NRTIs Saquinavir

APV, amprenavir ATV, atazanavir CNS, central nervous system CVD, cardiovascular disease D/C, discontinue ddC, zalcitabine ddl, didanosine DEXA, dual-energy x-ray absorptiometry d4T, stavudine EFV, efavirenz HDL, high-density lipoprotein HIV, human immunodeficiency virus HTN, hypertension IDV, indinavir LDL, low-density lipoprotein LPV/r, lopinavir+ ritonavir MRI, magnetic resonance imaging NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor RTV, ritonavir SQV, saquinavir TDF, tenofovir disoproxil fumarate TG, triglyceride TPV/r, tipranivir + ritonavir 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. 

As with all viruses, HIV relies on a viral protease to properly cleave viral proteins in preparation for creating new viral particles. Drugs that block HIV protease are known as protease inhibitors (PI). The first HIV PI was saquinavir (Invirase, A.167), which was approved by the FDA in 1995 (Figure A.47). Pis therefore trailed NRTIs by nearly 10 years. Other Pis have since been approved. The most recently approved PI is darunavir (Prezista, A.168), which reached the market in 2006. 

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 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. 

Saquinavir, the first anti-HIV drug as aPI 3TC (lamivudine) NRTI The FDA approves Saquinavir in a record 97 days... 

In general, efavirenz and nevirapine decrease the levels of protease inhibitors, whereas delavirdine increases them. Ritonavir is sometimes used to elevate the levels of other protease inhibitors when efavirenz or nevirapine are required. Amprenavir and nelflnavir decrease the levels of delavirdine. Most protease inhibitors do not appear to affect the levels of efavirenz or nevirapine. There is some evidence of increased adverse effects with antiviral doses of ritonavir and efavirenz, or saquinavir and delavirdine, including raised liver enzymes. Note that NNRTIs are not given with protease inhibitors in current first-line regimens for HIV infection either an NNRTI or protease inhibitors are combined with dual 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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