abacavir and Body-Weight

With longer life expectancy in people living with HIV (PLWH) on antiretroviral therapy, cardiovascular disease (CVD) has become a common cause of mortality among them. Abacavir has been associated with an increased risk of myocardial infarction, but the mechanism is unknown. Additionally, abacavir may be obesogenic which could mediate an additional risk factor of CVD. We aim to investigate if discontinuation of abacavir will have a favourable impact on body weight and cardiac parameters in PLWH.. Randomised, controlled, superiority trial of virologically suppressed PLWH on dolutegravir, abacavir and lamivudine (DTG/ABC/3TC) for ≥6 months. In total, 70 PLWH will be randomised 1:2 to either continue DTG/ABC/3TC or to switch to dolutegravir and lamivudine (DTG/3TC) providing the power of 80% at alpha 5% to detect a mean difference in weight change of 2 kg (Δ) given an SD of 2.7 kg. Follow-up will be 48 weeks. Data will be collected at baseline and week 48. Primary outcome will be change in mean body weight from baseline to week 24 and 48 evaluated in a linear mixed model. Secondary outcomes will be changes in cardiac, inflammatory and metabolic parameters, fat distribution, coagulation, endothelial, platelet function, quality of life and virological control from baseline to week 48. Measurements include CT of thorax and abdomen, external carotid artery ultrasound, liver elastography and dual energy X-ray absorptiometry and blood analysis. Plasma HIV RNA will be measured at baseline, week 4, 24 and 48. Forty participants (20 from each arm) will be included in a substudy involving cardiac MRI at baseline and week 48. Twenty non-HIV-infected controls will be included with a single scan to compare with baseline scan data.. Result from this study will lead to a better understanding of the association between antiretroviral therapy and the impact on weight and risk of CVD. Findings will be useful for both clinicians and PLWH in the guidance of a more individualised HIV treatment. Results from the main study and the substudies will be submitted for publication in a peer-reviewed journal(s). The AVERTAS study is approved by the Ethics Committee of the Capital Region, Denmark (H-20011433), Danish Medicines Agency (EudraCT no. 2019-004999-19) and Regional Data Protection Centre (P-2020-207).. Pre-results registration at ClinicalTrials.gov Identifier: NCT04904406, registered 27 May 2021.. Protocol version 9.0, 4 April 2023, approved 10-05-2023 by Ethics Committee of the Capital Region, Denmark (H-20011433). Danish Medicines Agency (EudraCT no. 2019-004999-19). Regional Data Protection Centre (P-2020-207) ClinicalTrials.gov.

Topics: Body Composition; Body Weight; Cardiovascular Diseases; Denmark; HIV Infections; Humans; Lamivudine; Quality of Life

Describe the pharmacokinetics (PK) of the antiretroviral drugs abacavir and lamivudine in malnourished paediatric patients and relate to viral load outcomes after 12 and 48 weeks of treatment.. Severely malnourished human immunodeficiency virus-infected children were randomized to early (within 14 days) or delayed (after nutritional recovery) initiation of antiretroviral treatment (ART) using World Health Organization weight-band dosages. Abacavir and lamivudine concentrations were measured as a secondary objective on day 1 and day 14 and patients were followed-up to week 48. Population PK of abacavir and lamivudine were described using NONMEM.. In total, 623 abacavir and 627 lamivudine concentrations were collected from 75 paediatric patients aged 0.1-10.8 (median 1.4) years. Abacavir PK was described by a 2-compartment model, patients randomized to early ART showed increased bioavailability of 31%. Apparent clearance (CL/F, L/h/7 kg) of abacavir increased from day 1 to day 14 from 3.33 (95% confidence interval 2.71-4.12) to 5.86 (95% confidence interval 4.78-7.3). A 1-compartment model described lamivudine PK, variability on CL/F was explained by maturation with age, with age at half-matured CL/F being 4 months. For both drugs allometrically scaled total body weight was related to CL/F and apparent volume of distribution. PK exposure did not correlate with virological outcomes or death at 12 or 48 weeks.. Increases in Abacavir's CL/F between day 1 to day 14, bioavailability and PK variability with early start of ART was found in this cohort of severely malnourished children; however, these changes did not influence virological outcomes. The study supports the use of weight-band dosage tables.

Topics: Anti-HIV Agents; Biological Availability; Body Weight; Child; Child Nutrition Disorders; Child, Preschool; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Follow-Up Studies; HIV; HIV Infections; Humans; Infant; Lamivudine; Male; Models, Biological; Nutritional Support; Severity of Illness Index; South Africa; Time Factors; Time-to-Treatment; Treatment Outcome; Viral Load

Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues.. HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP.. Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1-Q3, 221-277) dB/m and 286 (Q1-Q3, 269-314) dB/m for the EFV group (P = .035). The median decrease in CAP values was -20 (Q1-Q3, -67 to 15) dB/m for the RAL arm and 30 (Q1-Q3, -17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029).. After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL.. NCT01900015.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Body Mass Index; Body Weight; Cyclopropanes; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; Elasticity Imaging Techniques; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Raltegravir Potassium; Tenofovir; Triglycerides; Waist-Hip Ratio

Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa.. A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/microL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat.. The median pre-ART CD4 count was 99 cells/microL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/microL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24-1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34-1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46-0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001).. The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.

Topics: Adult; Body Weight; CD4 Lymphocyte Count; Dideoxynucleosides; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Medication Adherence; Middle Aged; Nevirapine; Recurrence; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Uganda; Viral Load; Zidovudine

To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations.. Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children (n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg(-1) day(-1) or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria.. A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration-time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l(-1) and 6.1 mg h l(-1) for toddlers and infants, and 3.6 mg l(-1) and 8.7 mg h l(-1) for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling.. The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny.

