BACKGROUND:Few studies have compared body composition changes in children living with HIV receiving integrase inhibitors or boosted protease inhibitors. METHODS:Children switching to second-line antiretroviral therapy were randomized to dolutegravir (DTG), darunavir/ritonavir (DRV/r), atazanavir/ritonavir (ATV/r) or lopinavir/ritonavir (LPV/r), and to tenofovir alafenamide (TAF) or standard of care (abacavir or zidovudine) using a factorial design. Body composition was measured using bioelectric impedance analysis over 96 weeks. Associations between baseline characteristics and changes in fat mass, fat-free mass, muscle mass and body fat percentage were estimated using robust regression with multivariable fractional polynomial selection (exit P = 0.05). RESULTS:Eight hundred forty-one participants were included in the analysis. Females compared with males had greater fat accrual (+4.66% body fat, +1.32 kg fat mass; both P < 0.001). Compared with LPV/r, ATV/r and DTG exposures were associated with higher fat-free mass [+0.85 kg (95% confidence interval: 0.43-1.27) and +0.79 kg (0.37-1.21) respectively] and muscle mass [+0.82 kg (0.41-1.23) and +0.82 kg (0.42-1.22), respectively] (all P < 0.001). TAF and DRV/r exposures were associated with higher fat mass [+0.32 kg (0.12-0.52) P = 0.002; +0.33 kg (0.04-0.61) P = 0.025, respectively]. Prior nevirapine exposure was also associated with greater fat accrual [+0.36 kg (0.13-0.58) vs. efavirenz, P = 0.002]. Baseline CD4 and viral load, time on first-line antiretroviral therapy, and site were also associated with composition changes. CONCLUSIONS:DTG and ATV/r were associated with greater gains in fat-free mass and muscle mass than LPV/r, while DRV/r, TAF and prior nevirapine exposure were associated with fat mass accrual. Fat gain may initially reflect return to health but sustained increases may have metabolic implications. These findings suggest the need to monitor fat compartments with long-term exposure.

Long-term impact of antiretroviral therapy (ART) on bone health in children living with HIV (CLWH) remains uncertain. We aimed to determine associations of change in bone mineral density (BMD) among CLWH in Uganda in a 2-year prospective sub-study in the CHAPAS-4 randomized trial (ISRCTN22964075). CLWH aged 3-15 years switched to second-line ART including tenofovir alafenamide fumarate-emtricitabine (TAF/FTC) or standard-of-care (SOC) (abacavir (ABC) or zidovudine (ZDV) with dolutegravir (DTG), atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r) or lopinavir/ritonavir (LPV/r). BMD was assessed by dual-energy X-ray absorptiometry (DXA) at baseline, weeks 48 and 96 and bone turnover markers measured at baseline, week 24, 48, and 96. Robust regression analysis determined associations of BMD and bone turnover markers through week 96. Of 196 participants,167 contributed BMD measurements. Median (IQR) age was 9.9(7.0,12.3) years, 47% male, median (IQR) CD4 T-cell count 797(537,1140) cells/µl and mean (SD) viral load (log10 copies/ml) 4.3(0.8). Change in Procollagen type I N-terminal propeptide (PINP), C-terminal telopeptide of type I collagen (CTX) and height-adjusted (HA) BMD were similar between TAF/FTC and SOC. Greater declines in total-body-less-head (TBLH) BMD were associated with higher baseline TBLH (HA) BMD (Coef. -0.30,95% CI: -0.46, -0.15], p < 0.001) and first-line nevirapine (NVP) exposure (-0.25,95% CI: -0.43, -0.06, p = 0.009). Smaller TBLH HA BMD declines were associated with higher baseline fat-mass (0.06, 95% CI:0.01, 0.11, p = 0.021), higher lumbar spine (LS) HA BMD (0.17, 95% CI:0.03, 0.31, p = 0.015), DRV/r (0.46, p < 0.001,95% CI:0.21,0.71), DTG (0.26, p = 0.041,95% CI:0.01,0.51) or ATV/r (0.28, p = 0.026, 95% CI: 0.03, 0.52) use compared with LPV/r. Smaller declines in TBLH BMD were associated with higher baseline fat mass, higher LS HA BMD, and use of DRV/r, DTG, or ATV/r compared with LPV/r. These findings emphasize the importance of ART selection and body composition in supporting bone health among CLWH.

