Safety Study of Raltegravir in HIV/HCV Co-infected Patients

An Open, Prospective Study to Compare the Safety and Efficacy of Raltegravir vs. Atazanavir / Ritonavir, Both in Combination With Tenofovir DF and Emtricitabine, in the Treatment of HIV-infection in ART Naive Subjects With HCV Co-infection.

Current European AIDS Clinical Society (EACS) guidelines for the treatment of HIV infection recommend a combination antiretroviral regimen composed of two nucleoside reverse transcriptase inhibitors plus a ritonavir boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor.

The non-nucleoside reverse transcriptase inhibitors licensed for naïve patients - nevirapine and efavirenz - have both been asociated with increased rates of hepatotoxicity (nevirapine) and CNS toxicity (efavirenz) in HIV/HCV co-infected patients. Although PI-based therapy has dramatically reduced morbidity and mortality, it has been limited by complex dosing regimens and toxicities, leading to adherence challenges. Varying degree of liver insufficiency may necessitate pharmacokinetic monitoring of the protease inhibitor and may necessitate dose adjustments. In HIV/HCV co-infected patients HAART based on another class of antiretrovirals than NNRTI or PI may thus offer advantages with regard to adverse events and thus long-term efficacy.

The overall intention of this trial is to examine in a non-inferiority design the safety and efficacy of a raltegravir based HAART with a standard-of-care HAART in HIV-/HCV co-infected patients. The standard of care used in this study will be atazanavir/ritonavir. All patients will in addition receive a fixed combination of tenofovir and emtricitabine.

The primary end-point is the rate of hepatotoxic events, defined by ALT elevations.

Study Overview

• Status: Withdrawn
• Conditions: Hepatitis C; HIV
• Intervention / Treatment: Drug: raltegravir; Drug: Atazanavir/ritonavir

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • Auguste Viktoria Hospital (AVK)
  • Berlin, Germany
    • Praxiszentrum Kaiserdamm
  • Berlin, Germany
    • Private Practice Dupke, Carganico, Baumgarten
  • Bonn, Germany
    • Department of Internal Medicine I, Bonn University
  • Essen, Germany
    • University of Essen
  • Frankfurt / Main, Germany
    • Infektiologikum Frankfurt
  • Frankfurt / Main, Germany
    • University of Frankfurt
  • Hamburg, Germany
    • Infektionsmedizinisches Centrum Hamburg (ICH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV and Hepatitis C co-infected patients
• indication for HAART according to current German-Austrian guidelines
• HAART naive
• no primary NRTI / Integrase / PI associated resistance mutation according to the Stanford algorithm at screening; every patient MUST have a genotypic resistance assay prior baseline available (< 6 months prior to baseline)
• women of childbearing age: negative pregnancy test
• ability to sign written informed consent

Exclusion Criteria:

• advanced liver cirrhosis Child-Pugh B or C or decompensated liver disease
• Pegylated interferon / ribavirin or other anti-HCV therapy; planned anti-HCV therapy for duration of the study (48 weeks).
• acute or chronic hepatitis B infection
• acute hepatitis A or other hepatotropic virus infections
• any other chronic liver disease such as alcohol abuse or hemosiderosis
• use or planned use (for the duration of the study, 48 weeks) of rifampicin, St. John´s wort and drugs that are metabolized via the cytochrome P450 system with a narrow therapeutic PK-range such as astemizole, terfenadine, cisapride, pimozide, chinidin, bepridil, triazolam, midazolam, ergotamine, dihydroergotamin, ergometrine, methyl-ergometrine. FOR OTHER COMEDICATIONS please consult with the SPC of Raltegravir (Isentress®), Atazanavir (Reyataz®), Ritonavir (Norvir®), your hospital pharmacist, www.hiv-drug-interactions.org or the principal investigator in case of uncertainty.
• new AIDS defining event, except for Kaposi sarcoma, < 1 months prior to screening
• malignancy, except for Kaposi sarcoma, with current radio- or chemotherapy
• history of organ transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Raltegravir; 45 patients will receive open label raltegravir, in addition to the common backbone tenofovir and emtricitabine	Drug: raltegravir; Patients will be randomized 1:1 to either the experimental or the active control arm
Active Comparator: Atazanavir/ritonavir; 45 patients will receive open label atazanavir/ritonavir	Drug: Atazanavir/ritonavir; Patients will be randomized 1:1 to either the experimental or the active control arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description
Primary objective	there is no difference in the rate of grade 1/2, or 3/4 ALT elevations; there is a higher incidence of grade 1 - 4 hyperbilirubinemias in the ATV/r arm

Secondary Outcome Measures

Outcome Measure	Measure Description
Secondary objectives	Other parameters of safety and efficacy will be compared between both arms

Collaborators and Investigators

• Sponsor: University Hospital, Bonn
• Collaborators: Dr. Axel Baumgarten, Berlin; Dr. Christoph Stephan, Frankfurt/M; Dr. Stefan Esser, Essen; Dr. Keikawus Arastéh, Berlin; Prof. Dr. Hans-Jürgen Stellbrink, Hamburg; Dr. Thomas Lutz, Frankfurt/M; Dr. Jörg Gölz , Berlin

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: October 20, 2010
• First Submitted That Met QC Criteria: October 20, 2010
• First Posted (Estimate): October 21, 2010

Study Record Updates

• Last Update Posted (Estimate): June 3, 2015
• Last Update Submitted That Met QC Criteria: June 2, 2015
• Last Verified: October 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Raltegravir Potassium; Ritonavir; Atazanavir Sulfate
• Other Study ID Numbers: UKB-2009-MED-I-JKR-01; 2009-015904-24 (EudraCT Number)