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First-Line Once-Daily Maraviroc Plus ATV/r Versus Triple Therapy
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
from Jules: this is a nuke-sparing regimen (MVC+Reyataz/r)
A slightly higher proportion of previously untreated people had an undetectable viral load at 48 weeks with a standard triple regimen of atazanavir/ritonavir plus tenofovir/emtricitabine (TDF/FTC) than with an experimental combination of once-daily maraviroc plus atazanavir/ritonavir [1]. Protocol-defined failures and treatment discontinuations were equal in the two arms of this pilot study.
Maraviroc, a CCR5 antagonist, is licensed at a dose of 150 or 300 mg twice daily, depending upon other drugs being taken, for people with or without antiretroviral experience. The recommended maraviroc dose with atazanavir/ritonavir is 150 mg twice daily.
This phase 2b open-label trial in the United States, Spain, and Germany randomized 121 antiretroviral-naive people to 150 mg of maraviroc once daily plus once-daily atazanavir/ritonavir or to atazanavir/ritonavir plus once-daily TDF/FTC. The study is not powered to show differences between study arms, and the investigators did not calculate comparative statistics.
All study participants were screened to make sure their HIV uses the CCR5 coreceptor, which maraviroc blocks. Enrollees all had a viral load above 1000 copies and a CD4 count above 100; no one had evidence of virus resistant to atazanavir/ritonavir, TDF, or FTC.
Age averaged 38.3 in the maraviroc arm and 35.3 in the TDF/FTC arm. Three quarters of study participants were white, and nearly half were women. Median starting CD4 count was 344 in the maraviroc arm and 358 in the TDF/FTC arm. Starting viral load averaged 4.6 log with maraviroc and 4.7 log with TDF/FTC (40,000 to 50,000 copies). Proportions with a pretreatment viral load above 100,000 copies were 27% in the maraviroc group and 36% in the TDF/FTC group.
The investigators randomized 60 people to maraviroc and 61 to TDF/FTC. Seven dropped out of the maraviroc group, 1 because of "insufficient clinical response" and 2 with adverse events. Seven people also quit the TDF/FTC arm, 1 because of possible TDF-related kidney failure and 1 because of pregnancy.
After 48 weeks, 44 of 59 people assigned to maraviroc (74.6%) and 51 of 61 assigned to TDF/FTC (83.6%) had a viral load under 50 copies. Most people in both arms with a detectable load at week 48 later reached a sub-50 load on the same regimen. At week 48, proportions with a viral load below 400 copies were 89.8% with maraviroc (53 of 59 people) and 86.9% with TDF/FTC (53 of 61 people).
Among people who began treatment with more than 100,000 HIV RNA copies, 11 of 16 (68.8%) in the maraviroc group and 17 of 22 (77.3%) in the TDF/FTC group had a viral load under 50 copies by week 48. Respective proportions in this high viral load group who had fewer than 400 copies at week 48 were 15 of 16 (93.8%) on maraviroc and 19 of 22 (86.4%) on TDF/FTC.
Two people in each arm had protocol-defined treatment failure. Three people in each study group had a viral load above 500 copies at treatment failure or discontinuation and could be genotyped for resistance mutations. No one with protocol-defined failure or who dropped out had evidence of resistance mutations, loss of susceptibility to study drugs, or change in CCR5 coreceptor use. In a last-observation-carried forward analysis, median CD4 gains through 48 weeks were similar with maraviroc (+173 CD4s) and TDF/FTC (+187 CD4s).
More people in the maraviroc group than the TDF/FTC group had grade 3 or 4 adverse events-29 (48%) with maraviroc versus 18 (29.5%) with TDF/FTC. But most of these problems were hyperbilirubinemia, which is usually associated with atazanavir. Ten people in the maraviroc arm and 12 in the TDF/FTC arm had a serious adverse event, but none of these problems were judged to be related to study drugs. Creatinine clearance, a signal of kidney function, remained stable in the maraviroc group while falling a median of 12 mL/min in the TDF/FTC group.
A phase 3 trial will pair once-daily maraviroc with darunavir/ritonavir and compare that regimen to darunavir/ritonavir plus TDF/FTC.
In a discussion after presentation of these results, Scott Letendre (University of California, San Diego) cautioned that nucleoside-sparing two-drug combinations may sacrifice some brain-penetrating potential. The standard triple regimen in the pilot study, atazanavir/ritonavir plus TDF/FTC, would have a central nervous system penetration effectiveness (CPE) score of 6 [2]. Twice-daily maraviroc plus atazanavir/ritonavir would tally a CPE score of 5, but maraviroc once-daily (that is, 150 versus 300 mg daily) plus atazanavir/ritonavir may not do as well crossing the blood-brain barrier.
References
1. Portsmouth S, Craig C, Mills A, et al. 48-week results of a dual-therapy regimen of once-daily maraviroc (MVC) 150 mg in combination with ritonavir-boosted atazanavir (ATV/r) compared to emtricitabine/tenofovir (FTC/TDF) + ATV/r in treatment-naïve (TN) patients infected with CCR5-tropic HIV-1 (Study A4001078). 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract TUAB0103.
2. Letendre S, FitzSimons C, Ellis R, et al, and the CHARTER Group. Correlates of CSF viral loads in 1221 volunteers of the CHARTER cohort. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 172.
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