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)

Adefovir dipivoxil [bis(pivaloyloxymethyl)-ester prodrug], an orally bioavailable prodrug of adefovir [9-(2-phosphonylmethoxyethyl)adenine], is currently in phase III clinical trials for the treatment of human immunodeficiency virus (HIV). In vitro experiments demonstrated that either a K65R or a K70E mutation in HIV reverse transcriptase (RT) was selected in the presence of adefovir, conferring a 16- or 9-fold decrease in susceptibility to adefovir, respectively. Previous data demonstrated that patients receiving adefovir dipivoxil monotherapy (125 mg daily) for 12 weeks experienced a median decrease in HIV RNA levels of 0.5 log10 copies/ml and that resistance to adefovir dipivoxil did not arise during that period. In the present investigation, a further study was undertaken to investigate whether RT mutations developed among viruses from patients who completed the 12-week study and who opted to enroll in a maintenance phase of prolonged (6- to 12-month) adefovir dipivoxil therapy (120 mg daily). Concomitant treatment with antiretroviral agents was permitted during the maintenance phase. The median decreases in HIV RNA levels for patients who completed 6 or 12 months of maintenance-phase dosing were 0.6 and 1.14 log10 copies/ml, respectively. The reductions in the HIV RNA levels were similar among patients who received adefovir dipivoxil with or without concomitant treatment with antiretroviral agents. Viruses from 8 of 29 patients dosed for up to 12 months developed RT mutations that were not present at baseline; these mutations may have been related to adefovir dipivoxil therapy. Viruses from two of the eight patients developed the K70E mutation while the patients were on therapy, but none of the viruses from patients developed the K65R RT substitution. Despite the development of RT mutations, sustained reductions (6 to 12 months) in viral load (> or = 0.7 log10 copies/ml decrease from baseline) were observed in all eight patients.
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PMID:Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from AIDS patients after prolonged adefovir dipivoxil therapy. 966 Sep 94

Adefovir dipivoxil [9-(2-(bispivaloyloxymethyl)phosphonylmethoxyethyl)adenine (bis-POM PMEA)], an oral prodrug of adefovir (PMEA), is currently in phase III clinical testing for the treatment of human immunodeficiency virus-1 (HIV-1) infection. Previous in vitro experiments have shown that HIV-1 recombinant viruses expressing either a K65R or a K70E mutation in reverse transcriptase (RT) have reduced sensitivity to PMEA and that the K70E mutant also has impaired replication capacity in vitro. Genotypic analyses of samples from patients enrolled in a phase I/II clinical trial of adefovir dipivoxil demonstrated that the K70E RT mutation developed in two of 29 patients during extended therapy. To further investigate the molecular mechanisms involved in the resistance to PMEA, we cloned, expressed, and purified HIV-1 RT enzymes carrying either the K65R or K70E and, for comparison, the M184V mutation. The Km values of dNTPs for these mutant enzymes were not significantly altered from wild-type RT. The Ki values for the K65R mutant were increased from wild-type by 2-5-fold against a variety of inhibitors, whereas the Ki values for the M184V mutant were increased 12-fold specifically for 2', 3'-dideoxy-3'-thiacytidine (3TC) triphosphate. The Ki values for the K70E mutant were increased for PMEA diphosphate and 3TC triphosphate by 2-3-fold. These results are in agreement with antiviral drug susceptibility assay results. The three recombinant enzymes were also evaluated for their specific activities and processivities. All mutants were reduced in specific activity with respect to wild-type RT. In single-cycle processivity studies, the M184V mutant was, as expected, notably impaired. The K70E mutant was also slightly impaired, whereas the K65R mutant was slightly more processive than wild-type. These results with recombinant K70E RT are consistent with the reduced in vitro replication capacity of the K70E RT mutant of HIV-1 and further demonstrate that the K70E mutation confers minor PMEA and 3TC resistance to HIV-1.
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PMID:Human immunodeficiency virus type 1 reverse transcriptase expressing the K70E mutation exhibits a decrease in specific activity and processivity. 968 70

