Differences in body circumferences, skin-fold thicknesses and lipid profiles among HIV-infected African children on and not on stavudine

Purpose of the study To compare body circumferences, skin-fold thickness (SFT) and lipid levels (LL), as measures of lipodystrophy, among antiretroviral therapy (ART)-naïve and experienced children at enrolment into the CHAPAS-3 trial. Methods HIV-infected children in Uganda and Zambia, either ART-naïve or on stavudine (d4T) for ≥2 years without clinical lipodystrophy, were randomised to receive d4T, abacavir (ABC) or zidovudine (ZDV) with lamivudine and efavirenz (EFV) or nevirapine. At enrolment, mid-upper arm (MUAC) and calf (CC) circumferences, SFT (biceps, triceps, sub-scapular, supra-iliac) and fasting lipids (total cholesterol (TC), low density lipo-protein (LDL), high density lipoprotein (HDL), triglycerides (TRIG)) were measured. Age/sex adjusted z-scores of MUAC, CC, SFT and the sum of SFT (SSF) used Dutch reference data. ART-naïve and ART-experienced children were compared with t-tests using Stata v11.0. Summary of results Among 444 children, 224 (51%) were male and 331 (74.5%) ART-naïve. Mean (sd) CD4% was 19.7% (10.2) versus (vs) 34.2% (7.7) in ART-naïve vs ART-experienced children. The ART-naïve were younger than the ART-experienced children (median [IQR] age 2.5 [1.5, 4.0] vs 6.0 [5.5, 7.0] years, p<0.0001). Among the ART-experienced, 4/108 (3.7%) were on EFV and median (IQR) d4T use was 3.5 (2.7, 4.2) years. As expected, MUAC, CC, weight-for-age (WAZ) and height-for-age (HAZ) z-scores were lower in the ART-naïve; the ART-experienced had lower SFT z-scores and higher TC and HDL, but lower TRIG (Table 1). Conclusions Failure-to-thrive likely contributed to lower circumference values in ART-naïve children. Among the ART-experienced, thinner SFT and higher TC values could be ART (particularly d4T)-related. Normal values, currently unavailable for African children, are being collected. During trial follow-up, we will evaluate the effect of ABC, ZDV and d4T on development of lipodystrophy in naïve children and its reversibility in d4T-treated children randomised to switch to ZDV/ABC

Replication Fork Polarity Gradients Revealed by Megabase-Sized U-Shaped Replication Timing Domains in Human Cell Lines

In higher eukaryotes, replication program specification in different cell types remains to be fully understood. We show for seven human cell lines that about half of the genome is divided in domains that display a characteristic U-shaped replication timing profile with early initiation zones at borders and late replication at centers. Significant overlap is observed between U-domains of different cell lines and also with germline replication domains exhibiting a N-shaped nucleotide compositional skew. From the demonstration that the average fork polarity is directly reflected by both the compositional skew and the derivative of the replication timing profile, we argue that the fact that this derivative displays a N-shape in U-domains sustains the existence of large-scale gradients of replication fork polarity in somatic and germline cells. Analysis of chromatin interaction (Hi-C) and chromatin marker data reveals that U-domains correspond to high-order chromatin structural units. We discuss possible models for replication origin activation within U/N-domains. The compartmentalization of the genome into replication U/N-domains provides new insights on the organization of the replication program in the human genome

Evidence for Sequential and Increasing Activation of Replication Origins along Replication Timing Gradients in the Human Genome

Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains of coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wide analysis of DNA replication kinetics in several human cell types that contradicts this view. DNA combing in HeLa cells sorted into four temporal compartments of S phase shows that replication origins are spaced at 40 kb intervals and fire as small clusters whose synchrony increases during S phase and that replication fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains constant and narrowly distributed through S phase. However, multi-scale analysis of a genome-wide replication timing profile shows a broad distribution of replication timing gradients with practically no regions larger than 100 kb replicating at less than 2 kb/min. Therefore, HeLa cells lack large regions of unidirectional fork progression. Temporal transition regions are replicated by sequential activation of origins at a rate that increases during S phase and replication timing gradients are set by the delay and the spacing between successive origin firings rather than by the velocity of single forks. Activation of internal origins in a specific temporal transition region is directly demonstrated by DNA combing of the IGH locus in HeLa cells. Analysis of published origin maps in HeLa cells and published replication timing and DNA combing data in several other cell types corroborate these findings, with the interesting exception of embryonic stem cells where regions of unidirectional fork progression seem more abundant. These results can be explained if origins fire independently of each other but under the control of long-range chromatin structure, or if replication forks progressing from early origins stimulate initiation in nearby unreplicated DNA. These findings shed a new light on the replication timing program of mammalian genomes and provide a general model for their replication kinetics