The aim of this study was to compare quantitative ultrasound (QUS) and dual energy X-ray absorptiometry (DXA) for determining bone mineral density (BMD) among children living with HIV (CLWH) who were switching to second-line antiretroviral therapy (ART). We conducted a cross-sectional study among CLWH as a sub-study of the CHAPAS-4 trial. Total body less head (TBLH) BMD and lumbar spine (LS) BMD were determined by DXA while the sound of speed (SOS), broad band ultrasound attenuation (BUA) and bone quality index (BQI) were determined by QUS. We evaluated the correlation between the DXA and QUS measurements using spearman correlation coefficient. A total of 167 children were enrolled; the median age was 9.4 (interquartile range = 6.0–12.0) years. Eighty-five (50.9

BACKGROUND:Children living with human immunodeficiency virus (HIV) have limited options for second-line antiretroviral therapy (ART). METHODS:In this open-label trial with a 2-by-4 factorial design, we randomly assigned children with HIV who had first-line treatment failure to receive second-line therapy with tenofovir alafenamide fumarate (TAF)-emtricitabine or standard care (abacavir or zidovudine, plus lamivudine) as the backbone and dolutegravir or ritonavir-boosted darunavir, atazanavir, or lopinavir as the anchor drug. The primary outcome was a viral load of less than 400 copies per milliliter at 96 weeks. We hypothesized that TAF-emtricitabine would be noninferior to standard care, that dolutegravir and ritonavir-boosted darunavir would each be superior to ritonavir-boosted lopinavir and atazanavir analyzed in combination, and that ritonavir-boosted atazanavir would be noninferior to ritonavir-boosted lopinavir. Safety was also assessed. RESULTS:A total of 919 children underwent randomization; 458 were assigned to receive TAF-emtricitabine, and 461 to receive standard care. Assigned anchor drugs were dolutegravir (229 participants), ritonavir-boosted darunavir (232), ritonavir-boosted atazanavir (231), and ritonavir-boosted lopinavir (227). The median age of participants was 10 years, and 497 (54.1%) were male. The median viral load at baseline was 17,573 copies per milliliter. At week 96, TAF-emtricitabine was superior to standard care: the adjusted difference in the percentage of participants with a viral load of less than 400 copies per milliliter was 6.3 percentage points (95% confidence interval [CI], 2.0 to 10.6; P = 0.004). Dolutegravir was superior to ritonavir-boosted lopinavir and atazanavir analyzed in combination (adjusted difference, 9.7 percentage points; 95% CI, 4.8 to 14.5; P<0.001), but ritonavir-boosted darunavir was not (adjusted difference, 5.6 percentage points; 95% CI, 0.3 to 11.0; P = 0.04 [prespecified threshold, P = 0.03]). Ritonavir-boosted atazanavir was noninferior to ritonavir-boosted lopinavir. One child died, and 29 (3.2%) had serious adverse events, with no significant between-group differences. CONCLUSIONS:Second-line ART regimens including TAF-emtricitabine and dolutegravir were effective for children, with no evidence of safety concerns. Ritonavir-boosted darunavir was also effective. (Funded by the European and Developing Countries Clinical Trials Partnership and others; CHAPAS-4 ISRCTN Registry number, ISRCTN22964075.).

