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ISENTRESS® (raltegravir) in Combination Therapy Demonstrated Long-Term Efficacy and Safety in Adult Patients Co-Infected with HIV-1 and Hepatitis B and/or C in a Subgroup Analysis at 240 Weeks
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GLASGOW, United Kingdom, November 14, 2012 - MSD, known as Merck in the United States and Canada, today presented new data from a post-hoc, subgroup analysis of three double-blind clinical trials, which found ISENTRESS® (raltegravir) demonstrated consistent long-term viral suppression and a well established safety profile in adult patients co-infected with HIV-1 and hepatitis C (HCV) and/or hepatitis B (HBV) when compared to adult patients with HIV-1 at 240 weeks. These studies were conducted in previously untreated or treatment-naïve (STARTMRK study) and treatment-experienced (BENCHMRK-1 and -2 studies) adult patients with HIV-1. The study results were presented during a poster discussion at the 11th International Congress on HIV and Drug Therapy in HIV Infection (HIV 11) in Glasgow, Scotland (Poster # P127).
Across these studies, moderate-to-severe liver enzyme elevations were more common among patients co-infected with HCV and/or HBV co-infection than among patients infected with HIV-1 alone.
Raltegravir is the first HIV-1 integrase inhibitor indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adults. This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients and one double-blind, active-controlled trial in treatment-naïve patients. Two of these studies were conducted in clinically advanced, three-class ARV [non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)] treatment-experienced adult patients through 96 weeks and one was conducted in treatment-naïve adults through 156 weeks. The use of other active agents with raltegravir is associated with a greater likelihood of treatment response.
"This new analysis provides valuable insight into the long-term safety and efficacy profile of ISENTRESS in patients co-infected with HIV-1 and HCV and/or HBV," said Dr. Jürgen Rockstroh, University of Bonn, Bonn-Venusberg, Germany. "Co-infection with HCV poses a serious challenge as it affects approximately a third of people globally living with HIV. In addition, HBV affects approximately five to 15 percent of the global HIV population. Of particular concern are co-infected patients who may be taking multiple therapies, which present issues related to managing potential drug-drug interactions."
STARTMRK and BENCHMRK-1 and -2 study designs
STARTMRK was a multi-centre, double-blind, randomised, active-controlled, Phase III non-inferiority 240-week study in which 563 previously untreated adult patients with HIV-1 RNA greater than 5000 copies/mL received either 400 mg raltegravir orally twice daily (n=281) or 600 mg efavirenz orally once daily (n=282), each in combination with tenofovir/emtricitabine.Hepatitis C and/or B co-infection was present across both treatment arms in 6 percent of treatment-naïve patients (n=34). Of the co-infected patients who received the regimen containing raltegravir (n=18), 28 percent co-infected with HCV (n=5) and 72 percent (n=13) were co-infected with HBV. The primary endpoint was a reduction in the HIV-1 viral load to less than 50 copies/mL at week 48.
BENCHMRK-1 and -2 were multi-centre, double-blind, randomised, placebo-controlled, Phase III 156-week studies in which 699 treatment-experienced adult patients with triple-class resistant HIV-1, who were failing HIV-1 antiretroviral therapies, received either 400 mg raltegravir orally twice daily (n=462) or placebo (n=237), each in combination with optimised background therapy (OBT). An open label extension study with raltegravir in combination therapy was conducted following the conclusion of the blinded trial, with data results analysed at 240 weeks. The primary endpoints for the two studies were HIV-1 viral load to less than 400 copies/mL at week 16. Sixteen percent of patients in these studies were co-infected with hepatitis C and/or B (n=114) across both treatment arms. Of patients who received the regimen containing raltegravir (n=77), 48 percent (n=37) were co-infected with HCV, 47 percent (n=36) were co-infected with HBV, and 5 percent (n=4) were co-infected with HCV and HBV.
