Stavudine Protease inhibitors

Nelfinavir is a nonpeptidic, rationally designed HIV protease inhibitor. Nelfinavir has demonstrated efficacy in both monotherapy and in combination with the reverse transcriptase inhibitors stavudine (d4T) or zivudine + 3TC. The major side effect is mild to moderate diarrhea. 

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. 

TC Lamivudine ABC Abacavir d4T Stavudine ddC Zalcitabine ddl Didanosine TDF Tenofovir ZDV Zidovudine, also abbreviated as AZT FTC Emtricitabine NVP Nevirapine DLV Delavirdine EFV Efavirenz RTV, r Ritonavir Pl/r Ritonavir boosted protease inhibitor SQV Saquinavir IDV Indinavir LPV Lopinavir NEV Nelfinavir APV Amprenavir ATV Atazanavir DRV Darunavir... 

Gathe Jr. J, Burkhardt B, Hawley P, Conant M, Peterkin J, Chapman S. A randomized Phase II study of Virocept , a novel HIV protease inhibitor, used in combination with stavudine (D4T) vs. stavudine (D4T) alone. Abstract Mo.B.413 In XI International Conference on AIDS, Vancouver, 1996 25. 

In the HIV infected population, further evidence suggested that visceral fat accumulation, dyslipidemia, and insulin resistance are closely linked and associated with antiretroviral treatment, most pronounced with the use of protease inhibitors. In contrast, subcutaneous fat wasting is primarily determined by the choice of nucleoside reverse transcriptase inhibitor (NRTI). Switching studies have supported this notion, since substitution of stavudine has been associated with improvement in fat wasting, while switching a protease inhibitor had no beneficial effect in more than 30 clinical trials (142). 

In a small randomized, open, comparative study patients who switched to abacavir from either stavudine or stavudine plus a protease inhibitor or NNRTI, or a protease inhibitor + NNRTI had improved total and LDL cholesterol (156). Total arm and leg fat mass, measured by DEXA scan, rose significantly in those who... 

A retrospective analysis of the development of diabetes in 1011 patients has been summarized (163). All were nondiabetic when antiretroviral treatment was started. Over 10 months, diabetes was diagnosed in 16 patients (2.06 per 100 person-years). Older age (HR = 1.1, 1.06-1.16) was associated with a higher risk. In multivariate analysis adjusted for age and sex, the onset of diabetes was not related to CD4 cell count, viral load, or type of antiviral therapy (with or without protease inhibitors). However, patients taking stavudine or indinavir were at significantly higher risks (stavudine HR = 16, 95% Cl — 3, 84 indinavir HR = 4.0,95% Cl = 1.3,13). The strong association of stavudine with diabetes is surprising and needs further confirmation. 

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. ... 

Eruptive angiolipomata occurred in a 49-year-old woman after she had taken stavudine 30 mg bd, lamivudine 150 mg bd, and saquinavir 600 mg 8-hourly for 3 months (11). This has also been reported with other protease inhibitors (12,13) and the mechanism is not known. In one case lipomata regressed after the introduction of indinavir (14). 

Gynecomastia has been reported in a series of men taking saquinavir (5). In these cases the association was clear (particularly since there was positive dechallenge), but this is a rare effect and has not previously been reported with either this or other protease inhibitors, although it has been associated with the nucleoside analogue reverse transcriptase inhibitor stavudine. 

Successful treatment of human immunodeficiency virus (HIV-1) infection has been achieved through successful implementation of highly active antiretroviral therapy, frequently referred to as HAART. This involves simultaneous administration of both nucleoside and nonnucleoside reverse transcriptase inhibitors and one or more protease inliibitors. The common nucleoside reverse transcriptase inhibitors are the thymidine analogs didanosine (ddl), lamivudine (3TC), and zalcitabine (ddC) and the non-thymidine analogs abacavir (Ziazen), stavudine (d4T), and zidovudine (AZT). The nonnucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. The protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Response to therapy is monitored by quantification of HIV-RNA copies (viral load) and CD-4+ T-lymphocyte count. Successful therapy is indicated when viral load is reduced to <50 copies/mL and CD-4+ count >500 per mL. 

See Protease Inhibitors, Stavudine, Zalcitabine, Zidovudine. ALBUMIN... 

Didanosine Stavudine Zalcitabine Zidovudine Protease inhibitors are ... 

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. 

Combination of 16 ARVs seven HIV protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfmavir, ritonavir, and saquinavir), seven nucleoside reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, and zidovudine), and two nonnucleoside reverse transcriptase inhibitors (efavirenz and nevirapine)... 

Time course Rifampicin induces CYP3A4 at about 15 days, and interaction studies have generally started treatment with protease inhibitors within 15 days of the start of rifampicin therapy. Furthermore, pharmacological tolerance to effects can occur. The problems of variations in pharmacokinetics with time have been illustrated by a study of the effects of rifampicin on the pharmacokinetics of nevirapine in 16 patients coinfected with HTV-1 and tuberculosis [39"]. They took standard antituberculosis therapy and a fixed-dose combination of stavudine, lamivudine, and nevirapine. The median AUC of nevirapine was reduced by rifampicin by 26% at 4 weeks, but by only 7.5% at 10 weeks. The median Crm was reduced by 20% at 4 weeks and by 7.1% at 10 weeks. The authors concluded that the effect of rifampicin on the pharmacokinetics of nevirapine substantially decreases over time. 

Peptidases encoded by many viruses play essential roles at various stages of viral replication, including the coordinated assembly and maturation of virons [7a]. Viral peptidases have become important drug targets in the treatment of viral infections. Of note are inhibitors of proteases of the human immunodeficiency virus (HIV), particularly HIV-1 protease (HIV-1 retropepsin, EC 3.4.23.16) and HIV-2 protease [47-50], Drugs in this class, which include indinavir, ritonavir, and saquinavir, are useful in the treatment of AIDS, especially when administered as a cocktail together with one of the drugs that act on the viral retrotranscriptase (e.g., didanosine, stavudine, and zidovudine (AZT)). 

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