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)

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

Highly active antiretroviral therapy (HAART) has been recommended for human immunodeficiency virus (HIV)-positive patients with a detectable viral load; it typically consists of two reverse transcriptase inhibitors combined with a protease inhibitor. In 1996, Madigan Army Medical Center began offering HAART to HIV-positive patients with a detectable viral load. We retrospectively reviewed the records of our HIV patients before and after the initiation of HAART to determine the impact of HAART on hospitalizations, mortality, and outpatient pharmacy expenditures. Comparing 1997 with 1994 and 1995, we found a greater than 700% increase in the average expenditure on antiretroviral agents after institution of HAART. At the same time, we found a dramatic reduction in hospitalizations and nontraumatic mortality. Therefore, the increase in expenditures on antiretroviral agents may be offset by a reduction in hospitalizations and mortality.
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PMID:Reduction in human immunodeficiency virus patient hospitalizations and nontraumatic mortality after adoption of highly active antiretroviral therapy. 1049 28

(-)-Beta-D-1',3'-Dioxolane guanosine (DXG) and 2,6-diaminopurine (DAPD) dioxolanyl nucleoside analogues have been reported to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1). We have recently conducted experiments to more fully characterize their in vitro anti-HIV-1 profiles. Antiviral assays performed in cell culture systems determined that DXG had 50% effective concentrations of 0.046 and 0.085 microM when evaluated against HIV-1(IIIB) in cord blood mononuclear cells and MT-2 cells, respectively. These values indicate that DXG is approximately equipotent to 2', 3'-dideoxy-3'-thiacytidine (3TC) but 5- to 10-fold less potent than 3'-azido-2',3'-dideoxythymidine (AZT) in the two cell systems tested. At the same time, DAPD was approximately 5- to 20-fold less active than DXG in the anti-HIV-1 assays. When recombinant or clinical variants of HIV-1 were used to assess the efficacy of the purine nucleoside analogues against drug-resistant HIV-1, it was observed that AZT-resistant virus remained sensitive to DXG and DAPD. Virus harboring a mutation(s) which conferred decreased sensitivity to 3TC, 2',3'-dideoxyinosine, and 2',3'-dideoxycytidine, such as a 65R, 74V, or 184V mutation in the viral reverse transcriptase (RT), exhibited a two- to fivefold-decreased susceptibility to DXG or DAPD. When nonnucleoside RT inhibitor-resistant and protease inhibitor-resistant viruses were tested, no change in virus sensitivity to DXG or DAPD was observed. In vitro drug combination assays indicated that DXG had synergistic antiviral effects when used in combination with AZT, 3TC, or nevirapine. In cellular toxicity analyses, DXG and DAPD had 50% cytotoxic concentrations of greater than 500 microM when tested in peripheral blood mononuclear cells and a variety of human tumor and normal cell lines. The triphosphate form of DXG competed with the natural nucleotide substrates and acted as a chain terminator of the nascent DNA. These data suggest that DXG triphosphate may be the active intracellular metabolite, consistent with the mechanism by which other nucleoside analogues inhibit HIV-1 replication. Our results suggest that the use of DXG and DAPD as therapeutic agents for HIV-1 infection should be explored.
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PMID:Mechanism of action and in vitro activity of 1',3'-dioxolanylpurine nucleoside analogues against sensitive and drug-resistant human immunodeficiency virus type 1 variants. 1050 10

New guidelines for the management of patients with HIV-1 infection emphasize early aggressive treatment using multi-drug combination regimens. Accurate assessment of the effectiveness of these treatments and their potential (small as it now seems) to eradicate HIV-1 infection requires testing for viral levels in the blood, and in other compartments that may serve as long-term viral reservoirs, using the most sensitive assays. At present, most of our information regarding triple-drug combination therapies (usually two nucleosides and a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor) has come from the assessment of viral levels in blood. Available results strongly support the virologic superiority of such treatments over monotherapy and two-drug combinations. There are important questions that remain to be answered regarding these highly effective therapies. Questions regarding the durability of these treatments in preventing the evolution of drug resistance can be addressed by using sensitive reverse transcription/polymerase chain reaction assays to assess treatment response. Others, such as how best to treat patients who have failed potent drug therapy, await results from new, large-scale, clinical trials. An important concern with respect to newer antiretroviral therapies is their complexity and thus the increased risk for non-compliance and resultant viral resistance. In addition, longer-term side-effects are increasingly recognized. Programs that enhance compliance with these treatments will increase the probability that they will provide durable suppression of viral replication and arrest the clinical progression of HIV disease.
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PMID:Advances in the medical management of patients with HIV-1 infection: an overview. 1054 80

