Tamara Kredo

Interaction between Artemether-Lumefantrine and Nevirapine-Based Antiretroviral Therapy in HIV-1-Infected Patients

ABSTRACT Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naïve patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naïve groups, respectively (P = 0.0002). The median artemether area under the plasma concentration-time curve from 0 to 8 h [AUC(0-8 h)] (P < 0.0001) and dihydroartemisinin AUC(60-68 h) (P = 0.01) were lower in the nevirapine group. Combined artemether and dihydroartemisinin exposure decreased over time only in the nevirapine group (geometric mean ratio [GMR], 0.76 [95% confidence interval {CI}, 0.65 to 0.90]; P < 0.0001) and increased with the weight-adjusted artemether dose (GMR, 2.12 [95% CI, 1.31 to 3.45]; P = 0.002). Adverse events were similar between groups, with no difference in electrocardiographic Fridericia corrected QT and P-R intervals at the expected time of maximum lumefantrine concentration (Tmax). Nevirapine-based ART decreased artemether and dihydroartemisinin AUCs but unexpectedly increased lumefantrine exposure. The mechanism of the lumefantrine interaction remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.

Integration of data from multiple sources for simultaneous modelling analysis: experience from nevirapine population pharmacokinetics.

AIMS To propose a modelling strategy to efficiently integrate data from different sources in one simultaneous analysis, using nevirapine population pharmacokinetic data as an example. METHODS Data from three studies including 115 human immunodeficiency virus-infected South African adults were used. Patients were on antiretroviral therapy regimens including 200 mg nevirapine twice daily and sampled at steady state. A development process was suggested, implemented in NONMEM7 and the final model evaluated with an external data set. RESULTS A stepwise approach proved efficient. Model development started with the intensively sampled data. Data were added sequentially, using visual predictive checks for inspecting their compatibility with the existing model. Covariate exploration was carried out, and auxiliary regression models were designed for imputation of missing covariates. Nevirapine pharmacokinetics was described by a one-compartment model with absorption through two transit compartments. Body size was accounted for using allometric scaling. The model included a mixture of two subpopulations with different typical values of clearance, namely fast (3.12 l h(-1)) and slow metabolizers (1.45 l h(-1)), with 17% probability of belonging to the latter. Absorption displayed large between-occasion variability, and food slowed the absorption mean transit time from 0.6 to 2.5 h. Concomitant antitubercular treatment including rifampicin typically decreased bioavailability by 39%, with significant between-subject variability. Visual predictive checks of external validation data indicated good predictive performance. CONCLUSIONS The development strategy succeeded in integrating data from different sources to produce a model with robust parameter estimates. This work paves the way for the creation of a nevirapine mega-model, including additional data from numerous diverse sources.

The impact of the National HIV Health Care Worker Hotline

To the Editor: The National HIV Health Care Worker (HCW) Hotline was established in 2008, in collaboration with the Foundation for Professional Development (FPD) and PEPFAR/USAID, to support the safe and effective roll-out of antiretroviral treatment in South Africa. It is based in the Medicines Information Centre, Division of Clinical Pharmacology, UCT, and has access to the latest information and numerous clinical experts. The toll-free hotline operates weekdays, 8h30 - 16h30, providing up-to-date information to all health care workers on aspects concerning the treatment of HIV infection and related diseases. Use of the service has consistently increased to over 300 calls a month. HCWs who called the hotline in August and September 2009 with patient-specific queries were asked to complete a standardised questionnaire which evaluated whether the information provided was used and how this affected patient care. The most frequent users of the hotline were doctors (69%), pharmacists (14%) and nurses (11%), which may reflect the fact that doctors remain predominant in decisions around HIV care. Of those who called the hotline with a clinical query, 96% reported that they changed their patient management as a result of the information provided. Most actions that were a consequence of the advice given concerned direct treatment-related decisions; these included treatment initiation (34%), dose adjustment (19%), discontinuation (44%) and change of ART. A substantial proportion of actions concerned the overall management of patients, such as the initiation of further diagnostic procedures, referrals to specialist services and hospital admissions. These figures demonstrate that the hotline is used for medicine-specific questions and the overall management of patients. Almost all callers interviewed confirmed that the information provided was useful, timely and of benefit to the patient. The public health sector aims to substantially increase the number of HIV-infected individuals receiving ART. Nurse-initiated management of ART (NIMART) is a goal of the Department of Health, 1