Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

HAART has resulted in dramatic declines in morbidity and mortality among patients infected with HIV. Increased experience with HAART has led to the detection of drug related toxicities that may compromise adherence and necessitate discontinuation of treatment and alteration of otherwise effective regimens. This article considers the major long-term complications associated with nucleoside reverse transcriptase inhibitor (NRTI) use--hyperlactatemia and lactic acidosis/hepatic steatosis, other hepatotoxicities, pancreatitis, lipodystrophy, lipoatrophy, neuropathy, and hematologic toxicities. Mechanisms by which NRTIs may produce these effects are discussed, as are differential effects of agents in this class and management options.
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PMID:Long-term complications of nucleoside reverse transcriptase inhibitor therapy. 1274 68

The non-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine (NVP), efavirenz (EFV), and delaviridine (DLV) are increasingly being used to treat HIV infection. Studies have shown excellent tolerance and efficacy and less development of virological resistance with HIV regimens that include NNRTIs. Nevertheless, abnormalities in liver enzymes are common in patients with HIV infection, and there are multiple etiologies for these abnormalities, including drug toxicity, viral hepatitis, opportunistic infections, and substance abuse. In particular, highly active antiretroviral therapy (HAART) can result in hepatotoxicity through a variety of mechanisms, such as mitochondrial toxicity, lipodystrophy syndrome, and steatohepatitis. The NNRTIs have been most frequently implicated in hypersensitivity reactions. NVP-containing HAART regimens may be more hepatotoxic than are those with EFV and DLV, at least for the first 6 weeks, although the data are still contradictory. Coinfection with hepatitis C and B viruses appears to significantly increase the risk of toxicity, and therefore all patients should be screened for viral hepatitis prior to commencing HAART. Close monitoring of transaminases is suggested in all patients commencing HAART, especially those with preexisting liver disease and coinfection with viral hepatitis.
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PMID:Toxicity of non-nucleoside analogue reverse transcriptase inhibitors. 1280 70

The aim of this study was to identify the first abnormalities of apolipoprotein B (apoB) metabolism in HIV-infected patients treated by antiretroviral therapy (ART) with protease inhibitors (PIs). The influence of ART on the metabolism of apoB in VLDL, IDL, and LDL was investigated in six patients receiving dual nucleoside reverse transcriptase inhibitors (NRTIs) and PI, and in five patients receiving NRTI and nevirapine. None of the patients had lipodystrophy. The study was performed in the fed state. Each subject received an intravenous injection of a 0.7 mg.kg-1 bolus of l-[1-13C]leucine, immediately followed by a 16 h constant infusion at 0.7 mg.kg-1.h-1. The VLDL- and IDL-apoB concentrations were significantly higher in PI-treated patients compared to non-PI-treated patients. The VLDL-apoB and IDL-apoB production rates were markedly higher in PI-treated patients compared to non-PI-treated patients (54.5 +/- 30.1 vs. 30.9 +/- 8.4 mg.kg-1.d-1, P = 0.04; and 43.5 +/- 20.0 vs. 18.7 +/- 7.8 mg.kg-1.d-1, P = 0.04, respectively). In conclusion, our study shows that patients receiving ART with PI present altered metabolism of the VLDL-IDL-LDL chain compared with patients treated without PI. These data confirm that PI therapy is associated with a physiopathological mechanism for dyslipidemia in addition to the effect of lipodystrophy on lipid metabolism.
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PMID:Increased VLDL-apoB and IDL-apoB production rates in nonlipodystrophic HIV-infected patients on a protease inhibitor-containing regimen: a stable isotope kinetic study. 1286 87

Highly active antiretroviral therapy (HAART) commonly leads to persistent dyslipidemia and insulin resistance that appear likely to confer an increased incidence of cardiovascular disease (CVD). Both protease inhibitors (PIs) and, to a lesser extent, nucleoside analog reverse transcriptase inhibitors (NRTIs) appear to be involved, through direct metabolic effects of PIs and an indirect effect of PI and NRTI-related lipodystrophy. Several studies have found a variable relationship between CVD incidence and HAART, but these studies were not prospective and may not have been adequately powered. A variety of treatment strategies have been evaluated for dyslipidemia and insulin resistance, including lifestyle changes, drugs, and antiretroviral switching, but their relative safety, efficacy and roles are unclear. Although treatment of dyslipidemia and insulin resistance is commonly recommended, it should be remembered that such therapy is likely to be of greater benefit in those with a greater perceived CVD risk (i.e., multiple risk factors) and the lowest risk of HIV disease progression.
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PMID:Cardiovascular risk factors in HIV-infected patients. 1456 61

HIV infection is associated with a number of metabolic abnormalities, including lipodystrophy, a difficult-to-define disorder whose characteristics include hyperlipidemia, insulin resistance, and fat redistribution. Current data suggest that lipodystrophy is caused by multiple factors. Dual-nucleoside reverse transcriptase inhibitor therapy combined with protease inhibitor therapy has been shown to increase the risk of metabolic abnormalities, but susceptibility independent of drug effects has also been shown. While many of the treatments for the broad range of signs and symptoms of lipodystrophy bring about improvements in patient status, none have been demonstrated to bring about a return to baseline levels.
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PMID:Current concepts of metabolic abnormalities in HIV patients: focus on lipodystrophy. 1495 94

