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Introduction: In recent years, the expansion of HIV treatment eligibility has resulted in an increase in people with antiretroviral therapy (ART) experience prior to pregnancy but little is known about postpartum engagement in care in this population. We examined differences in disengagement from HIV care after delivery by maternal ART history before conception., Methods: We analysed data from people living with HIV (aged 15-49) in Khayelitsha, South Africa, with ≥1 live birth between April 2013 and March 2019. We described trends over time in ART history prior to estimated conception, classifying ART history groups as: (A) on ART with no disengagement (>270 days with no evidence of HIV care); (B) returned before pregnancy following disengagement; (C) restarted ART in pregnancy after disengagement; and (D) ART new start in pregnancy. We used Kaplan-Meier curves and proportional-hazards models (adjusted for maternal age, number of pregnancy records and year of delivery) to examine the time to disengagement from delivery to 2 years postpartum., Results: Among 7309 pregnancies (in 6680 individuals), the proportion on ART (A) increased from 19% in 2013 to 41% in 2019. The proportions of those who returned (B) and restarted (C) increased from 2% to 13% and from 2% to 10%, respectively. There was a corresponding decline in the proportion of new starts (D) from 77% in 2013 to 36% in 2019. In the first recorded pregnancy per person in the study period, 26% (95% CI 25-27%) had disengaged from care by 1 year and 34% (95% CI 33-36%) by 2 years postpartum. Individuals who returned (B: aHR 2.10, 95% CI 1.70-2.60), restarted (C: aHR 3.32, 95% CI 2.70-4.09) and newly started ART (D: aHR 2.41, 95% CI 2.12-2.74) had increased hazards of postpartum disengagement compared to those on ART (A)., Conclusions: There is a growing population of people with ART experience prior to conception and postpartum disengagement varies substantially by ART history. Antenatal care presents an important opportunity to understand prior ART experiences and an entry into interventions for strengthened engagement in HIV care., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Daily oral pre-exposure prophylaxis (PrEP) can reduce HIV incidence in pregnant and breastfeeding women, but adherence is essential., Methods: We conducted a pilot randomized trial to evaluate an intervention package to enhance antenatal and postnatal PrEP use in Lilongwe, Malawi. The intervention was based on patient-centered counseling adapted from previous PrEP studies, with the option of a participant-selected adherence supporter. Participants were locally eligible for PrEP and randomized 1:1 to intervention or standard counseling (ie, control) and followed for 6 months. Participants received the intervention package or standard counseling at enrollment, 1, 3, and 6 months. Adherence was measured through plasma and intracellular tenofovir concentrations and scored using a published algorithm. Our primary outcome was retention in care with concentrations consistent with 4-7 doses/week., Results: From June to November 2020, we enrolled 200 pregnant women with the median gestational age of 26 (interquartile range: 19-33) weeks. Study retention was high at 3 months (89.5%) and 6 months (85.5%). By contrast, across the 2 time points, 32.8% of participants retained in the study had adherence scores consistent with 2-5 doses/week while 10.3% had scores consistent with daily dosing. For the composite primary end point, no substantial differences were observed between the intervention and control groups at 3 months (28.3% vs. 29.0%, probability difference: -0.7%, 95% confidence interval: -13.3%, 11.8%) or at 6 months (22.0% vs. 26.3%, probability difference: -4.3%, 95% confidence interval: -16.1%, 7.6%)., Conclusions: In this randomized trial of PrEP adherence support, retention was high, but less than one-third of participants had pharmacologically confirmed adherence of ≥4 doses/week. Future research should focus on antenatal and postnatal HIV prevention needs and their alignment across the PrEP continuum, including uptake, persistence, and adherence., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Despite widespread success in reducing vertical HIV transmission, most antenatal care (ANC) programmes in eastern and southern Africa have not emphasized primary prevention of maternal HIV acquisition during pregnancy and lactation/breastfeeding. We hypothesized that combination HIV prevention interventions initiated alongside ANC could substantially reduce maternal HIV incidence., Methods: We constructed a multi-state model describing male-to-female HIV transmission in steady heterosexual partnerships during pregnancy and lactation/breastfeeding, with initial conditions based on population distribution estimates for Malawi and Zambia in 2020. We modelled individual and joint increases in three HIV prevention strategies at or soon after ANC initiation: (1) HIV testing of male partners, resulting in HIV diagnosis and less condomless sex among those with previously undiagnosed HIV; (2) initiation (or re-initiation) of suppressive antiretroviral therapy (ART) for male partners with diagnosed but unsuppressed HIV; and (3) adherent pre-exposure prophylaxis (PrEP) for HIV-negative female ANC patients with HIV-diagnosed or unknown-status male partners. We estimated the percentage of within-couple, male-to-female HIV transmissions that could be averted during pregnancy and lactation/breastfeeding with these strategies, relative to base-case conditions in which 45% of undiagnosed male partners become newly HIV diagnosed via testing, 75% of male partners with diagnosed but unsuppressed HIV initiate/re-initiate ART and 0% of female ANC patients start PrEP., Results: Increasing uptake of any single strategy by 20 percentage points above base-case levels averted 10%-11% of maternal HIV acquisitions during pregnancy and lactation/breastfeeding in the model. Joint uptake increases of 20 percentage points in two interventions averted an estimated 19%-23% of transmissions, and with a 20-percentage-point increase in uptake of all three interventions, 29% were averted. Strategies achieving 95% male testing, 90% male ART initiation/re-initiation and 40% female PrEP use reduced incident infections by 45%., Conclusions: Combination HIV prevention strategies provided alongside ANC and sustained through the post-partum period could substantially reduce maternal HIV incidence during pregnancy and lactation/breastfeeding in eastern and southern Africa., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Efforts to prevent mother-to-child transmission of human immunodeficiency virus (HIV) have led to dramatic reductions in pediatric HIV worldwide. New advances in HIV treatment and prevention, focused on pregnant and breastfeeding women living with HIV, have improved maternal health while decreasing vertical and horizontal HIV transmission. In this article, we describe how such interventions-including antiretroviral therapy and HIV pre-exposure prophylaxis-can be incorporated into antepartum and postpartum care in global settings., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Pre-exposure prophylaxis (PrEP) is a promising tool for HIV prevention during pregnancy. With increasing rollout in antenatal settings, counselling strategies to help pregnant women make appropriate decisions about PrEP use are needed. Understanding women's motivations and concerns for PrEP use-and how these inform their decision making and feelings about the decision to start PrEP-are critical to inform these strategies., Methods: We conducted a convergent mixed-methods study from June 2020 to June 2021 in the context of a PrEP adherence support trial among HIV-negative pregnant women in Lilongwe, Malawi. Two hundred women completed a survey reporting their motivations and concerns about PrEP use, and their feelings about the decision to start PrEP (Decisional Regret Scale). Thirty women completed in-depth interviews to better understand the decision-making process, including motivations and concerns weighed in women's decision to use PrEP. Analyses comprised descriptive and bivariate statistics, thematic qualitative analysis, and integration of quantitative and qualitative results., Results: Women initiating PrEP during pregnancy were highly motivated to obtain HIV protection for themselves and their unborn child, often due to perceived HIV risk connoted by a recent sexually transmitted infection and/or concerns about partner non-monogamy. These motivations prevailed despite some concerns about safety and side effects, anticipated stigmatization, and concerns about adherence burden and pill attributes. Many women had informed their partner of their decision to use PrEP yet few felt their decision was contingent upon partner approval. Most women felt positively about the decision to start PrEP (mean decisional regret = 1.2 out of 5), but those with a greater number of concerns reported greater decisional regret (B = 0.036; p = 0.005). Furthermore, women who were specifically concerned about partner disclosure, who disliked pills or who had no perceived HIV risk reported greater decisional regret., Conclusions: Pregnant women were strongly motivated by the promise of HIV protection offered by PrEP and accepted it despite diverse concerns. A shared decision-making approach that centres pregnant women and offers partner involvement may help identify and address initial concerns about PrEP use and support prevention-effective use of PrEP during this important period., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Patients stable on antiretroviral therapy (ART) may require transfer between health care facilities to maintain continuous care, yet data on the frequency, predictors, and virologic outcomes of transfers are limited., Methods: Data for all viral load (VL) testing at public sector health facilities in the Western Cape Province (2011-2018) were obtained. Participant inclusion criteria were a first VL between 2011 and 2013, age >15 years at ART initiation, and >1 VL within 5 years of ART initiation, of which ≥1 was at a primary health care facility. Two successive VLs taken at different facilities indicated a transfer. We assessed predictors of transfer using generalized estimating equations with Poisson regression and the association between transfer and subsequent VL> 1000 copies/mL using generalized mixed effects., Results: Overall 84,814 participants (median age at ART initiation 34 years and 68% female) were followed up for up to 4.5 years after their first VL: 34% (n = 29,056) transferred at least once, and among these, 26% transferred twice and 11% transferred thrice or more. Female sex, age <30 years, and first VL > 1000 copies/mL were independently associated with an increased rate of transfer [adjusted rate ratio 1.24, 95% confidence interval (CI): 1.21 to 1.26; 1.34, 95% CI: 1.31 to 1.36; and 1.42, 95% CI: 1.38 to 1.45, respectively]. Adjusting for age, sex, and disengagement, transfer was associated with an increased relative odds of VL > 1000 copies/mL (odds ratio 1.35, 95% CI: 1.29 to 1.42)., Conclusions: Approximately one-third of participants transferred and virologic outcomes were poor post-transfer. Stable patients who transfer may require additional support to maintain adherence., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Pregnant and breastfeeding populations are at substantial risk of acquiring HIV in some settings, yet are underrepresented in clinical trials of new pre-exposure prophylaxis (PrEP) agents. Several PrEP formulations are in development (eg, vaginal rings, long-acting injectables, and other modalities). Pregnant and breastfeeding populations are typically excluded from initial clinical trials. We identified 14 PrEP trials of novel agents in non-pregnant or non-breastfeeding populations, and six phase 1-3 trials and open label extensions among pregnant and breastfeeding populations, that are currently ongoing or complete. A framework shift is needed to consider the ethical costs of excluding pregnant and breastfeeding populations at risk for HIV in PrEP clinical trials and promote inclusion to maximise the benefits from PrEP tools in the pipeline. Research on new PrEP agents should include pregnant and breastfeeding populations to avoid delays in reaching those who could benefit from PrEP after efficacy is established., Competing Interests: Declaration of interests DLJD received funding from the US National Institutes of Health (K01TW01187 from the Fogarty International Center and National Institute of Mental Health R01MH116771), an honorarium for a meeting on long-acting PrEP by ViiV, donations of the study drug (Truvada) from Gilead, and donations of the STI test kits from Cepheid. NM has an investigator initiated trial from Merck. ADL declared funding for the PHASES Project (grant number R01 AI108368-05; principal investigator) and The FAIRER Project (grant number R01 HG 011480), and is the chair and on the data safety monitoring board for TNF-alpha Blockade with Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS, is a member and on the interim review panel for MTN/042-DELIVER, is a member and on the external advisory board for the Infectious Diseases Clinical Research Consortium, and is a member and on the data safety monitoring board for the MOMPOD Study. CS is on the NIAID drug safety monitoring board for several HIV vaccine trials and has received an honorarium, is on a Clover biopharmaceuticals drug safety monitoring board for a COVID-19 vaccine trial and has received an honorarium, and is a member of the Coalition to Advance and Support Prevention Research funded by USAID. LMN received funding to their institution (the Magee-Womens Research Institute) from the US National Institutes of Health and funding from USAID and PEPFAR through a cooperative agreement (7200AA19CA00003; Jhpiego, Johns Hopkins University, Baltimore, MD, USA). The Microbicide Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, and UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the US National Institutes of Health. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Intracellular tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is used to monitor cumulative pre-exposure prophylaxis (PrEP) adherence. We evaluated TFV-DP in DBSs following daily oral PrEP (emtricitabine 200 mg/tenofovir diphosphate 300 mg) among pregnant and postpartum adolescent girls and young women (AGYW)., Methods: Directly observed PrEP was administered for 12 weeks in a pregnancy (14-24 weeks' gestation, n = 20) and postpartum (6-12 weeks postpartum, n = 20) group of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated., Results: Median age was 20 (IQR, 19-22) years. Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median (IQR) half-life was 10 (7-12) days in pregnancy and 17 (14-21) days postpartum, with steady state achieved by 5 and 8 weeks, respectively. Observed median (IQR) steady-state TFV-DP was 965 fmol/punch (691-1166) in pregnancy versus 1406 fmol/punch (1053-1859) postpartum (P = .006). Modeled median steady-state TFV-DP was 881 fmol/punch (667-1105) in pregnancy versus 1438 fmol/punch (1178-1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations., Conclusions: TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. These Population-specific benchmarks can be used to guide PrEP adherence support in pregnant/postpartum African women., Clinical Trials Registration: NCT03386578., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Introduction: To realise the expected gains from prevention of mother-to-child HIV transmission initiatives, adherence to preventative and therapeutic antiretroviral regimens is critical and interventions deployable in busy programmatic settings with a high HIV burden are needed. Based on formative research, we developed an approach that integrates patient-centred counselling and engagement of an adherence supporter for pregnant and breastfeeding women initiating HIV treatment (ie, antiretroviral therapy (ART)) or biomedical HIV prevention (ie, pre-exposure prophylaxis (PrEP))., Methods: Tonse Pamodzi 2 is a pilot study designed to provide acceptability, fidelity and clinical outcomes data on a set of behavioural interventions for adherence support. The study comprises two parallel randomised trials, enrolling HIV-positive pregnant women initiating ART (Trial 1, n=100) and HIV-negative pregnant women with risk of HIV acquisition and willing to initiate PrEP (Trial 2, n=200). Within each trial, participants are randomised 1:1 to either the intervention or control group. The Tonse Pamodzi adherence intervention comprises patient-centred counselling (adapted Integrated Next Step Counseling(iNSC)) and external adherence support tailored to the clinical context (ie, for ART or PrEP). Participants randomly assigned to the control group receive standard counselling based on local HIV guidelines. Participants are followed for 6 months. To assess intervention acceptability, we will employ a mixed method approach to describe participant engagement, satisfaction, and discussion content. We will audit and score recorded counselling sessions to evaluate the implementation fidelity of iNSC sessions. We will also assess clinical outcomes at 3 and 6 months for both Trial 1 (retention in care and viral suppression of HIV) and Trial 2 (retention in care, and plasma and intracellular tenofovir drug concentrations)., Ethics and Dissemination: The study protocol was approved by the Malawi National Health Science Research Committee (19/05/2334) and the University of North Carolina at Chapel Hill Institutional Review Board (19-1060)., Trial Registration Number: NCT04330989., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We evaluated the effect of an option B-plus Enhanced Adherence Package (BEAP), on early ART uptake in a randomized controlled trial. HIV-positive, ART naïve pregnant women in Lusaka, Zambia, were randomized to receive BEAP (phone calls/home visits, additional counseling, male partner engagement and missed-visit follow-up) versus standard of care (SOC). The primary outcome was initiating and remaining on ART at 30 days. Analysis was by intention to treat (ITT) using logistic regression. Additional per protocol analysis was done. We enrolled 454 women; 229 randomized to BEAP and 225 to SOC. Within 30 days of eligibility, 445 (98.2%) initiated ART. In ITT analysis, 82.5% BEAP versus 80.4% SOC participants reached primary outcome (crude relative risk [RR] 1.03; 95% confidence interval [CI] 0.91-1.16; Wald test statistic = 0.44; p-value = 0.66). In per protocol analysis, (92 participants (40.2%) excluded), 91.9% BEAP versus 80.4% SOC participants reached primary outcome (crude RR 1.14; 95% CI 1.02-1.29; Wald test statistic = 2.23; p-value = 0.03). Early ART initiation in pregnancy was nearly universal but there was early drop out suggesting need for additional adherence support.This trial was registered at ClinicalTrials.gov (trials number NCT02459678) on May 14, 2015.

