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Chapter: Basic & Clinical Pharmacology : Antiviral Agents

Entry Inhibitors

The process of HIV-1 entry into host cells is complex; each step presents a potential target for inhibition.


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 com-plex 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 sub-sequent 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 49–4). Enfuvirtide binds to the gp41 subunit of the viral envelope glycoprotein, pre-venting the conformational changes required for the fusion of the viral and cellular membranes. Enfuvirtide, which must be admin-istered by subcutaneous injection, is the only parenterally adminis-tered 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 associated with enfuvirtide therapy are local injection site reactions, consisting of painful erythematous nodules. Although frequent, these are typically mildto moderate and rarely lead to discontinuation. Other symptom-atic side effects may 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 prospective clinical trials, an increased rate of bacterial pneumonia was noted in patients receiving enfuvirtide. No drug-drug interac-tions have been identified that would require the alteration of the dosage of concomitant antiretroviral or other drugs.


Maraviroc binds specifically and selectively to the host protein CCR5, one of two chemokine receptors necessary for entrance of HIV into CD4+ cells. Maraviroc is approved for adults with CCR5-tropic (also known as R5) HIV-1 infection who are expe-riencing virologic failure due to resistance to other antiretroviral agents. Studies have shown that 52–60% of patients in whom at least two antiviral regimens had failed were infected with R5 HIV. Since maraviroc is active against HIV that uses the CCR5 co-receptor exclusively, and not against HIV strains with CXCR4, dual, or mixed tropism, tropism testing should be per-formed before initiating treatment with maraviroc. Clinical experience with the use of maraviroc in treatment-naïve patients is limited.

The absorption of maraviroc is rapid but variable, with the time to maximum absorption generally being 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 recom-mended dose of maraviroc varies according to renal function and the concomitant use of CYP3A inducers or inhibitors. Maraviroc is contraindicated in patients with severe or end-stage renal impairment who are taking concurrent CYP3A inhibitors or inducers, and caution is advised when used in patients with preex-isting hepatic impairment and in those co-infected with HBV or HCV. Maraviroc has been shown to have excellent penetration into the cervicovaginal fluid, with levels almost four times higher than the corresponding concentrations in blood plasma.

Resistance to maraviroc is associated with one or more mutations in the V3 loop of gp120. There appears to be no cross-resistance with drugs from any other class, including the fusion inhibitor enfu-virtide. However, virologic failure of regimens containing maraviroc may potentially be caused by emergence of non–CCR5-tropic virus (eg, CXCR4-tropic virus) or by changes in viral tropism, owing to the development of multiple mutations throughout gp160.

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 inhibi-tor other than tipranavir) and must be increased if co-administered with CYP3A inducers (eg, efavirenz, etravirine, rifampin, car-bamazepine, phenytoin, or St. John’s wort).

Potential adverse effects include cough, upper respiratory tract infections, postural hypotension (particularly in the setting of renal insufficiency), muscle and joint pain, abdominal pain, diarrhea, and sleep disturbance. Due to reports of hepatotoxicity, which may be preceded by evidence of a systemic allergic reaction (ie, pruritic rash, eosinophilia, or elevated IgE), discontinuation of maraviroc should be considered promptly if this constellation of signs occurs. Myocardial ischemia and infarction have been observed in patients receiving maraviroc; therefore caution is advised in patients at increased cardiovascular risk.

There has been some concern that blockade of the chemokine CCR5 receptor—a human protein—may result in decreased immune surveillance, with a subsequent increased risk of malig-nancy (eg, lymphoma) or infection. To date, however, there has been no evidence of an increased risk of either malignancy or infection in patients receiving maraviroc.

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