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BackgroundSuboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.MethodsWe systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially 0–24for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide.N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants ofCmaxwere generally similar to those for AUC0–24.ConclusionsThis study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

The emergence of COVID-19 by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) in 2019 has seen evolving data reporting infrequent infection in children and mostly mild disease for children who contract the infection. A severe form of COVID-19 in children recently reported in Europe and North America describes a multisystem inflammation syndrome in children (MIS-C), presenting as toxic-shock-like and Kawasaki-like syndromes. Data on MIS-C in Africa is being documented with recent reports from South Africa and Nigeria in black children, but information on MIS-C in Ghana is yet to be characterized. We report the first case of multisystem inflammatory syndrome in a child who tested PCR positive to SARS-CoV2 in a tertiary hospital in Ghana. The case describes a 10- year-old boy who reported Kawasaki-like syndrome without shock but with moderate respiratory distress requiring supportive acute care without the need for intensive care. © 2021 Ghana Medical Association. All Rights Reserved.

Nearly 50% of the world population and 60% of children aged 0 to 14 years live in low- or lower-middle–income countries. Paediatric nephrology (PN) in these countries is not a priority for allocation of limited health resources. This article explores advancements made and persisting limitations in providing optimal PN services to children in such under-resourced areas (URA). Medline, PubMed and Google Scholar online databases were searched for articles pertaining to PN disease epidemiology, outcome, availability of services and infrastructure in URA. The ISN and IPNA offices were contacted for data, and two online questionnaire surveys of IPNA membership performed. Regional IPNA members were contacted for further detailed information. There is a scarcity of published data from URA; where available, prevalence of PN diseases, managements and outcomes are often reported to be different from high income regions. Deficiencies in human resources, fluoroscopy, nuclear imaging, immunofluorescence, electron microscopy and genetic studies were identified. Several drugs and maintenance kidney replacement therapy are inaccessible to the majority of patients. Despite these issues, regional efforts with support from international bodies have led to significant advances in PN services and infrastructure in many URA. Equitable distribution and affordability of PN services remain major challenges in URA. The drive towards acquisition of regional data, advocacy to local government and non-government agencies and partnership with international support bodies needs to be continued. The aim is to optimise and achieve global parity in PN training, investigations and treatments, initially focusing on preventable and reversible conditions.

Background The prevalence of end-stage renal disease is purported to be increasing in Low- and Middle-Income Countries (LMIC) but interventions for renal replacement therapy in these settings are limited. There is limited data on the demography, clinical features, aetiology and outcomes of chronic kidney disease (CKD) admissions in LMIC. We aimed to describe the demographic profile and outcomes of End-Stage Kidney Diseases among children admitted to a paediatric renal unit in a resource-limited setting from January 2014 to December 2015. Methods A retrospective analysis of data of children admitted with ESRD was conducted by review of medical charts. Results Over the two year period reviewed there were 300 admissions into the renal unit of which 64 (21.3%) had ESRD. The mean ± SD age at presentation was 9.3 ± 3.0 years with a preponderance of females- 38 (60%) and no significant age differences according to gender. The mean ± SD eGFR on admission was 5.6 ± 2.9 ml/min/1.73m2. A total of 27 (42.2%) children with ESRD died in hospital. None of the children who survived acute admissions were offered long-term renal replacement therapy or renal transplant because these services are non-existent in Ghana. Conclusion ESRD is a frequent cause of admission among Ghanaian children presenting to the renal unit with no facility for Renal Replacement Therapy. All these children will thus invariably die from complications of uraemia. Steps to set up renal replacement therapy services for children in Ghana are thus urgently needed to reverse these disturbing trends.

BackgroundSDG3 stipulates good health and well-being for all. Dialysis has remained a specialized skill for nephrologists. In settings without nephrologists, many die from Acute Kidney Injury (AKI). In 2014, the International Society of Nephrology (ISN) launched the 0by25 initiative for zero death from AKI globally. In this paper, we report on training of district health practitioners in the performance of PD for AKI using improvised means. Methods PD training workshops with hands-on experienced were organized in 7 regional capitals in Ghana. Topics taught included: Recognition of a child with AKI Principles of PD Indications for dialysis therapy and writing of PD prescription Technique in insertion of PD catheter plus video exhibit Catheters suitable for use as PD catheters Fluids suitable for use as dialysate Performing the PD exchanges Complications related to PD Infection prevention in PD. Results A total of 150 health workers made up of 131 Doctors or Physician Assistants and 19 nurses were trained across Ghana. Feedback from trainees indicates that 42 PDs have been carried out in 7 district hospitals. 25 (59.5%) of the 42 dialyzed children survived and recovered renal function. Conclusion It is possible to build the capacity of non-nephrologists to identify AKI and institute PD in district level hospitals so SDG3 could be realized. Such achievement will also help to realize the ISN 0by25 initiative especially in resource-limited settings where nephrology expertise is lacking.

