Clinical Trial to Assess the Efficacy of Darunavir/Ritonavir (DRV/r), Etravirine (ETV) and Raltegravir (MK-0518) in HIV Patients With Resistant Viruses (ANRS139 TRIO)

Prospective Clinical Trial to Assess Safety and Efficacy of DRV/r(TMC 114/r), ETV(TMC 125) and MK-0518 in Addition to OBT in HIV-1 Infected Patients With Limited to No Treatment Options ANRS 139 TRIO

The purpose of this study is to look at the safety and efficacy of a combination of 3 new antiretroviral drugs: darunavir, etravirine and MK-0518 (raltegravir) in patients who have multi-resistant viruses and limited treatment options. An optimized background regimen that may include nucleoside reverse transcriptase inhibitors (NRTIs) and enfuvirtide can be added, if possible, to this combination. Patients will undergo treatment for 48 weeks and virological efficacy will be evaluated at week 24.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: raltegravir potassium; Drug: darunavir/ritonavir; Drug: etravirine; Drug: Optimized background regimen

Detailed Description

Methods: A phase II pilot, prospective, open label, single arm multicentric clinical trial assessing a darunavir/ritonavir, etravirine and MK-0518-containing regimen, if possible associated to an optimized background regimen that may include NRTIs and enfuvirtide, in HIV-1 infected patients failing combination antiretroviral therapy with multi-resistant viruses.

Treatment strategy: Patients will receive raltegravir (MK-0518), darunavir/ritonavir (TMC114/r) and etravirine (TMC125) and if possible an optimized background therapy.

• raltegravir (MK-0518) (400 mg x 2/d = one 400 mg pill twice daily)
• darunavir (600 mg x 2/d= two 300 mg pills twice daily with meal)
• ritonavir (100 mg x 2/d = one 100 mg pill twice daily with meal)
• etravirine (200 mg x 2/d = two 100 mg pills twice daily with meal)
• if possible an optimized background therapy: may include NRTI(s) and enfuvirtide but not nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). NRTIs choice is left to the clinician's discretion. Enfuvirtide is highly recommended in enfuvirtide-naive patients but is left to the clinician.

Main outcome: proportion of patients with HIV RNA levels of less than 50 copies/ml in an intent to treat analysis at W24.

Secondary outcomes: proportions of patients with HIV RNA levels of less than 50 copies/ml at week 48, with HIV RNA levels of less than 400 copies/ml at week 24 and 48; HIV RNA level evolution between baseline and week 48; HIV proviral DNA and 2LTR circle HIV DNA between baseline and week 48; number and type of resistance mutations in case of virologic failure occurrence; CD4 lymphocyte count and proportion evolution between baseline and week 48; HIV infection progression; frequency of the study regimen modifications and interruption; study regimen tolerance; study regimen adherence; association between study drugs' minimum concentrations at week 4 and virologic success at week 24; evolution of pharmacokinetic parameters of study drugs between week 1 and week 4 in the Pharmacokinetic substudy.

Sample size: 103 patients

Enrollment period: 24 weeks

Patient's participation duration: 52 weeks

An extended follow-up (from week 52 to week 96) has been added in April 2008.

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Tourcoing, France, 59208
    • Hôpital Gustave Dron, Service Maladies Infectieuses

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age: 18 years and above
• Documented HIV-1 infection.
• History of virological failure on NNRTIs (patients with a history of toxicity to nevirapine and efavirenz may be enrolled in this study).
• On a combination antiretroviral therapy for at least 8 weeks prior to the screening visit (if on tipranavir, or enfuvirtide these drugs should have been introduced more than 8 weeks before the screening visit).
• Patient naive to darunavir, etravirine and to integrase inhibitors
• Plasma viral load at screening visit over 1000 copies/ml, (no CD4 restriction).

• Genotypic resistance testing at the screening visit:

  • Protease inhibitor mutations: over or equal to 3 primary protease inhibitor mutations among: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54M, L76V, V82A/F/L/T/S, I84V, N88S and L90M (IAS list 2006) but below or equal to 3 mutations among the following: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V et L89V (virus sensitivity to darunavir/ritonavir).
  • Reverse transcriptase mutations: over or equal to 3 NRTI mutations (among IAS list) and below or equal to 3 mutations among: A98G, L100I, K101Q/P/E, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/I/V/C/H/L, Y188C/H/L, G190A/C/E/Q/S, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F (virus sensitivity to etravirine)

Exclusion Criteria:

• Non effective barrier contraception in women of child bearing potential
• Pregnant women or women who are breastfeeding
• Opportunistic infection at the acute phase
• Decompensated cirrhosis (stage B or C of Child-Pugh score)
• Malignancy requiring chemotherapy or radiotherapy
• Contraindicated medications being taken by the patient (listed in protocol)
• Allergy to the active substances and expedients of darunavir, etravirine and raltegravir.
• Haemoglobin < 7g/dl, neutrophil cell count < 500/mm3, platelets < 50,000/mm3, creatinine clearance < 50 ml/mn, P. alkaline, AST, ALT or total bilirubin over or equal to 3 times normal values.
• Patients receiving experimental agents with an exclusion period for participation in other studies applicable at the screening visit of the current study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients with HIV RNA levels of less than 50 copies/ml in an intent to treat analysis at week 24	week 24

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportions of patients with HIV RNA levels of less than 50 copies/ml at week 48, with HIV RNA levels of less than 400 copies/ml at weeks 24 and 48	week 24 and 48
HIV RNA level evolution between baseline and week 48	from week 0 to 48
HIV proviral DNA and 2LTR circle HIV DNA between baseline and week 48	from week 0 to 48
Number and type of resistance mutations in case of virologic failure occurrence	from week 0 to 48
CD4 lymphocyte count and proportion evolution between baseline and week 48	from week 0 to 48
HIV infection progression	from week 0 to 48
Frequency of the study regimen modifications and interruption	from week 0 to 48
Study regimen tolerance	from week 0 to 48
Study regimen adherence	from week 0 to 48
Association between study drugs' minimum concentrations at week 4 and week 12 and virologic success at week 24	from week 4 to 24
Evolution of pharmacokinetics parameters of study drugs in the PK substudy	betwwen week 1 and 4

Collaborators and Investigators

• Sponsor: French National Agency for Research on AIDS and Viral Hepatitis
• Collaborators: Merck Sharp & Dohme LLC; Janssen-Cilag Tibotec
• Investigators: Principal Investigator: Yazdan YAZDANPANAH, MD PHD, Hôpital Tourcoing FRANCE; Study Director: Geneviève Chêne, MD PHD, INSERM U897 Bordeaux France

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: April 12, 2007
• First Submitted That Met QC Criteria: April 12, 2007
• First Posted (Estimate): April 13, 2007

Study Record Updates

• Last Update Posted (Estimate): September 17, 2010
• Last Update Submitted That Met QC Criteria: September 16, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: HIV infections; Treatment Experienced; raltegravir; darunavir; etravirine; HIV integrase inhibitor; MK 0518; Antiviral drug resistance
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; 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; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Raltegravir Potassium; Ritonavir; Enfuvirtide; Darunavir; Etravirine
• Other Study ID Numbers: 2007-000670-23; ANRS 139 TRIO