Search

Introduction In low? and middle?income settings, more than a third of HIV?positive individuals starting antiretroviral therapy (ART) present with advanced disease (CD4 ? 200 cells/mm[sup.3] ); over half of these [...], : 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 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 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.

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Purpose of study Adults initiating ART in low‐income countries have higher mortality in the first 3 months on ART than those in high‐income countries, with more similar mortality risks after [...]

Abstract Background Clinical trials involving children previously considered unethical are now considered essential because of the inherent physiological differences between children and adults. An integral part of research ethics is the informed consent, which for children is obtained by proxy from a consenting parent or guardian. The informed consent process is governed by international ethical codes that are interpreted in accordance with local laws and procedures raising the importance of contextualizing their implementation. Findings In Zimbabwe the parental informed consent document for children participating in clinical research is modeled along western laws of ethics and requires that the parent or legally authorized representative provide consent on behalf of a minor. This article highlights the experiences and lessons learnt by Zimbabwean researchers in obtaining informed consent from guardians of orphaned children participating in a collaborative HIV clinical trial involving the Medical Research Council, United Kingdom and four centers, three of which are in Uganda. Researchers were faced with a situation where caregivers of orphaned children were not permitted to provide informed consent for trial participation. The situation contrasted with general clinical practice where consent for procedures on orphans is obtained from their caregivers who are not legal guardians. Conclusion The challenges faced in obtaining informed consent for orphans in this clinical trial underscores the need for the Zimbabwe ethics committee to develop an ethical and legal framework for pediatric research that is based on international guidelines while taking into account the cultural context. The Medical Research Council of Zimbabwe has since started the process that is expected to involve critical stakeholders namely the community including children, ethicists, the legal fraternity and researchers.

Abstract Background Serologic tests for HIV infection in infants less than 18 months do not differentiate exposure and infection since maternally acquired IgG antibodies may be detected in infants. Thus, the gold standard for diagnosis of HIV-1 infection in infants under the age of 2 years is DNA or reverse transcriptase polymerase chain reaction. There is an urgent need to evaluate alternative and cost effective laboratory methods for early diagnosis of infant HIV-1 infection as well as identifying infected infants who may benefit from cotrimoxazole prophylaxis and/or initiation of highly active antiretroviral therapy. Methods Whole blood was collected in EDTA from 137 infants aged 0 to 18 months. DNA polymerase chain reaction was used as the reference standard for diagnosis of HIV-1 infection. T-cell subset profiles were determined by flow cytometry. Results Seventy-six infants were DNA PCR positive while 61 were negative. The median CD4 counts of PCR negative infants were significantly higher than those of the PCR positive infants, p < 0.001. The median CD4/CD8 ratio and the %CD4 of the PCR positive infants were both significantly lower than those of the negative infants, p < 0.001. The CD4/CD8 ratio had a >98% sensitivity for diagnosis of HIV-1 infection and a specificity of >98%. Conclusion The CD4/CD8 ratio appears useful in identifying HIV-infected infants. The development of lower cost and more robust flow cytometric methods that provide both CD4/CD8 ratio and %CD4 may be cost-effective for HIV-1 diagnosis and identification of infants for cotrimoxazole prophylaxis and/or highly active antiretroviral therapy.

Children with severe acute malnutrition (SAM) have high infectious mortality and morbidity, implicating defects in their immune defenses. We hypothesized that circulating innate immune cells from children (0 to 59 months) hospitalized with SAM in Zambia and Zimbabwe ( n = 141) have distinct capacity to respond to bacteria relative to adequately nourished healthy controls ( n = 92). SAM inpatients had higher neutrophil and monocyte Escherichia coli binding capacity but lower monocyte activation and proinflammatory mediator secretion in response to lipopolysaccharide or heat-killed Salmonella typhimurium than controls. Among SAM cases, wasting severity was negatively associated with cytokine secretion, children with HIV had lower monocyte activation, and the youngest children released the least myeloperoxidase upon stimulation. Inpatient bacterial binding capacity and monocyte activation were associated with higher odds of persistent SAM at discharge, a risk factor for subsequent mortality. Thus, SAM shifts innate immune cell function, favoring bacterial containment over proinflammatory activation, which may contribute to health deficits after discharge.