The cost‐effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa

Introduction Many HIV‐positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced‐prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 <100 cells/mm3. We investigated the cost‐effectiveness of this enhanced‐prophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4 <200 cells/mm3 or <100 cells/mm3 at ART initiation and all individuals regardless of CD4 count. Methods The REALITY trial enrolled from June 2013 to April 2015. A decision‐analytic model was developed to estimate the cost‐effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard‐prophylaxis, enhanced‐prophylaxis, standard‐prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced‐prophylaxis (CrAg‐positive) or standard‐prophylaxis (CrAg‐negative), the second to enhanced‐prophylaxis (CrAg‐positive) or enhanced‐prophylaxis without fluconazole (CrAg‐negative) and the third to standard‐prophylaxis with fluconazole (CrAg‐positive) or without fluconazole (CrAg‐negative). The model estimated costs, life‐years and quality‐adjusted life‐years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results Enhanced‐prophylaxis was cost‐effective at cost‐effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost‐effectiveness ratio (ICER) of US$157 per QALY in the CD4 <200 cells/mm3 population providing enhanced‐prophylaxis components are sourced at lowest available prices. The ICER reduced in more severely immunosuppressed individuals (US$113 per QALY in the CD4 <100 cells/mm3 population) and increased in all individuals regardless of CD4 count (US$722 per QALY). Results were sensitive to prices of the enhanced‐prophylaxis components. Enhanced‐prophylaxis was more effective and less costly than all CrAg testing strategies as enhanced‐prophylaxis still conveyed health gains in CrAg‐negative patients and savings from targeting prophylaxis based on CrAg status did not compensate for costs of CrAg testing. CrAg testing strategies did not become cost‐effective unless the price of CrAg testing fell below US$2.30. Conclusions The REALITY enhanced‐prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost‐effective. Efforts should continue to ensure that components are accessed at lowest available prices

Late presentation with HIV in Africa : phenotypes, risk, and risk stratification in the REALITY trial

REALITY was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development, the Wellcome Trust, and Medical Research Council (MRC) (grant number G1100693). Additional funding support was provided by the PENTA Foundation and core support to the MRC Clinical Trials Unit at University College London (grant numbers MC_UU_12023/23 and MC_UU_12023/26). Cipla Ltd, Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, and Merck Sharp & Dohme donated drugs for REALITY, and ready-to-use supplementary food was purchased from Valid International. A. J. P. is funded by the Wellcome Trust (grant number 108065/Z/15/Z). J. A. B. is funded by the JGHTS (grant number MR/M007367/1). The Malawi-Liverpool–Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine (grant number 101113/Z/13/Z) and the Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Kilifi (grant number 203077/Z/16/Z) are supported by strategic awards from the Wellcome Trust, United Kingdom. Permission to publish was granted by the Director of KEMRI. This supplement was supported by funds from the Bill & Melinda Gates Foundation.Background. Severely immunocompromised human immunodefciency virus (HIV)-infected individuals have high mortality shortly afer starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes. Methods. Te Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children =5 years of age with CD4 counts .1). Results. Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P <.04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P =.02). Of fve late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/μL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/μL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/μL), but low symptom burden and maintained fat mass. Te remaining groups had 4%-6% mortality. Conclusions. Clinical and laboratory features identifed groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up.Peer reviewe

Mapping the medical outcomes study HIV health survey (MOS-HIV) to the EuroQoL 5 Dimension (EQ-5D-3L) utility index

10.1186/s12955-019-1135-8Health and Quality of Life Outcomes1718

Predictors of Unintended Pregnancy Among Adolescent Girls During the Second Wave of COVID-19 Pandemic in Oyam District in Northern Uganda

Background: In Uganda, unintended pregnancies are responsible for one in three births with detrimental consequences, a situation that worsened during COVID-19. Thus, the present examined unplanned pregnancy and its associated risks in Oyam district, northern Uganda during the COVID-19 epidemic. Methods and Methods: This study employed a cross-sectional study among adolescent girls aged 15– 19 years who had a pregnancy during the second phase of COVID-19 in Oyam district, northern Uganda in November 2022. A consecutive method was employed to recruit the participants attending health facilities. A structured questionnaire was utilized to collect data. For data analysis, both bivariate and multivariable regression methods with adjusted odds ratio and 95% CI were used. A p-value of 0.05 was used to determine the significance level. Results: Of the total respondents, 292 (69.5%) were aged between 18 and 19 years of age, 295 (70.2%) lived in rural areas, and 222 (52.9%) had no formal education. The results also show that 293 (69.8%) of the respondents had unintended pregnancies during COVID-19. The results indicate that participants who lacked knowledge of the ovulation period (AOR: 0.242; 95% CI: 0156– 0376; P< 0.001), sex education during COVID-19 (AOR: 0.563; 95% CI:: 0.365– 0.869; P=0.024) and lacked the freedom to discuss family planning-related issues with family members during COVID-19 (AOR: 0.228; 95% CI: 0.138– 0.376; P< 0.001) were more likely to have an unintended pregnancy compared to their counterparts. Conclusion: Our study shows that unwanted pregnancies among adolescent girls remain a public health issue in Oyam district with more than two-thirds of adolescents having unwanted pregnancies during the crisis of COVID-19. The major correlates of unwanted pregnancies among adolescent girls during COVID-19 pandemic were inadequate knowledge of the ovulation period, sex education, and lack of freedom to discuss family planning-related issues with family members. There is a need to prioritize interventions, especially in rural settings. Sex education to improve contraceptive use and delay sexual debut. In light of the possibility that social and cultural norms in the Oyam district prohibit parents and children from discussing sexual subjects, it is crucial to promote sexual health education through the mass media, including newspapers, television, radio, and social media