Raltegravir (Isentress) Activity Is Durable at 96 Weeks; Switch from Lopinavir/ritonavir Results in More Viral Breakthrough but Better Lipid Profiles

		SUMMARY: At 96 weeks, the integrase inhibitor raltegravir (Isentress) in combination with optimized background therapy (OBT) continued to demonstrate superior antiviral efficacy compared with OBT alone in highly treatment-experienced patients in the BENCHMRK trials. In the SWITCHMRK trials, however, people who switched from lopinavir/ritonavir (Kaletra) to raltegravir were more like to experience virological failure, though they also had improved blood lipid profiles.

By Liz Highleyman

BENCHMRK

BENCHMRK-1 and -2 were identical double-blind Phase 3 trials evaluating the safety and efficacy of raltegravir in people with extensively drug-resistant HIV. BENCHMRK-1 (Merck protocol MK-0518) was conducted in Europe, Asia, Australia, and Peru, while BENCHMRK-2 (MK-0518) was conducted in North and South America.

In the 2 studies combined, 699 participants with triple-class-resistant HIV and prior antiretroviral therapy (ART) failure were randomly assigned to receive 400 mg twice-daily raltegravir or placebo (2:1 ratio) in combination with OBT for 48 weeks. Most were white man and more than 90% had a current or past AIDS diagnosis.

As previously reported in the July 24, 2008 New England Journal of Medicine, raltegravir plus OBT provided significantly better viral suppression than placebo plus OBT at 48 weeks, with 62% in the raltegravir arms compared with 33% in the placebo arms achieving HIV RNA < 50 copies/mL. Mean CD4 cell gains were 109 versus 45 cells/mm3, respectively.

Now, in the January 19, 2010 advance online issue of Clinical Infectious Diseases, the BENCHMRK Study Teams have published 96 week follow-up data from the 2 trials.

From study weeks 16 to 48, virological failure was defined as < 1 log10 decrease in HIV RNA levels from baseline, confirmed > 1 log10 increase in HIV RNA from nadir (lowest-ever level), or 2 consecutive HIV RNA measurements >400 copies/mL after a prior result < 400 copies/mL. After week 48, it was defined as confirmed HIV RNA level >50 copies/mL (2 consecutive measurements at least 1 week apart).

Participants who experienced virological failure at any time after week 16 were given the choice to exit the double?blind study and enter an open?label phase to receive raltegravir, remain in the blinded study, or withdraw altogether; 65% of raltegravir recipients and 29% of placebo recipients opted to stay in the double-blind study.

Results

	Virological and immunological responses were consistent between the 2 BENCHMRK studies at week 96.
	In the combined studies, 57% of raltegravir recipients had sustained HIV RNA < 50 copies/mL at week 96, compared with 26% of placebo recipients (P < 0.001).
	33% of raltegravir recipients and 62% of placebo recipients experienced virological failure by week 96.
	The mean change in viral load from baseline to week 96 was significantly greater in the raltegravir arm than in the placebo group (-1.5 vs -0.6 log10 copies/mL, respectively; P < 0.001).
	The mean CD4 cell increase was also larger in the raltegravir arm (123 vs 49 cells/mm3, respectively; P < 0.001).
	There was a non-significant trend toward lower rates of AIDS?defining illness and mortality in the raltegravir arms.
	Among the 192 patients who entered the open?label phase after virological failure, 15% of those originally randomized to receive raltegravir and 43% originally assigned to placebo achieved HCV RNA < 50 copies/mL.
	Genotypic testing revealed that virus from 65% of patients with treatment failure had integrase resistance mutations
	Frequencies of drug-related clinical adverse events (33% in the raltegravir arms vs 52% in the placebo arms) and grade 3-4 laboratory abnormalities were statistically similar between the 2 groups.
	Creatine kinase elevations were slightly more common in the raltegravir arms, but were not associated with clinical muscle damage.

Based on these findings, the BENCHMRK investigators concluded, "At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone."

"Although the BENCHMRK studies were not powered to show statistically significant effects within subgroups, efficacy analyses by baseline prognostic factors continued to demonstrate a consistent treatment advantage of raltegravir over placebo, even in patients with high baseline HIV RNA levels or low baseline CD4 cell counts," they elaborated in their discussion.

"Raltegravir also demonstrated superior efficacy, compared with placebo, in patients who received OBT and had genotypic and/or phenotypic sensitivity scores of 0 -- generally regarded as the most challenging treatment scenario," they continued. "Among patients who received new, active antiretroviral therapy in their OBT, up to 79% of raltegravir recipients had undetectable HIV RNA levels at week 96."

Overall, they summarized, "these data demonstrate that raltegravir has a potent antiviral effect in most patients with few or no remaining treatment options and has even greater efficacy when used in combination with other active antiretroviral agents."

SWITCHMRK

While BENCHMRK showed that raltegravir has superior efficacy compared with placebo in heavily treatment-experienced patients, a more challenging -- and clinically relevant -- comparison is whether it works as well as the standard of care or best currently approved therapy.

Even people who are doing well on their current regimen may wish to switch to something new, for example to improve convenience or reduce side effects. The SWITCHMRK studies looked at maintenance of virological suppression among patients who substituted raltegravir for lopinavir/ritonavir, which can cause blood lipid abnormalities associated with increased cardiovascular risk. (Darunavir [Prezista] was not yet widely used when SWITCHMRK was designed.)

