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Human immunodeficiency virus (HIV) infection remains a significant public health burden globally. The role of viral co-infection in the rate of progression of HIV infection has been suggested but not empirically tested, particularly among children. We extracted and classified 42 viral species from whole-exome sequencing (WES) data of 813 HIV-infected children in Botswana and Uganda categorised as either long-term non-progressors (LTNPs) or rapid progressors (RPs). The Ugandan participants had a higher viral community diversity index compared to Batswana (p = 4.6 × 10−13), and viral sequences were more frequently detected among LTNPs than RPs (24% vs 16%; p = 0.008; OR, 1.9; 95% CI, 1.6–2.3), with Anelloviridae showing strong association with LTNP status (p = 3 × 10−4; q = 0.004, OR, 3.99; 95% CI, 1.74–10.25). This trend was still evident when stratified by country, sex, and sequencing platform, and after a logistic regression analysis adjusting for age, sex, country, and the sequencing platform (p = 0.02; q = 0.03; OR, 7.3; 95% CI, 1.6–40.5). Torque teno virus (TTV), which made up 95% of the Anelloviridae reads, has been associated with reduced immune activation. We identify an association between viral co-infection and prolonged AIDs-free survival status that may have utility as a biomarker of LTNP and could provide mechanistic insights to HIV progression in children, demonstrating the added value of interrogating off-target WES reads in cohort studies.

Purpose: The Collaborative African Genomics Network (CAfGEN) aims to establish sustainable genomics research programs in Botswana and Uganda through long-term training of PhD students from these countries at Baylor College of Medicine. Here, we present an overview of the CAfGEN PhD training program alongside trainees’ perspectives on their involvement. Background: Historically, collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs), or North–South collaborations, have been criticized for the lack of a mutually beneficial distribution of resources and research findings, often undermining LMICs. CAfGEN plans to address this imbalance in the genomics field through a program of technology and expertise transfer to the participating LMICs. Methods: An overview of the training program is presented. Trainees from the CAfGEN project summarized their experiences, looking specifically at the training model, benefits of the program, challenges encountered relating to the cultural transition, and program outcomes after the first 2 years. Conclusion: Collaborative training programs like CAfGEN will not only help establish sustainable long-term research initiatives in LMICs but also foster stronger North–South and South–South networks. The CAfGEN model offers a framework for the development of training programs aimed at genomics education for those for whom genomics is not their “first language.” Genet Med advance online publication 06 April 2017

Objective: Despite existing evidence about the benefits of nutrition, physical activity (PA) and sport to the overall health and wellbeing of children, knowledge gaps remain on this relationship in children living with chronic conditions like HIV/AIDS. Such knowledge should inform context specific programs that could enhance the quality of life of children. The purpose of this study was to examine the effects of integrating a nutrition intervention (culturally tailored food supplement) into antiretroviral therapy (ART) on psychosocial outcomes and physical activity among HIV-positive children in Botswana. Method: 201 HIV-positive children (6–15 years; M = 9.44, SD = 2.40) were recruited and randomly assigned (stratified by age and gender) to two groups. The intervention group (n = 97) received a high protein (bean-sorghum plus micronutrients) food supplement, while the control group (n = 104) received a sorghum plus micronutrients supplement. Participants were followed over 12 months. Anthropometric measures, PA, motor performance, and health related quality of life (HRQL) were collected at baseline, 6 and 12 months. Results: Mixed repeated-measures ANOVA revealed a significant time effect of the food supplement on target variables except body fat percentage, speed, and school functioning. Time×treatment interaction was found for physical functioning, psyioning achosocial functnd total quality of life score. Scores on physical functioning and total of quality life in the intervention group significantly increased from baseline to 6 months compared with the control group (p = 0.015). Conclusion: A combination of ART and nutritional intervention had a positive effect on physical functioning and total quality of life of HIV-positive children in this study. There were also improvements to physical activity and motor performance tests over time. More research is needed on long term effects of nutrition and PA interventions on HRQL in children living with HIV.

Little is known about whether physical activity and fitness could enhance cognition in adolescents and young adults living with HIV. The purpose of this study was to examine this relationship in a group of 250 HIV+ (n = 88) and HIV negative (n = 162) participants from Botswana, aged 12–23 years (Mean = 17.87, SD = 2.24). Fitness was operationalized as muscular strength (push-ups) and aerobic endurance (PACER). PA was assessed using items from the Youth Risk Behavior Surveillance Survey. Cognition was measured using the Corsi Test, Berg Card Sorting Task (BCST), and Stroop Color Word Task (Stroop). Multiple regression analyses indicated that the HIV x push-ups interaction was a significant predictor of Corsi performance, and HIV status was a significant predictor of BCST performance (p

Background 1.8 million new HIV infections occur every year, disproportionately affecting adolescent girls and young women. Abstinence-only risk avoidance approaches have had limited impact on reducing new infections. This cluster-randomized trial examines a risk reduction approach to curbing risky sex for school-going girls in Botswana. Methods The unit of randomization was the school (n = 229). Intervention participants received a 1-h intervention revealing a safer sex option: dating same-age partners which have 5-9x lower HIV prevalence than older partners. Primary outcomes were pregnancy as a proxy for unprotected sex and HIV. Secondary outcomes included self-reported sexual behavior. Generalized linear multilevel models with school-level robust variance for adjusted relative risk ratios were used in an intention-to-treat analysis. Results At a 12-month follow up, the intervention reduced pregnancy with an adjusted Relative Risk Ratio (aRRR) of .657 [95% CI .433–.997] significant at the 5% level. Effects were largest at junior school (aRRR = .575 [95% CI .394–.841]) and in rural areas (aRRR = .518 [95% CI .323–.831]), significant at the 1% level. There were no significant effects for primary school students, suggesting age of sexual debut and related mechanisms are critical factors in the intervention’s effectiveness. Moreover, baseline beliefs of which partner is riskiest mediate the magnitude of effects. Conclusions Information on safe sex options can change sexual behavior. The success of the intervention working across contexts will depend on various factors, such as age of sexual debut and baseline beliefs. Trial registration Pan African Clinical Trials Registry PACTR201901837047199. Registered 31 December 2018. Retrospectively registered. This study adheres to CONSORT guidelines.