Peritoneal dialysis (PD) for acute kidney injury (AKI) in children has a long track record and shows similar outcomes when compared to extracorporeal therapies. It is still used extensively in low resource settings as well as in some high resource regions especially in Europe. In these regions, there is particular interest in the use of PD for AKI in post cardiac surgery neonates and low birthweight neonates. Here, we present the update of the International Society for Peritoneal Dialysis guidelines for PD in AKI in paediatrics. These guidelines extensively review the available literature and present updated recommendations regarding peritoneal access, dialysis solutions and prescription of dialysis.Summary of recommendations1.1 Peritoneal dialysis is a suitable renal replacement therapy modality for treatment of acute kidney injury in children. (1C) 2. Access and fluid delivery for acute PD in children. 2.1 We recommend a Tenckhoff catheter inserted by a surgeon in the operating theatre as the optimal choice for PD access. (1B) (optimal) 2.2 Insertion of a PD catheter with an insertion kit and using Seldinger technique is an acceptable alternative. (1C) (optimal) 2.3 Interventional radiological placement of PD catheters combining ultrasound and fluoroscopy is an acceptable alternative. (1D) (optimal) 2.4 Rigid catheters placed using a stylet should only be used when soft Seldinger catheters are not available, with the duration of use limited to 2) may occur as tolerated by the patient. (practice point) 4.2 The initial exchange duration, including inflow, dwell and drain times, should generally be every 60–90 min; gradual prolongation of the dwell time can occur as fluid and solute removal targets are achieved. In neonates and small infants, the cycle duration may need to be reduced to achieve adequate ultrafiltration. (practice point) 4.3 Close monitoring of total fluid intake and output is mandatory with a goal to achieve and maintain normotension and euvolemia. (1B) 4.4 Acute PD should be continuous throughout the full 24-h period for the initial 1–3 days of therapy. (1C) 4.5 Close monitoring of drug dosages and levels, where available, should be conducted when providing acute PD. (practice point) 5. Continuous flow peritoneal dialysis (CFPD) 5.1 Continuous flow peritoneal dialysis can be considered as a PD treatment option when an increase in solute clearance and ultrafiltration is desired but cannot be achieved with standard acute PD. Therapy with this technique should be considered experimental since experience with the therapy is limited. (practice point) 5.2 Continuous flow peritoneal dialysis can be considered for dialysis therapy in children with AKI when the use of only very small fill volumes is preferred (e.g. children with high ventilator pressures). (practice point)

Despite available guidelines for disclosure of HIV status to children, most children living with HIV are unaware of their diagnosis. We sought to characterize the concepts of illness and treatment among children living with HIV who do not know their status. As part of the Sankofa trial we interviewed 435 children aged 6-18 enrolled in clinical care at pediatric HIV clinics at two teaching hospitals in Ghana. Theoretic thematic analysis generated themes among responses. The children believe they come to the clinic to collect medication, to address specific symptoms, to prevent and treat 'sickness', or as part of their routine. Most children learned of their 'illness' from a family member. A majority (73.5%) of children had never talked about their 'illness' with anyone else; many feared consequences. Children living with HIV who do not know their status exhibit signs of anticipated and internalized stigma regarding their unknown 'illness.' An understanding of the way children conceptualize their illness has implications for health promotion and the provision of appropriate information to children living with HIV.ClinicalTrials.gov Identifier NCT01701635.A pesar de las pautas disponibles para la divulgación del estado del VIH a los niños, la mayoría de los niños que viven con el VIH desconocen su diagnóstico. Intentamos describir los conceptos de enfermedad y tratamiento entre los niños que viven con el VIH que no conocen su estado de infeccion. Como parte del ensayo Sankofa, entrevistamos a 435 niños de 6 a 18 años inscritos en atención clínica cuidado en clínicas pediátricas de VIH en dos hospitales docentes en Ghana. El análisis temático teórico generó temas entre las respuestas obtenidas. Los niños creen que vienen a la clínica a recoger medicamentos, a tratar síntomas específicos, a prevenir y tratar “condiciones” o como parte de su cuidado rutinario. A traves de entrevistas, aprendimos que la mayoría de los niños aprendieron de su "enfermedad" de un miembro de la familia. Esta mayoría (73.5%) nunca habían hablado sobre su "enfermedad" con nadie más; debido a muchas consecuencias temidas. Los niños que viven con VIH que no conocen su estado, exhiben signos de estigma anticipado e internalizado con respecto a su "enfermedad" desconocida. El entender la forma en que los niños conceptualizan su enfermedad tiene implicaciones para la promoción de la salud y el suministro de información adecuada a los niños que viven con el VIH.

