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Potent Multidrug Salvage Without PIs or NRTIs: Raltegravir + Maraviroc + Etravirine
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
People with a record of triple-class failure responded well--virologically and immunologically--to 24 weeks of raltegravir, maraviroc, and etravirine without a protease inhibitor (PI) or nucleoside (NRTI) [1]. Other heavily pretreated people responded well to raltegravir and maraviroc or etravirine plus NRTIs, to raltegravir and maraviroc or etravirine plus a ritonavir-boosted PI, and to raltegravir plus a PI/NRTI mix. But none of these other regimens boosted CD4 cells nearly as high as raltegravir, maraviroc, and etravirine.
Results of this single-center nonrandomized study may not apply equally to all HIV clinics, but they offer perspective on the salvage possibilities with an integrase inhibitor (raltegravir), a CCR5 antagonist (maraviroc), and a nonnucleoside with activity against some nonnucleoside-resistant virus (etravirine). As the investigators noted, however, a maraviroc-raltegravir interaction study in healthy volunteers yielded some surprises and indicates an urgent need to study this combination more closely.
Choosing regimens on the basis of genotype, resistance history, and HIV coreceptor use, clinicians at Milan's San Raffaele clinic put 28 people on raltegravir, maraviroc, and etravirine (group 1), 20 on a PI-sparing regimen with raltegravir plus maraviroc or etravirine (group 2), 28 on raltegravir plus maraviroc or etravirine plus a ritonavir-boosted PI (group 3), and 19 on raltegravir plus a boosted PI and other drugs, but not maraviroc or etravirine (group 4). The study group averaged 45 years in age and three quarters were men. They had been infected for an average of 15.9 years and treated for 13.1 years. The group's average nadir CD4 count was 88, their current CD4 count 275, and their current viral load 4.12 log (about 15,000 copies).
All 95 people took their regimen for 24 weeks and at that point 24 in group 1 (85.7%), 18 in group 2 (90%), 22 in group 3 (78.5%), and 15 in group 4 (78.9%) had a viral load under 50 copies. People taking just raltegravir, maraviroc, and etravirine (group 1) had significantly better 24-week CD4 gains than any of the other groups:
Average CD4 gains through 24 weeks
· Group 1: 216.5 +/- 33.4 CD4s
· Group 2: 115.0 +/- 40.6 CD4s (P = 0.056 versus group 1)
· Group 3: 87.4 +/- 29.8 CD4s (P = 0.005 versus group 1)
· Group 4: 106.3 +/- 39.8 CD4s (P = 0.042 versus group 1)
Multivariate analysis determined that group 1 patients had an adjusted average CD4 gain of 110.3 cells compared with group 4; group 2 patients had an adjusted average 8.76-cell gain compared with group 4; and group 3 had an adjusted average 18.8-cell loss compared with group 4. It's hard to say whether this greater CD4 gain in group 1 is clinically meaningful, except perhaps to people at the lower end of the CD4 range in this study (about 75 CD4s in group 1). The San Raffaele team did not speculate on why raltegravir-maraviroc-etravirine had such a profound impact on CD4 cells in their patients. (from Jules: this may be in part due to the boost in CD4s being seen by maraviroc. We have seen reports by Pfizer researchers recently at ICCAC on the higher CD4 boost by maraviroc seen in their large clinical studies, and more research is planned to understand and characterize the CD4 boost reported with maraviroc).
People infected with HIV sexually had an adjusted average gain of 71.8 CD4 cells compared with injecting drug users. And people with a lower viral load when they began their salvage regimen gained more CD4 cells than people with higher viral loads. (The investigators did not specify the viral load decrement used in this analysis.)
A recent drug-interaction study of raltegravir plus maraviroc in healthy volunteers found a lower maraviroc maximum concentration and area under the curve, and a lower raltegravir trough concentration and area under the curve, when these drugs are taken together [2]. The investigators concluded that the interactions are "not likely to be clinically relevant" and that no dose adjustment is needed. However, HIV pharmacology maven Stephen Becker noted in a review for NATAP that the wide variability in raltegravir concentrations with maraviroc was unexpected and requires further study [3]. Two of the 17 volunteers had "striking reductions" in raltegravir troughs, one of 76% and the other of 69%. But 3 volunteers had higher raltegravir concentrations with maraviroc than without maraviroc.
References
1. Nozza S, Visco F, Soria A, et al. Excellent short-term CD4 recovery with a PI- and NRTI-sparing regimen in triple-class failure HIV-infected people: raltegravir, maraviroc, etravirine. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract P045.
2. Andrews E, Glue P, Fang J, et al. A pharmacokinetic study to evaluate an interaction between maraviroc and raltegravir in healthy adults. 48th ICAAC. October 25-28, 2008. Washington, DC (http://www.natap.org/2008/ICAAC/ICAAC_36.htm).
3. Becker S. The maraviroc and raltegravir interaction: do we know how to dose when using these two important agents? NATAP. November 2008.
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