The objectives of this study were to examine differences in physical activity behaviors as a function of human immunodeficiency virus (HIV) status and sex, to test differences in physical activity self-efficacy (PASE), body weight satisfaction (BWS), and enjoyment of physical activity as a function of HIV status, and to determine if PASE, BWS, and enjoyment are associated with daily physical activity (daily PA), muscle strengthening activities, and sedentary behavior of youth with and without HIV. A total of 250 HIV positive (HIV+) and HIV negative (HIV-) youth from Botswana aged 12-23 years (Mean = 17.87, SD = 2.24) participated in the study. The HIV+ group (n = 88) was recruited from a previous 12-month antiretroviral therapy (ART) and nutrition intervention study. The HIV- group (n = 162) was randomly selected from public junior and senior (secondary) high schools in and around Gaborone. Participants' PASE, BWS, enjoyment of physical activity, daily PA, muscle strengthening, body mass index (BMI), and sedentary behavior were obtained using items from the Youth Risk Behavior Surveillance Survey. Multivariate analysis of variance (MANOVA) showed that the HIV- group (M = 1.20, SE = 0.06, CI = 1.08 to 1.32) had significantly higher daily PA than the HIV+ group (M = 0.99, SE = 0.08, CI = 0.82 to 1.15). The HIV- group (M = 0.91, SE = 0.06, CI = 0.79 to 1.03) also reported participating significantly more in muscle strengthening activities than the HIV+ group (M = 0.63, SD = 0.08, CI = 0.47 to 0.78). Multiple regression analyses showed that higher PASE (p < .001) and greater enjoyment of PA (p < .01) were predictive of higher daily PA. HIV- participants had higher PASE but lower BWS compared to HIV+ participants. Sex and age differences were observed in muscle strengthening activities and sedentary behavior. This study supports previous findings on the association of efficacy beliefs to daily PA and muscle strengthening activities. The findings have implications for PA interventions aimed at health promotion and mitigation of the effects of living with HIV/AIDS.

Pill counts with calculated adherence percentages are used in many settings to monitor adherence, but can be undermined by patients discarding pills to hide nonadherence. Pill counts suggesting that >100% of prescribed doses were taken can signal "pill dumping." We defined "overadherence" among a cohort of 300 HIV-infected adolescents as having greater than one-third of pill counts with >100% adherence during a year of follow-up. Apparent overadherence was more common in those with virologic failure than in those with suppressed viral loads (33% vs 13%, χ(2) P = 0.001). Pill count adherence repeatedly >100% may identify HIV-infected adolescents at increased risk of treatment failure.

Loss to follow-up (LTFU) is a critical factor in determining clinical outcomes in HIV treatment programs. Identifying modifiable factors of LTFU is fundamental for designing effective patient-retention interventions. We analyzed factors contributing to children LTFU from a treatment program to identify those that can be modified. A case-control study involving 313 children was used to compare the sociodemographic and clinical characteristics of children LTFU (cases) with those remaining in care (controls) at a large pediatric HIV care setting in Botswana. We traced children through caregiver contacts and those we found, we conducted structured interviews with patients' caregivers. Children

In adults living with HIV, pharmacy refill data are good predictors of virologic failure (VF). The utility of pharmacy refill data for predicting VF in adolescents has not been reported. We evaluated data from 291 adolescents on antiretroviral therapy. The main outcome measure was VF, defined as two consecutive HIV viral load measurements ≥ 400 copies/mL during 24-months of follow-up. Pharmacy refill non-adherence was defined as two consecutive refill adherence measurements

Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in “real-life” settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5–5.2) years for the total cohort and 6.4 (3.6–8.0) years in Europe, 3.7 (2.0–5.4) years in North America, 2.5 (1.2–4.4) years in South and Southeast Asia, 5.0 (2.7–7.5) years in South America and the Caribbean, and 2.1 (0.9–3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3–2.1) years in North America to 7.1 (5.3–8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4–2.6) years in North America to 7.9 (6.0–9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%–2.8%), 15.6% (15.1%–16.0%), and 11.3% (10.9%–11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%–1.1%]) and highest in South America and the Caribbean (4.4% [3.1%–6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%–6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%–13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose The purpose of this study was to determine whether diary-driven adjustment of Medication Event Monitoring System (MEMS) data based on Supporting Information strengthens the relationship between measured antiretroviral medication adherence and plasma HIV viral load (VL). Methods HIV+ adolescents on antiretroviral treatment were monitored with MEMS for 30 days preceding a VL measurement. The primary outcome was VL ≥ 400 copies/mL. Handwritten diaries were used to comprehensively record deviations from recommended use (bottle opened but dose not taken or bottle not opened and dose taken). Data were adjusted (“cleaned”) based on diary events. Data were “capped” at the prescribed number of doses/day. Receiver operator characteristic analysis compared the relationships between (i) raw MEMS data, (ii) diary-cleaned, (iii) capped, or (iv) cleaned and capped MEMS data and VL. Results Over 30 days preceding VL measurements, 273 adolescents had 465 diary events. Capping resulted in fewer patients classified as 95% adherent (65.2%) compared with raw data (71.4%), p

