Nonnucleoside Reverse Transcriptase Inhibitors
The NNRTIs inhibit viral reverse transcriptase by bind-ing adjacent to its active site and inducing a conforma-tional change that causes the enzyme’s inactivation. When combined with NRTIs or protease inhibitors, NNRTIs produce additive and possibly synergistic ef-fects against HIV. The pharmacokinetic parameters of these agents are listed in Table 51.3.
All NNRTIs are active against HIV-1 reverse tran-scriptase only and do not require phosphorylation for activation. These agents share certain adverse effects (e.g., rash) and are subject to numerous drug interac-tions due to their metabolism by and induction of he-patic cytochrome P450 enzymes. NNRTIs may modify plasma levels of protease inhibitors, which are also me-tabolized by cytochrome P450 enzymes (Table 51.4). The list of drug interactions provided in this text is not all-inclusive; it is necessary to check for all drug interac-tions when prescribing NNRTIs. These agents should be used with caution in patients with hepatic disease.
When NNRTIs are used alone, resistance develops rapidly as a result of the development of mutations in reverse transcriptase; therefore, monotherapy with these agents is not recommended. Cross-resistance be-
tween NNRTIs occurs frequently but is not seen be-tween NNRTIs and NRTIs or the protease inhibitors.
Efavirenz (Sustiva) is approved for the therapy of HIV infection of adults and children and is also used for pos-texposure prophylaxis. It is the only NNRTI approved for once-daily dosing. Rash, although rarely severe, is a common adverse effect of efavirenz. Elevated liver en-zymes and serum cholesterol also may occur. Central nervous system (CNS) effects in approximately half of patients may include dizziness, headache, insomnia, drowsiness, euphoria, agitation, impaired cognition, nightmares, vivid dreams, and hallucinations. These ef-fects often subside after several weeks to months of therapy.
Efavirenz should be avoided during pregnancy be-cause primate studies have shown it to be teratogenic at doses near therapeutic levels. Women of childbearing potential should use two methods of birth control to avoid becoming pregnant when taking this drug.
Efavirenz interacts with many drugs via the cy-tochrome P450 pathways. It induces and is metabolized by CYP3A4 and inhibits CYP2C9 and CYP2C19. It should not be given with cisapride, ergot alkaloids, mi-dazolam, or triazolam because of the potential for life-threatening reactions. Efavirenz has the potential to decrease blood levels of methadone, rifabutin, keto-conazole, and itraconazole. It may inhibit the metabo-lism of drugs such as alosetron, diazepam, ethinyl es-tradiol, imipramine, losartan, omeprazole, warfarin, tolbutamide, and topiramate. Efavirenz interacts with cytochrome P450 inducers and substrates (e.g., phenyt-oin, phenobarbital) in a complex manner; blood levels and side effects should be closely monitored. Patients taking efavirenz should avoid herbal preparations con-taining St. John’s wort because the herb induces CYP3A4 and may cause drug failure or viral resistance. Saquinavir should not be used as the sole protease in-hibitor in a regimen containing efavirenz.
Nevirapine (Viramune) is approved for the treatment of HIV infection in adults and children as part of a combi-nation therapy. During the first 12 weeks of treatment, patients must be closely monitored for the development of potentially fatal hepatic toxicity (i.e., hepatitis, hepatic necrosis, and hepatic failure) and skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions). Although these toxici-ties are rare, common side effects include mild to mod-erate rash, fever, nausea, fatigue, headache, and ele-vated liver enzymes.
Nevirapine induces and is metabolized by CYP3A4; therefore, coadministration of drugs that induce or are metabolized by this isoenzyme may result in interac-tions. Nevirapine may decrease the effectiveness of ethinyl estradiol–based contraceptives and can lower plasma concentrations of methadone. Nevirapine should not be administered with ketoconazole, rifampin, or ri-fabutin.
Delavirdine (Rescriptor) is approved for the treatment of HIV-1 infection in adults and adolescents over age 16 as part of a combination therapy. Rash accompanied by pruritus is the most frequent adverse effect of this agent; however, it usually resolves within several weeks of treatment. Severe skin reactions are rare. Headache, nausea, vomiting, diarrhea, fatigue, and elevated hepatic enzymes also may be associated with delavirdine ad-ministration.
Drugs that decrease stomach acidity (e.g., antacids, H2 receptor blockers, and proton pump inhibitors) de- crease the absorption of delavirdine. In vivo and in vitro studies have shown that delavirdine is metabolized by and inhibits CYP3A4. In vitro studies have shown that it also is metabolized by CYP2D6 and inhibits CYP2C9, CYP2D6, and CYP2C19. Delavirdine should not be used in combination with alprazolam, cisapride, ergot al-kaloids, midazolam, or triazolam because of the poten-tial for serious adverse reactions. Delavirdine increases serum concentrations of certain protease inhibitors and may reverse the resistance of zidovudine-resistant HIV.
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