Introduction: Findings from biomedical, behavioural and implementation studies provide a rich foundation to guide programmatic efforts for the prevention of mother-to-child HIV transmission (PMTCT)., Methods: We summarized the current evidence base to support policy makers, programme managers, funding agencies and other stakeholders in designing and optimizing PMTCT programmes. We searched the scientific literature for PMTCT interventions in the era of universal antiretroviral therapy for pregnant and breastfeeding women (i.e. 2013 onward). Where evidence was sparse, relevant studies from the general HIV treatment literature or from prior eras of PMTCT programme implementation were also considered. Studies were organized into six categories: HIV prevention services for women, timely access to HIV testing, timely access to ART, programme retention and adherence support, timely engagement in antenatal care and services for infants at highest risk of HIV acquisition. These were mapped to specific missed opportunities identified by the UNAIDS Spectrum model and embedded in UNICEF operational guidance to optimize PMTCT services., Results and Discussion: From May to November 2019, we identified numerous promising, evidence-based strategies that, properly tailored and adopted, could contribute to population reductions in vertical HIV transmission. These spanned the HIV and maternal and child health literature, emphasizing the importance of continued alignment and integration of services. We observed overlap between several intervention domains, suggesting potential for synergies and increased downstream impact. Common themes included integration of facility-based healthcare; decentralization of health services from facilities to communities; and engagement of partners, peers and lay workers for social support. Approaches to ensure early HIV diagnosis and treatment prior to pregnancy would strengthen care across the maternal lifespan and should be promoted in the context of PMTCT., Conclusions: A wide range of effective strategies exist to improve PMTCT access, uptake and retention. Programmes should carefully consider, prioritize and plan those that are most appropriate for the local setting and best address existing gaps in PMTCT health services., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Pregnancy is a high-risk period for HIV acquisition in African women, and pregnant women who become acutely infected with HIV account for up to a third of vertical HIV transmission cases in African settings. To protect women and eliminate vertical transmission, WHO recommends offering oral pre-exposure prophylaxis (PrEP) based on tenofovir to HIV-negative pregnant and post-partum women with a substantial risk of HIV acquisition. PrEP implementation for pregnant and post-partum women lags behind implementation for other high-risk populations. Unique considerations for PrEP implementation arise during pregnancy and post partum, including the integration of provider training with clinical delivery and monitoring of PrEP exposure and outcomes within existing maternal health systems, yet scarce implementation data are available to generate evidence in this context., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: HIV incidence is high during pregnancy and breastfeeding with HIV acquisition risk more than doubling during pregnancy and the postpartum period compared to when women are not pregnant. The World Health Organization recommends offering pre-exposure prophylaxis (PrEP) to pregnant and postpartum women at substantial risk of HIV infection. However, maternal PrEP national guidelines differ and most countries with high maternal HIV incidence are not offering PrEP. We conducted a systematic review of recent research on PrEP safety in pregnancy to inform national policy and rollout., Methods: We used a standard Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) approach to conduct a systematic review by searching for completed, ongoing, or planned PrEP in pregnancy projects or studies from clinicaltrials.gov, PubMed and NIH RePORTER from 2014 to March 2019. We performed a systematic review of studies that assess tenofovir disoproxil fumarate (TDF)-based oral PrEP safety in pregnant and breastfeeding HIV-uninfected women., Results and Discussion: We identified 14 completed (n = 5) and ongoing/planned (n = 9) studies that evaluate maternal and/or infant outcomes following PrEP exposure during pregnancy or breastfeeding. None of the completed studies found differences in pregnancy or perinatal outcomes associated with PrEP exposure. Nine ongoing studies, to be completed by 2022, will provide data on >6200 additional PrEP-exposed pregnancies and assess perinatal, infant growth and bone health outcomes, expanding by sixfold the data on PrEP safety in pregnancy. Research gaps include limited data on (1) accurately measured PrEP exposure within maternal and infant populations including drug levels needed for maternal protection; (2) uncommon perinatal outcomes (e.g. congenital anomalies); (3) infant outcomes such as bone growth beyond one year following PrEP exposure; (4) outcomes in HIV-uninfected women who use PrEP during pregnancy and/or lactation., Conclusions: Expanding delivery of PrEP is an essential strategy to reduce HIV incidence in pregnancy and breastfeeding women. Early safety studies of PrEP among pregnant women without HIV infection are reassuring and ongoing/planned studies will contribute extensive new data to bolster the safety profile of PrEP use in pregnancy. However, addressing research gaps is essential to expanding PrEP delivery for women in the context of pregnancy., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Objective: To evaluate the association between HIV antiretroviral therapy (ART) and preterm birth (PTB), when defined by gold standard antenatal ultrasound versus newborn exam., Design: A secondary analysis of the PROMISE 1077BF/1077FF randomized controlled trial, which compared antiretroviral strategies to reduce perinatal HIV transmission and improve maternal health. The trial used newborn exam (i.e. New Ballard Score, NBS) to assess gestational age. This analysis included liveborn singleton pregnancies with both newborn exam and ultrasound data. The primary exposure was the trial's antiretroviral strategies: zidovudine with intrapartum nevirapine ('ZDV alone'); zidovudine/lamivudine/lopinavir-ritonavir ('ZDV-based ART'); or tenofovir/emtricitabine/lopinavir-ritonavir ('TDF-based ART'). The primary outcome was PTB less than 37 and less than 34 weeks based on the gold standard of ultrasound dating. We evaluated the association between antiretroviral strategy and PTB. We fit multivariable logistic regression models, adjusting for maternal characteristics, obstetric history, and HIV disease severity., Results: Among 720 assessed pregnant women, PTB less than 37 weeks was 15.4% by NBS and 18.3% by ultrasound. The NBS was specific but not sensitive for PTB less than 37 weeks (92.0% and 48.5%). Women receiving ZDV-based and TDF-based ART had significantly higher odds of PTB less than 37 by ultrasound compared with ZDV alone (adjusted odds ratios: 1.68; 95% confidence interval 1.10-2.57, and 2.71; 95% confidence interval 1.39-5.29), as well as for PTB less than 34 weeks. These results held for ultrasounds performed less than 24 weeks, and were generally consistent with prior analyses from the PROMISE trial using the NBS., Conclusion: Women starting HIV ART in pregnancy remained at higher risk of PTB when determined by ultrasound, consistent with prior data using newborn exam. However, newborn exam misclassified cases of PTB compared with gold standard ultrasound.

