HIV‐1 Infection. Part 3

A major advantage of maraviroc seen in the MERIT study was a lower rate of adverse effects compared with efavirenz, including those adverse events severe enough to lead to drug discontinuation—in fact, this occurred at a rate >3‐fold higher in the efavirenz arm than in the maraviroc arm (14% vs 4%; ). In addition, maraviroc‐treated subjects had fewer malignancies and AIDS‐defining events; although the differences were not statistically significant, they are somewhat reassuring given that maraviroc did not lead to unanticipated immunosuppresion. Data not included here but presented elsewhere in abstract form showed that lipid changes with maraviroc were generally more favorable than those seen with efavirenz. Overall, these data add to a body of evidence from studies conducted in treatment‐experienced patients indicating that maraviroc is both safe and well tolerated.

The above‐mentioned cellular target of maraviroc may well have salutatory immunologic effects. A consistent finding of this and other comparative studies of maraviroc is that CD4 cell count increases are greater than those in maraviroc comparator arms, with the effect being of greater magnitude than would be anticipated on the basis of a reduction in HIV RNA level alone. In MERIT, 48‐week CD4 cell count increases were 170 cells/μL for maraviroc and 144 cells/μL for efavirenz ( ). Although the mechanism of this effect is not known, proposed explanations include the blocking of gp120‐driven apoptosis or a reduction in systemic inflammation and immune activation. Studies are under way to evaluate whether maraviroc will increase CD4 cell counts among those who already have virologic suppression and inadequate CD4 cell responses, although pilot studies of this strategy have to date been negative.

CCR5 antagonists may one day have a particularly effective role in the prevention of HIV infection, both because they prevent entry of HIV‐1 and, as noted above, because R5‐tropic viruses are the predominant type involved in HIV transmission. The pharmacokinetic properties of maraviroc in particular seem ideal: in one study conducted in HIV‐negative women, concentrations of the drug in cervicovaginal fluid exceeded those found in plasma. Although ex vivo tests of maraviroc as a topical microbicide showed less activity than expected, a case report of successful control of HIV through a bone marrow transplant from a donor homozygous for the Δ32 mutation provides hope that potent blockage of CCR5 may ultimately play a broader role in HIV prevention.

How then should maraviroc be considered among first‐line choices for initial antiretroviral therapy—is the glass half empty or half full? If only because of the extraordinary antiviral potency and tolerability of the existing preferred choices, for now maraviroc‐based regimens must be considered an alternative choice, something to be used only when existing nonnucleoside reverse‐transcriptase inhibitor–based, boosted protease inhibitor–based, and integrase inhibitor–based regimens cannot be used. However, if cheaper and more rapid tropism testing becomes available and if additional studies demonstrate distinctive strengths of the drug related to immune response, metabolic changes, and prevention, one could envision a greater first‐line role for maraviroc—or other CCR5 antagonists—in the future.


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