Glutathione S-transferase (GST) family is involved in a two-stage detoxification process of a wide range of environmental toxins, carcinogen and antiretroviral (ARV) therapy (ART) drugs. The aim of this study is to describe the impact of genetic polymorphisms of GSTM1, GSTT1 and GSTP1-313A/G in the risk of ARV-associated hepatotoxicity in HIV-infected individuals and its modulation in hepatotoxic patients. We enrolled a total of 34 patients with hepatotoxicity, 131 HIV-infected individuals without hepatotoxicity under non-nucleoside reverse transcriptase inhibitor containing ART and 153 unrelated healthy individuals. With a case-control design, polymorphisms of GSTM1, GSTT1 and GSTP1-313A/G gene were genotyped by PCR and restriction enzyme-length polymorphism. Genotypes of GSTT1 null were significantly higher in HIV-infected individuals as compared with healthy controls (P=0.01, odds ratio (OR)=1.54). HIV-infected individuals with GSTM1-null genotype showed higher risk (P=0.09, OR=1.37) for hepatotoxicity, but risk was not significant. On evaluating gene-gene interaction models, GSTM1 null and GSTT1 null showed significant association with the risk of hepatotoxicity in HIV-infected individuals (P=0.004, OR=2.67) owing to synergistic effect of these genes. Individuals with GSTT1-null and GSTM1-null genotypes showed higher risk of hepatotoxicity with advanced stage of (CD4<200) of HIV infection (P=0.18, OR=1.39; P=0.63, OR=1.13). In case-only analysis, GSTT1-null genotype among alcohol users showed elevated risk of hepatotoxicity in HIV-infected individuals (P=0.12, OR=1.36, 95% confidence interval (CI): 0.94-1.97) as compared with GSTT1 genotypes. The carriers GSTM1-null+GSTT1-null genotype among nevirapine user showed prominent risk of hepatotoxicity in HIV-infected individuals (P=0.12, OR=4.21, 95% CI: 0.60-29.54). Hence, we can conclude that GSTT1-null and GSTM1-null genotypes alone and in combination may predict the acquisition of hepatotoxicity.

Non-nucleoside reverse transcriptase inhibitors are metabolized in the liver by cytochrome P450 (CYP) isoenzymes. Variations in the genes encoding these enzymes may influence the activity of corresponding metabolizing enzymes. This study aimed at assessing association of CYP2C9*2 430C/T, CYP2C9*31075A/C, and CYP1A1m1 3801T/C polymorphism with risk to develop ARV Antiretroviral-associated hepatotoxicity and its severity. In this case-control study, genotyping of CYP2C9*2, CYP2C9*3, and CYP1A1m1 genes was done in 34 HIV-infected individuals with hepatotoxicity and 131 without hepatotoxicity, and 153 unrelated healthy individuals using PCR-RFLP. CYP1A1m13801CC genotype was likely to be associated with severe ARV-associated hepatotoxicity (OR = 1.78, p = 0.70). CYP1A1m13801CC genotype and combined genotype TC + CC were likely to be associated with development of ARV-associated hepatotoxicity (OR = 2.57, p = 0.08; OR = 1.42, p = 0.17). CYP1A1m1 3801CC genotype among advanced and intermediate HIV disease stage was likely to be associated with advancement of disease (OR = 2.56, p = 0.77; OR = 2.37, p = 0.45). CYP2C9*31075AC genotype among alcohol users was likely to be associated with development of ARV-associated hepatotoxicity (OR = 1.67, p = 0.38). CYP1A1m1 3801TC genotype and combined genotype TC + CC among nevirapine users were likely to be associated with severe ARV-associated hepatotoxicity (OR = 3.68, p = 0.27; OR = 4.91, p = 0.13). Among those who received nevirapine, presence of CYP1A1m1 3801TC genotype was likely to be associated with increased risk of development of ARV-associated hepatotoxicity (OR = 1.50, p = 0.78). CYP1A1m1 3801TC, 3801CC, and CYP2C9*3 1075AC genotypes among combined alcohol + nevirapine users increased the risk of development of ARV-associated hepatotoxicity (OR = 1.41, p = 0.53; OR = 1.49, p = 0.83; OR = 1.78, p = 0.35). In conclusion, individuals with CYP1A1m13801CC and 3801TC genotypes independently and in the presence of alcohol and nevirapine usage is likely to be associated with increased risk of development of ARV-associated hepatotoxicity, its severity, and advancement of disease. CYP2C9*31075AC genotype with combined alcohol and nevirapine usage indicated a risk for development of ARV-associated hepatotoxicity.

