Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial.

BACKGROUND: We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin. METHODS: Infants with HIV aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported. RESULTS: Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively. CONCLUSIONS: Dolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

Influence of age and co-medication on dolutegravir glucuronidation in paediatric patients.

Dolutegravir (DTG) is primarily metabolized by uridine diphosphate glucuronosyltransferases, forming the pharmacologically inactive DTG glucuronide (DTG-gluc). We described the dolutegravir metabolic ratio (DTG-MR; DTG-gluc AUC0-24h divided by DTG AUC0-24h) in 85 children with HIV aged 3 months to 18 years receiving DTG in the CHAPAS-4 (ISRCTN22964075) and ODYSSEY (NCT02259127) trials. Additionally, we assessed the influence of age, body weight, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, rifampicin use and kidney function on DTG-MR. The overall geometric mean (CV%) DTG-MR was 0.054 (52%). Rifampicin use was the only significant factor associated with DTG-MR (P < .001) in multiple linear regression. DTG-MR geometric mean ratio was 1.81 (95% CI: 1.57-2.08) for children while on vs. off rifampicin. This study showed that overall DTG-MR in children was similar to adults, unaffected by age or NRTI backbone, and increased with rifampicin co-administration. These findings support future paediatric pharmacokinetic modelling and extrapolation from adult data.

Postnatal care and acceptability of emollient therapy in very low birthweight infants in Harare, Zimbabwe: a qualitative analysis.

BACKGROUND: Preterm birth (birth before 37 completed weeks of pregnancy) is the leading cause of neonatal and child under-five mortality globally, both of which are highest regionally in sub-Saharan Africa. The skin barrier plays a critical role in neonatal health and increasing evidence supports the use of topical emollient therapy to promote postnatal growth and reduce hospital-acquired infections in preterm infants. The World Health Organization (WHO) currently recommends emollient therapy in preterm or low birthweight infants globally but calls for further research on impacts of emollient use, especially in Africa. Little is known about postnatal skincare practices and the tradition of oil massage across sub-Saharan Africa. Further documentation is necessary to understand the context for future emollient intervention trials. METHODS: 61 semi-structured interviews with mothers who just delivered preterm or term infants and 4 focus group discussions (32 participants) with physician and nurse providers of newborn care were conducted at Sally Mugabe Central Hospital (SMCH), in Harare, Zimbabwe. SMCH is the principal public-sector tertiary care hospital for newborn infants in the northern part of the country. Mothers and healthcare professionals were questioned about newborn care at the hospital, current neonatal skincare and bathing practices, and the community's receptivity to a future emollient therapy clinical trial. RESULTS: Postnatal skincare is centrally important to Zimbabwean communities and petroleum jelly application is nearly universal. The use of cooking oil and other natural oils on infants is also part of traditional customs. The primary needs and desires of mothers who have just given birth to preterm infants are having greater agency in their children's care and financial support in purchasing prescribed medications while at the hospital. Community receptivity to emollient therapy as a cost-effective treatment is high, particularly if mothers are trained to assist with the intervention. CONCLUSION: Emollient therapy will likely be well-received by communities in and around Harare because of its accordance with current skincare practices and perceptions; however, cultural norms and the experiences of new mothers who have given birth at a facility highlight challenges and considerations for future clinical trial execution. TRIAL REGISTRATION: Clinicaltrials.gov NCT05461404.

Borrowing information across patient subgroups in clinical trials, with application to a paediatric trial.

BACKGROUND: Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. METHODS: We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined. RESULTS: The methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing < 14 kg in whom the treatment effect will be estimated separately. Expert clinical opinion was elicited and demonstrated that substantial borrowing is supported. Clinical experts chose on average to allocate a relative weight of 78% (reduced from 90% based on sample size) to data from children weighing ≥ 14 kg in a Bayesian analysis of the children weighing < 14 kg. The total effective sample size in the Bayesian analysis was 386 children, providing 84% predictive power to exclude a difference of more than 10% between arms, whereas the 85 younger children weighing < 14 kg provided only 20% power in a standalone frequentist analysis. CONCLUSIONS: Borrowing information from a larger subgroup or subgroups can facilitate estimation of treatment effects in small subgroups within a clinical trial, leading to improved power and precision. Informative prior distributions for interaction parameters are required to inform the degree of borrowing and can be informed by expert opinion. We demonstrated accessible methods for obtaining opinions.