The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic which is primarily considered a respiratory illness. However, emerging reports show that the virus exhibits both pulmonary and extra-pulmonary manifestations in humans, with the kidney as a major extra-pulmonary target due to its abundant expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, which facilitate entry of the virus into cells. Acute kidney injury has become prevalent in COVID-19 patients without prior any history of kidney dysfunction. In addition, the virus also worsens kidney conditions and increases mortality of COVID-19 patients with pre-existing chronic kidney disease, renal cancer, diabetic nephropathy, end-stage kidney disease as well as dialysis and kidney transplant patients. In the search for antiviral agents for the treatment of COVID-19, hydrogen sulfide (H2S), the third established member of gasotransmitter family, is emerging as a potential candidate, possessing important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties. A recent clinical study revealed higher serum H2S levels in survivors of COVID-19 pneumonia with reduced interleukin-6 levels compared to fatal cases. In this review, we summarize the global impact of COVID-19 on kidney conditions and discuss the emerging role of H2S as a potential COVID-19 therapy.

Variants in the Apolipoprotein L1 (APOL1) gene (G1-rs60910145, rs73885319, G2-rs71785313) are common in Africans and in individuals of recent African ancestry and are associated with an increased risk of non-diabetic chronic kidney disease (CKD) and in particular of HIV associated nephropathy (HIVAN). In light of the significantly increased risk of HIVAN in carriers of two APOL1 risk alleles, a role in HIV infectivity has been postulated in the mechanism of APOL1 associated kidney disease. Herein, we aim to explore the association between HIV viremia and APOL1 genotype. In addition, we investigated interaction between BK and JC viruria, CKD and HIV viremia. A total of 199 persons living with HIV/AIDS (comprising 82 CKD cases and 117 controls) from among the participants in the ongoing Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network case control study have been recruited. The two APOL1 renal risk alleles (RRA) genotypes were associated with a higher risk of CKD (OR 12.6, 95% CI 3.89–40.8, p < 0.0001). Even a single APOL1 RRA was associated with CKD risk (OR 4.42, 95% CI 1.49–13.15, p = 0.007). The 2 APOL1 RRA genotypes were associated with an increased probability of having HIV viremia (OR 2.37 95% CI 1.0–5.63, p = 0.05). HIV viremia was associated with increased CKD risk (OR 7.45, 95% CI 1.66–33.35, P = 0.009) and with a significant reduction of JC virus urine shedding (OR 0.35, 95% CI 0.12–0.98, p = 0.046). In contrast to prior studies, JC viruria was not associated with CKD but was restricted in patients with HIV viremia, regardless of CKD status. These findings suggest a role of APOL1 variants in HIV infectivity and emphasize that JC viruria can serve as biomarker for innate immune system activation.

Background/Aims: Acute kidney injury (AKI) is a relatively common condition encountered in everyday paediatric practice. It remains a significant contributor to preventable deaths especially in resource constraint regions of the world largely due to lack of dialysis services. AKI remains a significant contributor to the mortality of critically ill children. Mortality outcomes depend on such factors as aetiology, medical setting, co-morbidities, and availability of dialysis therapy. This 3-year data analysis (2010-2012) was undertaken to determine the aetiology and treatment/mortality outcomes of children with AKI presenting to a Teaching Hospital in Ghana. AKI was defined in this analysis by the RIFLE and KDIGO criteria. Results: Two hundred and six (206) cases of AKI were recorded over the period out of a total of 664 renal cases. Haemoglobinuria, obstructive uropathy and tumour infiltration of the kidneys were the leading causes of AKI (37.8%). 9.2% of cases were diarrhoeal-related with glomerulonephritides occurring in 12.1% of cases. Seventy-one (34.5%) of the 206 AKI cases required dialysis which could only be provided for 25 (35.2%), 16 (64%) of whom survived. Forty-three (20.9%) children died, while 144 (69.9%) survived. Thirty-one (72%) of the patients who died needed dialysis. Conclusion: In comparison to previous studies across the world, there is huge burden of AKI among hospitalized children in Kumasi, Ghana. Haemoglobinuria and tumour-related conditions accounted for most cases of AKI more than diarrhoea-associated conditions and postinfectious glomerulonephritis as were previously reported or postulated. Most AKI deaths were related to lack of dialysis service. In view of the less technical requirements compared with other modalities of renal replacement therapy, peritoneal dialysis should be promoted across Africa to curtail needless deaths from AKI.

