Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Identification of reliable markers to predict drug-related adverse events (DRAEs) is an important goal of the pharmaceutical industry and others within the healthcare community. We have used genetic polymorphisms, including the most frequent source of variation (single nucleotide polymorphisms, SNPs) in the human genome, in pharmacogenetic approaches designed to predict DRAEs. Three studies exemplify the principles of using polymorphisms to identify associations in progressively larger genomic regions: polymorphic repeats within the UDP-glucuronysltransferase I (UGT1A1) gene in patients experiencing hyperbilirubinemia after administration of tranilast, an experimental drug to prevent re-stenosis following coronary revascularization; high linkage disequilibrium within the Apolipoprotein E (ApoE) gene in patients with Alzheimer Disease (AD); and the polymorphic variant HLA-B57 in patients with hypersensitivity reaction after administration of abacavir, a nucleoside reverse transcriptase inhibitor for the treatment of HIV. Together, these studies demonstrate in a stepwise manner the feasibility of using pharmacogenetic approaches to predict DRAEs.
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PMID:Pharmacogenetics to predict drug-related adverse events. 1520 98

Hyperbilirubinemia is a common side effect of antiviral medications. The mechanisms underlying its development are multiple and unique to each therapy. During administration of antiviral medications, the hyperbilirubinemia observed in the absence of liver injury is most frequently manifested by isolated increases in the indirect-reacting fraction. Relevant mechanisms leading to indirect hyperbilirubinemia in this setting include hemolysis, decreased hepatic bilirubin clearance as a result of impairment of bilirubin conjugation, or circumstances in which both processes occur simultaneously. Underlying genetic susceptibilities may potentiate these side effects of antiviral therapy. Conjugated (direct-reacting) hyperbilirubinemia can be a consequence of generalized hepatocellular injury, selective cholestatic defects, biliary obstruction, or, rarely, genetic disorders of bilirubin transport. In the specific setting of antiviral therapy, preexisting liver disease or antiviral hepatotoxicity, such as is encountered with the use of the nucleoside and non-nucleoside human immunodeficiency virus reverse transcriptase inhibitors, are the most frequent causes of direct-reacting or mixed direct- and indirect-reacting hyperbilirubinemia. Modification in antiviral drug choice or dose may be required in cases of liver injury or of brisk hemolysis leading to significant anemia. The mild indirect hyperbilirubinemia associated with impairment in conjugation tends to be well tolerated and of little consequence. The decision to continue or discontinue antiviral therapy in the face of hyperbilirubinemia should be made after an assessment of the cause of the elevated bilirubin level and a thorough assessment of the risks and benefits of antiviral therapy.
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PMID:Hyperbilirubinemia in the setting of antiviral therapy. 1582 33

Recommendations for a highly active antiretroviral therapy (HAART) in either pretreated patients or symptomatic patients with an AIDS-defining event are based on a combination of three or more agents from different antiretroviral classes including two nucleoside reverse transcriptase inhibitors with at least one protease inhibitor. The majority of currently available protease inhibitors are coadministered with low-dose ritonavir as a pharmacoenhancer that significantly increases protease inhibitor plasma concentrations. Atazanavir is a highly active azapeptide inhibitor of the HIV protease. It was the first, and to date the only, protease inhibitor designed to be applied once daily (q.d.) and is expected to overcome the problems of earlier agents of this class of drugs, such as unfavorable adverse events like hyperlipidemia, diarrhea and lipodystrophy. Atazanavir, formerly known as BMS-232632, can be dosed either at 400 mg q.d. without a pharmacoenhancer as first-line HIV therapy or combined with ritonavir as atazanavir/ritonavir 300/100 mg q.d. for therapy-experienced patients. The pharmacoenhancing effect of ritonavir on atazanavir resulted in a potent, clinically effective and well-tolerated antiretroviral drug with high plasma concentrations and a sufficient genetic barrier to viral resistance. Nevertheless, noninferiority to lopinavir/ritonavir-containing HAART could not be shown when atazanavir was given unboosted in pretreated patients in the AI424-043 study. When atazanavir was boosted with low-dose ritonavir its efficacy was comparable to that of lopinavir/ritonavir in non-naive patients (AI424-045 study). Additionally, specific side effects were identified during clinical practice, such as an increased rate of patients with jaundice, and, more recently, genetic risk factors causing hyperbilirubinemia. Atazanavir inhibits glucuronyltransferase, an enzyme responsible for the metabolism of bilirubin in liver, thus increasing unconjugated bilirubin levels in blood. However, atazanavir itself also enhances plasma concentrations of other coadministered HIV-1 protease inhibitors, so that its use as a combination partner in boosted double protease inhibitor combinations, with or without the addition of nucleoside reverse transcriptase inhibitors, is being evaluated. Unboosted atazanavir is approved for first-line HIV therapy in adults in the United States, and atazanavir/ritonavir is recommended for the second-line therapy of HIV-1 infection in adult HIV-1-infected patients in the United States and the European Union. More recently, data from the CASTLE study (AI424-138) have been reported at the 15th Conference on Retroviruses and Opportunistic Infections by Molina et al., where boosted atazanavir-containing HAART was compared to a regimen with lopinavir/ritonavir in therapy-naive patients.
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PMID:Atazanavir/ritonavir: a review of its use in HIV therapy. 1838 89

To evaluate the rate of and risk factors for hepatotoxicity in tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) co-infected patients while receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and a rifampicin (RMP)-containing anti-TB regimen. We analyzed data from the N2R study which was an open label, randomized, comparative trial comparing treatment outcomes between 71 TB/HIV-1 co-infected patients receiving efavirenz (EFV)-based and nevirapine (NVP)-based ART; all of whom were receiving RMP-containing anti-TB treatment. Demographic data, liver function test, CD4 cell count, plasma HIV-1 RNA, hepatitis B surface antigen and anti-hepatitis C virus antibody were collected before initiating ART (week 0). Liver enzymes and total bilirubin levels were monitored at 6 weeks, 12 weeks and 24 weeks after ART initiation. All patients were followed until TB therapy was completed. Of 142 patients, 8 patients were excluded. Among the remaining 134 patients, the mean+/-SD age was 36.8+/-8.6 years and 67.2% were male. Severe hepatotoxicity (grade 3 or 4) developed in 4 patients (2.9%); 3 patients (4.6%) in the NVP group and 1 patient (1.4%) in the EFV group. Severe hyperbilirubinemia (grade 3 or 4) occurred in 7 patients (5.2%); 5 patients (7.7%) in the NVP group and 2 patients (2.9%) in the EFV group. Grade 1 or 2 hepatotoxicity occurred in 34 patients (31.4%). Hepatitis C virus co-infection (adjusted OR 3.03; 95%CI 1.26-7.29) was an independent risk factor associated with grade 1-4 hepatotoxicity (p=0.013). Monitoring of hepatotoxicity should be considered in TB/HIV-1 co-infected patients who are infected with HCV and receiving NVP.
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PMID:Hepatotoxicity in patients co-infected with tuberculosis and HIV-1 while receiving non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy and rifampicin-containing anti-tuberculosis regimen. 2170 43