Pediatric HIV Disclosure Intervention Improves Immunologic Outcome at 48 Weeks: The Sankofa Trial Experience.

BACKGROUND: The World Health Organization recommends disclosure of HIV status to children and adolescents living with HIV (CALWH). HIV disclosure improves adherence to antiretroviral therapy and immunologic and virologic outcomes. However, the prevalence of HIV disclosure is low in sub-Saharan Africa. We assessed the longitudinal effect of the Sankofa Pediatric HIV disclosure intervention on immunologic and virologic outcomes among CALWH in Ghana. METHODS: We conducted a secondary analysis of a two-arm site-randomized clinical trial among CALWH aged 7-18 years. Data were collected at baseline, 24, and 48 weeks. Generalized linear mixed models were used to compare immunologic (CD4) and virologic (viral load) outcomes as both continuous and categorical variables by disclosure status and by intervention group. RESULTS: Among participants who had their HIV status disclosed during this study, the proportion with CD4 percent >25% increased from 56.5% at baseline to 75.4% at week 48 ( P = 0.03), with a slight increase in the undisclosed group (69.5% vs. 74.3%, P = 0.56). In the intervention arm, there was a steady increase in proportion with CD4 percent >25% from 47.1% at baseline to 67.8% at week 48 ( P = 0.01) while it remained unchanged in the control arm (80.5% vs. 81.3% [ P = 0.89]). Concurrently, declines in detectable viral load were observed in both disclosed (63.3% vs. 51.5%, P = 0.16) and undisclosed (69.9% vs. 62.0%, P = 0.17) groups while the intervention group experienced a meaningful drop from 72.9% to 57.6% at 24 weeks ( P = 0.04), which was maintained at 48 weeks. CONCLUSIONS: A structured, culturally relevant disclosure intervention can improve clinical outcomes.

Pharmacokinetics and pharmacodynamics of adult dolutegravir tablets in treatment-experienced children with HIV weighing at least 20 kg.

OBJECTIVE: Limited pharmacokinetic/pharmacodynamic data are a barrier to the scale-up of dolutegravir-based antiretroviral therapy (ART) in children. We examined the pharmacokinetics/pharmacodynamics of the adult film-coated dolutegravir 50 mg tablets in children with HIV infection weighing at least 20 kg. DESIGN: A prospective, observational, pharmacokinetic, and safety study. METHODS: Treatment-experienced children with HIV weighing at least 20 kg and evidence of viral load suppression on ART were enrolled and switched to dolutegravir-based therapy. After at least 4 weeks and 7 months on dolutegravir-based therapy, blood samples were collected at 0, 1, 4, 8, 12, and 24-h postdose. Dolutegravir concentrations were measured using validated LCMS/MS and pharmacokinetic parameters calculated by noncompartmental analysis. Descriptive statistics were used to summarize pharmacokinetic parameters and comparisons with published reference values. RESULTS: Of 25 participants, 92% were on efavirenz-based ART and 60.0% were men. Dolutegravir mean exposure, peak and trough concentrations at both pharmacokinetic visits were higher than the mean reference values in adults and children weighing 20 kg to less than 40 kg treated with 50 mg once daily, but were closer to the mean values in adults given 50 mg twice a day. Children weighing 20 kg to less than 40 kg had even higher dolutegravir exposures. The regimens were well tolerated with good virologic efficacy through week 48. CONCLUSION: The higher dolutegravir exposure in our study population suggests that further studies and close monitoring should investigate the adverse effects of dolutegravir in more children and in the long term.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal 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. METHODS: We 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 (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were 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 <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This 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.

Renal consequences of the novel coronavirus disease 2019 (COVID-19) and hydrogen sulfide as a potential therapy.

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.

Paediatric nephrology in under-resourced areas.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Urine-Based Detection of Biomarkers Indicative of Chronic Kidney Disease in a Patient Cohort from Ghana.