Topics: Adolescent; Age Factors; Anti-HIV Agents; Body Weight; Child; Child, Preschool; Clinical Trials as Topic; Dideoxynucleosides; Female; HIV Infections; Humans; Infant; Male; Models, Biological; Sex Factors

Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg(-1) twice daily up to a maximum of 300 mg twice daily. Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children.. A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. A maximum a posteriori probability Bayesian estimator of AUC(0-) (t) based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration-time curve (AUC) targeted individualized therapy in infants and toddlers.. To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration-time curve (AUC) targeted dosage and individualize therapy.. The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation-estimation method.. The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 () h−1 (RSE 6.3%), apparent central volume of distribution 4.94 () (RSE 28.7%), apparent peripheral volume of distribution 8.12 () (RSE14.2%), apparent intercompartment clearance 1.25 () h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t.. The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC(0-) (t) was developed from the final model and can be used routinely to optimize individual dosing.

Topics: Anti-HIV Agents; Area Under Curve; Bayes Theorem; Body Weight; Child, Preschool; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Dosage Calculations; Female; HIV Infections; Humans; Infant; Male; Models, Biological

To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection.. We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART.. The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model.. The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152-2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339-3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494-5.139; p = 0.001) (61-68 kg: adjusted HR = 1.908; 95%CI, 0.764-4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318-3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003).. The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir.

Topics: Adenine; Adult; Antiretroviral Therapy, Highly Active; Body Weight; Demography; Dideoxynucleosides; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kaplan-Meier Estimate; Male; Multivariate Analysis; Organophosphonates; Risk Factors; Tenofovir

This cohort study was conducted amongst female patients manifesting lipoatrophy while receiving stavudine-containing first-line antiretroviral treatment regimens at two urban health centres in Rwanda. The objectives were to assess weight evolution after stavudine substitution and to describe any significant difference in weight evolution when zidovudine or tenofovir/abacavir was used for substitution. All adult patients on stavudine-containing first-line regimens who developed lipoatrophy (diagnosed using a lipodystrophy case definition study-based questionnaire) and whose treatment regimen was changed were included (n=114). In the most severe cases stavudine was replaced with tenofovir or abacavir (n=39), and in the remainder with zidovudine (n=75). For patients changed to zidovudine a progressive weight loss was seen, while those on tenofovir/abacavir showed a progressive weight increase from six months. The between-group difference in weight evolution was significant from nine months (difference at 12 months: 2.3 kg, P=0.02). These differences were confirmed by follow-up lipoatrophy scores. In multivariate analysis, substitution with tenofovir/abacavir remained significantly associated with weight gain. This is the first study in Africa assessing weight gain as a proxy for recovery after stavudine substitution due to lipoatrophy, providing supporting evidence that tenofovir/abacavir is superior to zidovudine. The weight loss with zidovudine might justify earlier substitution and access to better alternatives like tenofovir/abacavir.

Topics: Adenine; Adult; Anti-HIV Agents; Body Weight; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Organophosphonates; Rwanda; Stavudine; Tenofovir; Treatment Outcome; Weight Loss; Zidovudine

To study the possible influence of patient characteristics on abacavir pharmacokinetics.. A population pharmacokinetic model for abacavir was developed using data from 188 adult patients by the use of a nonlinear mixed effects modelling method performed with NONMEM.. Abacavir pharmacokinetics was well described by a two-compartment open model with linear absorption and elimination. Typical population estimates for the absorption rate constant (Ka), the apparent central distribution volume (Vc/F), the apparent peripheral distribution volume (Vp/F), the apparent intercompartmental clearance (Q/F) and the apparent plasma clearance (CL/F) were 1.8 h(-1), 75 l, 23.6 l, 10 l h(-1) and 47.5 l h(-1), respectively. Apparent plasma clearance was positively related to bodyweight. Individual Bayesian estimates of CL/F were used to calculate abacavir AUC. The latter decreased from 10.7 +/- 5.0 to 5.7 +/- 1.6 mgh l(-1) when bodyweight increased from 36 to 102 kg. This drop in abacavir exposure could lead to suboptimal treatment for the heaviest patients, as antiviral efficacy of abacavir is known to be related to its AUC. A 400 mg abacavir dose would be necessary to achieve adequate exposure to abacavir in patients weighing more than 60 kg.. The apparent plasma clearance of abacavir was positively related to bodyweight. The efficacy of the current recommended abacavir dosage for patients with high bodyweight should be evaluated in further studies.

Topics: Administration, Oral; Adolescent; Adult; Anti-HIV Agents; Area Under Curve; Body Weight; Chromatography, High Pressure Liquid; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors; Tablets

Abacavir pharmacokinetics was studied in 105 children by a population approach performed with NONMEM. A 1-compartment open model with linear absorption and elimination adequately described the data. Typical population estimates (percent interindividual variability) of absorption rate constant, apparent distribution volume, and apparent plasma clearance were 1.79 h(-1) (58%), 42.9 L (53%), and 24.3 L/h (30%), respectively. Apparent plasma clearance was positively related to body weight. Individual Bayesian estimates of apparent plasma clearance were used to calculate individual abacavir area under the concentration curve (AUC). For the current weight-based regimen, abacavir exposure was found to be constant throughout the age range of the study, with an overall mean AUC value of 8.5 +/- 2.5 mg x h/L, which is slightly greater than the mean AUC value reported in adults. This study confirms the relevance of the current weight-based abacavir dosage regimen in pediatric patients.

Topics: Adolescent; Age Distribution; Anti-HIV Agents; Area Under Curve; Body Weight; Child; Child, Preschool; Dideoxynucleosides; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infant; Male; Metabolic Clearance Rate; Models, Biological; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors