NRTIs Ritonavir

NRTIs (based on resistance testing) + PI (with or without low-dose ritonavir)... 

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. 

Based on HIV-1 drug resistance genotypic test results at the Screening Visit and prior treatment history, the investigator considers lopinavir/ritonavir plus at least two NRTIs to be an appropriate treatment for the subject. 

Subject does not require and agrees not to take any antiretroviral medication except lopinavir/ritonavir and NRTIs. 

In a patient whose antiretroviral regimen includes the PI, ritonavir, and one or more NRTIs. 

NRTIs and 1 PI 2 NRTIs and INNRTI 2 NRTIs and 1 PI with ritonavir 2 NRTIs and abacavir... 

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. 

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... 

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. ... 

Many recreational drugs such as benzodiazepines, amphetamines, and opioids are also metabolized by the liver. Although information is scant about the clinical significance and interactions between these drugs and antiretroviral agents, unintentional overdoses with methamphetamine and gamma hydroxybutyrate have been reported in patients using Pis, particularly ritonavir. Pis and NRTIs may alter metabohsm of methadone and precipitate opioid withdrawal (McCance-Katz et al., 2003). 

Four HIV-infected children undergoing intense antiretroviral combination therapy were switched to regimens including amprenavir and efavirenz after the failure of other drugs (9). Pharmacokinetic studies suggested that combinations of these drugs can result in suboptimal concentrations of amprenavir. This was evident in two of the children taking amprenavir and efavirenz, in combination with two NRTIs, who had undetectable concentrations of amprenavir within 4 hours of administration. The addition of ritonavir to the combination restored the blood concentrations of amprenavir to those normally recorded (median 3500 ng/ml). The most probable reason for this effect is enhanced metabolism of amprenavir due to induction by efavirenz. 

In a randomized, double-blind study in 70 patients taking a regimen containing protease inhibitors, lopina-vir + ritonavir 400/100 mg or 400/200 mg bd was substituted (4). On day 15 nevirapine 200 mg bd was added and NRTIs were changed to include at least one NRTI not previously taken. Despite a more than four-fold reduction in phenotypic susceptibility to the pre-entry protease inhibitor in 63% of the patients, mean plasma HIV-1 RNA concentrations fell by 1.14 log copies/ml after 2 weeks. At week 48, 86% had plasma HIV-1 RNA concentrations of... 

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. 

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. 

Higher incidence of lipoatrophy, hyperlipidemia, and mitochondrial toxicities reported with d4T than with other NRTIs. iLow-dose (100 00 mg) ritonavir per day. 

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. 

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. 

Tipranavir with Ritonavir. Tipranavir given with low-dose ritonavir decreased the AUC of abacavir by approximately 40%. The clinical relevance of this reduction has not been established,but it may decrease the efficacy of abacavir. Therefore the UK manufacturer states that the concurrent use of tipranavir and low-dose ritonavir with abacavir is not recommended unless there are no other available NRTIs suitable for patient management. ... 

Current UK guidelines give tenofovir as one of the preferred drugs as part of a dual NRTI regimen, to be used with either fosamprenavir/ritonavir or lopinavir/ritonavir, for the treatment of HIV infection in treatment... 

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