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Background: HPTN 084 compared the safety and efficacy of long-acting injectable cabotegravir (CAB) to daily oral TDF/FTC for prevention of HIV-1 in uninfected African women. Like a similar trial in MSM/TGW (HPTN 083), the trial was stopped early for efficacy, expediting the need to consider introduction strategies for different populations. We examine survey and qualitative data from a four-country sub-study to examine oral and injectable PrEP acceptability and considerations for CAB access among African women., Methods: Participants completed baseline and follow-up surveys on HIV risk perception, sexual behavior. product acceptability and adherence during the blinded trial. Additionally, up to two in-depth interviews each with 73 sub-study participants explored product use and trial-related experiences, during the blinded and unblinded study periods. Using survey data, we classified participants as: engaged in female sex work (FSW), having multiple non-transactional partners, or monogamous. A study statistician identified participants' assigned study arm. We followed a thematic analysis process to read transcripts, develop a codebook and apply codes in NVivo to transcripts with intermittent intercoder reliability checks; using Excel matrices to explore differences across risk categories and study arms., Findings: Participants overwhelmingly preferred injections to pills, appreciating the ease, convenience, and privacy of a long-acting formulation. Many participants described challenges with contraceptive and/or study pill adherence, impeded by late night work, unexpected travel, or heavy drinking. Women in the TDF/FTC arm were more likely to describe side effects, compared to those in the CAB arm. Pain also varied widely by study arm. When considering post-trial access to CAB, limited PrEP knowledge, cost and concerns around stigma and poor service quality were potential access barriers., Conclusion: Women's desire for privacy and ease of use outweighed injectable concerns, resulting in a strong preference for CAB. Cost and accessibility will need to be addressed by implementation programs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tolley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

HPTN 052 was a multi-country clinical trial of cART for preventing heterosexual HIV-1 transmission. The study allowed participation of pregnant women and provided access to cART and contraceptives. We explored associations between pregnancy and clinical measures of HIV disease stage and progression. Of 869 women followed for 5.70 (SD = 1.62) years, 94.7% were married/cohabitating, 96% initiated cART, and 76.3% had >2 past pregnancies. Of 337 women who experienced pregnancy, 89.3% were from countries with lower contraceptive coverage, 56.1% first started cART with PI-based regimens and 57.6% were 25-34 years old. Mean cART duration and condom use were similar among pregnant and nonpregnant individuals. Adjusting for confounders, viral load suppression (VLS) was not (aHR(CI) = 0.82(0.61, 1.08)) and CD4 was slightly associated with decreased rates of first pregnancy over time (aHR(CI) = 0.9(0.84, 0.95)); baseline VLS was associated with increased (aRR(CI) = 2.48(1.71, 3.59)) and baseline CD4 was slightly associated with decreased number of pregnancies (aRR(CI) = 0.9(0.85,0.96)) over study duration. Partner seroconversion was univariably associated with higher rates of first pregnancy (HR(CI) = 2.02(1.32,3.07)). Despite a background of higher maternal morbidity and mortality rates, our findings suggest that becoming pregnant does not pose a threat to maternal health in women with HIV when there is access to medical care and antiretroviral treatment.

Background: Long-acting injectable cabotegravir, a drug taken every 2 months, has been shown to be more effective at preventing HIV infection than daily oral tenofovir disoproxil fumarate and emtricitabine, but its cost-effectiveness in a high-prevalence setting is not known. We aimed to estimate the incremental cost-effectiveness of long-acting injectable cabotegravir compared with tenofovir disoproxil fumarate and emtricitabine in South Africa, using methods standard to government planning, and to determine the threshold price at which long-acting injectable cabotegravir is as cost-effective as tenofovir disoproxil fumarate and emtricitabine., Methods: In this modelled economic evaluation and threshold analysis, we updated a deterministic model of the South African HIV epidemic with data from the HPTN 083 and HPTN 084 trials to evaluate the effect of tenofovir disoproxil fumarate and emtricitabine and long-acting injectable cabotegravir provision to heterosexual adolescents and young women and men aged 15-24 years, female sex workers, and men who have sex with men. We estimated the average intervention cost, in 2021 US$, using ingredients-based costing, and modelled the cost-effectiveness of two coverage scenarios (medium or high, assuming higher uptake of long-acting injectable cabotegravir than tenofovir disoproxil fumarate and emtricitabine throughout) and, for long-acting injectable cabotegravir, two duration subscenarios (minimum: same pre-exposure prophylaxis duration as for tenofovir disoproxil fumarate and emtricitabine; maximum: longer duration than tenofovir disoproxil fumarate and emtricitabine) over 2022-41., Findings: Across long-acting injectable cabotegravir scenarios, 15-28% more new HIV infections were averted compared with the baseline scenario (current tenofovir disoproxil fumarate and emtricitabine roll-out). In scenarios with increased coverage with oral tenofovir disoproxil fumarate and emtricitabine, 4-8% more new HIV infections were averted compared with the baseline scenario. If long-acting injectable cabotegravir drug costs were equal to those of tenofovir disoproxil fumarate and emtricitabine for the same 2-month period, the incremental cost of long-acting injectable cabotegravir to the HIV programme was higher than that of tenofovir disoproxil fumarate and emtricitabine (5-10% vs 2-4%) due to higher assumed uptake of long-acting injectable cabotegravir. The cost per infection averted was $6053-6610 (tenofovir disoproxil fumarate and emtricitabine) and $4471-6785 (long-acting injectable cabotegravir). The cost per long-acting cabotegravir injection needed to be less than twice that of a 2-month supply of tenofovir disoproxil fumarate and emtricitabine to remain as cost-effective, with threshold prices ranging between $9·03 per injection (high coverage; maximum duration) and $14·47 per injection (medium coverage; minimum duration)., Interpretation: Long-acting injectable cabotegravir could potentially substantially change HIV prevention. However, for its implementation to be financially feasible across low-income and middle-income countries with high HIV incidence, long-acting injectable cabotegravir must be reasonably priced., Funding: United States Agency for International Development, The Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women., Methods: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564., Findings: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported., Interpretation: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women., Funding: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support., Competing Interests: Declaration of interests PLA has received fees from Merck, ViiV Healthcare, and Gilead Sciences, and research support from Gilead Sciences paid to his institution. AR, WRS, and KS are employees of ViiV Healthcare. JFR is an employee of Gilead Sciences. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate associations between hair antiretroviral hair concentrations as an objective, cumulative adherence metric, with self-reported adherence and virologic outcomes., Design: Analysis of cohort A of the ACTG-A5288 study. These patients in resource-limited settings were failing second-line protease inhibitor-based antiretroviral therapy (ART) but were susceptible to at least one nucleoside reverse transcriptase inhibitor (NRTI) and their protease inhibitor, and continued taking their protease inhibitor-based regimen., Methods: Antiretroviral hair concentrations in participants taking two NRTIs with boosted atazanavir (n = 69) or lopinavir (n = 112) were analyzed at weeks 12, 24, 36 and 48 using liquid-chromatography--tandem-mass-spectrometry assays. Participants' self-reported percentage of doses taken in the previous month; virologic failure was confirmed HIV-1 RNA at least 1000 copies/ml at week 24 or 48., Results: From 181 participants with hair samples (61% women, median age: 39 years; CD4+ cell count: 167 cells/μl; HIV-1 RNA: 18 648 copies/ml), 91 (50%) experienced virologic failure at either visit. At 24 weeks, median hair concentrations were 2.95 [interquartile range (IQR) 0.49-4.60] ng/mg for atazanavir, 2.64 (IQR 0.73--7.16) for lopinavir, and 0.44 (IQR 0.11--0.76) for ritonavir. Plasma HIV-1 RNA demonstrated inverse correlations with hair levels (rs -0.46 to -0.74) at weeks 24 and 48. Weaker associations were seen with self-reported adherence (rs -0.03 to -0.24). Decreasing hair concentrations were significantly associated with virologic failure, the hazard ratio (95% CI) for ATV, LPV, and RTV were 0.69 (0.56-0.86), 0.77 (0.68-0.87), and 0.12 (0.06-0.27), respectively., Conclusion: Protease inhibitor hair concentrations showed stronger associations with subsequent virologic outcomes than self-reported adherence in this cohort. Hair adherence measures could identify individuals at risk of second-line treatment failure in need of interventions., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: HIV and tuberculosis are frequently diagnosed concurrently. In March 2021, World Health Organization recommended that antiretroviral therapy (ART) should be started within two weeks of tuberculosis treatment start, at any CD4 count. We assessed whether earlier ART improved outcomes in people with newly diagnosed HIV and tuberculosis., Methods: We did a systematic review by searching nine databases for trials that compared earlier ART to later ART initiation in people with HIV and tuberculosis. We included studies published from database inception to 12 March 2021. We compared ART within four weeks versus ART more than four weeks after TB treatment, and ART within two weeks versus ART between two and eight weeks, and stratified analysis by CD4 count. The main outcome was death; secondary outcomes included IRIS and AIDS-defining events. We pooled effect estimates using random effects meta-analysis., Results and Discussion: We screened 2468 abstracts, and identified nine trials. Among people with all CD4 counts, there was no difference in mortality by earlier ART (≤4 week) versus later ART (>4 week) (risk difference [RD] 0%, 95% confidence interval [CI] -2% to +1%). Among people with CD4 count ≤50 cells/mm 3 , earlier ART (≤4 weeks) reduced risk of death (RD -6%, -10% to -1%). Among people with all CD4 counts earlier ART (≤4 weeks) increased the risk of IRIS (RD +6%, 95% CI +2% to +10%) and reduced the incidence of AIDS-defining events (RD -2%, 95% CI -4% to 0%). Results were similar when trials were restricted to the four trials which permitted comparison of ART within two weeks to ART between two and eight weeks. Trials were conducted between 2004 and 2014, before recommendations to treat HIV at any CD4 count or to rapidly start ART in people without TB. No trials included children or pregnant women. No trials included integrase inhibitors in ART regimens., Discussion: Earlier ART did not alter risk of death overall among people living with HIV who had TB disease. For logistical and patient preference reasons, earlier ART initiation for everyone with TB and HIV may be preferred to later ART., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

