HIV patients who are stable on a regimen of lopinavir-ritonavir can reduce their levels of blood fats by switching to raltegravir; however, switching also leads to a lower proportion of patients reaching the target for viral suppression. These are the conclusions of the SWTICHMRK 1 and 2 studies, reported in one Article published Online First (www.thelancet.com) and in an upcoming edition of The Lancet. The Article is by Professor Joseph J Eron, University of North Carolina School of Medicine, Chapel Hill, NC, USA, and colleagues.
Lopinavir and ritonavir are protease inhibitors (PI)—meaning they interfere in the HIV replication mechanism by preventing production of the viral protein coat. However, known complications associated with the drugs include an increase in blood fat concentrations. Raltegravir is an integrase inhibitor—which prevents HIV replication by stopping the HIV genetic material from 'integrating' into the DNA in host cells. The two SWITCHMRK trials compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy.
In these randomised and blinded phase 3 trials, 707 patients were assigned in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors*. Primary endpoints were the mean percentage change in blood fat concentrations from baseline to week 12; the proportion of patients with HIV RNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of % for each study**; and the frequency of adverse events up to 24 weeks.
The final results showed that 702 patients received at least one dose of study drug and were included in the efficacy and safety analyses (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were greater in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol •6% vs 1•0%, non-HDL or 'bad' cholesterol •0% vs 2•6%, and triglycerides •2% vs 6•2%. At week 24, 84% of patients in the raltegravir group had an HIV viral load of less than 50 copies per mL compared with 91% of patients in the lopinavir-ritonavir group (treatment difference •2%)**. Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group. The authors discuss that the failure of raltegravir to be as effective at viral suppression in these patients as lopinavir-ritonavir (despite raltegravir reducing blood fats) underlines the complex considerations involved in providing the best possible care for individual patients.
Since the studies were stopped early, a post-trial analysis was completed to understand why the differences in virological suppression had occurred. It was found that patients whose lopinavir-based regimen at screening was their first regimen or patients without previous virological failure had similar response rate at week 24 in both treatment groups in the two studies combined. Those patients who had previously failed other regimens may have had partial resistance to the nucleoside reverse transcriptase inhibitor in their regimen which could have contributed to the higher rate of virological failure when they switched to raltegravir.
The authors say: "In practice, clinicians need to gather all available background information, including past resistance tests and treatment outcomes, when contemplating the potential risks and benefits of modifying a suppressive antiretroviral regimen. Efficacy, tolerability, and safety data from rigorous clinical trials that can be applied contextually to individual patients will help to inform these difficult decisions."
They conclude: "Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir."
In an accompanying Comment, Dr J. Michael Kilby, Medical University of South Carolina, Charleston, SC, USA, says: "The unexpected SWITCHMRK results will probably generate some debate and controversy, both with respect to shortcomings in methodology and the importance of host adverse effects versus ease of viral escape in therapeutic choices. This protocol is a reminder that whenever possible, to assure sustained dependable activity, even our most promising antiretroviral agents should be used in combination with two or more fully active drugs. The shining image of protease inhibitors has diminished over the past decade relative to other first-line antiretrovirals. But for treatment-experienced patients stably controlled on protease-inhibitor-based therapy we should carefully consider the results before switching regimens too quickly."
Professor Joseph J Eron, University of North Carolina School of Medicine, Chapel Hill, NC, USA. T) +1 919 302 8183 E) joseph_eron@unc.edu
Dr J. Michael Kilby, Medical University of South Carolina, Charleston, SC, USA. T) +1 843 792-5762 E) mkilby@musc.edu
For full Article and Comment, see: http://press.thelancet.com/switchmrk.pdf
*Note to editors: reverse transcriptase inhibitors block the enzyme reverse transcriptase's enzymatic function, and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying.
** In the individual studies the treatment differences were -6.6% (95% confidence interval (CI) -14.4 to 1.2) for SWITCHMRK 1 and -5.8% (95% CI -12.2 to 0.2) for SWITCHMRK 2. The confidence interval tells us if we can be certain with 95% confidence that the difference is smaller than -12%. Because the lower end of the 95% CI in both studies exceeded -12% the conclusion is that raltegravir is not non-inferior to lopinavir-ritonavir in this analysis.
Journal
The Lancet