Background: Children who initiate antiretroviral therapy (ART) before age 5 years can recover height and weight compared to uninfected peers, but growth outcomes are unknown for children initiating ART at older ages. We investigated factors associated with growth failure at ART initiation and modelled growth by age on ART., Methods: We conducted secondary analysis of cohort of children aged 6-15 years late-diagnosed with HIV in Harare, Zimbabwe, with entry at ART initiation in 2013-2015. Factors associated with height-for-age (HAZ), weight-for-age (WAZ) and BMI-for-age (BAZ) z-scores <- 2 (stunting, underweight and wasting respectively) at ART initiation were assessed using multivariable logistic regression. These outcomes were compared at ART initiation and 12 month follow-up using paired t-tests. HAZ and BAZ were modelled using restricted cubic splines., Results: Participants (N = 302; 51.6% female; median age 11 years) were followed for a median of 16.6 months (IQR 11.0-19.8). At ART initiation 34.8% were stunted, 34.5% underweight and 15.1% wasted. Stunting was associated with age ≥ 12 years, CD4 count < 200 cells/μl, tuberculosis (TB) history and history of hospitalisation. Underweight was associated with older age, male sex and TB history, and wasting was associated with older age, TB history and hospitalisation. One year post-initiation, t-tests showed increased WAZ (p = 0.007) and BAZ (p = 0.004), but no evidence of changed HAZ (p = 0.85). Modelling showed that HAZ and BAZ decreased in early adolescence for boys on ART, but not girls., Conclusion: Stunting and underweight were prevalent at ART initiation among late-diagnosed children, and HAZ did not improve after 1 year. Adolescent boys with perinatally acquired HIV and late diagnosis are particularly at risk of growth failure in puberty., (© 2022. The Author(s).)

Background: Suboptimal adherence to antiretroviral therapy (ART) is responsible for most virologic failure among adolescents with HIV. Methods for objectively measuring adherence to ART are limited. This study assessed the association between ritonavir concentrations in hair and self-reported adherence and modified directly administered ART on virologic outcomes among HIV-infected adolescents who were virologically failing second-line ART in Harare, Zimbabwe., Methods: HIV-infected adolescents on atazanavir-based or ritonavir-based second-line treatment for >6 months with viral load ≥1000 copies/mL were randomized to either modified directly administered ART (mDAART) plus standard of care (intervention) or standard of care alone (control). Questionnaires were administered; viral load and hair samples were collected at baseline and after 90 days. Virological suppression was defned as <1000 copies/mL after follow-up., Results: Fifty adolescents (13-19 years) were enrolled in the study, and 42 adolescents had ritonavir concentrations measured in hair at baseline and at 90 days. Twenty-three participants (46%) were randomized to mDAART. Viral load suppression at follow-up [regression coefficient (standard error): -0.3 (0.1); 95% confidence interval (CI): -0.5 to -0.06; P = 0.01], self-reported adherence at follow-up [regression coefficient (standard error): 0.01 (0.005); 95% CI: 0.004 to 0.02; P = 0.006], and being male sex [regression coefficient (standard error): 0.3 (0.1); 95% CI: 0.08 to 0.5; P = 0.008] were associated with ritonavir concentrations in hair. The intervention, mDAART, was not associated with ritonavir concentrations [regression coefficient (standard error) 0.2 (0.1); 95% CI: -0.07 to 0.4; P = 0.2]., Conclusions: Ritonavir concentrations in hair predicted virological suppression and were associated with self-reported adherence and being male in this cohort of adolescents with treatment failure to atazanavir-based or ritonavir-based second-line ART. Measuring ritonavir concentrations in hair in adolescents on protease inhibitor-based regimens could assess adherence in this vulnerable group to avert subsequent virologic failure., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: prompt diagnosis and treatment are considered key to successful management of intussusception. We examined pre-treatment delay among intussusception cases in Zimbabwe and conducted an exploratory analysis of factors associated with intraoperative finding of gangrene., Methods: data were prospectively collected as part of the African Intussusception Network using a questionnaire administered on consecutive patients with intussusception managed at Harare Children´s Hospital. Delays were classified using the Three-Delays-Model: care-seeking delay (time from onset of symptoms to first presentation for health care), health-system delay (referral time from presentation to first facility to treatment facility) and treatment delay (time from presentation at treatment facility to treatment)., Results: ninety-two patients were enrolled from August 2014 to December 2016. The mean care-seeking interval was 1.9 days, the mean health-system interval was 1.5 days, and the mean treatment interval was 1.1 days. Mean total time from symptom onset to treatment was 4.4 days. Being transferred from another institution added 1.4 days to the patient journey. Gangrene was found in 2 (25%) of children who received treatment within 1 day, 13 (41%) of children who received treatment 2-3 days, and 26 (50%) of children who received treatment more than 3 days after symptom onset (p = 0.34)., Conclusion: significant care-seeking and health-system delays are encountered by intussusception patients in Zimbabwe. Our findings highlight the need to explore approaches to improve the early diagnosis of intussusception and prompt referral of patients for treatment., Competing Interests: The authors declare no competing interests., (©Dennis Mazingi et al.)