As in other sub-Saharan countries, the burden of depression is high among people living with HIV in Malawi. However, the association between depression at ART initiation and two critical outcomes-retention in HIV care and viral suppression-is not well understood. Prior to the launch of an integrated depression treatment program, adult patients were screened for depression at ART initiation at two clinics in Lilongwe, Malawi. We compared retention in HIV care and viral suppression at 6 months between patients with and without depression at ART initiation using tabular comparison and regression models. The prevalence of depression among this population of adults newly initiating ART was 27%. Those with depression had similar HIV care outcomes at 6 months to those without depression. Retention metrics were generally poor for those with and without depression. However, among those completing viral load testing, nearly all achieved viral suppression. Depression at ART initiation was not associated with either retention or viral suppression. Further investigation of the relationship between depression and HIV is needed to understand the ways depression impacts the different aspects of HIV care engagement.

Background: Pregnant and breastfeeding women in Option B+ in Malawi received antiretroviral drugs (ARVs) containing efavirenz (EFV) and tenofovir disoproxil fumarate (TDF). However, effects on growth, renal, bone metabolism, and neurodevelopment of long-term exposure to low doses of these drugs through breast milk in HIV-exposed infants are unclear., Methods: Prospective cohorts of TDF-and-EFV-exposed and TDF-and-EFV-unexposed breastfed infants of HIV-infected and HIV-uninfected mothers in Option B+ were recruited in 2:1 ratio, respectively, followed from birth to 18 months. Infants with low birth weight, premature birth, and congenital abnormalities were excluded. Anthropometrics were assessed at birth, 6 weeks, 3, 6, 12, and 18 months. Neurodevelopment assessments used the Bayley Scales of Infant and Toddler Development III from 6 weeks. Creatinine, alkaline phosphatase, and phosphorus were assessed at 3, 6, and 12 months., Results: Of 260 HIV-and-ARV-exposed and 125 HIV-and-ARV-unexposed infants enrolled at birth, 87% and 57%, 78% and 59%, 77% and 54%, 73% and 51%, and 65% and 43% completed 6-weeks, 3, 6, 12, and 18 months visits, respectively. There were no significant differences in the mean Z-scores for length-for-age, weight-for-age, weight-for-length, mid-upper arm circumference-for-age, and head circumference-for-age between groups except at 6-weeks for length-for-age. No bone fractures occurred. Neurodevelopment outcomes were similar between groups. Of creatinine, alkaline phosphatase, and serum phosphate measurements, 1.7%, 2.6%, and 3.3% reached any toxicity levels grades 1-4, respectively, with no differences between groups., Conclusion: Long-term exposure to EFV and TDF through breastfeeding in infants of HIV-infected mothers does not seem to result in significant growth, neurodevelopment, renal, or bone adverse outcomes. Data support safety of breastfeeding through 18 months within the Option B+ program.

Background: Early progression of AIDS-associated Kaposi sarcoma (KS-PD) and immune reconstitution inflammatory syndrome (KS-IRIS) sometimes occur after the initiation of antiretroviral therapy (ART)., Methods: Early KS-PD and KS-IRIS were assessed in the A5264/AMC-067 trial in which participants with mild-to-moderate AIDS-KS were randomized to initiate ART with either immediate or as-needed oral etoposide. Early KS-PD was defined as tumor progression within 12 weeks of ART initiation. When investigators had concern that early KS-PD was KS-IRIS, additional evaluations were performed. Suspected KS-IRIS was defined as early KS-PD accompanied by a CD4 count increase of ≥50 cells per cubic millimeter or plasma HIV-1 RNA decrease of ≥0.5 log10 copies/mL. Clinical outcome was a composite end point categorized as failure, stable, and response at 48 and 96 weeks compared with baseline., Results: Fifty of 190 participants had early KS-PD (27%): 28 had KS-IRIS and 22 were not evaluated for KS-IRIS. Early KS-PD and KS-IRIS incidences with immediate etoposide versus ART alone were 16% versus 39%, and 7% versus 21%, respectively. Week 48 clinical outcome was 45% failure, 18% stable, and 37% response for no early KS-PD; 82% failure, 2% stable, and 16% response for early KS-PD; and 88% failure, 0% stable, and 12% response for KS-IRIS. Cumulative incidence of KS tumor response by week 96 was 64% for no early KS-PD, 22% with early KS-PD, and 18% with KS-IRIS., Conclusions: Early KS-PD, including suspected KS-IRIS, was common after starting ART for AIDS-KS and was associated with worse long-term clinical outcomes. Starting ART concurrently with etoposide reduced the incidence of both early KS-PD and KS-IRIS compared with ART alone.

