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To establish the incidence, risk factors and prognostic effect of anemia in children living with HIV (CLWH).Retrospective nested case-control study of patients 0-18 years in five centers in sub-Saharan Africa, 2004-2014.Incident cases of anemia were identified from electronic records and matched with CLWH without anemia. We calculated the incidence density of anemia and used conditional logistic regression to evaluate its association with risk factors, stratified by severity and type of anemia. We used a Cox proportional hazards model to evaluate the impact of anemia on survival.Two thousand, one hundred and thirty-seven children were sampled. The incidence density of anemia was 1 per 6.6 CLWH-years. Anemia was moderate in 31.8% and severe in 17.3% of anemia cases, which had 10-year mortality hazards of 3.4 and 4.5, respectively. Microcytic anemia (36% cases) was associated with 2.3-fold hazard of 10-year mortality, and with malnutrition and CD4 + suppression. Normocytic anemia (50.5% cases) was associated with 2.6-fold hazards of 10-year mortality, and with more severe malnutrition, CD4 + suppression, and WHO stage, but inversely associated with lamivudine and nevirapine therapy. Macrocytic anemia (13.5% cases) was neither associated with higher 10-year mortality nor with severe malnutrition or CD4 + suppression but was associated with WHO stage II/III and negatively associated with lamivudine therapy.This large multicountry study of CLWH found a high incidence density of anemia. Higher severity, normocytic and microcytic types of anemia were independently associated with long-term mortality. Laboratory studies are needed to decipher the mechanisms of anemia and how it impacts mortality in CLWH.

Background: Pre-treatment HIV drug resistance is a threat to elimination of mother to child HIV transmission and could lead to virological failure among HIV-positive pregnant women. We analysed genotypic HIV drug resistance (HIVDR) of baseline samples of participants enrolled in the Option B+ clinical trial in Uganda.Methods: HIV-infected pregnant women attending antenatal care were enrolled from Uganda’s National Referral Hospital (Mulago) and Mityana District general hospital and surrounding health centers (HCs). Genotypic HIV testing was performed on blood samples from the first 135 enrolled women out of a subset of 136 participants (25%) who had a baseline VL>1000 copies/mL as one sample failed to amplify.Results: 159/540 (29.4%) had a VL < 1000 copies/ml and 381/540 (70.6%) had a VL >1,000 copies/ml. Of the women with VL>1000 copies/ml, 32 (23.7%) had resistance mutations including 29/135 (21.5%) NNRTI mutations, 6/135 (4.4%) NRTI mutations and 3/135 (2.2%) had both NNRTI and NRTI mutations. The most common NNRTI resistance mutations were: K103KN (5), K103N (5), V179T (4) and E138A (4).Conclusions: One quarter of the HIV-infected pregnant women in this trial at baseline had NNRTI genotypic resistance mutations. Our findings support new WHO guidelines for first-line ART that were changed to dolutegravir-based regimens.

Women who are pregnant or who could become pregnant experience delayed access to or underinformed use of important new antiretroviral (ARV) drugs because of traditional drug development processes that ostensibly aim to reduce potential harm but effectively fail to ensure that timely information about safe and effective use in pregnancy is available.The World Health Organization and International Maternal, Pediatric, Adolescent Antiretroviral Clinical Trials Network convened a year-long workshop on "Approaches to Enhance and Accelerate Study of New Drugs for HIV and Associated Infections in Pregnant Women." Workshop participants were tasked with defining key principles and optimal approaches to including pregnant women in pre- and post-licensure trials in order to accelerate the availability of pharmacokinetic and safety data for new ARV agents in pregnancy. ARV efficacy in pregnancy and ARV efficacy for prevention of vertical transmission can be extrapolated from proof of efficacy in non-pregnant adults, provided that drug levels in pregnancy are similar. However, short-term safety and pharmacokinetics must be studied directly in pregnant women and should be conducted and included in initial licensure for all new ARVs. Accelerating the timeline for completion of pre-clinical studies is essential for pregnancy short-term safety and pharmacokinetic studies to be safely completed by the time a drug is licensed. Composite key pregnancy, birth and neonatal outcomes are critical for drugs expected to have broad use, and studies should be initiated at or soon after drug licensure. Teratogenicity risk cannot be feasibly assessed before drug licensure and will depend on robust post-marketing surveillance systems. With some modifications, these principles will apply to ARVs used for prevention, two-drug regimens, long-acting ARVs and ARVs administered through novel delivery systems.Implementation of the proposed principles and framework will enhance and accelerate the study of new ARVs in pregnancy, resulting in more timely, equitable and informed access to new ARVs for pregnant women.

Item does not contain fulltext BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

Contains fulltext : 283099.pdf (Publisher’s version ) (Open Access) BACKGROUND: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. METHODS: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and

Contains fulltext : 282959.pdf (Publisher’s version ) (Open Access) BACKGROUND: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. METHODS: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to

Background There is a growing number of adolescents and young adults living with HIV (YPLHIV) who require the transfer of care from pediatric/ adolescent clinics to adult Antiretroviral therapy (ART) clinics. A successful transition is critical for optimum health outcomes, yet facilities may lack infrastructure, human resources (with appropriate knowledge and skills), and a supportive environment, as only 3% of clinics in Uganda caring for YPLHIV have a process for supporting this critical transition from pediatric to adult care, and, facilitators and barriers of a successful transition are not well documented. The purpose of this study was to explore the facilitators and barriers of transitioning among adolescents from adolescent clinics to adult ART clinics. Method Eighteen focus group discussions were held in nine health facilities with 174 adolescents and YPLHIV to assess barriers and facilitators regarding transitioning to adult clinics. The focus group discussions were audio-recorded and transcribed. The Silences Framework using a thematic approach guided the analysis. Results The key emerging issues were: Unfriendly adults in adult clinics, Care provided in the adolescent clinics, fear of stigma from health care providers, Congestion and long waiting time, fear to lose friends were barriers to transitioning. Transitioning preparation is key to a successful transition, moving as a cohort facilitates transition, and care in adult clinics offers new opportunities, could facilitate readiness and transition. Conclusion YPLHIV expressed fear to transition to adult clinics mainly because of the perceived better care provided in the adolescent clinic, thus constituting a barrier to smooth transition A range of individual, social and health system and services-related factors hindered transitioning. The expectation of transitioning as a group, assurance of similar care as in the adolescent clinic, and guarantees of confidentiality, privacy, and autonomy in decision-making for care was perceived as facilitators. Understanding barriers and facilitators can enable the Ministry of Health to improve the quality of life of YPLHIV through linkage to care, adherence, retention, and viral suppression. There is a need to better planning and preparation for clinical providers and YPLHIV with a focus on age-appropriate and individualized case management transition as well as focus on improving both clinical and psychosocial support throughout the process.

Background Viral load (VL) testing is key in monitoring adherence to antiretroviral therapy (ART) and documenting HIV treatment response. As per HIV treatment guidelines in Uganda, the first VL test is recommended 6 months after initiation of ART. Undetectable VL (uVL) at ART initiation may be helpful in detecting elite controllers in the absence of previous ART use. We investigated viral suppression at ART initiation among a cohort of HIV-positive pregnant women enrolled in the Friends for Life Circles (FLC) for Option B+ randomized controlled trial (RCT). Methods Pregnant women ≥ 18 years of age testing positive for HIV at their first antenatal care visit and starting on ART Option B+ as per the National PMTCT Program guidelines were enrolled into the FLC for Option B+ RCT in urban Kampala and rural Mityana districts of Uganda. Each participant had whole blood samples collected at enrolment to assess baseline VL. Plasma HIV-1 RNA was quantified using COBAS Ampliprep /COBAS Taqman. Baseline VL below 400 RNA copies/ml was considered as viral suppression while baseline VL below 20 RNA copies/ml was considered uVL. Results The mean duration from the date of ART initiation to time of sample collection for baseline VL assessment was 4.4 days (SD 3.6). Of the 532 HIV-positive pregnant women enrolled in the FLC for Option B+ study and newly starting Option B+ without a self-reported history of prior ART use, 29 (5.5%) had uVL and 113 (21.4%) had suppressed VL at baseline. There was no association between participants’ age, gravidity, marital status, mean monthly income, educational level, disclosure of HIV status to partner, and uVL or viral suppression at baseline. However, non-disclosure of HIV status to any other person was associated with decreased odds of viral suppression at baseline (OR 0.640; 0.416–0.982). Conclusion Twenty-one percent of HIV-positive Ugandan pregnant women initiating ART (Option B+) showed virological suppression at baseline and were presumed to be “elite controllers” or to have misreported being ART-naive. Further studies are needed to better understand the biologic mechanisms of elite controllers among pregnant women as well as to differentiate elite controllers from concealed ART use. Trial Registration The trial was registered as NCT02515370 (04/08/2015) on Clinicaltrials.gov.