Objectives The current WHO weight-based dosing recommendations for efavirenz result in a wide variability of drug exposure in children. Our objectives are to characterize the effects of rifampicin- and isoniazid-containing anti-TB therapy and CYP2B6 activity on efavirenz concentrations in children, using non-linear mixed-effects modelling. Methods This is a pharmacokinetic (PK) substudy of a prospective study that examined the interactions between anti-TB therapy and efavirenz in HIV-infected children with and without TB. PK samples were obtained 4 weeks after starting efavirenz (PK1) and repeated 4 weeks after completing TB therapy (PK2) in TB/HIV coinfected patients. Drug concentrations were measured using LC-MS/MS. Composite CYP2B6 516/983/15582 genotype was determined. Population PK modelling was performed in Monolix. Simulations were performed to obtain the predicted mid-dose concentrations (C12). Results One hundred and five HIV-infected Ghanaian children (46 with TB/HIV) were included. The median age and weight were 7 years and 19 kg. The efavirenz concentrations over time were adequately described using a one-compartment model. Weight, composite CYP2B6 genotype and PK visit had a significant influence on the PK parameters, while TB therapy had no significant effect. Simulations showed adequate C12 for intermediate composite CYP2B6 metabolizers only. Conclusions Our model showed that rifampicin- and isoniazid-containing anti-TB therapy does not influence efavirenz PK parameters. On the other hand, it describes the effect of efavirenz autoinduction after completing TB treatment. In addition, dosing efavirenz in children based only on weight results in a large variability in drug exposure. We propose dose adjustments for slow and extensive composite CYP2B6 metabolizers.

Chronic kidney disease (CKD) is assuming public health significance worldwide largely driven by the surge in diabetes mellitus, hypertension and obesity. CKD patients, particularly those from resource restraint regions of the world, face huge challenge in terms of accessibility and affordability to care. Besides these challenges in care, several other co-morbidities often exist among these patients in addition to the primary disease like diabetes and hypertension. Yet, these “subtle” co-morbidities are often overlooked by Caregivers. Hearing loss is one of such co-morbidities CKD patients face but it is often overlooked. The situation is worse among children who often cannot express themselves. The etiology of hearing loss among CKD patients are multifactorial. It is hoped that this neglected aspect of care for patients with chronic kidney disease will receive the needed attention for holistic care of the CKD patient.

BACKGROUND: Anti-TB drugs dosing based on weight alone may contribute to suboptimal drug concentrations and poor treatment outcomes in malnourished children. We examined the effect of malnutrition on the pharmacokinetics (PK) of first-line anti-TB drugs in children.METHODS: Drug concentrations were measured in Ghanaian children during the intensive phase of TB treatment. Weight-for-age (WFA), height-for-age (HFA), weight-for-height (WFH) and body mass index-for-age (BFA) were calculated and children with Z-scores < -2 SD (standard deviations) were considered as having malnutrition. PK differences of anti-TB drugs were compared by nutritional status.RESULTS: Of 100 participants, 24/48 (50.0%) of those younger than 5 years had wasting, 58/86 (67.4%) were underweight, and 56/99 (56.6%) had stunting; 22/51 (43.1%) children aged ≥5 years had low BFA. Children with stunting were more likely than controls to have lower mean peak concentration (Cmax) and area under the curve (AUC0–8h) of rifampin (RIF) and pyrazinamide (PZA), as well as a higher frequency of Cmax below the normal range. Wasting and underweight were associated with lower mean ethambutol (EMB) Cmax and AUC0–8h.CONCLUSIONS: The current WHO-recommended dosages were associated with lower plasma exposure of RIF, PZA and EMB in children with stunting, wasting and underweight. Anti-TB drugs dosing models for children may need to include height.

Supplemental Material, sj-pptx-1-ptd-10.1177_0896860820982120 for ISPD guidelines for peritoneal dialysis in acute kidney injury: 2020 Update (paediatrics) by Peter Nourse, Brett Cullis, Fredrick Finkelstein, Alp Numanoglu, Bradley Warady, Sampson Antwi and Mignon McCulloch in Peritoneal Dialysis International

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor that is used in the treatment of human immunodeficiency virus (HIV) infection in children younger than 3 years old. Identifying genetic predictors of NVP pharmacokinetics (PK) in young children is important because inter-individual variability in NVP concentrations contributes to variable treatment response and the information may be used to individualize dosing decisions. We examined the relationship between genetic variations in relevant drug disposition genes and NVP PK parameters in Ghanaian children living with HIV eligible to initiate NVP-based antiretroviral therapy. Participants received NVP plus zidovudine and lamivudine or abacavir and lamivudine twice daily, and those with tuberculosis (TB) coinfection received concurrent anti-TB therapy with NVP. Pharmacokinetic sampling was performed after at least 4 weeks of antiretroviral therapy. Nevirapine minimum concentration (Cmin), area under the concentration-time curve from time 0 to 12 h (AUC0–12h), and apparent clearance (CL/F) were calculated using non-compartmental analysis using Phoenix v8.0 software. Genotyping for CYP2B6, CYP2A6, CYP3A5, ABCB1, NR1I2, and NR1I3 single nucleotide polymorphism (SNPs) was performed by TaqMan® allelic discrimination method. The median (range) NVP dose received was 10 (7–14) mg/kg. Of the 53 participants, the median (range) Cmin was 3.3 (0.0–14.0) mg/L and AUC0–12h was 56.0 (16.7–202.6) mg.hr/L. Using step-wise regression, CYP2B6 rs3745274 and NR1I2 rs6785049 SNPs were independent as well as joint predictors of NVP AUC0–12h, Cmin, and CL/F. We concluded that genotyping for CYP2B6 rs3745274, and the NR1I2 rs6785049 G > A SNP (which encodes the transcriptional factor, pregnane X receptor), could improve prediction of NVP PK for individualized therapy.

