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Query: UMLS:C0019693 (HIV)
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Indinavir, an antiretroviral agent, has an influence on the pharmacokinetics of other drugs by acting as an inhibitor of cytochrome P450-mediated drug metabolism. The incidence of tuberculosis has increased dramatically in the past decade because of an epidemic of HIV infection. Rifampicin is still one of the most valuable drugs for the standard treatment of tuberculosis. The objective of this study was to investigate the effects of indinavir on the pharmacokinetics of rifampicin in man. Our study was conducted in eleven HIV-infected patients. All patients received a 600-mg single dose of oral rifampicin on day 1 and 15- and 800-mg oral indinavir three times a day from day 2 to day 15. Rifampicin pharmacokinetic studies were carried out on day 1 and day 15. The results showed that rifampicin concentrations were higher when it was administered with indinavir than when it was administered alone. With concomitant indinavir medication, the mean AUC0-24 of rifampicin was increased by 73%. Therefore, we conclude that indinavir has an inhibitory effect on the metabolism of rifampicin.
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PMID:Effect of indinavir on the pharmacokinetics of rifampicin in HIV-infected patients. 1129 58

The vast majority of HIV-1 infections in Africa are caused by the A and C viral subtypes rather than the B subtype prevalent in the United States and Western Europe. Genomic differences between subtypes give rise to sequence variations in the encoded proteins, including the HIV-1 protease. Because some amino acid polymorphisms occur at sites that have been associated with drug resistance in the B subtype, it is important to assess the effectiveness of protease inhibitors that have been developed against different subtypes. Here we report the enzymatic characterization of HIV-1 proteases with sequences found in drug-naive Ugandan adults. The A protease used in these studies differs in seven positions (I13V/E35D/M36I/R41K/R57K/H69K/L89M) in relation to the consensus B subtype protease. Another protease containing a subset of these amino acid polymorphisms (M36I/R41K/H69K/L89M), which are found in subtype C and other HIV subtypes, also was studied. Both proteases were found to have similar catalytic constants, k(cat), as the B subtype. The C subtype protease displayed lower K(m) values against two different substrates resulting in a higher (2.4-fold) catalytic efficiency than the B subtype protease. Indinavir, ritonavir, saquinavir, and nelfinavir inhibit the A and C subtype proteases with 2.5-7-fold and 2-4.5-fold weaker K(i)s than the B subtype. When all factors are taken into consideration it is found that the C subtype protease has the highest vitality (4-11 higher than the B subtype) whereas the A subtype protease exhibits values ranging between 1.5 and 5. These results point to a higher biochemical fitness of the A and C proteases in the presence of existing inhibitors.
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PMID:Catalytic efficiency and vitality of HIV-1 proteases from African viral subtypes. 1135 56

When HIV replicates, it forms large precursor proteins that are cleaved and processed by HIV protease to generate smaller viral proteins. HIV protease inhibitors interfere with this process, causing viral particles that are formed to be structurally disorganized, nonfunctional, and non-infectious. All of the HIV protease inhibitors in clinical trials, or nearing clinical development, are active against HIV-1 and HIV-2 at nanomolar concentrations, require no intracellular processing for activation, and are effective both in acutely and chronically infected cells. However, two pharmacokinetic problems have been identified: suboptimal oral bioavailability of peptidic inhibitors; and reduced cellular uptake of inhibitor that has become bound to alpha-acid glycoprotein. Three of the ten aforementioned protease inhibitors are in advanced development: saquinavir (Ro-31 8959), indinavir (MK-639), and ritonavir (ABT-538). Saquinavir has been extensively tested. It increases CD4 cell counts, reduces viral load, and its effects are magnified when administered in combination with AZT and ddC. Saquinavir recently entered accelerated approval procedures in the United States. Indinavir, an orally bioavailable protease inhibitor, engenders viral resistance after 12-24 weeks when administered at low doses, but higher doses may produce sustained effects lasting 52 weeks. Ritonavir, like indinavir, is an orally bioavailable protease inhibitor that is effective for a short time before viral mutants emerge. The emergence of resistance is the greatest problem with protease inhibitors.
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PMID:Update on HIV protease inhibitors. 1136 32

Reports from the Third Conference on Retroviruses detailed extraordinary antiviral and clinical effects when protease inhibitors were used in combination with nucleoside analogs. These treatments will be considerably more effective than the anti-HIV therapies of the past. Abbott is the first to demonstrate that its drug, ritonavir, extends survival and delays opportunistic infections. Merck's indinavir, used in combination with AZT/3TC, dramatically reduces viral loads. Agouron's nelfinavir, used in combination with d4T, reduces viral load by 99 percent after 45 days. However, while the effects of protease inhibitors are profound, there are no long-term studies to show that they will remain effective. The only long-term study, which covers 60 weeks, is from indinavir. Each of the drugs have significant side effects which may limit their use. Ritonavir is the least well tolerated due to severe gastrointestinal side effects. Indinavir's side effects, kidney stones and elevated bilirubin levels, do not seem to cause patients to stop therapy. Nelfinavir causes grade I/II diarrhea. Only one new compound, Ciba-Geigy's CGP 61755, is nearing clinical trials. Initial indications are that it may cause cross-resistance problems with ritonavir and indinavir.
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PMID:Protease inhibitors come of age. 1136 82