BACKGROUND Seizures are common among patients with HIV/AIDS in the developing world and are associated with significant morbidity and mortality. Early treatment with combination antiretroviral therapy (cART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. METHODS A case-control study of new-onset epilepsy among children aged 0-18 years with perinatally acquired HIV/AIDS followed in Gaborone, Botswana, during the period 2003-2009 was conducted. Children with epilepsy were identified and compared with age- and sex-matched controls without epilepsy with respect to timing of cART initiation. Early treatment was defined as treatment with cART before the age of 12 months, at a CD4% of greater than 25 in children aged 1-5 years, or at an absolute CD4 count of >350 cell per cubic millimeter in children aged 5 years and older. RESULTS We identified 29 cases of new-onset epilepsy and 58 age- and sex-matched controls. The most common identified etiologies for epilepsy were central nervous system infections and direct HIV neurotoxicity. Only 8 (28%) of the children who developed epilepsy received early treatment compared with 31 (53%) controls (odds ratio: 0.36, 95% confidence interval: 0.14 to 0.92, P = 0.03). This effect was primarily driven by differences in rates of epilepsy among children who initiated treatment with cART between the ages of 1 and 5 years (11% vs. 53%, odds ratio: 0.11, 95% confidence interval: 0.01 to 1.1, P = 0.06). CONCLUSIONS Earlier initiation of cART may be protective against epilepsy in children with HIV.

In the optional extension of clinical trial 1100.1518 39/40, human immunodeficiency virus-infected patients (aged 3 to

Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana—a Southern African country that is regionally underrepresented in genomic databases. Using whole-exome sequencing data from 164 Batswana and comparisons with 150 similarly sequenced HIV-positive Ugandan children, we found that 13%–25% of variation observed among Batswana was not captured by public databases. Uncaptured variants were significantly enriched (p = 2.2 × 10−16) for coding variants with minor allele frequencies between 1% and 5% and included predicted-damaging non-synonymous variants. Among variants found in public databases, corresponding allele frequencies varied widely, with Botswana having significantly higher allele frequencies among rare (

Levels of adherence to HIV treatment are lower among adolescents compared with older and younger individuals receiving similar therapies. We purposely sampled the most and least adherent adolescents from a 300-adolescent longitudinal HIV treatment adherence study in Gaborone, Botswana. Multiple objective and subjective measures of adherence were available and study participants were selected based on sustained patterns of either excellent or poor adherence over a one-year period. Focus group discussions (FGD) and in-depth interviews (IDI) were conducted with the adolescents and a subset of their caregivers with the goal of revealing barriers and facilitators of adherence. Focus groups were segregated by adherence classification of the participants. Following coding of transcripts, matrices were developed based on participants' adherence classifications in order to clarify differences in themes generated by individuals with different adherence characteristics. 47 adolescents and 25 adults were included. The non-adherent adolescents were older than the adherent adolescents (median age 18 years (IQR 16-19) vs. 14 years (IQR 12-15 years)), with median time on treatment near 10 years in both groups. Interference with daily activities, concerns about stigma and discrimination, side effects, denial of HIV status, and food insecurity arose as challenges to adherence among both those who were consistently adherent and those who were poorly-adherent to their medications. Low outcome expectancy, treatment fatigue, mental health and substance use problems, and mismatches between desired and received social support were discussed only among poorly adherent adolescents and their caregivers. Challenges raised only among adolescents and caregivers in the non-adherent groups are hypothesis-generating, identifying areas that may have a greater contribution to poor outcomes than challenges faced by both adherent and non-adherent adolescents. The contribution of these factors to poor outcomes should be explored in future studies.

High mortality among adolescents with HIV reflects delays and failures in the care cascade. We sought to elucidate critical missed opportunities and barriers to care among adolescents hospitalized with HIV at Botswana's tertiary referral hospital. We enrolled all HIV-infected adolescents (aged 10-19 years) hospitalized with any diagnosis other than pregnancy from July 2015 to January 2016. Medical records were reviewed for clinical variables and past engagement in care. Semi-structured interviews of the adolescents (when feasible) and their caregivers explored delays and barriers to care. Twenty-one eligible adolescents were identified and 15 were enrolled. All but one were WHO Clinical Stage 3 or 4. Barriers to diagnosis included lack of awareness about perinatal HIV infection, illness or death of the mother, and fear of discrimination. Barriers to adherence to antiretroviral therapy included nondisclosure, isolation, and mental health concerns. The number of hospitalized HIV-infected adolescents was lower than expected. However, among those hospitalized, the lack of timely diagnosis and subsequent gaps in the care cascade elucidated opportunities to improve outcomes and quality of life for this vulnerable group.

