HIV‐1 Infection. Part 2

Maraviroc must be given twice daily—a once‐daily dosing strategy in MERIT was stopped prematurely because insufficient virologic response—whereas most of the other first‐line treatments in wide use are given once a day. In addition, the nucleoside reverse‐transcriptase inhibitors (NRTIs) chosen for the study were zidovudine plus lamivudine, a combination no longer considered to be a preferred NRTI pair for initial therapy because of inferior tolerability and safety compared with abacavir‐lamivudine or tenofovir‐emtricitabine. Although there is no specific reason to believe that maraviroc with these newer NRTIs would be ineffective, study data on these combinations in treatment‐naive patients are not available.

An additional concern about the use of maraviroc for initial therapy relates to the mechanism of action of CCR5 antagonists. When virologic failure occurs, CCR5 antagonist use can result in the predominant circulating viruses being X4 strains, which likely arise from low levels of variants not detected before therapy. Both detection of X4 viruses in untreated patients and the switch from R5 to X4 have been associated with more rapid HIV disease progression. Fortunately, studies of patients treated with CCR5 antagonists do not show that emergence of X4 viruses leads to more rapid CD4 cell depletion, but the long‐term effects of the selection of a predominant X4 strain will bear ongoing monitoring.

CCR5 antagonists exert their antiviral effect through binding to a transmembrane CCR5 coreceptor pocket; they are therefore unique among available antiretroviral agents in having a cellular rather than a viral target. Congenital absence of the CCR5 receptor with Δ32 homozygosity appears to have a generally benign clinical course, but it is not known whether pharmacologic blockage of this receptor will have different long‐term effects. Indeed, the reporting of more severe West Nile and tickborne encephalitis virus infections among individuals with the Δ32 mutation [9, 10] raises the possibility that CCR5 antagonists will have potential immunomodulatory effects, some of which may be deleterious. For now, safety concerns related to this class of drugs (and maraviroc in particular) have been mostly reassuring, but in one study of the investigational CCR5‐antagonist vicriviroc more cancers were reported in those receiving the drug than in the comparator arm; importantly, the relationship between this treatment and the specific cancers diagnosed remains unknown.

With these concerns, might there still be a place for maraviroc (and potentially other CCR5 antagonists) as part of initial therapy? Aside from the narrow miss on the protocol’s 10% noninferiority threshold for virologic failure, additional data from the MERIT study are quite supportive, and the distinctive mechanism of action of the drug class may incur benefits outside of antiviral activity alone. Of critical importance to predicting the virologic efficacy of the drug was the subsequent development of an improved Trofile assay that is 10–100‐fold more sensitive in detecting minor X4 populations. Indeed, when this enhanced sensitivity tropism assay was retrospectively applied to the original 721 treated patients in MERIT, 107 were excluded as a result of having detectable X4 virus; the virologic response for the remaining 614 treated study subjects yielded a noninferior result for the maraviroc arm. Although the current Trofile assay will exclude a greater proportion of patients from receiving the drug—perhaps even some with such low levels of X4 virus that they could respond to maraviroc—clinicians can now prescribe maraviroc with much greater confidence that it will be a virologically active agent. In light of these retrospective data, in 2009 the FDA granted approval of maraviroc for first‐line treatment of HIV‐1 infection.

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