Ritonavir transcriptase inhibitors

Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine E, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J (2003a) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8 279-287... 

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. 

The purpose of this study is to determine whether once-daily dosing of the lopinavir/ritonavir (Kaletra) tablet in combination with investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors will reduce HIV viral load to very low levels in patients who have detectable viral loads with their current antiretroviral therapy. 

Study Design Treatment, randomized, open label, active control, parallel assignment, safety/efficacy study Official Title A Phase III, Randomized, Open-Label Study of Lopina-vir/Ritonavir Tablets 800/200mg Once-Daily Versus 400/100mg Twice-Daily When Co-administered With Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced, HIV-1 Infected Subjects Primary Outcome Measures ... 

Cross-resistance between indinavir and HIV reverse transcriptase inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of cross-resistance have been observed between indinavir and other HIV-protease inhibitors. 

Drugs that might affect amprenavir include abacavir, aldesleukin, antacids, anticonvulsants, azole antifungals, clarithromycin, cyclosporine, dexamethasone, buffered didanosine, disulfiram, ethanol, indinavir, methadone, metronidazole, nelfinavir, nonnucleoside reverse transcriptase inhibitors, oral contraceptives, rifamycins, ritonavir, saquinavir, St. John s wort, tacrolimus, and zidovudine. 

This class of antiretrovirals may be considered the most potent therapeutic agents for HIV to date. Protease inhibitors are used in combination regimens and combinations of reverse-transcriptase inhibitors and protease inhibitors have been proven most effective to decrease viral load and prolong survival. However, the protease inhibitors generally show poor penetration into the CNS and thus have no effect on aids dementia. The present Pis available for the treatment of HIV are indinavir, ritonavir, nel-finavir, saquinavir and (fos)amprenavir, atazanavir and lopinavir (in combination with ritonavir as ritonavir improves the bioavailability of lopinavir by inhibiting its metabolism in the liver by CYP3A). 

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. 

The advent of highly active antiretroviral therapy (HAART) to minimize the rapid development of viral resistance in the treatment of HIV infection may result in multiple drug interactions (110-113). Both the nonnucleoside reverse transcriptase inhibitors and the protease inhibitors are substrates and inhibitors of some CYP enzymes, and some act as inducers as well (110,111). The major effects are on the CYP3A isoforms, and this has been used to advantage to increase concentrations of some HIV drugs. For example, delavirdine is a mechanism-based irreversible inhibitor of CYP3A4, and thereby is used to increase exposure to protease inhibitors (114). Ritonavir is a protease inhibitor, but it is used primarily for its ability as a potent inhibitor of CYP3A4 to increase concentrations of other protease inhibitors (115). 

Raltegravir, or Isentress (1), is the first FDA-approved inhibitor of HIV integrase. HIV/AIDS drugs are categorized according to their mode of action as nucleoside and nucleotide reverse transcriptase inhibitors [NRTIs, e.g., tenofovir (2)], nonnucleotide reverse transcriptase inhibitors [NNRTIs, e.g., efavirenz (3)] protease inhibitors [Pis, e.g., ritonavir (4)], fusion inhibitors [e.g., enfuvirtide (5)], entry inhibitors... 

Bu HZ, Pool WF, Wu EY et al. (2004). Metabolism and excretion of capravirine, a new non-nucleoside reverse transcriptase inhibitor, alone and in combination with ritonavir in healthy volunteers. Drug Metab Dispos 32 689-698... 

ABACAVIR TIPRANAVIR + RITONAVIR Possible 1 efficacy risk of treatment failure of abacavir 1 plasma concentrations Not recommended unless there are no other available nucleoside reverse transcriptase inhibitors... 

The HIV protease inhibitor saquinavir has hmited and variable oral systemic availability and ritonavir, an inhibitor of CYP450 and P glycoprotein, is widely used to increase its systemic exposure. A small pilot study in three HIV-infected patients has suggested that oral itraconazole can have similar effects on the oral availability of saquinavir (109). Concomitant use of itraconazole 200 mg/day with a combination of saquinavir and two nucleoside reverse transcriptase inhibitors led to a 2.5-to 6.9-fold increase in the AUC of saquinavir, a 2.0- to 5.4-fold increase in peak plasma concentrations, and a 1.6-to 17-fold increase in trough plasma concentrations. The effect of itraconazole on saquinavir was comparable to that of ritonavir. 

Lopinavir and ritonavir are nucleoside analogue reverse transcriptase inhibitors that are used in combination in the treatment of AIDS. 

Benson CA, Deeks SG, Brun SC, Gulick RM, Eron JJ, Kessler HA, Murphy RL, Hicks C, King M, Wheeler D, Feinberg J, Stryker R, Sax PE, Riddler S, Thompson M, Real K, Hsu A, Kempf D, Japour AJ, Sun E. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis 2002 185(5) 599-607. 

Krogstad P, Lee S, Johnson G, Stanley K, McNamara J, Moye J, Jackson JB, Aguayo R, Dieudoime A, Khoury M, Mendez H, Nachman S, Wiznia A, BaUow A, Aweeka F, Rosenblatt HM, Perdue L, Frasia A, Jeremy R, Anderson M, Japour A, Fields C, Farnsworth A, Lewis R, Schnittman S, GigUotti M, Maldonaldo S, Lane B, Hernandez JE, et al Pediatric AIDS CUnical Trials Group 377 Study Team. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nehinavir, or ritonavir for pretreated children mfected with human immnnodeficiency virus type 1. Qin imect Dis 2002 34(7) 991-1001. 

Lichterfeld M, Nischalke HD, Bergmann F, Wiesel W, Rieke A, Theisen A, Fatkenheuer G, Oette M, Carls H, Fenske S, Nadler M, Knechten H, Wasmuth JC, Rockstroh JK. Long-term efficacy and safety of ritonavir/ indinavir at 400/400 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors as first line antiretroviral therapy. HIV Med 2002 3(l) 37-43. 

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. 

The FDA approves an HIV viral load test Nevirapine, the first anti-HIV drug of the non-nucleoside reverse transcriptase inhibitors (NNRTl) Ritonavir Pi Indinavir Pis... 

A. Hsu, J. Isaacson, S. Brun, B. Bernstein, W. Lam, R. Bertz, C. Foit, K. Rynkiewicz, B. Richards, M. King, R. Rode, D. J. Kempf, G. R. Granneman, and E. Sun, Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated hnman immunodeficiency virus-infected patients. Antimicrob Agents Chemother 47(l) 350-359 (2003). 

Indinavir (800 mg/t.i.d.) is an inhibitor of the HIV protease, which is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious viral particles. Cross-resistance between indinavir and HIV reverse-transcriptase inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of cross-resistance have been noted between indinavir and other HIV protease inhibitors. Indinavir is metabolized in the liver, and seven metabolites have been identified, and 20% of indinavir is excreted unchanged in the urine. 

Ritonavir exhibits additive to synergistic effects against HIV when used in combination with reverse-transcriptase inhibitors such as zidovudine or zalcitabine. Ritonavir pro-dnces a large increase in the plasma concentration of amio-darone, astemizole, bepridil, bupropion, cisapride, clozapine, encainide, flecainide, meperidine, peroxicam, propafenone, propoxyphene, quinidine, rifabutin, and terfenadine. 

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