Julia Kenny

Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial

Summary Background WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. Methods In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2–4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. Findings Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2–4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75–1·29]; abacavir vs stavudine: HR 0·88 [0·67–1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00). Interpretation All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines. Funding European Developing Countries Clinical Trials Partnership.

BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial

BACKGROUND For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings. OBJECTIVES To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy. DESIGN Open, randomised, non-inferiority trial. SETTING Europe, Thailand, Uganda, Argentina and the USA. PARTICIPANTS Young people (aged 8-24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of < 50 copies/ml for > 12 months. INTERVENTIONS Young people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART). MAIN OUTCOME MEASURES Follow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age. RESULTS In total, 199 young people (11 countries) were randomised (n = 99 SCT group, n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm(3), respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap(™) Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, n = 5; CT group, n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference -1.2%, 90% confidence interval (CI) -7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference -2.1%, 90% CI -6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, n = 2; CT group, n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group, n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, n = 1; CT group, n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial. CONCLUSIONS Non-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned. TRIAL REGISTRATION Current Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001-0001. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full in Health Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information.

Comparison of previous and present World Health Organization clinical staging criteria in HIV-infected Malawian children

In many settings, HIV infected children are looked after with limited access to CD4 cell count or viral load. The decision to initiate antiretroviral therapy (ART) is made clinically, based on the WHO paediatric staging criteria, which were revised in 2006. Results of using new and old criteria were compared. Of 694 children, 626 (90.2%) fulfilled criteria to start ART when applying the new WHO staging guidelines, whereas 330 (47.6%) children were eligible for ART when using the old WHO criteria. This signifies a marked rise in the number of paediatric patients qualifying for ART on clinical grounds.

Who Gets Severe Gynecomastia Among Hiv-infected Children in the United Kingdom and Ireland?

There are few data on gynecomastia in HIV-infected children. Within the UK/Ireland’s national cohort, 56 of 1873 (3%) HIV-infected children had gynecomastia, of which 10 (0.5%) were severe. All 10 had received antiretroviral therapy for a median of 27.5 (21, 42) months; 4 of 10 had received efavirenz, 7 of 10 and 6 of 10 had received stavudine and/or didanosine respectively. Five were nonreversible, despite changing antiretroviral therapy, and required breast reduction surgery.

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0–15 years) and 52/256 children (20%; 95%CI 15–25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71–82%), 123/240 (51%; 95%CI 45–58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36–49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8–35.1), dyspnea (OR 4.2; 95%CI 1.5–12.0) and HIV infection (OR 3.3; 95%CI 1.1–10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.

Insulin Resistance and Markers of Inflammation in HIV-Infected Ugandan Children in the CHAPAS 3 Trial

Background: Few studies have investigated metabolic complications in HIV-infected African children and their relation with inflammation. Methods: We compared baseline and changes in insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)] and in markers of inflammation over 48 weeks, in a subset of antiretroviral therapy (ART)–naive Ugandan children from the Children with HIV in Africa-Pharmacokinetics and Adherence/Acceptability of Simple Antiretroviral Regimens trial randomized to zidovudine-, stavudine- or abacavir (ABC)–based regimen. Nonparametric methods were used to explore between-group and within-group differences, and multivariable analysis to assess associations of HOMA-IR. Results: One-hundred eighteen children were enrolled, and median age (interquartile range) was 2.8 years (1.7–4.3). Baseline median HOMA-IR (interquartile range) was 0.49 (0.38–1.07) and similar between the arms. At week 48, median relative changes in HOMA-IR were 14% (−29% to 97%) in the zidovudine arm, −1% (−30% to 69%) in the stavudine arm and 6% (−34% to 124%) in the ABC arm (P ⩽ 0.03 for all the arms compared with baseline, but P = 0.90 for between-group differences). Several inflammation markers significantly decreased in all study arms; soluble CD14 increased on ABC and did not change in the other 2 arms. In multivariate analysis, only changes in soluble CD163 were positively associated with HOMA-IR changes. Conclusions: In ART-naive Ugandan children, HOMA-IR changed significantly after 48 weeks of ART and correlated with monocyte activation.