High-dose Rifampicin regimens have been shown to be more effective for tuberculosis (TB) treatment in TB/HIV co-infected patients. This study assessed the hepatic safety of a high-dose Rifampicin regimen among TB/HIV co-infected patients. 811 TB/HIV co-infected patients, antiretroviral treatment (ART) naïve, at least 18 years old with a CD4 T-cell count between 50 and 350 cells/mm 3 were enrolled. Patients with multidrug-resistant tuberculosis were excluded. Patients had received first-line antituberculosis treatment followed by ART after two weeks (arm A) or two months (arm B). In arm C, they received antituberculosis treatment with a high dose of Rifampicin (15 mg/kg/day instead of 10 mg/kg/day) during the TB intensive phase of treatment and ART after two months. The patients performed transaminases (ALT, AST), γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase (ALP), and total bilirubin blood tests. The study outcomes were an elevation of ALT at least 5 times the Upper Limit of Normal (Primary outcome), an isolated elevation grade 4 of AST, γ-GT, ALP, and/or total bilirubin (Secondary outcomes). The patients included were 53.97% men and 2.44% co-infected hepatitis B or C virus. There were no significant differences between ALT, AST, γ-GT, ALP, and total bilirubin between the standard regimens (Arms A and B) and high dose Rifampicin regimen (Arm C). This study showed that a high-dose Rifampicin regimen for TB treatment in TB/HIV co-infected patients was as safe as that of a standard regimen.
Introduction: Polymorphisms are the main genetic factors associated with toxicities of antituberculosis drugs. This literature review summarizes the polymorphisms of the genes that code for the enzymes of the metabolism of antituberculosis drugs and their transmembrane transporters. Some mechanisms of drug-associated toxicities and strategies for their management have also been described in this review. Methods: The bibliographic searches were exclusively carried out in PubMed, over a period of ten years (2010-2020). The search terms were the words "toxicity + antituberculosis drug + one or two word(s) among the following: polymorphism, genetics, mutation, SNP, HLA or haplotype". Publications in English or French, relating to the various toxicities associated with first-line anti-tuberculosis drugs (Rifampicin, Isoniazid, Ethambutol and Pyrazinamide) administered to patients with pulmonary tuberculosis, extrapulmonary tuberculosis or co-infected with TB/HIV were included in this review. Duplicates, in vitro, in silico or drug-induced toxicity studies other than antituberculosis drugs and genetic mutations of Mycobacteria strains were not included. Results: The studies selected and included were case reports, cohort studies, original research, systematic reviews and meta-analyses on human subjects of different ethnic origins. Hepatotoxicity is the most common toxicity associated with NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms in patients on antituberculosis drugs. Other forms of toxicity, less frequent, occurring in certain patients under concomitant treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), antiretrovirals (ARVs), antibiotics or antiepileptics have also been identified. Conclusion: The genetic polymorphisms associated with the toxicities of antituberculosis drugs concern both the main enzymes of the metabolic pathways (NAT2, CYP2E1, GST) and the transmembrane transporters (SLCO1B1 and ABCB1).
SLCO1B1 and NAT2 polymorphisms have been associated with the variability of Rifampicin and Isoniazid pharmacokinetic (PK). The objective of this study was to identify in African patients with tuberculosis (TB) or TB/HIV co-infection, the SLCO1B1 and NAT2 polymorphisms, associated with the variability of Rifampicin and Isoniazid pharmacokinetic. TB or TB/HIV co-infected patients from Benin, Guinea, Senegal, and South Africa were included in this study. The blood samples collected were stored at −80˚C until DNA extractions. The DNA extracts were then frozen at −80˚C after quality control. Double stranded DNA of the samples were quantified using a fluorimetric method to select suitable samples for the preparation of 96-well microplates, containing 100 µl of DNA extract per well at the concentration of 20 ng/µl. Illumina HumanOmniExpress-24 v1.2 microarray genotyping was performed by an external vendor. The genotyping data were analyzed and the polymorphisms with a call rate < 95% or presenting a departure from the Hardy-Weinberg Equilibrium (HWE) were excluded. The correlation between significant genetic polymorphisms, the clearance, and the AUC were tested by a multiple linear regression model using the PLINK2 software. Out of 385 samples, five (05) were excluded after quality controls. After the frequency test, 384,586 SNPs failed the Hardy-Weinberg Equilibrium. Finally, 378 samples and 318,751 SNPs were included in the genetic analyses. The SLCO1B1 and NAT2 polymorphisms were associated with the variability of Rifampicin and How to cite this paper:
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