Rash, usually a maculopapular eruption that spares the palms and soles, occurs in up to 20% of patients, usually in the first 4–6 weeks of therapy. Although typically mild and self-limited, rash is dose-limiting in about 7% of patients. Women appear to have an increased incidence of rash. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the incidence of rash. Severe and life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, are rare but are more common than with other NNRTIs. Nevirapine therapy should be immediately discontinued in patients with severe rash and in those with accompanying constitutional symptoms; since rash may accompany hepatotoxicity, liver tests should be assessed. Symptomatic liver toxicity may occur in up to 4% of patients, may be severe, and is more frequent in those with higher pretherapy CD4 cell counts (ie, >250 cells/mm3 in women and >400 cells/mm3 in men), in women, and in those with HBV or HCV co-infection. Fulminant, life-threatening hepatitis has been reported, typically within the first 18 weeks of therapy. Other adverse effects include fever, nausea, headache, and somnolence.
Nevirapine is a moderate inducer of CYP3A metabolism, resulting in numerous potential drug-drug interactions (see Tables 49–3 and 49–4). Co-administration of artemether/lumefantrine, atazanavir, dolutegravir, elvitegravir/cobicistat, fosamprenavir, ketoconazole, and rifampin should be avoided.
Rilpivirine, a diarylpyrimidine, must be administered with a meal (preferably high fat or >400 kcal). Its oral bioavailability is dependent on an acid gastric environment for optimal absorption; thus antacids and H2-receptor antagonists should be separated in time and proton pump inhibitors are contraindicated. The drug is highly protein bound and the terminal elimination half-life is 50 hours.
Rilpivirine is one of the NNRTI agents recommended for use in pregnancy (Table 49–5). Rilpivirine is primarily metabolized by CYP3A4, and drugs that induce or inhibit CYP3A4 may thus
TABLE 49–5 The use of antiretroviral agents in pregnancy.
Abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, zidovudine
Atazanavir/ritonavir, darunavir/ritonavir Lopinavir/ritonavir affect the clearance of rilpivirine (see Table 49–3). However, clinically significant drug-drug interactions with other antiretroviral agents have not been identified to date.
The most common adverse effects associated with rilpivirine therapy are rash, depression, headache, insomnia, and increased serum aminotransferases. Increased serum cholesterol, and fat redistribution syndrome have also been reported. Higher doses have been associated with QTc prolongation. Inhibition of renal tubular secretion of creatinine causes a reversible elevation in serum creatinine, but glomerular filtration rate is not affected.