Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study.

BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.

Bone mineral density among children living with HIV failing first-line anti-retroviral therapy in Uganda: A sub-study of the CHAPAS-4 trial.

BACKGROUND: Children living with perinatally acquired HIV (CLWH) survive into adulthood on antiretroviral therapy (ART). HIV, ART, and malnutrition can all lead to low bone mineral density (BMD). Few studies have described bone health among CLWH in Sub-Saharan Africa. We determined the prevalence and factors associated with low BMD among CLWH switching to second-line ART in the CHAPAS-4 trial (ISRCTN22964075) in Uganda. METHODS: BMD was determined using dual-energy X-ray Absorptiometry (DXA). BMD Z-scores were adjusted for age, sex, height and race. Demographic characteristics were summarized using median interquartile range (IQR) for continuous variables and proportions for categorical variables. Logistic regression was used to determine the associations between each variable and low BMD. RESULTS: A total of 159 children were enrolled (50% male) with median age (IQR) 10 (7-12) years, median duration of first -line ART 5.2(3.3-6.8) years; CD4 count 774 (528-1083) cells/mm3, weight-for-age Z-score -1.36 (-2.19, -0.65) and body mass index Z-score (BMIZ) -1.31 (-2.06, -0.6). Low (Z-score≤ -2) total body less head (TBLH) BMD was observed in 28 (18%) children, 21(13%) had low lumbar spine (LS) BMD, and15 (9%) had both. Low TBLH BMD was associated with increasing age (adjusted odds ratio [aOR] 1.37; 95% CI: 1.13-1.65, p = 0.001), female sex (aOR: 3.8; 95% CL: 1.31-10.81, p = 0.014), low BMI (aOR 0.36:95% CI: 0.21-0.61, p<0.001), and first-line zidovudine exposure (aOR: 3.68; 95% CI: 1.25-10.8, p = 0.018). CD4 count, viral load and first- line ART duration were not associated with TBLH BMD. Low LS BMD was associated with increasing age (aOR 1.42; 95% CI: 1.16-1.74, p = 0.001) and female sex: (aOR 3.41; 95% CI: 1.18-9.8, p = 0.023). CONCLUSION: Nearly 20% CLWH failing first-line ART had low BMD which was associated with female sex, older age, first-line ZDV exposure, and low BMI. Prevention, monitoring, and implications following transition to adult care should be prioritized to identify poor bone health in HIV+adolescents entering adulthood.

Brief Report: Efficacy and Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Females Living With HIV: An Integrated Analysis of 5 Trials.

BACKGROUND: We characterized the efficacy and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in a broad population of pediatric/adolescent/adult/elderly females living with HIV (FWH). SETTING: Integrated analysis. METHODS: Available data from 5 trials were integrated. Week 48 virologic suppression (HIV-1 RNA <50 copies/mL), resistance, adverse events (AEs), and laboratory parameters were assessed. RESULTS: Three hundred and seventy-three FWH [304 virologically suppressed; 69 antiretroviral therapy (ART)-naive] received B/F/TAF [data from comparator regimens available for 306 individuals (236 virologically suppressed and 70 ART-naive participants)]. Virologic suppression rates with B/F/TAF at week 48 were high regardless of age in participants virologically suppressed at baseline (≥95%) and in ART-naive participants (≥87%). Virologic suppression rates were similar in B/F/TAF and comparator regimens (both virologically suppressed and ART-naive groups). Treatment-emergent resistance was not detected in the B/F/TAF group. AEs considered related to study drugs were experienced by 9.2% (B/F/TAF) and 5.5% (comparator regimen) of virologically suppressed participants and 15.9% (B/F/TAF) and 31.4% (comparator regimen) of ART-naive participants. For virologically suppressed and ART-naive FWH combined, only 1 of the 373 B/F/TAF-treated and 2 of the 306 comparator-regimen participants discontinued because of AEs (none were bone/renal/hepatic AEs); grade 3/4 AEs were experienced by 5.1% (B/F/TAF) and 7.8% (comparator regimen); and grade 3/4 elevation of low-density lipoprotein/total cholesterol occurred in 2.7%/0.3% (B/F/TAF) and 5.9%/2.0% (comparator regimen). At week 48, median changes from baseline estimated glomerular filtration rate in adults were <5 mL/min; results were similar in B/F/TAF and comparator-regimen groups. CONCLUSION: B/F/TAF treatment was effective and well tolerated over 48 weeks, confirming B/F/TAF as an option for a broad population of FWH.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial.