The choice of initial antiretroviral regimen for treating people infected with HIV is crucial to successful long-term control of virus replication. Potent antiretroviral therapy substantially suppresses viral replication as measured by plasma HIV RNA levels to below limits of detection: the current standard of care is usually a combination of at least three drugs and frequently includes a protease inhibitor, or alternatively a non-nucleoside reverse transcriptase inhibitor (nnRTI). Patients who have low CD4+ cell counts (< or = 200 CD4+ cells/mm3) or high plasma HIV RNA levels (> or = 100,000 copies/ml) may not attain maximal suppression of HIV replication when treated with current regimens and may require more aggressive therapy. In contrast, patients with relatively normal CD4+ cell counts and low to non-measurable levels of plasma HIV RNA over prolonged periods (i.e., slow or non-progressors) may not require immediate antiretroviral therapy. These individuals should reconsider treatment when either the CD4+ cell count declines or the HIV RNA level increases. Early and potent antiretroviral therapy should provide more durable virological and clinical benefits for many patients, especially if they receive sufficient counselling and support to aid adherence to the treatment regimen. The optimum time to initiate antiretroviral therapy is not well established, but to maximise the recovery of the immune system and the virological and clinical benefits, initiation of therapy is generally recommended for individuals who have symptoms or those with plasma HIV RNA levels > 5000-10,000 copies/ml, or CD4+ cell counts < 500 cells/mm3. The current choice of initial antiretroviral regimens includes two nucleoside reverse transcriptase inhibitors (nRTI) with a potent, well-tolerated HIV-1 protease inhibitor or nnRTI. Recent short-term activity data (24-week comparative clinical trial data) indicate that regimens combining three nRTI, including abacavir, could also be considered. Other emerging combination regimens for consideration include two HIV-1 protease inhibitors with one or two nRTI, or a combination of drugs from all current categories (e.g., nRTI with a nnRTI and HIV-1 protease inhibitor). The goal of antiretroviral therapy is to maximise suppression of HIV replication and thereby prevent or delay viral resistance, restore immunological function and improve clinical outcome. Since evolution of the virus towards resistance can occur with plasma HIV RNA levels between 50 and 500 copies/ml, current standards for best suppression of HIV replication have shifted to declines in plasma HIV RNA to < 50 copies/ml. In addition, non-adherence to any regimen is associated with the greatest risk for virological failure. Therefore, both the decision to initiate therapy and the choice of initial therapy should be carefully weighted and balanced with the long-term implications of antiretroviral therapy.
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PMID:Antiretroviral therapy in 1999 for antiretroviral-naive individuals with HIV infection. 1054 85

When used as initial therapy in combination with two nucleoside reverse transcriptase inhibitors, indinavir, ritonavir, nelfinavir and possible saquinavir-soft gel capsule (saquinavir-sgc) are highly effective agents. Patients who have been extensively pretreated, have advanced immunodeficiency or are unable to adhere with therapy are at high risk of failing protease inhibitor therapy. Although relevant prospective, randomized controlled clinical trails have not been reported, failure of a first protease inhibitor appears to compromise future therapeutic options. After resistance to indinavir or ritonavir emerges, salvage therapy with a protease inhibitor-containing regimen may be difficult. Preliminary data indicate that salvage therapy after resistance to saquinavir or nelfinavir emerges may be possible; however, this requires further investigation. The activity of newer agents, such as amprenavir or ABT 378, in salvage regimens is unknown. Until these issues are addressed in large prospective studies, clinicians should assume that cross-resistance will be common among all protease inhibitors.
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PMID:Failure of HIV-1 protease inhibitors to fully suppress viral replication. Implications for salvage therapy. 1054 90

