Dataset Information

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

ABSTRACT:

Background

Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART).

Methods

We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed.

Results

From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01).

Conclusions

In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

SUBMITTER: Turkova A

PROVIDER: S-EPMC7614690 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

Turkova Anna A White Ellen E Mujuru Hilda A HA Kekitiinwa Adeodata R AR Kityo Cissy M CM Violari Avy A Lugemwa Abbas A Cressey Tim R TR Musoke Philippa P Variava Ebrahim E Cotton Mark F MF Archary Moherndran M Puthanakit Thanyawee T Behuhuma Osee O Kobbe Robin R Welch Steven B SB Bwakura-Dangarembizi Mutsa M Amuge Pauline P Kaudha Elizabeth E Barlow-Mosha Linda L Makumbi Shafic S Ramsagar Nastassja N Ngampiyaskul Chaiwat C Musoro Godfrey G Atwine Lorna L Liberty Afaaf A Musiime Victor V Bbuye Dickson D Ahimbisibwe Grace M GM Chalermpantmetagul Suwalai S Ali Shabinah S Sarfati Tatiana T Wynne Ben B Shakeshaft Clare C Colbers Angela A Klein Nigel N Bernays Sarah S Saïdi Yacine Y Coelho Alexandra A Grossele Tiziana T Compagnucci Alexandra A Giaquinto Carlo C Rojo Pablo P Ford Deborah D Gibb Diana M DM

The New England journal of medicine 20211201 27

<h4>Background</h4>Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART).<h4>Methods</h4>We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical ...[more]

PMID: 34965338

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Project description:IntroductionDolutegravir (DTG)-based antiretroviral therapy (ART) is recommended for first-line HIV treatment in the US and Europe. Efavirenz (EFV)-based regimens remain the standard of care (SOC) in India. We examined the clinical and economic impact of DTG-based first-line ART in the setting of India's recent guidelines change to treating all patients with HIV infection regardless of CD4 count.MethodsWe used a microsimulation of HIV disease, the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International model, to project outcomes in ART-naive patients under two strategies: (1) SOC: EFV/tenofovir disoproxil fumarate (TDF)/lamivudine (3TC); and (2) DTG: DTG + TDF/3TC. Regimen-specific inputs, including virologic suppression at 48 weeks (SOC: 82% vs. DTG: 90%) and annual costs ($98 vs. $102), were informed by clinical trial data and other sources and varied widely in sensitivity analysis. We compared incremental cost-effectiveness ratios (ICERs), measured in $/year of life saved (YLS), to India's per capita gross domestic product ($1600 in 2015). We compared the budget impact and HIV transmission effects of the two strategies for the estimated 444,000 and 916,000 patients likely to initiate ART in India over the next 2 and 5 years.ResultsCompared to SOC, DTG improved 5-year survival from 76.7% to 83.0%, increased life expectancy from 22.0 to 24.8 years (14.0 to 15.5 years, discounted), averted 13,000 transmitted HIV infections over 5 years, increased discounted lifetime care costs from $3040 to $3240, and resulted in a lifetime ICER of $130/YLS, less than 10% of India's per capita GDP in 2015. DTG maintained an ICER below 50% of India's per capita GDP as long as the annual three-drug regimen cost was ≤$180/year. Over a 2- or 5-year horizon, total undiscounted outlays for HIV-related care were virtually the same for both strategies.ConclusionsA generic DTG-based regimen is likely to be cost-effective and should be recommended for initial therapy of HIV infection in India.

Project description:BackgroundDarunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment.MethodsWe used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25-34.9 kg weight band.ResultsData from 59 children with median age and weight 10.9 (range 3.8-14.7) years and 26.0 (14.5-47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC0-24h, 94.3(50) mg·h/L and Cmax, 9.1(35) mg/L, above adult reference values and Ctrough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir.ConclusionsDarunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25-34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability.

Project description:BackgroundTenofovir diphosphate (TFV-DP) concentration in dried blood spots is a marker of long-term adherence. We investigated the relationship between TFV-DP concentrations and virological outcomes in participants initiating tenofovir-lamivudine-dolutegravir (TLD) as first-line or second-line antiretroviral therapy.SettingThree primary care clinics in Khayelitsha, Cape Town, South Africa.MethodsWe conducted a post hoc analysis of 2 randomized controlled trials of participants initiating TLD. TFV-DP concentrations and viral loads were measured at 12, 24, and 48 weeks. Multivariable logistic regression was performed to assess the association with virological suppression (<50 copies/mL) per natural logarithm increase in TFV-DP concentration. Generalized estimating equations with logit link were used to assess associations with virological rebound. The Akaike Information Criterion and Quasi-likelihood Information Criteria were used to compare models built on continuous TFV-DP data to 4 previously defined concentration categories.ResultsWe included 294 participants in the analysis, 188 (64%) of whom initiated TLD as second-line therapy. Adjusted odds ratios (95% CIs) of virological suppression were 2.12 (1.23, 3.75), 3.11 (1.84, 5.65), and 4.69 (2.81, 8.68) per natural logarithm increase in TFV-DP concentration at weeks 12, 24, and 48, respectively. In participants with virological suppression at week 12, the adjusted odds ratio for remaining virologically suppressed was 3.63 (95% CI: 2.21 to 5.69) per natural logarithm increase in TFV-DP concentration. Models using continuous TFV-DP data had lower Akaike Information Criterion and Quasi-likelihood Information Criteria values than those using categorical data for predicting virological outcomes.ConclusionTFV-DP concentrations in dried blood spots exhibit a dose-response relationship with viral load. Analyzing TFV-DP concentrations as continuous variables rather than conventional categorization may be appropriate.

Dataset Information

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

Background

Methods

Results

Conclusions

Publications

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

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