Increased carotid intima-media thickness (cIMT) is reported in both adults and children with human immunodeficiency virus (HIV) in high income settings and is associated with an increased risk of cardiovascular disease, but data from sub-Saharan Africa is lacking.We assessed cIMT using ultrasound in perinatally HIV-infected children aged 6 to 16 years taking antiretroviral therapy (ART) for ≥6 months compared with HIV-uninfected controls in Harare, Zimbabwe. Groups were compared using unpaired t test and potential predictors of cIMT were assessed using multiple linear regression.A total of 117 participants with HIV, of whom 55 (45%) were female and 75 healthy uninfected controls were included. Participants with HIV were younger than uninfected controls, 10.7 (2.4) years versus 11.9 (2.6) years (P = .001). Mean cIMT was 0.40 (0.05) mm in those with HIV versus 0.40 (0.04) mm in healthy controls (P = .377). There was no association between cluster of differentiation 4 count, HIV viral load, and duration on ART and cIMT.Children with HIV taking ART have similar cIMT to uninfected children. Increasing numbers of children with HIV are reaching adulthood and longitudinal studies to assess the effect of long-term HIV and ART on vascular changes are required.

Biobanks and human genomics applications are key for understanding health, disease and heredity in Africa and globally. Growing interest in these technologies calls for strengthening relevant legal, ethical and policy systems to address knowledge disparities and ensure protection of society, while supporting advancement of science. In Zimbabwe there is limited understanding of ethical, legal, and societal issues (ELSI) for biobanking and genomics. The Genomics Inheritance Law Ethics and Society (GILES) initiative was established in 2015 to explore the current status and gaps in the ethical and legal frameworks, knowledge among various stakeholders, and to establish capacity for addressing ELSI of biobanking and genomics as applied in biomedical and population research, and healthcare. The project was conducted over a countrywide geographical region and established one of the most comprehensive studies for ELSI of human biobanking and genomics in Africa. This paper outlines the strategy undertaken during the implementation of the GILES initiative and discusses the importance of such an initiative for characterisation of ELSI of human biobanking and genomics in Zimbabwe and Africa., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Matimba A et al.)

Introduction: Chronic respiratory disease is a common cause of morbidity in children with HIV infection. We investigated longitudinal lung function trends among HIV-infected children, to describe the evolution of lung disease and assess the effect of anti-retroviral therapy (ART)., Methods: Prospective follow-up of two cohorts of HIV-infected children, aged 6 to 16 years, in Harare, Zimbabwe; one group were ART-naïve at enrolment, the other established on ART for a median of 4.7-years. Standardised spirometric assessments were repeated over a 2-year follow-up period. Forced expiratory volume (FEV1) and forced vital capacity (FVC) were expressed as Global Lung Initiative defined z-scores (FEV1z and FVCz). Linear mixed-effects regression modelling of lung function was performed, with co-variate parameters evaluated by likelihood ratio comparison., Results: We included 271 ART-naïve and 197 ART-established children (median age 11 years in both groups) incorporating 1144 spirometric assessments. Changes in FEV1 and FVC were associated with age at ART initiation and body mass index for both cohorts. Our models estimate that ART initiation earlier in life could prevent a deterioration of 0.04 FVCz/year. In the ART-naïve cohort, likelihood ratio comparison suggested an improvement in 0.09 FVCz/year during the two years following treatment initiation, but no evidence for this among participants established on ART., Conclusion: Early ART initiation and improved nutrition are positively associated with lung function and are important modifiable factors. An initial improvement in lung growth was seen in the first 2-years following ART initiation, although this did not appear to be sustained beyond this timeframe., Competing Interests: The authors have declared that no competing interests exist.

Background: In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events., Methods and Findings: In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82-1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76-1.28], p = 0.91); in serious (aHR = 0.99 [0.81-1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71-1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63-1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76-1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes., Conclusions: Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals., Trial Registration: ClinicalTrials.gov NCT01825031., Trial Registration: International Standard Randomised Controlled Trials Number ISRCTN 43622374., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: the institution of ASW has received funding from Janssen and Gilead Sciences for DSMB membership and lectures; JH has received funding for advisory board membership from Mylan Pharmaceuticals; all other authors have no other relationships or activities that could appear to have influenced the submitted work.

