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48-Week Raltegravir Data Confirm Salvage Potency Across Pretreatment Variables
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
Combined 48-week analysis of the BENCHMRK-1 and -2 placebo-controlled trials found that the integrase inhibitor raltegravir reins in viral replication even in many people with high viral loads, low CD4 counts, and bad resistance profiles--and in most people not starting darunavir or enfuvirtide with raltegravir [1,2].
In his CROI Report for NATAP "ARTs & Clinical Trials" David Margolis MD said:
The 60-65% response rate achieved at weeks 16 and 24 appeared to be stable to 48 weeks, with nearly the full cohort of patients accounted for out to 48 weeks (462 patients on RAL in the studies at entry, 459 reported at 48 weeks).....As in the initial presentations at CROI 2007, 45-50% of patients with no active agents in background therapy (OBT) by genotypic score or by phenotypic score maintained <50 copies/ml at 48 weeks, only a little worse than 50-65% of patients with 1 active agent in OBT.....These results give reason to reconsider the view of raltegravir as a drug with a "low genetic barrier." Clearly, a single mutation results in significant viral resistance to RAL, however RAL appears to behave differently than an NNRTI. It is difficult to imagine that one would see success similar to that seen in BENCHMRK if one had treated patients with PI- and NRTI-resistance with OBT + efavirenz. Certainly, RAL should be used with at least one, if not two, fully active antiviral agents. But if that is not possible, there is still perhaps a nearly 50-50 chance of success.....In another related anecdote of interest, Harris and colleagues reported their experience in patients switched from enfuvirtide to raltegravir while on a virologically suppressive regimen (Abstr. 99). This clinical maneuver may appear attractive to patients having difficulty with continued administration of enfuvirtide. 29 patients had received ENF for 7 to 75 months (median 27.5), and had viral load of <50 copies/mL for 1 to 72 months (median 24) before starting RAL. Viral load remained <50 copies/mL in all patients at all time-points measured: month 1 (n = 21), month 2 (n = 13), month 3 (n = 9), and month 4 (n = 7). At least thus far, this preliminary, limited data suggests that such a switch may be safe."
The BENCHMRK trials randomized people with triple-class resistance and a viral load topping 1000 copies in a 2-to-1 ratio to 400 mg of raltegravir twice daily or placebo plus an optimized background regimen that could include darunavir or tipranavir--protease inhibitors not licensed when the trials began. In BENCHMRK 1 (Europe, Asia/Pacific, Peru), only 6 of 232 raltegravir-treated people (3%) dropped out of the study by week 48, only 4 of them (2%) because of side effects or other complications. In BENCHMRK 2 (North and South America), 18 of 230 people (8%) who started raltegravir dropped out by week 48, 7 of them (3%) because of side effects or complications.
Combined 48-week virologic-failure-carried-forward analyses of the two trials underlined the potency of raltegravir in salvage combinations, even in people with treatment-experience strikes against them when they started this integrase inhibitor with well-picked background drugs:
Percent below 50 copies by baseline CD4s and RNA:
· Pretreatment load above 100,000 copies: 48% raltegravir, 16% placebo
· Pretreatment load at or below 100,000: 73% raltegravir, 43% placebo
· Pretreatment CD4s at or below 50: 50% raltegravir, 20% placebo
· Pretreatment CD4s 50 to 200: 67% raltegravir, 39% placebo
· Pretreatment CD4s above 200: 76% raltegravir, 44% placebo
Percent below 50 copies by resistance score:
· Genotypic sensitivity score (GSS) 0: 45% raltegravir, 3% placebo
· GSS 1: 67% raltegravir, 37% placebo
· GSS 2 or more: 75% raltegravir, 59% placebo
· Phenotypic sensitivity score (PSS) 0 based on lower cutoff: 51% raltegravir, 2% placebo
· PSS 0 based on upper cutoff: 52% raltegravir, 8% placebo
· PSS 1 based on lower cutoff: 61% raltegravir, 29% placebo
· PSS 1 based on upper cutoff: 48% raltegravir, 13% placebo
· PSS 2 or more based on lower cutoff: 71% raltegravir, 48% placebo
· PSS 2 or more based on upper cutoff: 70% raltegravir, 43% placebo
Percent below 50 copies by enfuvirtide and darunavir use:
· With ENF, with DRV: 89% raltegravir, 68% placebo
· With ENF, without DRV: 80% raltegravir, 57% placebo
· Without ENF, with DRV: 69% raltegravir, 47% placebo
· Without ENF, without DRV: 60% raltegravir, 20% placebo
Virologic failure correlated with emergence of one of two primary mutations at position Q148 or N155 in HIV integrase, plus at least one other mutation. But resistance signaled by these mutations did not explain all raltegravir failures. Among 49 BENCHMRK-1 enrollees with pretreatment and failure genotyping, 28 (57%) had either a 148 or 155 mutation. Among 45 genotyped BENCHMRK-2 participants, 29 (64%) had one of those mutations. The remaining 43% in BENCHMRK-1 and 36% in BENCHMRK-2 had other known raltegravir mutations (10% and 4%), genotypic changes with unknown resistance potential (14% and 2%), or no detectable genotypic changes (18% and 29%).
Overall rates of drug-related adverse events stood at 48.7% with raltegravir and 54.2% with placebo after an average 54.5 weeks of follow-up in BENCHMRK-1 and at 60.9% with raltegravir and 56.3% with placebo at an average 51.7 weeks of follow-up in BENCHMRK-2. Dropouts attributed to adverse events stood at 1.7% with raltegravir and 3.4% with placebo in BENCHMRK-1 and at 3.0% with raltegravir and 2.5% with placebo in BENCHMRK-2.
Among 232 raltegravir-treated people in BENCHMRK-1, 8 got a cancer diagnosis for a rate of 3.4 per 100 person-years, compared with 4 of 178 people in the placebo group for a rate of 2.3 per 100-person years. In BENCHMRK-2 cancer developed in 8 of 224 people taking raltegravir for a rate of 3.6 per 100 person-years and in 3 of 91 taking placebo for a rate of 3.3 per 100 person-years. The overall relative risk of cancer with raltegravir versus placebo was 1.5, but that 50% higher risk lacked statistical significance because the 95% confidence interval broadly overlapped 1.0 (0.5 to 6.3).
References
1. Cooper D, Gatell J, Rockstroh J, et al. 48-Week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 788.
2. Steigbigel R, Kumar P, Eron J, et al. 48-Week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 789.
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