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)

There are 3 groups of drugs available for the treatment of patients with HIV disease. These are the nucleoside reverse transcriptase inhibitors ('nucleoside analogues') [zidovudine, didanosine, zalcitabine, lamivudine and abacavir]; the non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz); and the protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir and amprenavir). The preferred initial regimen should reduce and maintain plasma HIV RNA below the level of detection. Presently, the regimen of choice consists of 2 nucleoside analogues plus a protease inhibitor with high in vivo efficacy. An alternative combination consists of 2 nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor. Drug interactions are one of the major problems associated with these multidrug regimens. Changes in plasma concentrations of the nucleoside analogues are unlikely to be of clinical relevance as drug effect is mainly dependent on the rate and extent of intracellular phosphorylation. Combinations of zidovudine plus stavudine, and probably zalcitabine plus lamivudine, should be avoided as competition for phosphorylating enzymes may occur. The antiviral efficacy of some nucleoside analogues, e.g. stavudine, may be compromised by prior treatment with other nucleosides (e.g. zidovudine). However, these data need to be clarified in further studies. It is unlikely that administration of other antiretrovirals will influence the activity of nucleoside analogues. Protease inhibitors are metabolised by hepatic cytochrome P450 (CYP) 3A4. Combination protease inhibitor therapy can result in drug interactions mediated by enzyme inhibition. Ritonavir is the most potent inhibitor, saquinavir the least. The protease inhibitors also interact with the non-nucleoside reverse transcriptase inhibitors. Nevirapine and efavirenz induce drug metabolising enzymes and may reduce plasma concentrations of protease inhibitors. A study in healthy volunteers showed that nelfinavir concentrations are increased by combination with efavirenz. Delavirdine inhibits drug metabolising enzymes and increases the plasma concentration of coadministered protease inhibitors. The nucleoside analogues would not be expected to interact with the protease inhibitors. Apart from the ability of didanosine to reduce the area under the concentration-time curve of delavirdine, there are no reports of clinically significant interactions of other antiretrovirals with the non-nucleoside reverse transcriptase inhibitors. Triple therapy is the current standard of care for patients with HIV disease. However, studies of quadruple therapy are already under way. Drug interactions are likely to remain one of the major considerations when selecting a therapeutic regimen for patients with HIV.
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PMID:Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. 1032 Sep 51

(1) Recent consensus recommendations agree that first-line treatment of HIV infection should consist of a three-drug regimen combining a protease inhibitor and two nucleoside reverse transcriptase inhibitors. Some recommendations specifically advise against using the current formulation of saquinavir, but none express a preference for one of the other three protease inhibitors currently marketed in France (indinavir, nelfinavir and ritonavir). (2) These HIV protease inhibitors have established efficacy on viral load and the CD4+ lymphocyte count. Saquinavir may have lower virological efficacy. (3) The clinical efficacy of three-drug regimens containing indinavir or saquinavir is well demonstrated in patients at an advanced stage of HIV disease. (4) The risk of viral resistance is not currently a factor in choosing a HIV protease inhibitors. (5) Several epidemiological studies have compared the risk of adverse effects on three-drug regimens including indinavir, ritonavir or saquinavir. In these studies saquinavir was the best-tolerated drug and ritonavir the worst-tolerated. (6) Ritonavir interacts with many drugs. The poor bioavailability of the current saquinavir formulation also leads to risk of interactions. (7) Treatment constraints differ from one protease inhibitor to another, and these must be taken into account case by case. (8) The daily cost of treatment is not currently an important factor in choosing among the various preparations. (9) Taking into account efficacy, adverse effects, interactions and treatment constraints, the combination of indinavir with two nucleoside reverse transcriptase inhibitors currently seems to be the best choice for the largest number of patients. (10) If problems of compliance arise, nelfinavir can be an alternative to indinavir. (11) In patients at an advanced stage of HIV disease who comply well with their treatment, saquinavir can also be an alternative to indinavir.
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PMID:The choice of HIV protease inhibitor: indinavir is currently the best option. 1084 67

Acute hepatitis led to abnormal coagulopathy, bleeding, and death in a nonhemophiliac infant infected with the human immunodeficiency virus, possibly due to zidovudine or ritonavir or both. Acute hepatitis during ritonavir treatment and episodes of spontaneous bleeding have been reported in patients with hemophilia. Zidovudine is associated with elevated liver enzymes, elevated bilirubin, and hepatomegaly leading to abnormal coagulopathy, bleeding, and death in adults. A temporal relationship between the start of combination antiretroviral therapy and onset of hepatosplenomegaly and rise in liver enzymes suggests that zidovudine or ritonavir, or both, are the likely cause of this adverse event. Ritonavir is believed to cause direct hepatotoxicity, probably by inducing acute mitochondrial toxicity, and may hasten reverse transcriptase inhibitor-induced liver toxicity. Liver function of patients receiving a combination of nucleoside reverse transcriptase inhibitor and protease inhibitors should be closely monitored.
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PMID:Acute hepatitis and bleeding possibly induced by zidovudine and ritonavir in an infant with HIV infection. 1099 9