Background: Major challenges are being experienced in medical education in sub-Saharan African Universities. These include emigration of faculty, infrequent curriculum review, inadequate training in medical education, poor investments in infrastructure and lack of faculty development programs. The USA government committed funding to improve the quality of medical education and research capacity in sub-Saharan Africa through the Medical Education Partnership Initiative (MEPI)., Objectives: This article describes the implementation of faculty development at the University of Zimbabwe College of Health Sciences (UZCHS), a recipient of a MEPI award., Methods: Data sources included annual surveys and reports of UZCHS MEPI activities, exit evaluation reports of faculty development workshops; results of a survey conducted in 2015 at the end of the MEPI grant. Questionnaires were developed based on the MEPI Zimbabwe evaluation plan and logic model. Surveys were administered to faculty members, postgraduate and undergraduate students. Qualitative data was collected through in-depth key informer interviews of stakeholder., Findings: Different faculty development activities were implemented such as workshops, exchange visits, visiting professors program, advanced leadership training and curriculum development. The implementation of the activities brought positive developments to the college as confirmed by faculty and students. The majority of faculty interviewed (96%) confirmed that faculty development programs were very helpful in enhancing their expertise and skills. A similar number, i.e. 96%, also reported satisfaction with the training., Conclusions: We have described how the implementation of faculty development programs at the UZCHS contributed to the improvement of medical education at the College. The short term and long-term benefits of faculty development have been analyzed. Various forms of faculty development programs were described. Limitations of this analysis were the inability to collect data on students' performance and the demonstration of changes in teaching performance., Competing Interests: The authors have no competing interests to declare., (© 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.)

An economic crisis in Zimbabwe from 1999-2009 resulted in a shortage of faculty at the University of Zimbabwe College of Health Sciences (UZCHS) and declining enrollment and graduation rates. To improve proficiency and retention of graduates, the college sought to develop a competency-based curriculum using evidence-based educational methodologies. Achievement of this goal required a cadre of highly qualified educators to lead the curriculum review and innovation processes. The Health Education Advanced Leadership for Zimbabwe (HEALZ) program was established in 2012 to rapidly develop the needed faculty leadership. HEALZ is a one-year program of rigorous coursework delivered face-to-face in three intensive one-week sessions. Between sessions, scholars engage with mentors to conduct a needs assessment and to develop, implement, and evaluate a competency-based curriculum. Forty scholars completed training from 2012-15. All participants reported they were satisfied or extremely satisfied with the training after each week. Pre-post surveys identified significant knowledge gains in all key content domains. The program garnered significant organizational support. Scholars showed significant variation in progress toward implementing and evaluating their curricula as well as the quality of the work demonstrated by program end. Interviews of scholars and UZCHS leaders revealed important impacts of the program on the quality and culture of medical education at the college., Competing Interests: The authors have no competing interests to declare., (© 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.)

Objective: Increasing numbers of children with HIV are surviving to adolescence and encountering multiple clinical and social consequences of long-standing HIV infection. We aimed to investigate the association between HIV and disability, social functioning and school inclusion among 6- to 16-year-olds in Zimbabwe., Methods: HIV-infected children receiving antiretroviral therapy from a public-sector HIV clinic and HIV-uninfected children attending primary care clinics in the same catchment area were recruited. Standardised questionnaires were used to collect socio-demographic, social functioning and disability data. Multivariable logistic regression was used to assess the relationship between HIV status and disability and functioning., Results: We recruited 202 HIV-infected and 285 HIV-uninfected children. There was no difference in age and gender between the two groups, but a higher proportion of HIV-infected children were orphaned. The prevalence of any disability was higher in HIV-infected than uninfected children (37.6% vs. 18.5%, P < 0.001). HIV-infected children were more likely to report anxiety (adjusted odds ratio (aOR) 4.4; 95% CI 2.4, 8.1), low mood (aOR 4.2; 2.1, 8.4) and difficulty forming friendships (aOR 14.8; 1.9, 116.6) than uninfected children. Children with HIV also reported more missed school days, repeating a school year and social exclusion in class. These associations remained apparent when comparing children with HIV and disability to those with HIV but no disabilities., Conclusions: Children with HIV commonly experience disabilities, and this is associated with social and educational exclusion. Rehabilitation and support services are needed to facilitate educational attainment and social participation in this group., (© 2017 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Background: Adequate antiretroviral exposure is crucial to virological suppression. We assessed the relationship between atazanavir hair levels with self-reported adherence, virological outcomes, and the effect of a home-based adherence intervention in HIV-infected adolescents failing second-line antiretroviral treatment in Zimbabwe., Methods: HIV-infected adolescents on atazanavir/ritonavir-based second-line treatment for ≥6 months with viral load (VL) >1000 copies/mL were randomized to either standard care (control) or standard care plus modified directly administered antiretroviral therapy (intervention). Questionnaires were administered; VL and hair samples were collected at baseline and after 90 days in each group. Viral suppression was defined as <1000 copies/mL after follow-up., Results: Fifty adolescents (10-18 years) were enrolled; 23 (46%) were randomized to intervention and 27 (54%) to control. Atazanavir hair concentration <2.35 ng/mg (lower interquartile range for those with virological suppression) defined a cutoff below which most participants experienced virological failure. Male sex (P = 0.03), virological suppression at follow-up (P = 0.013), greater reduction in VL (P = 0.006), and change in average self-reported adherence over the previous month (P = 0.031) were associated with adequate (>2.35 ng/mg) hair concentrations. Participants with virological failure were more likely to have suboptimal atazanavir hair concentrations (RR = 7.2, 95% CI: 1 to 51, P = 0.049). There were no differences in atazanavir hair concentration between the arms after follow-up., Conclusions: A threshold of atazanavir concentrations in hair (2.35 ng/mg), above which virological suppression was likely, was defined for adolescents failing second-line atazanavir/ritonavir-based ART in Zimbabwe. Male sex and better self-reported adherence were associated with adequate atazanavir hair concentrations. Antiretroviral hair concentrations may serve as a useful clinical tool among adolescents.

