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)

For the last several years, the combination of ddI (didanosine, Videx) and d4T (stavudine, Zerit) as a backbone of three-drug therapy has been popular both in treatment and in research. Together, the two nucleoside analog reverse transcriptase inhibitor (NARTI) drugs offered relatively high strength and fairly simple use. Despite this, some researchers have long questioned the wisdom of the combination as it violates one of the key rules of combining drugs: combine only drugs with different side effect profiles. Both drugs are associated with the development of peripheral neuropathy and pancreatitis. Pancreatitis is more commonly seen with ddI and neuropathy with d4T, but both occur to a significant degree with each drug and to a higher degree than was seen with other drugs of their class. However, few if any studies were run comparing the ddI/d4T combination to alternatives such as AZT/3TC (Combivir) or even 3TC/d4T. Both ddI and d4T come from the same company, Bristol Myers Squibb.
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PMID:New questions about an old combination--ddI + d4T. 1264 75

In fall of 2001, the drug tenofovir (Viread) was approved based on data showing its effectiveness in people who had previously developed resistance to one or more of the older anti-HIV drugs of the NRTI class (nucleoside analogue reverse transcriptase inhibitors, such as AZT, ddI, 3TC, d4T, etc.). The drug filled an important niche since tens of thousands of people had been on such drugs for many years already. Since tenofovir also offered the advantage of once daily usage and an excellent side effect record, many people wondered how the drug would fare when used as a person's first therapy or in the early years of treatment. They didn't have long to wait for an answer, which was announced at the Barcelona Conference.
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PMID:New uses for tenofovir: more questions about d4T. 1264 76

We have expressed purified recombinant reverse transcriptase (RT) from clinical isolates of human immunodeficiency virus subtypes B, C, and A/E in Escherichia coli. The drug sensitivities of these RTs were then determined for both nucleoside RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs) in cell-free RT assays. Although A/E and C viruses contained numerous polymorphisms relative to subtype B (i.e., naturally occurring variations unrelated to drug resistance), the wild-type enzymes prepared from these or subtype A/E clinical isolates displayed <2-fold differences in drug sensitivities with regard to the active triphosphate active forms of NRTIs, as compared with RT expressed from BH-10 recombinant virus. Recombinant RTs from clinical isolates of subtypes B, C, and A/E that contained multiple resistance-associated mutations displayed expected variations in levels of resistance to the intracellular active forms of 3TC, ddI, ddC, and PMPA, that is, 3TCTP, ddATP, ddCTP, and PMPApp, respectively. Subtype A/E and C RT enzymes contained only minor NNRTI polymorphisms that distinguished them from wild-type subtype B enzymes and wild-type RTs from these various subtypes showed only 1- to 4-fold variability in IC(50) values for each of nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), and calanolide A. In contrast, RT enzymes from subtype B and C viruses harboring specific NNRTI mutations were highly resistant to all four tested NNRTIs. Subtype C variants containing the novel V106M resistance codon showed cross-resistance to all approved NNRTIs in cell-free RT assays.
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PMID:Drug resistance profiles of recombinant reverse transcriptases from human immunodeficiency virus type 1 subtypes A/E, B, and C. 1458 5

The FDA approved FTC (emtricitabine, Emtriva) in July 2003 for use by adults in combination with other anti-HIV drugs. FTC is a nucleoside analog reverse transcriptase inhibitor (NRTI). Other drugs in this class include 3TC, abacavir, AZT, Combivir, d4T, d4T XR, ddC, ddI, ddI EC and Trizivir.
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PMID:FTC (emtricitabine, Emtriva). 1469 67