Chronic kidney disease (CKD) is a global health burden with a continuously increasing prevalence associated with an increasing incidence of diabetes and hypertension in aging populations. CKD is characterized by low glomerular filtration rate (GFR) and other renal impairments including proteinuria, thus implying that multiple factors may contribute to the etiology this disease. While there are indications of ethnic differences, it is hard to disentangle these from confounding social factors. Usually, CKD is detected in later stages of the disease when irreversible renal damage has already occurred, thus suggesting a need for early non-invasive diagnostic markers. In this study, we explored the urine secretome of a CKD patient cohort from Ghana with 40 gender-matched patients and 40 gender-matched healthy controls employing a kidney injury and a more general cytokine assay. We identified panels of kidney-specific cytokine markers, which were also gender-specific, and a panel of gender-independent cytokine markers. The gender-specific markers are IL10 and MME for male and CLU, RETN, AGER, EGFR and VEGFA for female. The gender-independent cytokine markers were APOA1, ANGPT2, C5, CFD, GH1, ICAM1, IGFBP2, IL8, KLK4, MMP9 and SPP1 (up-regulated) and FLT3LG, CSF1, PDGFA, RETN and VEGFA (down-regulated). APOA1-the major component of HDL particles-was up-regulated in Ghanaian CKD patients and its co-occurrence with APOL1 in a subpopulation of HDL particles may point to specific CKD-predisposing APOL1 haplotypes in patients of African descent-this, however, needs further investigation. The identified panels, though preliminary, lay down the foundation for the development of robust CKD-diagnostic assays.

HIV Viremia Is Associated With APOL1 Variants and Reduced JC-Viruria.

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.

Pharmacogenetic predictors of nevirapine pharmacokinetics in Ghanaian children living with HIV with or without TB coinfection.

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.

ISPD guidelines for peritoneal dialysis in acute kidney injury: 2020 Update (paediatrics).

SUMMARY OF RECOMMENDATIONS: 1.1 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 <3 days to minimize the risk of complications. (1C) (minimum standard)2.5 Improvised PD catheters should only be used when no standard PD access is available. (practice point) (minimum standard)2.6 We recommend the use of prophylactic antibiotics prior to PD catheter insertion. (1B) (optimal)2.7 A closed delivery system with a Y connection should be used. (1A) (optimal) A system utilizing buretrols to measure fill and drainage volumes should be used when performing manual PD in small children. (practice point) (optimal)2.8 In resource limited settings, an open system with spiking of bags may be used; however, this should be designed to limit the number of potential sites for contamination and ensure precise measurement of fill and drainage volumes. (practice point) (minimum standard)2.9 Automated peritoneal dialysis is suitable for the management of paediatric AKI, except in neonates for whom fill volumes are too small for currently available machines. (1D)3. Peritoneal dialysis solutions for acute PD in children3.1 The composition of the acute peritoneal dialysis solution should include dextrose in a concentration designed to achieve the target ultrafiltration. (practice point)3.2  Once potassium levels in the serum fall below 4 mmol/l, potassium should be added to dialysate using sterile technique. (practice point) (optimal) If no facilities exist to measure the serum potassium, consideration should be given for the empiric addition of potassium to the dialysis solution after 12 h of continuous PD to achieve a dialysate concentration of 3-4 mmol/l. (practice point) (minimum standard)3.3  Serum concentrations of electrolytes should be measured 12 hourly for the first 24 h and daily once stable. (practice point) (optimal) In resource poor settings, sodium and potassium should be measured daily, if practical. (practice point) (minimum standard)3.4  In the setting of hepatic dysfunction, hemodynamic instability and persistent/worsening metabolic acidosis, it is preferable to use bicarbonate containing solutions. (1D) (optimal) Where these solutions are not available, the use of lactate containing solutions is an alternative. (2D) (minimum standard)3.5  Commercially prepared dialysis solutions should be used. (1C) (optimal) However, where resources do not permit this, locally prepared fluids may be used with careful observation of sterile preparation procedures and patient outcomes (e.g. rate of peritonitis). (1C) (minimum standard)4. Prescription of acute PD in paediatric patients4.1 The initial fill volume should be limited to 10-20 ml/kg to minimize the risk of dialysate leakage; a gradual increase in the volume to approximately 30-40 ml/kg (800-1100 ml/m2) 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).