Background The estimated prevalence of neural tube defects (NTDs) in Africa is 11.7 per 10,000 live births; however, data on the impact of antiretroviral therapy (ART) during pregnancy and the risk for birth defects in Africa are limited. Methods Data from a hospital-based surveillance program at four hospitals in Kampala, Uganda were used to estimate the baseline prevalence of NTDs and assess potential associations with HIV status and ART use. All live births, stillbirths, and spontaneous abortions delivered at the participating hospitals affected with selected birth defects between August 2015 and December 2018 were included. Trained midwives collected data from hospital records, maternal interviews, photographs, and narrative descriptions of birth defects. We estimated NTD prevalence per 10,000 births (live, stillbirths, spontaneous abortions), prevalence ratios, and 95% confidence intervals (CIs). Results A total of 110,752 births from 107,133 women were included in the analysis; 9,394 (8.8%) women were HIV-infected and among those with HIV infection, 95.6% (n = 8,977) were on ART at delivery. Overall, 109 births were affected with NTDs, giving a prevalence of 9.8 (95% CI [8.2, 11.9]). Spina bifida (n = 63) was the most common type of NTD, with a prevalence of 5.7 (95% CI [4.4, 7.3]), followed by anencephaly (n = 31), with a prevalence of 2.8 (95% CI [2.0, 4.0]). Conclusion The prevalence of NTDs among births in Kampala, Uganda is consistent with current estimates for Africa. With the continued introduction of new medications that may be taken during pregnancy, sustainable birth defect surveillance systems and pharmacovigilance are indicated.

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

Background: We evaluated the efficacy of a community health worker (CHW)–led intervention in supporting disclosure among adults living with HIV in heterosexual relationships. Methods: We conducted a quasi-experimental study with 2 arms allocated by geographically determined clusters and adjusted for between-group differences among adults living with HIV in the greater Luwero region of Uganda who had never disclosed their status to their current primary sexual partners. Clusters were allocated to either a CHW-led intervention or a control arm. In both arms, participants were consecutively recruited. As opposed to receiving routine care for the control arm, participants in the intervention arm received additional CHW disclosure support. The overall follow-up was 6 months, and the primary outcome was disclosure to the sexual partner. Data were analyzed using a clustered modified Poisson regression model with robust standard errors to determine independent factors associated with disclosure. Results: Of the 245 participants who enrolled, 230 (93.9%) completed the study, and 112 (48.7%) of those were in the intervention arm. The median age was 30 (interquartile range=25–37) years, the majority were women (76.5%), and most (80%) did not know their partners’ HIV status at study entry. At the end of follow-up, the overall disclosure prevalence was 74.4% (95% confidence interval [CI]=68.2, 79.9) and participants in the intervention arm were 51% more likely to disclose compared to those in the control (adjusted relative ratio [aRR]=1.51; 95% CI=1.28, 1.77). Men were 24% (aRR=1.24; 95% CI=1.07, 1.44) more likely to disclose compared to women, and membership in an HIV/AIDS association increased disclosure by 18% (aRR=1.18; 95% CI=1.01, 1.39). Conclusion: CHW support improved disclosure among adults living with HIV in heterosexual relationships when compared to routine care. Therefore, CHW-led mechanisms may be utilized in increasing disclosure among adults living with HIV in heterosexual relationships in rural settings.

Tenofovir disoproxil fumarate (TDF) and intramuscular depot medroxyprogesterone acetate (DMPA-IM) are independently associated with reduced bone mineral density (BMD). We aimed to assess the combined effects of DMPA-IM use and TDF initiation on BMD in young adult women living with HIV over two years, compared with age-matched people without HIV.Th BONE: CARE study was a prospective cohort study that recruited women aged 18-35 years from 11 HIV care and general health facilities in Kampala, Uganda. The participants were classified into four groups on the basis of their combination of HIV status, TDF use, and DMPA-IM use, as follows: women living with HIV initiating TDF-containing antiretroviral therapy (ART) with DMPA-IM (HIV positive, DMPA positive, and TDF positive); women living with HIV using DMPA-IM but not eligible for ART as per local guidelines at the time of enrolment into the study (HIV positive, DMPA positive, and TDF negative); women living with HIV initiating TDF-containing ART without DMPA-IM (HIV positive, DMPA negative, and TDF positive); and controls without HIV using non-hormonal contraceptives (HIV negative, DMPA negative, and TDF negative). BMD of the lumbar spine, total hip, and femoral neck were measured using semiannual dual-energy x-ray absorptiometry at enrolment and at intervals every 6 months thereafter. We assessed percentage change in mean BMD.Between March 30, 2016, and Oct 19, 2017, we enrolled 265 women living with HIV initiating ART (159 DMPA-IM users and 106 non-hormonal contraceptive users), 187 women living with HIV using DMPA-IM but not ART, and 69 controls without HIV. Mean age was 26·1 years (SD 4·2). BMD declined significantly from baseline in women living with HIV on TDF with versus without DMPA-IM at the lumbar spine (-3·406% [95% CI -3·969 to -2·844] vs -1·111% [-1·929 to -0·293]; p0·0001), total hip (-3·856% [-4·449 to -3·264] vs -1·714% [-2·479 to -0·949]; p=0·0002), and femoral neck (-4·422% [-5·078 to -3·766] vs -1·999% [-3·022 to -0·976]; p=0·0002), increased in controls at the lumbar spine (1·5% change), and remained unchanged at total hip and femoral neck (-0·1% change). Concurrent use of TDF and DMPA-IM resulted in significantly greater BMD decline (p0·0001) than TDF alone (lumbar spine -2·677% [95% CI -3·743 to -1·611]; p0·0001; total hip -2·518% [-3·575 to -1·461]; p0·0001; and femoral neck -2·907 [-4·132 to -1·683]; p0·0001) or than controls (lumbar spine -4·970% [-6·391 to -3·549]; p0·0001; total hip -4·151% [-5·579 to -2·724]; p0.0001; and femoral neck -4·773% [-6·424 to -3·122]; p0·0001) INTERPRETATION: Concomitant DMPA-IM use resulted in a doubling of BMD loss in women living with HIV initiating TDF-containing ART. Identification of safer contraceptive and bone-sparing ART options should be prioritised for optimal care of women living with HIV.National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.

Background HIV infection is associated with significant neurocognitive deficits making maximization of cognitive function among children receiving antiretroviral therapy (ART) a public health imperative. Non-protease inhibitors (non-PIs) achieve higher drug levels in the cerebral spinal fluid (CSF) compared to PIs, potentially leading to better neurocognitive function by reducing CSF viral load and inflammation. ART that maximises children’s neurodevelopment and school achievement could result in improved quality of life and productivity as adults, but little research to date has examined whether non-PI ART is associated with better neurocognitive outcomes. We compared the neurocognitive function between children living with HIV receiving PI-based and non PI-based ART. Methods We recruited a consecutive sample of clinically stable Ugandan children living with HIV aged 5–12 years who received PI-based or non PI-based ART for ≥ 1 year (viral load Results We enrolled 76 children living with HIV; 34 on PI ART and 42 on non-PI ART. Mean (±SD) age was greater in the non-PI vs. PI group (9.5 ± 1.9 vs. 8.5 ± 2.0) years (p = 0.03). Children in the non-PI group had lower socioeconomic scores (5.7 ± 3.3 vs. 7.4 ± 2.8, p = 0.02). There was no difference in neurocognitive function between the groups (adjusted p > 0.05) for KABC and TOVA. Children in the PI group had better total BOT scores than their counterparts (46.07 ± 1.40) vs. 40.51 (1.24), p = 0.03). Conclusions We detected no difference in neurocognitive function among children on PI and non PI-based ART therapy based on KABC and TOVA tests. Children on PI based ART had better motor function than their counterparts. We recommend a prospective study with a larger sample size.