BACKGROUND: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per µL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUCtau and 65·4% [58·3-73·3] for Ctau in adolescents; GLSM 125% [90% CI 117-134] for AUCtau and 88·9% [80·6-98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance. INTERPRETATION: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population. FUNDING: Gilead Sciences.

Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial.

BACKGROUND: No once-daily single-tablet regimen is available for HIV-infected children under 12 years. The single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a once-daily, integrase strand transfer inhibitor-based regimen approved in the USA and European Union for individuals aged 12 years or older. In this study, we aimed to assess the pharmacokinetics, safety, and efficacy of this regimen in virologically suppressed, HIV-infected children. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed, HIV-infected children from five hospital clinics in Uganda, the USA, and Thailand. Eligible participants were aged 6-11 years, weighed 25 kg or more, had virological suppression (<50 copies of HIV-1 RNA per mL) on a stable regimen for at least 6 months, CD4 count of more than 100 cells per µL, and no history of resistance to elvitegravir, emtricitabine, tenofovir alafenamide, or tenofovir. All participants received the available fixed-dose oral formulation of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once per day. Primary outcomes were the pharmacokinetic parameters area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) of tenofovir alafenamide, treatment-emergent serious adverse events, and all treatment-emergent adverse events. Results from baseline to week 24 are reported, unless specified otherwise. Primary and safety analyses included all enrolled participants who received one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01854775. FINDINGS: Between July 27 and Sept 28, 2015, we screened 26 children, of whom 23 were enrolled and initiated treatment. Median age was 10 years (IQR 8-11), median weight was 30·5 kg (IQR 27·5-33·0), and all participants had virological suppression. The mean AUCtau of elvitegravir was 33 814 ng × h/mL (coefficient of variation 58%), and the mean AUClast of tenofovir alafenamide was 333 ng × h/mL (45%). Exposures to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were higher, but modestly so, than those previously reported in adults. All 23 participants tolerated the regimen well; there were no serious adverse events or adverse event-related discontinuations. All participants maintained virological suppression (HIV-1 RNA <50 copies per mL) at week 24. CD4 count decreased by a median of -130 cells per µL (range -472 to 266) with little change in CD4 cell percentage (-2·1%, range -8·4 to 5·9). INTERPRETATION: The fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was efficacious and well tolerated in virologically suppressed, HIV-infected children. Although plasma exposure of all components was higher than has been reported in adults, there were no safety concerns and the overall bone and renal safety profile was favourable. These data support the use of this regimen in children at least 25 kg in weight. FUNDING: Gilead Sciences.

Pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda.

