Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB–rifampicin sensitivity among Ugandan patients

BACKGROUND: Suboptimal anti-TB drugs exposure may cause multidrug-resistant TB. The role of African predominant SLCO1B1 variant alleles on rifampicin pharmacokinetics and the subsequent effect on the occurrence of Mycobacterium tuberculosis-rifampicin sensitivity needs to be defined. We describe the rifampicin population pharmacokinetics profile and investigate the relevance of SLCO1B1 genotypes to rifampicin pharmacokinetics and rifampicin-TB sensitivity status. METHODS: Fifty patients with TB (n=25 with rifampicin-resistant TB and n=25 with rifampicin-susceptible TB) were genotyped for SLOC1B1 rs4149032 (g.38664C>T), SLOC1B1*1B (c.388A>G) and SLOC1B1*5 (c.521 T>C). Steady state plasma rifampicin levels were determined among patients infected with rifampicin-sensitive TB. Data were analysed using NONMEM to estimate population rifampicin pharmacokinetics as well as the effect of SLOC1B1 genotypes on rifampicin pharmacokinetics and on rifampicin-TB sensitivity status. RESULTS: Overall allele frequencies of SLOC1B1 rs4149032, *1B and *5 were 0.66, 0.90 and 0.01, respectively. Median (IQR) Cmax and Tmax were 10.2 (8.1-12.5) mg/L and 1.7 (1.125-2.218) h, respectively. Twenty-four percent of patients exhibited Cmax below the recommended 8-24 mg/L range. SLOC1B1 genotypes, gender and age did not influence rifampicin pharmacokinetics or TB-rifampicin sensitivity. CONCLUSIONS: Although SLOC1B1 genotype, age and gender do not influence either rifampicin pharmacokinetics or rifampicin-TB sensitivity status, one in every four Ugandan TB patients achieve subtherapeutic plasma rifampicin concentrations

Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-group Prospective Cohort Study in two sub-Saharan Africa Populations.

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations

Unsafe "crossover-use" of chloramphenicol in Uganda: importance of a One Health approach in antimicrobial resistance policy and regulatory action.

Since the introduction of antibiotics into mainstream health care, resistance to these drugs has become a widespread issue that continues to increase worldwide. Policy decisions to mitigate the development of antimicrobial resistance are hampered by the current lack of surveillance data on antibiotic product availability and use in low-income countries. This study collected data on the antibiotics stocked in human (42) and veterinary (21) drug shops in five sub-counties in Luwero district of Uganda. Focus group discussions with drug shop vendors were also employed to explore antibiotic use practices in the community. Focus group participants reported that farmers used human-intended antibiotics for their livestock, and community members obtain animal-intended antibiotics for their own personal human use. Specifically, chloramphenicol products licensed for human use were being administered to Ugandan poultry. Human consumption of chloramphenicol residues through local animal products represents a serious public health concern. By limiting the health sector scope of antimicrobial resistance research to either human or animal antibiotic use, results can falsely inform policy and intervention strategies. Therefore, a One Health approach is required to understand the wider impact of community antibiotic use and improve overall effectiveness of intervention policy and regulatory action

Liver Enzyme Abnormalities and Associated Risk Factors in HIV Patients on Efavirenz-Based HAART with or without Tuberculosis Co-Infection in Tanzania.

To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection. A total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7 per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI. Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians

Pharmacogenetic & Pharmacokinetic Biomarker for Efavirenz Based ARV and Rifampicin Based Anti-TB Drug Induced Liver Injury in TB-HIV Infected Patients

BACKGROUND: Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients. METHODS AND FINDINGS: Newly diagnosed treatment naïve TB-HIV co-infected patients (n = 353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001), higher plasma efavirenz level (p = 0.009), efavirenz/8-hydroxyefavirenz ratio (p = 0.036), baseline AST (p = 0.022), ALT (p = 0.014), lower hemoglobin (p = 0.008), and serum albumin (p = 0.007), NAT2 slow-acetylator genotype (p = 0.039) and ABCB1 3435TT genotype (p = 0.001). CONCLUSION: We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI

Poor immunological recovery among severely immunosuppressed antiretroviral therapy-na&iuml;ve Ugandans