Background Transition readiness refers to a client who knows about his/her illness and oriented towards future goals and hopes, shows skills needed to negotiate healthcare, and can assume responsibility for his/ her treatment, and participate in decision-making that ensures uninterrupted care during and after the care transition to adult HIV care. There is a paucity of research on effective transition strategies. This study explored factors associated with adolescent readiness for the transition into adult care in Uganda. Methods A cross-sectional study was conducted among 786 adolescents, and young people living with HIV randomly selected from 9 antiretroviral therapy clinics, utilizing a structured questionnaire. The readiness level was determined using a pre-existing scale from the Ministry of Health, and adolescents were categorized as ready or not ready for the transition. Bivariate and multivariate analyses were conducted. Results A total of 786 adolescents were included in this study. The mean age of participants was 17.48 years (SD = 4). The majority of the participants, 484 (61.6%), were females. Most of the participants, 363 (46.2%), had no education. The majority of the participants, 549 (69.8%), were on first-line treatment. Multivariate logistic regression analysis found that readiness to transition into adult care remained significantly associated with having acquired a tertiary education (AOR 4.535, 95% CI 1.243–16.546, P = 0.022), trusting peer educators for HIV treatment (AOR 16.222, 95% CI 1.835–143.412, P = 0.012), having received counselling on transition to adult services (AOR 2.349, 95% CI 1.004–5.495, P = 0.049), having visited an adult clinic to prepare for transition (AOR 6.616, 95% CI 2.435–17.987, P = < 0.001) and being satisfied with the transition process in general (AOR 0.213, 95% CI 0.069–0.658, P = 0.007). Conclusion The perceived readiness to transition care among young adults was low. A series of individual, social and health system and services factors may determine successful transition readiness among adolescents in Uganda. Transition readiness may be enhanced by strengthening the implementation of age-appropriate and individualized case management transition at all sites while creating supportive family, peer, and healthcare environments.

Background Whereas many adolescents and young people with HIV require the transfer of care from paediatric/adolescent clinics to adult ART clinics, this transition is beset with a multitude of factors that have the potential to hinder or facilitate the process, thereby raising ethical challenges of the transition process. Decisions made regarding therapy, such as when and how to transition to adult HIV care, should consider ethical benefits and risks. Understanding and addressing ethical challenges in the healthcare transition could ensure a smooth and successful transition. The purpose of this study was to analyze the ethical challenges of transitioning HIV care for adolescents into adult HIV clinics. Methods Data presented were derived from 191 adolescents attending nine different health facilities in Uganda, who constituted 18 focus group discussions. In the discussions, facilitators and barriers regarding adolescents transitioning to adult HIV clinics were explored. Guided by the Silences Framework for data interpretation, thematic data analysis was used to analyze the data. The principles of bioethics and the four-boxes ethics framework for clinical care (patient autonomy, medical indications, the context of care, and quality of life) were used to analyze the ethical issues surrounding the transition from adolescent to adult HIV care. Results The key emerging ethical issues were: reduced patient autonomy; increased risk of harm from stigma and loss of privacy and confidentiality; unfriendly adult clinics induce disengagement and disruption of the care continuum; patient preference to transition as a cohort, and contextual factors are critical to a successful transition. Conclusion The priority outcomes of the healthcare transition for adolescents should address ethical challenges of the healthcare transition such as loss of autonomy, stigma, loss of privacy, and discontinuity of care to ensure retention in HIV care, facilitate long-term self-care, offer ongoing all-inclusive healthcare, promote adolescent health and wellbeing and foster trust in the healthcare system. Identifying and addressing the ethical issues related to what hinders or facilitates successful transitions with targeted interventions for the transition process may ensure adolescents and young people with HIV infection remain healthy across the healthcare transition.

BackgroundThis study set out to determine the prevalence of low bone mass following long-term exposure to antiretroviral therapy in Ugandan people living with HIV.MethodsA cross-sectional study was conducted among 199 people living with HIV that had been on anti-retroviral therapy for at least 10 years. All participants had dual X-ray absorptiometry to determine their bone mineral density. The data collected included antiretroviral drug history and behavioral risk data Descriptive statistics were used to summarize the data. Inferential statistics were analyzed using multilevel binomial longitudinal Markov chain Monte Carlo mixed multivariate regression modelling using therstanarmpackage.ResultsOne hundred ninety nine adults were enrolled with equal representation of males and females. The mean age was 39.5 (SD 8.5) years. Mean durations on anti-retroviral treatment was 12.1 (SD 1.44) years, CD4 cell count was 563.9 cells/mm3. 178 (89.5%) had viral suppression with ConclusionThese results provide additional evidence that patients on long term ART achieve bone mass stabilization. Maintaining adequate body weight is important in maintaining good bone health in people on antiretroviral therapy.

Objectives To quantify association between in utero/peripartum antiretroviral (IPA) exposure and cognition, i.e. executive function (EF) and socioemotional adjustment (SEA), in school-aged Ugandan children who were perinatally HIV-infected (CPHIV, n = 100) and children who were HIV-exposed but uninfected (CHEU, n = 101). Methods Children were enrolled at age 6-10 years and followed for 12 months from March 2017 to December 2018. Caregiver-reported child EF and SEA competencies were assessed using validated questionnaires at baseline, 6 and 12 months. IPA type - combination antiretroviral therapy (cART), intrapartum single-dose nevirapine ± zidovudine (sdNVP ± ZDV), nevirapine + zidovudine + lamivudine (sdNVP + ZDV + 3TC) - or no IPA (reference) was verified via medical records. IPA-related standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) in cognitive competencies were estimated from regression models with adjustment for caregiver sociodemographic and contextual factors. Models were fitted separately for CPHIV and CHEU. Results Among CPHIV children, cART (SMD = -0.82, 95% CI: -1.37 to -0.28) and sdNVP ± ZDV (SMD = -0.41, 95% CI: -0.81 to -0.00) vs. no IPA predicted lower executive dysfunction over 12 months. Intrapartum sdNVP + ZDV + 3TC vs. no IPA predicted executive dysfunction (SMD = 0.80, 95% CI: 0.30-1.31), SEA problems (SMD = 0.63-0.76, 95% CI: 0.00-1.24) and lower adaptive skills (SMD = -0.36, 95% CI: -0.75-0.02) over 12 months among CHEU. Further adjustment for contextual factors attenuated associations, although most remained of moderate clinical importance (|SMD| > 0.33). Conclusions Among CPHIV children, cART and sdNVP ± ZDV IPA exposure predicted, on average, lower executive dysfunction 6-10 years later. However, peripartum sdNVP + ZDV + 3TC predicted executive and SEA dysfunction among CHEU 6-10 years later. These data underscore the need for more research into long-term effects of in utero ART to inform development of appropriate interventions so as to mitigate cognitive sequelae.

Objective To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa. Design Longitudinal cohort study. Methods In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.5 years on first-line ART. We classified each viral load measurement as consistent suppression, blip/post-blip, persistent low-level viral load or rebound. We used multi-level models to estimate rates of increase or decrease in laboratory markers, and Poisson regression to estimate the incidence of clinical events. Results Overall, 42% children experienced viral blips, but these had no significant impact on immune reconstitution or inflammation. Persistent detectable viraemia occurred in one-third of children and prevented further immune reconstitution, but had little impact on inflammatory biomarkers. Virological rebound to ≥5000 copies/ml was associated with arrested immune reconstitution, rising IL-6 and increased risk of clinical disease progression. Conclusions As viral load testing becomes more available in sub-Saharan Africa, repeat testing algorithms will be required to identify those with virological rebound, who need switching to prevent disease progression, whilst preventing unnecessary second-line regimen initiation in the majority of children with detectable viraemia who remain at low risk of disease progression.

Since 2012, PMTCT Option B+ has been recommended by the World Health Organization to reduce vertical transmission but numerous adherence challenges remain. We conducted a qualitative study at baseline using six focus group discussions and 14 in-depth interviews to explore knowledge, beliefs, attitudes and challenges towards the Option B+ strategy for PMTCT among HIV-infected pregnant and post-partum women and health workers engaged in Uganda's national Option B+ PMTCT programme. Data were analysed using a thematic approach to capture latent and manifest content with the social ecological model as a theoretic foundation in order to make contextual sense of key stakeholders' needs for an effective Option B+ intervention. Overall, among all study participants, we found multi-level barriers to adhering to Option B+ cutting across all levels of the social ecological model. In line with the model, our study revealed barriers at personal, relational, organizational and societal levels. Some personal beliefs such as that the baby's health is more important that the mother's, organizational (negative attitudes and behaviour of health workers), structural such as poverty, work conflicts, fear and lack of disclosure related to community stigma were all critical obstacles to women adhering to the Option B+ programme. We found that both health workers and participants in the programme have a relatively clear understanding of the benefits of adhering to their treatment; though a more nuanced understanding and thus emphasis in counselling on side effects, is critical to helping patients adhere.

Caregiver's and child's self-reported quality of life (QOL) was defined using standardized questionnaires in a sample (N = 277) of 6-10 years old HIV-infected, HIV-exposed uninfected, and HIV-unexposed uninfected children from Uganda. Psychosocial stress (acute stress and cumulative lifetime adversity) and physiologic stress (dysregulations across 13 biomarkers), perinatal HIV status, and their interaction were related to child QOL via general linear models. Lower child- and caregiver-reported psychosocial stress were dose-dependently associated with higher QOL (acute stress: mean difference coefficient b = 8.1-14.8, effect size [ES] = 0.46-0.83). Lower allostasis was dose-dependently associated with higher QOL (b = 6.1-9.7, ES = 0.34-0.54). Given low caregiver acute stress, QOL for HIV-infected was similar to HIV-uninfected children; however, given high caregiver acute stress, a QOL disadvantage (b = -7.8, 95% CI: -12.8, -2.8; ES = -0.73) was evident for HIV-infected versus uninfected children. Testing of caregiver stress reduction interventions is warranted to increase wellbeing in dependent children.

Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation.We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037.Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR.High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa.The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

BackgroundMortality among children under 5 years of age admitted to malnutrition units in sub-Saharan Africa remains high. The burden of HIV infection, a major risk factor for mortality among patients with severe acute malnutrition (SAM), has reduced due to concerted prevention and treatment strategies. None the less, anecdotal reports from the malnutrition unit at Uganda’s National Referral Hospital (NRH) indicate that there is high mortality among patients with severe acute malnutrition (SAM) in routine care. Uganda has recently adopted the revised World Health Organization (WHO) treatment guidelines for SAM to improve outcomes. The mortality among children with SAM in routine care has not been recently elucidated. We report the magnitude and factors associated with mortality among children under 5 years of age admitted to the NRH for routine care of SAM.MethodsThis was a cohort study of all severely malnourished children admitted to the NRH between June and October 2017. The primary outcome was two-week mortality. Mortality was calculated using simple proportions and Cox regression analysis was used to determine factors associated with time to mortality. Data was entered into Epidata and analysed using Stata v14.ResultsTwo-hundred-sixty (98.5%) children: 59.6% male; mean age 14.4 (SD 9.4) months, completed two weeks of follow-up. Of these, 25.2% (95% CI 19.9–30.4%) died. In-hospital mortality was 20.7% (95% CI15.9–25.6%). The prevalence of HIV infection was 12.2%. Factors associated with mortality included: positive HIV status (AHR 2.2, (95% CI; 1.2–4.2),p = 0.014), bacteraemia (AHR 9 (95% CI 3.4–23.0),p p = 0.001).ConclusionsA 25% mortality among children with severe malnutrition remains unacceptably high despite significant reduction in HIV prevalence. Children with SAM who are HIV infected, have eGFR below 60 mL/min/1.73m2or have bacteraemia, are more likely to die. Further studies to explore the relationship between eGFR and mortality among children with SAM are needed. Studies to establish efficacious antibiotics are urgently required to inform treatment guidelines for children with SAM.

The HIV Network for Prevention Trials (HIVNET) 012 trial showed that NVP resistance (NVPR) emerged in some women and children after the administration of single-dose nevirapine (SD-NVP). We tested whether K103N-containing human immunodeficiency virus (HIV)-1 variants persisted in women and infants 1 year or more after the administration of SD-NVP.We analyzed samples from 9 women and 5 infants in HIVNET 012 who had NVPR 6-8 weeks after the administration of SD-NVP. Samples were analyzed with the ViroSeq system and with 2 sensitive resistance assays, LigAmp and TyHRT.ViroSeq detected the K103N mutation in 8 of 9 women and in 2 of 5 infants. LigAmp detected the K103N mutation at low levels in 8 of 9 women and in 4 of 5 infants. K103N was not detected by ViroSeq 12-24 months after the administration of SD-NVP but was detected by LigAmp in 3 of 9 women and in 1 of 5 infants. K103N was also detected in those samples by use of the TyHRT assay.K103N-containing variants persist in some women and infants for 1 year or more after the administration of SD-NVP. Sensitive resistance assays may provide new insight into the impact of antiretroviral drug exposure on HIV-1 evolution.

BACKGROUND: The objective of this study was to evaluate the comparative effects of three breastfeeding promotion interventions on the duration of exclusive breastfeeding (EBF) and any breastfeeding (BF) among human immunodeficiency virus (HIV)-infected women in Uganda. METHODS: Between February 2012 and February 2013, 218 HIV-infected pregnant mothers were randomly assigned to (A) standard care (n=73), (B) enhanced family/peer support (n=72) or (C) enhanced nutrition education (n=73). RESULTS: The prevalence (%) of EBF/BF did not differ between intervention arms at the sixth (A, 85/92; B, 84/91; C, 87/89) and ninth (A, 17/91; B, 18/89; C, 16/87) postpartum month assessments (p>0.05). However, the risk of early BF cessation differed between intervention arms depending on the mother’s level of formal education (p=0.04). Among women with no formal education, the risk of early BF cessation was 88% (adjusted hazard ratio [aHR] 0.12 [95% confidence interval {CI} 0.05–0.30]) and 93% (aHR 0.07 [95% CI 0.03–0.18]) lower in arms B and C, respectively, than in arm A (p

To examine quality of life (QOL) in perinatally HIV-infected (PHIV) or HIV-exposed uninfected (PHEU) vs. healthy HIV-unexposed uninfected (HUU) children during school-age/adolescence.PHIV infection was diagnosed via DNA PCR. Current HIV status was confirmed by HIV rapid diagnostic test. Three HIV groups were defined: PHIV, PHEU, and HUU. QOL was assessed with proxy and self-report versions of the PedsQL™ 4.0 instrument at 6-18 years of age. QOL scores ranged from zero (least QOL) to 100 (highest QOL) in the following dimensions: combined QOL inventory (CQOLI), multi-dimensional vigor (MDV), general wellbeing (GWB), present functioning, and general cognitive functioning (CF). Multivariable linear regression models estimated HIV-related percent differences (β) in QOL scores and 95% confidence intervals (CI).Compared to HUU CQOLI deficits ranged from 6.5 to 9.2% (95% CI -15.4, -1.6), GWB deficit ranged from 6.5 to 10.5% (95% CI -16.0, -1.3), MDV deficit ranged from 6.8 to 11.6% (95% CI -14.5, 0.9), and CF deficit ranged from 9.7 to 13.1% for PHIV children. QOL deficits of similar magnitude and direction in most domains were observed for PHIV compared to PHEU. However, self-reported indicators of GWB (β = -3.5; 95% CI -9.0, 2.0) and present functioning (β = 4.0; 95% CI -4.6, 12.5) were similar for PHIV compared to PHEU. QOL scores were generally similar for PHEU compared to HUU.PHEU and HUU had similar QOL profile but PHIV predicted sustained deficits in multiple QOL domains. PHIV and PHEU children were similar with respect to general wellbeing and present functioning. Psychosocial and scholastic interventions in combination with HIV care are likely to improve QOL in PHIV.

