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:3.4.23.16 (HIV-1 protease)
2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Structures of the complexes of HIV protease inhibitor L--756,423 with the HIV-1 wild-type protease and of the inhibitors Indinavir, L-739,622 and Saquinavir with the mutant protease (9X) containing nine point mutations (Leu10Val, Lys20Met, Leu24Ile, Ser37Asp, Met46Ile, Ile54Val, Leu63Pro, Ala71Val, Val82Thr) have been determined. Comparative analysis of these structures reveals an alternate binding pocket for the P1-P3 group of Indinavir and L--756, 423. The alternate binding pocket is a result of concerted structural change in the 80s loop (residues 79-82) of the protease. The 80s loop is pulled away from the active site in order to accommodate the P1-P3 group, which is sandwiched between the flap and the 80s loop. This structural change is observed for the complexes of the wild type as well as the 9X mutant protease. The study reveals that the 80s loop is an intrinsically flexible loop in the wild-type HIV-1 protease and that mutations in this loop are not necessary to result in conformational changes. Conformation of this loop in the complex depends primarily upon the nature of the bound inhibitor and may be influenced by mutations in the protease. The results underscore the need to understand the intrinsic structural plasticity of the protease for the design of effective inhibitors against the wild-type and drug-resistant enzyme forms. In addition, the alternate binding pocket for the P1-P3 group of Indinavir and L--756,423 may be exploited for the design of potent inhibitors.
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PMID:An alternate binding site for the P1-P3 group of a class of potent HIV-1 protease inhibitors as a result of concerted structural change in the 80s loop of the protease. 1073 10

The effects of HIV-1 protease inhibitors on proteolytic processing and infectivity of virions produced from lymphocytes chronically infected with the virus were studied. Protease inhibition was detected by the accumulation of the polyprotein precursors Pr55gag and Pr160gag-pol and their cleavage intermediates. Immunoblot analysis demonstrated that while the processing of Pr55gag was largely irreversible, cleavage of Pr160gag-pol proceeded once the inhibitor was removed, although it was not completed during 96 h of subsequent observation. Virions produced during exposure of cells to protease inhibitors regained some degree of infectivity post-withdrawal of the inhibitor, suggesting that the processing of Pr160gag-pol following drug withdrawal resulted in the production of those enzymes necessary to enable at least limited viral replication. When cells were exposed to a protease inhibitor for 72 h then the inhibitor withdrawn, a lag phase of up to 24 h occurred before these cells produced virions with equivalent infectivity to virus produced from cells not exposed to drug. These observations may reflect a clinical situation likely to occur as trough plasma concentrations of protease inhibitors fall below the IC100 for HIV, highlighting the need for adherence to drug regimens containing these inhibitors.
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PMID:Effect of protease inhibitors on HIV-1 maturation and infectivity. 1077 90

The delineation of optimal regimens for combinations of agents is a difficult problem, in part because, to address it, one needs to (i) have effect relationships between the pathogen in question and the drugs in the combination, (ii) have knowledge of how the drugs interact (synergy, antagonism, and additivity), and (iii) address the issue of true between-patient variability in pharmacokinetics for the drugs in the population. We have developed an approach which employs a fully parametric assessment of drug interaction using the equation of W. R. Greco, G. Bravo, and J. C. Parsons (Pharmacol. Rev. 47:331-385, 1995) to generate an estimate of effects for the two drugs and have linked this approach to a population simulator, using Monte Carlo methods, which produce concentration-time profiles for the drugs in combination. This software automatically integrates the effect over a steady-state dosing interval and produces an estimate of the mean effect over a steady-state interval for each simulated subject. In this way, doses and schedules can be easily evaluated. This software allows for a rational choice of dose and schedule for evaluation in clinical trials. We evaluated different schedules of administration for the combination of the nucleoside analogue abacavir plus the human immunodeficiency virus type 1 protease inhibitor amprenavir. Amprenavir was simulated as either 800 mg every 8 h (q8h) or 1,200 mg q12h, each along with 300 mg q12h of abacavir. Both regimens produced excellent effects over the simulated population of 500 subjects, with average percentages of maximal effect (as determined from the in vitro assays) of 90.9%+/- 11.4% and 80.9%+/-18.6%, respectively. This difference is statistically significant (P<<0.001). In addition, 68.8 and 46.0% of the population had an average percentage of maximal effect which was greater than or equal to 90% for the two regimens. We can conclude that the combination of abacavir plus amprenavir is a potent combination when it is given on either schedule. However, the more fractionated schedule for the protease inhibitor produced significantly better effects in combination. Clinicians need to explicitly balance the improvement in antiviral effect seen with the more fractionated regimen against the loss of compliance attendant to the use of such a regimen. This approach may be helpful in the preclinical evaluation of multidrug anti-infective regimens.
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PMID:Use of drug effect interaction modeling with Monte Carlo simulation to examine the impact of dosing interval on the projected antiviral activity of the combination of abacavir and amprenavir. 1081 24

Despite potent antiretroviral activity, the HIV-1 protease inhibitors have recently been associated with abnormal serum lipoprotein concentrations. The purpose of this review is to describe serum lipid abnormalities related to protease inhibitor use. A MEDLINE search up to June 1, 1999, and abstracts from recent scientific meetings were primary data sources. Lipid disturbances in HIV-infected patients receiving protease inhibitors generally consist of elevated triglycerides and total cholesterol levels; HDL cholesterol is often reduced. The pathophysiological mechanism by which the protease inhibitors induce these lipid abnormalities has been hypothesized, but is unknown. Cases of pancreatitis and coronary heart disease have been described in hyperlipidemic patients receiving protease inhibitors. Treatment of protease inhibitor-related hyperlipidemia is unknown. Exchanging the offending protease inhibitor for nevirapine may be helpful in certain patients. Atorvastatin in combination with gemfibrozil has been used with limited success in a small number of individuals.
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PMID:Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment. 1082 94