Incidence and Progression of Echocardiographic Abnormalities in Older Children with Human Immunodeficiency Virus and Adolescents Taking Antiretroviral Therapy: A Prospective Cohort Study.

BACKGROUND: A high prevalence of cardiac abnormalities has been reported in children with human immunodeficiency virus (HIV) taking antiretroviral therapy (ART) in sub-Saharan Africa. We investigated the incidence and progression of cardiac abnormalities among children taking ART in Zimbabwe. METHODS: A prospective cohort study was conducted at a pediatric HIV clinic from 2014 to 2017. Children with HIV aged between 6 and 16 years and taking ART ≥6 months were enrolled. Transthoracic echocardiography was performed at baseline and after 18 months. RESULTS: Of 197 participants recruited at baseline, 175 (89%; 48% female; median age 12 years, interquartile range 10-14 years) were followed up. The incidences of left and right heart abnormalities were 3.52 and 5.64 per 100 person-years, respectively. Stunting was associated with the development of any cardiac abnormality (adjusted odds ratio 2.59, 95% confidence interval 1.03-6.49; P = .043). Right ventricular (RV) dilatation persisted at follow-up in 92% of participants and left ventricular (LV) diastolic dysfunction in 88%. Cardiac abnormalities present at baseline reverted to normal over the follow-up period in 11 (6%). There was an overall increase in mean z scores for LV, left atrium (LA), RV, interventricular septum, and LV posterior wall diameters at 18 months (P < .001). CONCLUSIONS: Despite ART, children with HIV have a high incidence of cardiac abnormalities, with only a minority being transient. Mean z scores for LV, LA, RV, interventricular septum, and LV posterior wall diameters increased over a relatively short follow-up period, suggesting the potential for progression of cardiac abnormalities. Longer follow-up is required to understand the clinical implications of these abnormalities.

Monovalent Rotavirus Vaccine Effectiveness Against Rotavirus Hospitalizations Among Children in Zimbabwe.

BACKGROUND: Rotavirus is a leading cause of mortality among children <5 years old. We evaluated monovalent rotavirus vaccine effectiveness (VE) under conditions of routine use at 2 surveillance sites in Harare, Zimbabwe, after vaccine introduction in May 2014. METHODS: Children aged <5 years hospitalized or treated in the accident and emergency department (A&E) for acute watery diarrhea were enrolled for routine surveillance. Copies of vaccination cards were collected to document vaccination status. Among children age-eligible to receive rotavirus vaccine, we estimated VE, calculated as 1 - odds ratio, using a test-negative case-control design. RESULTS: We included 903 rotavirus-positive cases and 2685 rotavirus-negative controls in the analysis; 99% had verified vaccination status. Rotavirus-positive children had more severe diarrhea than rotavirus-negative children; 61% of cases and 46% of controls had a Vesikari score ≥11 (P < .01). Among cases and controls, 31% and 37%, respectively, were stunted for their age (P < .01). Among children 6-11 months old, adjusted 2-dose VE against hospitalization or treatment in A&E due to rotavirus of any severity was 61% (95% confidence interval [CI], 21%-81%) and 68% (95% CI, 13%-88%) against severe rotavirus disease. Stratified by nutritional status, adjusted VE was 45% (95% CI, -148% to 88%) among stunted infants and 71% (95% CI, 29%-88%) among infants with a normal height for age. CONCLUSIONS: Monovalent rotavirus vaccine is effective in preventing hospitalizations due to severe rotavirus diarrhea among infants in Zimbabwe, providing additional evidence for countries considering rotavirus vaccine introduction that live, oral rotavirus vaccines are effective in high-child-mortality settings.

Racial Variation in Echocardiographic Reference Ranges for Left Chamber Dimensions in Children and Adolescents: A Systematic Review.

