Antimicrobial use-related drug therapy problems and associated factors among patients in the medical ward of Wachemo University Nigist Eleni Mohammed Memorial Comprehensive Specialized Hospital, Southwest Ethiopia.

Objective: This study assessed the antimicrobial use-related drug therapy problems (DTPs) among patients admitted to the medical ward of Wachemo University Nigist Eleni Mohammed Memorial Comprehensive Specialized Hospital (WCUNEMMCSH), Southwest Ethiopia. Methods: A hospital-based prospective observational study design was used to assess antimicrobial use-related DTPs among patients admitted to the medical ward of WCUNEMMCSH from June to August 2021. Data were collected using a structured data abstraction format. Results: In all, 128 patients admitted to the medical ward were enrolled. Among the study participants, at least one form of antimicrobial DTP occurred in 98 (76.6%) of them. The most prevalent DTPs were unnecessary drug treatment in 42 (32.8%), the need for additional drug treatment in 36 (28.1%), and non-adherence in 30 (23.4%) of the patients. There were a total of 288 antimicrobial drug orders. Ceftriaxone 120 (41.7%) and azithromycin 69 (24.0%) were the most commonly prescribed antimicrobial drugs. In multivariate logistic analysis, the length of hospital stay (adjusted odds ratio (AOR) = 2.97, 95% confidence interval (CI): 1.06-8.32; p = 0.04) and the number of diagnosed diseases (AOR = 3.10, 95% CI: 1.12-8.15, p = 0.02) were predictors of antimicrobial use-related DTPs. Conclusion: Antimicrobial use-related DTPs are common among patients admitted to the medical ward of WCUNEMMCSH. Health professionals should work together to reduce the high prevalence of DTPs among medical ward admitted patients in this hospital.

Constitutive androstane receptor and pregnane X receptor genotype influence efavirenz plasma concentration and CYP2B6 enzyme activity.

Efavirenz is metabolized by CYP2B6, an inducible enzyme whose expression is regulated by the constitutive androstane receptor and pregnane X receptor nuclear receptors. CAR and PXR are encoded by genetically polymorphic NR1I2 and NR1I3, respectively. We examined the impact of NR1I2 and NR1I3 genotype on plasma EFV concentration and CYP2B6 enzyme activity among TB-HIV co-infected patients in Ethiopia. Treatment-naïve HIV patients with TB co-infection (n = 80) were enrolled and received first-line EFV-based antiretroviral and rifampicin-based anti-TB therapy. Plasma EFV and 8-hydroxy-EFV concentrations at the 4th and 16th week of EFV treatment were determined using LC/MS/MS. EFV/8-hydroxy-EFVmetabolic ratio was used as CYP2B6 metabolic activity index. In multivariate regression analysis, NR1I3 rs3003596C or NR1I2 rs2472677T variant allele carriers had significantly lower plasma EFV concentrations than non-carriers. Patients with NR1I2 rs3814057C/C genotype or NR1I3 rs3003596C allele carriers had significantly lower mean log EFV MR. Among CYP2B6*6 allele carriers, patients with NR1I3 rs2502815T/T or NR1I2 rs3814057C/C genotype had significantly lower mean log EFV MR. In conclusion, genetic variants in NR1I2 and NR1I3 genes influence plasma EFV exposure and CYP2B6 enzyme activity in TB-HIV co-infected patients on drug treatment.

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs.

Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV- and ARV-ATD-induced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-naïve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G→A, R919Q, p = 1.4 × 10-6, odds ratio [OR] = 18.2, 95% confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH (p = 5.3 × 10-7, OR = 5.4, 95% CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.

HLA-B*57 Allele Is Associated with Concomitant Anti-tuberculosis and Antiretroviral Drugs Induced Liver Toxicity in Ethiopians.

Drug-induced liver injury (DILI) is a known adverse effect of both anti-tuberculosis (anti-TB) and antiretroviral (ARV) drugs. Recent studies highlight the implications of genetic predispositions to DILI. We performed a case-control study to identify Human Leukocyte Antigen-B (HLA-B) variant alleles associated with anti-TB and ARV co-treatment induced liver toxicity in Ethiopian TB and HIV co-infected patients. A total of 495 newly diagnosed TB and HIV co-infected patients were enrolled and received rifampicin based anti-TB and efavirenz based ARV therapy. Change in liver enzyme level from baseline was monitored 1st, 2nd, 4th, 8th, 12th, and 24th weeks after treatment initiation to identify patients who developed DILI (cases) and those who did not (treatment tolerants). Genomic DNA from 46 cases and 46 sex and age matched treatment tolerants were genotyped for HLA-B variant alleles using Olerup SSP®HLA-B DNA Typing Kits. The proportion of HLA-B*57 allele carriers in DILI cases (37.0%), particularly in those who developed cholestatic type of DILI (44.8%) was significantly higher compared with those who tolerated the treatment (2.2%). The HLA-B*57 allele frequency was significantly higher in cases (25%) than treatment tolerants (1.1%). In a multivariate logistic analysis, the proportion of patients carrying HLA-B*57 (P = 0.002) and HLA-B*14 (P = 0.014) alleles were significantly higher in DILI cases compared with treatment tolerants. HLA-B*57 was significantly associated with cholestatic (P = 0.001) and mixed (P = 0.017) types of liver toxicity, and mild-to-moderate severity (P = 0.001). Of all HLA-B*57 alleles detected, HLA-B*57:03 accounted 58.3% and HLA-B*57:02 accounted 41.7%. HLA-B*57:01 was not detected. The variant allele frequencies of HLA-B*57:03 (15.2 vs. 0%) and HLA-B*57:02 (9.8 vs. 1.1%) were significantly higher in the DILI cases than treatment tolerants (P < 0.03). We conclude that HLA-B*57 alleles (B*57:03 and B*57:02) confer susceptibility to the development of anti-TB and ARV drugs co-treatment induced liver toxicity, which is mainly of cholestatic type. The possible association of HLA-B*14 with anti-TB and ARV drugs co-treatment induced liver toxicity requires further investigations.