Chikungunya, caused by the chikungunya virus (CHIKV) mostly presents as acute and chronic articular inflammatory manifestations. Interleukin 1 receptor antagonist (IL-1RN) is a potent endogenous competitive inhibitor of IL-1α and 1β and has an antiinflammatory role. The present study evaluated the possible association of IL1RN variable number tandem-repeat (VNTR) alleles and genotypes, and CHIKV stimulated IL-1RN cytokine production with resistance and/or susceptibility to chikungunya infection and disease state in 224 patients with chikungunya (61 patients with acute chikungunya and 163 patients with chronic chikungunya) and 355 healthy controls.Polymerase chain reaction, CHIKV stimulated cytokine assay and luminex platform were used for assessing polymorphism and protein levels respectively. The study revealed a significant association of IL1RN*1/*1 genotype under recessive genetic model with the risk of developing chikungunya infection. Our findings also indicated that IL1RN *2 allele under dominant mode was associated with protection to chronic chikungunya. The results also revealed a higher production of IL-1 RN protein in patients with chronic chikungunya. To conclude, the results suggest the association of ILRN VNTR polymorphism and IL-RN protein levels with chronic chikungunya.

Hepatic CYP2D6 enzyme metabolizes antiretroviral drugs (ARVs) including nevirapine. Polymorphism in CYP2D6 gene affects drug metabolism and displays distinctive phenotypes in the population. Hence, we investigated the prevalence of CYP2D6*4 1934G/A polymorphism in a total of 165 HIV patients that include 34 with and 131 without hepatotoxicity and 160 unrelated healthy controls by the PCR‐RFLP method. The prevalence of CYP2D6*4 1934AA genotype was higher in total HIV patients as compared to healthy controls (1.81% vs 0.6%, OR = 2.86). Similarly, CYP2D6*4 1934AA genotype was much more prevalent in HIV patients without hepatotoxicity as compared to healthy controls (2.3% vs 0.6%, OR = 2.87). Likewise, CYP2D6*4 1934AA genotype was predominant in advanced HIV disease stage as compared to healthy controls (3.8% vs 0.6%, OR = 6.15). CYP2D6*4 1934GA genotype was distributed higher in HIV patients taking tobacco and nevirapine as compared to non‐users (23.3% vs 19.3%, OR = 1.21, 21.0% vs 16.7%, OR = 1.2). Likewise, CYP2D6*4 1934GA genotype was overrepresented in patients with hepatotoxicity taking alcohol + nevirapine as compared to alcohol non‐users + nevirapine users (20.00% vs 16.67%, OR = 1.25). Thus, there was no significant difference in genotype or allele frequencies of CYP2D6*4 1934G/A polymorphism between the patients with hepatotoxicity and those without or healthy controls.

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Background Plasma concentrations of antiretrovirals (ARVs) regimens have considerably varied in individuals of human immunodeficiency virus (HIV) because of variations in the expression of drug‐metabolizing and transporter genes. Transporter genes play an important role in the disposition of drugs. Polymorphism in transporter gene (ABCC3) affects the MRP3 expression and varies the treatment outcome. Method We examined the polymorphism of ABCC3‐1767G/A gene in a total of 165 HIV patients (out of 165 HIV patients, 34 were with and 131 were without hepatotoxicity) and 156 healthy individuals using the polymerase chain reaction–restriction fragment length polymorphism method. Results In univariate analysis, we found a decreased prevalence of ABCC3 1767GA, 1767GA+AA genotypes, and 1767A allele in patients with hepatotoxicity as compared to patients without hepatotoxicity (23.5% vs. 28.2% and 23.5% vs. 30.53%; 11.76% vs. 16.41%), while a higher prevalence of 1767AA genotype was observed in HIV patients in comparison with healthy controls (2.3% vs. 1.3%, odds ratio [OR] = 1.71, 95% confidence interval [CI]: 0.23–15.03, p = .89). The frequency of ABCC3‐1767AA genotype was dispersed higher in individuals with early and advanced HIV disease stage in comparison with healthy controls (5.3% vs. 1.3%, OR = 4.73, p = .70; 8.9% vs. 1.3%, OR = 1.89, p = .91). A higher occurrence of ABCC3‐1767AA genotype was found in tobacco using HIV patients without hepatotoxicity compared with nonusers (4.7% vs. 1.1%, OR = 4.28, p = .52). The distribution of ABCC3‐1767GA genotype was higher in nevirapine receiving HIV patients irrespective of their hepatotoxicity status as compared to nonusers (30.4% vs. 9.1%, OR = 3.34, p = .22; 29.4% vs. 16.7%, OR = 1.69, p = .77). In multivariate analysis, HIV patients receiving nevirapine and with hepatotoxicity was found to have a significant risk for severity of hepatotoxicity (OR = 4.56, 95% CI: 1.60–12.99, p = .004). Conclusion ABCC3 1767G/A polymorphism was not significantly associated with susceptibility to ARV‐associated hepatotoxicity, although ABCC3 1767AA genotype designated a risk for acquisition of hepatotoxicity and advancement of the disease. Nevirapine usage emerged as an independent risk factor for hepatotoxicity severity.

