|Year : 2013 | Volume
| Issue : 2 | Page : 141-144
Abstracts from global literature: Role of genetic factors in anti-retroviral therapy
Zarna Marfatia1, Ipsa Pandya2
1 Department of Biological Sciences, Pittsburg State University, Kansas, USA
2 Department of Skin and VD, Medical College, Vadodara, Gujarat, India
|Date of Web Publication||25-Oct-2013|
Department of Skin and VD, Medical College, Vadodara, Gujarat
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Marfatia Z, Pandya I. Abstracts from global literature: Role of genetic factors in anti-retroviral therapy. Indian J Sex Transm Dis 2013;34:141-4
|How to cite this URL:|
Marfatia Z, Pandya I. Abstracts from global literature: Role of genetic factors in anti-retroviral therapy. Indian J Sex Transm Dis [serial online] 2013 [cited 2019 Nov 17];34:141-4. Available from: http://www.ijstd.org/text.asp?2013/34/2/141/120566
Plasma efavirenz concentrations and the association with CYP2B6-516G > T polymorphism in HIV-infected Thai children
Puthanakit T, Tanpaiboon P, Aurpibul L, Cressey TR, Sirisanthana V. Antivir Ther 2009;14:315-20.
Background: Concerns have been raised about the possibility of sub therapeutic efavirenz (EFV) plasma levels in children with the current dosing guideline. Single nucleotide polymorphisms of the hepatic cytochrome P450 isoenzyme 2B6 (CYP2B6) gene have been associated with high inter-individual variations in EFV plasma concentrations. Our objective was to determine the adequacy of EFV dosing and explore the influence of CYP2B6-516G > T polymorphisms on EFV plasma concentrations in Thai human immunodeficiency virus (HIV)-infected children. Methods: A total of 63 HIV-infected children receiving EFV for > or = 4 weeks were assessed. Children received EFV daily doses on the basis of body weight bands. Between 12 and 16 h after EFV intake, a blood sample was drawn to measure the EFV plasma concentration and to determine the CYP2B6-516G > T polymorphism using high-performance liquid chromatography and direct gene sequencing, respectively. Results: The median age (range) was 12.3 years (3.1-18.7). The mean ± standard deviation (SD) EFV plasma concentration was 3,138 ng/ml (3.313). 8 (13%), 45 (71%) and 10 (16%) children had an EFV concentration < 1,000 ng/ml, 1,000-4,000 ng/ml and > 4,000 ng/ml, respectively. CYP2B6-516 G/G, G/T and T/T genotypes were found in 48%, 41% and 11% children, respectively. The CYP2B6-516G > T allele frequency was 31.75%. The mean ± SD EFV concentration for children with G/G, G/T and T/T genotypes were 1,604 ng/ml (729), 2,635 ng/ml (1,199) and 11,582 ng/ml (2,972), respectively (P < 0.001). A correlation between EFV concentrations > 4,000 ng/ml and psychiatric side-effects was observed (P = 0.02), but there was no association with rash, hepatotoxicity or central nervous system disturbances. Conclusions: Current EFV dosing guidelines provide adequate plasma drug concentrations in Thai HIV-infected children. CYP2B6-516G > T polymorphisms significantly affect the drug metabolism of EFV in children.
Predictors of kidney tubular dysfunction in human immunodeficiency virus-infected patients treated with tenofovir: A pharmacogenetic study
Rodríguez-Nóvoa S, Pablo L, Soriano V, Egan D, Albalater M, Morello J, Cuenca L, González-Pardo G, Khoo S, Back D, Owen A. Clin Infect Dis 2009;48 (11):e108-16.
