Switching from Lopinavir/ritonavir (Kaletra) to Raltegravir (Isentress) Leads to Poorer HIV Suppression, but Better Lipid Profiles: SWITCHMRK

By Liz Highleyman

Antiretroviral therapy has improved to a remarkable extent over the past decade, and even highly treatment-experienced HIV patients now have an excellent chance of achieving good viral suppression. Today, decisions about which drugs to include in a regimen often come down to small differences in HIV suppression and CD4 recovery on one hand, and concerns about side effects on the other.

At the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last week in Montreal, Joe Eron from the University of North Carolina at Chapel Hill and colleagues presented findings from a pair of studies comparing the first-in-class HIV integrase inhibitor raltegravir (Isentress) against the coformulated protease inhibitor lopinavir/ritonavir (Kaletra).

SWITCHMRK 1 and 2 were parallel double-blind multicenter trials that shared the same study design. SWITCHMRK 1 (also known as Merck protocol 032) included 348 patients in North America, Europe, and Australia. SWITCHMRK 2 (protocol 033) included 354 participants both from these industrialized countries and from Latin America, Africa, and Southeast Asia.

About 80% of participants in both studies were men, the median age was about 43 years, and the median CD4 cell count was about 475 cells.mm3. About 17% in SWITCHMRK 1 and about 52% in SWITCHMRK 2 were of non-white race/ethnicity. Baseline characteristics, including blood lipid levels, were generally similar across treatment arms. None of the patients were taking lipid-lowering medications.

In both studies, HIV positive patients who had maintained viral suppression < 50 copies/mL for at least 3 months on a stable lopinavir/ritonavir-based regimen were randomly assigned (1:1) to either stay on the same therapy or to replace 400/100 mg twice-daily lopinavir/ritonavir with 400 mg twice-daily raltegravir. Participants stayed on the same background therapy, which included at least 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), but no other PIs.

Patients were stratified by whether they had taken lopinavir/ritonavir-based therapy for more than 1 year (82% in SWITCHMRK 2) vs 1 year or less. Past treatment failures were allowed. Notably -- in contrast with the pivotal BENCHMRK trials -- background regimens were not optimized based on prior treatment history or resistance testing, and few patients used enfuvirtide (T-20; Fuzeon). Participants had taken a median of 5 previous antiretroviral drugs, up to a maximum of 16. Treatment history was similar in the 2 arms of each study, but differed considerably between SWITCHMRK 1 and 2.

The primary endpoints were proportion of patients with HIV RNA < 50 copies/mL at week 24, mean percentage change in blood lipid levels at week 12, and safety and tolerability for as long as 24 weeks.

Results

At 24 weeks, using a "non-completer = failure" analysis, raltegravir did not demonstrate non-inferiority compared with lopinavir/ritonavir based on the pre-defined margin of -12%.

SWITCHMRK 1: 80.8% of patients in the raltegravir arm maintained HIV RNA < 50 copies/mL, compared with 87.4% in the lopinavir/ritonavir arm, a difference of -6.6.

SWITCHMRK 2: 88.0% in the raltegravir arm vs 93.8% in the lopinavir/ritonavir arm had HIV RNA < 50 copies/mL, a difference of -5.8%.

Most viral rebounds in the raltegravir group occurred within the first 4 weeks after switching.

In the 2 studies combined, a majority of patients who experienced virological rebound after switching to raltegravir were treatment-experienced (84%) and had a history of prior virological failure (66%).

Virological response varied according to demographic factors including sex and geographic region (currently under analysis).

Changes in CD4 count were statistically similar in the raltegravir and lopinavir/ritonavir arms in both studies.

At 12 weeks, raltegravir was associated with significantly more favorable mean percentage changes from baseline in blood lipid levels compared with lopinavir/ritonavir:

SWITCHMRK 1:

Triglycerides: -41% in the raltegravir arm vs +4 in the lopinavir/ritonavir arm;

Total cholesterol: -13% vs +1%, respectively;

Non-HDL ("bad") cholesterol (including LDL): -15 vs +2%.

HDL ("good") cholesterol: no significant difference (-1% vs +1%).

SWITCHMRK 2:

Triglycerides: -43% vs +8%, respectively;

Total cholesterol: -12% vs +1%;

Non-HDL cholesterol: -15% vs +3%.

HDL cholesterol: no significant difference (-1% vs -3%).

Overall rates of clinical adverse events (AEs) were similar in the raltegravir and lopinavir/ritonavir arms (69.9% vs 62.9% in SWITCHMRK 2).

Rates of drug-related AEs were also similar (13.1% vs 19.7%, respectively, in SWITCHMRK 2).

Rates of severe (Grade 3-4) AEs were < 5% in both arms of both studies.

Discontinuation rates were statistically similar in the raltegravir and lopinavir/ritonavir arms of both studies, but were about twice as high in SWITCHMRK 1 (14.4% vs 9.8%) compared with SWITCHMRK 2 (5.7% vs 5.4%).

Raltegravir resistance mutations were uncommon, but most patients who experienced virological rebound on raltegravir had NRTI and NNRTI resistance mutations (more so than patients who failed lopinavir/ritonavir).

Based on these findings, the SWITCHMRK investigators concluded, "In virologically suppressed patients on lopinavir/ritonavir-based therapy, switching to raltegravir was well tolerated and resulted in improved lipid parameters at week 12, but did not demonstrate non-inferiority with respect to HIV RNA < 50 copies/mL at week 24 as compared to remaining on lopinavir/ritonavir."

Based on these results, Merck halted the SWITCHMRK studies, and is further analyzing the data to look for factors than contributed to good or poor treatment response. Very preliminary analysis indicates that the difference in sustained viral suppression was smaller in Africa, where patients had less treatment experience. In discussing the study results, Eron urged caution when switching only raltegravir in a regimen and recommended resistance testing.

This study supports the growing trend in HIV management that decisions about antiretroviral therapy -- including whether to switch from lopinavir/ritonavir to raltegravir -- should be tailored to individual patients, based on factors such as prior treatment experience, lipid levels, and overall cardiovascular risk profile.

2/17/09

Reference
J Eron, J Andrade, R Zajdenverg, and others. 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 Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 70aLB.