Human immunodeficiency virus (HIV) and Kaposi's sarcoma-associated herpesvirus (KSHV) coinfect many individuals in North America and in parts of Africa. Infection with HIV is a leading risk factor for the development of Kaposi's sarcoma (KS). In this study, we tested the hypothesis that HIV infection of common or adjacent cells would stimulate replication and spread of KSHV. Infection of a primary effusion lymphoma cell line by vesicular stomatitis virus type G-pseudotyped HIV type 1 led to a rapid induction of lytic-phase KSHV replication. Induction of lytic KSHV replication by HIV required active replication of HIV. The addition of the nucleoside reverse transcriptase inhibitor azidothymidine or the protease inhibitor indinavir to the culture prevented HIV spread and inhibited the associated induction of KSHV lytic replication. Lytic replication occurred in both HIV-infected and HIV-uninfected cells within the culture, and could be induced in uninfected cells via a soluble factor released from the HIV-infected cells. Transmission of infectious KSHV to an uninfected target cell was enhanced by HIV replication and was inhibited by antiretroviral drugs. These results may have implications for the pathogenesis and treatment of KS in individuals coinfected with KSHV and HIV.
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PMID:Human immunodeficiency virus replication in a primary effusion lymphoma cell line stimulates lytic-phase replication of Kaposi's sarcoma-associated herpesvirus. 1055 51

Highly active antiretroviral therapy fails to reach its recommended goal of sustained suppression of viral replication in a substantial proportion of patients. We analyzed incidence and predictors of virologic failure of the first regimen of a triple-drug combination therapy, including a protease inhibitor and two nucleoside analog reverse transcriptase inhibitors (NRTIs), in 274 HIV-infected patients. Long-term virologic response to combination therapy including salvage regimens was assessed 2.5 years after treatment initiation. During an initial observation period of up to 1.8 years (median, 0.8 years) 152 patients (55%) experienced sustained suppression of HIV-1 RNA to <500 copies/ml. Failure to reduce viral load to <500 copies/ml within 6 months (initial failure) was observed in 51 patients (19%). Independent risk factors for initial failure included higher baseline viral load; addition of a protease inhibitor to an unchanged NRTI regimen; use of saquinavir hard-gel capsules; and longer duration of prior NRTI treatment. Within a median of 7 months viral load rebound above 500 copies/ml occurred in 71 of 223 patients (32%) whose viral load had initially decreased below this threshold. In proportional hazard analysis none of the potential risk factors was significantly associated with viral load rebound. However, in 40 patients (56%) with viral load rebound, incomplete adherence to therapy or treatment interruptions preceded the rebound. Virologic outcome after 2.5 years correlated with initial response to the first regimen: viral load was <500 copies/ml in 88, 55, and 21% of patients with sustained suppression, viral load rebound, and initial failure, respectively.
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PMID:Incidence and predictors of virologic failure of antiretroviral triple-drug therapy in a community-based cohort. 1060 86

Since 1996 indinavir in combination with zidovudine + lamivudine has been the standard regimen in the treatment of HIV infection. Although protease inhibitor (PI) containing therapies are very potent, many problems have now been identified that reduce quality of life such as a high pill burden, multiple daily dosing and dietary constraints. In addition, adverse events, such as lipodystrophy and lipid metabolism changes are being reported more frequently as long-term experience with PI therapy is gained. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be potent partners for antiretroviral combined therapies. Efavirenz is one of the most recent NNRTIs to be developed. Evidence to date suggests that given its potency, convenience and tolerability, efavirenz will have a major role to play in first-line, PI-sparing regimens and long-term suppressive therapy. However, many questions remain unanswered and future research should attempt to address these issues.
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PMID:Review of NNRTIs: 'today and tomorrow'. 1062 38

Highly active antiretroviral therapy (HAART) consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI) or a non nucleoside reverse transcriptase inhibitor (NNRTI) is now regarded as the standard of care in the treatment of HIV infection. However, over the next few years it is anticipated that clinician will become increasingly concerned with the quality of clinical data, the cost of treatment and virological failure. Several causes of virological failure have already been identified including compliance, toxicity, pharmacokinetic interactions, resistance and lack of potency. Many studies have been performed to investigate new combination regimens and new drugs to find solutions to these problems. In addition, new targets for antiviral drugs are also being investigated.
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PMID:The picture of future therapy. 1062 45


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