The process of HIV-1 entry into host cells is complex; each step presents a potential target for inhibition. Viral attachment to the host cell entails binding of the viral envelope glycoprotein complex gp160 (consisting of gp120 and gp41) to its cellular receptor CD4. This binding induces conformational changes in gp120 that enable access to the chemokine receptors CCR5 or CXCR4. Chemokine receptor binding induces further conformational changes in gp120, allowing exposure to gp41 and leading to fusion of the viral envelope with the host cell membrane and subsequent entry of the viral core into the cellular cytoplasm.
Enfuvirtide is a synthetic 36-amino-acid peptide fusion inhibitor that blocks HIV entry into the cell (Figure 49–3). Enfuvirtide binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.
Enfuvirtide, which must be administered by subcutaneous injection, is the only parenterally administered antiretroviral agent. Metabolism appears to be by proteolytic hydrolysis without involvement of the CYP450 system. Elimination half-life is 3.8 hours.
Resistance to enfuvirtide can result from mutations in gp41; the frequency and significance of this phenomenon are being investigated. However, enfuvirtide lacks cross-resistance with the other currently approved antiretroviral drug classes.
The most common adverse effects are local injection site reactions, consisting of painful erythematous nodules. Although frequent, these are typically mild-to-moderate in severity and rarely lead to discontinuation. Other potential side effects include insomnia, headache, dizziness, and nausea. Hypersensitivity reactions may rarely occur, are of varying severity, and may recur on rechallenge. Eosinophilia is the primary laboratory abnormality seen with enfuvirtide administration. In Phase 3 studies, bacterial pneumonia was seen at a higher rate in patients who received enfuvirtide than in those who did not receive enfuvirtide. No drug-drug interactions have been identified that would require the alteration of the dosage of concomitant antiretroviral or other drugs.
Maraviroc is approved for use in combination with other antiretroviral agents in adult patients infected only with CCR5-tropic HIV-1. Maraviroc binds specifically and selectively to the host protein CCR5, one of two chemokine receptors necessary for entrance of HIV into CD4+ cells. Since maraviroc is active against HIV that uses the CCR5 co-receptor exclusively, and not against HIV strains with CXCR4, dual, or mixed tropism, co-receptor tropism should be determined by specific testing before maraviroc is started. Substantial proportions of patients, particularly those with advanced HIV infection, are likely to have virus that is not exclusively CCR5-tropic.
The absorption of maraviroc is rapid but variable, with the time to maximum absorption generally 1–4 hours after ingestion of the drug. Most of the drug (≥ 75%) is excreted in the feces, whereas approximately 20% is excreted in urine. The recommended dose of maraviroc varies according to renal function and the concomitant use of CYP3A inducers or inhibitors (Table 49–3). Maraviroc is contraindicated in patients with severe or end-stage renal impairment and caution is advised when used in patients with preexisting hepatic impairment and in those co-infected with HBV or HCV. Maraviroc has excellent penetration into the cervicovaginal fluid, with levels almost four times higher than the corresponding concentrations in blood plasma.