Background: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial., Methods: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t 1/2app ) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800., Findings: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t 1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015)., Interpretation: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials., Funding: National Institute of Allergy and Infectious Diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: As a user-controlled HIV prevention method, oral pre-exposure prophylaxis (PrEP) holds particular promise for adolescent girls and young women (AGYW). HIV prevention cascades, critical frameworks for the design and evaluation of PrEP programmes, outline the priorities of identifying individuals at greatest HIV risk and motivating them to initiate PrEP through perceived HIV risk. To inform future iterations of these cascades and PrEP delivery for AGYW, the objective of this study was to understand the level of interest in PrEP among AGYW at highest HIV risk, and the potential role of perceived risk in motivating PrEP interest., Methods: Using data from a cohort study of HIV-negative AGYW in Lilongwe, Malawi (February 2016 to August 2017), we assessed the relationship between epidemiologic HIV risk (risk index developed in a previous analysis) and PrEP interest, and the extent to which perceived risk explains the relationship between HIV risk and PrEP interest. We further aimed to operationalize the pre-initiation steps of the HIV prevention cascade in the study population., Results: In total, 825 AGYW were included in analyses, of which 43% met the criterion for high epidemiologic HIV risk. While epidemiologic risk scores were positively associated with PrEP interest, high numbers of AGYW both above and below the high-risk cutoff were very interested in PrEP (68% vs. 63%). Perceived risk partially explained the relationship between HIV risk and PrEP interest; greater epidemiologic HIV risk was associated with high perceived risk, which was in turn associated with PrEP interest. Many more high-risk AGYW were interested in PrEP (68%) than expressed a high level of perceived HIV risk (26%)., Conclusions: These results highlight key relationships between epidemiologic HIV risk, risk perception and interest in PrEP. While risk perception did partially explain the relationship between epidemiologic risk and PrEP interest, there may be other important motivational mechanisms that are not captured in many HIV prevention cascades. The high number of participants with risk scores below the high-risk cutoff who both expressed high perceived risk and interest in PrEP suggests that demand for PrEP among AGYW may not be well aligned with epidemiologic risk., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Female sex workers (FSW) in Malawi have among the highest HIV prevalence estimates worldwide. Daily oral pre-exposure prophylaxis (PrEP) is an effective HIV prevention method, yet preferences for PrEP delivery among FSW are lacking. Eight focus group discussions, a literature review, and cognitive interviews were conducted to identify modifiable PrEP delivery attributes and inform discrete-choice experiment (DCE) development for FSW in Lilongwe. Enrolled FSW received an interviewer-assisted DCE. Data were analyzed using mixed logit regression. Dispensing location was most preferred, followed by the provision of additional services. Women preferred receiving PrEP at family planning clinics or non-governmental organization run drop-in centers. Cervical cancer screening was the most preferred additional service, while pregnancy testing and partner risk reduction counseling were less valued. This study was the first study to examine PrEP delivery preferences in Malawi using DCE-a powerful elicitation tool to apply to other key populations at risk for HIV.

Sustained engagement in HIV care is critical to the success of Option B+ for HIV-infected pregnant women. However, monitoring women's engagement in care across clinics and over time is challenging due to migration and clinic transfers. Improved strategies to identify and monitor women's engagement in HIV care across a network of clinics are needed, but have not been pilot tested. We evaluated the feasibility and acceptability of biometric fingerprint scanning to identify women and monitor HIV visit attendance among women in Option B+. Over a 3-month period, we enrolled HIV-infected pregnant women receiving care at two antenatal clinics in Lilongwe, Malawi and monitored their engagement in care using biometric fingerprint scanning and the standard-of-care electronic medical record (EMR) monitoring system. Biometric data was collected by trained research assistants, who uploaded and synced data across study sites daily using wireless internet. We collected data weekly on the biometric scanner performance, reliability, and usability. We assessed the feasibility and acceptability of using biometric fingerprint scanning to record HIV visits during exit interviews with a sample of participants and healthcare workers and by comparing visit concordance between the biometric fingerprint scanning and EMR systems. We enrolled 314 HIV-infected pregnant women and 51 HCWs (n = 365 total participants). The majority of participants felt the biometric fingerprint scanning system was easy to use (64%), required no additional assistance (69%) and met their expectations (76%). No major issues with data security, privacy, or scanner functionality were reported by HIV-infected women or healthcare workers. Of the 542 HIV visits captured during the study period among women in Option B+, 80% were recorded in the biometric fingerprint system versus 51% in the EMR system (PR 1.57, 95% CI 1.43, 1.72, p-value < 0.05). Among HIV-infected pregnant women engaged in HIV care, biometric fingerprint scanning is a feasible and acceptable way to monitor HIV visits and may improve the ability to monitor women's engagement in HIV care over time and across clinics. Biometric fingerprint scanning should be scaled-up and evaluated as an implementation strategy to support sustained engagement in HIV care for women during the perinatal period.

Studies in human immunodeficiency virus (HIV)-infected individuals suggest excess weight gain with integrase inhibitor-based antiretroviral therapy. The HIV Prevention Trials Network Study 077 evaluated changes in weight and fasting metabolic parameters in HIV-uninfected individuals randomized to cabotegravir or a placebo. No differences between arms were found for change in weight or fasting metabolic parameters overall or for subgroups., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Malawi's Option B+ universal antiretroviral therapy (ART) program for pregnant and breastfeeding women does not include routine laboratory monitoring. We report safety outcomes of pregnant women who initiated ART through Option B+., Methods: We analysed 12-month data from an observational cohort study on Option B+ among women newly initiating tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) at a government antenatal clinic in Lilongwe, Malawi. Proportions of women engaged in care, incidence of DAIDS grade ≥ 2 laboratory toxicity, grade ≥ 3 adverse events (AEs), viral suppression (<1000 copies/mL), birth outcomes and infant HIV infections are reported., Results: At ART initiation, participants (n = 299) had a median age of 26 years (IQR 22-30), median CD4 count of 352 cells/μl (IQR 231-520) and 94% were in WHO Stage 1. We noted 76 incident DAIDS Grade ≥ 2 laboratory results among 58 women, most commonly elevated liver function tests (n = 30 events) and low haemoglobin (n = 27). No women had elevated creatinine. Clinical AEs (n = 45) were predominantly infectious diseases and Grade 3. Five participants (2%) discontinued TDF/3TC/EFV due to virologic failure (3) or toxicity (2). Twelve months after ART initiation, most women were engaged in care (89%) and had HIV RNA < 1000 copies/ml (90%). 8% of pregnancies resulted in preterm birth, 9% were low birthweight (<2500 g), and 2% resulted in infant HIV infection at 6 weeks post-delivery., Conclusion: Most women remained on ART and were virally suppressed 12 months after starting Option B+. Few infants contracted HIV perinatally. While some women experienced adverse laboratory events, clinical symptom monitoring is likely reasonable., (© 2019 John Wiley & Sons Ltd.)

Female sex workers (FSW) are disproportionately at risk for HIV. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention method, yet approaches for incorporating PrEP within prevention strategies used by FSW are lacking. Semistructured focus group discussions were conducted with 44 HIV-negative FSW in Lilongwe, Malawi to explore perceptions of PrEP: acceptability, integration within HIV prevention behaviors, and barriers to use. Acceptability of PrEP was high. Motivation to use PrEP was rooted in love for one's life, anticipated negative economic effects associated with HIV acquisition. PrEP was viewed as complementary to existing norms for engaging in healthy sexual behaviors. Many felt PrEP may provide extra protection from HIV, along with condoms and frequent STI testing. Unpredictable daily lives, stigma, and side effects were barriers that could affect PrEP use. Leveraging existing HIV prevention strategies and social norms surrounding HIV prevention behaviors may positively impact PrEP uptake among FSW in Malawi and sub-Saharan Africa.