Caregiver socio-emotional attributes are major determinants of child well-being. This investigation in vulnerable school-aged Ugandan children estimates relationships between children's well-being and their caregiver's anxiety, depression and social support.Perinatally HIV-infected, HIV-exposed uninfected and HIV-unexposed Ugandan children and their caregivers were enrolled. Perinatal HIV status was determined by 18 months of age using DNA-polymerase chain-reaction test; status was confirmed via HIV rapid diagnostic test when children were 6-18 years old. Five indicators of child well-being (distress, hopelessness, positive future orientation, esteem and quality of life (QOL)) and caregivers' socioemotional status (depressive symptoms, anxiety and social support) were measured using validated, culturally adapted and translated instruments. Categories based on tertiles of each caregiver psychosocial indicator were defined. Linear regression analyses estimated percent differences (β) and corresponding 95% confidence intervals (CI) for child well-being in relation to caregiver's psychosocial status.As per tertile increment, caregiver anxiety was associated with 2.7% higher distress (95%CI:0.2%, 5.3%) and lower self-esteem/QOL (β = -1.3%/-2.6%; 95%CI: -5.0%,-0.2%) in their children. Child distress/hopelessness increased (β = 3.3%/7.6%; 95%CI:0.4%, 14.7%) and self-esteem/QOL decreased 2.3% (β = -2.3%/-4.4%; 95%CI: -7.2%, -1.3%) as per tertile increment in caregiver depression. Higher caregiver social support was associated with lower distress and higher positive outlook (β = 3%; 95%CI:1.4%, 4.5%) in their children. HIV-infected/exposed children had most caregiver depression-related QOL deficit (β = -5.2%/-6.8%; 95%CI: -12.4%, -0.2%) and HIV-unexposed children had most caregiver social support-related enhancements in positive outlook (β=4.5%; 95%CI:1.9%, 7.1%).Caregiver anxiety, depressive symptoms and low social support were associated with worse well-being in school-aged and adolescent children. Improvement of caregiver mental health and strengthening caregiver social support systems may be a viable strategy for improving well-being of vulnerable children and adolescents in this setting.Les attributs socio-affectifs des responsables d'enfants sont des déterminants majeurs du bien-être des enfants. Cette investigation menée auprès d'enfants ougandais vulnérables d’âge scolaire a estimé les relations entre le bien-être des enfants et l'anxiété, la dépression et le soutien social de leur responsable. MÉTHODES: Des enfants ougandais infectés par le VIH de manière périnatale, exposés au VIH mais non infectés, et non exposés au VIH ainsi que leurs responsables ont été inscrits. Le statut VIH périnatal a été déterminé à l’âge de 18 mois à l'aide du test de PCR de l’ADN; le statut a été confirmé par un test de diagnostic rapide du VIH chez les enfants âgés de 6 à 18 ans. Cinq indicateurs du bien-être de l'enfant (détresse, désespoir, orientation future positive, estime et qualité de vie (QV)), et le statut psychosocial des responsables (symptômes dépressifs, anxiété et soutien social) ont été mesurés à l'aide de méthodes validées, adaptées à la culture et respectées et d'outils traduits. Des catégories basées sur les tertiles de chaque indicateur psychosocial du responsable ont été définies. Des analyses de régression linéaire ont estimé les différences en pourcentage (β) et les intervalles de confiance (IC) à 95% correspondants pour le bien-être de l'enfant par rapport au statut psychosocial de leurs responsables. RÉSULTATS: Par incrément de tertile, l'anxiété des responsables était associé à 2,7% de détresse plus élevé (IC95%: 0,2%, 5,3%) et de faible estime de soi/QV (β = −1,3%/−2,6%; IC95%: −5,0%, −0,2%) chez leurs enfants. La détresse et le désespoir des enfants augmentaient (β = 3,3%/7,6%; IC95%: 0,4%, 14,7%) et l'estime de soi/QV diminuait de 2,3% (β = −2,3%/−4,4%; IC95%: −7,2%, −1,3%) par incrément de tertile de la dépression chez le responsable. Un soutien social plus élevé des responsables était associé à une détresse moindre et à une perspective positive plus élevée (β = 3%; IC95%: 1,4%, 4,5%) chez leurs enfants. Les enfants infectés/exposés au VIH présentaient pour la plupart un déficit de QV lié à la dépression de leurs responsables (β = −5,2%/−6,8%; IC95%: −12,4%, −0,2%), et ceux non exposés au VIH présentaient pour la plupart des améliorations en perspective positive liées au soutien social de leurs responsables (β = 4,5%; IC95%: 1,9%, 7,1%).L'anxiété, les symptômes dépressifs et un faible soutien social du responsable étaient associés à un bien-être précaire chez les enfants d’âge scolaire et les adolescents. L'amélioration de la santé mentale des responsables et le renforcement des systèmes de soutien social pour les responsables peuvent constituer une stratégie viable pour améliorer le bien-être des enfants et des adolescents vulnérables dans cette région.

About 2.1 million adolescents aged 10-19years are living with HIV, 80% of them in sub-Saharan Africa. Early sexual activity remains an important risk factor for HIV transmission and potentially result in negative health consequences including onward transmission of sexually transmitted infections. Cross-sectional data of 580 adolescents living with HIV (ALHIV) aged 13-17years (317 girls and 263 boys) from Kenya and Uganda were analyzed to assess factors associated with risk to become sexually active. Factors associated with risk of sexual intercourse were identified using Kaplan-Meier survival curves and Cox regression with gender-stratified bi-and multivariable models. Slightly more females (22%) than males (20%) reported they have had sex. Multivariable models showed that being aware of one's own HIV infection, and receiving antiretroviral treatment were negatively associated with risk of becoming sexually active, while subjective norms conducive to sexuality, and girls' poor health experience increased the risk. In the final multi-variable models, schooling was protective for girls, but not for boys. Being more popular with the opposite sex was negatively associated with the outcome variable only for girls, but not for boys. This study expands the knowledge base on factors associated with onset of sexual activity among ALHIV, potentially informing positive prevention interventions. ResumenAlrededor de 2.1 millones de adolescentes de entre 10 y 19 anos viven con el VIH, el 80% de ellos residen en el africa subsahariana. La actividad sexual precoz sigue siendo un factor de riesgo importante para la transmision del VIH y puede tener consecuencias negativas para la salud, incluida la transmision de infecciones de transmision sexual. Los datos transversales de 580 adolescentes entre los 13-17 anos (317 ninas y 263 ninos) viviendo con el VIH y originarios de Kenia y Uganda fueron analizados para evaluar los factores asociados con el riesgo de volverse sexualmente activos. Los factores asociados con el riesgo de tener relaciones sexuales se identificaron usando las curvas de supervivencia de Kaplan-Meier y la regresion de Cox con modelos bi y multivariables estratificados por genero. Un poco mas de mujeres adolescentes (22%) que de hombres adolescentes (20%) informaron haber tenido relaciones sexuales. Los modelos multivariables mostraron que ser conscientes de la propia infeccion por VIH y recibir tratamiento antiretroviral se asociaron negativamente con el riesgo de volverse sexualmente activos, mientras que las normas subjetivas promoviendo la sexualidad y la mala salud experimentada por las mujeres adolescentes aumentaron el riesgo. En los modelos finales de variables multiples, la escolarizacion resulto ser un factor de proteccion para las mujeres, pero no para los hombres adolescentes. Ser mas popular con el sexo opuesto se asocio negativamente con la variable de resultado pero solo para las mujeres, no para los hombres adolescentes. Este estudio amplia la base de conocimientos sobre los factores asociados con el inicio de la actividad sexual en el VIH lo que podria contribuir a las intervenciones de prevencion positivas.

The World Health Organization (WHO) recommends that HIV-positive children are told their diagnosis by age 12 years. However, most perinatally-infected children reach adolescence without being told their HIV status. Effective strategies are needed to promote disclosure, and optimise children’s health outcomes as they transition to adolescence and adulthood. This qualitative study explored how caregivers of HIV-positive children aged 7–12 years perceived and related to a video used as part of a larger behavioural intervention to promote full disclosureto children by age 12 years. Eight semi-structured interviews and 3 group reflection sessions with 28 caregivers were analysed thematically. Five themes were generated: courage and confidence; reasoning and empathy; child–caregiver relationship; foreign but relatable; and not reaching everyone.The video was found acceptable and appropriate for fostering readiness to disclose. Through watching it, participants reported they could see people similar to themselves prevail despite challenges, which gave them courage.Keywords: video intervention, self-efficacy, pediatric HIV, behaviour change, qualitative

Background Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. Methods/design SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations. Discussion Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020. Trial registration International Standard Randomised Controlled Trials Number: ISRCTN63579542, 14 October 2014. Pan African Clinical Trials Registry Number: PACTR201505001141379, 14 May 2015. Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-2608-5) contains supplementary material, which is available to authorized users.

Globally, 150,000 new paediatric human immunodeficiency virus type 1 (HIV‐1) infections occurred in 2015. There remain complex challenges to the global elimination of paediatric HIV‐1 infection. Thus, for the global community to achieve elimination of new paediatric HIV‐1 infections, innovative approaches need to be explored. Immune‐based approaches to prevention of mother‐to‐child transmission (MTCT) may help fill some of the remaining gaps and provide new opportunities to achieve an AIDS‐free generation. Immune‐based interventions to prevent MTCT of HIV‐1 may include paediatric HIV vaccines and passive immunization approaches. Recent discoveries providing evidence of robust immune responses to HIV in infants open new and exciting prospects for paediatric HIV vaccines. Moreover, successful vaccination of infants has a different set of requirements than vaccination of adults and may be easier to achieve. Proof‐of‐concept has been established over the last two decades that passively administered HIV‐1 Env‐specific monoclonal antibody (mAbs) can prevent chimeric simian human immunodeficiency virus (SHIV) transmission to newborn nonhuman primates. There has been tremendous progress in isolating and characterizing broadly neutralizing antibodies to HIV, and clinical testing of these antibodies for treatment and prevention in both infants and adults is a major effort in the field. Immune‐based interventions need to be actively explored as they can provide critically important tools to address persistent challenges in MTCT prevention. It is a pivotal time for the field with active discussions on the best strategy to further reduce HIV infection of infants and accomplish the World Health Organization Fast‐Track 2030 goals to eliminate new paediatric HIV infections.

