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First-Line Darunavir/Raltegravir Riskier With Viral Load Above 100,000
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
People who began a first-line nucleoside-free regimen of darunavir/ritonavir plus raltegravir with a viral load above 100,000 copies ran a higher risk of virologic failure and raltegravir resistance than if they started with a lower viral load [1]. At week 48 of this single-arm study by the AIDS Clinical Trials Group (ACTG), one quarter of study participants had protocol-defined virologic failure, a rate higher than those seen with first-line triple-drug combinations including once-daily darunavir/ritonavir [2] or raltegravir [3].
The primary objective of this 52-week 112-person trial was to estimate the cumulative proportion of previously untreated people with virologic failure within 24 weeks of starting a first-line regimen consisting of 800/100 mg of darunavir/ritonavir once daily plus 400 mg of raltegravir twice daily. The ACTG team defined virologic failure as (1) a confirmed viral load above 1000 copies by week 12, or (2) a confirmed half-log or greater viral rebound from the week 4 viral load at week 12 (or a rebound above 50 copies if below 50 copies at week 4), or (3) a confirmed viral load above 50 copies by week 24.
Study participants had to be 18 or older with a viral load at or above 5000 copies. They could have no integrase inhibitor mutations and no more than one darunavir resistance mutation, but they could have pretreatment mutations to nucleosides or nonnucleosides. Three of 112 study participants had protease inhibitor mutations when the study began. People with renal dysfunction not requiring dialysis were eligible for the trial.
The ACTG team enrolled 113 people, but 1 did not start treatment. Median age was 36 years (interquartile range 27 to 45), 98 (88%) were men, 49 (44%) were white, 40 (36%) had a CD4 count under 200, and 49 (44%) had a viral load above 100,000. Fifteen people (13% of 112) dropped out early: 7 could not get to the clinic, 4 could not be contacted, 2 withdrew consent, 1 could not comply with study requirements, and 1 died with cryptosporidiosis.
Through 24 weeks of treatment, 17 people (15% of 112) met protocol-defined virologic failure criteria, including 11 whose regimen failed to control viral replication and 6 whose viral load rebounded after initial control. By week 48 there were 11 additional rebounds for a cumulative failure rate of 25%. In an intention-to-treat analysis that ignored missing data or off-study patients, 79% had a viral load below 50 copies at week 24 and 71% had a sub-50 load at week 48.
Statistical analysis that factored in age and gender determined that a pretreatment viral load above 100,000 copies nearly quadrupled the risk of virologic failure (hazard ratio [HR] 3.76, 95% confidence interval [CI] 1.52 to 9.31, P = 0.004). Every 100-cell higher pretreatment CD4 count lowered the risk of failure almost 25% (HR 0.77, 95% CI 0.61 to 0.98, P = 0.037).
The researchers could genotype virus from 25 of 28 people with virologic failure. They detected raltegravir-related mutations in 5 people (20%), all of whom began treatment with a viral load above 100,000 copies. Substitutions at integrase position N155 could be detected in all 5, and 2 had Q148 changes. One of these 5 also had the nucleoside mutation M41L.
Twenty-two study participants (20%) had a grade 3 or 4 adverse event, 5 possibly related to study drugs. Three people changed or stopped treatment because of adverse events. Fasting total, high-density lipoprotein, and low-density lipoprotein cholesterol, and fasting lipids, all rose significantly by week 48.
References
1. Taiwo B, Zheng S, Gallien S, et al. Results from a single arm study of DRV/r + RAL in treatment-naive HIV-1-infected patients (ACTG A5262). 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 551. Poster online at http://www.retroconference.org/2011/PDFs/551.pdf.
2. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008;22:1389-1397.
3. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374:796-806.
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