Hypertension is the most important risk factor for cardiovascular mortality and morbidity in Sub-Saharan Africa. In western populations, high haemoglobin levels are associated with raised BP unlike in Sub-Saharan Africa where there is a paucity of data. Our study examines the association between haematological indices with BP variables. Weight, height, BP, and whole blood indices of viscosity (Hb, haematocrit, RBC count, and MCV) were measured in 921 adults (340 men, 581 women; aged 40–75) in 12 communities in Ghana. Mean values for Hb (12.3 g/dl ± 1.7 SD), haematocrit (36.7%±5.2), RBC (4.10 million/μL ± 0.64), and MCV were lower than reference values used in Sub-Saharan Africa. Mean BMI was 21.1±4.1 indicating a lean population. Systolic BP increased by 1.0 mmHg (95% CI 0.5–1.5), p<0.001, for women and 0.5 (0.1–1.0), p=0.027, for men per unit increase in haematocrit. Similar relationships were found for Hb and RBC but not for MCV or platelets. The relationships were weaker when adjusted for BMI, 0.7 mmHg (0.2–1.2) in women and 0.5 (0.0–1.0) in men. Findings for diastolic BP were similar. Overall haematological indices were low. We have found a significant, positive relationship between BP, Hb, Haematocrit, and RBC count in our population.

BACKGROUND The World Health Organization recommended increased dosages of the first-line antituberculosis (anti-TB) drugs for children in 2010. We examined the frequency of and factors associated with low plasma maximum concentration (Cmax) of each drug in children treated with the revised dosages. METHODS Children on anti-TB therapy for at least 4 weeks underwent pharmacokinetic testing. Plasma Cmax below the lower limit of proposed reference range was considered low. Bivariate and multivariate analyses were used to examine the factors associated with low Cmax of each drug. RESULTS Of the 100 children, 58% were male, 50% HIV-infected and 49% younger than 5 years old. The median (interquartile range) Cmax was 5.9 (4.5-7.7) µg/mL for isoniazid, 6.5 (4.9-8.8) µg/mL for rifampin, 26.0 (21.2-33.4) µg/mL for pyrazinamide and 1.7 (0.9-2.7) µg/mL for ethambutol. There was a strong correlation between Cmax and AUC0-8h for all drugs. Low Cmax occurred in 9/100 (9.0%), 61/100 (61.0%), 17/97 (17.5%) and 60/97 (61.9%) for isoniazid, rifampin, pyrazinamide and ethambutol, respectively. In addition, 75/97 (77.3%) children had pyrazinamide Cmax < 35 µg/mL. Factors associated with low Cmax were NAT2 metabolizer phenotype status for isoniazid; height, dosage and HIV coinfection status for rifampin; height for pyrazinamide; and age, dosage and HIV coinfection status for ethambutol. CONCLUSIONS The high frequency of low rifampin and ethambutol Cmax in our study is consistent with emerging pharmacokinetic data in children treated according to the new WHO recommendations. Higher dosages than currently recommended especially for rifampin may be necessary in children.

In December 2015, as part of the First African Dialysis Conference organized in Dakar, Senegal, 5 physicians from West African countries who have participated in the Saving Young Lives Program reviewed their experiences establishing peritoneal dialysis (PD) programs to treat patients with acute kidney injury (AKI). Thus far, nearly 200 patients have received PD treatment in these countries. The interaction and discussion amongst the participants at the meeting was meaningful and informative. The presentations highlighted the creativity, conviction, and determination of the physicians in overcoming the various barriers and challenges they encountered to establish PD/AKI programs. Hopefully, these successes and the increased awareness of the importance of early diagnosis and treatment of AKI will inspire much needed support from government, hospital, and international organizations.

Nevirapine-based antiretroviral therapy (ART) is one of the limited options in HIV-infected children younger than 3 years old (young children) with tuberculosis (TB) coinfection. To date, there are insufficient data to recommend nevirapine-based therapy during first-line antituberculosis (anti-TB) therapy in young children. We compared nevirapine pharmacokinetics (PK) in HIV-infected young children with and without TB coinfection. In the coinfected group, nevirapine PK was evaluated while on anti-TB therapy and after completing an anti-TB therapy regimen. Of 53 participants, 23 (43%) had TB-HIV coinfection. While the mean difference in nevirapine PK parameters between the two groups was not significant (P > 0.05), 14/23 (61%) of the children with TB-HIV coinfection and 9/30 (30%) with HIV infection had a nevirapine minimum concentration (C(min)) below the proposed target of 3.0 mg/liter (P = 0.03). In multivariate analysis, anti-TB therapy and the CYP2B6 516G>T genotype were joint predictors of nevirapine PK parameters. Differences in nevirapine PK parameters between the two groups were significant in children with CYP2B6 516GG but not the GT or TT genotype. Among 14 TB-HIV-coinfected participants with paired data, the geometric mean C(min) and area under the drug concentration-time curve from time zero to 12 h (AUC(0–12)) were about 34% lower when patients were taking anti-TB therapy, while the nevirapine apparent oral clearance (CL/F) was about 45% higher. While the induction effect of anti-TB therapy on nevirapine PK in our study was modest, the CYP2B6 genotype-dependent variability in the TB drug regimen effect would complicate any dose adjustment strategy in young children with TB-HIV coinfection. Alternate ART regimens that are more compatible with TB treatment in this age group are needed. (This study has been registered at ClinicalTrials.gov under identifier NCT01699633.)