Echocardiography plays a critical role in the assessment of cardiac disease. Important differences in echocardiographically derived cardiac chamber dimensions have been previously highlighted in different population groups in adult studies, but this has not been systematically studied in children, whose body size changes throughout childhood. The aim of this study was to review the distribution of available reference ranges for the left cardiac chamber dimensions in older children and adolescents. The following electronic data bases were searched: Medline, Embase and Web of Science were searched to identify studies which have established echocardiographic reference ranges of left heart parameters in children and adolescents from 1975 to December 2017. There was no geographical limitation. All results were imported into Endnote. Retrieved articles were screened and data extracted by two independent reviewers. A total of 4398 studies were retrieved, with 36 studies finally included in this review. 29 (81%) references were from North America and European (Caucasians) populations, with only one study each from Africa and South America. Two-dimensional and M-mode techniques were the most commonly used echocardiography techniques. There were methodological variations in techniques and normalisation of references. Comparison of selected cardiac measures showed significant differences for interventricular septal thickness among Black African, Indian, German and US American children. Available echocardiographic references cannot be generalised to all settings and therefore, there is need for locally relevant reference ranges. Africa and South America are particularly under-represented. Future studies should focus on developing comprehensive echocardiographic reference ranges for children from different racial backgrounds and should use standardised techniques.

Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children.

BACKGROUND: Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS: In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS: A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06). CONCLUSIONS: Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

Hematological and biochemical laboratory reference intervals for Zimbabwean adolescents.

BACKGROUND: Reference intervals are used as an aid in the interpretation of laboratory results. Most developing countries do not have reference intervals specific to adolescents. This study was aimed at establishing hematological and biochemical reference intervals for adolescents aged ≥ 12 years to < 18 years. METHODS: A community based, cross sectional study was conducted using the multistage sampling technique. Participants were enrolled from the UZ-UCSF research study catchment areas of Harare, Chitungwiza, and Mutoko. Samples were transported for analysis at the UZ-UCSF Central Laboratory under recommended conditions. The data analysis presented in this paper is for 302 adolescents aged ≥ 12 to < 18. Non-parametric statistical methods were used to estimate the 95% reference limits for the hematological and biochemical parameters, with the lower limit defined as the 2.5 percentile and the upper limit defined as the 97.5 percentile of the distribution. RESULTS: A total of 302 adolescents were included. Results show significant differences between males and females in hematological parameters except platelets, eosinophils, basophils, and red cell distribution width. The biochemical parameters which showed significant differences between males and females were phosphate, ALP, ALT, AST, GGT, and lipase. CONCLUSIONS: Hematological indices and liver function tests differ significantly by gender and this should be considered when defining normal intervals.

Overview of the Global and US Burden of Preterm Birth.

Preterm birth (PTB) is the leading cause of morbidity and mortality in children globally, yet its prevalence has been difficult to accurately estimate due to unreliable methods of gestational age dating, heterogeneity in counting, and insufficient data. The estimated global PTB rate in 2020 was 9.9% (95% confidence interval: 9.1, 11.2), which reflects no significant change from 2010, and 81% of prematurity-related deaths occurred in Africa and Asia. PTB prevalence in the United States in 2021 was 10.5%, yet with concerning racial disparities. Few effective solutions for prematurity prevention have been identified, highlighting the importance of further research.

Electronic monitoring device informed interventions for treatment adherence and clinical outcomes in children and adolescents: A systematic review.