We hypothesized that longer and more frequent dosing gaps among boys in Botswana taking antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection compared to girls could account for previously seen gender-specific differences in outcomes. We monitored 154 male and 134 female adolescents for 2 years with medication event monitoring systems (MEMS). Median adherence was 95.6 % for males and 95.7 % for females (p = 0.40). There were no significant gender differences in the number of ≥7 day (p = 0.55) and ≥14 day (p = 0.48) dosing gaps. The median maximal gap was 7.7 days for males and 8.0 days for females (p = 0.47). These findings are not consistent with clinically meaningful gender differences in adherence.

SETTING Four public hospitals in Botswana, a high tuberculosis (TB) burden setting. OBJECTIVES To assess the feasibility and utility of sputum induction in the diagnosis of paediatric TB. DESIGN From 2008 to 2010, children aged ≤18 years referred for suspected pulmonary TB underwent sputum induction. Confirmed TB was defined as the presence of at least one of the signs and symptoms suggestive of TB and positive Mycobacterium tuberculosis culture. Information on TB-associated symptoms (cough, fatigue, night sweats, low appetite, chest pain, weight loss, haemoptysis and contact with a TB case) was collected for three risk groups: human immunodeficiency virus (HIV) positive children, HIV-negative children aged

A commentary is presented on the urgent need for a comprehensive effort to improve the practice of pediatric therapeutics in Africa. A call for action is addressed to a variety of practitioners internationally, many of whom possess skills that could be fruitfully applied to the improvement of health outcomes for African children. Successful engagement with the many challenges requires the complementary effort of researchers in basic and clinical pharmacology and toxicology, nurses, pharmacists, physicians, clinical pharmacologists, clinical pharmacists, and political leaders and civil servants. While a comprehensive or systematic review of the relevant literature has not been attempted, the authors have highlighted promising initiatives driven by international agencies and academic networks. Two African perspectives are presented to reinforce the prospect of child health gains that can be achieved through consistent pursuit of optimal therapy for conditions such as respiratory infection, diarrhea, malaria, and HIV/AIDS. There is an imperative for development of north-south and south-south partnerships that will amplify current research efforts and mobilize existing knowledge concerning pediatric drugs. The overall goal is a multidisciplinary commitment to making essential medicines available at the right time, the right place, and in the right formulation for African children from infancy to adolescence.

Antiretroviral treatment means many HIV infected children are surviving with a highly stigmatised condition. There is a paucity of data to inform policies for this growing cohort. Hence we carried out a study on the health, schooling, needs, aspirations, perspectives and knowledge of HIV infected and affected children in Botswana.A cross-sectional survey using interviews and focus group discussions among HIV infected children aged 6-18 years versus HIV aged matched HIV uninfected counterparts living in the same households between August 2010 and March 2011. Supplemental clinical data was abstracted from medical records for HIV infected participants.Nine hundred eighty-four HIV infected and 258 affected children completed the survey. Females predominated in the affected group (63.6 % versus 50.3 %, P 0.001). School attendance was high in both groups (98.9 % versus 97.3 %, P = 0.057). HIV infected children were mostly in primary school (grades 3-7) while affected children were mostly in upper primary or secondary grades. Sixty percent HIV infected children reported having missed school at least 1 day in the preceding month. Significantly more infected than affected children reported experiencing problems at school (78 % versus 62.3 %, P 0.001). Twenty-two percent of 15-18 year old HIV infected children were in standard seven and below compared to only 8 % of HIV affected children (p = 0.335). School related problems included poor grades, poor health/school attendance, stigma and inadequate scholastic materials. The wish-list for improving the school environment was similar for both groups and included extra learning support; better meals; protection from bullying/teasing; more scholastic materials, extracurricular activities, love and care; structural improvements; improved teacher attendance and teaching approaches. Significantly more HIV infected children reported feeling hungry all the time (50.6 % versus 41 %, P = 0.007) and more trouble hearing (26.8 % versus 12.5 %, P = 0.028). The mean age for HIV disclosure 10 years was high. Sexual activity (9.2 % versus 3 %, P = 0.001) and emotions of anger (71 % versus 55.3 %, P 0.001) were significantly higher among HIV affected children. Future perspectives were equally positive (93 % versus 96 %, P = 0.080), were predicated on children's school performance, self-belief/determination and/or ARVs and preference for medical or military careers was common.In Botswana almost all school-age HIV infected and affected children are attending school but many face daunting challenges that call for the creation of an empowering, empathetic, supportive, caring, and non-discriminating school environment.

Background Antiretroviral treatment means many HIV infected children are surviving with a highly stigmatised condition. There is a paucity of data to inform policies for this growing cohort. Hence we carried out a study on the health, schooling, needs, aspirations, perspectives and knowledge of HIV infected and affected children in Botswana. Methods A cross-sectional survey using interviews and focus group discussions among HIV infected children aged 6–8 years versus HIV aged matched HIV uninfected counterparts living in the same households between August 2010 and March 2011. Supplemental clinical data was abstracted from medical records for HIV infected participants. Results Nine hundred eighty-four HIV infected and 258 affected children completed the survey. Females predominated in the affected group (63.6 % versus 50.3 %, P

Clinical mentoring by providers skilled in HIV management has been identified as a cornerstone of scaling-up antiretroviral treatment in Africa, particularly in settings where expertise is limited. However, little data exist on its effectiveness and impact on improving the quality-of-care and clinical outcomes, especially for HIV-infected children. Since 2008, the Botswana-Baylor Children’s Clinical Centre of Excellence (COE) has operated an outreach mentoring programme at clinical sites around Botswana. This study is a retrospective review of 374 paediatric charts at four outreach mentoring sites (Mochudi, Phutadikobo, Molepolole, Thamaga) evaluating the effectiveness of the programme as reflected in a number of clinically-relevant areas. Charts from one visit prior to initiation of mentoring and from one visit after approximately one year of mentoring were assessed for statistically-significant differences (p