Background: HIV viral load (VL) and resistance testing are limited in sub-Saharan Africa, so individuals may have prolonged time on failing first-line antiretroviral therapy (ART). Our objective was to describe the evolution of drug resistance mutations among adults failing first-line ART in Zambia., Methods: We analysed data from a trial of VL monitoring in Lusaka, Zambia. From 2006 to 2011, 12 randomized sites provided either routine VL monitoring (intervention) or discretionary (control) after ART initiation. Samples were collected prospectively following the same schedule in each arm but analysed retrospectively in the control group. For those with virological failure (VF; >400 copies/ml), HIV genotyping was performed retrospectively on baseline (BL) and on all subsequent specimens until censored due to study completion, withdrawal or death., Results: Of 1,973 enrollees, 165 (8.4%) developed VF. 464 genotype results were available including 132 (80%) at BL, 116 (70%) at VF and 125 (76%) had at least one result between VF and censoring. Major nucleoside reverse transcriptase inhibitor (NRTI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations increased from 26% (BL) to 82% (VF) to 89% at last genotype (LG). M184 mutations increased from 2% to 59% to 71%; K65R from 2% to 11% to 13%; 2 or more thymidine analogue mutations from 1% to 3% to 12%. Among those on a failing tenofovir disoproxil fumarate (TDF)-based regimen, TDF resistance increased from 42% to 58%., Conclusions: We found substantial resistance to NRTIs and NNRTIs at VF with incremental increases after VF while still on a failing first-line ART; this resistance may compromise attainment of the UNAIDS 90-90-90 goals.

Background: IMPAACT PROMISE 1077BF/FF was a randomized study of antiretroviral therapy (ART) strategies for pregnant and postpartum women with high CD4+ T-cell counts. We describe postpartum outcomes for women in the study who were randomized to continue or discontinue ART after delivery., Methods: Women with pre-ART CD4+ cell counts ≥350 cells/mm 3 who started ART during pregnancy were randomized postpartum to continue or discontinue treatment. Women were enrolled from India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. The primary outcome was a composite of progression to AIDS-defining illness or death. Log-rank tests and Cox regression models assessed treatment effects. Incidence rates were calculated per 100 person-years. A post hoc analysis evaluated WHO Stage 2/3 events. All analyses were intent-to-treat., Findings: 1611 women were enrolled (June 2011-October 2014) and 95% were breastfeeding. Median age at entry was 27 years, CD4+ count 728 cells/mm 3 and the majority of women were Black African (97%). After a median follow-up of 1.6 years, progression to AIDS-defining illness or death was rare and there was no significant difference between arms (HR: 0·55; 95%CI 0·14, 2·08, p = 0.37). WHO Stage 2/3 events were reduced with continued ART (HR: 0·60; 95%CI 0·39, 0·90, p = 0.01). The arms did not differ with respect to the rate of grade 2, 3, or 4 safety events (p = 0.61)., Interpretation: Serious clinical events were rare among predominately breastfeeding women with high CD4+ cell counts over 18 months after delivery. ART had significant benefit in reducing WHO 2/3 events in this population.

Background: Lifelong antiretroviral therapy (ART) is now recommended for all human immunodeficiency virus (HIV)-infected pregnant and breastfeeding women; however, few have described overall infant outcomes in this new era for the prevention of mother-to-child HIV transmission (PMTCT)., Methods: As part of an assessment of PMTCT program impact, we enrolled a prospective cohort study in 4 predominantly rural districts in Zambia. HIV-infected mothers and their newborns (≤30 days old) were recruited and followed at 6 weeks, 6 months and 12 months postpartum; infant specimens were tested via HIV DNA polymerase chain reaction. In Kaplan-Meier analyses, we estimated overall infant HIV-free survival and then stratified by district, community and maternal ART use. We investigated the relationship between community-level 12-month, self-reported maternal ART use and infant HIV-free survival via linear regression., Results: From June 2014 to November 2015, we enrolled 827 mother-infant pairs in 33 communities. At 12 months, small proportions of infants had died (2.8%), were HIV-infected (3.0%) or were lost to follow-up (4.3%). Overall, infant HIV-free survival was 99.0% [95% confidence interval (CI): 98.0%-99.5%] at 6 weeks, 97.5% (95% CI: 96.1%-98.4%) at 6 months and 96.3% (95% CI: 94.8%-97.4%) at 12 months. Women reporting ART use at enrollment had higher infant HIV-free survival than those who did not (97.4% vs. 89.0%, P = 0.01). Differences were noted at the district and site levels (P = 0.01). In community-level analysis, no relationship was observed between 12-month infant HIV-free survival and self-reported maternal ART use (P = 0.65)., Conclusion: Although encouraging, these findings highlight the need for rigorous monitoring and evaluation of PMTCT services at the population level.

