HIV‐1 Infection

In 2007, the US Food and Drug Administration (FDA) approved maraviroc for the treatment of human immunodeficiency virus type 1 (HIV‐1) infection, making it the first (and to date only) CCR5 antagonist available for clinical use. Approval stipulated that maraviroc be used only in treatment‐experienced patients who have viremia with a virus using the CCR5 receptor (R5 virus)—the latter being a critical limitation because maraviroc has no antiviral activity against non–CCR5‐using viruses. Because a substantial proportion of treatment‐experienced patients harbor these strains—roughly 50% in surveys using the original tropism assay —maraviroc use thus far has been necessarily limited.

Unlike in treatment‐experienced patients, R5 viruses are the dominant type in transmission and predominate early during HIV disease, with an estimated 80% of untreated patients having R5 strains. It is therefore plausible that maraviroc would have its greatest role earlier during HIV disease, especially among those who have never received therapy. In this issue of the Journal, investigators report results of the MERIT (Maraviroc versus Efavirenz in Treatment‐Naive Patients) study, a large, double‐blind, prospective randomized trial comparing maraviroc to efavirenz as part of initial treatment. More than 1700 subjects were recruited from study sites from 5 continents and were eligible if they had never received treatment and were found to have R5 virus at screening.

Ultimately, 721 patients entered the study for the comparison of interest here, with 360 receiving twice‐daily maraviroc and 361 receiving once‐daily efavirenz, along with matching placebos for maraviroc and efavirenz and coformulated zidovudine‐lamivudine. In the primary 48‐week analyses, maraviroc was noninferior to efavirenz at the <400 copies/mL threshold (70.6% response rate for maraviroc vs 73.1% for efavirenz) but not at the <50 copies/mL threshold (65.3% for maraviroc vs 69.3% for efavirenz). Importantly, the study used a relatively strict 10% threshold for noninferiority; nonetheless, virologic failure was 3 times more common with maraviroc than with efavirenz (11.9% vs 4.2%), with a substantial proportion of maraviroc failures occurring in study subjects who harbored non–CCR5‐using virus at baseline that, in hindsight, was not detected on screening. Regardless of the explanation, the primary results favored efavirenz, which remarkably has still not been bettered with respect to virologic response in a clinical trial despite its FDA approval more than a decade ago.

In addition to these results, several other concerns—some from this study, some about the CCR5 antagonist class of drugs in general—are important if a clinician were to consider using maraviroc as part of a first‐line antiretroviral regimen. Before starting maraviroc‐based therapy, patients must undergo viral tropism testing; only 1 tropism test, the original Trofile assay (Monogram Biosciences), has been prospectively validated in clinical trials to correlate with antiviral response to a CCR5 antagonist. Such testing excludes a significant minority of even treatment‐naive patients: in the MERIT study, 26% of 1730 patients screened did not have an evaluable tropism result, and 17% had X4 virus. Furthermore, the Trofile assay is relatively expensive compared with other baseline tests in patients with HIV infection—the price is 4–5 times higher than that for resistance genotype testing—and as a modification of resistance phenotype testing typically requires 3 weeks or longer for results to return to the clinician. While this delay is rarely of clinical significance, people with HIV infection who are ready to begin treatment are understandingly eager to do so as soon as possible. Fortunately, more rapid and less expensive viral tropism tests are under development, but none have been endorsed by HIV treatment guidelines.

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