To detect and characterize polymerase gene (pol) polymorphisms and mutation patterns in HIV-1C-infected Batswana patients treated with reverse transcriptase inhibitors, samples from AIDS patients treated with highly active antiretroviral therapy (HAART) were sequenced for the region encompassing the entire HIV-1 protease (PR) and the first 335 amino acids of reverse transcriptase (RT). Amongst the 16 patients treated with antiretroviral (ARV) drugs, eight started HAART regimens containing didanosine, stavudine and nevirapine (ddI/d4T/NVP) or efavirenz (EFV) (arm A) while the others started with zidovudine (AZT) and lamivudine (3TC) given together as combivir (CBV) with either NVP or EFV as arm B. Arm B is the first line regimen currently provided by the Botswana ARV national programme. Greater efficacy, in terms of treatment duration, was observed in patients in arm B (14 months) as compared with patients in arm A (9 months); P<0.05, n=8. Appearance of the M184V mutation in the arm B patients coincided with a rebound of viral load (VL) (4.3 +/-0.1 log10 RNA copies/ml) and a significantly improved immunological parameter (deltaCD4=207.0+/-48.1 cells/microl; P<0.05). Interestingly, patients developing the M184V mutation preferentially harboured polymorphisms Q174K and/or I178L located in close proximity to pol position 184. The M184V mutation occurred following a clear clinical benefit consisting of increased CD4 cell counts and lower plasma viral loads. Primary mutations known to be associated with NNRTI and NRTI resistance for HIV-1B were observed in 10 of the 16 treated patients.
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PMID:Mutations and polymorphisms associated with antiretroviral drugs in HIV-1C-infected African patients. 1545 80

The aim of this study was to evaluate the genotypic resistance profiles of HIV-1 in children failing highly active antiretroviral therapy (HAART). Forty-one children (median age = 67 months) receiving HAART were submitted to genotypic testing when virological failure was detected. cDNA was extracted from PBMCs and amplified by nested PCR for the reverse transcriptase and protease regions of the pol gene. Drug resistance genotypes were determined from DNA sequencing. According to the genotypic analysis, 12/36 (33.3%) and 6/36 (16.6%) children showed resistance and possible resistance, respectively, to ZDV; 5/36 (14%) and 4/36 (11.1%), respectively, showed resistance and possible resistance to ddI; 4/36 (11.1%) showed resistance to 3TC and D4T; and 3/36 (8.3%) showed resistance to Abacavir. A high percentage (54%) of children exhibited mutations conferring resistance to NNRTI class drugs. Respective rates of resistance and possible resistance to PIs were: RTV (12.2%, 7.3%); APV (2.4%, 12.1%); SQV(0%, 12.1%); IDV (14.6%, 4.9%), NFV (22%, 4.9%), LPV/RTV (2.4%, 12.1%). Overall, 37/41 (90%) children exhibited virus with mutations related to drug resistance, while 9% exhibited resistance to all three antiretroviral drug classes.
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PMID:Analysis of HIV- type 1 protease and reverse transcriptase in Brazilian children failing highly active antiretroviral therapy (HAART). 1572 67

The multi-drug resistance HIV-1 genotype A62V/V75I/F77L/F116Y/Q151M is associated with resistance to many nucleoside reverse transcriptase inhibitors including AZT, ddI, ddC, d4T, abacavir, and 3TC. In this study, we evaluated the antiviral activity of (-)-beta-D-1',3'-dioxolan guanine (DXG) towards mutant HIV-1 containing V75I/F77L/F116Y/Q151M (V75Icomplex) and A62V/V75I/F77L/F116Y/Q151M (A62Vcomplex) in MT-2 cells. We further investigated the mechanism of resistance by studying the incorporation of DXG 5'-triphosphate (DXG-TP) during DNA synthesis by mutant enzymes containing single mutations at Q151M or A62V, and the V75Icomplex and A62Vcomplex using pre-steady state kinetic analysis. Our studies showed that mutant virus containing V75Icomplex and A62Vcomplex were both more than 23-fold resistant to DXG, and this correlated with the 68- and 20-fold resistance changes observed in the enzymatic assay. Compared to the wild-type enzyme, DXG-TP was incorporated 39- and 21-fold less efficiently by the mutant enzyme containing V75Icomplex and A62Vcomplex, mainly due to decreases in the rate of incorporation. The A62V mutation significantly increased the rate of incorporation (k(pol)) for both dGTP (3-fold) and DXG-TP (7.9-fold), while the binding affinity of A62V HIV-1 RT for DXG-TP was decreased 14-fold. At the enzyme level, the addition of the A62V mutation to V75I/F77L/F116Y/Q151M moderately (3.4-fold) reversed the resistance to DXG-TP.
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PMID:Effects of HIV Q151M-associated multi-drug resistance mutations on the activities of (-)-beta-D-1',3'-dioxolan guanine. 1588 14