Background: Tenofovir is one of the most widely used antiretroviral drugs. Tenofovir undergoes renal clearance by a combination of glomerular filtration and active tubular secretion. Although rare, the mechanism by which tenofovir causes renal damage is not well characterized. We have explored the association between kidney tubular dysfunction (KTD) and polymorphisms in genes encoding drug transporters. Methods: All consecutive, human immunodeficiency virus (HIV)-infected patients receiving tenofovir-containing antiretroviral regimens who were seen at a single institution during the first trimester of 2008 were enrolled in the study. KTD was defined by the presence of at least two of the following abnormalities: non-diabeticglucosuria, urine phosphate wasting, hyperaminoaciduria, β2-microglobulinuria, and increased fractional excretion of uric acid. 12 single-nucleotide polymorphisms in the ABCC2, ABCC4, SCL22A6, SLC22A11, and ABCB1 genes were analyzed using TaqMan 5'- nuclease assays. Results: A total of 115 HIV-infected patients were examined, of whom 19 (16.5%) had KTD. The percentage of patients with KTD was higher among those with genotype CC at position − 24 of ABCC2 than among those with genotypes computed CT and TT (24% [16 of 68 patients] vs. 6% [3 of 47 patients]; P = 0.020). In a multivariate analysis, older age (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.0-1.2; P = 0.024), lower body weight (OR, 0.9; 95% CI, 0.8-0.9; P = 0.048), and genotype CC at ABCC2 position − 24 (OR, 5; 95% CI, 1.2-21; P = 0.027) were independently associated with KTD. Conclusions: Approximately 17% of HIV-infected patients treated with tenofovir had KTD. Homozygosity for the C allele at position − 24 of the ABCC2 gene was strongly associated with KTD in this population. This polymorphism may help to identify patients at greater risk for developing tenofovir-associated tubulopathy, and close monitoring of renal function is warranted for these patients.
Changes in mitochondrial deoxyribonucleic acid as a marker of nucleoside toxicity in HIV-infected patients
Côté HC, Brumme ZL, Craib KJ, Alexander CS, Wynhoven B, Ting L, Wong H, Harris M, Harrigan PR, O'Shaughnessy MV, Montaner JS. N Engl J Med. 2002;346:811-20.
Background: Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human deoxyribonucleic acid (DNA) polymerase γ. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia. Methods: Total DNA was extracted from blood cells. A nuclear gene and a mitochondrial gene were quantified by real-time polymerase chain reaction. Three groups were studied: 24 controls not infected with the human immunodeficiency virus (HIV), 47 HIV-infected asymptomatic patients who had never been treated with antiretroviral drugs, and 8 HIV-infected patients who were receiving antiretroviral drugs and had symptomatic hyperlactatemia. The patients in the last group were studied longitudinally before, during, and after antiretroviral therapy. Results: Symptomatic hyperlactatemia was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68% lower than those of non-HIV-infected controls and 43% lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA (P = 0.02). In the patients followed longitudinally, the decline in mitochondrial DNA preceded the increase in venous lactate levels. Conclusions: Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside-related hyperlactatemia, an effect that resolves on the discontinuation of therapy
Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to human immuno deficiency virus-1 reverse-transcriptase inhibitor abacavir
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT. The Lancet 2002;359:727-73.
Background: The use of abacavir a potent human immunodeficiency virus (HIV)-1 nucleosideanalogue reverse - transcriptase inhibitor is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC (Major histocompatibility complex) alleles and abacavir hypersensitivity in HIV − 1-positive individuals treated with abacavir. Methods: MHC region typing was done in the first 200 Western Australian HIV cohort study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks' exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. P values were corrected for comparisons of multiple human leukocyte antigen (HLA) alleles (Pc ) by multiplication of the raw P value by the estimated number of HLA alleles present within the loci examined. Findings HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in 4 (2%) of the 167 abacavir tolerant patients (odds ratio 117 (95% confidence interval [CI] 29-481), Pc < 0·0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and 5 (3%) of tolerant patients (73 (20-268), Pc < 0·0001). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 (43-15 675), Pc < 0·0001). Other MHC markers also present on the 57·1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n = 200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%. Interpretation: Genetic susceptibility to abacavir hypersensitivity is carried on the 57·1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2·5% without inappropriately denying abacavir to any patient
HLA-dependent hypersensitivity to nevirapine in sardinian human immunodeficiency virus patients
Littera R, Carcassi C, Masala A, Piano P, Serra P, Ortu F, Corso N, Casula B, La Nasa G, Contu L, Manconi PE. AIDS 2006;20:1621-6.
