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Raltegravir non-inferior to efavirenz: 48 week, phase III results
Derek Thaczuk, Monday, October 27, 2008
Raltegravir (Isentress), the new integrase inhibitor manufactured by Merck, showed equivalent anti-HIV activity to efavirenz during the first 48 weeks of a large phase III trial in treatment-naive patients, and those who received raltegravir had greater increases in CD4 counts and fewer central nervous system symptoms, delegates heard at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy on Sunday in Washington DC.

Several ongoing trials are comparing raltegravir to efavirenz in combination with other antiretroviral agents in first-line treatment. Results of a phase II trial recently reported in Mexico City found favourable tolerability for raltegravir and "almost identical" efficacy results in a group of just under 200 patients after 96 weeks.

In the STARTMRK study, investigators compared raltegravir (Isentress)-based regimes with those based upon efavirenz (Sustiva) in a larger group of patients starting HIV treatment for the first time. The STARTMRK participants were randomised to receive either raltegravir (400 mg, twice daily) or efavirenz (600 mg daily) in combination with tenofovir and FTC.

A total of 563 patients were treated, 281 with raltegravir and 282 with efavirenz. The study was blinded and lasted 48 weeks. All the patients were treatment-naïve and had a viral load above 5000 copies/ml; none had primary resistance to efavirenz, tenofovir, or FTC. The raltegravir and efavirenz groups were very similar in terms of age (mean, 37 vs. 38 years), sex (81 vs. 82% male), race (59 vs. 56% non-white), mean baseline viral load (103,205 vs. 106,215 copies/ml), and CD4 cell count (219 vs. 217 cells/mm3.

The primary end-point of the study was the proportion of patients in each of the study arms with a viral load below 50 copies/ml at the end of the study. The study was intended to show non-inferiority of raltegravir to efavirenz within +/- 12%. Data were also gathered on changes in CD4 cell count and on side-effects (in particular, CNS side effects at the eight-week point).

In an intent-to-treat analysis (which counted patients who withdrew from the study for any reason as treatment failures), at week 48, viral loads < 50 copies/ml were achieved in 86% of patients on raltegravir and 82% of those on efavirenz. The difference between the two was 4.2% (95% confidence interval [CI], -1.9 to 10.3%), demonstrating, as intended, that raltegravir was virologically non-inferior to efavirenz. Patients who achieved an undetectable viral load did so significantly faster with raltegravir than with efavirenz (p < 0.001).

By the end of the study, mean CD4 cell count increases were 189 cells/mm3 in the raltegravir treated patients compared to 163 cells/mm3 amongst those who were treated with efavirenz.

Virologic failures were relatively infrequent in both arms; no new raltegravir-associated resistance mutations were identified in the people who failed virologically during this study.

Overall, adverse events were reported by nearly all patients in this study (90% with raltegravir vs. 96% with efavirenz; p=0.002). Adverse events judged to be drug related were less common with raltegravir than efavirenz, both at all degrees of severity (44% vs. 77%; p<.001) and for moderate/severe AEs only (16% vs. 32%, p<.001). Individual moderate/severe side-effects were, respectively: headache (3.9% vs. 4.6%), nausea (2.8% vs. 3.5%), dizziness (1.4% vs. 6.4%), insomnia (3.6% vs. 3.2%), diarrhea (1.1% vs. 2.8%), fatigue (1.4% vs. 2.8%), rash (0.0% vs. 2.8%) and maculo-papular rash (0.0% vs. 2.5%).

One of the planned study outcomes was a comparison of central nervous system (CNS) side-effects during the first eight weeks of treatment. By week eight, at least one CNS symptom had occurred in significantly more efavirenz than raltegravir recipients (52% vs. 20%, p<0.001). (One delegate asked to what extent these symptoms persisted later into the study, as efavirenz-associated CNS symptoms are often seen to lessen after the initial eight weeks of therapy; however, these data was not provided.)

Serious clinical events were similar for both (10% each, p=0.89). Two deaths (0.7%) occurred in patients on raltegravir, and none on efavirenz. Cancer occurred in 1 raltegravir (0.4%) and a surprising 9 (3.2%) efavirenz recipients, two of the cancers in the efavirenz-treated patients were thought to be treatment-related, although this was not elaborated on in the presentation.

The investigators also found that treatment with raltegravir was associated with smaller increases in LDL-cholesterol (5.9 mg/dl vs. 16.1 mg/dl), total cholesterol (10 mg/dl vs. 32.7 mg/dl) and triglycerides (-2.8 mg/dl vs. +37.4 mg/dl) than efavirenz (p < 0.001 for each measure). Efavirenz had a better effect on HDL-cholesterol (often called “good cholesterol”), which increased modestly in both groups of patients, but more so in the efavirenz-treated group (10.0 mg/dl vs. 4.2 mg/dl; p < 0.001). Numeric data on visible body fat changes were not presented, but changes were described as minimal to unobservable for all participants; detailed data will be presented at a later date.

In a press release accompanying the study presentation, Robin Isaacs MD of Merck Research Laboratories said: "These findings reinforce the efficacy and safety data seen with Isentress in Phase II trials in treatment-naïve patients, and are consistent with efficacy already established in treatment-experienced patients for whom it is currently approved. Viral load reductions and CD4 cell count increases were sustained through 48 weeks in this study."


Reference

Lennox J. et al. STARTMRK, a phase III study of the safety and efficacy of raltegravir-based vs. efavirenz-based combination therapy in treatment-naïve HIV-infected patients. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract H-896a, Washington, 2008.