Building Capability for Clinical Pharmacology Research in Sub-Saharan Africa.

A strong scientific rationale exists for conducting clinical pharmacology studies in target populations because local factors such as genetics, environment, comorbidities, and diet can affect variability in drug responses. However, clinical pharmacology studies are not widely conducted in sub-Saharan Africa, in part due to limitations in technical expertise and infrastructure. Since 2012, a novel public-private partnership model involving research institutions and a pharmaceutical company has been applied to developing increased capability for clinical pharmacology research in multiple African countries.

Mycobacterium tuberculosis in central Ethiopia: drug sensitivity patterns and association with genotype.

Drug resistance tuberculosis (TB) and the emergence of multidrug resistant (MDR) isolates are significant concerns regarding TB control programs in several countries. This study was undertaken to evaluate the drug sensitivity of Mycobacterium tuberculosis and to assess its association with strains and lineages of M. tuberculosis. A total of 279 M. tuberculosis strains isolated from Central Ethiopia were tested for their drug sensitivity patterns to first line TB drugs using the conventional proportion method on Löwenstein Jensen media. The association between drug sensitivity and strain type was assessed on 263 isolates of the 279 isolates. Of the 268 M. tuberculosis isolates obtained from new cases, 209 (78%) were susceptible to first line TB drugs, and 59 (22.2%) bacterial isolates were resistant to at least one of the first line drugs. The highest mono-resistance (7.5%) pertained to streptomycin (STM). Remarkably, seven of eleven isolates (63.6%) previous treatment for TB were resistant to at least one of the first line drugs. The prevalence of MDR-TB was 1.5% (4/268) for newly identified TB cases, all of which were members of the Euro-American Lineage. There was no statistically significant association (P > 0.05) between drug sensitivity, and either strains, sub-lineages or main lineages of M. tuberculosis. A significant proportion of M. tuberculosis was resistant to at least one first line anti-TB drug. Moreover, the frequencies of resistance to either isoniazid or rifampicin were high compared to data that were previously reported in some part of the country.

Ambulatory care for multidrug-resistant tuberculosis: lessons learned in Addis Ababa, Ethiopia.

SETTING: Ethiopia is one of the high multidrug-resistant tuberculosis (MDR-TB) burden countries. Efforts by the National TB Programme to control MDR-TB include expanding ambulatory care. OBJECTIVE: To investigate the opportunities and challenges faced by treatment follow-up health centres (TFCs) when managing MDR-TB patients, with greater focus on recording, TB infection control (IC) and supervision practices. METHODS: A facility-based cross-sectional study was conducted by reviewing the records of all MDR-TB cases in all 25 TFCs in Addis Ababa, Ethiopia. The TB focal point, pharmacy and laboratory heads were also interviewed. RESULT: A total of 221 MDR-TB patients were registered; 157 (71%) patients had been referred from one of the two treatment initiating centres. While some TFCs oversaw up to 41 patients, others had just one patient. The majority of the TFCs (n = 21, 84%) followed standardised TB IC procedures. Poor documentation of patient information was observed at all sites; for example, human immunodeficiency virus and current treatment status was not indicated for respectively 86 (38%) and 41 (18%) patients. CONCLUSION: The study revealed that infection prevention practices were largely adhered to. Documentation of patient-related information was a major challenge, and regular supervision of the TFCs should be emphasised. Record keeping is critical.

Contexte : L'Ethiopie est l'un des pays durement frappés par la tuberculose multirésistante (TB-MDR). Les efforts du programme national de lutte contre la TB pour contrôler la TB-MDR incluent l'expansion des soins ambulatoires.Objectif : Etudier les opportunités et les défis affrontés par les centres de santé qui suivent le traitement des patients (TFC) dans la prise en charge de patients atteints de TB-MDR avec un accent sur la tenue des dossiers, la lutte contre l'infection tuberculeuse et les pratiques de supervision.Méthodes : Une étude transversale a été réalisée dans des centres de santé grâce à une revue des dossiers de tous les cas de TB-MDR dans les 25 TFC à Addis Ababa, Ethiopie. Le point focal TB, le chef de service de la pharmacie et du laboratoire ont également été interviewés.Résultats: Un total de 221 patients TB-MDR ont été inscrits ; 157 (71%) patients ont été transférés de l'un des deux centres de mise en route du traitement. Si certains TFC ont suivi jusqu'à 41 patients, d'autres n'ont vu qu'un patient. La majorité des TFC (n = 21, 84%) ont suivi les procédures standardisées de lutte contre l'infection TB. Dans tous les sites, on a observé une documentation insuffisante des informations relatives aux patients. Le statut à l'égard du virus de l'immunodéficience humaine et le traitement en cours n'étaient, par exemple, pas indiqués pour 86 (38%) et 41 (18%) patients, respectivement.Conclusion : L'étude a révélé que les pratiques de prévention de l'infection étaient largement observées. Le principal défi résidait en la documentation des informations relatives aux patients ; la supervision régulière des TFC devrait également être renforcée. La bonne tenue des dossiers est cruciale.

Marco de referencia: Etiopía es uno de los países con alta carga de morbilidad por tuberculosis multidrogorresistente (TB-MDR). Entre las iniciativas del programa nacional contra la TB, encaminadas a luchar contra este tipo de TB, se encuentra la ampliación de la prestación de atención ambulatoria.Objetivo: Investigar las oportunidades que encuentran y los obstáculos que afrontan los centros donde se practica el seguimiento terapéutico de los pacientes con TB-MDR, con un interés especial en las prácticas de registro, iniciación del control de la infección tuberculosa y supervisión del tratamiento.Métodos: Se llevó a cabo un estudio transversal de los centros de atención sanitaria (TFC) mediante el examen de las historias clínicas de todos los casos de TB-MDR en los 25 centros de seguimiento terapéutico de Addis Abeba, Etiopía. Se practicaron además entrevistas en el centro de coordinación de la TB, en las farmacias y a los directores de laboratorio.Resultados: Se registraron 221 pacientes con diagnóstico de TB-MDR. Ciento cincuenta y siete pacientes habían sido transferidos de uno de los dos centros de iniciación del tratamiento antituberculoso (TIC) de la ciudad. Algunos de los TFC supervisaban 41 pacientes, pero otros practicaban el seguimiento de un solo paciente. En la mayoría de los TFC se cumplía con los procedimientos normalizados de control de la infección tuberculosa (n = 251, 84%). En todos los centros se observó una documentación deficiente de la información sobre los pacientes; por ejemplo, en 86 casos no se indicó su situación frente al virus de la inmunodeficiencia humana (38%) y en 41 casos no existía información sobre el estado del tratamiento antituberculoso en el momento de la recogida de los datos (18%).Conclusión: El presente estudio reveló una alta tasa de cumplimiento de las prácticas de prevención de la infección tuberculosa en los centros participantes. Un escollo importante que se observó fue la deficiencia en la documentación de la información sobre los pacientes. Se debe reforzar la supervisión periódica de los TFC y es primordial mantener al día los registros clínicos.

Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients.

We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4ß-hydroxycholesterol/cholesterol (4ß-OHC/Chol) as a marker for CYP3A induction. Plasma 4ß-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy-naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4ß-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4ß-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4ß-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure.

High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study.

The objective of this study was to assess the incidence, timing and identify pharmacogenetic, efavirenz (EFV) pharmacokinetic and biochemical predictors of EFV-based antiretroviral therapy (ART) drug-induced liver injury (DILI). ART-naïve HIV patients (n = 285) were prospectively enrolled. Pretreatment laboratory evaluations included hepatitis B surface antigen and C antibody, CD4 count and viral load. Liver tests were done at baseline, 1st, 2nd, 4th, 8th, 12th, 24th and 48th weeks during ART. Plasma EFV and 8-hydroxyefvairenz concentration was determined at week 4 using liquid chromatography-mass spectrometry. CYP2B6, CYP3A5, ABCB1 3435C/T and UGT2B7*2 genotyping was done using Taqman genotyping assay. Data were analyzed using survival analysis and Cox proportional hazards model. The incidence of DILI was 15.7% or 27.9 per 100 person-years and that of severe injury was 3.4% or 6.13 per 100 person-years. The median time for the development of DILI and severe injury was 2 and 4 weeks after initiation of ART, respectively. There was significant association of DILI with lower baseline platelet, albumin, log plasma viral load and CD4 count (P = 0.031, 0.037, 0.06 and 0.019, respectively). Elevated baseline alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, plasma EFV level and CYP2B6*6 were good predictors for the development of DILI (P = 0.03, 0.01, 0.016, 0.017 and 0.04, respectively). We report for the first time CYP2B6*6 as a putative genetic marker and high plasma EFV concentration as intermediate biomarker for vulnerability to EFV-induced liver injury in HIV patients. CYP2B6 genotyping and/or regular monitoring of EFV and lever enzymes level during early therapy is advised for early diagnosis and management of DILI.