Background : The 2016 World Health Organization (WHO) consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, recommended to start all HIV-infected children on antiretroviral therapy (ART). Here, we explore the possible benefits and risks of implementing universal ART for all HIV-infected children and adolescents and outline some of the key considerations that led to the 2016 revision of WHO guidelines. Methods : We conducted a review of the published data from 2000 to 2016, to ascertain the clinical and programmatic benefits, as well as the risks of implementing universal ART for all children. Results and discussion : Universal ART for all children has the potential to increase treatment coverage, which in 2015 was only 51% globally, as well as providing several biological benefits, by preventing: premature death/loss to follow-up, progressive destruction of the immune system, poor growth and pubertal delay, poor neuro-cognitive outcomes and future burden to the health care system with complications of untreated HIV-infection. However, the strategy could be associated with risks, notably development of HIV drug resistance, antiretroviral drug toxicities and increased costs to an already stretched health system. Conclusion : Overall, our findings suggest that the benefits could outweigh the risks and support universal ART for all HIV-infected children, but recognize that national programmes will need to put measures in place to minimize the risks if they choose to implement the strategy. Keywords Universal antiretroviral therapy; children; adolescents; resource limited settings; review; Sub Saharan Africa; WHO guidelines (Published: 27 June 2017) Barlow-Mosha L et al. Journal of the International AIDS Society 2017, 20 :21552 http://www.jiasociety.org/index.php/jias/article/view/21552 | http://dx.doi.org/10.7448/IAS.20.1.21552

Objective Maternal-to-child-transmission of HIV-1 infection remains a significant cause of HIV-1 infection despite successful prevention strategies. Testing protective HIV-1 vaccines remains a critical priority. The immunogenicity of ALVAC-HIV vCP1521 (ALVAC) in infants born to HIV-1-infected women in Uganda was evaluated in the first pediatric HIV-1 vaccine study in Africa. Design HIV Prevention Trials Network 027 was a randomized, double-blind, placebo-controlled phase I trial to evaluate the safety and immunogenicity of ALVAC in 60 infants born to HIV-1-infected mothers with CD4 counts of >500 cells per microliter, which were randomized to the ALVAC vaccine or placebo. ALVAC-HIV vCP1521 is an attenuated recombinant canarypox virus expressing HIV-1 clade E env, clade B gag, and protease gene products. Methods Infants were vaccinated at birth and 4, 8, and 12 weeks of age with ALVAC or placebo. Cellular and humoral immune responses were evaluated using interferon-γ enzyme-linked immunosorbent spot, carboxyfluorescein diacetate succinimidyl ester proliferation, intracellular cytokine staining, and binding and neutralizing antibody assays. Fisher exact test was used to compare positive responses between the study arms. Results Low levels of antigen-specific CD4 and CD8 T-cell responses (intracellular cytokine assay) were detected at 24 months (CD4-6/36 vaccine vs. 1/9 placebo; CD8-5/36 vaccine vs. 0/9 placebo) of age. There was a nonsignificant trend toward higher cellular immune response rates in vaccine recipients compared with placebo. There were minimal binding antibody responses and no neutralizing antibodies detected. Conclusions HIV-1-exposed infants are capable of generating low levels of cellular immune responses to ALVAC vaccine, similar to responses seen in adults.

An impact of vitamin D in neurocognitive function has been theorized but it remains unknown whether vitamin-D insufficiency (VDI) is associated with worse socio-emotional adjustment (SEA) in vulnerable early school-aged children. This study examines the thesis that deficits in SEA are related to VDI using longitudinal data from 254 children that are perinatally HIV-infected (PHIV), exposed-uninfected (HEU), or unexposed-uninfected (HUU). In utero/peripartum antiretroviral (IPA) exposure was established per medical record documentation of biological mother&rsquo, s ART regimen in pregnancy. Four caregiver-reported age- and sex-standardized measures of SEA were obtained at months 0, 6, and 12 for dependent children aged 6&ndash, 10 years: externalizing problems (EPC), internalizing problems (IPC), behavioral symptoms index (BSI), and adaptive skills index (ASI). VDI was highly prevalent (74%, n = 188), and its association with change in SEA measures over 12 months varied by HIV-status (VDI*HIV, all p-values &lt, 0.03). There was further variation in relationship of vitamin-D to SEA by IPA among PHIV (for ASI, BSI, and EPC, vitamin-D*IPA, p-value &le, 0.01) and HEU (for BSI and EPC, vitamin-D*IPA, p-value &le, 0.04). Among HUU, BSI (&beta, = &minus, 0.32, 95% CI: &minus, 0.50, &minus, 0.13), IPC (&beta, 0.28, 95% CI: &minus, 0.47, &minus, 0.09), and EPC (&beta, 0.20, 95% CI: &minus, 0.37, &minus, 0.02) all declined moderately per quartile increment in VD. Among PHIV, on the one hand higher vitamin D predicted ASI gains (moderate vs. low VD, &beta, = 0.52, p = 0.002), but this protective association was absent for BSI, EPC, and IPC (&beta, = 0.36&ndash, 0.77, p &lt, 0.05). In absence of IPA-exposure, increasing vitamin-D predicted declines in BSI and EPC (moderate vs. low Vitamin D, &beta, 0.56 to &minus, 0.71, p &le, 0.02) among HEU. However, given IPA exposure among HEU, higher VDI predicted moderate elevation in BSI (&beta, = 0.39, 95% CI: 0.00, 0.78) and IPC (&beta, = 0.48, 95% CI: 0.05, 0.92). Interaction between VD and IPA exposure for SEA outcomes among HEU and PHIV children warrants further investigation. The vitamin-D associated SEA improvement among HUU and HEU without IPA exposure suggests vitamin-D supplementation may remediate behavioral and adaptive deficits in this groups.

HIV-infected infants usually have homogenous viral populations, suggesting that one or a few HIV variants initiate the infection [1]. Several factors promote rapid evolution of HIV viruses following infection, including the short half-life of HIV virions, the large number of virions in an infected individual (large viral population size), lack of proof-reading by HIV reverse transcriptase, and frequent viral recombination [2]. Children with established HIV infection generally harbor diverse viral populations [3]. The high level of viral diversity and the capacity of HIV to evolve rapidly in response to selective pressures can complicate HIV treatment [4, 5]. To date, studies of HIV diversity in HIV-infected infants and children have been limited because of the time, effort, and cost associated with analyzing sequences from individual HIV variants. We recently developed a rapid assay for analysis of HIV diversity that is based on high resolution melting (HRM) of DNA duplexes [6]. The HRM diversity assay uses the LightScanner instrument (Idaho Technology, Inc., Salt Lake City, UT) to measure the range of melting temperatures for DNA duplexes amplified from HIV. The assay provides a simple, single numeric measure of the level of genetic diversity in each region analyzed, which we refer to as the HRM score [6]. DNA duplexes with different sequences have different melting properties, and DNA heteroduplexes also have unique melting characteristics. In the HRM diversity assay, more diverse DNA populations (e.g., amplicons from more diverse HIV populations in clinical samples) melt over a broader range of temperatures, which is reflected in higher HRM scores. Our recent work demonstrates that the HRM diversity assay can detect single base mutations that are present at levels as low as 5% in plasmid mixtures, and can also detect insertions and deletions at low levels [7]. The HRM diversity assay is highly reproducible [8], and HRM scores are significantly associated with sequence-based measures of HIV diversity obtained from analysis of cloned HIV DNA [6] and next generation sequencing [9]. This assay facilitates studies of factors associated with HIV diversity and diversification in different regions of the viral genome. In a previous study, we used the HRM diversity assay to compare the level of diversity in the HIV gag region in HIV-infected Ugandan infants and their mothers [6]. That study confirmed that the viral populations in 6–8 week old HIV-infected infants were very homogeneous [6]. In a subsequent study, we used the HRM diversity assay to analyze diversity in three regions of the HIV genome (two regions in HIV gag and one region in HIV pol) in 31 HIV-infected Ugandan infants 6 weeks to 18 months of age. Higher HRM scores in all three regions were associated with older age, demonstrating diversification of the virus in these regions over time following infection. Furthermore, higher HRM scores at 6–8 weeks of age (scores above the 75th percentile) were associated with a significantly increased risk of death by 5 years of age [8]. In this report, we examined HIV diversity in the gag, pol, and env regions in 76 Ugandan children from 0.6 to 12.4 years of age who were enrolled in an observational study of antiretroviral therapy (ART). We analyzed the association of pre-treatment HRM scores with age (as a surrogate for the duration of HIV infection), the relationship between HIV diversity and treatment outcome, and the impact of exposure to non-suppressive ART on HIV diversity.

Background There are few data on tuberculosis (TB) incidence in HIV-infected children on antiretroviral therapy (ART). Observational studies suggest co-trimoxazole prophylaxis may prevent TB, but there are no randomized data supporting this. The ARROW trial, which enrolled HIV-infected children initiating ART in Uganda and Zimbabwe and included randomized cessation of co-trimoxazole prophylaxis, provided an opportunity to estimate the incidence of TB over time, to explore potential risk factors for TB, and to evaluate the effect of stopping co-trimoxazole prophylaxis. Methods Of 1,206 children enrolled in ARROW, there were 969 children with no previous TB history. After 96 weeks on ART, children older than 3 years were randomized to stop or continue co-trimoxazole prophylaxis; 622 were eligible and included in the co-trimoxazole analysis. Endpoints, including TB, were adjudicated blind to randomization by an independent endpoint review committee (ERC). Crude incidence rates of TB were estimated and potential risk factors, including age, sex, center, CD4, weight, height, and initial ART strategy, were explored in multivariable Cox proportional hazards models. Results After a median of 4 years follow-up (3,632 child-years), 69 children had an ERC-confirmed TB diagnosis. The overall TB incidence was 1.9/100 child-years (95 % CI, 1.5–2.4), and was highest in the first 12 weeks following ART initiation (8.8/100 child-years (5.2–13.4) versus 1.2/100 child-years (0.8–1.6) after 52 weeks). A higher TB risk was independently associated with younger age (

International audience; BACKGROUND: Strategies to prevent postnatal mother-to-child transmission of HIV-1 in Africa, including infant prophylaxis, have never been assessed past 6 months of breastfeeding, despite breastfeeding being recommended up to 12 months after birth. We aimed to compare the efficacy and safety of infant prophylaxis with the two drug regimens (lamivudine or lopinavir-ritonavir) to prevent postnatal HIV-1 transmission up to 50 weeks of breastfeeding.METHODS: We did a randomised controlled trial in four sites in Burkina Faso, South Africa, Uganda, and Zambia in children born to HIV-1-infected mothers not eligible for antiretroviral therapy (CD4 count >350 cells per μL). An independent researcher electronically generated a randomisation schedule; we then used sequentially numbered envelopes to randomly assign (1:1) HIV-1-uninfected breastfed infants aged 7 days to either lopinavir-ritonavir or lamivudine (paediatric liquid formulations, twice a day) up to 1 week after complete cessation of breastfeeding or at the final visit at week 50. We stratified the randomisation by country and used permuted blocks of four and six. We used a study label on drug bottles to mask participants, study physicians, and assessors to the treatment allocation. The primary outcome was infant HIV-1 infection between age 7 days and 50 weeks, diagnosed every 3 months with HIV-1 DNA PCR, in the modified intention-to-treat population (all who attended at least one follow-up visit). This trial is registered with ClinicalTrials.gov, number NCT00640263.FINDINGS: Between Nov 16, 2009, and May 7, 2012, we enrolled and randomised 1273 infants and analysed 1236; 615 assigned to lopinavir-ritonavir or 621 assigned to lamivudine. 17 HIV-1 infections were diagnosed in the study period (eight in the lopinavir-ritonavir group and nine in the lamivudine group), resulting in cumulative HIV-1 infection of 1.4% (95% CI 0.4-2.5) and 1.5% (0.7-2.5), respectively. Infection rates did not differ between the two drug regimens (hazard ratio [HR] of lopinavir-ritonavir versus lamivudine of 0.90, 95% CI 0.35-2.34; p=0.83). Clinical and biological severe adverse events did not differ between groups; 251 (51%) infants had a grade 3-4 event in the lopinavir-ritonavir group compared with 246 (50%) in the lamivudine group.INTERPRETATION: Infant HIV-1 prophylaxis with lopinavir-ritonavir was not superior to lamivudine and both drugs led to very low rates of HIV-1 postnatal transmission for up to 50 weeks of breastfeeding. Infant pre-exposure prophylaxis should be extended until the end of HIV-1 exposure and mothers should be informed about the persistent risk of transmission throughout breastfeeding.FUNDING: INSERM/National Agency for Research on AIDS and Viral Hepatitis (including funds from the Total Foundation), European Developing Countries Clinical Trials Partnership, Research Council of Norway.

BackgroundHIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed.MethodsThirty-one children from Malawi aged 4-62 months were followed every 3 months and at intercurrent illness visits for ≤47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor.ResultsWe found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03).ConclusionsLPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings.Trial registrationClinicalTrials.gov NCT00719602.

Background. In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission. Methods. Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks. Results. The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%–7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%–5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%–6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%–3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P

To investigate the effect of subsequent pregnancies on HIV disease progression among HIV-infected women at Mulago Hospital, Uganda.In a retrospective cohort study, data were analyzed from women enrolled in the Mother-To-Child Transmission Plus program from March 2003 to December 2011. The CD4 cell count, the development of new AIDS-defining opportunistic infections, and the AIDS-related mortality were compared between women with and without subsequent pregnancies.Overall, 409 women were enrolled and 195 (47.7%) had subsequent pregnancies. Antiretroviral therapy (ART) was initiated in 143 (73.3%) women with and 155 (72.4%) women without subsequent pregnancies. Kaplan-Meier analysis for women receiving ART showed no differences between women with and without subsequent pregnancies in the median times to clinical failure (62.7 vs 64.7 months; P=0.31), immunological failure (68.8 vs 75.5 months; P=0.10), and death (68.8 vs 75.5 months; P=0.53). In a Cox regression analysis, subsequent pregnancies were not associated with immunological failure during follow-up (adjusted hazard ratio 1.13, 95% confidence interval 0.06-2.09).Subsequent pregnancies could have no detrimental effect on HIV disease progression among HIV-infected women whose treatment is well managed.

BACKGROUND This phase III, randomized, clinical trial compared single-dose nevirapine (sdNVP) plus HIV hyperimmune globulin (HIVIGLOB) with sdNVP alone for preventing maternal-to-child transmission of HIV. Primary objectives were to determine rates of HIV infection among infants and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants. METHODS Mother-infant pairs were randomized to receive 200 mg of nevirapine to women in labor and 2 mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240-mL dose of HIVIGLOB given to women at 36- to 38-week gestation and a single intravenous 24-mL dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6, and 12 months of age. RESULTS Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm vs. the sdNVP arm [18.7% vs. 15.0%; risk ratio = 1.240 (95% confidence interval: 0.833 to 1.846); P = 0.290]. Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively, for mothers (18.9% vs. 19.3%; P = 0.91) and infants (62.6% vs. 59.5%; P = 0.51) was not significantly different. CONCLUSIONS Giving mother-infant pairs an infusion of peripartum HIV hyperimmune globulin in addition to sdNVP for preventing maternal-to-child transmission was as safe as sdNVP alone but was no more effective than sdNVP alone in preventing HIV transmission.

HIV viruses are usually genetically homogeneous shortly after infection, and become more heterogeneous over time. We developed a high-resolution melting (HRM) assay to analyze HIV diversity without sequencing. Plasma samples from the HIVNET 012 trial were obtained from nine Ugandan mother–infant pairs. DNA amplified from the HIV gag region was analyzed to determine the number of degrees over which the DNA melted (HRM score). HRM gag DNA was also cloned and sequenced (50 clones/mother; 20 clones/infant). The median HRM score for infants (4.3, range 4.2–5.3) was higher than that for control plasmids (3.4, range 3.2–3.8, p

To determine the utility of total lymphocyte count (TLC) in predicting the 12-month mortality in HIV-infected Ugandan children and to correlate TLC and CD4 cell %.This is a retrospective data analysis of clinical and laboratory data collected prospectively on 128 HIV-infected children in the HIV Network for Prevention Trials 012 trial.TLC and CD4 cell % measurements were obtained at birth, 14 weeks, and 12, 24, 36, 48, and 60 months of age and assessed with respect to risk of death within 12 months.Median TLC per microliter (CD4 cell %) was 4150 (41%) at birth, 4900 (24%) at 12 months, 4300 (19%) at 24 months, 4150 (19%) at 36 months, 4100 (18%) at 48 months, and 3800 (20%) at 60 months. The highest risk of mortality within 12 months was 34% - 37% at birth and declined to 13%-15% at 24 months regardless of TLC measurement. The correlation between CD4 cell % and TLC was extremely low overall (r = 0.01).The TLC did not predict a risk of progression to death within 12 months in HIV-infected Ugandan children. Therefore, TLC alone may not be a useful surrogate marker for determining those children at highest risk of death, who require antiretroviral therapy most urgently.

