Prevalence of viral load suppression, predictors of virological failure and patterns of HIV drug resistance after 12 and 48 months on first-line antiretroviral therapy: a national cross-sectional survey in Uganda.

OBJECTIVES: We implemented the WHO cross-sectional survey protocol to determine rates of HIV viral load (VL) suppression (VLS), and weighted prevalence, predictors and patterns of acquired drug resistance (ADR) in individuals with virological failure (VF) defined as VL ≥1000 copies/mL. METHODS: We enrolled 547 and 1064 adult participants on first-line ART for 12 (±3) months (ADR12) and ≥48 months (ADR48), respectively. Dried blood spots and plasma specimens were collected for VL testing and genotyping among the VFs. RESULTS: VLS was 95.0% (95% CI 93.4%-96.5%) in the ADR12 group and 87.9% (95% CI 85.0%-90.9%) in the ADR48 group. The weighted prevalence of ADR was 96.1% (95% CI 72.9%-99.6%) in the ADR12 and 90.4% (95% CI 73.6-96.8%) in the ADR48 group, out of the 30 and 95 successful genotypes in the respective groups. Initiation on a zidovudine-based regimen compared with a tenofovir-based regimen was significantly associated with VF in the ADR48 group; adjusted OR (AOR) 1.96 (95% CI 1.13-3.39). Independent predictors of ADR in the ADR48 group were initiation on a zidovudine-based regimen compared with tenofovir-based regimens, AOR 3.16 (95% CI 1.34-7.46) and ART duration of ≥82 months compared with <82 months, AOR 1.92 (95% CI 1.03-3.59). CONCLUSIONS: While good VLS was observed, the high prevalence of ADR among the VFs before they underwent the recommended three intensive adherence counselling (IAC) sessions followed by repeat VL testing implies that IAC prior to treatment switching may be of limited benefit in improving VLS

HIV drug resistance among adults initiating antiretroviral therapy in Uganda.

BACKGROUND: WHO revised their HIV drug resistance (HIVDR) monitoring strategy in 2014, enabling countries to generate nationally representative HIVDR prevalence estimates from surveys conducted using this methodology. In 2016, we adopted this strategy in Uganda and conducted an HIVDR survey among adults initiating or reinitiating ART. METHODS: A cross-sectional survey of adults aged ≥18 years initiating or reinitiating ART was conducted at 23 sites using a two-stage cluster design sampling method. Participants provided written informed consent prior to enrolment. Whole blood collected in EDTA vacutainer tubes was used for preparation of dried blood spot (DBS) specimens or plasma. Samples were shipped from the sites to the Central Public Health Laboratory (CPHL) for temporary storage before transfer to the Uganda Virus Research Institute (UVRI) for genotyping. Prevalence of HIVDR among adults initiating or reinitiating ART was determined. RESULTS: Specimens from 491 participants (median age 32 years and 61.5% female) were collected between August and December 2016. Specimens from 351 participants were successfully genotyped. Forty-nine had drug resistance mutations, yielding an overall weighted HIVDR prevalence of 18.2% with the highest noted for NNRTIs at 14.1%. CONCLUSIONS: We observed a high HIVDR prevalence for NNRTIs among adults prior to initiating or reinitiating ART in Uganda. This is above WHO's recommended threshold of 10% when countries should consider changing from NNRTI- to dolutegravir-based first-line regimens. This recommendation was adopted in the revised Ugandan ART guidelines. Dolutegravir-containing ART regimens are preferred for first- and second-line ART regimens

Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria

Background: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). Methods: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m–<1 y: 1.25 mg, 1–5 y: 2.5 mg, 6–9 y: 5 mg, 10–11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. Findings: 258 children (median age 5 [interquartile range (IQR) 3–7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10–0.40 (median 0.21, IQR 0.16–0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3–447 (median 103.0, IQR 72.1–140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m–<1 y, n = 12), 582.8 (1–5 y, n = 126), 871.1 (6–9 y, n = 80), and 931.0 (10–11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8–5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. Interpretation: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. Funding: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Mapping the medical outcomes study HIV health survey (MOS-HIV) to the EuroQoL 5 Dimension (EQ-5D-3L) utility index

10.1186/s12955-019-1135-8Health and Quality of Life Outcomes1718

PARIST study protocol: a phase I/II randomised, controlled clinical trial to assess the feasibility, safety and effectiveness of paracetamol in resolving acute kidney injury in children with severe malaria