Introduction: Decentralized HIV care for adults does not appear to compromise clinical outcomes. HIV care for children poses additional clinical and social complexities. We conducted a prospective cohort study to investigate clinical outcomes in children aged 6-15 years who registered for HIV care at seven primary healthcare clinics (PHCs) in Harare, Zimbabwe., Methods: Participants were recruited between January 2013 and December 2014 and followed for 18 months. Rates of and reasons for mortality, hospitalization and unscheduled PHC attendances were ascertained. Cox proportional modelling was used to determine the hazard of death, unscheduled attendances and hospitalization., Results: We recruited 385 participants, median age 11 years (IQR: 9-13) and 52% were female. The median CD4 count was 375 cells/mm 3 (IQR: 215-599) and 77% commenced ART over the study period, with 64% of those who had viral load measured achieving an HIV viral load <400 copies/ml. At 18 months, 4% of those who started ART vs. 24% of those who remained ART-naïve were lost-to-follow-up ( p  < 0.001). Hospitalization and mortality rates were low (8.14/100 person-years (pyrs) and 2.86/100 pyrs, respectively). There was a high rate of unscheduled PHC attendances (34.94/100 pyrs), but only 7% resulted in hospitalization. Respiratory disease was the major cause of hospitalization, unscheduled attendances and death. CD4 count <350cells/mm 3 was a risk factor for hospitalization (aHR 3.6 (95%CI 1.6-8.2))., Conclusions: Despite only 64% of participants achieving virological suppression, clinical outcomes were good and high rates of retention in care were observed. This demonstrates that in an era moving towards differentiated care in addition to implementation of universal treatment, decentralized HIV care for children is achievable. Interventions to improve adherence in this age-group are urgently needed., Competing Interests: The authors have no conflict of interests

Community circulation of oral poliovirus vaccine (OPV) likely begins with household transmission. We analyzed stool collected from Zimbabwean mothers who were infected with human immunodeficiency virus (HIV) and those who were uninfected with HIV 1 to 24 weeks after infant oral poliovirus vaccination. Overall, only 5% of the mothers had detectable OPV (16 of 304) despite high infant shedding rates. OPV shedding was similar between HIV-infected mothers and those who were uninfected (11 [6.4%] of 171 vs 5 [3.8%] of 133, respectively) and between mothers of HIV-infected infants and those of uninfected infants (2 [3.5%] of 57 vs 9 [6.3%] of 144, respectively). Mothers of vaccinated infants are unlikely to shed OPV, even when they are infected with HIV., (© Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sustaining virological suppression among HIV-infected adolescents is challenging. We evaluated a home-based adherence intervention and characterized self-reported adherence, virological response and drug resistance among adolescents failing atazanavir/ritonavir (ATV/r)-based 2 nd line treatment., Methods: HIV-positive adolescents (10-18 years) on ATV/r-based 2 nd line treatment with virological failure (viral load (VL) ≥1 000 copies/ml) were randomized to either standard care (SC) or SC with addition of modified directly administered antiretroviral therapy (mDAART) for 90 days. VL was measured and questionnaires were administered at study entry and at 3 months. Genotyping was done for participants with continued failure. Primary outcome was suppression to VL < 1 000 copies/ml., Results: Fifty adolescents aged 10-18 years on 2 nd line treatment for >180 days were enrolled, 23(46%) were randomized to mDAART and 27(54%) to SC. Fifty-four percent were female; mean age was 15.8 years; mean baseline VL was 4.8(log 10 ) copies/ml; 40% reported adherence <80% in previous 1 month at baseline; 40% suppressed (VL <1 000 copies/ml) after follow-up. mDAART resulted in significantly increased self-reported adherence (RR= 0.1; 95% CI=0.02-0.8, p=0.023); closely following dosing schedule (RR= 4.8; 95% CI=1.6-13.8, p=0.004); VL decrease (p=0.031) and modest increase in virological suppression to <1 000 copies/ml (p=0.105). Genotyping in 28/30 participants with continued virological failure demonstrated high level atazanavir resistance (I50L, N88S and I84V) in 6(21%); 3(11%) of whom also had high level resistance to lopinavir and darunavir (V32I, I50L, I54V, 147V and V82A)., Discussion: The mDAART intervention modestly improved virological suppression among adolescents with ATV/r-based 2 nd line treatment failure, significantly increased self-reported adherence and decreased viral load. High level ATV/r resistance was demonstrated., Conclusion: Targeting mDAART to adolescents who are virologically failing PI-based 2 nd line treatment decreases viral load and increases self-reported adherence. Early drug-resistance testing could reduce morbidity and mortality., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest regarding the publication of this manuscript. Preliminary results were presented as a poster at the AIDS 2016 conference in Durban.