Background Limited data are available on patterns of resistance mutations in pediatric patients in southern Africa, where HIV-1 subtype C (HIV-1C) predominates. Methods Retrospective chart review of pediatric patients. Nucleoside reverse transcriptase inhibitor (NRTI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations quantified from population-based sequencing genotypic resistance assay results taken at time of first-line antiretroviral therapy (ART) failure (first-line ART = stavudine [d4T] or zidovudine [ZDV] + lamivudine [3TC] + nevirapine [NVP] or efavirenz [EFV]). Results Total number of patients with resistance assays analyzed is 45. Nucleoside reverse transcriptase inhibitor-associated mutation frequencies noted were M184V (n = 41; 91.1%); thymidine analogue mutations (TAMs; n = 20; 44.4%); >1 TAM (n = 9; 20%); TAM-2 pathway (n = 10; 22.2%); TAM-1 pathway (n = 7; 15.6%); TAM-1 and TAM-2 pathways (n = 3; 6.7%); K65R (n = 2; 4.4%); Q151M (n = 1; 2.2%); and L74V (n = 0; 0%). Nonnucleoside reverse transcriptase inhibitor-associated mutation frequencies noted were associated with notable resistance to either/both NVP and EFV (n = 40; 88.9%); K103N (n = 15; 33.3%); ≥1 mutations associated with etravirine (ETR) failure (K101E, Y181C, and G190A; n =20; 44.4%); and ≥2 notable NNRTI mutations (n = 12; 26.7%). Conclusions In this cohort, low-genetic barrier mutations were common, as were TAMs, including more than 1 TAM. Mutations compromising nonthymidine analogue backbones were rare, suggesting that it is likely that children who fail first-line NRTI backbones containing d4T or ZDV/3TC would still respond to abacavir (ABC), didanosine (ddI), and, for adolescents, tenofovir (TDF). Our data support the empiric continuation of 3TC in second-line regimens.

Background: The Human Heredity and Health in Africa consortium (H3Africa) was conceived to facilitate the application of genomics technologies to improve health across Africa. Here, we describe how the Collaborative African Genomics Network (CAfGEN) of the H3Africa consortium is using genomics to probe host genetic factors important to the progression of HIV and HIV-tuberculosis (TB) coinfection in sub-Saharan Africa. Methods: CAfGEN is an H3Africa collaborative centre comprising expertise from the University of Botswana; Makerere University; Baylor College of Medicine Children’s Clinical Centers of Excellence (COEs) in Botswana, Uganda, and Swaziland; as well as Baylor College of Medicine, Texas. The COEs provide clinical expertise for community engagement, participant recruitment and sample collection while the three University settings facilitate processing and management of genomic samples and provide infrastructure and training opportunities to sustain genomics research. Results: The project has focused on utilizing whole-exome sequencing to identify genetic variants contributing to extreme HIV disease progression phenotypes in children, as well as RNA sequencing and integrated genomics to identify host genetic factors associated with TB disease progression among HIV-positive children. These cohorts, developed using the COEs’ electronic medical records, are exceptionally well-phenotyped and present an unprecedented opportunity to assess genetic factors in individuals whose HIV was acquired by a different route than their adult counterparts in the context of a unique clinical course and disease pathophysiology. Conclusions: Our approach offers the prospect of developing a critical mass of well-trained, highly-skilled, continent-based African genomic scientists. To ensure long term genomics research sustainability in Africa, CAfGEN contributes to a wide range of genomics capacity and infrastructure development on the continent, has laid a foundation for genomics graduate programs at its institutions, and continues to actively promote genomics research through innovative forms of community engagement brokered by partnerships with governments and academia to support genomics policy formulation.

Psychosocial dysfunction is a risk factor for treatment non-adherence among children and adolescents. A previous study showed that high scores on the Pediatric Symptom Checklist (PSC) were associated with a history of HIV virologic failure. We assessed whether high scores on the PSC could predict virologic failure in HIV-infected youth. Caregivers of 234 adolescents between the ages of 10 and 16 years were asked to complete a PSC at baseline. Elevated PSC scores were associated with virologic failure in the subsequent 6 months. PSC scores may help guide resource utilization when viral load monitoring is limited.

The purpose of this study was to determine whether diary-driven adjustment of Medication Event Monitoring System (MEMS) data based on Supporting Information strengthens the relationship between measured antiretroviral medication adherence and plasma HIV viral load (VL).HIV+ adolescents on antiretroviral treatment were monitored with MEMS for 30 days preceding a VL measurement. The primary outcome was VL ≥ 400 copies/mL. Handwritten diaries were used to comprehensively record deviations from recommended use (bottle opened but dose not taken or bottle not opened and dose taken). Data were adjusted ("cleaned") based on diary events. Data were "capped" at the prescribed number of doses/day. Receiver operator characteristic analysis compared the relationships between (i) raw MEMS data, (ii) diary-cleaned, (iii) capped, or (iv) cleaned and capped MEMS data and VL.Over 30 days preceding VL measurements, 273 adolescents had 465 diary events. Capping resulted in fewer patients classified as 95% adherent (65.2%) compared with raw data (71.4%), p 0.001. Adherence was highly associated with VL (OR 1.05, p 0.001). The area under the receiver operating characteristic curve for continuous adherence compared with VL was 0.89 (95%CI: 0.82-0.95). Neither diary-cleaning, capping, nor cleaning and capping MEMS data significantly altered the association between adherence and VL (p = 0.14, 0.40, and 0.19, respectively).Medication Event Monitoring System data-cleaning based on diary entries did not affect the adherence-VL relationship.