OBJECTIVE: To systematically review literature from randomised controlled trials (RCTs) investigating the effectiveness of electronic monitoring device informed interventions on adherence and clinical outcomes in children and adolescents with chronic conditions. STUDY DESIGN: A systematic review was conducted. An electronic literature search covering studies, with no pre-specified starting date up to June 2024, was performed in Medline, EMBASE, Web of Science, Cochrane and Trials databases was conducted. PARTICIPANTS: RCTs of electronic monitoring device informed interventions in individuals aged 0 to 18 years with chronic conditions, were identified, with no restriction on geography or publication date. METHODS: Extracted data was synthesised. As a result of differences in definitions and analysis of adherence and clinical outcomes across the studies a pooled meta-analysis was not possible therefore, a descriptive analysis was conducted. Risk of bias across all studies was assessed using the Cochrane Collaboration risk of bias tool. RESULTS: 11 RCTs, with 1485 children and adolescents were included. Studies were all from high- and middle-income countries, conducted among children and adolescents with asthma, and one each among children and adolescents with kidney transplant, multiple sclerosis, and epilepsy. Eight of the 11 studies reported a positive effect on adherence. Only four studies reported a positive effect on clinical outcomes and seven studies found no effect on clinical outcomes. CONCLUSIONS: Electronic monitoring device interventions show promise in improving adherence in children and adolescents with chronic conditions, in a limited number of chronic conditions, mostly asthma. Evidence for the efficacy of electronic monitoring device informed interventions on clinical outcomes and from low-income settings is lacking. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022312057, registered in March 2022. TWEETABLE ABSTRACT: Electronic monitoring device informed interventions may improve treatment adherence in children and adolescents with chronic conditions but evidence from low-income settings is lacking @nyasha_dzavakwa @KatharinaKranz4 @dopapus @hilda_mujuru @rashida_abbferr @vickysimms_epi.

Prevalence of chronic conditions and multimorbidity among healthcare workers in Zimbabwe: Results from a screening intervention.

The burden of non-communicable diseases (NCDs) in southern Africa is expanding and is superimposed on high HIV prevalence. Healthcare workers are a scarce resource; yet are vital to health systems. There are very limited studies on the burden of chronic conditions among healthcare workers in Africa, and none exploring multimorbidity (≥2 chronic conditions). We describe the epidemiology of infectious (HIV) and non-communicable chronic conditions, and multimorbidity, among Zimbabwean healthcare workers. Healthcare workers (≥18 years) in eight Zimbabwean provinces were invited to a voluntary, cross-sectional health-check, including HIV, diabetes, hypertension and mental health screening. Statistical analyses described the prevalence and risk factors for multimorbidity (two or more of HIV, diabetes, hypertension or common mental disorder) and each condition. Missing data were handled using multiple imputation. Among 6598 healthcare workers (July 2020-July 2022) participating in the health-check, median age was 37 years (interquartile range 29-44), 79% were women and 10% knew they were living with HIV. Half had at least one chronic condition: 11% were living with HIV, 36% had elevated blood pressure, 12% had elevated HbA1c and 11% had symptoms of common mental disorder. The overall prevalence of multimorbidity was 15% (95% CI: 13-17%); 39% (95% CI: 36-43%) among people aged 50 and older. Whilst most HIV was diagnosed and treated, other chronic conditions were usually undiagnosed or uncontrolled. Limiting our definition of multimorbidity to two or more screened conditions sought to reduce bias due to access to diagnosis, however, may have led to a lower reported prevalence than that found using a wider definition. Half of healthcare workers screened were living with a chronic condition; one in seven had multimorbidity. Other than HIV, most conditions were undiagnosed or untreated. Multisectoral action to implement contextually relevant, chronic disease services in Africa is urgently needed. Specific attention on health workers is required to protect and retain this critical workforce.

Asthma symptoms, severity, and control with and without a clinical diagnosis of asthma in early adolescence in sub-Saharan Africa: a multi-country, school-based, cross-sectional study.