Indinavir (Crixivan) is one of the protease inhibitors approved for HIV treatment by the Food and Drug Administration (FDA). All studies to date have been limited to examining its effect on T4 cell changes and HIV viral load levels. Current studies are looking at indinavir in combination with AZT and 3TC. After sixteen weeks of combination therapy, viral loads in patients dropped to levels below those that can be measured with standard tests. However, these studies were done on small groups, and there are larger tests currently being held. Reducing the amount of virus also reduces the risk of disease progression and death. HIV can become resistant to the effects of indinavir, but this resistance occurs more slowly than with the other protease inhibitors. Using it in combination with a nucleoside analog drug seems to significantly delay resistance.
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PMID:Indinavir (Crixivan). 1136 98

Study data are presented on the use of protease inhibitors. Indinavir shows particularly potent antiviral activity and a modest side effect profile. Three indinavir studies are highlighted. Ritonavir appears to be effective in people with advanced HIV disease by helping to stem the progression of disease. Highlights from two ritonavir studies are presented. Two small studies involving nelfinavir are discussed, showing potent antiviral activity with high doses of the drug, and better performance when used in combination with d4T. It is cautioned that use of these drugs requires careful strategic thinking.
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PMID:Update on protease inhibitors. 1136 12

DMP 266, a nonnucleoside reverse transcriptase inhibitor, has been effective as a monotherapeutic agent in reducing viral load. How long it remains effective is unknown, and resistance development is a problem. Two trials testing combinations with DMP 266 are beginning. One test using DMP 266 with indinavir is already considered flawed because indinavir is provided as a monotherapy first. Indinavir monotherapy is believed to help HIV resistance to evolve, especially in people with high baseline viral loads. Participants who are on the monotherapy risk not receiving the full benefit from indinavir and other protease inhibitors because they trigger similar resistance mutations.
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PMID:DMP 266: keep the drug but dump the trial? 1136 85

The Food and Drug Administration (FDA) approved two new protease inhibitors--ritonavir and indinavir--for the treatment of HIV infection in adults. Ritonavir (Norvir), developed by Abbott Laboratories, received full approval for use alone or in combination with nucleoside analogue medications in patients with advanced HIV disease. Two encouraging studies on ritonavir are described. An ongoing phase III trial showed mortality to be 43 percent lower than for patients receiving standard therapy alone. In a separate study, untreated HIV-infected individuals who were given a triple combination of ritonavir plus AZT and ddC showed significant increases in CD4+ T cells counts and decreases in viral load for at least six months. Indinavir (Crixivan), developed by Merck, received accelerated approval for monotherapy and combination therapy for the treatment of HIV infection in adults when therapy is warranted. New data on indinavir showed decreases in levels of HIV in 22 out of 25 patients who had taken a triple combination of indinavir, AZT and 3TC. In another study of patients taking a combination of indinavir, ddI, and AZT, 60 percent of the patients' HIV levels were reduced to undetectable levels. In addition to ritonavir and indinavir, saquinavir (Invirase, Hoffmann-La Roche) is another protease inhibitor approved for use in conjunction with nucleoside analogues for the treatment of HIV infection.
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PMID:Two new protease inhibitors approved by FDA. Food and Drug Administration. 1136 99

The revised HIV Adult Standard of Care guidelines, produced by ACT UP/Philadelphia, are printed. The extensive table summarizes the minimum standard of care needed for individuals with HIV infection to maximize their quality and length of life. Divided into sections by T4 cell count, the table includes diagnostic tests and exams that patients may wish to have done at certain times in their disease progression. Treatment options are suggested for HIV disease, opportunistic infections, and other AIDS-related symptoms. Highlights of the many discussions on protease inhibitors at the 11th International AIDS Conference in Vancouver are described. Saquinavir has the lowest bioavailability of the three approved protease inhibitors and is awaiting new formulation. Ritonavir works to raise CD4 counts, drop viral load and decrease morbidity and mortality. However, it is poorly tolerated in about half of all users who describe gastrointestinal trauma. Indinavir has been shown to decrease viral loads to undetectable levels for 48 weeks, and shows promise for sustaining that measure for longer periods. Nelfinavir will likely be approved in early 1997. In addition, viral load monitoring has become a significant measure in guiding the efficacy of combination therapies, when used in conjunction with CD4 tests. The Philadelphia Water and Health Departments are suggesting that individuals not boil their water, despite outbreaks among people with AIDS of cryptosporidium. Filtered and bottled water are safer alternatives until there is a resolution.
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PMID:HIV adult standard of care. ACT UP. 1136 24

Studies are investigating drug interactions in dual protease therapies. Thus far, studies show nelfinavir has a beneficial effect on indinavir while indinavir has a limited effect on nelfinavir. Indinavir/nelfinavir studies are ongoing. Small European clinical trials indicate that while ritonavir (400 mg twice daily) and saquinavir (400 mg twice daily) continue to be the only well-validated combination, nelfinavir (750mg bid) and saquinavir-soft gel capsule (800mg tid) may be an option. European studies also indicate that all dual protease inhibitor combinations, including ritonavir/saquinavir, should be used with at least one nucleoside reverse transcriptase inhibitor.
HIV Hotline 1998 Mar
PMID:Dual protease inhibitor therapy. 1136 54


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