Objective: This review was conducted to identify interventions effective in improving uptake and retention of HIV-positive mothers and their infants in prevention of mother to child transmission (PMTCT) services in low-income and middle-income countries (LMICs) in order to inform programme planning., Methods: We conducted a systematic review of studies comparing usual care with any intervention to improve uptake and retention of HIV-positive pregnant or breastfeeding women and their children from birth to 2 years of age in PMTCT services in LMICs. Twenty-two electronic databases were searched from inception to 15 January 2018, for randomised, quasi-randomised and non-randomised controlled trials, and interrupted time series studies; reference lists of included articles were searched for relevant articles. Risk of bias was assessed using the Cochrane Effective Practice and Organisation of Care group criteria. Random-effects meta-analysis was conducted for studies reporting similar interventions and outcomes., Results: We identified 29 837 articles, of which 18 studies were included in our review. Because of heterogeneity in interventions and outcome measures, only one meta-analysis of two studies and one outcome was conducted; we found a statistically significant increase in antiretroviral therapy (ART) use during pregnancy for integration of HIV and antenatal care relative to standard non-integrated care (pooled AOR=2.69; 95% CI 1.25 to 5.78, p=0.0113). The remaining studies assessing other patient, provider or health system interventions were synthesised narratively, with small effects seen across intervention categories for both maternal and infant PMTCT outcomes based predominately on evidence with moderate to high risk of bias., Conclusions: Evidence on the effectiveness of interventions to improve uptake and retention of mothers and infants in PMTCT care is lacking. Our findings suggest that integration of HIV and antenatal care may improve ART use during pregnancy. Future studies to replicate promising approaches are needed. Improved reporting of key methodological criteria will facilitate interpretation of findings and improve the utility of evidence to PMTCT programme planners., Prospero Registration Number: CRD42015020829., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

High rates of non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance was a key consideration in the WHO policies transitioning first-line regimens to include integrase inhibitors (dolutegravir [DTG]). However, recent data suggests a relationship between DTG and neural tube defects among women exposed during conception, giving providers and policymakers pause regarding the planned regimen changes. We examined HIV drug resistance among a cohort of 46 acutely infected persons in Malawi. Our data demonstrates high levels of transmitted resistance, 11% using standard resistance surveillance mutations and 20% when additional NNRTI polymorphisms that may affect treatment response are included. High resistance rates in this treatment-naïve patient population reinforces the critical nature of DTG-based options in the context of public-health driven treatment programs.

Background: In Malawi's PMTCT Option B+ program, HIV-infected pregnant women who are already receiving ART are continued on their current therapy regimen without testing for treatment failure at the first antenatal care (ANC) visit. HIV RNA screening at ANC may identify women with treatment failure and ensure that viral suppression is maintained throughout the pregnancy., Methods: We conducted a cross-sectional study of HIV-infected pregnant women who had been receiving ART for at least 6 months at the first ANC visit under the PMTCT Option B+ program at Bwaila Hospital in Lilongwe, Malawi from June 2015 to December 2017. Poisson regression models with robust variance were used to investigate the predictors of ART treatment failure defined as viral load ≥1000 copies/ml., Results: The median age of 864 women tested for ART failure was 31.1 years (interquartile range: 26.9-34.5). The prevalence of treatment failure was 7.6% (95% confidence interval (CI): 6.0-9.6). CD4 cell count (adjusted prevalence ratio (aPR) = 0.57; 95% CI: 0.50-0.65) was strongly associated with treatment failure., Conclusion: The low prevalence of treatment failure among women presenting for their first ANC in urban Malawi demonstrates success of Option B+ in maintaining viral suppression and suggests progress towards the last 90% of the UNAIDS 90-90-90 targets. Women failing on ART should be identified early for adherence counseling and may require switching to an alternative ART regimen., Competing Interests: The authors have declared that no competing interests exist.

Background: Depression and suicide ideation among people living with HIV (PLHIV) can threaten the success of HIV care and treatment programs, particularly within high HIV prevalence settings. We describe the prevalence and correlates associated with depression and suicidal ideation among PLHIV receiving HIV care in Lilongwe, Malawi., Methods: From July to September 2013, 206 HIV clinic patients, who were ≥18 years of age and either pre-antiretroviral therapy (ART) or established on ART for ≥6 months prior to study, participated in a survey to assess the prevalence of a likely depressive disorder and suicidal ideation using the Patient Health Questionnaire-9. We explored factors associated with depression using bivariable linear regression and suicidal ideation using bivariable log-binomial regression., Results: The prevalence of a likely depressive disorder and suicidal ideation was 12% (95% CI: 8%, 17%) and 16% (95% CI: 11%, 21%), respectively. Pre-ART patients (β=1.17, 95% CI: 0.03, 2.30, p-value=0.04) and those with problematic alcohol use (β=0.49, 95% CI: 0.07, 0.92, p-value=0.02) were associated with a higher depression severity. Suicidal ideation was relatively common (8%, 95% CI: 5%, 13%) among those without a likely depressive disorder and significantly correlated with having no primary, secondary, or tertiary education (β=-1.52, 95% CI: -2.46, -0.59, p-value<0.01)., Conclusions: Interventions that enhance identification and management of depressive disorders and suicidal ideation should be integrated within HIV care clinics in Malawi., (© 2018 The College of Medicine and the Medical Association of Malawi.)

Background: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States., Methods and Findings: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population., Conclusions: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress., Trial Registration: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800., Competing Interests: RJL has received study medication, consulting fees and travel support from Gilead Sciences. He has received consulting fees and travel support from Merck, Inc. HD has received honoraria from Pfizer-South Africa, Novartis-South Africa, MSD-South Africa and Adcock Ingram for speaking engagements and has received travel support from Mylan-South Africa, Novartis-South Africa and Aspen-South Africa. AYL received research grants from NIH and has led studies in which study drug was donated by Gilead Sciences. DM and ARR are paid employees of ViiV Healthcare. WRS is a paid employee of ViiV Healthcare with stock in ViiV Healthcare and GlaxoSmithKline. CWH has research contracts with ViiV/GlaxoSmithKline and the NIH through Johns Hopkins and the University of Washington. MAM received grant support through the NIH, and received grant support through ViiV/GSK on work external to this study. JS is a member of Merck KGaA's Bioethics Advisory Panel and Stem Cell Research Oversight Committee; and he is a member of IQVIA's (formerly Quintiles) Ethics Advisory Panel. JJE is a consultant to Merck, Gilead Sciences, Janssen, and ViiV Healthcare; and he is an investigator on research contracts from ViiV Healthcare, Janssen, and Gilead Sciences.

Background: In the era of increased access to HIV testing and antiretroviral treatment (ART), the impact of HIV and ART status on inpatient mortality in Malawi is unknown., Methods: We prospectively followed adult inpatients at Kamuzu Central Hospital medical wards in Lilongwe, Malawi, between 2011 and 2012, to evaluate causes of mortality, and the impact of HIV and ART status on mortality. We divided the study population into five categories: HIV-negative, new HIV-positive, ART-naïve patients, new ART-initiators, and ART-experienced. We used multivariate binomial regression models to compare risk of death between categories., Results: Among 2911 admitted patients the mean age was 38.5 years, and 50% were women. Eighty-one percent (81%) of patients had a known HIV status at the time of discharge or death. Mortality was 19.4% and varied between 13.9% (HIV-negative patients) and 32.9% (HIV-positive patients on ART ≤1 year). In multivariable analyses adjusted for age, sex and leading causes of mortality, being new HIV-positive (RR = 1.64 95% CI: 1.16-2.32), ART-naive (RR = 2.28 95% CI: 1.66-2.32) or being a new ART-initiator (RR = 2.41 95% CI: 1.85-3.14) were associated with elevated risk of mortality compared to HIV-negative patients. ART-experienced patients had comparable mortality (RR = 1.33 95% CI: 0.94-1.88) to HIV-negative patients., Conclusion: HIV related mortality remains high among medical inpatients, especially among HIV-positive patients who recently initiated ART or have not started ART yet.