Adefovir dipivoxil is an ester prodrug of the nucleoside reverse transcriptase inhibitor adefovir (PMEA), the prototype compound of the acyclic nucleoside phosphonates. It has better oral bioavailability than the parent compound. Adefovir dipivoxil 120mg once daily significantly reduced viral load compared with placebo when added to standard antiretroviral therapy in a 6-month, double-blind study in patients with HIV infection. Viral suppression was maintained during an additional 6-month nonblind extension phase. The drug was most effective in patients with baseline isolates containing the M184V lamivudine resistance mutation according to data from a virological substudy of a large placebo-controlled trial. Adefovir dipivoxil 60mg was as effective as 120mg (both once daily) after 20 weeks' treatment in a randomised double-blind study in antiretroviral-experienced (protease inhibitor-naive) patients. Viral suppression was generally maintained in patients who developed new reverse transcriptase mutations during adefovir dipivoxil monotherapy or combination therapy for up to 12 months. No clear pattern of particular clinical resistance mutations has emerged. GI disturbances, hepatic effects and delayed renal abnormalities are the principal adverse events seen with adefovir dipivoxil. Reductions in serum free carnitine levels may occur and coadministration of L-carnitine is recommended.
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PMID:Adefovir dipivoxil. 1049 75

Adefovir dipivoxil (Preveon), a nucleotide analog and a prodrug of PMEA, has been approved for a limited expanded access program for patients who have failed approved treatments. Earlier results from phase I/II trials reveal Preveon has modest anti-HIV activity. Preveon is active against virus that has developed resistance to AZT, 3TC, and other approved nucleoside analogs. To be eligible, patients must be at least 13 years old, failed at least two nucleoside analog reverse transcriptase inhibitors and one protease inhibitor, and within the last 2 months have had a CD4 count of 50 or less and a viral load of at least 30,000 by PCR or at least 15,000 by bDNA. The program will supply only Preveon and the L-carnitine. The AIDS community has expressed concerns about the drug's potential kidney toxicity with long-term use, a condition that becomes clinically evident usually after the first 4 months, possibly leading physicians into complacency in performing regular laboratory tests after that time. The study requires monthly urine testing, including serum creatinine, urine protein, and urine glucose. Another concern is the study's CD4 and viral load restrictions; AIDS advocates believe the restrictions do not allow physicians flexibility in their drug treatment decision-making.
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PMID:Adefovir dipivoxil (Preveon) expanded access begins. 1136 18

Sustiva (DMP 266 or efavirenz) has been available on an expanded access program since October 1. Sustiva is a non-nucleoside reverse transcriptase inhibitor, has fewer side effects than other drugs of its class, and is taken once a day at bedtime. Criteria for the program are T4 counts under 50 in patients whose current therapy is not working. Adefovir dipivoxil (bis-POM PMEA or Preveon) is a nucleotide analog that is also available through an expanded access program. Adefovir's properties make it less vulnerable to resistance. It is not as potent as other drugs of the same class; however, its effect seems to last longer. It is also effective against some herpesviruses and hepatitis B. Contact information is provided for both programs.
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PMID:Expanded access programs. 1136 31

Four new drugs have been developed to overcome the limitations of the currently available anti-HIV drugs, including inconvenient schedules, side effects, and drug interactions. It is hoped that abacavir, efavirenz, adefovir dipivoxil, and amprenavir will be widely available in the near future. Abacavir, a nucleoside reverse transcriptase inhibitor with a twice-daily schedule, offers good bioavailability and generally mild side effects. Efavirenz, a non-nucleoside reverse transcriptase inhibitor with a once daily schedule, may produce side effects such as rash and dizziness. Adefovir dipivoxil, a nucleotide analog with once daily dosing, can cause carnitine depletion and carnitine supplementation is recommended. Amprenavir, a protease inhibitor with twice-daily dosing, has rather mild side effects. Information on efficacy, availability, and resistance for each of these drugs is given.
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PMID:Antiretroviral agents: the next generation. 1136 27

