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AIDS 2012: Raltegravir Remains Effective and Well-tolerated at 5 Years

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The HIV integrase inhibitor raltegravir (Isentress) continued to demonstrate good efficacy as part of a first-line antiretroviral regimen and had a consistently favorable safety profile at 240 weeks in the STARTMRK trial, researchers reported at the recent XIX International AIDS Conference (AIDS 2012) in Washington, DC.Another long-term analysis showed continued efficacy for treatment-experienced patients with extensive drug resistance.

[Editor's note: This article has been corrected. In the second to last paragraph, exposure-adjusted rates of drug-related clinical adverse events in BENCHMRK were 20 vs 37 per 100 patient-years.]

Current antiretroviral therapy (ART) is expected to be life-long, so it is important to collect data on long-term effectiveness and safety. The Phase 3 STARTMRK study was among the longest of its type, with randomized treatment assignments remaining blinded through 240 weeks.

Treatment-naive

As described in a late-breaker poster by Jürgen Rockstroh from the University of Bonn and colleagues, 563 treatment-naive adults with HIV in North and South America, Europe, and Southeast Asia were randomly assigned to start a regimen containing 400 mg twice-daily raltegravir or 600 mg once-daily efavirenz, both in combination with tenofovir /emtricitabine (the drugs in Truvada).

Most STARTMRK participants (about 80%) were men, about 40% were white, and the average age was approximately 37 years. About half had CD4 cell counts below 200 cells/mm3 at enrollment. They were not resistant to the study drugs at baseline.

The primary endpoint was HIV RNA < 50 copies/mL at 48 weeks (non-completer = failure), with a secondary analysis week 96 and exploratory follow-up at 240 weeks.

Results

  • At 48 weeks, raltegravir was shown to be non-inferior to efavirenz, with 86.1% and 81.9%, respectively, in the 2 arms achieving undetectable viral load.
  • At 96 weeks, the corresponding virological response rates were 81.1% and 78.7, respectively.
  • By 192 weeks, response rates had slipped to 76.2% and 67.0%, respectively.
  • At the final analysis at 240 weeks, response rates were 71.0% with raltegravir and 61.3% with efavirenz, a difference that now met the criteria for superiority.
  • CD4 T-cell gains at 48 weeks were 189 cells/mm3 in the raltegravir arm and 163 cells/mm3 in the efavirenz arm.
  • By 240 weeks, CD4 cell gains had risen to 374 and 312 cells/mm3, respectively.
  • 25% of raltegravir recipients and 35% of efavirenz recipients discontinued the study before 240 weeks.
  • Both raltegravir and efavirenz were generally well-tolerated over the long term, though side effects were common.
  • Significantly fewer people in the raltegravir arm experienced drug-related clinical adverse events overall (52% vs 80%, respectively):

o   Nausea: 8.9% vs 10.3%, respectively;

o   Diarrhea: 5.0% vs 9.6%, respectively;

o   Nervous system symptoms: 18.1% vs 49.5%, respectively;

o   Dizziness: 7.8% vs 35.1%, respectively;

o   Abnormal dreams: 6.8% vs 13.1%, respectively;

o   Psychiatric disorders: 18.5% versus 30.9%, respectively;

o   Skin side effects: 5.3% versus 22.3%

  • 5% of raltegravir recipients and 9% of efavirenz recipients discontinued therapy due to adverse events.
  • Raltegravir was associated with smaller increases in total cholesterol, LDL "bad" cholesterol, and triglycerides, but also HDL "good" cholesterol.

"In this exploratory analysis of combination therapy with [tenofovir/emtricitabine] in treatment-naive patients at Week 240, the [HIV RNA] suppression rate was significantly higher with raltegravir than with efavirenz," the investigators summarized. "Generally consistent virologic and immunologic effects between treatment groups were maintained within the examined demographic subpopulations and prognostic subgroups at baseline."

"Follow-up at 4 and 5 years suggest that raltegravir/[tenofovir/emtricitabine] was superior to efavirenz/[tenofovir/emtricitabine] in terms of better virologic and immunologic efficacy," they continued. "Over the course of the entire 5-year study, raltegravir-based therapy had a consistently favorable safety profile compared with efavirenz-based therapy."

Raltegravir/tenofovir/emtricitabine "offers a efficacious and well-tolerated option for the initial therapy of treatment-naive HIV-patients irrespective of baseline viral load and CD4-cell count," they concluded.

While efficacy and safety of the 2 drugs were similar during the first 3 years of the study, by 5 years the advantage of raltegravir had widened enough to meet statistical criteria for considering raltegravir superior, rather than simply non-inferior, to efavirenz.

Treatment-experienced

The BENCHMRK studies -- which compared 400 mg twice-daily raltegravir plus optimized background therapy (OBT) versus placebo plus OBT -- found that raltegravir also showed continued efficacy at 5 years for a substantial proportion of treatment-experienced patients with highly resistant HIV.

A total of 352 patients mainly in Europe and Asia were enrolled in BENCHMRK-1 and 351 participants in North and South America were enrolled in BENCHMRK-2. Nearly 90% were men, the average age was 45, and they had a low median CD4 cell count of approximately 120 cells/mm3. Their current antiretroviral regimen was failing and they were resistant to 3 antiretroviral drug classes.

Participants were randomly assigned (2:1) to blinded treatment with raltegravir or placebo for 156 weeks, after which all patients received open-label raltegravir

People randomized to raltegravir "maintained superior response rates" compared with placebo through 5 years of treatment, Joseph Eron and colleagues reported.

In this difficult-to-treat population, 42% of raltegravir recipients had HIV RNA < 50 copies/mL, compared with just 16% of placebo recipients. Results were similar (45% vs 17%, respectively) for viral load < 400 copies/mL.

Mean CD4 cell gains were 183 vs 61 cells/mm3, respectively, in the 2 arms, but reached the 200s for people who maintained continuous viral suppression or only low-level viremia. Exposure-adjusted rates of drug-related clinical adverse events over the entire study period were 20 vs 37 per 100 patient-years, respectively.

"In patients failing ART with 3-class resistant HIV, raltegravir maintained favorable efficacy and safety profiles over 5 years of treatment," the BENCHMRK researchers concluded. "Viral suppression and CD4 increases were maintained in the majority of patients on raltegravir in both the low-level viremia and continuous suppression groups."

8/7/12

References

J Rockstroh, E deJesus, M Saag, et al. Long-term safety and efficacy of raltegravir (RAL)-based versus efavirenz (EFV)-based combination therapy in treatment-naive HIV-1-infected patients: final 5-year double-blind results from STARTMRK. XIX International AIDS Conference (AIDS 2012).  Washington, DC, July 22-27, 2012. Poster LBPE19.

J Eron, D Cooper, R Steigbigel, et al (BENCHMRK-1 and 2 Study Groups). Final five-year results of the BENCHMRK studies: sustained antiretroviral effect of raltegravir and exploratory analysis of late outcomes based on early virologic response. XIX International AIDS Conference (AIDS 2012).  Washington, DC, July 22-27, 2012. Poster TUPE025.

Other Source

Merck. ISENTRESS (raltegravir) in Combination Therapy Demonstrated Long-Term Efficacy, Safety and Tolerability in Previously Untreated Adult Patients with HIV-1 for up to 240 Weeks. Press release. July 22, 2012.