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back-Looking Forward to Next-Generation Innovation.

Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systematically searched in the PubMed electronic database. We found that the genetic risk variants that were identified genome-wide, and replication confirmed, are mainly related to polymorphisms in the human leukocyte antigen (HLA) region that include HLA-DQB1*06:02 for amoxicillin-clavulanate, HLA-B*57:01 for flucloxacillin, HLA-DRB1*15:01 for lumiracoxib, and HLA-DRB1*07:01 for lapatinib and ximelagatran-induced hepatotoxicity. Additionally, polymorphisms in ST6 ß-galactosamide α-2, 6-sialyltranferase-1 (ST6GAL1), which plays a role in systemic inflammatory response, and variants in intron of family with sequence similarity-65 member-B (FAM65B) that play roles in liver inflammation displayed association with flucloxacillin and antituberculosis drug-induced hepatotoxicity, respectively. Taken together, these GWAS findings offer molecular leads on the central role that the immune system plays in idiosyncratic drug-induced hepatotoxicity. We conclude the expert review with a brief discussion of the salient challenges ahead. These include, for example, the need for discursive discovery paradigms that incorporate alternating GWASs and candidate gene studies, as well as the study of the environtome, the entire complement of environmental factors, including science and innovation policies that enact on global society and the human host, and by extension, on susceptibility for idiosyncratic drug-induced hepatotoxicity.

Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity.

BACKGROUND: Drug-induced liver injury (DILI) is a well-recognized adverse event of anti tuberculosis drugs (ATD) possibly associated with genetic variations. The objective of this study was to perform genome-wide association study (GWAS) to identify genetic variants associated with the risk for ATD induced liver toxicity in Ethiopian patients. RESULT: Treatment-naïve newly diagnosed tuberculosis patients (n = 646) were enrolled prospectively and treated with rifampicin based short course anti-tuberculosis therapy. Whole genome genotyping was done using Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on 48 DILI cases and 354 ATD tolerants. Replication study was carried out for 50 SNPs with the lowest P-values (top SNPs) using an independent cohort consisting of 27 DILI cases and 217 ATD tolerants. In the combined analysis, the top SNP identified was rs10946737 (P = 4.4 × 10-6, OR = 3.4, 95 % confidence interval = 2.2-5.3) in the intron of FAM65B in chromosome 6. In addition, we identified a cluster of SNPs with suggestive genome-wide significance in the intron of ATP/GTP binding protein-like 4 (AGBL4). CONCLUSION: We identified genetic variants that are potentially associated with ATD induced liver toxicity. Further studies with larger sample sizes are essential to confirm the findings.

Evaluation of patterns of liver toxicity in patients on antiretroviral and anti-tuberculosis drugs: a prospective four arm observational study in ethiopian patients.

OBJECTIVES: To evaluate the incidence, type, severity and predictors of antiretroviral and/or anti-tuberculosis drugs induced liver injury (DILI). METHODS: A total of 1,060 treatment naive patients were prospectively enrolled into four treatment groups: HIV patients receiving efavirenz based HAART alone (Arm-1); TB-HIV co-infected patients with CD4≤200 cells/µL, receiving concomitant rifampicin based anti-TB and efavirenz based HAART (Arm-2); TB-HIV co-infected patients with CD4>200 cells/µL, receiving anti-TB alone (Arm-3); TB patients taking rifampicin based anti-TB alone (Arm-4). Liver enzyme levels were monitored at baseline, 1st, 2nd, 4th, 8th, 12th and 24th weeks during treatment. CD4 and HIV viral load was measured at baseline, 24th and 48th weeks. Data were analyzed using multivariate Cox Proportional Hazards Model. RESULTS: A total of 159 patients (15%) developed DILI with severity grades 1, 2, 3 and 4 of 53.5%, 32.7%, 11.3% and 2.5% respectively. The incidence of cholestatic, hepatocellular or mixed pattern was 61%, 15% and 24%, respectively. Incidence of DILI was highest in Arm-2 (24.2%)>Arm-3 (10.8%)>Arm-1 (8.8%)>Arm-4 (2.9%). Concomitant anti-TB-HIV therapy increased the risk of DILI by 10-fold than anti-TB alone (p<0.0001). HIV co-infection increased the risk of anti-TB DILI by 4-fold (p = 0.004). HAART associated DILI was 3-fold higher than anti-TB alone, (p = 0.02). HAART was associated with cholestatic and grade 1 DILI whereas anti-TB therapy was associated with hepatocellular and grade ≥ 2. Treatment type, lower CD4, platelet, hemoglobin, higher serum AST and direct bilirubin levels at baseline were significant DILI predictors. There was no effect of DILI on immunologic recovery or virologic suppression rate of HAART. CONCLUSION: HAART associated DILI is mainly cholestatic and mild whereas hepatocellular or mixed pattern with high severity grade is more common in anti-tuberculosis DILI. TB-HIV co-infection, disease severity and concomitant treatment exacerbates the risk of DILI.