No change in calculated creatinine clearance after tenofovir initiation among Thai patients

Objectives Thai patients have a lower average body weight than patients from western Europe or the USA. Tenofovir is largely prescribed at the standard dosage of 300 mg once daily: therefore, the per kilogram dose is higher in Thailand than in the USA. We asked the question whether this higher per kilogram dose was associated with more nephrotoxicity. Methods Thai patients from the Staccato trial were treated with tenofovir/lamivudine combined with ritonavir-boosted saquinavir. Creatinine values were measured before the start of tenofovir and then every 12 weeks. Renal function was assessed using the Cockcroft-Gault formula and the MDRD formula. To compare CLCR before and after tenofovir, the t-paired or Wilcoxon signed rank tests were used. One-way analysis of variance and Spearman's correlation coefficient were used to study CLCR longitudinally. Results CLCR remained stable after a median of 21 weeks on tenofovir (difference of +1.06 mL/min; 95% CI −2.7-4.8, P = 0.58), even among patients with underlying diseases. The mean CLCR remained stable across time (P = 0.17). Conclusions We did not find renal dysfunction on tenofovir among Thai patients included in the Staccato trial. Tenofovir could be safely prescribed at a standard dosage of 300 mg once daily in the Thai populatio

Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine—a Staccato trial substudy

Objectives Stavudine is widely used in Thailand and is associated with mitochondrial toxicity. Here, we evaluated the effect of switching from stavudine/didanosine to tenofovir/lamivudine on measures of metabolic and mitochondrial toxicity in Thai patients. Methods Thirty-five Thai patients with full HIV RNA suppression were switched from stavudine/didanosine to tenofovir/lamivudine while receiving saquinavir/ritonavir 1600/100 mg once daily. Patients were assessed at the time of switch and 24 and 48 weeks after for lipids, liver enzymes, lactate, mitochondrial DNA content and limb/total fat mass by dual energy X-ray absorptiometry (DEXA) scanning. Results Forty-eight weeks after the switch, there were significant reductions in lipids and lactate, but no change in liver enzymes. There was reversal of lipoatrophy, as shown by rises in limb fat mass (+0.38 kg, P = 0.006) and total fat mass (+0.69 kg, P = 0.02) on DEXA scan. Patients perceived weight improvement, but did not report reversal of lipoatrophy of individual body parts. The mitochondrial DNA/nuclear DNA ratio rose (+1.06, P < 0.0001). Conclusions After the nucleoside reverse transcriptase inhibitor switch, reversal of mitochondrial toxicity was consistent with switch studies of mainly Caucasian patients, although the peripheral mononuclear cell mitochondrial DNA rise exceeded previous report

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

No change in calculated creatinine clearance after tenofovir initiation among Thai patients

OBJECTIVES: Thai patients have a lower average body weight than patients from western Europe or the USA. Tenofovir is largely prescribed at the standard dosage of 300 mg once daily: therefore, the per kilogram dose is higher in Thailand than in the USA. We asked the question whether this higher per kilogram dose was associated with more nephrotoxicity. METHODS: Thai patients from the Staccato trial were treated with tenofovir/lamivudine combined with ritonavir-boosted saquinavir. Creatinine values were measured before the start of tenofovir and then every 12 weeks. Renal function was assessed using the Cockcroft-Gault formula and the MDRD formula. To compare CL(CR) before and after tenofovir, the t-paired or Wilcoxon signed rank tests were used. One-way analysis of variance and Spearman's correlation coefficient were used to study CL(CR) longitudinally. RESULTS: CL(CR) remained stable after a median of 21 weeks on tenofovir (difference of +1.06 mL/min; 95% CI -2.7-4.8, P=0.58), even among patients with underlying diseases. The mean CL(CR) remained stable across time (P=0.17). CONCLUSIONS: We did not find renal dysfunction on tenofovir among Thai patients included in the Staccato trial. Tenofovir could be safely prescribed at a standard dosage of 300 mg once daily in the Thai population

Reduced Time to Suppression Among Neonates With HIV Initiating Antiretroviral Therapy Within 7 Days After Birth