SWITCHMRK 1 and 2 were again identical double-blind Phase 3 trials. SWITCHMRK 1 (Merck protocol 032) included participants in North America, Europe, and Australia, while SWITCHMRK 2 (protocol 033) included participants from these same industrialized areas as well as Latin America, Africa, and Southeast Asia. About 80% of participants in both studies were men; about 17% in SWITCHMRK 1 and about 52% in SWITCHMRK 2 were of non-white race/ethnicity.

Study participants had maintained viral suppression < 50 copies/mL for at least 3 months on a stable ART regimen containing lopinavir/ritonavir. Overall, they had mild immune deficiency, with a median CD4 count of about 475 cells.mm3. Past treatment failures were permitted.

A total of 707 participants were randomly assigned (1:1 ratio) to either remain on the same regimen or to replace 400/100 mg twice-daily lopinavir/ritonavir with 400 mg twice-daily raltegravir; 702 patients received at least 1 dose and were include in the combined analysis. Participants stayed on the same background therapy, which included at least 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) (i.e., the background regimen was not optimized at the time of randomization).

As previously reported at the 2009 Conference on Retroviruses and Opportunistic Infections, the trials were halted at 24 weeks after data showed that raltegravir did not demonstrate non-inferiority compared with lopinavir/ritonavir. Complete study findings have now been published in the January 13, 2010 advance online issue of The Lancet.

Results

	At week 24 in a non-completer=failure analysis, 84% of patients in the raltegravir arms maintained HIV RNA < 50 copies/mL, compared with 91% in the lopinavir/ritonavir arms.
	The treatment difference of -6.2% did not meet the pre-set non-inferiority threshold of -12%.
	However, in an unplanned post hoc analysis that excluded patients with a history of treatment failure (about one-third in both treatment groups), efficacy was similar in raltegravir and lopinavir/ritonavir arms (89% vs 90%).
	Changes in lipid levels from baseline to week 12 were significantly more favorable in the raltegravir arms than in the lopinavir/ritonavir arms (P < 0.0001):
	total cholesterol: -12.6% vs +1.0%, respectively; non-HDL ("bad") cholesterol: -15.0% vs +2.6%, respectively; triglycerides: -42.2% vs +6.2%, respectively.
	Clinical and laboratory adverse events occurred with statistically similar frequencies in the raltegravir and lopinavir/ritonavir arms.
	The only moderate-to-severe drug-related adverse event reported by 1% of either treatment group was diarrhea (no raltegravir recipients vs 3% of lopinavir/ritonavir recipients).

These results led the SWITCHMRK investigators to conclude, "Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir/ritonavir."

"Our finding that substitution of lopinavir/ritonavir for raltegravir did not achieve non-inferiority compared with continuation of lopinavir/ritonavir underscores the complex considerations involved in providing the best possible treatment regimens for individual patients," they continued in their discussion. "In practice, clinicians need to gather all available background information, including past resistance tests and treatment outcomes, when contemplating the potential risks and benefits of modifying a suppressive antiretroviral regimen."

In an accompanying editorial, J. Michael Kirby from the Medical University of South Carolina noted that SWITCHMRK offers "a reminder that whenever possible, to assure sustained dependable activity, even our most promising antiretroviral agents should be used in combination with two or more fully active drugs."

BENCHMRK: State University of New York at Stony Brook; Aaron Diamond Research Center, Rockefeller University, New York, NY; Merck Research Laboratories, North Wales, PA; University of North Carolina, Chapel Hill; Georgetown University Medical Center, Washington, DC; Emory University School of Medicine, Atlanta, GA; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Hospital Clinic-IDIBAPS, University of Barcelona; Hospital Germans Trias i Pujol, Fundación Irsicaixa, UAB, Barcelona, Spain; Department of Medicine I, University of Bonn, Bonn, Germany; Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Hospital Pitié Salpêtrière, Université Pierre et Marie Curie; Hospital Bichat-Claude Bernard, Paris, France; University of Toronto, Ontario, Canada; San Raffaele Scientific Institute, Milan, Italy.

SWITCHMRK: University of North Carolina School of Medicine, Chapel Hill, NC; Denver Infectious Disease Consultants, Denver, CO; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW, Australia; Garrett Anderson Ward Royal Free Hospital, London, UK; Orlando Immunology Center, Orlando, FL; Antiguo Hospital Civil de Guadalajara, Guadalajara, Mexico; AIDS Research Initiative, Darlinghurst, NSW, Australia; Projeto Praça Onze, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Department of Internal Medicine, University of Cologne, Cologne, Germany; Northstar Medical Center, University of Illinois at Chicago, Chicago, IL; Georgetown University Medical Center, Washington, DC; Merck Research Laboratories, North Wales, PA.

1/26/10

Reference

RT Steigbigel, DA Cooper, H Teppler, and others. Long-term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clinical Infectious Diseases (Abstract). January 19, 2010 (Epub ahead of print).

JJ Eron, B Young, DA Cooper, and others. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. The Lancet (Abstract). January 13, 2010 (Epub ahead of print).

JM Kilby. Switching HIV therapies: competing host and viral factors (Editorial comment). The Lancet. January 13, 2010 (Epub ahead of print).