Background: Children with HIV infection are often reported to be short. The aim of this study was to assess the prevalence of HIV-associated short stature in HIV endemic setting. Methods: Data were obtained by retrospective review of the electronic medical records. Patients were grouped into various clinical categories. For each category, the proportion of patients with height-for-age Z score of less than −2 standard deviation [SD] and of less than −3 SD was determined. Results: The prevalence of short stature (less than −2 SD) was 28.4%. Severe short stature (less than −3 SD) is more likely with percentage of CD4 400 copies/mL (OR 2.64, CI 1.27-5.38, P = .008) and poor adherence (Conclusion: In Botswana, short stature affects a quarter of HIV-infected children and severe short stature is associated with poor adherence to antiretroviral treatment, severe immunosuppression, and virologic failure.

We investigated the association between household food insecurity (HFI) and CD4% among 2-6-year old HIV+ outpatients (n = 78) at the Botswana-Baylor Children's Clinical Center of Excellence in Gaborone, Botswana. HFI was assessed by a validated survey. CD4% data were abstracted from the medical record. We used multiple linear regression with CD4% (dependent variable), HFI (independent variable), and controlled for sociodemographic and clinical covariates. Multiple linear regression showed a significant main effect for HFI [beta = -0.6, 95% confidence interval (CI): -1.0 to -0.1] and child gender (beta = 5.6, 95% CI: 1.3 to 9.8). Alleviating food insecurity may improve pediatric HIV outcomes in Botswana and similar Sub-Saharan settings.

H3Africa is developing capacity for health-related genomics research in Africa

Study Objectives Psychosocial factors such as outcome expectancy, perceived stigma, socio-emotional support, consideration of future consequences, and psychological reactance likely influence adolescent adherence to antiretroviral treatments. Culturally-adapted and validated tools for measuring these factors in African adolescents are lacking. We aimed to identify culturally-specific factors of importance to establishing local construct validity in Botswana. Methods Using in-depth interviews of 34 HIV+ adolescents, we explored how the psychosocial factors listed above are perceived in this cultural context. We evaluated six scales that have been validated in other contexts. We also probed for additional factors that the adolescents considered important to their HIV medication adherence. Analyses were conducted with an analytic framework approach using NVivo9 software. Results While the construct validity of some Western-derived assessment tools was confirmed, other tools were poorly representative of their constructs in this cultural context. Tools chosen to evaluate HIV-related outcome expectancy and perceived stigma were well-understood and relevant to the adolescents. Feedback from the adolescents suggested that tools to measure all other constructs need major modifications to obtain construct validity in Botswana. The scale regarding future consequences was poorly understood and contained several items that lacked relevance for the Batswana adolescents. They thought psychological reactance played an important role in adherence, but did not relate well to many components of the reactance scale. Measurement of socio-emotional support needs to focus on the adolescent-parent relationship, rather than peer-support in this cultural context. Denial of being HIV-infected was an unexpectedly common theme. Ambivalence about taking medicines was also expressed. Discussion In-depth interviews of Batswana adolescents confirmed the construct validity of some Western-developed psychosocial assessment tools, but demonstrated limitations in others. Previously underappreciated factors related to HIV medication adherence, such as denial and ambivalence, should be further explored.

Background: Data on the use of ritonavir-boosted darunavir (DRV/r) and/or raltegravir (RAL) in resource-limited settings are rare and there is currently no published data regarding their use among African children. Botswana has recently made DRV/r and RAL available for patients failing second-line antiretroviral therapy (ART). Methods: Retrospective chart review of 4 multidrug-resistant pediatric patients on DRV/r- and/or RAL-based regimens. Viral load, CD4 count, adherence by pill count, and World Health Organization (WHO) clinical stage prior to and after switch to DRV/r- and/or RAL-based regimen were assessed. Antiretroviral therapy history, duration of virologic failure, and time to viral suppression were also noted. Genotypic resistance assays reviewed for mutations present prior to switch. Results: All patients achieved viral suppression, showed improved/stable CD4 counts, and obtained or maintained WHO clinical treatment stage I, even after long-standing virologic/immunologic failure. Conclusions: Well tolerated by and effective in our patients, DRV/r and RAL provide potentially lifesaving ART options for children and adolescents in resource-limited settings failing ART due to ritonavir-boosted lopinavir (LPV/r) resistance.

