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and Hepatitis.com Coverage of the
XVIII International AIDS Conference (AIDS 2010) July 18 - 23, 2010, Vienna, Austria
Switching from Boosted Protease Inhibitor to Raltegravir Maintains Viral Suppression in Absence of NRTI Resistance
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.
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.
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.
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.
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.
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.
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]."