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)

Tenofovir is an acyclic nucleotide analogue reverse transcriptase inhibitor that is commonly prescribed as part of a highly active antiretroviral therapy (HAART) regimen in HIV-infected patients. Although it is generally well tolerated, renal insufficiency has been associated with its use. We report a biopsy-proven case of acute renal failure that developed within weeks of initiating a HAART regimen containing tenofovir, and review the literature with specific attention to cases of renal failure occurring within 8 weeks of tenofovir initiation. Our patient developed renal insufficiency within 3 weeks of initiating tenofovir-containing HAART and overt renal failure was noted within 5 weeks. Renal biopsy demonstrated histopathologic changes suggestive of HIV nephropathy, despite normal baseline serum creatinine values. Thirty additional cases of tenofovir-associated renal failure have been reported. In the majority (n = 22, 73%), renal failure occurred months after initiating therapy (range: 5-26 months). However, in a significant subset (n = 8, 27%), renal failure occurred within 8 weeks of treatment initiation. Our data suggest that some patients are at risk for developing renal failure within weeks of tenofovir initiation. Thorough evaluation of renal function should be undertaken before prescription of tenofovir-containing HAART. For those in whom subclinical renal disease is discerned, added vigilance when monitoring renal function may be warranted.
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PMID:Early onset of tenofovir-induced renal failure: case report and review of the literature. 1766 Aug 85

Genotype testing for HIV-1 drug resistance is useful for selecting antiretroviral drug regimens for patients experiencing therapeutic failure, but the optimal means for interpreting the test results is unknown because many HIV-1 protease and reverse transcriptase (RT) mutations contribute to drug resistance. This study identified common combinations of resistance mutations related to antiretroviral resistance profiles. From April 2002 to March 2004, 101 protease and RT sequences were determined for HIV-1 isolates from patients who were failing antiretroviral therapy. The resistance profile was evaluated using the Stanford Database program. Male patients predominated (76.2%), the median age was 38 years, the average CD4 count was 279.21 cells/mm(3) and the average viral load was 4.49 log. In relation to protease inhibitors (IP) 31 mutation patterns were detected, 49 mutation patterns were detected in Nucleoside RT Inhibitors (NRTI), and 17 patterns were found in the Non Nucleoside RT Inhibitors (NNRTI). K65R was detected in 5.9% of the isolates. The most frequent mutations were: L90M, M184V and K103N related to PI's, NRTI's and NNRTI's, respectively. The best antiretroviral susceptibility was found to be Lopinavir in the PI class and Tenofovir in the NRTI class. The top six mutation patterns accounted for 49% of the resistance to PI's, for 38.5% of NRTI resistance, and the top two mutation patterns accounted for 40.9% of resistance to NNRTI's.
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PMID:Genotype testing and antiretroviral resistance profiles from HIV-1 patients experiencing therapeutic failure in northeast Brazil. 1787 90

Highly active antiretroviral therapy has significantly reduced HIV-related morbidity and mortality. Increasingly, fixed-dose antiretroviral combinations with equal or greater potency than traditional antiretrovirals, along with fewer side effects, reduced toxicity, and simplified dosing convenience are being utilized. Tenofovir-emtricitabine (TDF-FTC) represents one of the more recent fixed-dose combinations. In combination with either a ritonavir-boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, TDF-FTC is a preferred choice in recent treatment guidelines on the basis of demonstrated potency in randomized clinical trials, one-pill-a-day dosing convenience, and relatively low toxicity. In addition, the drug is active against hepatitis B virus. Caution must be exercised in patients with renal insufficiency, or when the drug is used with certain other drugs. This manuscript reviews the use of TDF-FTC in the treatment of HIV.
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PMID:Review of tenofovir-emtricitabine. 1851 68

Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported.
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PMID:[Tenofovir: pharmacology and interactions]. 1919 31

Tenofovir is one of the drugs of choice in first-line combinations of antiretroviral therapy. Most data on safety and efficacy in this scenario initially came from clinical trials in which tenofovir was combined with non-nucleoside reverse transcriptase inhibitors. Because of this, as well as the possible interaction of tenofovir with some protease inhibitors and the suspicion that this combination could increase the risk of nephrotoxicity, analysis of the clinical experience available on the combination of tenofovir (associated with emtricitabine or another nucleoside analogue) with a protease inhibitor is essential. The present review reports data on efficacy and safety, mainly from clinical trials. Taken together, these studies provide sufficient information to indicate that the combination of tenofovir and protease inhibitors is safe and effective, justifying its selection in first-line therapy or rescue therapy after virological failure.
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PMID:[Clinical data II. Clinical experience of tenofovir DF in combination with protease inhibitors]. 1919 33

Tenofovir disoproxil fumarate (TDF) is an analog of adenosine monophosphate that inhibits HIV reverse transcriptase in HIV/AIDS. Despite its therapeutic success, renal tubular side effects are reported. The mechanisms and targets of tenofovir toxicity were determined using '2 x 2' factorial protocols, and HIV transgenic (TG) and wild-type (WT) littermate mice with or without TDF (5 weeks). A parallel study used didanosine (ddI) instead of TDF. At termination, heart, kidney, and liver samples were retrieved. Mitochondrial DNA (mtDNA) abundance, and histo- and ultrastructural pathology were analyzed. Laser-capture microdissection (LCM) was used to isolate renal proximal tubules for molecular analyses. Tenofovir increased mtDNA abundance in TG whole kidneys, but not in their hearts or livers. In contrast, ddI decreased mtDNA abundance in the livers of WTs and TGs, but had no effect on their hearts or kidneys. Histological analyses of kidneys showed no disruption of glomeruli or proximal tubules with TDF or ddI treatments. Ultrastructural changes in renal proximal tubules from TDF-treated TGs included an increased number and irregular shape of mitochondria with sparse fragmented cristae. LCM-captured renal proximal tubules from TGs showed decreased mtDNA abundance with tenofovir. The results indicate that tenofovir targets mitochondrial toxicity on the renal proximal tubule in an AIDS model.
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PMID:Tenofovir renal toxicity targets mitochondria of renal proximal tubules. 1927 46

