Entry and Integrase Inhibitors

Agents: maraviroc (MVC), raltegravir (RAL), enfuvirtide (T20)

The three newest classes of antiretrovirals focus on preventing the HIV virus from binding to target cells  (maraviroc), fusion of the viral particle with the cell membrane and entry into the cell (enfuvirtide), or integration of the intracellular virus into the chromosomal DNA (raltegravir). Enfuvirtide is administered as a subcutaneous injection associated with substantial injection site reactions; thus, it is gen-erally reserved for patients with the most difficult-to-treat, multidrug-resistant strains of virus.

Spectrum

Only current clinical use is for HIV.

Adverse Effects

Dermatologic: Injection site reactions, including pain, erythema, pruritis, and nodule formation, occur in essentially all patients using subcutaneous enfuvirtide.

Hepatotoxicity: Maraviroc has a black box warning regarding hepatotoxicity, based on case reports from healthy subjects who received the drug in early clinical trials. The effect seems to be rare in patients treated with maraviroc.

Musculoskeletal: Raltegravir has been associated with increases in creatine phosphokinase. Most of these cases have been asymptomatic;  clinically evident myositis or rhabdomyolysis is rare.

Important Facts

• Maraviroc has a unique mechanism of action—binding to and blocking one of the host cell receptors (known as CCR5) that the HIV virus attaches to. Thus, its target is a human protein,  not a viral one. HIV can also use another host cell receptor (CXCR4) to attach to, and different strains of HIV have different “preferences” for CCR5 versus CXCR4. Thus, before a patient is started on maraviroc, a tropism test must be performed to see whether the patient’s virus  “prefers” CCR5 (in which case maraviroc may be useful) or CXCR4 (thus ruling out maraviroc use).

• Maraviroc is a substrate of P450 drug-metabolizing enzymes, and thus there are different dosage recommendations depending on which other potentially interacting drugs the patient is taking. Enfuvirtide and raltegravir have minimal drug interactions.

What They’re Good For

These drugs are mainly for use in treatment-experienced patients, although raltegravir in particular may become a standard initial drug for therapy.

Don’t Forget!

Pretty much the only drug raltegravir has an inter-action with is the anti-TB drug rifampin. Rifampin is a potent inducer of drug-metabolizing enzymes, and its co-administration with many HIV drugs reduces their serum levels below the effective range. Thus, seeing rifampin on the profile of a patient receiving antiretrovirals is a huge red flag and war-rants investigation to make sure the patient’s antiretroviral therapy is adequate.

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.