BACKGROUND:Adult participants taking tenofovir alafenamide (TAF) in clinical trials had a better bone safety profile than those taking tenofovir disoproxil fumarate. Herein, we report medium- to long-term effects of TAF-containing regimens on bone health in children and adolescents with human immunodeficiency virus (HIV). METHODS:This post hoc pooled analysis of data from 2 phase 2/3 clinical studies (NCT01854775 and NCT02285114) evaluated the pharmacokinetics, safety, and efficacy of TAF-based regimens in children and adolescents with HIV-1. Participants were categorized into group 1 (aged 12 to < 18 years, weighing ≥ 35 kg), group 2 (aged 6 to < 12 years, weighing ≥ 25 kg), and group 3 (aged ≥ 2 years, weighing 14 to < 25 kg). Evaluations included virologic suppression, height Z-score, Tanner stage, bone mineral density (BMD) of the spine and total body less head (TBLH; absolute and height-for-age Z-score adjusted [HAZ-adjusted] for both), bone serum markers, bone-related adverse events, and pharmacokinetic assessments. RESULTS:Overall, 169 participants were enrolled and treated (78, 61, and 30 in groups 1, 2, and 3, respectively). Median (range) exposure to study drug was 320.3 (8.3-492.3), 290.1 (24.0-393.9), and 168.3 (9.0-193.0) weeks in groups 1, 2, and 3, respectively. Virologic suppression (HIV-1 RNA < 50 copies/mL) rates were high across all groups. Spine and TBLH absolute BMD increased over time in all groups, and spine and TBLH HAZ-adjusted BMD Z-scores increased or remained stable in all groups. There were no significant changes in bone serum markers, and no treatment-related fractures or bone-related adverse events. CONCLUSIONS:TAF-based regimens demonstrated acceptable medium- to long-term bone safety in children and adolescents with HIV.

Abstract Introduction Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) was efficacious and well tolerated in children/adolescents with HIV (aged ≥6 years, weighing ≥25 kg) in a Phase 2/3 study. Here, we report data from children aged ≥2 years and weighing ≥14–<25 kg. Methods This is an analysis of data from the youngest cohort in an open‐label, multicentre, multi‐cohort, single‐group, international study of children/adolescents with HIV. Participants in this cohort were children aged ≥2 years, weighing ≥14–<25 kg at screening and able to swallow tablets, on stable antiretroviral therapy with virologic suppression (HIV‐1 RNA <50 copies/ml for ≥6 consecutive months) and a CD4 count ≥400 cells/µl. Eligible participants received low‐dose E/C/F/TAF (90/90/120/6 mg) once daily through Week 48. The study included pharmacokinetic evaluation of the low‐dose E/C/F/TAF tablet at Week 2. Safety, efficacy, palatability and acceptability were also evaluated. Results Between 16 January and 25 November 2019, 27 participants were enrolled with a median (quartile [Q]1, Q3) age of 6 (4, 8) years, body weight of 19.3 (17.0, 20.5) kg, CD4 count of 1061 (895, 1315) cells/µl and CD4 cell percentage of 37.4 (30.6, 40.3). Most (92.6%) participants acquired HIV through vertical transmission. On 6 October 2020 (data‐cut), median (Q1, Q3) exposure to E/C/F/TAF was 48.3 (48.0, 60.1) weeks. Pharmacokinetic parameters were within the safe and efficacious range of previous data in adult and paediatric populations. Drug‐related treatment‐emergent adverse events occurred in 4/27 (15%) participants. There were no Grade 3/4 adverse events, or adverse events leading to E/C/F/TAF discontinuation. One participant experienced a serious treatment‐emergent adverse event (Grade 2 pneumonia not considered E/C/F/TAF related). Virologic suppression (US FDA Snapshot algorithm) was maintained by 26/27 (96%) participants at Weeks 24 and 48. At Week 48, most children reported positive palatability (84.6%) and acceptability (96.2%). Conclusions These data support the use of single‐tablet E/C/F/TAF (90/90/120/6 mg) regimen for the treatment of HIV in children aged ≥2 years and weighing ≥14–<25 kg. Clinical Trial Number NCT01854775