Background As life expectancy of HIV-infected patients improves due to antiretroviral treatment (ART) and the importance of associated co-morbidities and chronic diseases increases, preventive care will become increasingly important. Adaptation of existing preventive guidelines to local environments will become a priority for HIV treatment programmes. Methods Guidance from the World Health Organization, a focused evidenced-based literature review, Botswana national guidelines, Botswana-specific morbidity and mortality data and centre-specific data were used to adapt a published general primary care package for limited-resource areas to our centre's specific setting. Results The preventive care package contains recommendations on tuberculosis prevention, malnutrition, depression, cervical and breast cancer, hepatitis B coinfection, cardiovascular risk factors, external injury prevention, domestic violence screening, tobacco and substance-abuse counselling, contraception and screening and treatment of sexually transmitted infections. Conclusion This preventive care package addresses the comprehensive health needs of HIV-infected adults in the FMC in an evidence-based manner. The process of combining clinic-specific prevalence data, national guidelines, regional literature and assessment of public-sector resources to adapt an existing general package could be utilised to develop similar guidelines in other resource-limited locales. Contexte Alors que l'esperance de vie des patients infectes par le VIH s'ameliore grâce au traitement antiretroviral (ART) et l'importance des co-morbidites et maladies chroniques associees augmente, les soins preventifs deviendront de plus en plus importants. L'adaptation des directives de prevention existantes a l'environnement local deviendra une priorite pour les programmes de traitement du VIH. Methodes Les directives de l'Organisation Mondiale de la Sante, une revue de la litterature centree sur l’evidence, les directives nationales du Botswana, les donnees sur la morbidite et la mortalite specifiques au Botswana et les donnees centrales specifiques ont ete utilisees pour adapter un ensemble de soins primaires generaux publies sur des zones a ressources limitees, a notre contexte central specifique. Resultats L'ensemble des soins preventifs contient des recommandations sur la prevention contre la tuberculose, la malnutrition, la depression, le cancer du sein et de l'uterus, la coinfection avec l'hepatite B, les facteurs de risque cardiovasculaire, la prevention des blessures externes, le depistage de la violence domestique, le conseil sur le tabagisme et la toxicomanie, la contraception et le depistage et le traitement des infections sexuellement transmissibles. Conclusion Cet ensemble de soins preventifs repond aux besoins complets de sante des adultes infectes par le VIH, sur base d’evidence. Le processus de combinaison des donnees de prevalence specifiques a la cliniques, les directives nationales, la litterature regionale et l’evaluation des ressources du secteur public afin d'adapter un ensemble general existant pourrait etre utilise pour elaborer des directives similaires dans d'autres contextes locaux a ressources limitees. Antecedentes A medida que la expectativa de vida de los pacientes infectados con VIH mejora debido al tratamiento antirretroviral (TAR) y la importancia de las comorbilidades asociadas y las enfermedades cronicas aumentan, los cuidados preventivos seran cada vez mas importantes. La adaptacion de las guias preventivas existentes a ambientes locales se convertira en una prioridad para los programas de tratamiento del VIH. Metodos Se utilizaron las guias de la Organizacion Mundial de la Salud, una revision centrada en literatura basada en evidencia, las guias nacionales de Botswana, datos de morbilidad y mortalidad especificos para Botswana y datos especificos del centro, para adaptar un paquete ya publicado de cuidados primarios generales para areas con recursos limitados a las especificidades de nuestro emplazamiento. Resultados El paquete contiene recomendaciones para la prevencion de la tuberculosis, la desnutricion, depresion, el cancer cervical y de mama, la coinfeccion por hepatitis B, factores de riesgo cardiovascular, prevencion de danos externos, rastreo de violencia domestica, aconsejamiento sobre el tabaco y abuso de sustancias, metodos anticonceptivos, y analisis y tratamiento de enfermedades de transmision sexual. Conclusion Este paquete preventivo aborda de forma integral las necesidades sanitarias de adultos infectados con VIH con una estrategia basada en la evidencia. El proceso de combinar datos clinicos especificos de prevalencia, guias nacionales, literatura regional y evaluacion de los recursos del sector publico para adaptarse al paquete general existente podrian utilizarse para desarrollar unas guias similares en otras localidades con recursos limitados.

Forty-four children were studied to compare the pathogenesis of fever in cerebral malaria, uncomplicated malaria and measles at the Eldoret District Hospital (EDH). A control group of normal children was used. The three patient groups were studied for three consecutive days measuring skin and core temperature three-times a day using the Liquid Crystal Device (LCD) thermometer. A statistical analysis of the results within and between the groups was carried out for core and skin temperature over the study period. No statistical differences were found between the groups for either the skin or the core temperature, but a significant statistical difference was demonstrated between the core and the skin temperature for all of the groups for each of the three days. No statistical difference was found when the differences between the core and skin temperature were compared between cerebral malaria and uncomplicated malaria. The possible roles of fever in morbidity and mortality are discussed, with special reference to cerebral malaria.

In recent years, southern Africa has experienced a widespread measles outbreak. Given the high human immunodeficiency virus (HIV) prevalence in the region, the particular features of measles in HIV-infected individuals are of interest to clinicians, especially as regards children, as are measles immunisation strategies for this population. This review discusses a case of severe measles in an HIV-infected child in Botswana, focusing on its implications for clinical case management in Botswana and similar settings and for policies on measles immunisation.

The objective of this study was to assess the prevalence of hepatitis B and hepatitis C coinfections in human immunodeficiency virus (HIV) -infected adults at an HIV center in Gaborone, Botswana. A retrospective review was performed of charts of currently active HIV-infected adult patients in the Family Model Clinic (FMC) of the Botswana-Baylor Children's Clinical Center of Excellence (BCOE) in Gaborone, Botswana, for the results of serum hepatitis B surface antigen (HBsAg) and antihepatitis C IgG tests performed between January 1, 2005 and December 15, 2009. Of 308 active FMC patients, 266 underwent HBsAg serology testing within the period of study. The HBsAg coinfection prevalence was 5.3% (14/266); 2 of 252 patients had at least one positive antihepatitis C IgG serology, a 0.8% prevalence. Hepatitis B coinfection is relatively common in HIV-infected adults at our center in Botswana, whereas hepatitis C coinfection is rare. In this setting, where the diagnosis of hepatitis B coinfection with HIV has implications for choice of first-line antiretroviral therapy and prevention of perinatal hepatitis B transmission, broader sampling to establish the true population prevalence of hepatitis B coinfection and the desirability of adding screening to HIV management should be considered. These findings provide little justification for adding hepatitis C coinfection screening to the management of HIV infection in Botswana.

