Resistance to maraviroc is associated with one or more mutations in the V3 loop of gp120. However, emergence of CXCR4 virus (either previously undetected or newly developed) appears to be a more common cause of virologic failure than the development of resistance mutations. There appears to be no cross-resistance with drugs from any other class, including the fusion inhibitor enfuvirtide.
Maraviroc is a substrate for CYP3A4 and therefore requires adjustment in the presence of drugs that interact with these enzymes (Tables 49–3 and 49–4). It is also a substrate for P-glycoprotein, which limits intracellular concentrations of the drug. The dosage of maraviroc must be decreased if it is co-administered with strong CYP3A inhibitors (eg, delavirdine, ketoconazole, itraconazole, clarithromycin, or any protease inhibitor other than tipranavir) and must be increased if co-administered with CYP3A inducers (eg, efavirenz, etravirine, carbamazepine, phenytoin, or St. John’s wort). Concurrent use of rifampin is contraindicated.
Potential adverse effects of maraviroc include upper respiratory tract infection, cough, pyrexia, rash, dizziness, muscle and joint pain, diarrhea, sleep disturbance, and elevations in serum aminotransferases. Hepatotoxicity has been reported, which may be preceded by a systemic allergic reaction (ie, pruritic rash, eosinophilia, or elevated IgE); discontinuation of maraviroc should be prompt if this constellation occurs. Myocardial ischemia and infarction have been observed in patients receiving maraviroc; therefore caution is advised in patients at increased cardiovascular risk. There is an increased risk of postural hypotension in patients with severe renal impairment.
There has been concern that blockade of the chemokine CCR5 receptor—a human protein—may result in decreased immune surveillance, with a subsequent increased risk of malignancy or infection. To date, however, there has been no evidence of an increased risk of either malignancy or infection in patients receiving maraviroc.
This class of agents binds integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2. By doing so, it inhibits strand transfer, the third and final step of provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells (Figure 49–3). As a class, these agents tend to be well tolerated, with headache and gastrointestinal effects the most commonly reported adverse events. Their use in combination antiretroviral regimens or with cobicistat (ie, elvitegravir) means that additional adverse events and/or drug-drug interactions need to be considered as well. The available data suggest that effects upon lipid metabolism are favorable compared with efavirenz and PIs. Rare severe events include systemic hypersensitivity reactions and rhabdomyolysis.
The frequency of dosing of dolutegravir depends on the presence or absence of integrase inhibitor-associated resistance mutations and the concurrent use of efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin. Dolutegravir should be taken 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications. Peak plasma concentrations occur within 2–3 hours of ingestion. Dolutegravir is highly protein bound (99%). The terminal half-life is ~14 hours. Serum levels may be reduced in patients with severe renal insufficiency.