In addition to the other inclusion and exclusion criteria, patients co-infected with HIV-1 and HCV and/or HBV could enroll in the three studies if they had stable chronic HCV and/or HBV infection with baseline aspartate aminostransferase (AST) and alanine aminotransferase (ALT) levels at or below five times the upper limit of normal. A post-hoc, subgroup analysis of the three studies was conducted using the observed failure approach for these co-infected patients. Co-infected patients who discontinued therapy due to a lack of efficacy were considered failures, and those who discontinued for other reasons were not included at subsequent time points.
Post-hoc, subgroup analysis showed raltegravir in combination therapy demonstrated sustained efficacy in treatment-naïve and treatment-experienced adult HIV-1 patients co-infected with HCV and/or HBV at 240 weeks
In the STARTMRK trial - the longest double-blind Phase III non-inferiority study evaluating an integrase inhibitor in treatment-naïve adults with HIV-1 - the regimen containing raltegravir demonstrated consistent efficacy in suppressing HIV-1 viral loads to below 50 copies/mL at 240 weeks in 90.9 percent (10/11) of co-infected patients and 89.1 percent (188/211) of HIV-1 mono-infected patients. In the efavirenz arm, HIV-1 viral loads were suppressed to below 50 copies/mL at 240 weeks in 91.7 percent (11/12) of co-infected patients and 80.0 percent (160/200) of HIV-1 mono-infected patients.
In the BENCHMRK-1 and -2 trials, a secondary endpoint included HIV-1 viral load to less than 50 copies/mL at 156 weeks. The regimen containing raltegravir suppressed HIV-1 viral loads to below 50 copies/mL at 156 weeks in 62.3 percent (38/61) of co-infected patients and 57.9 percent (195/337) of HIV-1 mono-infected patients. In the open-label extension of the study, the regimen containing raltegravir demonstrated consistent efficacy in suppressing HIV-1 viral loads at 240 weeks to below 50 copies/mL in 50 percent (27/54) of co-infected patients and 52.5 percent (166/316) of mono-infected patients. The regimen containing placebo plus OBT suppressed HIV-1 viral loads to below 50 copies/mL at 156 weeks in 14.7 percent (5/34) of co-infected patients and 26.3 percent (46/175) of HIV-1 mono-infected patients. In the open-label extension of the study, HIV-1 viral loads in the placebo plus OBT arm were suppressed to below 50 copies/mL at 240 weeks in 14.7 percent (5/34) of co-infected patients and 20.5 percent (33/161) of HIV-1 mono-infected patients.
The new analysis also examined CD4 cell counts for these populations across the studies. The median baseline and mean change from baseline at 240 weeks:
Well established safety profile of raltegravir in combination therapy reinforced in treatment-naïve and treatment-experienced HIV-1 and HCV and/or HBV co-infected adult patients at 240 weeks
Across all studies and treatment arms, moderate-to-severe liver enzyme elevations (including grade 3 and 4 liver enzyme elevations) were more common among adult HIV-1 patients with HCV and/or HBV co-infection than among patients infected with HIV-1 alone.
At week 240 in the STARTMRK trial, hepatobiliary events occurred in 5.6 percent (n=1) of co-infected patients and 5.7 percent (n=15) of HIV-1 mono-infected patients in the raltegravir arm, and no patients among co-infected patients and 3.4 percent (n=9) of HIV-1 mono-infected patients in the efavirenz arm. Taking into account the duration on treatment in the BENCHMRK trials, hepatobiliary events occurred at a rate of 2.5 events per 100 patient-years in co-infected patients and 1.7 events per 100 patient-years in HIV-1 mono-infected patients in the raltegravir arm, and 3.8 events per 100 patient-years in co-infected patients and 2.9 events per 100 patient-years in HIV-1 mono-infected patients in the placebo plus OBT arm.