Objective: To describe engagement along the HIV continuum of care using a large network of clinics in Zambia., Methods: We employed a practical framework to describe retention along the HIV treatment cascade, using routinely collected clinical data available in resource-constrained settings. We included health facilities in four Zambian provinces with more than 300 enrolled patients over the age of 5 years. We described attrition at each step, from HIV enrolment to 720 days after ART initiation. The population was further stratified by year of enrolment to describe temporal trends in patient engagement., Results: From January 2004 to December 2014, 444 439 individuals over the age of 5 years sought HIV care at 75 eligible health facilities. Among those enrolled into HIV care, 82.1% (95% confidence interval [CI]: 79.4-84.5%) were fully assessed for ART eligibility within 180 days of enrolment and 63.6% (95% CI: 61.7-65.3) were found to be eligible for ART based on the HIV treatment guidelines at the time. Of those patients eligible for ART, 81.1% (95% CI: 79.5-82.7%) initiated ART within 180 days. Patient retention in ART programme was 81.2% (95% CI: 80.4-81.9%) at 90 days, 70.0% (95% CI: 68.7-71.2%) at 360 days and 61.6% (95% CI: 60.0-63.2%) at 720 days. We noted a steady decline in proportions assessed for ART eligibility and deemed eligible for ART in the time frame. Proportions that started ART and remained in care remained relatively consistent., Conclusion: We describe a simple approach for assessing patient engagement after enrolment into HIV care. Using limited types of data routinely available, we demonstrate an important and replicable approach to monitoring programmes in resource-constrained settings., (© 2017 John Wiley & Sons Ltd.)

Background: Investigations of the association of combination antiretroviral therapy (ART) with pregnancy outcomes often rely on routinely collected clinical data, which are prone to missing data and measurement error. Measurement error in gestational age may bias the relation between combination ART and gestational age-based outcomes., Methods: We demonstrate the use of multiple overimputation to address missing data and measurement error in gestational age. Using routinely collected clinical data from public health facilities in Lusaka, Zambia, we multiply imputed missing data and multiply overimputed observed values of gestational age. Poisson models with robust variance estimators were used to estimate risk ratios (RRs) for the associations of duration of combination ART with small for gestational age (SGA) and preterm birth. We compared results from a complete-case analysis, using multiple imputation to address missing data only and using multiple overimputation to address missing data and measurement error., Results: In the complete-case analysis, there was no evidence of an association between duration of combination ART and SGA or preterm birth. When we performed multiple overimputation, RRs for SGA moved past the null, but remained imprecise. For preterm birth, RRs for 9-32 weeks of combination ART moved away from the null as the variance due to measurement error increased., Conclusion: When we used multiple overimputation to account for measurement error and missing data, we observed an increased risk of preterm birth with longer duration of combination ART. Future analyses examining associations between combination ART and pregnancy outcomes should consider using multiple overimputation to address measurement error in gestational age.

Objective: To investigate the association between HIV, antiretroviral therapy (ART), and pregnancy-associated hypertension (PAH) in an HIV-endemic setting., Methods: A retrospective cohort study was undertaken of pregnant women for whom information was recorded between February 2006 and December 2012 in the Zambia Electronic Perinatal Record System, which captures data from 25 facilities in Lusaka, Zambia. PAH was defined as eclampsia, pre-eclampsia, hypertension, or elevated blood pressure (>140/80mm Hg) during delivery admission. Logistic regression estimated the odds of PAH among women by HIV serostatus, and by most recent CD4 T lymphocyte count and ART status among women with HIV infection., Results: Among 249 771 women included in the analysis, 5354 (2.1%) had PAH. Compared with women without HIV infection, women with HIV infection not receiving ART had lower odds of PAH (adjusted odds ratio [AOR] 0.86, 95% confidence interval 0.78-0.95), whereas those with HIV infection who had initiated ART had higher odds of PAH (AOR 1.15, 95% CI 1.01-1.32). No association was found between PAH and timing of ART initiation or CD4 lymphocyte count., Conclusion: In a large African urban cohort, women with untreated HIV infection had the lowest odds of PAH. Treatment with ART could increase PAH risk beyond that of women without HIV infection and those with untreated infection., (Published by Elsevier Ireland Ltd.)

Introduction: Antiretroviral pre-exposure prophylaxis (PrEP) for the prevention of HIV acquisition is cost-effective when delivered to those at substantial risk. Despite a high incidence of HIV infection among pregnant and breastfeeding women in sub-Saharan Africa (SSA), a theoretical increased risk of preterm birth on PrEP could outweigh the HIV prevention benefit., Methods: We developed a decision analytic model to evaluate a strategy of daily oral PrEP during pregnancy and breastfeeding in SSA. We approached the analysis from a health care system perspective across a lifetime time horizon. Model inputs were derived from existing literature and local sources. The incremental cost-effectiveness ratio (ICER) of PrEP versus no PrEP was calculated in 2015 U.S. dollars per disability-adjusted life year (DALY) averted. We evaluated the effect of uncertainty in baseline estimates through one-way and probabilistic sensitivity analyses., Results: PrEP administered to pregnant and breastfeeding women in SSA was cost-effective. In a base case of 10,000 women, the administration of PrEP averted 381 HIV infections but resulted in 779 more preterm births. PrEP was more costly per person ($450 versus $117), but resulted in fewer disability-adjusted life years (DALYs) (3.15 versus 3.49). The incremental cost-effectiveness ratio of $965/DALY averted was below the recommended regional threshold for cost-effectiveness of $6462/DALY. Probabilistic sensitivity analyses demonstrated robustness of the model., Conclusions: Providing PrEP to pregnant and breastfeeding women in SSA is likely cost-effective, although more data are needed about adherence and safety. For populations at high risk of HIV acquisition, PrEP may be considered as part of a broader combination HIV prevention strategy., Competing Interests: BHC received grant funding from the Gilead Foundation to support global health research training. The remaining authors have no conflicts of interest to disclose.

Background: Family planning (FP) is an essential health service and an important part of comprehensive HIV care. However, there is limited information about the contraceptive needs of people living with HIV in sub-Saharan Africa, which in turn has hampered efforts to expand and integrate FP services into existing HIV programs., Methods: We performed a cross-sectional survey to determine FP prevalence and predictors among HIV-positive women and men attending 18 public antiretroviral therapy (ART) clinics in Lusaka, Zambia. Trained peer counselors administered the 10-question survey to those seeking care for five days at each of the target sites., Results: From February to April 2014, we surveyed 7,046 HIV-infected patients receiving routine HIV services. Use of modern contraception was reported by 69 % of female ART patients and 79 % of male ART patients. However, highly effective contraceptive use and dual method use were low among women (38 and 25 %, respectively) and men (19 and 14 %, respectively). HIV disclosure status (adjusted odds ratio (AOR) = 4.91, 95 % confidence interval (CI) = 3.32-7.24 for women, AOR = 3.58, 95 % CI = 2.39-5.38 for men) and sexual activity in the last 6 months (AOR = 5.80, 95 % CI = 4.51-7.47 for women, AOR = 6.24, 95 % CI = 3.51-11.08 for men) were associated with modern contraceptive use in multivariable regression. Most respondents said they would access FP services if made available within ART clinic., Conclusions: While FP-ART integration may be a promising strategy for increasing FP service uptake, such services must focus on assessing sexual activity and advocating for dual method use to increase effective contraceptive use and prevent unintended pregnancies.