Nucleoside reverse transcriptase inhibitors (NRTIs), which are used for the treatment of human immunodeficiency virus (HIV) infection have been associated with a wide spectrum of clinical manifestations, including hepatic steatosis, lipodystrophy, myopathy, and lactic acidosis. Such adverse effects are postulated to result from the inhibition of mitochondrial DNA gamma polymerase, which causes the depletion of mitochondrial DNA and eventual the disruption of oxidative phosphorylation. Although cases of severe decompensated lactic acidosis are rare, this syndrome is associated with a high mortality rate. We report upon the first Korean case, of severe lactic acidosis in an acquired immunodeficiency syndrome (AIDS) patient receiving stavudine, an anti-HIV drug.
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PMID:A case of lactic acidosis caused by stavudine in an AIDS patient. 1505 48

This is the first study where HIV-associated body composition changes are described in a Scandinavian cohort. All HIV-positive patients living in Oslo who attended our outpatient clinic (n = 407) were invited to participate. 308 patients (78%) were included. Lipodystrophy (LD) prevalence was 37.3% in patients on antiretroviral therapy (ART+) compared to 10.9% in patients without ART (p < 0.001). Prominent veins and combined fat atrophy/accumulation were exclusively found in the ART+ group. Determinants of prominent veins were skin fold thickness, duration of nucleoside reverse transcriptase inhibitor treatment, duration of protease inhibitor treatment and current use of stavudine. When patients with and without LD were compared, breast circumference was 10.6 cm larger in LD+ women than in LD- women (p = 0.003). Chest pain was reported in 26.5% of LD+ compared to 3.9% (p < 0.001) of LD- patients. This may be associated with an increased level of creatin kinase in LD+ compared to LD- patients (161 +/- 179 U/I vs 102 +/- 68, p = 0.004). Eight years after HIV diagnosis 59.1% of the patients with LD had a regular job and 59.4% reported no or small problems with ART.
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PMID:Body composition changes in 308 Norwegian HIV-positive patients. 1511 63

The recent clinical use of potent HIV-1 drugs, including nucleoside reverse transcriptase inhibitors (NRTIs) and non-peptidic viral protease inhibitors (PIs), and their combinations, termed highly active antiretroviral therapy (HAART), has dramatically reduced the infection-related mortality of AIDS patients, but it is associated with severe metabolic adverse events such as lipodystrophy syndrome, dyslipidaemia, insulin resistance and diabetes mellitus. The aetiology of this syndrome and metabolic alterations appear to be multifactorial, including HIV drug inhibitory effects on adipocyte differentiation, alteration of mitochondrial functions in adipocytes and altered leptin, adiponectin and cytokine expression in adipose tissue of patients. Adipose tissue may thus be a central regulator in disorganized lipid metabolism and insulin resistance associated with antiretroviral therapy, and we propose in this review to explore how adipose tissue may be a target, but also an actor, in the aetiopathogenesis of the lipodystrophy syndrome.
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PMID:Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations. 1513 78

Fat redistribution associated with the use of antiretroviral therapy, which has been broadly termed 'lipodystrophy', incorporates distinct body composition changes including lipoatrophy (subcutaneous fat loss) as well as fat accumulation. This review examines the role of nucleoside reverse transcriptase inhibitor (NRTI) therapy in the overall context of lipodystrophy, providing converging evidence from observational cohort studies, clinical trials and pathological studies that lipoatrophy is strongly and specifically associated with the use of certain NRTI drugs (stavudine more than zidovudine), and that host factors also have a modulating effect on risk of NRTI-associated lipoatrophy. Implications for clinical assessment and management are also considered, within a broader contest that incorporates treatment efficacy as well as toxicity.
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PMID:The role of nucleoside reverse transcriptase inhibitors in the fat redistribution syndrome. 1523 74

There have been few major advances in paediatric HIV management over the last 2 years. Decisions about starting antiretroviral therapy can now be based on a recent large meta-analysis of the predictive value of CD4 and HIV RNA viral load (VL) in nearly 4000 untreated children, which is discussed in these updated guidelines. Risk estimates for progression to AIDS and death using surrogate markers can now be broken down by age, allowing more accurate discussion with families. In addition, there is increasing recognition of the problems of long-term adherence, drug resistance and cumulative toxicity in adults and children. The controversy over whether to treat asymptomatic infants continues. For older children more data on the efficacy of ritonavir boosted protease inhibitor (PI) regimens suggests that these may be the PI option of first choice. There is still no adult or paediatric trial evidence on which to base decisions about whether to start with PI- or non-nucleoside reverse transcriptase inhibitor (NNRTI)- based regimens, but the PENPACT 1 trial, which is addressing this question, is ongoing. There are increasing moves to provide simpler antiretroviral therapy (ART) regimens, including once daily dosing, but these lag behind adult regimens because of the paucity of pharmacokinetic data. Resistance assays should now be performed in all HIV-infected infants exposed to ART in pregnancy. Therapeutic drug monitoring may be very important in children because of high between- and within-child variability in drug absorption and metabolism. A trial to evaluate this should start shortly in Europe (PENTA 14 trial). The value of resistance tests for choice of second-line and subsequent choices of ART regimens remain unproven (the PERA trial will report late in 2004), but resistance assays are increasingly being used. The issue of when to switch therapy also remains unanswered and is being addressed within the PENPACT 1 trial. Regular formal assessment of adherence is now the standard of care, and routine monitoring in the clinic for lipodystrophy syndrome (LDS) and other ART toxicities is increasingly important. These guidelines will be updated again in 2006.
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PMID:PENTA guidelines for the use of antiretroviral therapy, 2004. 1523 17


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