Atypical Kawasaki syndrome in COVID-19 infection: a case report of a multisystem inflammatory syndrome in a child (MIS-C).

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. FUNDING: None declared.

Sankofa pediatric HIV disclosure intervention did not worsen depression scores in children living with HIV and their caregivers in Ghana.

BACKGROUND: The 'Sankofa' pediatric HIV disclosure study (2013-2017) was an intervention that aimed to address the low prevalence of disclosure of HIV status in Ghana. METHODS: We conducted a cross-sectional study at the intervention site in Kumasi, Ghana, in 2019, (2 years after study closure) and administered the 21-item Beck Depression Inventory (BDI) and the 10-item Child Depression Inventory (CDI) to caregiver-child dyads who received the intervention. RESULTS: We enrolled 65% (N = 157) of the original dyads in the present study. Between Sankofa enrollment baseline and the present study, both children and caregivers had significant (p < 0.0001) mean reductions in CDI scores and BDI scores, respectively. CDI scores of the children were significantly correlated with BDI scores of the caregivers (r = 0.019, p = 0.019). No statistically significant associations between disclosure status and either CDI score or BDI score were found. CONCLUSIONS: Our findings did not support caregivers' fears that disclosure leads to depression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01701635 (date of registration Oct 5, 2012).

Illness Narratives of Children Living with HIV Who Do Not Know Their HIV Status in Ghana: I'm Sick, But I Don't Know the Sickness-A Qualitative Study.

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.

RESUMEN: 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.

Clinic-Based Pediatric Disclosure Intervention Trial Improves Pediatric HIV Status Disclosure in Ghana.

BACKGROUND: Disclosing HIV status to HIV-positive children is a major challenge facing families and health care providers. Despite recommendations for disclosure, rates remain low. We tested whether a pediatric HIV disclosure intervention delivered as an integral component of routine HIV health care in Ghana would improve disclosure to children. METHODS: Dyads of HIV-infected children aged 7-18 years and their caregivers were enrolled from 2 HIV clinics in Accra and Kumasi, Ghana. The sites were randomly assigned to one of the 2 intervention arms to avoid treatment contamination between intervention and control participants. Trained interventionist used theory-guided therapeutic communication and personalized interaction to promote disclosure. Disclosure outcomes were measured at 12-week intervals. All analyses were completed using a modified intention-to-treat approach. RESULTS: We enrolled 446 child-caregiver dyads (N = 240 intervention group; N = 206 control group); 52% of the children were boys, mean age 9.78 (±2.27) years. For disclosure at 1 year, a better overall treatment effect was observed (P < 0.001). Children in the treatment group had greater disclosure at each time point (P < 0.001) and a higher proportion of them had been disclosed to by 1 year (51.4% vs. 16.2%; P < 0.001; un-adjusted hazard ratio = 3.98: 95% confidence interval: 2.63 to 6.03) and 3 years (71.3% vs. 34.0%; unadjusted hazard ratio = 4.21: 95% confidence interval: 3.09 to 5.72). In the multivariate Cox model, factors associated with disclosure were treatment group (P < 0.001), children <11 years of age (P < 0.001), HIV-infected caregivers (P = 0.015), and caregiver's with greater education (P = 0.022). CONCLUSIONS: This practical clinic-based disclosure intervention shows excellent promise as a means of improving HIV pediatric disclosure outcomes.

Effect of First-Line Antituberculosis Therapy on Nevirapine Pharmacokinetics in Children Younger than Three Years Old.

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 (Cmin) 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 Cmin and area under the drug concentration-time curve from time zero to 12 h (AUC0-12) 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.).

Population pharmacokinetics of efavirenz in HIV and TB/HIV coinfected children: the significance of genotype-guided dosing.

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.

Effect of Rifampin-Isoniazid-Containing Antituberculosis Therapy on Efavirenz Pharmacokinetics in HIV-Infected Children 3 to 14 Years Old.

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.).