We compared efavirenz pharmacokinetic (PK) parameters in children with tuberculosis (TB)/human immunodeficiency virus (HIV) coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children 3 to 14 years old with HIV infection, with and without TB, were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments., We compared efavirenz pharmacokinetic (PK) parameters in children with tuberculosis (TB)/human immunodeficiency virus (HIV) coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children 3 to 14 years old with HIV infection, with and without TB, were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization-recommended antituberculosis drug dosages were used in the coinfected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon rank-sum test and within group by signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age Z score, and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz peak concentration (Cmax), concentration at 12 h (C12h), Cmin, and total area under the curve from time 0 to 24 h (AUC0–24h) values were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz C12h, Cmin, and AUC0–24h values were lower in TB/HIV-coinfected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC0–24h was higher on than in patients off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children. (The study was registered with ClinicalTrials.gov under registration number NCT01704144.)

Prior studies show an association between caregiver depression and child health outcomes. There has been little examination of depression among caregivers of HIV-infected children in sub-Saharan countries where pediatric HIV is concentrated. Using baseline data collected in the pediatric HIV disclosure intervention trial, Sankofa, we examined the prevalence and factors associated with depression among caregivers (N = 446) of children infected with HIV in Ghana. Data were analyzed with descriptive and regression analyses. The mean age of the caregivers was 42.2 ± 10.4 years. Eighty percent of the caregivers were female and 59% were HIV-infected. Twenty-eight percent (n = 126) of the caregivers were found to have mild to severe depression. In the adjusted model, factors significantly associated with caregiver depression included: HIV-positive caregiver status (P = 0.04), low income (P = 0.02), lower social support, (P = 0.01), lower HIV knowledge, (P = 0.01), worse HIV illness perceptions (P≤0.001), and greater perceived HIV stigma (P≤0.001). Although we found a high prevalence of depression among our study participants, several of the risks factors identified are modifiable and amenable to interventions that are locally available and affordable.

Millions of people in under-privileged regions of the world continue to drink heavily polluted water and die from diarrhoea-related acute kidney injury whilst world super-powers continue to offer military aid to these regions. This gun aid must convert into water aid.

Adherence to antiretroviral therapy (ART) remains one of the greatest obstacles in pediatric HIV care. We sought to determine the prevalence of adherence to ART among undisclosed HIV-infected children and adolescents in Ghana. We analyzed baseline data from HIV-infected children and adolescents aged 7 to 18 years old enrolled in the SANKOFA Pediatric HIV disclosure intervention study in Ghana. Antiretroviral medication adherence was measured using caregiver 3-day recall; child 3-day recall; and pharmacy records for antiretroviral time-to-refill. Four hundred and twenty child-caregiver dyads were enrolled from January 2013 to June 2016. The median adherence (interquartile range), as measured by time-to-refill, was 93.2% (68.0% – 100.0%). However, only 47.5% of children had ≥95% adherence (“good adherence”) using time-to-refill data. Children of caregivers who had received secondary or higher level of education versus no school (aOR, 2.90, 95% Confidence Interval, CI 1.29 to 6.56), p = 0.010) or elementary education only (aOR, 2.20, CI, 1.24 to 3.88, p = 0.007) were more likely to have “good adherence” (≥95%). In this cohort of children unaware of their HIV positive status, median ART adherence rate was sub-optimal (by World Health Organization definition) while 38% had poor adherence (

Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N-acetyltransferase type 2 ( NAT2 ) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by SLCO1B1 ) and carboxylesterase 2 ( CES2 ) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 h postdose in children with tuberculosis on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and pharmacokinetic parameters were calculated using noncompartmental analysis. Genotyping of NAT2 , SLCO1B1 , and CES2 SNPs were performed using validated TaqMan genotyping assays. The Kruskal-Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups and was followed by the Wilcoxon rank sum test for pairwise group comparisons. Genotype status inferred by the NAT2 4-SNP and 7-SNP genotyping panels identified children with a slow acetylator phenotype but not the rapid genotype. For rifampin, only the rare SLCO1B1*1b homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that NAT2 and SCLCO1B1*1b genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have a high frequency of implicated genotypes. Further studies in other populations are warranted.