Drug-related adverse events for co-infected and HIV-1 mono-infected patients at 240 weeks were 66.7 percent (n=12) and 51.0 percent (n=134) in the raltegravir arm, 75.0 percent (n=12) and 80.5 percent (n=214) in the efavirenz arm, respectively, in STARTMRK; and, at a rate of 18.3 events per 100 patient-years and 19.9 events per 100 patient-years in the raltegravir arm, 41.5 events per 100 patient-years and 35.7 events per 100 patient-years in the placebo plus OBT arm, respectively, in BENCHMRK-1 and -2 studies. Additionally, serious adverse events at 240 weeks in co-infected and HIV-1 mono-infected patients were 22.2 percent (n=4) and 20.2 percent (n=53) in the raltegravir arm; 18.8 percent (n=3) and 20.3 percent (n=54) in the efavirenz arm, respectively, in STARTMRK; and, at a rate of 12.0 events per 100 patient-years and 10.6 events per 100 patient-years in the raltegravir arm, 17.0 events per 100 patient-years and 15.1 events per 100 patient-years in the placebo plus OBT arm, respectively, in BENCHMRK-1 and -2 studies.
The proportion of co-infected and HIV-1 mono-infected patients who discontinued therapy at 240 weeks were 5.6 percent (n=1) and 4.9 percent (n=13) in the raltegravir arm; 6.3 percent (n=1) and 8.3 percent (n=22) in the efavirenz arm, respectively, for STARTMRK; and, at a rate of 2.1 events per 100 patient-years and 2.0 events per 100 patient-years in the raltegravir arm, 3.8 events per 100 patient-years and 3.8 events per 100 patient-years in the placebo plus OBT arm, respectively, for BENCHMRK-1 and -2.
Selected Safety Information
Therapeutic indications
ISENTRESS is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.
This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients and one double-blind, active-controlled trial in treatment-naïve patients
Contraindications
ISENTRESS is contraindicated in patients who are hypersensitive to any component of this medicine.
Precautions
Immune Reconstitution Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Drug Interactions
Caution should be used when co-administering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered.
Side Effects
For treatment-experienced patients in the group receiving ISENTRESS 400 mg twice daily + optimized background therapy (OBT) and the comparator group receiving placebo + OBT in the pooled analysis for phase III studies, the most commonly reported adverse experiences (≥ 1/100 to < 1/10), of all intensities and regardless of causality were: abnormal dreams, insomnia, dizziness, headache, vertigo, abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting, rash, asthenia, fatigue, pyrexia, alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased.
In the pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9% in patients receiving ISENTRESS + OBT and 4.6% in patients receiving placebo + OBT. The rates of discontinuation of therapy in naïve patients due to adverse reactions were 3.6% in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 6.7% in patients receiving efavirenz + emtricitabine (+) tenofovir.
Selected Adverse Experiences
Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions
Serious Events
The following serious drug-related adverse experiences were reported in clinical studies: gastritis, hepatitis, renal failure, genital herpes, accidental overdose, anaemia, immune reconstitution syndrome, mental disorder, and suicide attempt.
Coexisting Conditions
In Phase 3 studies, treatment-experienced patients (N=114/699 or 16%) and treatment-naïve patients (N = 34/563 or 6%) with chronic (but not acute) active hepatitis B and/or hepatitis C coinfection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In general, the safety profile of ISENTRESS in patients with hepatitis B and/or hepatitis C coinfection was similar to that in patients without hepatitis B and/or hepatitis C coinfection, although the rates of aspartate aminotransferase and alanine aminotransferase abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C coinfection for both treatment groups.
Dosage and Administration
For the treatment of patients with HIV-1 infection, the dosage of ISENTRESS is 400 mg administered orally, twice daily with or without food. ISENTRESS is to be given in a combination regimen with other antiretroviral agents.
About ISENTRESS
ISENTRESS is MSD's integrase inhibitor for the treatment of HIV-1 infection in adult patients as part of combination HIV therapy. Raltegravir works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. Other HIV-1 drugs in use inhibit two other enzymes critical to the HIV-1 replication process - protease and reverse transcriptase. Raltegravir is now approved in combination therapy in more than 45 countries for use in treatment-naïve adult patients with HIV-1 and in more than 90 countries for use in treatment-experienced adult patients with HIV-1. Merck is continuing to move forward with filings in additional countries around the world.
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