With the current elimination of mother to child transmission (EMTCT) of HIV, the number of HIV-positive newborns has greatly reduced. Some countries have successfully eliminated HIV infections among newborn babies. This study was nested within the DRIBS (Drug Resistance testing among Infants at Baseline Study), which enrolled 100 infants at the time of treatment initiation between 2017 and 2023. Infants were followed for two years. Viral load (VL) was measured every six months and after completion of the three sessions of intensified adherence counseling (IAC). IAC and HIV drug resistance testing were performed for VL greater than 1000 copies/ml. The median age at diagnosis was 79 (IQR, 57.75;140.75) days, with 4

BACKGROUND:Rilpivirine has shown adequate antiviral activity, consistent pharmacokinetics and safety in adults and adolescents living with HIV-1. Pharmacokinetics, safety, and antiviral activity of rilpivirine were assessed in children, following at least 48 weeks of treatment. METHODS:Cohort 2 of the open-label, phase 2 PAINT study (NCT00799864) included antiretroviral-naïve children living with HIV-1 ≥6 to <12 years old, with a viral load ≤100,000 RNA copies/mL. Participants received weight-based doses of rilpivirine in combination with a background regimen containing 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). RESULTS:Of the 18 children enrolled, 17 completed the 48-week treatment period. Participants were mostly boys (61%), median (range) age of 9.0 years (6-11 years) and weight of 25.0 kg (17-51 kg). Most children [14/18 (78%)] were adherent (>95%) to the treatment. Pharmacokinetic exposures were similar across the recommended weight-based doses and within a range comparable to exposures seen in adult studies. At week 48, 13/18 (72%) children achieved virologic response (HIV-1 RNA <50 copies/mL, FDA Snapshot). The mean (SE) increase from baseline to week 48 in CD4+ count was 213.4 (77.80) cells/μL. Overall postbaseline, 2 participants experienced virologic failure, of which 1 carried treatment-emergent rilpivirine resistance-associated mutations (RAMs); 3 of 5 participants with suspected virologic failure carried rilpivirine and NRTI RAMs. No new safety signals were identified in this population. CONCLUSIONS:At week 48, rilpivirine achieved adequate viral suppression in antiretroviral-naïve children ≥6 to <12 years of age. The pharmacokinetic, safety and virologic profile of rilpivirine in this age group was consistent with observations in adults and adolescents living with HIV-1.

[This corrects the article DOI: 10.1371/journal.pone.0288877.].

BackgroundCoformulated 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.MethodsWe 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.FindingsOverall, 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.InterpretationData 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.FundingGilead Sciences.