Background: Hypersensitivity reaction to nevirapine, which in some cases can be fatal, shows a higher prevalence in Sardinia in comparison with other Italian regions. Objective: This study demonstrates that hypersensitive reaction to nevirapine in Sardinian human immunodeficiency virus (HIV)-infected patients is associated with the human leukocyte antigen (HLA) Cw8-B14 haplotype. These two HLA class I antigens are in strong linkage disequilibrium in the Sardinian population. Methods: 49 Sardinian HIV-positive patients treated with nevirapine were studied. 13 (26%), developed a hypersensitive reaction thus requiring the drug to be discontinued. HLA Class I and II molecular typing was performed in both nevirapine-hypersensitive and nevirapine-tolerant patients. To avoid biased representation of the allele frequencies in the two groups of treated patients, molecular typing was also performed in 82 HIV-positive patients who had not been treated with nevirapine . Results: Considerable overlap was observed for the clinical, immunological and demographic characteristics of the 13 hypersensitive patients and 36 tolerant patients. Clinical parameters included viral load, status of HIV infection, CD4 and CD8 cell counts, Hepatitis C virus/hepatitis B virus co-infections. 46% (6/13) of the nevirapine-hypersensitive subjects had the HLA-Cw8 and HLA-B14 (65) antigens compared with 5% (2/36) of the nevirapine-tolerant group (P = 0.004; Pc = 0.05 ). Conclusion: In agreement with other recent reports, the utility of HLA typing in HIV patients to identify genetic factors that may confer susceptibility to drug-induced hypersensitive reaction was confirmed. A careful choice of antiretroviral therapy in susceptible individuals should significantly reduce the risk of severe hypersensitive reaction.
Nevirapine-induced hepatotoxicity and pharmacogenetics: A retrospective study in a population from Mozambique
Ciccacci C, Borgiani P, Ceffa S, Sirianni E, Marazzi MC, Altan AM, Paturzo G, Bramanti P, Novelli G, Palombi L. Pharmacogenomics 2010;11:23-31.
Aim: Nevirapine is widely used to treat human immunodeficiency virus (HIV)-1 infection to prevent mother-to-child transmission; unfortunately adverse drug reactions have been reported. Our aim was to identify genes/variants involved in nevirapine-induced hepatotoxicity. Methods: Patients from Mozambique, 78 with nevirapine-induced hepatotoxicity and 78 without adverse events, were genotyped for ABCB1, CYP2B6, CYP3A4 and CYP3A5 gene variants. We conducted a case-control association study and a genotype/phenotype correlation analysis. Results: The ABCB1c. 3435C > T single-nucleotide polymorphisms (SNP) was associated with hepatotoxicity (P = 0.038), with the variant T allele showing a protective effect (odds ratio: 0.42). Moreover, four SNPs in the CYP2B6 and CYP3A5 genes resulted significantly correlated with transaminase values. In particular, for the CYP2B6c. 983T > C SNP, the difference in the alanine aminotransferase mean values were highly significant between TT and TC genotypes (P < 0.001). Conclusion: Our preliminary results confirm the contribution of the ABCB1 c. 3435C > T SNP in nevirapine-induced hepatotoxicity risk and at the same time, suggest the necessity for further studies
Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study
Hulgan T, Haas DW, Haines JL, Ritchie MD, Robbins GK, Shafer RW, Clifford DB, Kallianpur AR, Summar M, Canter JA. AIDS 2005;19:1341-9.
Objective: Human immunodeficiency virus nucleoside reverse transcriptase inhibitors (NRTI) can cause peripheral neuropathy that is a result of mitochondrial injury. Polymorphisms in the mitochondrial genome define haplogroups that may have functional implications. The objective of this study was to determine if NRTI-associated peripheral neuropathy is associated with European mitochondrial haplogroups. Design: Case-control study of adult acquired immunodeficiency syndrome clinical trials group (ACTG) study 384 and ACTG human DNA repository participants. Methods: ACTG study 384 was a treatment strategy trial of antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine given with efavirenz, nelfinavir, or both. Subjects were followed for up to 3 years. Peripheral neuropathy was ascertained based on signs and symptoms. For this analysis, polymorphisms that define European mitochondrial haplogroups were characterized in a majority of ACTG 384 participants, and associations with peripheral neuropathy were assessed using logistic regression. Results: A total of 509 subjects were included in this analysis of whom 250 (49%) were self-identified as white, non-Hispanic. Mitochondrial haplogroup T was more frequent in subjects who developed peripheral neuropathy. Among 137 white subjects randomized to receive ddI plus d4T, 20.8% of those who developed peripheral neuropathy belonged to mitochondrial haplogroup T compared to 4.5% of control subjects (odds ratio, 5.4; 95% confidence interval, 1.4-25.1; P = 0.009). Independent predictors of peripheral neuropathy were randomization to receive ddI plus d4T, older age, and mitochondrial haplogroup T. Conclusions: A common European mitochondrial haplogroup may predict NRTI-associated peripheral neuropathy. Future studies should validate this relationship, and evaluate non-European mitochondrial haplogroups and other NRTI toxicities.