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Chokephaibulkit K.,Mahidol University | Nuntarukchaikul M.,Mahidol University | Phongsamart W.,Mahidol University | Wittawatmongkol O.,Mahidol University | And 5 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2012

Objectives: Data on lopinavir/ritonavir tablets administered once daily in children are limited. We compared the pharmacokinetics (PK) of lopinavir/ritonavir twice daily versus once daily in virologically suppressed, HIV-infected children, and assessed the virological outcome, at 48 weeks, in children receiving the regimen of lopinavir/ritonavir once daily. Patients and methods: HIV-infected children receiving a twice-daily lopinavir/ritonavir-based regimen and with an HIV-1 RNA viral load (VL) <40 copies/mL for at least 3 months were enrolled. Intensive steady-state 12 h blood sampling for PK assessment was performed at enrolment. Immediately afterwards, the lopinavir/ritonavir dose was changed to once daily with the equivalent daily dose, and intensive steady-state 24 h blood sampling was repeated 2 weeks later. If the lopinavir Ctrough was <1.0 μg/mL, the lopinavir/ritonavir dose was increased by 20%-30% and Ctrough measurement repeated. CD4 cell counts and VL were determined at baseline and at 12, 24 and 48 weeks. Results: Twelve children were enrolled. The median age was 13.1 years. Lopinavir AUC0-24 following twice-daily and once-daily dosing was 169.7 (124.0-200.8) and 167.1 (95.1-228.1) · h/mL, respectively. Seven children, including all six concomitantly receiving efavirenz, had a Ctrough <1.0 μg/mL with once-daily lopinavir/ritonavir dosing, and four of seven children had a Ctrough <1.0 μg/mL after dose adjustment. All children maintained virological suppression throughout the 48 week period. Conclusions: Lopinavir/ritonavir-based once-daily regimens could simplify therapy in children/adolescents with virological control, but a lower lopinavir Ctrough was evident. Further efficacy studies of lopinavir/ritonavir once daily in children are necessary before routinely recommending this dosing strategy. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Source

Nouhin J.,Institute Pasteur in Cambodia | Nouhin J.,University Paris Diderot | Madec Y.,Institute Pasteur Paris | Ngo-Giang-Huong N.,Institute Of Recherche Pour Le Developpement Ird Umi 174 | And 5 more authors.
PLoS ONE | Year: 2013

Background:Multi-nucleos(t)ide resistance (MNR) mutations including Q151M, K65R mutations, and insertion at codon 69 of HIV-1 reverse transcriptase coding region may confer resistance to all molecules of nucleos(t)ide reverse transcriptase inhibitors (NRTI). The presence of these mutations is an emerging problem compromising non-nucleoside reverse transcriptase inhibitors and protease inhibitors-based therapies. Furthermore, factors associated with selection of these mutations are still not well defined. The current study aimed to evaluate the frequency and to characterize factors associated with the occurrence of multi-nucleos(t)ide resistance mutations among HIV-1 infected patients failing recommended first-line antiretroviral regimens in Cambodia.Methodology/Principal Finding:This is a retrospective analysis of HIV-1 drug resistance genotyping of 520 HIV-1 infected patients in virological failure (viral load > 250 copies/mL) while on first-line antiretroviral therapy in Cambodia with at least one reverse transcriptase inhibitor resistance associated mutation. Among these 520 patients, a total of 66 subjects (66/520, 12.7%) presented ≥1 MNR mutation, including Q151M, K65R, and Insert69 for 59 (11.3%), 29 (5.6%), and 2 (0.4%) patients, respectively. In multivariate analysis, both Q151M (p = 0.039) and K65R (p = 0.029) mutations were independently associated with current stavudine- compared to zidovudine-use.Conclusion:Such selection of mutations by stavudine drastically limits the choice of antiretroviral molecules available for second-line therapy in resource-limited settings. This finding supports the World Health Organization's recommendation for stavudine phase-out. © 2013 Nouhin et al. Source

Duong T.,Institute Of Recherche Pour Le Developpement Ird Umi 174 | Duong T.,London School of Hygiene and Tropical Medicine | Jourdain G.,Institute Of Recherche Pour Le Developpement Ird Umi 174 | Jourdain G.,Chiang Mai University | And 17 more authors.
PLoS ONE | Year: 2012

Background: Data on determinants of long-term disease progression in HIV-infected patients on antiretroviral therapy (ART) are limited in low and middle-income settings. Methods: Effects of current CD4 count, viral load and haemoglobin and diagnosis of AIDS-defining events (ADEs) after start of combination ART (cART) on death and new ADEs were assessed using Poisson regression, in patient aged ≥18 years within a multi-centre cohort in Thailand. Results: Among 1,572 patients, median follow-up from cART initiation was 4.4 (IQR 3.6-6.3) years. The analysis of death was based on 60 events during 6,573 person-years; 30/50 (60%) deaths with underlying cause ascertained were attributable to infections. Analysis of new ADE included 192 events during 5,865 person-years; TB and Pneumocystis jiroveci pneumonia were the most commonly presented first new ADE (35% and 20% of cases, respectively). In multivariable analyses, low current CD4 count after starting cART was the strongest predictor of death and of new ADE. Even at CD4 above 200 cells/mm3, survival improved steadily with CD4, with mortality rare at ≥500 cells/mm3 (rate 1.1 per 1,000 person-years). Haemoglobin had a strong independent effect, while viral load was weakly predictive with poorer prognosis only observed at ≥100,000 copies/ml. Mortality risk increased following diagnosis of ADEs during cART. The decline in mortality rate with duration on cART (from 21.3 per 1,000 person-years within first 6 months to 4.7 per 1,000 person-years at ≥36 months) was accounted for by current CD4 count. Conclusions: Patients with low CD4 count or haemoglobin require more intensive diagnostic and treatment of underlying causes. Maintaining CD4≥500 cells/mm3 minimizes mortality. However, patient monitoring could potentially be relaxed at high CD4 count if resources are limited. Optimal ART monitoring strategies in low-income settings remain a research priority. Better understanding of the aetiology of anaemia in patients on ART could guide prevention and treatment. © 2012 Duong et al. Source

Homkham N.,Institute Of Recherche Pour Le Developpement Ird Umi 174 | Homkham N.,Chiang Mai University | Cressey T.R.,Institute Of Recherche Pour Le Developpement Ird Umi 174 | Cressey T.R.,Chiang Mai University | And 13 more authors.
Journal of Clinical Pharmacology | Year: 2016

Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment. © 2016, The American College of Clinical Pharmacology. Source

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