Sarah Nanzigu,1,2 Ronald Kiguba,1 Joseph Kabanda,3 Jackson K Mukonzo,1 Paul Waako,1 Cissy Kityo,4 Fred Makumbi31Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, Kampala, Uganda; 2Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden; 3Institute of Public Health, Makerere University College of Health Sciences, Kampala, Uganda; 4Joint Clinic Research Centre, Kampala, UgandaIntroduction: CD4 T lymphocytes remain the surrogate measure for monitoring HIV progress in resource-limited settings. The absolute CD4 cell counts form the basis for antiretroviral therapy (ART) initiation and monitoring among HIV-infected adults. However, the rate of CD4 cell change differs among patients, and the factors responsible are inadequately documented.Objective: This study investigated the relationship between HIV severity and ART outcomes among ART-na&iuml;ve Ugandans, with the primary outcome of complete immunological recovery among patients of different baseline CD4 counts.Methods: Patients&#39; records at two HIV/ART sites &ndash; the Joint Clinic Research Centre (JCRC) in the Kampala region and Mbarara Hospital in Western Uganda &ndash; were reviewed. Records of 426 patients &ndash; 68.3% female and 63.2% from JCRC &ndash; who initiated ART between 2002 and 2007 were included. HIV severity was based on baseline CD4 cell counts, with low counts considered as severe immunosuppression, while attaining 418 CD4 cells/&micro;L signified complete immunological recovery. Incidence rates of complete immunological recovery were calculated for, and compared between baseline CD4 cell categories: <50 with &ge;50, <100 with &ge;100, <200 with &ge;200, and &ge;200 with &ge;250 cells/&micro;L.Results: The incidence of complete immunological recovery was 158 during 791.9 person-years of observation, and patients with baseline CD4 &ge; 200 cells/&micro;L reached the end point of immunological recovery 1.89 times faster than the patients with baseline CD4 < 200 cells/&micro;L. CD4 cell change also differed by time, sex, and site, with a faster increase observed during the first year of treatment. CD4 cell increase was faster among females, and among patients from Mbarara.Conclusion: Initiating ART at an advanced HIV stage was the main reason for poor immunological recovery among Ugandans. Earlier ART initiation might lead to better immunological responses.Keywords: baseline CD4 cells, HIV severity, immunological recovery, ART outcome, AR

Pharmacokinetics, pharmacodynamics, and pharmacogenetics of Efavirenz 400 mg once daily during pregnancy and post-partum

Background A clinical trial showed that efavirenz 400 mg once daily (EFV400) is as effective as the standard adult dose. World Health Organization recommends EFV400 as an alternative first-line agent, but data are lacking in the third trimester of pregnancy (TT). We investigated the pharmacokinetics, efficacy, and CYP2B6 pharmacogenetics in HIV-infected women (WLWH) on EFV400 during TT and post-partum (PP). Methods An open-label 2-center study (United Kingdom, Uganda) was conducted in WLWH receiving antiretroviral regimens containing efavirenz 600 mg, who had their efavirenz dose reduced to EFV400. Weekly therapeutic drug monitoring (TDM), steady-state pharmacokinetic profiles (TT and PP), safety, virological efficacy, and CYP2B6 polymorphisms at positions 516 (C > T) and 938 (T > C) were evaluated. Results Twenty-five WLWH of African origin were enrolled. All had viral loads <50 copies/mL at baseline, which were maintained throughout the study. No infant was HIV infected. No WLWH were withdrawn due to low EFV400 TDM results. Geometric mean ratios (TT/PP; 90% confidence interval) for EFV400 maximum observed plasma concentration, area under the curve, and plasma concentration measured 24 hours after the observed dose were 0.97 (.85–1.10), 0.87 (.76–.99), and 0.77 (.65–.91), respectively. Five of 25 WLWH were slow metabolizers. Conclusions Although EFV400 pharmacokinetic parameters were slightly lower for TT compared with PP values, efavirenz concentrations exceeded cutoff levels established by the study and those measured in antiretroviral-naive patients receiving EFV400 in ENCORE1. All subjects maintained a viral load <50 copies/mL, suggesting that EFV400 can be used in pregnant WLWH