Malawi launched Option B+, a program for all pregnant or breastfeeding HIV-positive women to begin lifelong combination antiretroviral therapy (cART), in July 2011. This study characterises a portion of the continuum of care within an antenatal setting in Lilongwe. Women testing HIV-positive and having a cART initiation record at Bwaila Antenatal Clinic from July 2013 to January 2014 were included. Using logistic regression models, we analysed relationships between maternal characteristics and return for infant testing. Among 490 HIV-positive women with a cART initiation record, 360 (73%) were retained at three months. Of these, 203 (56%) were adherent. Records of infant testing were located for 204 women (42%). Women who were not retained were less likely to have an early infant diagnosis record (aOR = 0.20; 95% CI: 0.10, 0.41). Among the women retained, there was a non-significant association between maternal adherence and infant testing (OR = 1.35; 95% CI: 0.89, 2.06). Women lost at earlier continuum stages, who are at higher risk for mother-to-child-transmission, were less likely to bring infants for testing. Even with a test-and-treat program, many women did not remain in care or bring their infant for testing. Facilitating strategies to improve these measures remains an important unmet need.

Malawi's Option B+ program provides all HIV-infected pregnant women free lifelong antiretroviral therapy (ART), but challenges remain regarding retention and ART adherence, potentially due to male partner barriers. We explored relationships between male partner involvement and Option B+ retention and adherence. In 2014, a randomized controlled trial in Malawi compared male recruitment strategies for couple HIV testing and counseling (cHTC) at an antenatal clinic. This secondary analysis was conducted among the entire cohort (N = 200) of women, irrespective of randomization status. We assessed whether cHTC attendance, early disclosure of HIV-positive status, and partner ART reminders were associated with retention and adherence at one month after starting treatment. Retention was defined as attending HIV clinic follow-up within one day of running out of pills. Adherence was defined as taking ≥95% of ARTs by pill count. We used binomial regression to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI). Median female age was 26 years. Most women (79%) were retained; of these, 68% were adherent. Receiving cHTC was associated with improved retention (aRR 1.33, 95% CI 1.12, 1.59). Receiving male partner ART reminders was weakly associated with retention (aRR 1.16, 95% CI 0.96, 1.39). Disclosure within one day was not associated with retention (aRR 1.08, 95% CI: 0.91, 1.28). Among those who were retained, these three behaviors were not associated with improved 95% adherence. CHTC could play an important role in improving Option B+ retention. Increasing cHTC participation and enhancing adherence-related messages within cHTC are important.

Background: Antiretroviral therapy (ART) can downregulate antibody responses to HIV infection. We evaluated the impact of early vs. delayed ART on the performance of HIV diagnostic and incidence assays., Methods: Samples were obtained from 207 participants in the HPTN 052 trial, who were stably suppressed on ART for ≥4 years [Malawi sites; pre-ART CD4 cell count 350-550 cells/mm (early ART arm, N = 180) or <250 cells/mm or an AIDS-defining illness (delayed ART arm, N = 27)]. Samples were tested with 2 HIV rapid tests and 2 HIV incidence assays; selected samples were also tested with two fourth-generation immunoassays and a Western blot (WB) assay. A pre-ART sample was analyzed if the follow-up sample had a false-negative or weakly-reactive rapid test result, or had an incidence assay result indicative of recent infection (false-recent result)., Results: Ten (4.8%) samples had a nonreactive or weakly-reactive rapid test result (7/180 early ART arm, 3/27 delayed ART arm, P = 0.13); one sample had nonreactive fourth-generation assay results and 3 had indeterminate WBs. Forty (18.9%) samples had a false-recent incidence assay result; 16 (7.8%) had false-recent results with both incidence assays. Baseline samples had stronger rapid test and WB bands, higher fourth-generation assay signal-to-cutoff values, and fewer HIV incidence assay results indicative of recent infection., Conclusions: False-negative/weakly-reactive HIV rapid tests and false-recent HIV incidence assay results were observed in virally-suppressed individuals, regardless of pre-ART CD4 cell count. Downregulation of the antibody response to HIV infection in the setting of ART may impact population-level surveys of HIV prevalence and incidence.

Background: Malawi's national antiretroviral therapy program provides atazanavir/ritonavir-based second line regimens which cause concentration-dependent rise in indirect bilirubin. We sought to determine if elevated bilirubin, as a surrogate of atazanavir/ritonavir adherence, can aid in the evaluation of second line virological failure in Malawi., Methods: We conducted a cross-sectional study of HIV-infected patients ≥15 years who were on boosted protease inhibitor-based second line antiretroviral therapy for at least 6 months in two urban HIV clinics in Lilongwe, Malawi. Antiretroviral therapy history and adherence data were extracted from the electronic medical records and blood was drawn for viral load, complete blood count, total bilirubin, and CD4 cell count at a clinic visit. Factors associated with virological failure were assessed using multivariate logistic regression model., Results: Out of 376 patients on second line antiretroviral therapy evaluated, 372 (98.9%) were on atazanavir/ritonavir-based therapy and 142 (37.8%) were male. Mean age was 40.9 years (SD ± 10.1), mean duration on second line antiretroviral therapy was 41.9 months (SD ± 27.6) and 256 patients (68.1%) had elevated bilirubin >1.3 mg/dL. Overall, 35 (9.3%) patients had viral load >1000 copies/ml (virological failure). Among the virologically failing vs. non-failing patients, bilirubin was elevated in 34.3% vs. 72.0% respectively (p < 0.001), although adherence by pill count was similar (62.9% vs. 60.7%, p = 0.804). The odds of virological failure were higher for adults aged 25-40 years (adjusted odds ratio (aOR) 2.5, p = 0.048), those with CD4 cell count <100 (aOR 17.5, p < 0.001), and those with normal bilirubin levels (aOR 5.4, p < 0.001); but were lower for the overweight/obese patients (aOR 0.3, p = 0.026). Poor pill count adherence (aOR 0.7, p = 0.4) and male gender (aOR 1.2, p = 0.698) were not associated with second line virological failure., Conclusions: Among patients receiving atazanavir/ritonavir-based second line antiretroviral therapy, bilirubin levels better predicted virological failure than pill count adherence. Therefore, strategic use of bilirubin and viral load testing to target adherence counseling and support may be cost-effective in monitoring second line antiretroviral therapy adherence and virological failure. Drug resistance testing targeted for patients with virological failure despite elevated bilirubin levels would facilitate timely switch to third line antiretroviral regimens whenever available.