The 38th Interscience Conference on Antimicrobial Agents and Chemotherapy featured information on new antiretroviral treatments, changes in dosing, and new vaccine information. Adefovir dipivoxil (Preveon) is a new nucleoside reverse transcriptase inhibitor that is administered once daily. A study of adefovir dipivoxil is described and the side effects are detailed. A clinical trial of the protease inhibitor Nelfinavir (Viracept) has shown that dosing twice a day may be as effective as the currently prescribed three times a day. Since lower dosing tends to increase a patient's adherence to treatment, it may have a long-term positive effect on treating HIV. Other drug treatments and possible changes in dosing are presented. A pneumococcal vaccine study is described, and it was found that the vaccine did not lead to an increase in viral load. Immunization against Pneumococcus is suggested for all adults who are HIV-infected.
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PMID:Antimicrobial agents and chemotherapy: highlights of the 38th Interscience Conference. 1136 34

Adefovir dipivoxil (ADV) at a suboptimal concentration for human immunodeficiency virus type 1 (HIV-1) (10 mg once daily) can be used to treat hepatitis B virus (HBV) infection in HIV-1-HBV-coinfected patients and does not, even in the case of uncontrolled HIV-1 replication, select for either ADV mutations at codons 65 and 70 or any other particular HIV-1 reverse transcriptase resistance profile.
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PMID:Human immunodeficiency virus (HIV) Type 1 reverse transcriptase resistance mutations in hepatitis B virus (HBV)-HIV-coinfected patients treated for HBV chronic infection once daily with 10 milligrams of adefovir dipivoxil combined with lamivudine. 1195 7

Current therapies for chronic hepatitis B virus (HBV) infection do not provide adequate long-term control of viral replication in the majority of patients. Monotherapy with nucleoside analogs, such as lamivudine and famciclovir, is effective for short periods but results in the emergence of drug-resistant HBV in a substantial number of patients within 1 year of therapy. Adefovir dipivoxil (ADV) has demonstrated clinical activity against wild-type and lamivudine-resistant HBV, but it is unclear whether resistance mutations will emerge after long-term therapy with this drug. To determine whether extended treatment with ADV led to the emergence of drug-resistant populations of HBV, we analyzed virus isolated from patients currently enrolled in a long-term open-label study. The reverse transcriptase domain of HBV polymerase was amplified and sequenced from patients that had received a cumulative exposure of up to 60 weeks of ADV. During our analyses, several previously unreported amino acid substitutions were observed in the reverse transcriptase domain of HBV. Importantly, none of the observed mutations occurred in more than 1 patient, nor were they associated with an adefovir-resistant phenotype in vitro. Furthermore, none of the patients from whom these mutant viruses were isolated had evidence of virologic rebound. In conclusion, these results, although based on a limited number of patients, suggest that treatment with ADV does not lead to the emergence of resistant virus after up to 60 weeks of therapy.
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PMID:Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks. 1214 57

Lamivudine is a nuleoside analog with potent inhibitory effects on hepatitis B virus (HBV) replication. Prolonged therapy is required for sustained suppression. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV-RNA-dependent DNA polymerase confering resistance to lamivudine may emerge after 6-9 months therapy with an incidence of 38% and 67% after 2 and 4 years of lamivudine therapy, respectively. During continued lamivudine therapy, patients with YMDD mutant HBV usually show serum alanine aminotransferase (ALT) and HBV-DNA elevations at lower median levels than their baseline. Marked flare of serum ALT or acute exacerbation may occurred as the results of cytotoxic T lymphocyte mediated immune response directed against YMDD mutant. Although viral clearance with or without emergence of distinct lamivudine resistant mutants may occur after such exacerbations, 20% of the exacerbations are complicated with decompensation or even fatality. The exacerbations appear to be more severe than those occur during the natural course of wild type HBV chronic infection. The current practice of continuing lamivudine therapy, therefore, requires careful evaluation. Alternatives include interferon therapy but this seems ineffective. Adefovir dipivoxil and entecavir may effectively suppress the YMDD mutant but these treatments have not yet been available for use. Recent studies have shown no benefit to continuing lamivudine therapy in patients with YMDD mutantions. Before a rescue drug becomes available, the most cost-effective strategy is to select patients with stronger endogenous anti-HBV immunity to increase efficacy and to shorten the duration of lamivudine therapy to avoid the emergence of YMDD mutations.
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PMID:Management of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. 1247 59


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