Switching from Boosted Protease Inhibitor to Raltegravir Maintains Viral Suppression in Absence of NRTI Resistance

		SUMMARY: Switching from a ritonavir-boosted protease inhibitor to the integrase inhibitor raltegravir (Isentress) can maintain viral load at an undetectable level for most patients, but those with pre-existing nucleoside/nucleoside reverse transcriptase inhibitors (NRTIs) resistance mutations have an increased risk of virological failure if the drug is taken only once-daily, according to 2 studies from Spain presented at the XVIII International AIDS Conference (AIDS 2010) last month in Vienna.

By Liz Highleyman

Protease inhibitors are an effective component of combination antiretroviral therapy (ART) regimens but can cause side effects including elevated blood lipids, which may increase the risk of cardiovascular disease. Raltegravir, the first approved integrase inhibitor, is generally safe and well-tolerated.

SPIRAL

Jose Gatell and colleagues assessed the safety and efficacy of switching from a ritonavir (Norvir) boosted protease inhibitor to twice-daily raltegravir in patients with fully suppressed viral load.

The study included 282 participants on stable ART with HIV RNA < 50 copies/mL for at least 6 months, though the median duration of suppression was much longer at about 6 years. They were randomly assigned to either continue their existing regimen or exchange their protease inhibitor -- most often lopinavir/ritonavir (Kaletra) or atazanavir (Reyataz) -- for raltegravir, while staying on the same NRTI "backbone."

About 75% of participants were men and the median age was about 45 years. The current median CD4 cell count was about 500 cells/mm3, but one-third had a prior AIDS diagnosis and nearly 40% had a history of past treatment failure.

The researchers assessed how many people maintained undetectable viral load 48 weeks after switching to raltegravir, using an intent-to-treat "missing = failure" analysis. Virological failure was defined as 2 consecutive HIV RNA measurements >50 copies/mL. The margin for determining non-inferiority of the new vs old regimen was 12.5%.

The earlier SWITCHMRK studies showed that people who switched from lopinavir/ritonavir to raltegravir were more likely to experience viral rebound. After these findings were reported, a Data and Safety Monitoring Board re-evaluated the SPIRAL study and recommended that it continue.

In addition to evaluating HIV suppression, investigators also looked at changes in blood levels of triglycerides, total cholesterol, low-density lipoprotein (LDL) "bad" cholesterol, and high-density lipoprotein (HDL) "good" cholesterol. Participants who switched to raltegravir in SWITCHMRK showed improvements in lipid profiles.

Results

	At 48 week, 89% of participants who switched to raltegravir and 87% who stayed on their boosted protease inhibitor remained free of treatment failure.
	In an as-treated analysis, 97% and 95%, respectively, remained free of viral rebound.
	These differences were smaller than 12.5%, allowing the conclusion that raltegravir was non-inferior to continuing on a boosted protease inhibitor.
	Differences in favor of raltegravir were larger among patients with prior virological failure, prior use of suboptimal therapy (e.g., NRTI monotherapy), and pre-existing drug-resistance mutations.
	Half the patients who experienced viral rebound in the raltegravir arm had pre-existing resistance mutations, compared with 83% in the protease inhibitor arm.
	About 10% of participants in both arms discontinued treatment prematurely, including 2 people (3%) in each arm due to adverse events.
	4% of patients in both arms experienced serious adverse events.
	Participants who switched to raltegravir showed improved lipid profiles:
	Triglycerides: -22.0% with raltegravir vs +4.7 with continued protease inhibitor; Total cholesterol: -11.2% vs +1.8%, respectively; LDL cholesterol: -6.5% vs +2.9%, respectively; HDL cholesterol: -3.2% vs +5.8%, respectively; Total-to-HDL ratio: -4.9% vs -1.3%, respectively.
	The number of raltegravir recipients taking lipid-lowering drugs fell from 19 at baseline to 12 at week 48, while rising from 21 to 24 in the continued protease inhibitor arm.

Based on these findings, the SPIRAL researchers concluded that switching to raltegravir was non-inferior to continuing on a boosted protease inhibitor.

To explain the higher virological failure rate in SWITCHMRK, Gatell suggested that the longer duration of viral suppression before the switch in SPIRAL may have led to better outcomes.

ODIS

The second study, presented by Eugenia Vispo, also evaluated people whether people with viral suppression on a protease inhibitor-based regimen -- also < 50 copies/ml for at least 6 months -- could safely switch to raltegravir taken once or twice daily. Though approved for once-daily dosing, raltegravir's long intracellular half-life suggests less frequent dosing may be possible.

The ODIS study included 222 participants at Hospital Carlos III in Madrid who were randomly assigned (2:1) to switch from their protease inhibitor (again, mostly lopinavir/ritonavir or atazanavir) to raltegravir taken either 400 mg twice-daily or 800 mg once-daily. After 3 months, patients with undetectable viral load in the twice-daily arm were randomized again to either stay on twice-daily or switch to once-daily.

About 67% of study participants were men, the average age was 46 years, and nearly half were coinfected with hepatitis C virus (HCV). The average CD4 cell count was 574 cells/mm3 (significantly higher in the once-daily arm). About 70% had a history of virological failure and 40% had taken suboptimal regimens.

Results

	More participants taking raltegravir once-daily experienced virological failure compared with the twice-daily regimen:
	Overall: 6.4% with once-daily raltegravir vs 2.9% with twice-daily; Patients with prior suboptimal treatment: 4.9% vs 0%, respectively; Prior virological failure: 8.7% vs 4.3%, respectively; Pre-existing NRTI resistance: 17.7% vs 8.3%, respectively.
	In univariate and multivariate analyses, pre-existing NRTI resistance mutations was the only significant predictor of virological failure.
	Lipid levels decreased after switching in both the once-daily and twice-daily arms.

Due to the poorer outcomes in the once-daily arm, the study was halted ahead of schedule.

"A switch from protease inhibitors to raltegravir in HIV-infected patients with undetectable plasma HIV RNA effectively sustains viral suppression as long as prior NRTI resistance had not been selected in the past," the ODIS investigators concluded. "In this setting, the efficacy of raltegravir may not differ providing the drug [once-daily] or [twice-daily]."

Investigator affiliations:

MOAB0102: Hospital Carlos III, Infectious Diseases Department, Madrid, Spain; Hospital Carlos III, Pharmacology Unit, Madrid, Spain.

MOAB0103: Hospital Clínic - IDIBAPS, Barcelona, Spain; Hospital Germans Trías i Pujol and IrsiCaixa Foundation, Badalona, Spain; Hospital General Universitario de Elche, Elche, Spain; Hospital de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain; Hospital Clinico Universitario, Santiago de Compostela, Spain; Hospital del Mar, Barcelona, Spain; Hospital Son Dureta, Palma de Mallorca, Spain; Hospital Gregorio Marañon, Madrid, Spain; Hospital Vall d'Hebron, Barcelona, Spain.

8/3/10

References

E Martinez, M Larrousse, JM Llibre, and others. Simplification of antiretroviral therapy by switching from ritonavir-boosted protease inhibitors to raltegravir in virologically suppressed HIV-1-infected patients (SPIRAL): a randomised open-label trial. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract MOAB0103.

E Vispo, P Barreiro, I Maida, and others. Simplification from protease inhibitors to once or twice daily raltegravir: the ODIS trial. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract MOAB0102.