Background: Many sub-Saharan African countries have adopted Option B+, a prevention of mother-to-child transmission approach providing HIV-infected pregnant and lactating women with immediate lifelong antiretroviral therapy. High maternal attrition has been observed in Option B+. Peer-based support may improve retention., Methods: A 3-arm stratified cluster randomized controlled trial was conducted in Malawi to assess whether facility- and community-based peer support would improve Option B+ uptake and retention compared with standard of care (SOC). In SOC, no enhancements were made (control). In facility-based and community-based models, peers provided patient education, support groups, and patient tracing. Uptake was defined as attending a second scheduled follow-up visit. Retention was defined as being alive and in-care at 2 years without defaulting. Attrition was defined as death, default, or stopping antiretroviral therapy. Generalized estimating equations were used to estimate risk differences (RDs) in uptake. Cox proportional hazards regression with shared frailties was used to estimate hazard of attrition., Results: Twenty-one facilities were randomized and enrolled 1269 women: 447, 428, and 394 in facilities that implemented SOC, facility-based, and community-based peer support models, respectively. Mean age was 27 years. Uptake was higher in facility-based (86%; RD: 6%, confidence interval [CI]: -3% to 15%) and community-based (90%; RD: 9%, CI: 1% to 18%) models compared with SOC (81%). At 24 months, retention was higher in facility-based (80%; RD: 13%, CI: 1% to 26%) and community-based (83%; RD: 16%, CI: 3% to 30%) models compared with SOC (66%)., Conclusions: Facility- and community-based peer support interventions can benefit maternal uptake and retention in Option B+.

Higher HIV diversity has been associated with virologic outcomes in children on antiretroviral treatment (ART). We examined the association of HIV diversity with virologic outcomes in adults from the HPTN 052 trial who initiated ART at CD4 cell counts of 350-550 cells/mm3. A high resolution melting (HRM) assay was used to analyze baseline (pre-treatment) HIV diversity in six regions in the HIV genome (two in gag, one in pol, and three in env) from 95 participants who failed ART. We analyzed the association of HIV diversity in each genomic region with baseline (pre-treatment) factors and three clinical outcomes: time to virologic suppression after ART initiation, time to ART failure, and emergence of HIV drug resistance at ART failure. After correcting for multiple comparisons, we did not find any association of baseline HIV diversity with demographic, laboratory, or clinical characteristics. For the 18 analyses performed for clinical outcomes evaluated, there was only one significant association: higher baseline HIV diversity in one of the three HIV env regions was associated with longer time to ART failure (p = 0.008). The HRM diversity assay may be useful in future studies exploring the relationship between HIV diversity and clinical outcomes in individuals with HIV infection.

Objective: To estimate preterm birth risk among infants of HIV-infected women in Lilongwe, Malawi, according to maternal antiretroviral therapy (ART) status and initiation time under Option B+., Design: A retrospective cohort study of HIV-infected women delivering at ≥27 weeks of gestation, April 2012 to November 2015. Among women on ART at delivery, we restricted our analysis to those who initiated ART before 27 weeks of gestation., Methods: We defined preterm birth as a singleton live birth at ≥27 and <37 weeks of gestation, with births at <32 weeks classified as extremely to very preterm. We used log-binomial models to estimate risk ratios and 95% confidence intervals for the association between ART and preterm birth., Results: Among 3074 women included in our analyses, 731 preterm deliveries were observed (24%). Overall preterm birth risk was similar in women who had initiated ART at any point before 27 weeks and those who never initiated ART (risk ratio = 1.14; 95% confidence interval: 0.84 to 1.55), but risk of extremely to very preterm birth was 2.33 (1.39 to 3.92) times as great in those who never initiated ART compared with those who did at any point before 27 weeks. Among women on ART before delivery, ART initiation before conception was associated with the lowest preterm birth risk., Conclusions: ART during pregnancy was not associated with preterm birth, and it may in fact be protective against severe adverse outcomes accompanying extremely to very preterm birth. As preconception ART initiation appears especially protective, long-term retention on ART should be a priority to minimize preterm birth in subsequent pregnancies.

Background: Human immunodeficiency virus (HIV) contributes to nearly 20% of all deaths in children under five years of age in Malawi. Expanded coverage of antiretroviral therapy has allowed children to access treatment on an outpatient basis. Little is known about characteristics of the final outpatient encounter prior to mortality in the outpatient setting., Methods: This retrospective cohort study assessed clinical factors associated with mortality among HIV-exposed infants and HIV-infected children less than 18 years of age at the Baylor College of Medicine Abbott Fund Children's Center of Excellence in Lilongwe, Malawi. We compared clinical indicators documented from the final outpatient encounter for patients who died in the outpatient setting versus those who were alive after their penultimate clinical encounter., Results: Of the 8,546 patients who were attended to over a 10-year period at the Baylor Center of Excellence, 851 had died (10%). Of children who died, 392 (46%) were directly admitted to the hospital after their last clinical encounter and died as inpatients. Of the remaining 459 who died as outpatients after their last visit, 53.5% had a World Health Organization (WHO) stage IV condition at their last visit, and 25% had a WHO stage III condition. Multivariate regression analysis demonstrated that poor nutritional status, female gender, shorter time as a patient, more clinical encounters in the prior month, if last visit was an unscheduled sick visit, and if the patient had lost weight since their prior visit independently predicted increased mortality in the outpatient setting after the final clinical encounter., Conclusion: Clinical indicators may assist in identifying children with HIV who have increased risk of mortality in the outpatient setting. Recognizing these indicators may aid in identifying HIV-infected children who require a higher level of care or closer follow-up., Competing Interests: The authors have declared that no competing interests exist.

Background: Both wasting and obesity are associated with inflammation, but the extent to which body weight changes influence inflammation during human immunodeficiency virus infection is unknown., Methods: Among a random virologically suppressed participants of the Prospective Evaluation of Antiretrovirals in Resource-Limited Settings trial, inflammatory markers were measured at weeks 0, 24, and 48 after antiretroviral therapy (ART) initiation. Associations between both baseline and change in body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and changes in inflammation markers were assessed using random effects models., Results: Of 246 participants, 27% were overweight/obese (BMI, ≥ 25), and 8% were underweight (BMI < 18.5) at baseline. After 48 weeks, 37% were overweight/obese, and 3% were underweight. While level of many inflammatory markers decreased 48 weeks after ART initiation in the overall group, the decrease in C-reactive protein (CRP) level was smaller in overweight/obese participants (P = .01), and the decreases in both CRP (P = .01) and interleukin 18 (P = .02) levels were smaller in underweight participants. Each 1-unit gain in BMI among overweight/obese participants was associated with a 0.02-log10 increase in soluble CD14 level (P = .05), while each 1-unit BMI gain among underweight participants was associated with a 9.32-mg/L decrease in CRP level (P = .001)., Conclusions: Being either overweight or underweight at ART initiation was associated with heightened systemic inflammation. While weight gain among overweight/obese persons predicted increased inflammation, weight gain among underweight persons predicted reduced inflammation., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Early initiation of antiretroviral treatment (ART) reduces HIV transmission and has health benefits. HIV drug resistance can limit treatment options and compromise use of ART for HIV prevention. We evaluated drug resistance in 85 participants in the HIV Prevention Trials Network 052 trial who started ART at CD4 counts of 350-550 cells per cubic millimeter and failed ART by May 2011; 8.2% had baseline resistance and 35.3% had resistance at ART failure. High baseline viral load and less education were associated with emergence of resistance at ART failure. Resistance at ART failure was observed in 7 of 8 (87.5%) participants who started ART at lower CD4 cell counts.