Background Children living with HIV have few second-line antiretroviral therapy(ART) options, especially fixed-dose-combinations(FDC). Methods Children from Uganda, Zambia, Zimbabwe were randomised to second-line tenofovir alafenamide(TAF)/emtricitabine(FTC) or standard-of-care(SOC) backbone (abacavir(ABC) or zidovudine(ZDV) with lamivudine(3TC)) in the factorial CHAPAS-4 trial. The second randomisation (reported elsewhere) was to dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r) or lopinavir(LPV/r) as anchor drug. All drugs were dosed using WHO weight-bands and children <25kg received a new paediatric TAF/FTC(15/120mg) FDC tablet. The primary endpoint was viral load(VL)<400copies/ml at week-96, analysed using logistic regression, hypothesising that TAF/FTC would be non-inferior to SOC (10% margin). Secondary endpoints included safety and immunological outcomes. Analyses were intention-to-treat. Results 919 children 3–15years, 497(54%) male, median[IQR] baseline viral load(VL) 17,573copies/ml [5549-55,700] and CD4 count 669cells/mm3[413-971], spent 99% of time on allocated NRTI backbone. At week-96, 406/454(89.4%) receiving TAF/FTC vs. 378/454(83.3%) receiving SOC had VL<400copies/mL (adjusted difference[95%CI]: 6.3%[2.0%,10.6%], p=0.004), with no evidence that this varied by ABC/3TC or ZDV/3TC SOC. CD4 count improved similarly in both arms. Growth was better with TAF/FTC vs. SOC, without evidence of excess weight-gain with any backbone/anchor drug combination (including DTG±TAF/FTC, interaction p=0.51). Bone health parameters were similar between arms, irrespective of anchor drug. One child died (treatment-unrelated); 29(3%) had serious adverse events without differences between arms. Conclusions TAF/FTC was virologically superior to SOC ZDV/3TC or ABC/3TC with a favourable safety profile, irrespective of anchor drug. Development of child-friendly TAF/FTC FDCs (±anchor drug) would increase cost-effective ART options for children and reduce drug access gaps between children and adults.([ISRCTN22964075][1]) ### Competing Interest Statement V Musiime declares membership of DSMB/advisory board: ViiV Health Care. The institution of ASW received funding to support a course on Critical Appraisal. ### Clinical Trial ISRCTN22964075 ### Clinical Protocols <http://www.mrcctu.ucl.ac.uk/studies/all-studies/c/chapas-4> ### Funding Statement The CHAPAS-4 Trial is sponsored by University College London (UCL), with central management by the Medical Research Council (MRC) Clinical Trials Unit at UCL supported by MRC core funding (MC\_UU\_00004/03). The main funding for this study is provided by the European and Developing Countries Clinical Trials Partnership. This project is part of the EDCTP programme supported by the European Union (EDCTP; TRIA2015-1078). This publication was produced by CHAPAS-4 which is part of the EDCTP programme supported by the European Union. The views and opinions of authors expressed herein do not necessarily state or reflect those of EDCTP. Additional funding for the CHAPAS-4 extended follow up was provided by UNIVERSAL project. This project, grant number RIA2019PD- 2882, is part of the EDCTP2 programme supported by the European Union. Additional funding and drug donations were received from Janssen Pharmaceuticals, and Gilead Sciences Inc. Drug donations were also received from Viiv Healthcare and Cipla. Drugs were also purchased from Emcure Pharmaceuticals. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by ethics committees in Uganda (Joint Research Ethics Committee (JREC)), Zambia (University of Zambia Biomedical Research Ethics Committee (UNZABREC)), Zimbabwe (Joint Research Ethics Committee University of Zimbabwe College of Health Sciences (JREC), Research Council Zimbabwe (RCZ)), South Africa (University of Cape Town Human Research Ethics Committee) and United Kingdom (University College London (UCL) Research Ethics Committee). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes MRC CTU at UCL supports a controlled access approach based on completion of a data request proforma available from the corresponding author (mrcctu.ucl.ac.uk/our-research/other-research-policy/data-sharing). [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN22964075

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/mm 3 , 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.

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.

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.

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.

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.

R. Katuramu1, T. Mhute2, A. Cook3, P. Mugyenyi4, P. Musoke5, P. Nahirya-Ntege1, M. Bwakura-Dangarembizi2, M. Spyer3, P. Okello4, N. Kyakuwa1, S. Chigonde2, E. Natukunda4, A. Kekitiinwa5, D.M.Gibb3, on behalf of the ARROW Trial team 1MRC / UVRI , Uganda Research Unit on AIDS, Entebbe, Uganda, 2University of Zimbabwe Medical School, Harare, Zimbabwe, 3MRC Clinical Trials Unit, London, United Kingdom, 4Joint Clinical Research Centre, Kampala, Uganda, 5Baylor College of Medicine Children's Foundation, Block 5, Mulago Hospital, Kampala, Uganda Bacteriology of ear discharge in HIV-infected children on ART in the ARROW trial in Uganda and Zimbabwe

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. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

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.