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Switch to Raltegravir From Lopinavir in Highly Treatment-Experienced Patient Group: SWITCHMRK 1 & 2 Studies
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16th Conference on Retroviruses and Opportunistic Infections,
February 8-11, 2009, Montreal
Mark Mascolini
People with extensive prior 3-class ART experience taking a lopinavir-based regimen did better virologically if they stayed with the protease inhibitor (PI) than if they swapped lopinavir for the integrase inhibitor raltegravir, according to 24-results of two double-blind, placebo-controlled trials, SWITCHMRK 1 and 2 [1]. Apparently, the study patients had prior NRTI, NNRTI, and PI resistance mutations. The patients were stable on a Kaletra plus 2 NRTI regimen. (from Jules: these patients had extensive experience of up to 22 years (see slides in link) with ART therapy suggesting NRTI monotherapy in the past. The data suggests they might have been stable on the Kaletra therapy but perhaps just barely and swapping out to raltegravir allowed prior NRTI resistance to emerge and cause viral failure for some patients). People who switched to raltegravir had a better lipid profile after 12 weeks.
The virologic findings come as a surprise because raltegravir performed so well as a salvage regimen in the BENCHMRK trials [2] and as first-line therapy versus efavirenz in the STARTMRK trials [3].
The SWITCHMRK trials enrolled people taking a suppressive lopinavir/ritonavir regimen for at least 3 months. Because about 80% of participants had taken lopinavir/ritonavir for more than 1 year and because people taking lipid-controlling drugs were excluded from the trials, one can assume most enrollees were tolerating lopinavir/ritonavir well. Eron and colleagues randomized 178 people to stay on lopinavir/ritonavir (400/100 mg twice daily) and 176 to switch to raltegravir (400 mg twice daily). Everyone kept the same background regimen, which had to include at least two nucleosides and could include no other PI.
SWITCHMRK 1 and 2 were active-controlled trials, meaning people randomized to lopinavir took dummy raltegravir pills, and vice versa. That design is more robust than an open-label format, in which patients and physicians know which drug a person is taking, but it is more demanding for patients, who must take more pills than in an open-label trial. Nevertheless, discontinuation rates were low--14.4% with raltegravir and 9.8% with lopinavir in SWITCHMRK 1, and 5.7% with raltegravir and 5.4% with lopinavir in SWITCHMRK 2. Trial sites included Europe, Australia, North America, Latin America, Africa, and Southeast Asia.
Together, the two trials randomized 350 people to trade lopinavir/ritonavir for raltegravir and 352 to stick with the PIs. Median age stood around 42 years, and about 80% of enrollees were men. CD4 count averages stood in the high 400s across the four study arms. Median years of antiretroviral experience exceeded 3 in the four arms, and median number of previous antiretrovirals stood at 5 or more.
After 24 weeks of treatment in SWITCHMRK 1, a noncompleter-equals-failure analysis determined that 87% taking lopinavir versus 81% taking raltegravir had a viral load below 50 copies for a treatment difference of -6.6 (95% confidence interval -14.4 to +1.2). In SWITCHMRK 2, 94% taking lopinavir and 88% taking raltegravir were under the 50-copy mark at week 24, for a treatment difference of -5.8 (95% CI -12.2% to +0.2%). Those results meant that switching to raltegravir is "not noninferior" to staying with lopinavir.
Eron and coworkers determined that 27 of 32 raltegravir-treated people (84%) with a confirmed virologic failure above 50 copies were not taking their first antiretroviral regimen when the trial began. And 18 of these 27 (66%) had at least one virologic failure before starting their lopinavir regimen. A preliminary analysis of resistance mutations in people with a viral load above 400 copies at failure showed an array of nucleoside and nonnucleoside mutations in most people with raltegravir failure, but fewer reverse transcriptase mutations with lopinavir failure. Together these findings suggest that at least some of the people in whom raltegravir faltered had archived reverse transcriptase mutations that re-emerged during failure.
The higher raltegravir failure risk with greater antiretroviral experience seemed buttressed by results from African sites, where antiretroviral experience is more limited than at other sites, and where raltegravir did as well as lopinavir virologically.
Switching to raltegravir was superior to maintaining lopinavir/ritonavir in several lipid measures 12 weeks into the trial, measured as average percentage change from baseline. In SWITCHMRK 1:
• Total cholesterol: -13% raltegravir vs +1% lopinavir, P < 0.001
• Triglycerides: -41% raltegravir vs +4% lopinavir, P < 0.001
• Non-high-density lipoprotein cholesterol: -15% raltegravir vs +2% lopinavir, P < 0.001
The groups did not differ significantly in high-density lipoprotein (HDL) cholesterol change, and the researchers did not present changes in total-to-HDL cholesterol ratio, which gives a balanced view of overall cholesterol shifts. Lipid results were similar in SWITCHMRK 2.
Equivalent proportions of patients in the two treatment arms had any clinical adverse event (69.9% with raltegravir vs 62.9% with lopinavir) or drug-related side effects (13.1% with raltegravir vs 19.7% with lopinavir).
Eron concluded that "one needs to be extremely cautious about making one-drug substitutions to raltegravir," even in people with suppressed viremia. He suggested that further analyses of background regimens and resistance mutations will be necessary to determine why raltegravir failed more often than continued lopinavir in these trials.
References
1.Eron J, Andrade J, Zajdenverg R, 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 Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal. Abstract 70aLB.
2. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339-354.
3. Lennox J, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive HIV-1 infected patients: STARTMRK Protocol 021. 48th Annual ICAAC/IDSA, October 25-28, 2008, Washington, DC. Abstract H-896a.
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