Background: Few data on the virological determinants of hepatitis B virus (HBV) infection are available from southern Africa., Methods: We enrolled consecutive HIV-infected adult patients initiating antiretroviral therapy (ART) at two urban clinics in Zambia and four rural clinics in Northern Mozambique between May 2013 and August 2014. HBsAg screening was performed using the Determine® rapid test. Quantitative real-time PCR and HBV sequencing were performed in HBsAg-positive patients. Risk factors for HBV infection were evaluated using Chi-square and Mann-Whitney tests and associations between baseline characteristics and high level HBV replication explored in multivariable logistic regression., Results: Seventy-eight of 1,032 participants in Mozambique (7.6%, 95% confidence interval [CI]: 6.1-9.3) and 90 of 797 in Zambia (11.3%, 95% CI: 9.3-13.4) were HBsAg-positive. HBsAg-positive individuals were less likely to be female compared to HBsAg-negative ones (52.3% vs. 66.1%, p<0.001). Among 156 (92.9%) HBsAg-positive patients with an available measurement, median HBV viral load was 13,645 IU/mL (interquartile range: 192-8,617,488 IU/mL) and 77 (49.4%) had high values (>20,000 UI/mL). HBsAg-positive individuals had higher levels of ALT and AST compared to HBsAg-negative ones (both p<0.001). In multivariable analyses, male sex (adjusted odds ratio: 2.59, 95% CI: 1.22-5.53) and CD4 cell count below 200/μl (2.58, 1.20-5.54) were associated with high HBV DNA. HBV genotypes A1 (58.8%) and E (38.2%) were most prevalent. Four patients had probable resistance to lamivudine and/or entecavir., Conclusion: One half of HBsAg-positive patients demonstrated high HBV viremia, supporting the early initiation of tenofovir-containing ART in HIV/HBV-coinfected adults.

Background: In rural settings, HIV-infected pregnant women often live significant distances from facilities that provide prevention of mother-to-child transmission (PMTCT) services., Methods: We offered universal maternal combination antiretroviral regimens in 4 pilot sites in rural Zambia. To evaluate the impact of services, we conducted a household survey in communities surrounding each facility. We collected information about HIV status and antenatal service utilization from women who delivered in the past 2 years. Using household Global Positioning System coordinates collected in the survey, we measured Euclidean (i.e., straight line) distance between individual households and clinics. Multivariable logistic regression and predicted probabilities were used to determine associations between distance and uptake of PMTCT regimens., Results: From March to December 2011, 390 HIV-infected mothers were surveyed across four communities. Of these, 254 (65%) had household geographical coordinates documented. One hundred sixty-eight women reported use of a PMTCT regimen during pregnancy including 102 who initiated a combination antiretroviral regimen. The probability of PMTCT regimen initiation was the highest within 1.9 km of the facility and gradually declined. Overall, 103 of 145 (71%) who lived within 1.9 km of the facility initiated PMTCT versus 65 of 109 (60%) who lived farther away. For every kilometer increase, the association with PMTCT regimen uptake (adjusted odds ratio: 0.90, 95% confidence interval: 0.82 to 0.99) and combination antiretroviral regimen uptake (adjusted odds ratio: 0.88, 95% confidence interval: 0.80 to 0.97) decreased., Conclusions: In this rural African setting, uptake of PMTCT regimens was influenced by distance to health facility. Program models that further decentralize care into remote communities are urgently needed.

Background: HIV-1 RNA viral load (VL) testing is recommended to monitor antiretroviral therapy (ART) but not available in many resource-limited settings. We developed and validated CD4-based risk charts to guide targeted VL testing., Methods: We modeled the probability of virologic failure up to 5 years of ART based on current and baseline CD4 counts, developed decision rules for targeted VL testing of 10%, 20%, or 40% of patients in 7 cohorts of patients starting ART in South Africa, and plotted cutoffs for VL testing on colour-coded risk charts. We assessed the accuracy of risk chart-guided VL testing to detect virologic failure in validation cohorts from South Africa, Zambia, and the Asia-Pacific., Results: In total, 31,450 adult patients were included in the derivation and 25,294 patients in the validation cohorts. Positive predictive values increased with the percentage of patients tested: from 79% (10% tested) to 98% (40% tested) in the South African cohort, from 64% to 93% in the Zambian cohort, and from 73% to 96% in the Asia-Pacific cohort. Corresponding increases in sensitivity were from 35% to 68% in South Africa, from 55% to 82% in Zambia, and from 37% to 71% in Asia-Pacific. The area under the receiver operating curve increased from 0.75 to 0.91 in South Africa, from 0.76 to 0.91 in Zambia, and from 0.77 to 0.92 in Asia-Pacific., Conclusions: CD4-based risk charts with optimal cutoffs for targeted VL testing maybe useful to monitor ART in settings where VL capacity is limited.

Background: Programs to prevent mother-to-child HIV transmission are plagued by loss to follow-up (LTFU) of HIV-exposed infants. We assessed if providing combination antiretroviral therapy (cART) to HIV-infected mothers was associated with reduced LTFU of their HIV-exposed infants in Kinshasa, DR Congo., Methods: We constructed a cohort of mother-infant pairs using routinely collected clinical data. Maternal cART eligibility was based on national guidelines in effect at the time. Infants were considered LTFU after 3 failed tracking attempts after a missed visit or if more than 6 months passed since they were last seen in clinic. Statistical methods accounted for competing risks (eg, death)., Results: A total of 1318 infants enrolled at a median age of 2.6 weeks (interquartile range: 2.1-6.9), at which point 24% of mothers were receiving cART. Overall, 5% of infants never returned to care after enrollment and 18% were LTFU by 18 months. The 18-month cumulative incidence of LTFU was 8% among infants whose mothers initiated cART by infant enrollment and 20% among infants whose mothers were not yet on cART. Adjusted for baseline factors, infants whose mothers were not on cART were over twice as likely to be LTFU, with a subdistribution hazard ratio of 2.75 (95% confidence limit: 1.81 to 4.16). The association remained strong regardless of maternal CD4 count at infant enrollment., Conclusions: Increasing access to cART for pregnant women could improve retention of HIV-exposed infants, thereby increasing the clinical and population-level impacts of prevention of mother-to-child HIV transmission interventions and access to early cART for HIV-infected infants.

Background & Aims: We investigated the association between significant liver fibrosis, determined by AST-to-platelet ratio index (APRI), and all-cause mortality among HIV-infected patients prescribed antiretroviral therapy (ART) in Zambia., Methods: Among HIV-infected adults who initiated ART, we categorized baseline APRI scores according to established thresholds for significant hepatic fibrosis (APRI ≥1.5) and cirrhosis (APRI ≥2.0). Using multivariable logistic regression we identified risk factors for elevated APRI including demographic characteristics, body mass index (BMI), HIV clinical and immunological status, and tuberculosis. In the subset tested for hepatitis B surface antigen (HBsAg), we investigated the association of hepatitis B virus co-infection with APRI score. Using Kaplan-Meier analysis and Cox proportional hazards regression we determined the association of elevated APRI with death during ART., Results: Among 20 308 adults in the analysis cohort, 1027 (5.1%) had significant liver fibrosis at ART initiation including 616 (3.0%) with cirrhosis. Risk factors for significant fibrosis or cirrhosis included male sex, BMI <18, WHO clinical stage 3 or 4, CD4(+) count <200 cells/mm(3) , and tuberculosis. Among the 237 (1.2%) who were tested, HBsAg-positive patients had four times the odds (adjusted odds ratio, 4.15; 95% CI, 1.71-10.04) of significant fibrosis compared HBsAg-negatives. Both significant fibrosis (adjusted hazard ratio 1.41, 95% CI, 1.21-1.64) and cirrhosis (adjusted hazard ratio 1.57, 95% CI, 1.31-1.89) were associated with increased all-cause mortality., Conclusion: Liver fibrosis may be a risk factor for mortality during ART among HIV-infected individuals in Africa. APRI is an inexpensive and potentially useful test for liver fibrosis in resource-constrained settings., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In settings of resource constraint, an understanding of HIV drug resistance can guide antiretroviral therapy (ART) at switch to second-line therapy. To determine the prevalence of such HIV drug resistance mutations (HIV DRM), we used an in-house sequencing assay in the pol gene (protease and partial reverse transcriptase) in a cohort of patients suspected of failing a first-line regimen, which in Zambia comprises two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Our analysis cohort (n = 68) was referred to the University Teaching Hospital in Lusaka from November 2009 to October 2012. Median duration on first-line ART to suspected treatment failure was 3.2 years (IQR 1.7-4.7 years). The majority of patients (95%) harbored HIV-1 subtype C virus. Analysis of reverse transcriptase revealed M184V (88%), K103N/S (32%), and Y181C/I/V (41%) DRMs, with the latter conferring reduced susceptibility to the salvage therapy candidates etravirine and rilpivirine. Three patients (5%) had major protease inhibitor (PI) resistance mutations: all three had the V82A mutation, and one patient (Clade J virus) had a concurrent M46I, Q58E, and L76V DRM. HIV-1 genotyping revealed major and minor DRMs as well as high levels of polymorphisms in subtype C isolates from patients failing first-line antiretroviral therapy. Closer monitoring of DRM mutations at first-line failure can inform clinicians about future options for salvage therapy., (© 2015 Wiley Periodicals, Inc.)

