Telaprevir in HIV-HCV Coinfected Patients Who Had Previously Failed a Peginterferon-Ribavirin Regimen (TelapreVIH)

ANRS, Emerging Infectious Diseases

Status and phase

Completed

Phase 2

Conditions

Hepatitis C, Chronic

HIV Infection

Treatments

Biological: pegIFN alfa-2a

Drug: Telaprevir

Drug: Ribavirin

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT01332955

2010-023287-41

ANRS HC26 TelapreVIH (Other Identifier)

Details and patient eligibility

About

This phase II, multicentric, national pilot trial is designed to estimate the sustained virological response rate (SVR) following a 12 weeks treatment by telaprevir combined with a 48 or 72 weeks treatment by peginterferon and ribavirin, based upon the rapid virological response (RVR) at week 8 (4 weeks after telaprevir start), and to compare the observed SVR to 20%, a rate determining a significant therapeutic benefit in this population of patients. The primary endpoint will be the SVR defined as undetectable HCV-RNA measured 24 weeks after the end of therapy (EOT).

Full description

This phase II pilot trial is designed for HIV-1 and HCV genotype 1 coinfected patients who had previously failed a peginterferon-ribavirin regimen.

Intervention Design:

Induction, Lead-in, phase: day 0 to week 4 PegInterferon alpha-2a, 180 µg subcutaneous injection, once weekly + Ribavirin (weight-based dose) 1000 mg for subjects weighing <75 kg or 1200 mg for subjects weighing ≥75 kg, b.i.d.
Telaprevir phase: week 4 to week 16 PegInterferon alpha-2a, 180 µg subcutaneous injection, once weekly + Ribavirin (weight-based dose) 1000 mg for subjects weighing <75 kg or 1200 mg for subjects weighing ≥75 kg, b.i.d.
- Telaprevir 750 mg q 8h (or 1125 mg q 8h in association with Efavirenz)
Maintenance phase: week 16 to week 48 or 72 PegInterferon alpha-2a, 180 µg subcutaneous injection, once weekly + Ribavirin (weight-based dose) 1000 mg for subjects weighing <75 kg or 1200 mg for subjects weighing ≥75 kg, b.i.d.

The duration of the maintenance phase is determined by the RVR at week 8 (4 weeks after Telaprevir start.

Complete RVR (not measurable HCV-RNA at week 8): maintenance from week 16 to week 48

_Partial RVR (HCV-RNA below 1 000 UI/mL but still measurable at week 8): maintenance phase from week 16 to week 48

And stable antiretroviral treatment for over 3 months among the authorized combinations: (tenofovir 300 mg, emtricitabine 200 mg, atazanavir 300 mg, ritonavir 100 mg) q.d. or (tenofovir 300 mg, emtricitabine 200 mg, efavirenz 600 mg) q.d. or (tenofovir 300 mg, emtricitabine 200 mg q.d. and raltegravir 400 mg b.i.d.) once Drug-Drug interaction data will be available. Patients who could not receive one of these 3 combinations can be included if they are receiving a stable combination of at least 3 drugs among the following: tenofovir, emtricitabine/lamivudine, efavirenz, atazanavir-boosted or not, raltegravir (once Drug-Drug interaction data will be available). These patients cannot participate in the pharmacokinetic study.

The trial will enroll 80 subjects. The proportion of patients included, presenting with cirrhosis (METAVIR F4) will remain below 50% of all patients The proportion of patients included, null-responders to previous HCV treatment (HCV-RNA decline at week 12 less than 2 log10 UI/ml) but no cirrhosis (maximum equal METAVIR F3) will remain below 30% of patients.

Enrollment

70 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Informed consent form signed at screening visit at the latest
Patient registered with or covered by a social security scheme
HIV-1 infection
Chronic, genotype 1, hepatitis C with detectable HCV RNA at screening
Virological failure following a previous treatment of at least 12 weeks by peginterferon alpha-2a ≥ 135 µg once weekly or peginterferon alpha-2b ≥ 1.0 µg per kg once weekly + ribavirin ≥ 600 mg once daily. Virological failure defined by persistence of a detectable HCV-RNA, with the same genotype than before. Null responder patient, with less than 2 Log10 HCV-RNA decline at week 12 with cirrhosis are excluded from the study. Null responder patients without cirrhosis (equal or below METAVIR F3) are limited to less than 30 % of all patients included
No Interferon and/or Ribavirin within past 6 months
Stable antiretroviral treatment for over 3 months at screening. Authorized combinations: tenofovir-emtricitabine-boosted atazanavir,tenofovir-emtricitabine-efavirenz,tenofovir-emtricitabine-raltegravir, once Drug-Drug interaction data will be available. Patients with a stable combination of at least 3 of the following drugs: tenofovir, emtricitabine/lamivudine, efavirenz, atazanavir-boosted or not, raltegravir. These patients cannot participate in the pharmacokinetic study
CD4 >200/mm3 and >15% at screening
Plasma HIV-RNA <50 copies/mL for at least 6 months at screening visit
Body weight ≥ 40 kg to equal or below 125 kg
Fibrosis stage have to be documented by a significant liver biopsy (cumulative length ≥ 15 mm or ≥ 6 portal spaces), within 3 years. Patients with a previous liver biopsy exhibiting cirrhosis lesions (METAVIR F4) are allowed to enter the study without a new biopsy. The proportion of patients with cirrhosis lesions (METAVIR F4) is limited to 50% of all patients.
Male patients, female patients with child-bearing potency and their heterosexual partners must use an adequate contraception from 1 month before initiation of treatment to 7 months following the end of treatment for men and to 4 months following the end of treatment for women. Subjects (or their female partners) must not be pregnant or planning to become pregnant within 2 years after enrolling in the study

Exclusion criteria

Patient with liver failure (Child B and C) or past history of decompensated cirrhosis
Significant oesophageal varices (Stages 2-3) on a gastrointestinal endoscopy within 3 years
Detectable AgHBs
HIV-2 co-infection
Contra-indication to ribavirin or peginterferon
Severe pre-existing cardiac or pulmonary disease
Untreated dysthyroidism
Uncontrolled Type 2 diabetes
Optic neuritis past history and retinal condition
History of organ transplant
Severe hemoglobinopathy
Congenital QT prolongation, family history of congenital QT prolongation or sudden unexpected death
Contra-indication to telaprevir, hypersensitivity to any component of the drug product
Any disease requiring long term, systemic corticotherapy or immunosuppressive therapy during study
Alcohol intake that may represent an obstacle for the participation of the subject
Substance abuse that may represent an obstacle for the participation of the subject
Acute CDC stage C opportunistic infection within the previous 6 months
Past history of cancer within the previous 5 years (except skin basal cell carcinoma, Kaposi's disease in stable remission, in situ cervical cancer and in situ anal cancer)
Any active malignant disease including hepatocellular carcinoma
Patients unable to observe the study procedures
Participation to another clinical trial within the previous 30 days
Haemoglobin <120 g/L for women and <130 g/L for men
Platelets <90 000/mm3
Neutrophils <1 500/mm3
Renal insufficiency defined by an estimated Glomerular Filtration Rate < 60 mL/mn (MDRD equation)
Associated medication susceptible to interfere with the pharmacokinetic parameters of telaprevir and/or antiretroviral associated drugs