Background. Single-dose nevirapine (SD NVP) at birth plus NVP prophylaxis for the infant up to 6 weeks of age issuperiortoSDNVPaloneforpreventionofverticaltransmissionofhumanimmunodeficiencyvirus(HIV)through breastfeeding. We analyzed NVP resistance in HIV-infected Ugandan infants who received either SD NVP or extended NVP prophylaxis. Methods. We tested plasma HIV by using a genotyping assay (ViroSeq; Celera Diagnostics), a phenotypic resistance assay (PhenoSense; Monogram Biosciences), and sensitive point mutation assay (LigAmp, for K103N, Y181C, and G190A). Results. Wheninfantswere6weeksold,ViroSeqdetectedNVPresistanceinahigherproportionofinfantsinthe extended NVP arm than in the SD NVP arm (21 of 25 [84%] vs. 12 of 24 [50%]; P .01). Similar results were obtained with LigAmp and PhenoSense. In both study arms, infants who were HIV infected at birth frequently had NVP resistance detected. In contrast, infants in the extended NVP arm who were HIV infected after birth were more likely to have resistance detected at 6 weeks, compared with infants in the SD NVP arm. The use of extended NVP prophylaxiswasalsoassociatedwithdetectionofNVPresistancebyViroSeqat6months(7of7[100%]infantsinthe extended NVP arm had resistance detected, compared with 1 of 6 [16.7%] infants in the SD NVP arm; P .005). Conclusions. TheuseofextendedNVPprophylaxiswasassociatedwithincreasedselectionforandpersistenceof NVP resistance in HIV-infected Ugandan infants. Single-dose nevirapine (SD NVP) can reduce the risk of mother-to-child transmission (MTCT) of HIV [1, 2] but may lead to the emergence of resistant variants in infants who are HIV infected despite prophylaxis. After exposure to SD NVP, 46% of Ugandan infants [3] and 87%ofMalawianinfants[4]whowereHIVinfectedhad NVP-resistant variants detected in plasma samples ob

Human immunodeficiency virus type 1 (HIV-1) may utilize the CXCR4 coreceptor (X4 virus) the CCR5 coreceptor (R5 virus) or both (dual/mixed [DM] virus). We analyzed HIV-1 coreceptor tropism in Ugandan infants enrolled in the HIVNET (HIV Network for Prevention Trials) 012 trial. Plasma or serum was analyzed using a commercial coreceptor tropism assay. HIV env subtype was determined by phylogenetic methods. Tropism results were obtained for 57 samples from infants collected 6-14 weeks after birth. Fifty-two infants had only R5 virus and 5 had either X4 or DM virus. The mothers of those 5 infants also had X4 or DM virus. In infants subtype D infection was associated with high-level infectivity in CCR5-bearing cells and also with the detection of X4 or DM strains. High-level infectivity in CCR5-bearing cells was associated with decreased infant survival but infection with X4 or DM virus was not. HIV clones from infants with DM viral populations showed different patterns of coreceptor use. V3 loop sequence-based algorithms predicted the tropism of some but not all env clones. Complex patterns of HIV tropism were found in HIV-infected newborn infants. Subtype D infection was associated with X4 virus and with high-level replication in CCR5-bearing cells. High-level replication of R5 virus was associated with decreased infant survival. (authors)

Objective To determine costs for adverse event (AE) procedures for a large HIV perinatal trial by analyzing actual resource consumption using activity-based costing (ABC) in an international research setting. Methods The AE system for an ongoing clinical trial in Uganda was evaluated using ABC techniques to determine costs from the perspective of the study. Resources were organized into cost categories (eg, personnel, patient care expenses, laboratory testing, equipment). Cost drivers were quantified, and unit cost per AE was calculated. A subset of time and motion studies was performed prospectively to observe clinic personnel time required for AE identification. Results In 18 months, there were 9028 AEs, with 970 (11%) reported as serious adverse events. Unit cost per AE was $101.97. Overall, AE-related costs represented 32% ($920,581 of $2,834,692) of all study expenses. Personnel ($79.30) and patient care ($11.96) contributed the greatest proportion of component costs. Reported AEs were predominantly nonserious (mild or moderate severity) and unrelated to study drug(s) delivery. Conclusions Intensive identification and management of AEs to conduct clinical trials ethically and protect human subjects require expenditure of substantial human and financial resources. Better understanding of these resource requirements should improve planning and funding of international HIV-related clinical trials.

In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from ∼20% in early infection to ∼50% in advanced disease. Coreceptor use by non-subtype B HIV is less well characterized. We studied coreceptor tropism of subtype A and D HIV-1 collected from 68 pregnant, antiretroviral drug-naive Ugandan women (HIVNET 012 trial). None of 33 subtype A or 10 A/D-recombinant viruses used the CXCR4 coreceptor. In contrast, nine (36%) of 25 subtype D viruses used both CXCR4 and CCR5 coreceptors. Clonal analyses of the nine subtype D samples with dual or mixed tropism revealed heterogeneous viral populations comprised of X4-, R5-, and dual-tropic HIV-1 variants. In five of the six samples with dual-tropic strains, V3 loop sequences of dual-tropic clones were identical to those of cocirculating R5-tropic clones, indicating the presence of CXCR4 tropism determinants outside of the V3 loop. These dual-tropic variants with R5-tropic-like V3 loops, which we designated “dual-R,” use CCR5 much more efficiently than CXCR4, in contrast to dual-tropic clones with X4-tropic-like V3 loops (“dual-X”). These observations have implications for pathogenesis and treatment of subtype D-infected individuals, for the association between V3 sequence and coreceptor tropism phenotype, and for understanding potential mechanisms of evolution from exclusive CCR5 use to efficient CXCR4 use by subtype D HIV-1.

Non-adherence reduces the effectiveness of antiretroviral therapy in children attending the paediatric HIV/AIDS clinic at Mulago Hospital, Kampala.To determine the levels of adherence to HAART and identify factors associated with non-adherence.A cross-sectional study of 170 children aged 2-18 years. Adherence to HAART was defined as takingor =95% of prescribed medication. It was determined using three measures: a 3-day self-report by the caregivers, clinic-based pill counts at enrolment and home-based unannounced pill counts 2-3 weeks later.The 3-day self-reportedor =95% adherence was 89.4% (n=170). Using clinic-based pill counts, 94.1% (n=170) hador =95% adherence to treatment compared with only 72% (n=164) by unannounced pill counts. When the primary caregiver was the only one who knew the child's serostatus, he/she was three times more likely to be non-adherent (p=0.02, OR 3.34, 95% CI 1.14-9.82). Those who had been hospitalised twice or more before starting HAART were more likely to haveor =95% adherence (p=0.02, OR 0.44, 95% CI 0.20-0.92).The majority of children had good adherence levels when estimated by unannounced pill counts. Disclosing the child's HIV serostatus only to the primary caregiver and having been hospitalised only once or not at all were associated with poor adherence.

Background The global tuberculosis (TB) estimate in 2011 was 500,000 cases among children under 15 years representing 5.7 % of all cases and 64, 000 deaths among HIV negative children representing 6.5 % of the total deaths. In Uganda, the child TB cases reported in 2012 made up less than 3 % of the total cases while recent modelling estimates it at 15–20 % of adult cases. Mapping of these cases in Kampala district most especially for the children under five years would reflect recent transmission in the various communities in the district. We therefore conducted a retrospective study of reported child TB cases in Kampala district Uganda for 2009–2010 to provide an estimate of child TB incidence and map the cases. Methods This was a retrospective cross-sectional study on data collected from the health unit TB registers in the five divisions of Kampala district, Uganda. The data was a starting point in preparation for a TB Vaccine study in children. The extracted data spanned a period from 1st January 2009 to 31st December 2010. The projected population of children below 15 years was 637,922 in 2009 and 744,750 in 2010 for Kampala district. We based our projections on the National Bureau of Statistics most recent census report of 2002 before the study duration while assuming a population growth rate of 3.7 % each year. We captured the data into EPI DATA 3.1 and analysed it using STATA version 12. Results We accessed 15,499 records and analysed 1167 records that were of children below 15 years old. The child TB cases represented 7.5 % (7.3 in 2009 & 7.6 % in 2010) of all the registered cases in Kampala district. The females were 47 % and the median age was 4 years (IQR 1, 10). The percent of children less than 5 years old was 54 %. The percent of pulmonary TB cases was 89 % (1041/1167) with 15 % smear positive. The proportion of extra-pulmonary TB cases was 11 % (126/1167). Among those that tested for HIV, 60 % (359/620) had test results available with an HIV co-infection rate of 47 % (168/359). Antiretroviral treatment uptake was 24 % among the co-infected. The incidence of child TB in Kampala was 56 (95 % CI 50–62) per 100,000 in 2009 and 44 (95 % CI 40–49) per 100,000 in 2010. Most of the TB cases (60 % (410/685)) in Kampala live in slum areas. Conclusion There was a higher child TB incidence of 56 per 100,000 in 2009 compared with 44 per 100,000 in 2010. The percentage of child TB cases was much higher at 7.5 % of all the reported TB cases than the WHO reported national average. For the review period, the TB cases clustered in particular slums in Kampala district.

OBJECTIVES: To assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children ( 0.3) or NNRTIs (P > 0.1) (n = 88) at week 144. CONCLUSION: Given the limited global availability of lopinavir/ritonavir, its significant formulation challenges in young children, and the significant paediatric treatment gap, tablet fixed-dose-combination NVP-based ART remains a good alternative to syrup lopinavir-based ART for children, particularly those over 1 year and even if exposed to sdNVP.This is an open access article distributed under the Creative Commons Attribution-Non Commercial License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.