Background: In resource-limited settings, where resistance testing is unavailable, confirmatory testing for patients with high viral loads (VL) delays antiretroviral therapy (ART) switches for persons with resistance. We developed a risk score algorithm to predict need for ART change by identifying resistance among persons with persistently elevated VL., Methods: We analyzed data from a Phase IV open-label trial. Using logistic regression, we identified demographic and clinical characteristics predictive of need for ART change among participants with VLs ≥1000 copies/ml, and assigned model-derived scores to predictors. We designed three models, including only variables accessible in resource-limited settings., Results: Among 290 participants with at least one VL ≥1000 copies/ml, 51 % (148/290) resuppressed and did not have resistance testing; among those who did not resuppress and had resistance testing, 47 % (67/142) did not have resistance and 53 % (75/142) had resistance (ART change needed for 25.9 % (75/290)). Need for ART change was directly associated with higher baseline VL and higher VL at time of elevated measure, and inversely associated with treatment duration. Other predictors included body mass index and adherence. Area under receiver operating characteristic curves ranged from 0.794 to 0.817. At a risk score ≥9, sensitivity was 14.7-28.0 % and specificity was 96.7-98.6 %., Conclusions: Our model performed reasonably well and may be a tool to quickly transition persons in need of ART change to more effective regimens when resistance testing is unavailable. Use of this algorithm may result in public health benefits and health system savings through reduced transmissions of resistant virus and costs on laboratory investigations.

Background: For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings., Methods: A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715., Findings: Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes., Interpretation: In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity., Funding: National Institutes of Health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Informal care, the health care provided by the patient's social network is important in low income settings although its monetary value is rarely estimated. The lack of estimates of the value of informal care has led to its omission in economic evaluations but this can result in incorrect decisions about cost effectiveness of an intervention. We explore the use of contingent valuation methods of willingness to pay (WTP) and willingness to accept (WTA) to estimate the value of informal care provided to HIV infected women that are accessing antiretroviral therapy (ART) under the Option B+ approach to prevention of mother-to-child transmission (PMTCT) of HIV in Malawi., Methods: We collected cross sectional data from 93 caregivers of women that received ART care from six health facilities in Malawi. Caregivers of women that reported for ART care on the survey day and consented to participate in the survey were included until the targeted sample size for the facility was reached. We estimated the value of informal care by using the willingness to accept (WTA) and willingness to pay (WTP) approaches. Medians were used to summarize the values and these were compared by the Wilcoxon signed-rank test., Results: The median WTA to provide informal care in a month was US$30 and the median WTP for informal care was US$13 and the two were statistically different (p < 0.000). Median WTP was higher in the urban areas than in the rural areas (US$21 vs. US$13, p < 0.001) and for caregivers from households from higher wealth quintile than in the lower quintile (US$15 vs. US$13, p < 0.0462)., Conclusion: Informal caregivers place substantial value on informal care giving. In low income settings where most caregivers are not formally employed, WTP and WTA approaches can be used to value informal care., Clinical Trial Number: NCT02005835.

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings., Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080., Findings: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5-7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4-7·8); absolute risk difference of -0·06% (95% CI -3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group., Interpretation: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease., Funding: National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the feasibility and effectiveness of dried blood spots (DBS) use for viral load (VL) monitoring, describing patient outcomes and programmatic challenges that are relevant for DBS implementation in sub-Saharan Africa., Methods: We recruited adult antiretroviral therapy (ART) patients from five district hospitals in Malawi. Eligibility reflected anticipated Ministry of Health VL monitoring criteria. Testing was conducted at a central laboratory. Virological failure was defined as >5000 copies/ml. Primary outcomes were program feasibility (timely result availability and patient receipt) and effectiveness (second-line therapy initiation)., Results: We enrolled 1,498 participants; 5.9% were failing at baseline. Median time from enrollment to receipt of results was 42 days; 79.6% of participants received results within 3 months. Among participants with confirmed elevated VL, 92.6% initiated second-line therapy; 90.7% were switched within 365 days of VL testing. Nearly one-third (30.8%) of participants with elevated baseline VL had suppressed (<5,000 copies/ml) on confirmatory testing. Median period between enrollment and specimen testing was 23 days. Adjusting for relevant covariates, participants on ART >4 years were more likely to be failing than participants on therapy 1-4 years (RR 1.7, 95% CI 1.0-2.8); older participants were less likely to be failing (RR 0.95, 95% CI 0.92-0.98). There was no difference in likelihood of failure based on clinical symptoms (RR 1.17, 95% CI 0.65-2.11)., Conclusions: DBS for VL monitoring is feasible and effective in real-world clinical settings. Centralized DBS testing may increase access to VL monitoring in remote settings. Programmatic outcomes are encouraging, especially proportion of eligible participants switched to second-line therapy.

Background: Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown., Methods: The analysis included participants in randomized trials who experienced VF on a first-line regimen of PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) and had at least 24 weeks of follow-up after VF. Antiretroviral management and virologic suppression (human immunodeficiency virus type 1 [HIV-1] RNA <400 copies/mL) after VF were assessed., Results: Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19). Participants remaining on the same regimen had lower NRTI resistance rates (11% vs 30%; P = .003) and higher CD4(+) cell counts (median, 275 vs 213 cells/µL; P = .005) at VF than those who changed. Among participants remaining on their first-line regimen, factors at or before VF significantly associated with subsequent virologic suppression were achieving HIV-1 RNA <400 copies/mL before VF (odds ratio [OR], 3.39 [95% confidence interval {CI}, 1.32-8.73]) and lower HIV-1 RNA at VF (OR for <10 000 vs ≥10 000 copies/mL, 3.35 [95% CI, 1.40-8.01]). Better adherence after VF was also associated with subsequent suppression (OR for <100% vs 100%, 0.38 [95% CI, .15-.97]). For participants who changed regimens, achieving HIV-1 RNA <400 copies/mL before VF also predicted subsequent suppression., Conclusions: For participants failing first-line PI/r with no or limited drug resistance, remaining on the same regimen is a reasonable approach. Improving adherence is important to subsequent treatment success., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral and Nutrition (BAN) Study was performed to describe drug exposure and antiviral response., Methods: Women using Combivir(®) (zidovudine [ZDV] + lamivudine [3TC]) +Aluvia(®) (lopinavir/ritonavir [LPV/RTV]) were enrolled. Breast milk (BM), mother plasma (MP) and infant plasma (IP) samples were obtained over 6 h after observed dosing at 6, 12 or 24 weeks post-partum for drug concentrations and HIV RNA., Results: A total of 30 mother/infant pairs (10 each at 6, 12 and 24 weeks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, respectively, whereas LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24 weeks. The majority (98.3%) of BM concentrations were >HIV(wt) IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA., Conclusions: ZDV and 3TC concentrated in BM whereas LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low antiretroviral concentrations in IP suggest prevention of transmission while breastfeeding may be due to antiretroviral effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.

Objective: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs)., Design: An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000  copies/ml., Methods: Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100  mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r., Results: Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400  copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40  copies/ml and 30 had levels 40-200  copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400  copies/ml., Conclusion: In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.

Objectives: HIV-infected women identified through antenatal care (ANC) often fail to access antiretroviral treatment (ART), leaving them and their infants at risk for declining health or HIV transmission. We describe results of measures to improve uptake of ART among eligible pregnant women., Methods: Between October 2006 and December 2009, interventions implemented at ANC and ART facilities in urban Lilongwe aimed to better link services for women with CD4 counts <250/μl. A monitoring system followed women referred for ART to examine trends and improve practices in referral completion, on-time ART initiation and ART retention., Results: Six hundred and twelve women were ART eligible: 604 (99%) received their CD4 result, 344 (56%) reached the clinic, 286 (47%) started ART while pregnant and 261 (43%) were either alive on ART or transferred out after 6 months. Between 2006 and 2009, the median (IQR) time between CD4 blood draw and ART initiation fell from 41 days (17, 349) to 15 days (7,42) (P = 0.183); the proportion of eligible individuals starting ART while pregnant and retained for 6 months improved from 17% to 65% (P < 0.001). Delays generally shortened within the continuum of care from 2006 to 2009; however, time from CD4 blood draw to ART referral increased from 7 to 14 days., Conclusions: Referrals between facilities and delays through CD4 count measurements create bottlenecks in patient care. Retention improved over time, but delays within the linkage process remained. ART initiation at ANC plus use of point-of-care CD4 tests may further enhance ART uptake., (© 2012 Blackwell Publishing Ltd.)

