Two Phase III studies ( SWITCHMRK-1 and -2 ) evaluating the effect of switching patients whose HIV is controlled on a Lopinavir and Ritonavir-based regimen ( Kaletra ) to a regimen containing HIV integrase inhibitor Raltegravir ( Isentress ) tablets showed that Raltegravir significantly improved total cholesterol, triglycerides and non-HDL-cholesterol. Also, the study showed that Raltegravir did not demonstrate non-inferior virologic efficacy at maintaining viral load suppression.
As a result of the viral load findings in these trials, Merck discontinued these two studies.

Findings from the 24-week interim analyses of SWITCHMRK-1 and -2 were presented at the 16th Conference on Retroviruses and Opportunistic Infections ( CROI ) in Montreal, Canada.

In one study, Protocol 032 ( also called SWITCHMRK-1 ), 81% of patients receiving a regimen with Raltegravir maintained undetectable viral levels ( less than 50 copies/mL ) compared with 87% of patients receiving a regimen with Lopinavir and Ritonavir. In the second study, Protocol 033 ( also called SWITCHMRK-2 ), the regimen with Raltegravir maintained undetectable viral load levels in 88% of patients compared with 94% of patients receiving a regimen with Lopinavir and Ritonavir. In both studies, switching treatment to a regimen with Raltegravir resulted in significantly greater decreases in total cholesterol, triglycerides and non-HDL-cholesterol ( p<0.001 ) compared to continuing the Lopinavir and Ritonavir-based regimen.
Primary endpoints from the study include mean percent change in fasting lipids ( total cholesterol, triglycerides, non-HDL and LDL ) at week 12, proportion of patients with viral load suppressed to undetectable levels ( less than 50 copies/mL ) at Week 24 and safety and tolerability at Week 24.

In regard to suppression of viral load, results at week 24 showed that Raltegravir did not demonstrate non-inferiority ( one of the primary endpoints for both trials ) as compared to Lopinavir and Ritonavir as measured by proportion of patients with undetectable viral levels.
These results were based on an intent-to-treat analysis which assumes all study dropouts are virologic failures.
Based on post-hoc data collection, 84% of patients with confirmed virologic failure (viral levels greater than 50 copies/mL ) in the group receiving Raltegravir reported that their regimen at study entry was not their first antiretroviral regimen; and 66% of these patients reported a history of virologic failure on prior regimens.

Clinical adverse experiences of all severities were similar among patients treated with Raltegravir as compared to those treated with the Lopinavir and Ritonavir-based regimen respectively ( 69.9% vs 62.9% in Protocol 033; 62.6% vs 60.9% in Protocol 032 ) and drug-related adverse events ( 13.1% vs 19.7% in Protocol 033; 13.8% vs 10.9% in Protocol 032 ).

As a result of the viral load findings in these trials, Merck has stopped Protocols 032 and 033 and has notified the appropriate regulatory agencies and trial investigators for Raltegravir about these data.

Study background

Protocol 032 and 033 studies are multi-centre, double-blind, randomised, active-controlled, non-inferiority studies to evaluate the safety, tolerability and efficacy of Raltegravir in patients who are well controlled ( viral load <50 copies/mL ) on a stable Lopinavir and Ritonavir based regimen ( 400/100 mg twice daily ) and were randomised to switch to Raltegravir or continue on Lopinavir and Ritonavir. In these studies, 354 patients in Protocol 033 and 348 patients in Protocol 032 were randomised to remain on the Lopinavir and Ritonavir-based regimen or be switched to Raltegravir 400 mg twice daily.
Patients enrolled in the study were required to be stable on the Lopinavir and Ritonavir-containing regimen, defined as having viral load suppressed to less than 50 copies/mL for at least three months, and were taking at least two nucleoside reverse transcriptase inhibitors ( NRTIs ) as part of their regimen. Because patients were enrolled in the study regardless of whether they had been on previous regimens prior to their Lopinavir amd Ritonavir-based regimen, and regardless of the number of treatment failures previously experienced, the patient population in these studies had very diverse treatment experiences.

Raltegravir

Raltegravir attacks the HIV virus in a way that’s different to other available antiretroviral treatments. It is the only drug approved that blocks the action of integrase, an enzyme that is critical to the HIV replication process. By targeting the integrase enzyme, Raltegravir limits the ability of the virus to replicate and infect new cells. Used in combination with other antiretroviral agents, Raltegravir has been shown to be effective at both reducing viral load to undetectable levels and raising CD4 cell count in people living with HIV-AIDS who were previously treated with other antiretroviral agents. Raltegravir is administered as a single 400 mg tablet taken twice daily with or without food with other HIV medications.

Source: Merck, 2009

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