BACKGROUND: Rapid urbanisation and population growth in sub-Saharan Africa has increased the incidence of asthma in children and adolescents. One major barrier to achieving good asthma control in these adolescents is obtaining a clinical diagnosis. To date, there are scant data on prevalence and severity of asthma in undiagnosed yet symptomatic adolescents. We therefore aimed to assess symptom prevalence and severity, the effect of symptoms on daily life, and objective evidence of asthma in young adolescents from sub-Saharan Africa with and without a clinical diagnosis of asthma by spirometry and fractional exhaled nitric oxide (FeNO). METHODS: We designed a two-phase, multi-country, school-based, cross-sectional study to assess symptom prevalence and severity in sub-Saharan African adolescents. In phase 1 we surveyed young adolescents aged 12-14 years who were attending selected primary and secondary schools in Blantyre in Malawi, Durban in South Africa, Harare in Zimbabwe, Kampala in Uganda, Kumasi in Ghana, and Lagos in Nigeria. The adolescents were screened for asthma symptoms using the International Study of Asthma and Allergies in Children (ISAAC) questionnaire. Then, after opt-in consent, symptomatic adolescents were invited to complete a detailed survey on asthma severity, treatment, and exposure to environmental risk factors for phase 2. Adolescents performed the European Respiratory Society's diagnostic tests for childhood asthma. A positive asthma test was classified as a forced expiratory volume in 1 sec (FEV1) predicted under 80%, a FEV1 under the lower limits of normal, or FEV1 divided by forced vital capacity (FEV1/FVC) under the lower limits of normal; positive bronchodilator responsiveness or reversibility was defined as either an increase in absolute FEV1 of 12% or more, or an increase of 200 mL or more, or both, after 400 µg of salbutamol (shortacting ß2 agonist) administered via a metered-dose inhaler and spacer, or FeNO of 25 parts per billion or higher, or any combination of these. The study was registered with ClinicalTrials.gov (NCT03990402) and is complete. FINDINGS: Between Nov 1, 2018, and Nov 1, 2021, we recruited 149 schools from six regions in six sub-Saharan countries to participate in the study. We administered phase 1 asthma questionnaires from Jan 20, 2019 to Nov 11, 2021, and from 27 407 adolescents who were screened, we obtained data for 27 272 (99·5%). Overall, 14 918 (54·7%) adolescents were female and 12 354 (45·3%) adolescents were male, and the mean age was 13 years (IQR 12-13); nearly all recruited adolescents were of black African ethnicity (26 821 [98·3%] of 27 272). In phase 1, a total of 3236 (11·9% [95% CI 11·5-12·3]) reported wheeze in the past 12 months, and 644 (19·9%) of 3236 had a formal clinical diagnosis of asthma. The prevalence of adolescents with asthma symptoms ranged from 23·8% in Durban, South Africa to 4·2% Blantyre, Malawi. Using ISAAC criteria, severe asthma symptoms were reported by 2146 (66·3%) of 3236 adolescents, the majority of whom (1672 [77·9%] of 2146) had no diagnosis of asthma by a clinician. Between July 16, 2019, and Nov 26, 2021, we administered the phase 2 questionnaire to the 1654 adolescents who had asthma symptoms in phase 1 and consented to proceed to the second phase. In the phase 2 cohort, 959 (58·0%) were female and 695 (42·0%) were male, and the mean age was 13 years (IQR 12-14). One or more diagnostic tests for asthma were obtained in 1546 (93·5%) of 1654 participants. One or more positive asthma tests were found in 374 (48·8%) of 767 undiagnosed adolescents with severe symptoms, and 176 (42·4%) of 415 of undiagnosed adolescents with mild-to-moderate symptoms. Of the 392 adolescents in phase 2 with clinician-diagnosed asthma, 294 (75·0%) reported severe asthma symptoms, with 94 (32·0%) of those with severe symptoms not using any asthma medication. In general, findings in both phases 1 and 2 were consistent across sub-Saharan African countries. INTERPRETATION: A large proportion of adolescents in sub-Saharan Africa with symptoms of severe asthma do not have a formal diagnosis of asthma and are therefore not receiving appropriate asthma therapy. To improve the poor state of asthma control in sub-Saharan Africa, potential solutions such as educational programmes, better diagnosis, and treatment and screening in schools should be considered. FUNDING: UK National Institute for Health and Care Research and UK Medical Research Council.

Renal abnormalities among HIV-infected, antiretroviral naive children, Harare, Zimbabwe: a cross-sectional study.