There are limited data on infants with HIV starting antiretroviral therapy (ART) in the neonatal period. We investigated the association between the timing of ART initiation and time-to-suppression among infants who tested HIV-positive and initiated ART within the first 28 days of life. The effect was estimated using cumulative probability flexible parametric spline models and a multivariable generalized additive mixed model was performed to test non-linear associations. Forty-four neonates were included. Nineteen (43.2%) initiated ART within 7 days of life and 25 (56.8%) from 8 to 28 days. Infants treated within 7 days were 4-fold more likely to suppress earlier than those treated after 7 days (HR 4.01 [1.7;9.5]). For each week the ART initiation was delayed, the probability of suppression decreased by 35% (HR 0.65 [0.46;0.92]). Age at ART start was linearly associated with time-to-suppression. However, a linear association with normally distributed residuals was not found between baseline VL and time-to-suppression, with no association found when baseline viral loads were ≤ 5 log(10) copies/ml, but with exponential increase in time-to-suppression with > 5 log(10) copies/ml at baseline. Starting ART within 7 days of life led to 4-fold faster time to viral suppression, in comparison to initiation in 8 to 28 days.Proyecto EPIICAL, Fundación PENTA-ID.3.475 JCR (2019) Q2, 79/159 Inmunology2.165 SJR (2019) Q1, 24/303 Infectious DiseasesNo data IDR 2019UE

Supersensitive Viral Load Assay in Predicting CD4-Guided Treatment Failure

In HIV patients who discontinue highly active antiretroviral therapy (HAART), the degree of HIV RNA suppression at the time of treatment interruption may predict success of re-treatment after the interruption (STI). A case-control substudy of the Staccato trial in Thailand included CD4-guided STI subjects with HIV RNA > 50 copies /ml (virological failure cases, n=11) and HIV RNA < 50 copies/ml (controls, n=22) after 12-24 weeks of HAART re-treatment following a median of 2 STI cycles. Controls were matched for age, gender and pre-ART CD4 count. HIV RNA with 5 copies/ml detection limit was determined on pre-virological failure samples. HIV RNA increased in cases compared to controls with each successive STI cycle (p-trend across time-points 0.004). The last HIV RNA below 50 copies/ml was significantly higher among cases compared to controls (p=.004). Measuring HIV RNA below 50 copies/ml may be useful in predicting virological failure to STI

Corrigendum to ‘Decision making for invasive and non-invasive optional procedures within an acute HIV research cohort in Bangkok,’ [Contemporary Clinical Trials Communication (2023)101054](S2451865422001715)(10.1016/j.conctc.2022.101054)

The authors regret that Dr. Sandhya Vasan was missed in the author list for this article. The revised author order is as follows: Sinéad Isaacson1,2, Kristine Kuczynski1, Nuchanart Ormsby1, Holly L. Peay3, Stuart Rennie1,4, R. Jean Cadigan1,4, Eugène Kroon5, Nittaya Phanuphak 5, Jintanat Ananworanich6, Sandhya Vasan7,8, Thidarat Jupimai9, Peeriya Prueksakaew5, Gail E. Henderson1§ 1 Social Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 2 Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 3 RTI International, Research Triangle Park, Durham, North Carolina, USA. 4 Center for Bioethics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 5 SEARCH, Institute of HIV Research and Innovation, Bangkok, Thailand. 6 Department of Global Health, Amsterdam University Medical Centers, University of Amsterdam, and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands. 7 US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA. 8 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA. 9 Center of Excellence in Pediatric Infectious Diseases and Vaccines Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. The authors regret that Acknowledgements omitted reference to cooperative agreements that funded this work, and the Disclaimer was omitted. The corrected versions are as follows

Absence of resistance mutations in antiretroviral-naive patients treated with ritonavir-boosted saquinavir

BACKGROUND: There are few data on the selection of resistance by ritonavir-boosted saquinavir (SQV/r), particularly in antiretroviral (ARV)-naive patients. OBJECTIVE: To assess the incidence of virological failure and evolution of resistance in ARV-naive individuals receiving SQV/r in the induction phase of the Staccato trial. METHODS: ARV-naive subjects (n = 272) received SQV/r 1,600/100 mg once daily with two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 24 weeks. Patients were defined as having virological failure (VF) when there were two consecutive HIV-1 RNA measurements > 500 copies/ml after week 12. Viral genotypes (reverse transcriptase [RT] and protease [PRO]) were determined at baseline in all patients and as close as possible to the time of initial failure in patients experiencing VF. RESULTS: VF was observed in 9/272 patients receiving SQV/r 1,600/100 mg once daily with two NRTIs (3.3%) and occurred 19-48 weeks after treatment initiation. Eight of these patients were evaluable at failure. No major PRO mutations were detected, but 2/8 displayed single new minor PRO substitutions (M36I, L10I) at VF that were known or suspected not to have been present at baseline; both these substitutions exist as natural polymorphisms. A third patient displayed a single new RT mutation (M184I). CONCLUSIONS: SQV/r plus two NRTIs (1,600/100 mg once daily) is an effective initial treatment option for ARV-naive patients, resulting in a low rate of viral rebound (3.3%). Furthermore, no major protease mutations were detected following VF, suggesting that future treatment options are preserved