Background Chronic kidney disease (CKD) is an important global health challenge with increasing burden worldwide. CKD and acute kidney injury (AKI) may require renal replacement therapy (RRT) at some stages of the disease. Ghana currently has no renal transplant program. Dialysis services still remain a mirage to many chronic kidney disease patients in Ghana due to cost and paucity of hemodialysis machines. This survey highlights the geographical distribution of dialysis services in Ghana. Methods A cross-sectional situational survey of dialysis centers in the ten regions of Ghana was conducted by interviewing doctors and other health care professionals in all health institutions. Information on dialysis services, staff status, and number of hemodialysis machines and presence of peritoneal dialysis services in both private and government facilities was obtained and mapped out. Results Fifteen dialysis centers with a total of 103 hemodialysis machines were identified with majority 59 (57.2%) in state-owned facilities. One half of regions in Ghana do not have any form of dialysis facilities. Majority 65 (63.1%) of hemodialysis machines are in the Greater Accra region. Private hemodialysis services are available only in Greater Accra and Ashanti regions. There is no chronic peritoneal dialysis in Ghana but limited acute peritoneal dialysis. Ghana currently has eight nephrologists found only in the three government teaching hospitals. Most dialysis units across the country are supported by non-nephrologists. Conclusion There are few hemodialysis centers in Ghana; the distribution of which is skewed to few regions across the country. There is a need to improve dialysis services and equitable distribution across the country.

Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration (C(max)) and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for N-acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N-acetyltransferase type 2 (NAT2) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by SLCO1B1) and carboxylesterase 2 (CES2) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 h postdose in children with tuberculosis on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and pharmacokinetic parameters were calculated using noncompartmental analysis. Genotyping of NAT2, SLCO1B1, and CES2 SNPs were performed using validated TaqMan genotyping assays. The Kruskal-Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups and was followed by the Wilcoxon rank sum test for pairwise group comparisons. Genotype status inferred by the NAT2 4-SNP and 7-SNP genotyping panels identified children with a slow acetylator phenotype but not the rapid genotype. For rifampin, only the rare SLCO1B1*1b homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that NAT2 and SCLCO1B1*1b genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have a high frequency of implicated genotypes. Further studies in other populations are warranted.

Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC 0–8 ), maximum concentration ( C max ), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores ( P < 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC 0–8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC 0–8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

Chronic Kidney Disease (CKD) is assuming alarming proportion lately in Sub-Saharan Africa, a continent already saddled with infectious disease leading to the description of the continent as being hit with a double burden of diseases.1 Despite the huge challenges faced by CKD patients in this region in terms of accessibility and affordability to care, several co-morbidities exist among these patients and their caregivers also suffer numerous psychological problems which are often overlooked. The two studies published in this issue of the journal highlight the need to embrace these additional burdens amongst patients with CKD and their caregivers.

Background: Developing sustainable treatment programs for kidney failure in most countries of sub-Saharan Africa continues to remain an imposing challenge. While long-term renal replacement therapies in end-stage renal disease appear beyond national financial capabilities, there exist opportunities for a short-term and affordable treatment of acute kidney injury (AKI). Peritoneal dialysis (PD) is an effective and simpler modality compared to hemodialysis (HD) and can be performed without the need for machinery or electricity, making it an ideal choice in a low-resource setting. Methods: Since cost of treatment is the major obstacle, the goal is to develop a program that is cost effective. Developing an HD program requires a large capital investment by the hospital, needing water treatment systems and machinery and providing for their ongoing repair and maintenance. Gravity-driven PD is a simple, effective modality and can be performed in low-resource locales. Results: In a pediatric program that we started in the Komfo Anokye Teaching Hospital in Kumasi, Ghana, 28 patients have been treated with PD for AKI so far. Half of them were treated successfully and were discharged having fully recovered kidney function. Seven patients (25%) were determined to have end-stage renal disease, whereas 7 others (25%) died during hospitalization. In these cases, late presentation for dialysis may have contributed to the inability to recover. Conclusion: For individuals and governments alike, who are concerned about the cost of providing or paying for dialysis, using PD to treat AKI is an effective and simpler modality compared to HD and can be performed without the need for machinery or electricity, making it an ideal choice in a low-resource setting.

