed to these findings, they nevertheless highlight the potentially complex mechanisms underpinning adverse birth outcomes and HIV.

Milk Calcium and Phosphorus in Ugandan Women with HIV on Tenofovir-Based Antiretroviral Therapy.

BACKGROUND: Breastfed infants depend on human milk calcium and phosphorus for bone mineral accretion and growth. We reported greater mobilization of bone mineral and delayed skeletal recovery in lactating Ugandan women with HIV initiated on tenofovir-based antiretroviral therapy during pregnancy compared to HIV-uninfected counterparts in the Gumba Study. However, it is unknown if these disruptions in maternal bone metabolism affect milk mineral concentrations. RESEARCH AIM: To compare concentrations and patterns of change in milk calcium and phosphorus between lactating women with and without HIV. METHODS: A longitudinal observational study was conducted to compare milk mineral concentrations between women with HIV receiving tenofovir-based ART and uninfected women in the Gumba Study. Milk collected at 2, 14, 26, and 52 weeks lactation was analyzed for calcium and phosphorus. Sodium and potassium were measured at 2 and 14 weeks to detect sub-clinical mastitis. Differences in milk composition between 84 women with HIV and 81 uninfected women were investigated. RESULTS: Women with HIV had higher milk calcium than uninfected women at 14 weeks. The percent difference was +10.2% (SE = 3.0, p = .008) and there was a tendency to greater values at 2 and 26 weeks. Milk calcium decreased in both groups during lactation (p ≤ .001) but was more pronounced in women with HIV. The magnitude of change within individuals in the 1st year of lactation from 2 to 52 weeks was -28.3% (SE 3.9) versus -16.5% (SE 3.5), p for interaction = .05. Differences in milk phosphorus and calcium-to-phosphorus ratio were smaller and mostly not significant. CONCLUSIONS: Participants with HIV on tenofovir-based antiretroviral therapy had altered milk mineral composition. Studies are needed to investigate mechanisms and health implications for the woman and infant.

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.

Twenty years of Prevention of Mother to Child HIV Transmission: research to implementation at a national referral hospital in Uganda.

Background: Over 90% of new paediatric HIV infections are acquired through mother to child transmission. Prevention of mother to child HIV transmission (PMTCT) research in sub-Saharan Africa informed WHO guidelines which enabled implementation of PMTCT programs globally. Objectives: To describe Makerere University-Johns Hopkins University (MU-JHU) perinatal HIV prevention research and implementation of the Mulago National Referral Hospital (MNRH) PMTCT program. Methods: Perinatal HIV prevention studies conducted at MU-JHU between 1997-2016 were summarized. Program aggregated data was extracted and analyzed using STATA 15. Results: In 1999, the HIVNET 012 study demonstrated that single-dose nevirapine (sdNVP) to the mother at onset of labor and to her newborn, reduced MTCT by nearly 50%. In 2016, the PROMISE study documented the safety and efficacy of ART during pregnancy and breastfeeding period. Program implementation at MNRH started in 2000. Uptake of HIV testing increased from 70% to 99% from 2006 onwards. sd NVP was the initial ARV regimen but by 2012, MOH recommended Option B+(triple therapy). MTCT rates reduced from 16.9% in 2001 to 2.3% in 2020. Conclusion: Perinatal HIV prevention clinical trials conducted at MU-JHU provided evidence to inform WHO PMTCT guidelines. MNRH program evaluation demonstrated the significant decline in MTCT rates over the last two decades.

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.

Neurodevelopmental outcomes of HIV/antiretroviral drug perinatally exposed uninfected children aged 3-6 years.

OBJECTIVE: Given the roll out of maternal antiretroviral therapy (ART) for prevention-of-perinatal-HIV-transmission, increasing numbers of children are perinatally HIV/antiretroviral exposed but uninfected (CAHEU). Some studies suggest CAHEU may be at increased risk for neurodevelopmental (ND) deficits. We aimed to assess ND performance among preschool CAHEU. DESIGN: This cross-sectional study assessed ND outcomes among 3-6-year-old CAHEU at entry into a multicountry cohort study. METHODS: We used the Mullen Scales of Early Learning (MSEL) and Kaufman Assessment Battery for Children (KABC-II) to assess ND status among 3-6-year-old CAHEU at entry into the PROMISE Ongoing Treatment Evaluation (PROMOTE) study conducted in Uganda, Malawi, Zimbabwe and South Africa. Statistical analyses (Stata 16.1) was used to generate group means for ND composite scores and subscale scores, compared to standardized test score means. We used multivariable analysis to adjust for known developmental risk factors including maternal clinical/socioeconomic variables, child sex, growth-for-age measurements, and country. RESULTS: 1647 children aged 3-6 years had baseline ND testing in PROMOTE; group-mean unadjusted Cognitive Composite scores on the MSEL were 85.8 (standard deviation [SD]: 18.2) and KABC-II were 79.5 (SD: 13.2). Composite score group-mean differences were noted by country, with South African and Zimbabwean children having higher scores. In KABC-II multivariable analyses, maternal age >40 years, lower education, male sex, and stunting were associated with lower composite scores. CONCLUSIONS: Among a large cohort of 3-6 year old CAHEU from eastern/southern Africa, group-mean composite ND scores averaged within the low-normal range; with differences noted by country, maternal clinical and socioeconomic factors.