Background: Substantial numbers of children with HIV present to health care services in older childhood and adolescence, previously undiagnosed. These "slow-progressors" may experience considerable chronic ill health, which is not well characterized. We investigated the prevalence of chronic morbidity among children aged 6-15 years at diagnosis of HIV infection., Methods: A cross-sectional study was performed at 7 primary care clinics in Harare, Zimbabwe. Children aged 6-15 years who tested HIV positive following provider-initiated HIV testing and counseling were recruited. A detailed clinical history and standardized clinical examination was undertaken. The association between chronic disease and CD4 count was investigated using multivariate logistic regression., Results: Of the 385 participants recruited [52% female, median age 11 years (interquartile range 8-13)], 95% were perinatally HIV infected. The median CD4 count was 375 (interquartile range 215-599) cells per cubic millimeter. Although 78% had previous contact with health care services, HIV testing had not been performed. There was a high burden of chronic morbidity: 23% were stunted, 21% had pubertal delay, 25% had chronic skin disease, 54% had a chronic cough of more than 1 month-duration, 28% had abnormal lung function, and 12% reported hearing impairment. There was no association between CD4 count of <500 cells per cubic millimeter or <350 cells per cubic millimeter with WHO stage or these chronic conditions., Conclusions: In children with slow-progressing HIV, there is a substantial burden of chronic morbidity even when CD4 count is relatively preserved. Timely HIV testing and prompt antiretroviral therapy initiation are urgently needed to prevent development of chronic complications., Competing Interests: The authors have no conflicts of interest to disclose.

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 (<3 years), female sex, lower pre-ART weight-for-age Z-score, and current CD4 percent; fewer TB diagnoses were observed in children on maintenance triple nucleoside reverse transcriptase inhibitor (NRTI) ART compared to standard non-NRTI + 2NRTI. Over the median 2 years of follow-up, there were 20 ERC-adjudicated TB cases among 622 children in the co-trimoxazole analysis: 5 in the continue arm and 15 in the stop arm (hazard ratio (stop: continue) = 3.0 (95% CI, 1.1-8.3), P = 0.028). TB risk was also independently associated with lower current CD4 percent (P <0.001)., Conclusions: TB incidence varies over time following ART initiation, and is particularly high during the first 3 months post-ART, reinforcing the importance of TB screening prior to starting ART and use of isoniazid preventive therapy once active TB is excluded. HIV-infected children continuing co-trimoxazole prophylaxis after 96 weeks of ART were diagnosed with TB less frequently, highlighting a potentially important role of co-trimoxazole in preventing TB.

Background: Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery., Methods and Findings: CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4-17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization-recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled., Conclusions: Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development. Please see later in the article for the Editors' Summary.

Background: In Africa without antiretroviral treatment more than half of the HIV infected children die by 2 years. The recommended HIV virological testing for early infant diagnosis is not widely available in developing countries therefore a presumptive diagnosis is made in infants presenting with symptoms suggestive of HIV disease., Objectives: To identify presenting signs and symptoms predictive of HIV infection in hospitalized children aged between 2- 18 months at Harare Hospital, Zimbabwe., Methods: In a cross sectional study the baseline clinical information was collected and HIV infection confirmed using DNA PCR. Multiple logistic regression analysis was used to identify significant predictors of symptomatic HIV infection. Diagnostic parameters (sensitivity, specificity) and their 95% confidence intervals were calculated., Results: 355 children with an overall median age of 6 months (IQR: 3, 10.5 months) of whom 203 (57.2%) were HIV DNA PCR positive. Clinical signs independently predictive of HIV infection were cyanosis, generalized lymphadenopathy, oral thrush, weight for age z-score <-2 and splenomegaly. The sensitivity of these signs ranged from 43-49% with a higher specificity (ranging from 72.3-89.5%)., Conclusion: Clinical identification using individual signs for probable HIV infection in hospitalized children below 18 months would provide an opportunity for early diagnosis, treatment.