Objectives: Evaluating treatment failure is critical when deciding to modify antiretroviral therapy (ART). Virologic Assessment Forms (VAFs) were implemented in July 2008 as a prerequisite for ordering viral load. The form requires assessment of clinical and immunologic status., Methods: Using the Electronic Medical Record (EMR), we retrospectively evaluated patients who met 2006 WHO guidelines for immunologic failure (≥15 years old; on ART ≥6 months; CD4 count 50% drop from peak OR CD4 persistently <100 cells) at the Lighthouse Trust clinic from December 2007 to December 2009. We compared virologic screening, VAF implementation and ART modification during the same period using Fisher's exact tests and unpaired t-tests as appropriate., Results: Of 7000 enrolled ART patients ≥15 years old with at least two CD4 counts, 10% had immunologic failure with a median follow-up time on ART of 1.4 years (IQR: 0.8-2.3). Forty (6%) viral loads were ordered: 14 (35%) were detectable (>400 HIV RNA copies/mL) and one (7%) patient was switched to second-line therapy. Overall, 259 VAFs were completed: 67% for immunologic failure and 33% for WHO Stage 4 condition. Before VAF implementation, 1% of patients had viral loads drawn during routine care, whereas afterwards, 8% did (P<0.0001; 95% CI: 0.03-0.08)., Conclusions: Clinicians did not identify a large proportion of immunologic failure patients for screening. Implementation of VAFs produced little improvement in virologic screening during routine care. Better training and monitoring systems are needed., (© 2011 Blackwell Publishing Ltd.)

As Antiretroviral Therapy (ART) is scaled up in low- and middle-income countries, it is important to understand Quality of Life (QOL) correlates including disease severity and person characteristics and to determine the extent of between-country differences among those with HIV. QOL and medical data were collected from 1,563 of the 1,571 participants at entry into a randomized clinical trial of ART conducted in the U.S. (n = 203) and 8 resource-limited countries (n = 1,360) in the Caribbean, South America, Asia, and Africa. Participants were interviewed prior to initiation of ART using a modified version of the ACTG SF-21, a health-related QOL measure including 8 subscales: general health perception, physical functioning, role functioning, social functioning, cognitive functioning, pain, mental health, and energy/fatigue. Other measures included demographics, CD4+ lymphocyte count, plasma HIV-1 RNA viral load. Higher quality of life in each of the 8 QOL subscales was associated with higher CD4+ lymphocyte category. General health perception, physical functioning, role functioning, and energy/fatigue varied by plasma HIV-1 RNA viral load categories. Each QOL subscale included significant variation by country. Only the social functioning subscale varied by sex, with men having greater impairments than women, and only the physical functioning subscale varied by age category. This was the first large-scale international ART trial to conduct a standardized assessment of QOL in diverse international settings, thus demonstrating that implementation of the behavioral assessment was feasible. QOL indicators at study entry varied with disease severity, demographics, and country. The relationship of these measures to treatment outcomes can and should be examined in clinical trials of ART in resource-limited settings using similar methodologies.

Aim: Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians., Materials & Methods: CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects., Results: Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27-2.40) for area under the concentration time curve (AUC)(0-12 h), 1.58 (1.03-2.42) for C(0), and 0.53 (0.31-0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027)., Conclusion: Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure.

Background: Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world., Methods and Findings: 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007)., Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen., Trial Registration: www.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.

Background: The Malawian government recently changed its prevention of mother-to-child transmission (PMTCT) regimen and plans to change its first-line antiretroviral therapy (ART) regimen to Tenofovir(TDF)/Lamivudine/Efavirenz as a fixed-dose combination tablet. Implementation could be challenging if baseline creatinine clearance (CrCl) screening were required to assess renal function prior to TDF therapy. Our goal is to determine predictors of CrCl<50 ml/min among HIV-infected, ART-naïve individuals., Methodology: Data on HIV-infected, ART-naïve adults screened for enrollment into 5 HIV clinical trials in Lilongwe, Malawi were combined for a pooled analysis of predictors for CrCl<50 ml/min. CrCl was derived from the Cockroft-Gault equation. Multivariable logistic regression modeled the association of age, body mass index (BMI), hemoglobin, CD4 cell count <350 cells/mm(3), gender, and pregnancy with CrCl<50 ml/min., Results: The analysis included 3508 patients with values for creatinine clearance. Most subjects were female (90.6%) with a median age of 26 years (IQR 22-29). The median CD4 cell count was 444 (IQR 298.0-561.0), and 85.2% percent of women in our study were pregnant. Few patients had CrCl<50 ml/min (n = 38, 1.1%). A BMI less than 18.5 in non-pregnant females (OR = 8.87, 95% CI = 2.45-32.09)) was associated with CrCl<50 ml/min. Hemoglobin level higher than 10 g/dL in males (OR = 0.69, 95% CI = 0.56-0.86) and non-pregnant females (OR = 0.21, 95% CI = 0.04-0.97) was protective against CrCl<50 ml/min., Discussion: Our findings indicate few patients would be excluded from a TDF-based antiretroviral regimen, suggesting baseline creatinine clearance assessment may not be necessary for implementation. However, in ART settings individuals with low BMI or anemia could potentially be at increased risk for lower CrCl.

Background: Loss to follow-up is a major challenge of antiretroviral treatment (ART) programs in sub-Saharan Africa. Our objective was to a) determine true outcomes of patients lost to follow-up (LTFU) and b) identify risk factors associated with successful tracing and deaths of patients LTFU from ART in a large public sector clinic in Lilongwe, Malawi., Methods: Patients who were more than 2 weeks late according to their last ART supply and who provided a phone number or address in Lilongwe were eligible for tracing. Their outcomes were updated and risk factors for successful tracing and death were examined., Results: Of 1800 patients LTFU with consent for tracing, 724 (40%) were eligible and tracing was successful in 534 (74%): 285 (53%) were found to be alive and on ART; 32 (6%) had stopped ART; and 217 (41%) had died. Having a phone contact doubled tracing success (adjusted odds ratio, aOR = 2.1, 95% CI 1.4-3.0) and odds of identifying deaths [aOR = 1.8 (1.2-2.7)] in patients successfully traced. Mortality was higher when ART was fee-based at initiation (aOR = 2.3, 95% CI 1.1-4.7) and declined with follow-up time on ART. Limiting the analysis to patients living in Lilongwe did not change the main findings., Conclusion: Ascertainment of contact information is a prerequisite for tracing, which can reveal outcomes of a large proportion of patients LTFU. Having a phone contact number is critical for successful tracing, but further research should focus on understanding whether phone tracing is associated with any differential reporting of mortality or LTFU.

Due to the rapid expansion of first-line antiretroviral therapy in resource-limited settings (RLS), increasing numbers of people are living with HIV for prolonged periods of time. Treatment programs must now decide how to balance monitoring costs necessary to maximize health benefits for those already on treatment with the continued demand to initiate more patients on first-line treatment. We review currently available evidence related to monitoring strategies in RLS and discuss their implications on timing of switching to second-line treatment, development of HIV resistance, and clinical outcome.