Background: The CD4 cell count or percent (CD4%) at the start of combination antiretroviral therapy (cART) is an important prognostic factor in children starting therapy and an important indicator of program performance. We describe trends and determinants of CD4 measures at cART initiation in children from low-, middle-, and high-income countries., Methods: We included children aged <16 years from clinics participating in a collaborative study spanning sub-Saharan Africa, Asia, Latin America, and the United States. Missing CD4 values at cART start were estimated through multiple imputation. Severe immunodeficiency was defined according to World Health Organization criteria. Analyses used generalized additive mixed models adjusted for age, country, and calendar year., Results: A total of 34,706 children from 9 low-income, 6 lower middle-income, 4 upper middle-income countries, and 1 high-income country (United States) were included; 20,624 children (59%) had severe immunodeficiency. In low-income countries, the estimated prevalence of children starting cART with severe immunodeficiency declined from 76% in 2004 to 63% in 2010. Corresponding figures for lower middle-income countries were from 77% to 66% and for upper middle-income countries from 75% to 58%. In the United States, the percentage decreased from 42% to 19% during the period 1996 to 2006. In low- and middle-income countries, infants and children aged 12-15 years had the highest prevalence of severe immunodeficiency at cART initiation., Conclusions: Despite progress in most low- and middle-income countries, many children continue to start cART with severe immunodeficiency. Early diagnosis and treatment of HIV-infected children to prevent morbidity and mortality associated with immunodeficiency must remain a global public health priority.

We analyzed the association of age at antiretroviral therapy (ART) initiation with CD4(+) T cell count recovery, death, and loss to follow-up (LTFU) among HIV-infected adults in Zambia. We compared baseline characteristics of patients by sex and age at ART initiation [categorized as 16-29 years, 30-39 years, 40-49 years, 50-59 years, and 60 years and older]. We used the medication possession ratio to assess adherence and analysis of covariance to measure the adjusted change in CD4(+) T cell count during ART. Using Cox proportional hazard regression, we examined the association of age with death and LTFU. In a secondary analysis, we repeated models with age as a continuous variable. Among 92,130 HIV-infected adults who initiated ART, the median age was 34 years and 6,281 (6.8%) were aged ≥50 years. Compared with 16-29 year olds, 40-49 year olds (-46 cells/mm(3)), 50-59 year olds (-53 cells/mm(3)), and 60+ year olds (-60 cells/mm(3)) had reduced CD4(+) T cell gains during ART. The adjusted hazard ratio (AHR) for death was increased for individuals aged ≥40 years (AHR 1.25 for 40-49 year olds, 1.56 for 50-59 year olds, and 2.97 for 60+ year olds). Adherence and retention in care were poorest among 16-29 year olds but similar in other groups. As a continuous variable, a 5-year increase in age predicted reduced CD4(+) T cell count recovery and increased risk of death. Increased age at ART initiation was associated with poorer clinical outcomes, while age <30 years was associated with a higher likelihood of being lost to follow-up. HIV treatment guidelines should consider age-specific recommendations.

Objective: To follow the trends in all-cause mortality in Lusaka, Zambia, during the scale-up of a national programme of antiretroviral therapy (ART)., Methods: Between November 2004 and September 2011, we conducted 12 survey rounds as part of a cross-sectional study in Lusaka, with independent sampling in each round. In each survey, we asked the heads of 3600 households to state the number of deaths in their households in the previous 12 months and the number of orphans aged less than 16 years in their households and investigated the heads' knowledge, attitudes and practices related to human immunodeficiency virus (HIV)., Findings: The number of deaths we recorded - per 100 person-years - in each survey ranged from 0.92 (95% confidence interval, CI: 0.78-1.09) in September 2011, to 1.94 (95% CI: 1.60-2.35) in March 2007. We found that mortality decreased only modestly each year (mortality rate ratio: 0.98; 95% CI: 0.95-1.00; P = 0.093). The proportion of households with orphans under the age of 16 years decreased from 17% in 2004 to 7% in 2011. The proportions of respondents who had ever been tested for HIV, had a comprehensive knowledge of HIV, knew where to obtain free ART and reported that a non-pregnant household member was receiving ART gradually increased., Conclusion: The expansion of ART services in Lusaka was not associated with a reduction in all-cause mortality. Coverage, patient adherence and retention may all have to be increased if ART is to have a robust and lasting impact at population level in Lusaka.

Objective: To evaluate if a pilot programme to prevent mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV) was associated with changes in early childhood survival at the population level in rural Zambia., Methods: Combination antiretroviral regimens were offered to pregnant and breastfeeding, HIV-infected women, irrespective of immunological status, at four rural health facilities. Twenty-four-month HIV-free survival among children born to HIV-infected mothers was determined before and after PMTCT programme implementation using community surveys. Households were randomly selected and women who had given birth in the previous 24 months were asked to participate. Mothers were tested for HIV antibodies and children born to HIV-infected mothers were tested for viral deoxyribonucleic acid. Multivariable models were used to determine factors associated with child HIV infection or death., Findings: In the first survey (2008-2009), 335 of 1778 women (18.8%) tested positive for HIV. In the second (2011), 390 of 2386 (16.3%) tested positive. The 24-month HIV-free survival in HIV-exposed children was 0.66 (95% confidence interval, CI: 0.63-0.76) in the first survey and 0.89 (95% CI: 0.83-0.94) in the second. Combination antiretroviral regimen use was associated with a lower risk of HIV infection or death in children (adjusted hazard ratio: 0.33, 95% CI: 0.15-0.73). Maternal knowledge of HIV status, use of HIV tests and use of combination regimens during pregnancy increased between the surveys., Conclusion: The PMTCT programme was associated with an increased HIV-free survival in children born to HIV-infected mothers. Maternal utilization of HIV testing and treatment in the community also increased.

Background: Although tenofovir disoproxil fumarate (TDF) use has increased as part of first-line antiretroviral therapy (ART) across sub-Saharan Africa, renal outcomes among patients receiving TDF remain poorly understood. We assessed changes in renal function and mortality in patients starting TDF- or non-TDF-containing ART in Lusaka, Zambia., Methods: We included patients aged ≥16 years who started ART from 2007 onward, with documented baseline weight and serum creatinine. Renal dysfunction was categorized as mild (estimated glomerular filtration rate [eGFR], 60-89 mL/min), moderate (30-59 mL/min), or severe (<30 mL/min) according to the chronic kidney disease-epidemiology (CKD-EPI) formula. Differences in eGFR during ART were analyzed using linear mixed-effect models. The odds of developing moderate or severe eGFR decrease and mortality were assessed using logistic and competing risk regression, respectively., Results: We included 62 230 adults, of which 38 716 (62.2%) initiated a TDF-based regimen. The proportion with moderate or severe renal dysfunction at baseline was lower in the TDF than in the non-TDF group (1.9% vs 4.0%). Among patients with no or mild renal dysfunction, those receiving TDF were more likely to develop moderate (adjusted odds ratio, 3.11; 95% confidence interval, 2.52-3.87) or severe (2.43; 1.80-3.28) eGFR decrease, although the incidence in such episodes was low. Among patients with moderate or severe renal dysfunction at baseline, renal function improved independently of ART regimen, and mortality rates were similar in both treatment groups., Conclusions: TDF use did not attenuate renal function recovery or increase the mortality rate in patients with renal dysfunction. Further studies are needed to determine the role of routine renal function monitoring before and during ART use in Africa.

We evaluated the association of the number of late antiretroviral therapy (ART) refills with patient outcomes in a large public-sector human immunodeficiency virus treatment program in Lusaka, Zambia. Using pharmacy data routinely collected during 2004-2010, we calculated the number of late refills during the initial year of ART. We used multivariable Cox proportional hazard regression to examine the association between the number of late refills and death or program failure (i.e., death, loss to follow-up, or program withdrawal) >12 months after ART initiation, with and without stratification by the medication possession ratio (MPR) during the initial year of ART. Of 53,015 adults who received ART for ≥12 months (median follow-up duration, 86.1 months; interquartile range, 53.2-128.2 months), 26,847 (50.6%) had 0 late refills, 16,762 (31.6%) had 1, 6,505 (12.3%) had 2, and 2,901 (5.5%) had ≥3. Kaplan-Meier analysis revealed that ≥3 late refills was associated with a greater mortality risk than 1 and 2 late refills (p<0.001, by the log-rank test). The mortality risk was greater for patients with 2 late refills [adjusted hazard ratio (HR), 1.17; 95% confidence interval (CI), 0.99-1.38] or ≥3 late refills (adjusted HR, 1.51; 95% CI, 1.23-1.87), compared with that for patients with 0-1 late refills. Program failure was associated with ≥2 late refills. An MPR of <80% was associated with similar increases in mortality risk across late-refill strata. Monitoring late refills during the initial period of ART may help resource- and time-constrained clinics identify patients at risk for program failure.