Background: Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)-recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure., Methods and Findings: Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0-4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12-38) months. From mothers' ART, 62/9/111 infants had no/20%-89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75-212) days. Overall, 14 infants died at median (IQR) age 9 (3-23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens., Conclusions: Overall 1-year 5% infant mortality was similar to the 2%-4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children., Trial Registration: www.controlled-trials.com ISRCTN13968779

Objectives: We investigated attitudes toward provider-initiated HIV testing and counseling (PITC) in the suburbs of Harare, Zimbabwe, where late presentation after mother-to-child HIV transmission (MTCT) is a major cause of adolescent mortality., Methods: Adolescents (10-18 years) attending 2 primary clinics were offered PITC. Participants completed a questionnaire investigating acceptability of PITC, and in-depth interviews with 41 adolescents and 30 guardians explored understanding of long-term survival after MTCT., Results: Of 506 participants, 16 were known to be HIV-positive; of the remaining 490, only 5 (1%) declined HIV testing. Infected adolescents and their guardians often anticipated a positive result and reported being advised by relatives (but not health workers) to be tested because of chronic illness, especially if parents or siblings had died or were HIV-infected. However, HIV-negative participants were not aware that long-term survival following MTCT could occur. All adolescents felt that HIV diagnosed at their age would be assumed to have been sexually acquired regardless of the true mode of transmission., Conclusions: Including late diagnosis of MTCT in pretest counseling and health educational messages may facilitate PITC for older children and adolescents, especially for those who have not had their sexual debut.

Objective: To present an algorithm for primary-care health workers for identifying HIV-infected adolescents in populations at high risk through mother-to-child transmission., Methods: Five hundred and six adolescent (10-18 years) attendees to two primary care clinics in Harare, Zimbabwe, were recruited. A randomly extracted 'training' data set (n = 251) was used to generate an algorithm using variables identified as associated with HIV through multivariable logistic regression. Performance characteristics of the algorithm were evaluated in the remaining ('test') records (n = 255) at different HIV prevalence rates., Results: HIV prevalence was 17%, and infection was independently associated with client-reported orphanhood, past hospitalization, skin problems, presenting with sexually transmitted infection and poor functional ability. Classifying adolescents as requiring HIV testing if they reported >1 of these five criteria had 74% sensitivity and 80% specificity for HIV, with the algorithm correctly predicting the HIV status of 79% of participants. In low-HIV-prevalence settings (<2%), the algorithm would have a high negative predictive value (≥ 99.5%) and result in an estimated 60% decrease in the number of people needing to test to identify one HIV-infected individual, compared with universal testing., Conclusions: Our simple algorithm can identify which individuals are likely to be HIV infected with sufficient accuracy to provide a screening tool for use in settings not already implementing universal testing policies among this age-group, for example immigrants to low-HIV-prevalence countries., (© 2010 Blackwell Publishing Ltd.)

Background: Mother-to-child transmission of human immunodeficiency virus (HIV) infection was extremely common in southern Africa during the 1990s, and a substantial minority of infected infants have survived to reach adolescence undiagnosed. Studies have shown a high prevalence of HIV infection in hospitalized adolescents who have features associated with long-standing HIV infection, including stunting and frequent minor illnesses. We therefore investigated the epidemiology of HIV infection at the primary care level., Methods: Adolescents (aged 10-18 years) attending two primary care clinics underwent HIV and Herpes simplex virus-2 (HSV-2) serological testing, clinical examination, and anthropometry. All were offered routine HIV counseling and testing. Patients attending for acute primary care (APC) who were HIV infected were asked about their risk factors., Results: Five hundred ninety-four participants were systematically recruited (97% participation), of whom 88 (15%) were attending for antenatal care. HIV infection prevalence was higher among APC attendees than among antenatal care attendees (17% vs 6%; P < .007), but for the prevalence of HSV-2 infection, a marker of sexually acquired HIV, the converse was true (4% vs 14%; P < .002). Seventy (81%) of 86 HIV-positive APC attendees were previously undiagnosed. They had a broad range of presenting complaints, with a median CD4 cell count of 329 cells/microL (interquartile range, 176-485 cells/microL) and a high prevalence of stunting, compared with the corresponding prevalence among HIV-negative attendees (40% vs 12%; P < .001). Maternal transmission was considered to be likely by 69 (80%) of the 86 HIV-positive APC attendees, only one of whom was HSV-2 positive., Conclusions: Unrecognized HIV infection was a common cause of primary care attendance. Routine HIV counseling and testing implemented at the primary care level may provide a simple and effective way of identifying older long-term survivors of mother-to-child transmission before the onset of severe immunosuppression and irreversible complications.