We developed an automated on-line weak anion exchange (WAX) solid-phase extraction (SPE) method coupled with ion-pair (IP) chromatography-tandem mass spectrometry (MS/MS) detection for quantitatively measuring triphosphorylated metabolites of three reverse transcriptase inhibitors (RTI). The administered pro-drugs were Tenofovir disoproxil fumarate (TDF), Emtricitabine (FTC) and Lamivudine (3TC). Their intracellular metabolites Tenofovir-diphosphate (TFV-DP), Emtricitabine-triphosphate (FTC-TP), and Lamivudine-triphosphate (3TC-TP) were measured in peripheral blood mononuclear cells (PBMC). We coupled the WAX and IP chromatography systems using a combination of 6-port and 10-port switching valves, and we mixed the WAX elute with 1,5-dimethyl-hexyl-amine before IP chromatography separation. Multiple waste outlets allowed for eliminating potential matrix components interfering with MS/MS detection. Limits of detection were 9, 200 and 75 pg per sample for TFV-DP (448/176 m/z), FTC-TP (488/130 m/z) and 3TC-TP (468/119 m/z), respectively.
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PMID:On-line coupling of anion exchange and ion-pair chromatography for measurement of intracellular triphosphate metabolites of reverse transcriptase inhibitors. 1978 32

Tenofovir disoproxil fumarate is a nucleotide analog reverse transcriptase inhibitor recently approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B virus (HBV) infection in adults. Tenofovir has been available in the United States for the treatment of human immunodeficiency virus (HIV) since 2001. It blocks HBV replication in liver cells and is available as a once-daily oral formulation. The efficacy of tenofovir for the treatment of chronic HBV has been demonstrated to be superior to adefovir in randomized controlled trials, which led to its FDA approval for use in chronic HBV. Because of its potent antiviral activity, favorable safety profile, and higher barrier to the development of resistance, tenofovir should replace adefovir as a first-line monotherapy option in the treatment of HBV in monoinfected patients. In the HIV-HBV-coinfected population, tenofovir is already a preferred agent in combination with other anti-HBV agents (lamivudine or emtricitabine), which are cotreatments for HIV as well. In addition, tenofovir monotherapy or in combination with nucleoside analogs are options for patients who have developed resistance to other therapies for chronic HBV, including lamivudine and adefovir.
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PMID:Tenofovir for the treatment of hepatitis B virus. 1979 94

Tenofovir disoproxil fumarate (tenofovir DF) is an orally administered ester prodrug of tenofovir, a nucleotide reverse transcriptase inhibitor that shows potent in vitro activity against both hepatitis B virus (HBV) and HIV-1. As a component of antiretroviral combination therapy regimens, tenofovir DF is well established in the treatment of adults with HIV-1 infection. Tenofovir DF, administered once daily, is also used in the treatment of adults with chronic hepatitis B (CHB) [the main focus of this profile]. In CHB, the efficacy of tenofovir DF against HBV has been evaluated in two large randomized, phase III clinical studies in hepatitis B e antigen (HBeAg)-negative or HBeAg-positive adults, with compensated liver function. The trials (planned duration 8 years) were double-blind for the first 48 weeks; thereafter, patients received open-label tenofovir DF. Results at 48 and 96 weeks are available. In these studies, at week 48, a significantly greater proportion of recipients of tenofovir DF 300 mg once daily than oral adefovir dipivoxil 10 mg once daily achieved a complete response (primary endpoint). A complete response was defined as a reduction from baseline in plasma HBV DNA level to <400 copies/mL and histological improvement (reduction of 2 or more points in Knodell necroinflammatory score without worsening of fibrosis). The efficacy of tenofovir DF in the treatment of CHB was also demonstrated over a 96-week treatment period in both studies. Tenofovir DF was generally well tolerated by adults with CHB in the two phase III trials.
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PMID:Tenofovir disoproxil fumarate: in chronic hepatitis B. 1985 27

The widespread introduction of highly active antiretroviral therapy (HAART) in the mid-1990s dramatically altered the course of human immunodeficiency virus (HIV) infection, with improvements in survival and reductions in the incidence of AIDS-defining illnesses. Although antiretroviral therapy has been shown to reduce the incidence of both AIDS-defining and non-AIDS conditions, long-term exposure to HAART may also be associated with significant toxicity. This article reviews the potential nephrotoxicity of specific antiretroviral agents and the impact of antiretroviral therapy on related metabolic disorders. The antiretroviral agents most strongly associated with direct nephrotoxicity include the nucleotide reverse transcriptase inhibitor, tenofovir, and the protease inhibitor indinavir, although other agents have been implicated less frequently. Tenofovir and related nucleotide analogs have primarily been associated with proximal tubular dysfunction and acute kidney injury, whereas indinavir is known to cause nephrolithiasis, obstructive nephropathy, and interstitial nephritis. Kidney damage related to antiretroviral therapy is typically reversible with early recognition and timely discontinuation of the offending agent, and nephrologists should be familiar with the potential toxicity of these agents to avoid delays in diagnosis.
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PMID:Antiretroviral medications: adverse effects on the kidney. 2000 91


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