BACKGROUND: Data on the prevalence of renal and urine abnormalities among HIV-infected children in Sub-Saharan Africa are limited. We set out to determine the prevalence of proteinuria; low estimated glomerular filtration rate (eGFR), urinary tract infection and associated factors among HIV-infected antiretroviral therapy (ART) naive children, aged 2-12 years, attending the paediatric HIV clinic at a tertiary hospital in Harare. METHODS: Consecutive ART naive children attending the clinic between June and October 2009 were recruited. Detailed medical history was obtained and a complete physical examination was performed. Children were screened for urinary tract infection and for significant persistent proteinuria. Serum creatinine was used to estimate GFR using the modified Counahan-Barratt formula. The Student's t-test was used to analyse continuous variables and the chi-square or Fisher's exact test was used to analyse categorical data. Logistic regression was performed to assess the relationship between study factors and urine abnormalities, persistent proteinuria and the eGFR. RESULTS: Two hundred and twenty children were enrolled into the study. The median age was 90 months (Q1=65.5; Q3=116.5). The prevalence of urinary tract infection was 9.5%. Escherichia coli was the predominant organism. There was uniform resistance to cotrimoxazole. Persistent proteinuria (urine protein to creatinine ratio greater than 0.2, a week apart) was found in 5% of the children. Seventy-five children (34.6%) had mild to moderate renal impairment shown by a low eGFR (30 to <90 ml/min/1.73 m2). Persistent proteinuria was more likely to be found in children who were wasted, weight-for-height (WHZ) z-score <-2 (p=0.0005). Children with WHO clinical stage 4 were more likely to have a low eGFR than children with less advanced stages (OR 2.68; CI 1.24-5.80). Urine abnormalities were more likely to be observed in children with WHO clinical stages 3 and 4 (OR 2.20; CI 1.06-4.60). CONCLUSION: There is significant renal impairment among HIV-infected, ART naive children aged 2-12 years attending the outpatient paediatric HIV clinic at Harare Central Hospital. The abnormalities are more likely to occur in children with advanced HIV/AIDS. Screening for renal impairment and urinary tract infections in HIV-infected children before initiation of ART and regularly thereafter would be helpful in their management. KEYWORDS: HIV, renal disease, persistent proteinuria, glomerular filtration rate, urinary tract infection.

Brief Report: Suboptimal Lopinavir Exposure in Infants on Rifampicin Treatment Receiving Double-dosed or Semisuperboosted Lopinavir/Ritonavir: Time for a Change.

BACKGROUND: Although super-boosted lopinavir/ritonavir (LPV/r; ratio 4:4 instead of 4:1) is recommended for infants living with HIV and receiving concomitant rifampicin, in clinical practice, many different LPV/r dosing strategies are applied due to poor availability of pediatric separate ritonavir formulations needed to superboost. We evaluated LPV pharmacokinetics in infants with HIV receiving LPV/r dosed according to local guidelines in various sub-Saharan African countries with or without rifampicin-based tuberculosis (TB) treatment. METHODS: This was a 2-arm pharmacokinetic substudy nested within the EMPIRICAL trial (#NCT03915366). Infants aged 1-12 months recruited into the main study were administered LPV/r according to local guidelines and drug availability either with or without rifampicin-based TB treatment; during rifampicin cotreatment, they received double-dosed (ratio 8:2) or semisuperboosted LPV/r (adding a ritonavir 100 mg crushed tablet to the evening LPV/r dose). Six blood samples were taken over 12 hours after intake of LPV/r. RESULTS: In total, 14/16 included infants had evaluable pharmacokinetic curves; 9/14 had rifampicin cotreatment (5 received double-dosed and 4 semisuperboosted LPV/r). The median (IQR) age was 6.4 months (5.4-9.8), weight 6.0 kg (5.2-6.8), and 10/14 were male. Of those receiving rifampicin, 6/9 infants (67%) had LPV Ctrough <1.0 mg/L compared with 1/5 (20%) in the control arm. LPV apparent oral clearance was 3.3-fold higher for infants receiving rifampicin. CONCLUSION: Double-dosed or semisuperboosted LPV/r for infants aged 1-12 months receiving rifampicin resulted in substantial proportions of subtherapeutic LPV levels. There is an urgent need for data on alternative antiretroviral regimens in infants with HIV/TB coinfection, including twice-daily dolutegravir.

First-Line Antituberculosis Drug Concentrations in Infants With HIV and a History of Recent Admission With Severe Pneumonia.

Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants.

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial.

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124-159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir. FUNDING: Penta Foundation, ViiV Healthcare, and UK Medical Research Council.

Proinflammatory and cardiovascular biomarkers are associated with echocardiographic abnormalities in children with HIV taking antiretroviral therapy.

OBJECTIVES: Children with perinatally acquired HIV (PHIV) and taking antiretroviral therapy (ART) have a high prevalence of subclinical cardiac disease. We hypothesized that cardiac disease may be a consequence of dysregulated systemic immune activation driven by HIV infection. We examined cardiovascular and proinflammatory biomarkers and their association with echocardiographic abnormalities in children with PHIV. DESIGN: Cross-sectional analysis of soluble biomarkers from a prospective cohort of children aged 6-16 years with PHIV and age-matched HIV-uninfected comparison group. METHODS: Cryopreserved plasma samples were used to measure seven soluble biomarkers using multiplex bead assay (Luminex). Multivariable logistic regression assessed how biomarker levels related to cardiac abnormalities. RESULTS: A total of 406 children participated in this study (195 PHIV and 211 HIV-uninfected). Mean [standard deviation (SD)] ages of PHIV and HIV-uninfected participants were 10.7 (2.6) and 10.8 (2.8) years, respectively. Plasma levels of CRP, TNF-α, ST2, VCAM-1 and GDF-15 were significantly higher in the PHIV group compared with uninfected control ( P  < 0.001). Among children with PHIV, with one-unit representing one SD in biomarker level, a one-unit increase in CRP and GDF-15, was associated with increased odds of having left ventricular (LV) diastolic dysfunction [adjusted odds ratio (aOR), 1.49 (1.02-2.18; P  < 0.040)] and [aOR 1.71 (1.18-2.53; P  = 0.006)], respectively. Each one unit increase in GDF-15 was associated with increased odds of LV hypertrophy [aOR 1.84 (95% CI 1.10-3.10; P  < 0.021)]. CONCLUSION: Children with PHIV had higher levels of proinflammatory and cardiovascular biomarkers compared with HIV-uninfected children. Increased CRP and GDF-15 were associated with cardiac abnormalities in children with PHIV.

Enhanced surveillance for adverse events following immunization during the 2019 typhoid conjugate vaccine campaign in Harare, Zimbabwe.

BACKGROUND: During February 25-March 4, 2019, Zimbabwe's Ministry of Health and Child Care conducted an emergency campaign using 342,000 doses of typhoid conjugate vaccine (TCV) targeting individuals 6 months-15 years of age in eight high-risk suburbs of Harare and up to 45 years of age in one suburb of Harare. The campaign represented the first use of TCV in Africa outside of clinical trials. METHODS: Three methods were used to capture adverse events during the campaign and for 42 days following the last dose administered: (1) active surveillance in two Harare hospitals, (2) national passive surveillance, and (3) a post-campaign coverage survey. RESULTS: Thirty-nine adverse events were identified during active surveillance, including 19 seizure cases (16 were febrile), 16 hypersensitivity cases, 1 thrombocytopenia case, 1 anaphylaxis case, and two cases with two conditions. Only 21 (54%) of 39 patients were hospitalized and 38 recovered without sequelae. Attack rates per 100,000 TCV doses administered were highest for seizures (6.27) and hypersensitivity (5.02). Only 6 adverse events were reported through passive surveillance by facilities other than the two active surveillance hospitals. A total of 177 (10%) of 1,817 vaccinees surveyed reported experiencing an adverse event during the post-campaign coverage survey, of which 25 (14%) sought care. CONCLUSIONS: In line with previous evaluations of TCV, enhanced adverse event monitoring during an emergency campaign supports the safety of TCV. The majority of reported events were minor or resulted in recovery without long-term sequelae. Attack rates for seizures and hypersensitivity were low compared with previous active surveillance studies conducted in Kenya and Burkina Faso. Strengthening adverse event monitoring in Zimbabwe and establishing background rates of conditions of interest in the general population may improve future safety monitoring during new vaccine introductions.