The suppression of human immunodeficiency virus (HIV) infection has been greatly enhanced by newer multi-drug regimens; however, a significant portion of patients eventually develops a rebound in viral replication, often caused by the difficulty of complying with complicated treatment schemes and their inherent toxicities. Salvage therapy in patients with viral rebound is most likely to succeed if the regimen includes an agent from a class of antiretroviral drugs to which the patient has not yet been exposed. Enfuvirtide is a 36-amino-acid peptide that is injected subcutaneously and works by blocking the fusion site where HIV enters the CD4⁺ cell. Lalezari and colleagues from the T-20 vs. Optimized Regimen Only Study 1 (TORO 1) report on the use of enfuvirtide in patients who have HIV infection with elevated viral loads despite multi-drug treatment.

This randomized, open-label trial enrolled 501 patients from various HIV treatment centers in North and South America who had viral loads of at least 5,000 copies of HIV-1 RNA per mL despite at least six months of treatment with drugs from three classes of antiretroviral medications (i.e., nucleoside reverse-transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors). All patients had initial genotypic and phenotypic resistance testing, and an optimal antiretroviral salvage regimen was designed, based on each patient's drug tolerance and resistance measures. Patients were randomized in a 2:1 fashion to receive enfuvirtide (90 mg injected subcutaneously twice daily) plus the optimized regimen or the optimized regimen alone.

After 24 weeks of injections, the best response to treatment (HIV-1 RNA viral load less than 50 copies per mL) occurred in 19.6 percent of patients assigned to the enfuvirtide group, compared with 7.3 percent of those receiving an optimized regimen alone. An intermediate response (HIV-1 RNA viral load less than 400 copies per mL) occurred in 31.7 percent of patients in the enfuvirtide group and 16.4 percent of those receiving an optimized regimen alone. At least some response (decrease in viral load of at least one log₁₀ copy of HIV-1 RNA per mL from pretreatment level) was achieved in 51.8 percent of those taking the study drug versus 29.1 percent of patients in the control group subjects.

Adverse events from the optimized oral regimens occurred in 77.6 percent of patients receiving enfuvirtide and 74.5 percent of control patients. The most common side effect specifically related to enfuvirtide was injection-site reactions, which occurred at least once in 98.2 percent of patients. Erythema, induration, and nodules or cysts at the injection sites were common, and the discomfort was enough to require analgesics or limitation of usual activities in 8.7 percent of participants. Systemic hypersensitivity developed in two patients receiving enfuvirtide injections.

Data after 48 weeks of use was available for patients from TORO 1 and TORO 2. Eosinophilia (11.2 percent), bacterial pneumonia (5.6 percent), and sepsis (1.8 percent) were significantly more frequent in those receiving enfuvirtide than those receiving placebo.

The authors conclude that enfuvirtide injections improve salvage therapy results more than optimized oral therapy alone in patients who have HIV with viral rebound despite previous multi-drug treatment.

editor's note: An accompanying editorial by Steinbrook¹ notes that in the United States, the anticipated annual wholesale cost for enfuvirtide is almost $20,000. The manufacturer reports that synthesis of the oligopeptide requires 106 steps, compared with eight to 12 steps for HIV medications. The modest success achieved in re-suppresion of HIV infection with this fusion inhibitor, combined with the nearly universal injection site reactions, occasional systemic toxicity, and steep cost likely will limit its role in salvage therapy. It is hoped that oral versions of HIV fusion inhibitors with better efficacy, fewer side effects, and lower cost will become available after further research.—B.Z.