OBJECTIVES: To evaluate international pediatric efavirenz dosing recommendations using full pharmacokinetic (PK) information. DESIGN: Open-label, multicenter, PK study. METHODS: Forty-one HIV-infected Ugandan children (3-12 years) on efavirenz + lamivudine + abacavir were enrolled in a study of twice-daily to once-daily lamivudine + abacavir 36 weeks after antiretroviral therapy initiation in the ARROW trial. Once-daily efavirenz doses were 200, 250, 300, 350 mg for children weighing 10 to <15, 15 to <20, 20 to <25, 25 to <30 kg, respectively, using 200/50 mg capsules or halved 600 mg tablets in case of 300 and 350 mg doses. Intensive plasma PK sampling (t = 0, 1, 2, 4, 6, 8, 12 hours postobserved ingestion) was performed at steady state (PK1) and repeated 4 weeks later (PK2, including a further 24-hour sample). RESULTS: Forty-one and 39 children had evaluable efavirenz profiles at PK1 and PK2, respectively. Seventeen (41%) were boys. Five, 16, 17, 3 were in the 10 to <15, 15 to <20, 20 to <25, 25 to <30 kg weight bands. The geometric mean (%CV) the area under the concentration-time curve 0-24 hours postdose was 50.8 (90.8%) and 55.5 (82.7%) h·mg·L(-1) at PK1 and PK2, respectively. Six children at PK1 and 7 at PK2 had subtherapeutic C(8h) and/or C(12h) (<1.0 mg/L), 7 of 41 (17%) at either visit. At PK2, 15 of 39 (38%) children had C(24h) <1.0 mg/L (median (interquartile range) [range] 1.1 (0.7-2.9) [0.3-18.4]). Ten children at PK1 and 11 at PK2 had C(8h) and/or C(12h) >4.0 mg/L; 12 of 41 (29%) at either visit. CONCLUSIONS: African children aged 3-12 years, on efavirenz dosed according to 2006 WHO/manufacturer's recommendations, had lower and highly variable efavirenz PK parameters compared with adult data from manufacturer's leaflet. There were no differences across weight bands, suggesting no major effect of using half tablets. Higher pediatric efavirenz doses, as per WHO 2010 recommendations, should be used and investigated further but may risk increasing the proportion of children with potentially toxic levels.

Hospitalization for severe malnutrition among HIV-infected children starting antiretroviral therapy.

OBJECTIVE: To describe early hospitalization for severe malnutrition in HIV-infected children initiating antiretroviral therapy (ART). DESIGN: Randomized trial of induction-maintenance and monitoring strategies in HIV-infected children. SETTING: Three tertiary hospitals in Uganda and one in Zimbabwe. PARTICIPANTS: 1207 HIV-infected children, median age 6 years (range, 3 months to 17 years). INTERVENTION: Abacavir, lamivudine and nevirapine or efavirenz were given; children in induction-maintenance arms also received zidovudine to week 36. Pre-ART inpatient/outpatient nutritional rehabilitation for children with baseline severe malnutrition. MAIN OUTCOME MEASURES: : Hospitalization for severe malnutrition and change in CD4 cell percentage by week 12 after ART. Mortality and change in weight-for-age Z-score (WAZ) by week 24 after ART. RESULTS: Thirty-nine of 1207 (3.2%) children were hospitalized for severe malnutrition (20 with oedema), median 28 days [interquartile range (IQR) 14, 36] after ART for marasmus and 26 days (IQR 14, 56) after ART for kwashiorkor. Hospitalized children had lower baseline and greater 24-week rise in WAZ than nonhospitalized children (P < 0.001). Twenty-nine of 39 (74%) children admitted for severe malnutrition had underlying infections. Of 220 children with advanced disease (baseline WAZ and CD4 cell Z-scores both <-3), 7.3% [95% confidence interval (CI) 3.8, 10.7] developed kwashiorkor and 3.6% (95% CI 1.2, 6.1) developed marasmus by week 12. CD4 cell percentage rise was similar among groups (P = 0.37). Twenty-four-week mortality was 32, 20 and 1.7% among children hospitalized with marasmus, kwashiorkor and not hospitalized, respectively, (P < 0.001). CONCLUSION: One in nine children with advanced HIV required early hospitalization for severe malnutrition after ART, with a 15-fold increase in 6-month mortality compared with nonhospitalized children. Integration of HIV/malnutrition services and further research to determine optimal ART timing, role of supplementary feeding and antimicrobial prophylaxis are urgently required.

A Case of Cryptococcal Lymphadenitis in an HIV-Infected Child.

An 8-year-old HIV-positive antiretroviral therapy-naive child developed severe headache and generalized lymphadenopathy. The serum cryptococcal antigen (CRAG) test was positive, the histology on the lymph node biopsy revealed budding yeast cells, and Cryptococcus neoformans was isolated on culture of his cerebrospinal fluid. He was treated with intravenous amphotericin B followed by oral fluconazole with a good response. Therefore cryptococcal lymphadenitis should be considered in the differential diagnosis of children presenting with lymphadenopathy and a positive serum CRAG.