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Maraviroc Plus Darunavir Vulnerable With Pretreatment Load Above 100,000?
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(from Jules: we need to be careful about eliminating nukes from therapy, i have concerns that eliminating nukes may cause more problems than using nukes)
XIX International AIDS Conference, July 22-27, 2012, Washington, DC
Mark Mascolini
Three of four virologic failures after 48 weeks of a pilot study combining maraviroc with darunavir/ritonavir as a once-daily first-line regimen occurred in people with a pretreatment viral load above 100,000 copies [1]. Everyone with virologic failure in this 24-person trial reported perfect antiretroviral adherence.
As the quest for a nucleoside-sparing two-drug regimen continues, researchers are finding that some such combinations do not measure up to standard triple therapy. Another study presented at this International AIDS Conference found moderately lower 48- and 96-week response rates with once-daily maraviroc plus atazanavir/ritonavir versus tenofovir/emtricitabine plus those protease inhibitors (reviewed separately by NATAP) [2].
The maraviroc-darunavir trial is a multicenter, single-arm, open-label 96-week pilot study that enrolled antiretroviral-naive adults with a viral load between 5000 and 500,000 copies and a CD4 count above 100. Everyone had HIV that could use the CCR5 receptor, which maraviroc blocks, or had enhanced sensitivity on the Trofile assay. Study participants could not have darunavir-associated resistance mutations, but they could have single or combination nonnucleoside and nucleoside mutations.
Twenty-five people enrolled, but 1 never took study drugs and is not included in this analysis. The other 24 people completed 48 weeks of treatment with 150 mg of maraviroc plus 800/100 mg of darunavir/ritonavir once daily. Median age was 38 years, 22 participants were men, and 15 were white. Median pretreatment CD4 count stood at 455 and median viral load at 42,050 copies. Four people (17%) had a pretreatment load above 100,000 copies. Twenty people had no pretreatment mutations, and only 1 had a protease inhibitor mutation, D30N, associated with resistance to nelfinavir.
With a target virologic response of fewer than 50 copies, 3 of 24 people (12.5%) had confirmed virologic failure by week 24, and 4 (16.7%) had confirmed failure by week 48. Three of the four people with virologic failure had a pretreatment viral load above 100,000 copies, and a load above 100,000 was significantly associated with virologic failure (P = 0.008). Two people with virologic failure never got their viral load below 50 copies, while the other 2 did then rebounded.
Everyone with virologic failure reported perfect adherence to study drugs, and none had pretreatment resistance mutations.
Geometric mean maraviroc trough concentrations lay between 24 and 39 ng/mL and were similar in people with and without virologic failure. These concentrations are consistent with those recorded in other studies of maraviroc dosed at 150 mg once daily with a ritonavir-boosted protease inhibitor. Maraviroc levels are also consistent with those seen when the drug is taken at the licensed dose of 300 mg twice daily without inducers or inhibitors.
CD4 counts rose by a median of 117 (interquartile range 64 to 202) at week 24 and 247 (interquartile range 119 to 340) by week 48. One person had a grade 3 elevation in low-density lipoprotein cholesterol.
The researchers suggested that "these findings should be evaluated with caution in larger randomized studies." A phase 3 trial comparing maraviroc plus darunavir/ritonavir with tenofovir/emtricitabine plus those protease inhibitors is being planned.
References
1. Taiwo B, Swindells S, Berzins B, et al. Week 48 results of the Maraviroc Plus Darunavir/ritonavir Study (MIDAS) for treatment-naive patients infected with R5-tropic HIV-1.. XIX International AIDS Conference. July 22-27, 2012, Washington, DC. Abstract TUPE099.
2. Mills A, Mildvan D, Podzamczer D, et al. Once-daily maraviroc in combination with ritonavir-boosted atazanavir in treatment-naive patients infected with CCR5-tropic HIV-1 (study A4001078): 96-week results. XIX International AIDS Conference. July 22-27, 2012, Washington, DC. Abstract TUAB0102.
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