Background: There is debate over using tenofovir or zidovudine alongside lamivudine in second-line antiretroviral therapy (ART) following stavudine failure. We analysed outcomes in cohorts from South Africa, Zambia and Zimbabwe, Methods: Patients aged ≥16 years who switched from a first-line regimen including stavudine to a ritonavir-boosted lopinavir-based second-line regimen with lamivudine or emtricitabine and zidovudine or tenofovir in seven ART programmes in southern Africa were included. We estimated the causal effect of receiving tenofovir or zidovudine on mortality and virological failure using Cox proportional hazards marginal structural models. Its parameters were estimated using inverse probability of treatment weights. Baseline characteristics were age, sex, calendar year and country. CD4(+) T-cell count, creatinine and haemoglobin levels were included as time-dependent confounders., Results: A total of 1,256 patients on second-line ART, including 958 on tenofovir, were analysed. Patients on tenofovir were more likely to have switched to second-line ART in recent years, spent more time on first-line ART (33 versus 24 months) and had lower CD4(+) T-cell counts (172 versus 341 cells/μl) at initiation of second-line ART. The adjusted hazard ratio comparing tenofovir with zidovudine was 1.00 (95% CI 0.59, 1.68) for virological failure and 1.40 (0.57, 3.41) for death., Conclusions: We did not find any difference in treatment outcomes between patients on tenofovir or zidovudine; however, the precision of our estimates was limited. There is an urgent need for randomized trials to inform second-line ART strategies in resource-limited settings.

Objective: To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC), and high-income (HIC) countries., Methods: Patients aged 16 years or older starting cART in a clinic participating in a multicohort collaboration spanning 6 continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multilevel linear regression models were adjusted for age, gender, and calendar year; missing CD4 counts were imputed., Results: In total, 379,865 patients from 9 LIC, 4 LMIC, 4 UMIC, and 6 HIC were included. In LIC, the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/μL between 2002 and 2009. Corresponding increases in LMIC, UMIC, and HIC were from 87 to 155 cells/μL (76% increase), 88 to 135 cells/μL (53%), and 209 to 274 cells/μL (31%). In 2009, compared with LIC, median counts were 13 cells/μL [95% confidence interval (CI): -56 to +30] lower in LMIC, 22 cells/μL (-62 to +18) lower in UMIC, and 112 cells/μL (+75 to +149) higher in HIC. They were 23 cells/μL (95% CI: +18 to +28 cells/μL) higher in women than men. Median counts were 88 cells/μL (95% CI: +35 to +141 cells/μL) higher in countries with an estimated national cART coverage >80%, compared with countries with <40% coverage., Conclusions: Median CD4 cell counts at the start of cART increased 2000-2009 but remained below 200 cells/μL in LIC and MIC and below 300 cells/μL in HIC. Earlier start of cART will require substantial efforts and resources globally.

Objective: To evaluate the effectiveness of maternal combination antiretroviral prophylaxis for prevention of mother-to-child transmission of HIV (PMTCT) in a program setting., Design: Prospective cohort study., Setting: Nine primary care clinics in rural Zambia., Participants: Two hundred and eighty-four HIV-infected pregnant women at at least 28 weeks gestation initiating PMTCT services between April 2009 and January 2011 and their newborn infants., Intervention: In four 'intervention' sites, PMTCT comprised universal combination antiretroviral prophylaxis (i.e. irrespective of CD4 cell count) from pregnancy until the cessation of breastfeeding. In five 'control' sites, women received antenatal zidovudine and peripartum nevirapine, the standard of care at the time. Prophylaxis during breastfeeding was not available in control sites., Main Outcome Measure: Cumulative infant HIV infection and death at 12 months postpartum., Results: At 12 month postpartum, one of 104 (1.0%) infants born to mothers at the intervention sites were HIV-infected, compared with 14 of 116 (12.1%) receiving care in the control sites [relative risk (RR): 12.6, 95% CI: 2.2-73.1; P = 0.005]. When we considered the composite outcome of HIV infection or death, similar trends were observed in the overall study population (RR: 3.4, 95% CI: 1.6-7.6; P = 0.002) and in a sub-analysis of women with CD4 cell count more than 350 cells/μl (RR: 3.2; 95% CI: 1.1-9.6; P = 0.04)., Conclusion: When compared with PMTCT services based on antenatal zidovudine and peripartum nevirapine, the provision of maternal combination prophylaxis imparted measurable health benefits to HIV-exposed infants. Implementation research is needed to further tailor and optimize these strategies for similar field settings.

Background: HIV and combination antiretroviral therapy (cART) may increase cardiovascular disease (CVD) risk. We assessed the early effects of cART on CVD risk markers in a population with presumed low CVD risk., Methods: Adult patients (n=118) in Lusaka, Zambia were recruited at the time of initiation of cART for HIV/AIDS. Cardiometabolic risk factors were measured before and 90 days after starting cART. Participants were grouped according to cART regimens: Zidovudine + Lamivudine + Nevirapine (n=58); Stavudine + Lamivudine + Nevirapine (n=43); and 'other' (Zidovudine + Lamivudine + Efavirenz, Stavudine + Lamivudine + Efavirenz, Tenofovir + Emtricitabine + Efavirenz or Tenofovir + Emtricitabine + Nevirapine, n=17). ANOVA was used to test whether changes in cardiometabolic risk markers varied by cART regimen., Results: From baseline to 90 days after initiation of cART, the prevalence of low levels of high-density lipoprotein cholesterol (<1.04 mmol/L for men and <1.30 mmol/L for women) significantly decreased (78.8% vs. 34.8%, P<0.001) while elevated total cholesterol (TC ≥5.18 mmol/L, 5.1% vs. 11.9%, P=0.03) and the homeostasis model assessment of insulin resistance ≥3.0 (1.7% vs. 17.0%, P<0.001) significantly increased. The prevalence of TC:HDL-c ratio ≥5.0 significantly decreased (44.9% vs. 6.8%, P<0.001). These changes in cardiometabolic risk markers were independent of the cART regimen., Conclusion: Our results suggest that short-term cART is associated with a cardioprotective lipid profile in Zambia and a tendency towards insulin resistance regardless of the cART regimen.

Background: Although generic anti-retroviral drugs are in common use throughout the developing world, studies comparing their clinical effectiveness with that of proprietary formulations are lacking., Methods: We analysed observational data from a large cohort of adults on anti-retroviral therapy (ART) to assess potential differences between generic and proprietary zidovudine (ZDV) formulations in post-90-day mortality, 'programme failure' (a composite of death, follow-up losses and withdrawals) and other clinical outcomes. We accounted for drug exposure in three ways: an 'initial dispensation' approach that categorized patients according to the first prescription; 'time-varying' approach that attributed an outcome to the formulation taken at the time of event; and 'predominant exposure' approach that considered only those with >75% exposure to either brand or generic ZDV. Proprietary formulations were used as the reference group in all adjusted Cox proportional hazard regressions., Results: Among 14 736 patients eligible for analysis, 7277 (49%) initiated a generic formulation of ZDV and 7459 (51%) initiated a proprietary formulation. When categorized according to initial dispensation, no difference in post-90-day mortality was observed between the two groups [adjusted hazard ratio (AHR): 0.93, 95% confidence interval (CI): 0.77-1.12]. Similar findings were noted when drug formulation was treated as a time-varying exposure (AHR: 1.15, 95% CI: 0.89-1.48) when analysis was limited to those with a predominant exposure to one formulation or the other (AHR: 0.59, 95% CI: 0.24-1.49). Results were consistent across all approaches when programme failure was considered as an outcome. No longitudinal differences were detected between formulations for CD4 response, weight change and haemoglobin concentration. Generic ZDV formulations were associated with slight decreases in single-drug substitution., Conclusions: In this large programmatic cohort of adults starting ZDV-based first-line therapy, clinical outcomes appeared similar among patients on generic or proprietary formulations. These findings support continued use of generic anti-retroviral drug formulations in resource-constrained settings.

Objectives: We examined the effect of switching to second-line antiretroviral therapy (ART) on mortality in patients who experienced immunological failure in ART programmes without access to routine viral load monitoring in sub-Saharan Africa., Design and Setting: Collaborative analysis of two ART programmes in Lusaka, Zambia and Lilongwe, Malawi., Methods: We included all adult patients experiencing immunological failure based on WHO criteria. We used Cox proportional hazards models weighted by the inverse probability of switching to compare mortality between patients who switched and patients who did not; and between patients who switched immediately and patients who switched later. Results are expressed as hazard ratios with 95% credible intervals (95% CI)., Results: Among 2411 patients with immunological failure 324 patients (13.4%) switched to second-line ART during 3932 person-years of follow-up. The median CD4 cell count at start of ART and failure was lower in patients who switched compared to patients who did not: 80 versus 155 cells/μl (P < 0.001) and 77 versus 146 cells/μl (P < 0.001), respectively. Adjusting for baseline and time-dependent confounders, mortality was lower among patients who switched compared to patients remaining on failing first-line ART: hazard ratio 0.25 (95% CI 0.09-0.72). Mortality was also lower among patients who remained on failing first-line ART for shorter periods: hazard ratio 0.70 (95% CI 0.44-1.09) per 6 months shorter exposure., Conclusion: In ART programmes switching patients to second-line regimens based on WHO immunological failure criteria appears to reduce mortality, with the greatest benefit in patients switching immediately after immunological failure is diagnosed.

