The most common adverse effects of indinavir are unconjugated hyperbilirubinemia and nephrolithiasis due to urinary crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of approximately 10%. Acute renal failure and interstitial fibrosis have also been reported. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration, and serum creatinine levels should be monitored. Nausea, diarrhea, sicca syndrome, headache, blurred vision, and elevations of serum aminotransferase levels have also been reported. Insulin resistance may be more common with indinavir than with the other PIs, occurring in 3–5% of patients. In some studies but not in others, indinavir has been associated with a higher risk of myocardial infarction. There have also been rare cases of acute hemolytic anemia.
Since indinavir is an inhibitor of CYP3A4, numerous and complex drug interactions can occur (Tables 49–3 and 49–4). Boosting with ritonavir allows for twice-daily rather than thrice-daily dosing and eliminates the food restriction associated with use of indinavir. However, there is potential for an increase in nephrolithiasis with this combination compared with indinavir alone; thus, a high fluid intake (1.5–2 L/d) is advised. Indinavir should not be co-administered with astemizole, cerivastatin, efavirenz, ergotamine, etravirine, lovastatin, pimozide, rifampin, simvastatin, terfenadine, or triazolam. Levels of amlodipine, levodopa, and trazodone may be increased with concurrent administration of indinavir.
Lopinavir is available only in combination with low-dose ritonavir as a pharmacologic “booster” via inhibition of its CYP3Amediated metabolism, resulting in increased exposure and a reduced pill burden.
Lopinavir is highly protein bound (98–99%), and its half-life is 5–6 hours. It is extensively metabolized by CYP3A, which is inhibited by ritonavir. Lopinavir/ritonavir is one of the recommended antiretroviral agents for use in pregnant women (Table 49–5).
The most common adverse effects of lopinavir are diarrhea, nausea, vomiting, increased serum lipids, and increased serum aminotransferases (more common in patients with HBV or HCV co-infection). Prolongation of the PR and/or QT interval may occur. In some studies but not in others, lopinavir/ritonavir has been associated with a higher risk of myocardial infarction. Pancreatitis has rarely been reported. Ritonavir-boosted lopinavir may be more commonly associated with gastrointestinal adverse events than other PIs.
Potential drug-drug interactions are extensive (Tables 49–3 and 49–4). Levels of lamotrigine and methadone may be reduced with co-administration, and levels of bosentan may be increased. Concurrent use of darunavir, elvitegravir/cobicistat, fosamprenavir, and tipranavir is contraindicated. Since the oral solution of lopinavir/ritonavir contains alcohol, concurrent disulfiram and metronidazole are contraindicated. The oral solution also contains propylene glycol, contraindicating the co-administration of other drugs containing propylene glycol.
Nelfinavir has high absorption in the fed state (70–80%), undergoes metabolism by CYP3A, and is excreted primarily in the feces. The plasma half-life in humans is 3.5–5 hours, and the drug is more than 98% protein-bound.