The authors are indebted to the collaborators in the participating centres and all parents, children, teachers and other school staff who participated in the surveys. There are many field workers and funding agencies who supported data collection and national, regional and international meetings, including the meetings of the ISAAC Steering Committee. Unfortunately, these are too numerous to mention (they are acknowledged elsewhere) but the authors particularly wish to thank the funders who supported the ISAAC International Data Centre including the Health Research Council of New Zealand, the Asthma and Respiratory Foundation of New Zealand, the National Child Health Research Foundation, the Hawke’s Bay Medical Research Foundation, the Waikato Medical Research Foundation, Glaxo Wellcome New Zealand and Astra New Zealand, as well as Glaxo Wellcome International Medical Affairs for finding the regional coordinating centres. The International Data Centre is now supported by a grant from the BUPA Foundation., The International Study of Asthma and Allergies in Childhood (ISAAC) Phase One showed large worldwide variations in the prevalence of symptoms of asthma, rhinoconjunctivitis and eczema, up to 10 to 20 fold between countries. Ecological analyses were undertaken with ISAAC Phase One data to explore factors that may have contributed to these variations, and are summarised and reviewed here. In ISAAC Phase One the prevalence of symptoms in the past 12 months of asthma, rhinoconjunctivitis and eczema were estimated from studies in 463,801 children aged 13 - 14 years in 155 centres in 56 countries, and in 257,800 children aged 6-7 years in 91 centres in 38 countries. Ecological analyses were undertaken between symptom prevalence and the following: Gross National Product per capita (GNP), food intake, immunisation rates, tuberculosis notifications, climatic factors, tobacco consumption, pollen, antibiotic sales, paracetamol sales, and outdoor air pollution. Symptom prevalence of all three conditions was positively associated with GNP, trans fatty acids, paracetamol, and women smoking, and inversely associated with food of plant origin, pollen, immunisations, tuberculosis notifications, air pollution, and men smoking. The magnitude of these associations was small, but consistent in direction between conditions. There were mixed associations of climate and antibiotic sales with symptom prevalence. The potential causality of these associations warrant further investigation. Factors which prevent the development of these conditions, or where there is an absence of a positive correlation at a population level may be as important from the policy viewpoint as a focus on the positive risk factors. Interventions based on small associations may have the potential for a large public health benefit., peer-reviewed

Introduction Healthcare providers (nurses, physicians, and social workers), by virtue of their experiences in interacting with HIV-infected children and their caregivers, are an important source of information on the causes of loss to follow-up (LTFU). We explored perceptions of healthcare providers regarding factors that lead to paediatric HIV-infected patients becoming lost to follow-up from care and treatment. Methods The study was conducted at a large paediatric HIV clinic in Gaborone, Botswana and involved conducting in-depth interviews with clinical staff (n = 10). The interviews targeted information about the magnitude of LTFU problems and possible solutions as perceived by the healthcare providers. Results Respondents perceived factors of LTFU to include issues of HIV-related stigma, caregiver’s religious beliefs of being healed, teenage-child rebellion, and concerns about disclosure of their HIV status to others, were characteristic of the patients LTFU. The results also revealed that mental health issues such as depression might not be adequately addressed in HIV clinic settings, perceived as a key underlying factor of LTFU. Conclusion Our study underscores the psychosocial nature of the issues of LTFU and the need to develop a more holistic approach to treating HIV-infected children. Disclosure of interest statement Funding for this study was made possible through Fogarty International Centre of the National Institutes of Health, (M. W. Kline – Principal Investigator) under grant number D43 TW01036.

Introduction Loss to follow-up (LTFU) is a critical factor in determining clinical outcome in HIV treatment programs. Identifying modifiable factors of LTFU is fundamental for designing effective patient retention interventions. We analysed factors contributing to children LTFU from a treatment program to identify those that can be modified. Methods A case-control study involving 313 children was used to compare the sociodemographic and clinical characteristics of children LTFU (cases) with those remaining in care (controls) at a large paediatric HIV care setting in Botswana. We traced children through caregiver contacts and those we found, we conducted structured interviews with the patients’ caregivers. Results Children Conclusion Paediatric patients and their caregivers need to be targeted and engaged at their initial clinic visit, with special attention to children Disclosure of interest statement Funding for this study was made possible through Fogarty International Centre of the National Institutes of Health, (M. W. Kline – Principal Investigator) under grant number D43 TW01036.

It is estimated that more than 2.1 million adolescents (10–19 years of age) live with human immunodeficiency virus (HIV) in low-income and middle-income countries.1 When compared with both adults and younger children, HIV-infected adolescents have higher rates of nonadherence, virologic failure, and death.2,3 As they age, adolescents generally increase their health care–related autonomy. Adolescents may attend a clinic with or without an adult caregiver (parent). The relationship between parental attendance at clinic visits and adolescent chronic disease outcomes is unknown. We hypothesized that routine clinic attendance without a parent would be associated with the risk of HIV treatment failure, particularly in younger adolescents.