A genome-wide association study in Ghana, West Africa, to identify genetic variants associated with malaria pathogenesis reveals two previously unknown loci on chromosomes 1 and 16. This genome-wide association study in 2,645 cases and 3,050 controls from Ghana in West Africa identifies genetic variants that might affect any one of the many steps in malaria pathogenesis. Two novel loci are described. The first is on chromosome 1, in the vicinity of the ATP2B4 gene, which encodes the main calcium pump of erythrocytes, the host cells of the pathogenic stage of the malaria parasite. The second is on chromosome 16, close to MARVELD3, which encodes a tight-junction protein that is expressed on endothelial cells. These genetic variants may confer resistance by affecting key steps in disease development that could generate possible antimalarial targets. Malaria causes approximately one million fatalities per year, mostly among African children1. Although highlighted by the strong protective effect of the sickle-cell trait2,3, the full impact of human genetics on resistance to the disease remains largely unexplored4. Genome-wide association (GWA) studies are designed to unravel relevant genetic variants comprehensively; however, in malaria, as in other infectious diseases, these studies have been only partly successful5. Here we identify two previously unknown loci associated with severe falciparum malaria in patients and controls from Ghana, West Africa. We applied the GWA approach to the diverse clinical syndromes of severe falciparum malaria, thereby targeting human genetic variants influencing any step in the complex pathogenesis of the disease. One of the loci was identified on chromosome 1q32 within the ATP2B4 gene, which encodes the main calcium pump of erythrocytes6, the host cells of the pathogenic stage of malaria parasites. The second was indicated by an intergenic single nucleotide polymorphism on chromosome 16q22.2, possibly linked to a neighbouring gene encoding the tight-junction protein MARVELD3. The protein is expressed on endothelial cells7 and might therefore have a role in microvascular damage caused by endothelial adherence of parasitized erythrocytes. We also confirmed previous reports on protective effects of the sickle-cell trait and blood group O5,8,9. Our findings underline the potential of the GWA approach to provide candidates for the development of control measures against infectious diseases in humans.

Background/Aims: Acute kidney injury (AKI) is a relatively common condition encountered in everyday paediatric practice. It remains a significant contributor to preventable deaths especially in resource constraint regions of the world largely due to lack of dialysis services. This 3-year data analysis (2010-2012) was undertaken to determine the aetiology and treatment/mortality outcomes of children with AKI presenting to a Teaching Hospital in Ghana. AKI was defined in this analysis by the RIFLE and KDIGO criteria. Results: Two hundred and six (206) cases of AKI were recorded over the period out of a total of 664 renal cases. Haemoglobinuria, obstructive uropathy and tumour infiltration of the kidneys were the leading causes of AKI (37.8%). 9.2% of cases were diarrhoeal-related with glomerulonephritides occurring in 12.1% of cases. Seventy-one (34.5%) of the 206 AKI cases required dialysis which could only be provided for 25 (35.2%), 16 (64%) of whom survived. Forty three (20.9%) children died, while 144 (69.9%) survived. Thirty-one (72%) of the patients who died needed dialysis.

In Sub-Saharan Africa, increasing numbers of children with perinatally acquired HIV (PAHIV) are living into adolescence. These adolescents face numerous unique challenges such as parent illness/death and years of medication use. Optimizing care for these youth requires an understanding of the factors that contribute to physical health, psychological wellbeing, social relationships, and quality of life. This mixed methods study collected quantitative questionnaire data from 40 Ghanaian adolescents with PAHIV (50% female, 12–19 years old) who received care through an adolescent HIV clinic in Kumasi, Ghana. The study also presents results from qualitative interviews conducted with 20 adolescents. Results from quantitative analyses suggested that a significant number of participants were not virally suppressed (67%) and participants reported barriers to treatment adherence, limited social support, concerns about disclosure and HIV-related stigma, limited resources, and lower than expected quality of life (QOL). Salient themes from the qualitative analyses included limited understanding of how HIV is transmitted, the interplay between food insecurity and treatment adherence and the need for developing safe relationships through which adolescents can discuss their illness without fear of accidental disclosure of their HIV status.

Prevalence of pediatric HIV disclosure is low in resource-limited settings. Innovative, culturally sensitive, and patient-centered disclosure approaches are needed. Conducting such studies in resource-limited settings is not trivial considering the challenges of capturing, cleaning, and storing clinical research data. To overcome some of these challenges, the Sankofa pediatric disclosure intervention adopted an interactive cyber infrastructure for data capture and analysis. The Sankofa Project database system is built on the HUBzero cyber infrastructure ( https://hubzero.org ), an open source software platform. The hub database components support: (1) data management - the "databases" component creates, configures, and manages database access, backup, repositories, applications, and access control; (2) data collection - the "forms" component is used to build customized web case report forms that incorporate common data elements and include tailored form submit processing to handle error checking, data validation, and data linkage as the data are stored to the database; and (3) data exploration - the "dataviewer" component provides powerful methods for users to view, search, sort, navigate, explore, map, graph, visualize, aggregate, drill-down, compute, and export data from the database. The Sankofa cyber data management tool supports a user-friendly, secure, and systematic collection of all data. We have screened more than 400 child-caregiver dyads and enrolled nearly 300 dyads, with tens of thousands of data elements. The dataviews have successfully supported all data exploration and analysis needs of the Sankofa Project. Moreover, the ability of the sites to query and view data summaries has proven to be an incentive for collecting complete and accurate data. The data system has all the desirable attributes of an electronic data capture tool. It also provides an added advantage of building data management capacity in resource-limited settings due to its innovative data query and summary views and availability of real-time support by the data management team.