Background: Survival to older childhood with untreated, vertically acquired HIV infection, which was previously considered extremely unusual, is increasingly well described. However, the overall impact on adolescent health in settings with high HIV seroprevalence has not previously been investigated., Methods and Findings: Adolescents (aged 10-18 y) systematically recruited from acute admissions to the two public hospitals in Harare, Zimbabwe, answered a questionnaire and underwent standard investigations including HIV testing, with consent. Pre-set case-definitions defined cause of admission and underlying chronic conditions. Participation was 94%. 139 (46%) of 301 participants were HIV-positive (median age of diagnosis 12 y: interquartile range [IQR] 11-14 y), median CD4 count = 151; IQR 57-328 cells/microl), but only four (1.3%) were herpes simplex virus-2 (HSV-2) positive. Age (median 13 y: IQR 11-16 y) and sex (57% male) did not differ by HIV status, but HIV-infected participants were significantly more likely to be stunted (z-score<-2: 52% versus 23%, p<0.001), have pubertal delay (15% versus 2%, p<0.001), and be maternal orphans or have an HIV-infected mother (73% versus 17%, p<0.001). 69% of HIV-positive and 19% of HIV-negative admissions were for infections, most commonly tuberculosis and pneumonia. 84 (28%) participants had underlying heart, lung, or other chronic diseases. Case fatality rates were significantly higher for HIV-related admissions (22% versus 7%, p<0.001), and significantly associated with advanced HIV, pubertal immaturity, and chronic conditions., Conclusion: HIV is the commonest cause of adolescent hospitalisation in Harare, mainly due to adult-spectrum opportunistic infections plus a high burden of chronic complications of paediatric HIV/AIDS. Low HSV-2 prevalence and high maternal orphanhood rates provide further evidence of long-term survival following mother-to-child transmission. Better recognition of this growing phenomenon is needed to promote earlier HIV diagnosis and care.

Objectives: Clinical algorithms can be helpful in decisions about treatment and feeding options in infancy, but have had limited exposure to real data. This analysis uses data from a large clinical trial to test such algorithms, and thereby develop a successor which performs usefully in poor countries with high HIV-prevalence., Methods: The ZVITAMBO trial followed 14 110 mother-baby pairs through infancy. 32% of mothers were HIV-positive. Infants were HIV tested regularly using DNA PCR. Clinical signs were evaluated in terms of identifying HIV-infection at 6 weeks, 6 and 12 months, using Zimbabwean, South African, and WHO generic adaptations of the WHO integrated management of childhood illness HIV algorithm. A modification, in which HIV-exposed infants are first divided into being at least or less than median weight-for-age, was derived and evaluated., Results: At 6 weeks 65% of all infected babies are less than median weight-for-age. Adding at least two clinical signs reduces sensitivity to 20% but those identified are 1.5 (95% CI 1.1-2.1) times more likely to die by 6 months than other infected infants. At 6 months, 86% of uninfected babies of HIV-infected mothers can be identified by selecting those whose weight is greater than median or, if less than median, who exhibit <2 clinical signs., Conclusions: In poor settings a simple clinical algorithm can identify children with probable HIV infection, especially those at risk of early death, who can then be referred for further testing and care, including highly active antiretroviral therapy. Most infants who are HIV-uninfected can be identified at 6 months and provided with support to maintain infection-free survival, including focussed infant-feeding counselling.

We assessed the sensitivity and specificity of a newly developed DNA PCR kit (Roche Diagnostic Corporation, Indianapolis, Ind.) that incorporates primers for all the group M viruses for the detection of human immunodeficiency virus (HIV) type 1 (HIV-1) infection in Zimbabwe. A total of 202 whole-blood samples from adults whose HIV status was known were studied. This included 100 HIV-1-positive and 102 HIV-1-negative samples selected on the basis of concordant results obtained with two enzyme-linked immunosorbent assay kits. The prototype Roche DNA PCR assay had a 100% sensitivity for the detection of HIV-1 DNA and a specificity of 100%. We conclude that the new Roche DNA PCR kit is accurate for the detection of HIV DNA in Zimbabwean samples, in which HIV-1 subtype C dominates.

Despite rapidly increasing measles immunization coverage in Harare city, measles remains endemic, and regular outbreaks occur. The most recent occurred in 1988, when the measles immunization coverage was 83%. We have carried out a retrospective study of the clinical and epidemiological features of this outbreak to assess whether the present immunization policy needs to be changed. Of 4357 cases of measles seen at primary health care centres and hospitals in Harare during the outbreak, 1399 (32%) were severe or involved complications that required hospital admission. The peak incidence occurred among under-2-year-olds, followed by that among 5-7-year-olds. Poor nutritional status was significantly more frequent among children who were hospitalized and among those who died. A total of 59% of all cases aged 9-59 months had documented evidence of measles immunization. The most frequent complications, which occurred most often among under-5-year-olds, were diarrhoea with dehydration, pneumonia, laryngotracheobronchitis, and convulsions, which together affected 56% of hospitalized cases. The hospital case fatality rate was low (1.43%). In Harare, measles transmission remains a problem, despite high measles immunization coverage rates; the failure rate for the standard Schwarz measles vaccine also appears to be high. There is a need to reduce the number of measles cases among under-9-month-olds and young children. Further studies into alternative measles vaccines and schedules are required.