As both an inducer and an inhibitor of CYP3A4, efavirenz induces its own metabolism and interacts with the metabolism of many other drugs (Tables 49–3 and 49–4). Co-administration with boceprevir, elvitegravir/cobicistat, etravirine, indinavir, itraconazole, ketoconazole, and simeprevir is contraindicated. Levels of efavirenz may be reduced by concomitant nevirapine. Levels of lopinavir/ritonavir, maraviroc, methadone, and telaprevir may be reduced when administered with efavirenz.
Etravirine, a diarylpyrimidine, was designed to be effective against strains of HIV that had developed resistance to first-generation NNRTIs due to mutations such as K103N and Y181C. Although etravirine has a higher genetic barrier to resistance than the other NNRTIs, mutations selected by etravirine usually are associated with resistance to efavirenz, nevirapine, and delavirdine.
Etravirine should be taken with a meal to increase systemic exposure. It is highly protein-bound and is primarily metabolized by the liver. Mean terminal half-life is ~41 hours.
The most common adverse effects of etravirine are rash, nausea, and diarrhea. The rash is typically mild and usually resolves after 1–2 weeks without discontinuation of therapy. Rarely, rash has been severe or life-threatening. Laboratory abnormalities include elevations in serum cholesterol, triglyceride, glucose, and hepatic aminotransferase levels. Aminotransferase elevations are more common in patients with HBV or HCV co-infection.
Etravirine is a substrate as well as an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19 and thus has potential for numerous drug-drug interactions (Tables 49–3 and 49–4). Some of the interactions are difficult to predict. For example, etravirine may decrease itraconazole and ketoconazole concentrations but increase voriconazole concentrations. Etravirine should not be given with atazanavir, clopidogrel, efavirenz, elvitegravir/ cobicistat, fosamprenavir, indinavir, and tipranavir. In addition, co-administration with clarithromycin or with the antimalarial agent artemether/lumefantrine should be avoided if possible.
The oral bioavailability of nevirapine is excellent (>90%) and is not food-dependent. The drug is highly lipophilic and achieves cerebrospinal fluid levels that are 45% of those in plasma. Serum half-life is 25–30 hours. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.
A single dose of nevirapine (200 mg) is effective in the prevention of transmission of HIV from mother to newborn when administered at the onset of labor and followed by a 2-mg/kg dose to the neonate within 3 days of delivery. However, nevirapine is no longer recommended for use in pregnancy due to the potential for adverse events and low barrier to resistance.