The use of reduced doses of Ritonavir (RIT) and Saquinavir (SQV) is considered a potent alternative in treating patients infected by HIV-1. We tested a combination of 300mg of RIT plus 600mg of SQV, twice daily, in association with two reverse transcriptase inhibitors to treat AIDS patients for a period of 6 months. Evaluation of HIV-1 RNA plasma levels, CD4+/CD8+ cell count and biochemical/hematological parameters (liver enzymes, serum electrolytes, creatinin, blood glucose, uric acid, white blood cell count, platelet count, and hemoglobin level) were performed after 30, 90 and 180 days of therapy. Clinical failure and adverse reactions were also recorded in order to assess safety and efficacy of the treatment. A total of 30 AIDS patients (25 male; 5 female) were enrolled in the study. Eight patients discontinued the therapy due to intolerance, 2 patients presented clinical failure (onset of AIDS-defining events during the study period), 2 patients werc excluded due to protocol violation. Five patients tolerated only a lower dose of RIT (400mg/day). Patients who completed 6 months of therapy had a drop in viral load from 4.8+/-.7 log(10) median 4.9 log) to 3.4 +/- 1.0 log(10) (median 2.6 log), and an increase in CD4+ count from 109 +/- 86cells/ml (median 84cells/ml) to 249+/- 114 cells/ml (median 265 cells/ml), compared to baseline values. However, patients who used a lower dose of RIT (400mg/day) had a less impressive drop in viral load values (mean 0.6 log(10) NA copies/ml) when compared with those using the 600mg/day of the drug (mean 2.4 log(10)). The percentage of patients presenting undetectable levels of HIV-1 RNA in plasma was quite different for the 2 groups: 92% of patients with a viral load <400 RNA copies/ ml were using 600mg of RIT. The combination of reduced doses of RIT and SQV reduced viral load >1.0 log(10) after 6 months in 83% of study patients. The dose of 600mg/day of RIT was morc effective in reducing viral load than 400mg/day, but was less well-tolerated. CD4+ cell counts increased in all patients regardless of the RIT dose used.
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PMID:Safety and Efficacy of Reduced Doses of Ritonavir (RTV) Plus Saquinavir (SQV) in the Treatment of AIDS Patients in Brazil. 1109 12

Ritonavir is a potent, orally bioavailable inhibitor of HIV-1 protease. Our investigators undertook a retrospective study to compare the effectiveness of ritonavir (600mg twice daily) associated with 2 reverse transcriptase inhibitors (RTIs) in 38 patients in 3 situations. Group I patients previously treated with 2 RTIs, Group II treatment-naive patients, and Group III patients previously treated with 2 RTIs and saquinavir. Routine hematological and biochemical studies, HIV-1 viremia, and CD4+ lymphocyte counts were performed before and after ritonavir. In Group I, the median of HIV-1 RNA plasma levels decreased from 4.8 to 3.4 log(10) copies/mL, in Group II from 5.9 to 2.9 log(10) copies/mL, and in Group III from 5.2 to 4.1 log(10) copies/mL. (p=0.003, p=0.014, p=0.002, respectively, Wilcoxon signed rank test). The median increases of CD4(+) cells occurred as follows: in Group I from 173 to 282 cells/mm(3), in Group II from 92 to 254 cell/mm(3), and in Group III from 68 to 133 cell/mm(3) (p=0.002, p=0.008, p<0.001, respectively, Wilcoxon signed rank test). In Group II the mean weight increased from 55.2 +/-14.3 kg to 59.4+/-15.7 kg and, in Group III, from 62.2+/-10.5 kg to 67.5+/-12 kg (p = 0.026, p = 0.002, respectively, paired T test). Patients in Group I presented no weight gain. Mild reversible hypertriglyceridemia occurred in 6 of 38 patients. The results of this study showed that ritonavir is a good choice for treatment naive patients and as a sequential option, not only after 2 RTIs, but also after a 3 drug regimen with saquinavir.
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PMID:Comparison of Ritonavir in a First Choice Three Drug Regimen, After Two Nucleoside Analogues and in Saquinavir Experienced Patients. 1110 13

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Ritonavir strongly inhibits lopinavir metabolism; coadministration of lopinavir and ritonavir in healthy volunteers increased the area under the lopinavir plasma concentration-time curve >100-fold. Trough plasma concentration: antiviral 50% effective concentration ratio for lopinavir was >75 for wild-type HIV at the dose used in clinical trials, compared to values of < or = 4 for other commonly used protease inhibitors. Coformulated lopinavir and ritonavir (lopinavir/ ritonavir) 400/100mg twice daily for 48 weeks suppressed HIV replication in significantly more antiretroviral-naive patients than nelfinavir 750mg 3 times daily (all patients also received stavudine and lamivudine). Suppression of viral replication was observed in most protease inhibitor-experienced patients with lopinavir/ ritonavir (400/100, 400/200 or 533/133mg twice daily for 48 or 96 weeks) in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either efavirenz or nevirapine. 48 weeks of treatment with twice daily lopinavir/ ritonavir (230/57.5 or 300/75 mg/m2 for the first 12 weeks and then 300/75 mg/m2) in combination with 1 or2 NRTIs, with or without nevirapine, suppressed viral replication in the majority of antiretroviral-naive and -experienced paediatric patients (aged 6 months to 12 years). Diarrhoea, nausea and asthenia were the most frequently reported adverse effects in patients receiving lopinavir/ritonavir-based regimens. Elevated total cholesterol, triglyceride and hepatic enzyme levels were also reported.
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PMID:Lopinavir. 1115 17

