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Durability and tolerability of first-line combination including two
NRTI and RAL or ATV/r or DRV/r in patients enrolled in the ICONA Foundation Cohort
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Lower Failure and Stopping Rates With RAL Than DRV/r in Large Italian Cohort
HIV Drug Therapy, Glasgow Oct 23-26 2016
Mark Mascolini
People starting their first antiretroviral regimen with raltegravir (RAL) had a lower virologic failure rate (at the 50-copy cutoff) and a lower toxicity discontinuation rate than people starting a darunavir/ritonavir (DRV/r) regimen in a 2200-person Italian ICONA cohort analysis [1]. People starting atazanavir/ritonavir (ATV/r) had a higher toxicity discontinuation rate than the DRV/r group.
In US guidelines DRV/r and integrase inhibitors (including RAL) remain preferred first-line antiretroviral options. Some other countries favor only integrase inhibitors for initial therapy, but the protease inhibitors DRV/r and ATV/r remain popular options because of their potency and high barrier to resistance. ICONA cohort investigators conducted this analysis to compare efficacy and safety of the three regimens tested in the 1809-person ACTG 5257 trial [2]--RAL, DRV/r, and ATV/r--each taken with either tenofovir/emtricitabine or abacavir/lamivudine.
The analysis included all ICONA cohort members who started one of those regimens after January 2008. The primary endpoint was treatment failure defined as a confirmed viral load above 200 copies after 6 months of treatment or discontinuation for any cause. Secondary endpoints were a confirmed viral load above 50 copies after 6 months, discontinuation for any reason, and discontinuation for intolerance or toxicity.
The study group included 1023 people starting DRV/r, 985 starting ATV/r, and 241 starting RAL. Most cohort members, 86.5%, started tenofovir/emtricitabine. Overall median age stood at 40 years, 21% of cohort members were women, and 40% were men who have sex with men. Median pretreatment CD4 count measured 289 and median pretreatment viral load about 79,000 copies.
People starting RAL had the highest median pretreatment CD4 count and the lowest median viral load; those starting DRV/r had the lowest median CD4 count, the highest median viral load, and the largest proportion with AIDS; those starting ATV/r included the lowest proportion of men and began treatment earlier than the other two groups.
Kaplan-Meier analysis discerned no between-group differences in treatment failure (above 200 copies or stopping for any reason). But at 3 years the RAL group had a significantly lower proportion with a viral load above 50 copies than the DRV/r or ATV/r groups (5.5% vs 19.8% vs 19.4%, P = 0.004). Discontinuation for any reason did not differ significantly between groups. But discontinuation for toxicity proved significantly lower with RAL than with DRV/r or ATV/r (5.3% vs 13.0% vs 18.4%, P < 0.001). Toxicity or intolerance explained 12.0% of discontinuations with RAL, 28.7% with DRV/r, and 42.4% with ATV/r. The RAL and DRV/r groups had similar proportions who stopped the regimen to simplify therapy (42.7% and 41.2%), while a lower proportion stopped ATV/r for that reason (22.3%).
To calculate relative hazards of virologic failure or discontinuation, the researchers used Cox regression analysis adjusted for age, gender, nation of birth, HIV transmission mode, hepatitis coinfection, AIDS diagnosis, nucleoside pair, and pretreatment CD4 count and viral load. Compared with people starting DRV/r, those starting ATV/r had a 19% higher risk of a viral load above 200 copies or discontinuation for any reason (adjusted relative hazard [aHR] 1.19, 95% confidence interval 1.04 to 1.36, P = 0.009). Those two regimens did not differ in relative hazard of a viral load above 50 copies. But people starting RAL had almost a 60% lower risk of virologic failure at the 50-copy cutoff than people starting DRV/r (aHR 0.42, 95% CI 0.20 to 0.86, P = 0.018).
Compared with the DRV/r group, the ATV/r group had a 20% higher chance of quitting for any reason (aHR 1.20, 95% CI 1.05 to 1.38, P = 0.008) and a doubled chance of quitting for toxicity (aHR 1.97, 95% CI 1.51 to 2.57, P < 0.001). The RAL group did not differ from the DRV/r group in risk of quitting for any reason but had almost a 60% lower risk of quitting for toxicity (aHR 0.42, 95% CI 0.21 to 0.85, P = 0.017).
Virologic failure rates did not differ substantially between the three regimens in ACTG 5257 [2]. But as in the ICONA analysis, the ACTG trial found higher toxicity discontinuation rates with ATV/r than with DRV/r or RAL, primarily because of hyperbilirubinemia. In the ICONA cohort, hyperbilirubinemia or hepatotoxicity accounted for the most discontinuations with ATV/r (40.5%), compared with gastrointestinal toxicity with DRV/r (30.5%) and allergic reactions/rash with RAL (33.3%).
The ICONA team stressed that comparisons of results in observational cohorts and randomized trials are always difficult because cohort analyses cannot rule out all possible confounding variables or bias "introduced by the subjective nature of the data reported," such as the reason for stopping a drug.
References
1. d'Arminio Monforte A, Lorenzini P, Cozzi-Lepri A, et al. Durability and tolerability of first-line combination including two NRTI and RAL or ATV/r or DRV/r in patients enrolled in the ICONA Foundation cohort. HIV Drug Therapy, Glasgow 2016. October 23-26, 2016. Abstract P021.
2. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461-471.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412467/
Durability and tolerability of first-line combination including two NRTI and RAL or ATV/r or DRV/r in patients enrolled in the ICONA Foundation Cohort
Antonella d'Arminio Monforte, Patrizia Lorenzini, Alessandro Cozzi-Lepri, Cris5na Mussini, Antonella Castagna, Franco Baldelli, Massimo Puo5, Francesco MazzoKa, Nicola Abrescia, Sergio Lo Caputo, Nicola GianoN, Andrea An5nori on behalf of the Icona Founda5on Study Group
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