Switching boosted-PIs to raltegravir
1 October 2010. Related: Conference reports, Antiretrovirals, Treatment strategies, World AIDS 18 Vienna 2010.
Simon Collins, HIV i-Base
Two studies, both from Spain, looked at switching a boosted protease inhibitor to raltegravir in people on stable, virally suppressed treatment.
The first study (called ODIS) included 222 people on stable treatment (<50 copies/mL for at least 24 weeks) who switched the boosted PI (48% on atazanavir, 28% on lopinavir and 13% on fosamprenavir) to raltegravir. 
The study randomised patients 2:1 to raltegravir once-daily (n=149) or twice daily (n=73). At three months, patients on the twice-daily arm with undetectable viral load were randomised 1:1 to either once-daily raltegravir or to continue BID dosing (n=35). The primary endpoint was viral suppression 24-weeks after the initial randomisation, with secondary endpoints that included metabolic changes.
Although median time on prior antiretrovirals was over 8 years, 40% people had previously used sub-optimal HAART, with just under 70% having prior recorded virological failure and 33% having documented NRTI resistance. Approximately half the patients had HCV coinfection.
By 24 weeks, more people had viral load rebound in the once-daily group (6.4% vs 2.9%, NS p=0.18). More importantly, a much bigger difference in failure rates was seen in people who had a previous history of resistance to nukes: 16.2% (12/74) vs less than 0.7% (1/148), p<0.001. This was associated with previous virological failure, especially if previous NRTI-resistance was documented.
Median total cholesterol, HDL and LDL reduced by 10 mg/dL, 3 mg/dL and 6 mg/dL respectively (p<0.05) but TC:HDL and TG changes were not significant. In a multivariate analysis, only prior NRTI resistance predicted risk of virological failure OR 28.45 (95% CI: 3.62-223.56), p=0.001.
In the second study (called SPIRAL) 273 people on stable treatment with similar treatment experience to the ODIS study were randomised 1:1 to either continue on their boosted-PI or switch the PI to raltegravir. 
The main difference in baseline factor compared to ODIS was a higher use of lopinavir/r (over 40%) as the baseline PI. The primary endpoint was viral suppression at week 48. After a year, 90% of people in each group remained on the assigned treatment. Reasons for discontinuations were similar between groups. By ITT analysis 89% vs 87% remained free from virological failure respectively, (difference NS 2.6%; 95%CI: 5.2%, 10.6%), meeting the predefined criteria for non-inferiority (lower limit of 95%CI 12.5%). Virological failure occurred in four (raltegravir) vs six (PI) patients, with prior resistance history impacting slight more in the PI group, although these are small numbers. Tolerability was good with only 2% patients in each group discontinuing
due to side effects; and grade 4 events occurred in 4% patients in each group.
Mean changes in baseline lipids reduced significantly in the raltegravir group: TC 11% vs +2%; LDL 6% vs 3%; HDL 3 vs +6%; TC:HDL 5% vs 1%; TG 22% vs 5%.
This significantly reduced the percentage of people in the raltegravir group who needed lipid-lowering treatment based on guidelines (NCEP).
These results were compared to the pooled results from the SWITCHMRK I and II studies which were stopped prematurely based on poorer virological responses in the raltegravir switch groups compared to the maintained lopinavir/r arms (approximately 88% vs 95% maintaining virological suppression at 24 weeks).  The publication of these results detailed a similar relationship between prior treatment failure and risk of virological failure after switching to raltegravir. 
A previous history of virological failure, as seen in the SWITCHMRK studies clearly increases the risk of virological failure when changing a boosted-PI to raltegravir.
If resistance, especially to NRTIs is not a concern, the lipid improvements may warrant the use of raltegravir, though these are less significant when switching from PIs that affect lipids to a lesser extent than lopinavir/r. The current cost of raltegravir in the UK limits the use of raltegravir as a switch option based on better tolerability.
Other studies looking at once-daily raltegravir dosing are ongoing.
- Vispo E et al. Simplification from protease inhibitors to once or twice daily raltegravir: the ODIS trial. Oral abstract MOAB0102.
- Martinez E et al. 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. Oral abstract MOAB0103. http://pag.aids2010.org/Abstracts.aspx?SID=631&AID=5931
- Eron J et al. Switching from stable lopinavir/ritonavir-based to raltegravir-based combination art resulted in a superior lipid profile at week 12 but did not
demonstrate non-inferior virologic efficacy at week 24.16th CROI, 811 February 2009, Montreal. Abstract 70aLB. http://www.retroconference.org/2009/Abstracts/36597.htm
- Eron JJ et al. 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, Volume 375, Issue 9712, Pages 396 – 407, 30 January 2010. doi:10.1016/S0140-6736(09)62041-9. Full text: http://www.natap.org/2010/HIV/011410_01.htm