The extent to which human immunodeficiency virus (HIV) type 1 drug resistance compromises therapeutic efficacy is intimately tied to drug potency and exposure. Most HIV-1 protease inhibitors maintain in vivo trough levels above their human serum protein binding-corrected IC(95) values for wild-type HIV-1. However, these troughs are well below corrected IC(95) values for protease inhibitor-resistant viruses from patients experiencing virologic failure of indinavir and/or nelfinavir. This suggests that none of the single protease inhibitors would be effective after many cases of protease inhibitor failure. However, saquinavir, amprenavir, and indinavir blood levels are increased substantially when each is coadministered with ritonavir, with 12-h troughs exceeding corrected wild-type IC(95) by 2-, 7-, and 28-79-fold, respectively. These indinavir and amprenavir troughs exceed IC(95) for most protease inhibitor-resistant viruses tested. This suggests that twice-daily indinavir-ritonavir and, to a lesser extent, amprenavir-ritonavir may be effective for many patients with viruses resistant to protease inhibitors.
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PMID:Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. 1123 20

BMS-232632 is an azapeptide human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor that displays potent anti-HIV-1 activity (50% effective concentration [EC(50)], 2.6 to 5.3 nM; EC(90), 9 to 15 nM). In vitro passage of HIV-1 RF in the presence of inhibitors showed that BMS-232632 selected for resistant variants more slowly than nelfinavir or ritonavir did. Genotypic and phenotypic analysis of three different HIV strains resistant to BMS-232632 indicated that an N88S substitution in the viral protease appeared first during the selection process in two of the three strains. An I84V change appeared to be an important substitution in the third strain used. Mutations were also observed at the protease cleavage sites following drug selection. The evolution to resistance seemed distinct for each of the three strains used, suggesting multiple pathways to resistance and the importance of the viral genetic background. A cross-resistance study involving five other protease inhibitors indicated that BMS-232632-resistant virus remained sensitive to saquinavir, while it showed various levels (0. 1- to 71-fold decrease in sensitivity)-of cross-resistance to nelfinavir, indinavir, ritonavir, and amprenavir. In reciprocal experiments, the BMS-232632 susceptibility of HIV-1 variants selected in the presence of each of the other HIV-1 protease inhibitors showed that the nelfinavir-, saquinavir-, and amprenavir-resistant strains of HIV-1 remained sensitive to BMS-232632, while indinavir- and ritonavir-resistant viruses displayed six- to ninefold changes in BMS-232632 sensitivity. Taken together, our data suggest that BMS-232632 may be a valuable protease inhibitor for use in combination therapy.
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PMID:In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. 1095 74

Salvage therapy with ritonavir (RTV) and saquinavir (SQV) failed to achieve virological and immunological improvement in 24 HIV-infected patients who discontinued triple therapy with RTV or indinavir (IDV) because of failure or intolerance to treatment. Changes in the HIV-1 protease gene sequence were analyzed prospectively in 14 patients. No primary protease mutation was found prior to the use of protease inhibitors. After 7 months of treatment with IDV or RTV, primary resistance mutations at codons pol 46 and/or pol 82 were observed in 11 of 13 patients. After 16 weeks on RTV-SQV, novel primary mutations related to SQV emerged in 7 of 13 patients, together with an increase in the number of secondary resistance mutations. Our observations indicate that the cumulative occurrence of resistance mutations in the protease gene was associated with failure of antiretroviral therapy. The presence of mutations to a first protease inhibitor may represent a risk factor for the failure of a subsequent treatment with a second line protease inhibitor.
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PMID:The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients. 1097 70

We prospectively followed 20 consecutive patients with human immunodeficiency virus type 1 (HIV-1) with viral loads of <200 RNA copies/mL. These patients had been treated with 2 nucleoside reverse transcriptase inhibitors and > or =1 HIV-1 protease inhibitor for > or =3 months; they developed body changes consistent with lipodystrophy and requested they be switched from protease inhibitor to efavirenz. At baseline and every 3 months, we assessed the following: body mass index, waist-to-hip ratio, regional fat thickness (assessed by sonography), fasting total and high-density lipoprotein cholesterol, triglycerides, glucose, insulin, CD4(+) cells, and viral load. At baseline, hypertriglyceridemia (> or =200 mg/dL) was present in 17 (85%) patients, hypercholesterolemia (> or =200 mg/dL) in 14 (70%), and impaired fasting glucose (> or =110 mg/dL) in 8 (40%); CD4(+) T cells were 280x10(6) cells/L (range, 64-942x10(6) cells/L). HIV-1 RNA had been at <200 copies/mL for a median of 14 months (range, 3-24 months). Six months after switching to efavirenz, there was a reduction in triglyceride levels (a decrease of 31%; P=.03) and fasting insulin resistance index (a decrease of 28%; P=.03), but total and high-density lipoprotein cholesterol and glucose did not change. Waist-to-hip ratio decreased from 0.92 to 0.87 (P=.06). Subcutaneous fat thickness did not change. CD4(+) cells remained stable (363x10(6) cells/L; range, 102-741x10(6) cells/L; P=.65). Nineteen patients (95%) had HIV-1 RNA levels that remained at <200 copies/mL. Although CD4(+) response and viral suppression remained preserved after 6 months of switching from protease inhibitor to efavirenz, the benefits of this approach on the evolution of lipodystrophy were limited, and our findings do not support its routine recommendation to treat lipodystrophy.
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PMID:Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. 1107 62

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


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