Background Hepatic enzyme cytochrome P450 2B6 (CYP2B6) plays a role in the metabolism of efavirenz drugs. CYP2B6 516G>T variation showed an implication for HIV treatment. Methods CYP2B6 516G>T polymorphism was genotyped in a total 165 HIV patients that include 34 with and 131 without hepatotoxicity and 155 healthy individuals by the PCR‐RFLP. Results In patients with hepatotoxicity, the prevalence of CYP2B6 516TT genotype was higher as compared to healthy individuals (35.3% vs. 30.5%, OR = 1.74). Patients with hepatotoxicity using tobacco had a higher prevalence of genotypes CYP2B6 516GT, 516TT, 516GT+TT as compared to healthy individuals (28.57% vs. 25.93%; 57.14% vs. 29.63%; 85.71% vs. 55.56%). Likewise, hepatotoxicity in patients consuming alcohol showed higher distributions of CYP2B6 516GT, 516TT, 516GT+TT genotypes (57% vs. 25.93%; 42.86% vs. 33.33%; 71.43% vs. 59.26%). Nevirapine users with hepatotoxicity overrepresented genotypes CYP2B6 TT and 516GT+TT as compared to efavirenz users (47.83% vs. 45.45%, OR = 6.88, 65.22% vs. 54.55%, OR = 1.56). Similarly, in nevirapine +alcohol users with hepatotoxicity, the frequency of CYP2B6 516GT, 516GT+TT genotypes was higher than with nevirapine +alcohol nonusers (40.0% vs. 11.11%, OR = 8.00, 80.0% vs. 27.78%, OR = 4.00). In HIV patients, nevirapine users had higher frequency of CYP2B6 516GT, 516GT+TT genotypes as compared to efavirenz users (42.02% vs. 25.00%, OR = 2.53; 72.27% vs. 58.33%, OR = 1.86). Likewise, in HIV patients, genotypes CYP2B6 516GT, 516GT+TT were predominant with nevirapine +alcohol users as compared to nevirapine +alcohol nonusers (57.89% vs. 34.57%, OR = 2.46; 78.95% vs. 69.14%, OR = 1.67). In multivariate logistic regression, taking nevirapine had a protection for severity of ARV‐associated hepatotoxicity (OR = 0.23, p = 0.005). Conclusions No significant association was detected between CYP2B6 516G>T polymorphism and susceptibility to ARV‐associated hepatotoxicity.

Background: Antiretroviral treatment (ART) have been reported to make changes in the functioning of dopaminergic neurons by altering the expression of dopamine active transporter (DAT). ART containing efavirenz drug have been related to show the adverse reactions on the central nervous system (CNS). Reported literature indicates the correlation of DAT19/10 genotype with the risk of progression of human immunodeficiency virus (HIV) infection. Objective: To assess the polymorphism in the human gene DAT1 including variable number tandem repeats (VNTR) from individuals having an infection of HIV. Methods: Genotyping was completed by performing a polymerase chain reaction (PCR) in a total of 165 HIV positive patients on ART treatment (34 were HIV-infected patients with hepatotoxicity, 131 HIV-infected patients) and 160 healthy controls without HIV infection. Results: Incidence of DAT19/9, 8/9 genotypes, and allele with 9 repeats were higher in individuals having hepatotoxicity compared to those who do not have hepatotoxicity (5.9 vs. 0.8%, OR = 7.73; 2.9 vs. 0.8%, OR = 3.86; 20.58% vs. 14.12%, OR = 1.56). DAT19/10 genotype was related to severity of hepatotoxicity (OR = 1.86; P = 0.05). Upon comparison of genotype between individuals who do not have hepatotoxicity but having HIV infection and healthy controls without HIV infection, the dispersion of DAT1 10/11, 6/10 genotypes were greater in individuals with HIV infection (1.5% vs. 0.6%, OR = 2.73; 3.1% vs. 1.3%, OR = 2.73). DAT19/10 genotype was related to the people of advanced stage of HIV infection (OR = 2.05, P = 0.04). A higher incidence of DAT19/10 genotype was found in individuals with early stage of HIV infection than healthy controls (26.3 vs. 15.6%, OR = 1.93). In alcohol and tobacco consuming individuals with HIV infection and hepatotoxicity, DAT19/10 genotype has demonstrated hazard in the progression of HIV infection and increasing severity of hepatotoxic condition (OR = 1.40, P = 0.91, OR = 1.50; P = 0.91 and OR = 1.57, P = 0.39; OR = 2.70; P = 0.53). In patients with hepatotoxicity, nevirapine utilization with DAT19/10 genotype had demonstrated an increase in severity of hepatotoxicity (OR = 4.00, P = 0.41). In individuals with HIV infection and hepatotoxicity, alcohol and nevirapine usage along with DAT1 9/10 genotype have indicated a hazard for progression of HIV infection and increase in severity of hepatotoxicity (OR = 1.47, P = 0.85; OR = 1.73; P = 0.32). Conclusion: The genetic polymorphism with DAT19/10 genotype was linked with the progression of HIV infection and in the advancement of HIV-related illnesses.