Raltegravir Atazanavir Etravirine, tipranavir
Rilpivirine2 Darunavir, lopinavir/ritonavir 1Dose adjustment may be necessary if co-administered. 2NNRTI-NNRTI drug-drug interactions are not listed. 3Drug-drug interactions are rare with elvitegravir as a single agent but multiple if co-administered with either cobicistat or ritonavir.
Given the large number of non-HIV medications that are also metabolized by this pathway (see Chapter 4), drug-drug interactions must be expected and looked for; dosage adjustments are frequently required and some combinations are contraindicated.
Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids or H2-blockers. It is extensively bound (~98%) to plasma proteins and has correspondingly low cerebrospinal fluid levels. Serum half-life is approximately 6 hours.
Skin rash occurs in up to 38% of patients receiving delavirdine; it typically occurs during the first 1–3 weeks of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other possible adverse effects are headache, fatigue, nausea, diarrhea, and increased serum aminotransferase levels. Delavirdine has been shown to be teratogenic in rats, causing ventricular septal defects and other malformations at dosages not unlike those achieved in humans. Thus, pregnancy should be avoided when taking delavirdine.
Delavirdine is extensively metabolized by CYP3A and CYP2D6 enzymes. Therefore, there are numerous potential drug-drug interactions to consider (Tables 49–3 and 49–4). The concurrent use of delavirdine with fosamprenavir is not recommended because of bidirectional interactions. Co-administration of delavirdine with indinavir or saquinavir prolongs the elimination half-life of the latter agents, thus allowing them to be dosed twice rather than thrice daily.
Efavirenz can be given once daily because of its long half-life (40–55 hours). It is moderately well absorbed following oral administration (45%). Since toxicity may increase owing to increased bioavailability after a high-fat meal, efavirenz should be taken on an empty stomach. Efavirenz is principally metabolized by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites; the remainder is eliminated in the feces as unchanged drug. It is highly bound to albumin (~ 99%), and cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels.
The principal adverse effects of efavirenz involve the central nervous system. Dizziness, drowsiness, insomnia, nightmares, and headache tend to diminish with continued therapy; dosing at bedtime may also be helpful. Psychiatric symptoms such as depression, mania, and psychosis have been observed in the weeks following initiation and may necessitate discontinuation. Skin rash has been reported early in therapy in up to 28% of patients; the rash is usually mild to moderate in severity and typically resolves despite continuation. Rarely, rash has been severe or life-threatening. Other potential adverse reactions are nausea, vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10–20%. High rates of fetal abnormalities, such as neural tube defects, occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage; several cases of congenital anomalies have been reported in humans. Efavirenz is one of the NNRTI agents recommended for use in pregnancy (Table 49–5), but should be initiated after the first 8 weeks due to birth defects observed in a primate study.