This study compared the alterations in p-triglyceride (PT) in 111 protease inhibitor (PI)-naive patients on randomized treatment with either indinavir (800 mg 3 times daily), ritonavir (600 mg twice daily) or ritonavir/saquinavir (400 mg each twice daily) and 2 nucleoside reverse transcriptase inhibitors (NRTIs). PT (non-fasting) was measured at regular intervals until week 48. PT levels were evaluated in relation to PI regime, CD4 cell count and prior NRTI experience. The effect on PT levels of changing PI regime was analysed. For 24 patients fasting and non-fasting PT values were correlated. In the ritonavir-containing arms PT levels increased significantly (median PT at baseline: 1.80 mmol/l; week 36: 2.3 mmol/l; p < 0.001). In the indinavir arm no significant rise in PT levels was observed. Comparing the PI arms at week 48 showed significantly higher levels of PT in the ritonavir-containing arms than in the indinavir arm (p < 0.001). There was a high correlation between fasting and non-fasting PT values (p < 0.001, p = 0.88). A significant decline in PT values when changing PI treatment was observed (n = 13, p = 0.016). Ritonavir-containing regimens caused a rapid and sustained elevation of PT values, while indinavir did not significantly affect PT levels.
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PMID:Comparison of P-triglyceride levels among patients with human immunodeficiency virus on randomized treatment with ritonavir, indinavir or ritonavir/saquinavir. 1134 23

Saquinavir, a protease inhibitor, received Food and Drug Administration (FDA) approval. Ritonavir and indinavir are likely to receive FDA approval by mid-1996, and three others are currently in clinical trials. Clinicians who treat HIV-positive patients will be faced with conflicting test results and multiple choices in drug therapy. All tests currently show that protease inhibitors are most effective in combination with nucleoside analog reverse transcriptase inhibitors. The issue of cross-resistance is controversial, with differing opinions on whether these treatments reduce the effectiveness of later treatments with other compounds. For the most effective treatment, patients should begin therapy with the maximum tolerated dosage of any of these drugs. A chart summarizes each of the six drugs' developmental statuses. Clinicians are cautioned to consider variables other than viral load in determining which drugs to prescribe; side effects, cost, drug interactions, tissue distribution and palatability are also important factors to consider. Test results of the six drugs are reviewed.
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PMID:The rolling uncertainties of antiprotease prescribing. 1136 41

The 1998 Retrovirus Conference in Chicago presented what is known about specific dual-protease inhibitor (PI) therapies. The effectiveness of the following therapies are highlighted: ritonavir/saquinavir, nelfinavir/saquinavir, ritonavir/indinavir, indinavir/saquinavir, amprenavir in dual-protease inhibitor combinations, and ABT-378/ritonavir. Growing evidence supports the use of dual PIs in treating HIV disease. Effectiveness is enhanced when they are combined with reverse transcriptase inhibitors. Ritonavir/saquinavir is the therapy of choice so far, particularly for salvage therapy. Less support is found for nelfinavir/saquinavir, following the failure of other PIs. Failure on dual PI therapy is likely to cause extensive cross-resistance within the PI class. Therefore, caution is warranted in using dual PI therapy in patients who have problems with adherence.
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PMID:A review of dual protease inhibitor therapy. 1136 90

Highly active antiretroviral therapies (HAART) that do not incorporate a protease inhibitor (PI) have received much attention in attempts to find effective treatment alternatives. HAART without PIs can extend the future options of some patients, to allow switching to a PI therapy later in treatment, or to avoid unpleasant side effects reported with some PIs. A study of combination therapy employing efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) showed encouraging results, as did a similar study employing abacavir. However, researchers are cautious about the ability of these drugs to sustain high antiviral activity over a long-term period. As a potent alternative to HAART, NNRTI's offer easier dosing and appear to have similar results, albeit in the short-term. Studies of Hydroxyurea have reported a positive antiviral response. However, one study indicated that the positive response came with significant side effects. The use of anti-HIV therapy in pregnant women and their newborns is the subject of another study, that assessed the safety of treatment and the possible side effects. Comparisons of protease inhibitor-containing regimens are also reviewed. Alternative two-drug combinations of Indinavir and Ritonavir, and abacavir and amprenavir are explored.
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PMID:Antivirals update. 1136 49


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