Stavudine is a nucleoside analogue reverse transcriptase inhibitor of HIV-1 and HIV-2 and demonstrates in vitro activity with an acceptable therapeutic index in a range of T-lymphocyte and haematopoietic precursor cell lines. It is additive or synergistic in vitro with a range of other antiretrovirals, including the proteinase inhibitor saquinavir, in two- and three-way combinations and is active against zidovudine (ZDV)-resistant virus. It exhibits excellent oral bioavailability, with cerebrospinal fluid (CSF)/plasma penetration. In clinical use, stavudine monotherapy exhibits similar antiretroviral activity to ZDV, and is of proven clinical benefit in ZDV-pre-treated patients. In combination with ddI and/or nelfinavir it results in more substantial and durable responses in immunological and virological markers than reported with either drug alone. Further data on stavudine in combination with other antiretrovirals are now awaited. Comparative trials in ZDV-experienced patients suggest a similar frequency of adverse events to that observed with ZDV. Peripheral neuropathy is the most common dose-limiting toxicity, with haematological and hepatic function disturbance being infrequent. Resistance to stavudine develops slowly in vitro and in vivo but may lead to co-resistance to ZDV or ddI. Stavudine will be used clinically as a combination agent both in initial therapy and in patients with prior ZDV experience.
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PMID:Stavudine:pharmacology,clinical use and future role. 1598 2

Recent progress in our understanding of the viral dynamics and immunobiology of HIV infection, coupled with the introduction of a new generation of antiretroviral agents, has led to significant advances in the medical management of HIV infection. Eleven antiretroviral drugs are currently licensed in the United States, and eight are licensed in Europe. These include the nucleoside reverse transcriptase inhibitors (AZT, ddI, ddC, 3TC and d4T); the non-nucleoside reverse transcriptase inhibitors (nevirapine and delavirdine) and the protease inhibitors (saquinavir, indinavir and ritonavir). This report summarises recent developments in the use of antiretroviral therapies and the main treatment strategies under evaluation in current trials. These strategies include the evaluation of novel antiretroviral agents; combinations to achieve maximal viral suppression; optimal sequencing of antiretroviral agents; and subtraction therapy. However, many important issues in the use of antiretroviral therapies remain unresolved, including the optimal role of new agents, such as protease inhibitors (PIs), and the use of triple combination therapy in initial and subsequent treatment regimens; when therapy should be changed; which alternative agents should then be used; and the most appropriate methods for monitoring the efficacy of therapy.
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PMID:Antiretroviral therapies in HIV-1 infection. 1598 63

Early in the HIV epidemic, zalcitabine (ddC) emerged as a nucleoside analogue reverse transcriptase inhibitor (NRTI) alternative to zidovudine (ZDV). However, a comparative study suggested ZDV monotherapy provided superior clinical benefit in treatment-naive patients with advanced immunodeficiency. Thus, ddC became most widely used in those patients no longer benefitting from or intolerant of ZDV. In ZDV-failed or -intolerant patients, ddC demonstrated similar benefit (or absence of benefit) to ddI monotherapy. In the first clinical end-point study of combination therapy, addition of ddC to on-going ZDV in patients substantially pre-treated with ZDV resulted in no overall benefit but some clinical advantage in a subset of patients with CD4 cell counts of 150 - 300/mm. Furthermore, initial studies of ddC, mostly performed in persons with advanced immunodeficiency and symptomatic HIV infection, indicated that 10 - 20% of ddC recipients developed a treatment-limiting peripheral neuropathy. Based on these early trials, a widespread perception that ddC was an antiviral with both limited activity and a potentially problematic safety profile evolved. More recent data suggest that the role of ddC requires re-evaluation. Indeed, the European Medicines Evaluation Agency (EMEA) has recently expanded the licencing claim of ddC stating that it "is indicated in HIV-infected adults in combination with other antiretroviral agents". The purpose of this short review is to discuss data that have shed new light on what in antiretroviral terms is an 'old' drug.
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PMID:A re-evaluation of zalcitabine. 1599 85


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