Background: Although tenofovir (TDF) is a common component of antiretroviral therapy (ART), recent evidence suggests inferior outcomes when it is combined with nevirapine (NVP)., Methods: We compared outcomes among patients initiating TDF + emtricitabine or lamivudine (XTC) + NVP, TDF + XTC + efavirenz (EFV), zidovudine (ZDV) + lamuvidine (3TC) + NVP, and ZDV + 3TC + EFV. We categorized drug exposure by initial ART dispensation by a time-varying analysis that accounted for drug substitutions and by predominant exposure (>75% of drug dispensations) during an initial window period. Risks for death and program failure were estimated using Cox proportional hazard models. All regimens were compared with ZDV + 3TC + NVP., Results: Between July 2007 and November 2010, 18,866 treatment-naive adults initiated ART: 18.2% on ZDV + 3TC + NVP, 1.8% on ZDV + 3TC + EFV, 36.2% on TDF + XTC + NVP, and 43.8% on TDF + XTC + EFV. When exposure was categorized by initial prescription, patients on TDF + XTC + NVP [adjusted hazard ratio (AHR): 1.45; 95% confidence interval (CI): 1.03 to 2.06] had a higher post-90-day mortality. TDF + XTC + NVP was also associated with an elevated risk for mortality when exposure was categorized as time-varying (AHR: 1.51; 95% CI: 1.18 to 1.95) or by predominant exposure over the first 90 days (AHR: 1.91, 95% CI: 1.09 to 3.34). However, these findings were not consistently observed across sensitivity analyses or when program failure was used as a secondary outcome., Conclusion: TDF + XTC + NVP was associated with higher mortality when compared with ZDV + 3TC + NVP but not consistently across sensitivity analyses. These findings may be explained in part by inherent limitations to our retrospective approach, including residual confounding. Further research is urgently needed to compare the effectiveness of ART regimens in use in resource-constrained settings.

Objectives: To determine the impact of time between initiating highly active antiretroviral therapy (HAART) and delivery-duration of antenatal HAART-on perinatal HIV infection., Design: We conducted a retrospective cohort analysis of pregnant HIV-infected women in Lusaka, Zambia. Women in our cohort were receiving HAART and had an infant HIV polymerase chain reaction test between 3 and 12 weeks of life., Methods: We examined factors associated with infant HIV infection and performed a locally weighted regression analysis to examine the effect of duration of antenatal HAART on perinatal HIV infection., Results: : From January 2007 to March 2010, 1813 HIV-infected pregnant women met inclusion criteria. Mean gestational age at first antenatal visit was 21 weeks (SD ± 6), median CD4+ cell count was 231 cells per microliter (interquartile range: 164-329), and median duration of antenatal HAART was 13 weeks (interquartile range 8-19). Fifty-nine (3.3%) infants were HIV infected. Duration of antenatal HAART was the most important predictor of perinatal HIV transmission. Compared with women initiating HAART at least 13 weeks before delivery, women on HAART for ≤4 weeks had a 5.5-fold increased odds of HIV transmission (95% confidence interval: 2.6 to 11.7). Locally weighted regression analysis suggested limited additional prophylactic benefit beyond 13 weeks on antenatal HAART., Conclusions: Low rates of mother-to-child HIV transmission can be achieved within programmatic settings in Africa. Maximal effectiveness of prevention of mother-to-child transmission programs is achieved by initiating HAART at least 13 weeks before delivery.

Objectives: To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with those in Malawi and Zambia, where monitoring is based on CD4 cell counts., Methods: We included 18,706 adult patients starting ART in South Africa and 80,937 patients in Zambia or Malawi. We examined CD4 responses in models for repeated measures and the probability of switching to second-line regimens, mortality and loss to follow-up in multistate models, measuring time from 6 months., Results: In South Africa, 9.8% [95% confidence interval (CI) 9.1-10.5] had switched at 3 years, 1.3% (95% CI 0.9-1.6) remained on failing first-line regimens, 9.2% (95% CI 8.5-9.8) were lost to follow-up and 4.3% (95% CI 3.9-4.8) had died. In Malawi and Zambia, more patients were on a failing first-line regimen [3.7% (95% CI 3.6-3.9], fewer patients had switched [2.1% (95% CI 2.0-2.3)] and more patients were lost to follow-up [15.3% (95% CI 15.0-15.6)] or had died [6.3% (95% CI 6.0-6.5)]. Median CD4 cell counts were lower in South Africa at the start of ART (93 vs. 132 cells/μl; P < 0.001) but higher after 3 years (425 vs. 383 cells/μl; P < 0.001). The hazard ratio comparing South Africa with Malawi and Zambia after adjusting for age, sex, first-line regimen and CD4 cell count was 0.58 (0.50-0.66) for death and 0.53 (0.48-0.58) for loss to follow-up., Conclusion: Over 3 years of ART mortality was lower in South Africa than in Malawi or Zambia. The more favourable outcome in South Africa might be explained by viral load monitoring leading to earlier detection of treatment failure, adherence counselling and timelier switching to second-line ART.

Background: In resource-limited settings, CD4 testing is a barrier to antiretroviral therapy initiation in pregnancy., Methods: We used logistic regression to identify predictors of CD4 cell count ≤ 350 cells/uL in 20,233 pregnant women., Results: The best-performing model included any 3 of: age ≥ 28 years old, hemoglobin ≤ 9.8 g/dL, gestational age ≤ 30 weeks, weight ≤ 64 kg, history of tuberculosis or previous death of an infant prior to one year old. Sensitivity was 45.7% (95% CI: 44.5-47.0), specificity 70.7% (95% CI: 69.6-71.8), and misclassification rate 41.4% (95% CI: 40.5-42.2)., Conclusion: CD4 triage remains a critical element of maternal HIV care and PMTCT.

Background: Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland., Methods and Findings: HIV-infected patients aged ≥18 years who started ART 2004-2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/µl and 15.4% among patients starting with ≥ 350 cells/µL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naïve and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up., Conclusions: In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings.

Context: Few studies have objectively evaluated the coverage of services to prevent transmission of human immunodeficiency virus (HIV) from mother to child., Objective: To measure the coverage of services to prevent mother-to-child HIV transmission in 4 African countries., Design, Setting, and Patients: Cross-sectional surveillance study of mother-infant pairs using umbilical cord blood samples collected between June 10, 2007, and October 30, 2008, from 43 randomly selected facilities (grouped as 25 service clusters) providing delivery services in Cameroon, Côte d'Ivoire, South Africa, and Zambia. All sites used at least single-dose nevirapine to prevent mother-to-child HIV transmission and some sites used additional prophylaxis drugs., Main Outcome Measure: Population nevirapine coverage, defined as the proportion of HIV-exposed infants in the sample with both maternal nevirapine ingestion (confirmed by cord blood chromatography) and infant nevirapine ingestion (confirmed by direct observation)., Results: A total of 27,893 cord blood specimens were tested, of which 3324 were HIV seropositive (12%). Complete data for cord blood nevirapine results were available on 3196 HIV-seropositive mother-infant pairs. Nevirapine coverage varied significantly by site (range: 0%-82%). Adjusted for country, the overall coverage estimate was 51% (95% confidence interval [CI], 49%-53%). In multivariable analysis, failed coverage of nevirapine-based services was significantly associated with maternal age younger than 20 years (adjusted odds ratio [AOR], 1.44; 95% CI, 1.18-1.76) and maternal age between 20 and 25 years (AOR, 1.28; 95% CI, 1.07-1.54) vs maternal age of older than 30 years; 1 or fewer antenatal care visits (AOR, 2.91; 95% CI, 2.40-3.54), 2 or 3 antenatal care visits (AOR, 1.93; 95% CI, 1.60-2.33), and 4 or 5 antenatal care visits (AOR, 1.56; 95% CI, 1.34-1.80) vs 6 or more antenatal care visits; vaginal delivery (AOR, 1.22; 95% CI, 1.03-1.44) vs cesarean delivery; and infant birth weight of less than 2500 g (AOR, 1.34; 95% CI, 1.11-1.62) vs birth weight of 3500 g or greater., Conclusion: In this random sampling of sites with services to prevent mother-to-child HIV transmission, only 51% of HIV-exposed infants received the minimal regimen of single-dose nevirapine.