NRTIs Indinavir

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Preferred Pl-based regimens are lopinavir/ritonavir plus lamivudine or emtricitabine plus another NRTI, usually zidovudine, stavudine or abacavir. Alternative combinations include other Pis with or without ritonavir, and two NRTIs. The combination of a protease inhibitor with ritonavir provides inhibition of cytochrome p450 enzymes and permits less frequent dosing of amprenavir, indinavir, lopinavir and saquinavir. Use of ritonavir in this setting is also known as boosting. ... 

The combination of indinavir + ritonavir 400/400 mg bd plus two NRTIs has been studied in 93 patients in an open, uncontrolled, multicenter trial (7). Raised triglycerides (n = 78) and cholesterol (n = 63) were the commonest adverse effects, followed by nausea (n — 22) and circumoral paresthesia (n = 9). Withdrawal was required in four cases of nausea, four of lipodystrophy, one of diarrhea, and one of osteonecrosis. 

In a multicenter, open, uncontrolled trial of protease inhibitors in conjunction with NRTIs for at least 96 weeks in 32 children, the pharmacokinetics of indinavir and nelfinavir showed large interindividual differences (8). In all, 17 children suffered adverse events. The most common adverse events in those taking indinavir were diarrhea (n = 6), vomiting (n = 6), anorexia (n — 5), hematuria ( = 5), abdominal pain (n — 4), and headache (n = 3) most were mild and occurred early in treatment. The rates of drug-related adverse effects were 0.4 per patient-year in those taking indinavir and 0.16 per patient-year in those taking nelfinavir. 

The two Pis used most in the last 5 to 6 years, nearly always in combination regimens with two NRTIs, are indinavir and ritonavir. Saquinavir, one of the least toxic, has very low (and variable) oral bioavailability that predisposes to resistance development. 

There is no cure for AIDS. Treatment seeks to suppress symptoms (e.g., antibiotics for the infections) and slow viral reproduction. Mortality rates have decreased since 1995 because of the introduction of a treatment protocol called highly active antiretroviral therapy (HAART) that consists of combinations of drugs from the following categories (1) nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., azidothymidine, also called zidovudine or AZT), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz) and protease inhibitors (e.g., indinavir). Both NRTIs and NNRTIs inhibit vDNA synthesis catalyzed by reverse transcriptase. Protease inhibitors are a class of drugs that prevent the processing of viral protein that is required for the assembly of new virions. 

Pharmacokinetics and clinical use Oral bioavailability is good except in the presence of food. Clearance is mainly via the liver, with about 10% renal excretion. Like the other protease inhibitors, indinavir is used in dmg combinations, most often with two NRTIs. 

In a study in 11 HTV-positi ve patients taking efavirenz 600 mg once daily with various NRHs, there was no change in the pharmacokinetics of efavirenz after they took valproic acid 250 mg twice daily for 7 days. Valproic acid levels achieved in these patients were not significantly different from those in 11 HIV-positive control patients mainly taking NRTI antiretrovirals, even when the 3 control patients taking a protease inhibitor or NNRTI (amprenavir, indinavir, or nelfrnavir plus nevirapine) were excluded. ... 

Buffered didanosine decreases the AUC of indinavir, and the drugs shouid be given one hour apart. Buffered didanosine interacts simiiarly with atazanavir. Tipranavir with low-dose ritonavir modestly reduced the AUC of abacavir and zidovudine, and such combinations are not recommended in the UK. The changes in pharmacokinetics seen when giving other combinations of protease inhibitors with NRTIs do not appear to be clinically significant. Protease inhibitors do not affect the intracellular activation of NRTIs. 

The protease inhibitors indinavir, ritonavir, and saquinavir had no effect on intracellular activation of various NRTIs (didanosine, lamivu-dine, stavudine, zalcitabine and zidovudine). No interaction would be expected by this mechanism. Other potential interactions are discussed below. 

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