Background Acute kidney injury (AKI) has in the past been considered a rare complication of malaria in children living in high-transmission settings. More recently, however, a growing number of paediatric case series of AKI in severe malaria studies in African children have been published (Artesunate vs Quinine in the Treatment of Severe P. falciparum Malaria in African children and Fluids Expansion as Supportive Therapy trials). The Paracetamol for Acute Renal Injury in Severe Malaria Trial (PARIST) therefore, aims to assess feasibility, safety and determine the effective dose of paracetamol, which attenuates nephrotoxicity of haemoproteins, red-cell free haemoglobin and myoglobin in children with haemoglobinuric severe malaria.Methods PARIST is a phase I/II unblinded randomised controlled trial of 40 children aged &gt;6 months and &lt;12 years admitted with confirmed haemoglobinuric severe malaria (blackwater fever), a positive blood smear for P. falciparum malaria and either serum creatinine (Cr) increase by ≥0.3 mg/dL within 48 hours or to ≥1.5 times baseline and elevated blood urea nitrogen (BUN) &gt;20 mg/dL. Children will be randomly allocated on a 1:1 basis to paracetamol intervention dose arm (20 mg/kg orally 6-hourly for 48 hours) or to a control arm to receive standard of care for temperature control (ie, tepid sponging for 30 min if fever persists give rescue treatment). Primary outcome is renal recovery at 48 hours as indicated by stoppage of progression and decrease of Cr level below baseline, BUN (&lt;20 mg/dL). Data analysis will be on the intention-to-treat principle and a per-protocol basis.Results from this phase I/II clinical trial will provide preliminary effectiveness data of this highly potential treatment for AKI in paediatric malaria (in particular for haemoglobinuric severe malaria) for a larger phase III trial.Ethics and dissemination Ethical and regulatory approvals have been granted by the Mbale Hospital Institutional Ethics Review Committee (MRRH-REC OUT 002/2019), Uganda National Council of Science and Technology (UNCST-HS965ES) and the National drug Authority (NDA-CTC 0166/2021). We will be disseminating results through journals, conferences and policy briefs to policy makers and primary care providers.Trial registration number ISRCTN84974248

Unusual clinical spectra of childhood severe malaria during malaria epidemic in eastern Uganda: a prospective study

Abstract Background In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with wide-ranging clinical spectra and outcomes that have been reported to vary by age, geographical location, transmission intensity over time. There are reports of recent malaria epidemics or resurgences, but few data, if any, focus on the clinical spectrum of severe malaria during epidemics. This describes the clinical spectrum and outcomes of childhood severe malaria during the disease epidemic in Eastern Uganda. Methods This prospective cohort study from October 1, 2021, to September 7, 2022, was nested within the ‘Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda’ (TMA2016SF-1514-MEPIE Study) at Mbale Regional Referral Hospital, Uganda. Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical WHO criteria for surveillance of severe malaria were enrolled on the study. Follow-up was performed until day 28. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, malaria RDT (SD BIOLINE Malaria Ag P.f/Pan, Ref. 05FK60-40-1) and blood slide, lactate, glucose, blood gases and electrolytes. In addition, urinalysis using dipsticks (Multistix® 10 SG, SIEMENS, Ref.2300) at the bedside was done. Data were analysed using STATA V15.0. The study had prior ethical approval. Results A total of 300 participants were recruited. The median age was 4.6 years, mean of 57.2 months and IQR of 44.5 months. Many children, 164/300 (54.7%) were under 5 years, and 171/300 (57.0%) were males. The common clinical features were prostration 236/300 (78.7%), jaundice in 205/300 (68.3%), severe malarial anaemia in 158/300 (52.7%), black water fever 158/300 (52.7%) and multiple convulsions 51/300 (17.0%), impaired consciousness 50/300(16.0%), acidosis 41/300(13.7%), respiratory distress 26/300(6.7%) and coma in 18/300(6.0%). Prolonged hospitalization was found in 56/251 (22.3%) and was associated with acidosis, P = 0.041. The overall mortality was 19/300 (6.3%). Day 28 follow-up was achieved in 247/300 (82.3%). Conclusion During the malaria epidemic in Eastern Uganda, severe malaria affected much older children and the spectrum had more of prostration, jaundice severe malarial anaemia, black water fever and multiple convulsions with less of earlier reported respiratory distress and cerebral malaria

Safety of age-dosed, single low-dose primaquine in children with glucose-6-phosphate dehydrogenase deficiency who are infected with Plasmodium falciparum in Uganda and the Democratic Republic of the Congo: a randomised, double-blind, placebo-controlled, non-inferiority trial

Background: WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. Methods: We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A− variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether–lumefantrine or dihydroartemisinin–piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants. Findings: Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether–lumefantrine plus single low-dose primaquine group, 286 to the artemether–lumefantrine plus placebo group, 283 to the dihydroartemisinin–piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin–piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study—these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference −0·66%, 95% CI −1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (−0·014%, −0·68 to 0·65; p=0·97). Interpretation: Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa