Clinical trial NCT01335529: Boceprevir in HIV-HCV Coinfected Patients Who Have Failed to a Previous Therapy With Peg-Interferon/Ribavirin
Official title: Pilot Study to Assess the Efficacy and Safety of Boceprevir, in Combination With Peg-Interferon Alfa and Ribavirin, in Patients With HCV/HIV Co-infection Who Have Failed to a Previous Therapy With Peg-Interferon/Ribavirin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HCV Coinfection
HIV-1 Infection
Keywords: HCV infection
HIV-1 infection
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Rennes University Hospital
name: Merck Sharp & Dohme LLC
First posted: 2011-04-14
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The majority of Human immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) co-infected patients are non responders after 48 weeks of the current standard-of-care with Peg-Interferon/Ribavirin. The results of re-treatment are disappointing. The addition of Boceprevir to the current standard-of-care has been shown to increase the efficacy of therapy in HCV mono-infected patients previously treated with a bi-therapy. Knowing that HIV/HCV co-infected patients are subject to more rapid hepatic fibrosis as well as to increased risks of cirrhosis, end-stage liver disease and hepatocellular carcinoma, it is important to improve the response rate of the re-treatment of hepatitis C in these patients.

The aim of this pilot study is to evaluate the efficacy and safety of Boceprevir in combination with Peg-Interferon alfa 2b plus ribavirin, in patients co-infected with HIV and chronic genotype 1 HCV, and previously treated with Peg-Interferon/Ribavirin. 80 subjects will be enrolled. The primary endpoint will be the Sustained Virologic Response (SVR) defined as undetectable HCV-RNA at Week 24 after the end of therapy.

Detailed description: The majority of HIV/HCV co-infected patients are non responders after 48 weeks of the current standard-of-care with Peg-Interferon/Ribavirin. The results of re-treatment are disappointing. The addition of Boceprevir to the current standard-of-care has been shown to increase the efficacy of therapy in HCV mono-infected patients previously treated with a bi-therapy. Knowing that HIV/HCV co-infected patients are subject to more rapid hepatic fibrosis as well as to increased risks of cirrhosis, end-stage liver disease and hepatocellular carcinoma, it is important to improve the response rate of the re-treatment of hepatitis C in these patients.

Subjects enrolled in this trial will have many predictive factors of failure: HIV co-infection, previous failure to Peg-Interferon/Ribavirin, HCV genotype 1 infection. One study reported a SVR rate of 9% after re-treatment with Peg-Interferon/Ribavirin in such patients. Another trial has shown a substantial increase of the response rate with a tri-therapy in HCV mono-infected patients.

The investigators propose to carry out a multicentric, national, non-randomized phase II trial in 80 patients.

The proportion of patients with F4 cirrhosis will have to be inferior to 50% of enrolled subjects.

The number of null responders to a previous treatment (HCV RNA drop \< 2 log10 at W12) and without F4 cirrhosis will have to be lower or equal to 20.

The primary objective of the study is to estimate, in Genotype 1 - HCV/HIV co-infected patients, non responders to a previous therapy with Peg-Interferon/Ribavirin, the rate of SVR after 48 or 72 weeks of a three-drug regimen containing Peg-Interferon, Ribavirin and Boceprevir according to the Virologic Response and to compare the SVR rate to a threshold rate 20%, lowest rate to consider a therapeutic benefit in this population.

A pharmacokinetic sub-study including 30 patients will be performed to estimate pharmacokinetic parameters of antiretroviral treatment (Atazanavir combined with Ritonavir, Raltegravir, Tenofovir) in combination with anti HCV treatment at baseline and W8 and pharmacokinetic parameters of Boceprevir at W8.

Eligibility criteria: Inclusion Criteria:

* Adult ≥18 years
* HIV-1 infection
* Infection to genotype 1 HCV only
* Patients must have received at least 12 weeks of treatment with Peg-Interferon alfa 2a ≥ 135 µg / once weekly or Peg-Interferon alfa 2b ≥ 1,0 µg/kg/ once weekly + Ribavirin ≥ 600 mg daily and must have failed to treatment.
* Anti-HCV treatment stopped for at least 6 months
* Patients must be already treated at screen since at least 3 months with a stable combination of antiretroviral treatment as following:

  * Either tenofovir - emtricitabine, and atazanavir in combination with ritonavir
  * Or tenofovir - emtricitabine, and raltegravir
  * If patients cannot receive neither of the two antiretroviral regimens proposed, for virologic, safety or toxicity reasons, patients could receive any effective antiretroviral therapy including : tenofovir, emtricitabine, lamivudine, atazanavir alone or in combination with ritonavir, raltegravir, abacavir. These patients are not allowed to take part in the pharmacokinetic sub-study.
* CD4 \> 200/mm3 et \>15%, at screen
* HIV-RNA \< 50 copies/ml since at least 6 months at screen
* ≥ 40 Kg and ≤ 125 Kg
* Patients with any fibrosis grade. Proportion of F4 subjects should not excess 50% of the overall subjects.
* Male and female subjects must agree to use acceptable methods of contraception 1 month prior to starting the study treatment and to continue until 7 months after the last doses of study drugs for male subjects and their partner(s), 4 months for female subjects.
* Subjects must be willing to give written informed consent for principal study (signed at least at screen visit and prior to any study investigation)and + for the pharmacokinetic sub-study (for the concerned centers).
* Subjects must be willing to give written informed consent for biological collection.
* Subjects must be willing to give written informed consent for treatment of genetics data.
* Subjects affiliated or beneficiary to a medical insurance.

Exclusion Criteria:

History:

* Patients with cirrhosis (F4) and nul responders to prior treatment
* Cirrhosis classified Child-Pugh B or C or history of decompensated cirrhosis of the liver. If Child A classification, significant varicose veins (grade 2 or 3) observed with a fibroscopy realized for \< 3 years.
* History of ocular neuritis, retinal disorders, transplant
* Opportunistic infections (classification C), active or occurred within the 6 months prior to baseline.
* History of neoplasia within the last 5 years, except cutaneous basocellular carcinoma, recovering Kaposi's sarcoma, in situ cervical or anal canal cancer.

Current condition:

* Co-infection with Hepatitis B virus
* Pregnancy and lactation
* Cardiac or severe pulmonary disease
* Untreated dysthyroidism
* Autoimmune disease contraindicating to an interferon treatment
* Severe haemoglobinopathies
* Any condition needing a systemic corticotherapy or an immunosuppressive treatment
* Evolutive current malignancy, including hepatocarcinoma which should be specifically controlled prior to baseline.
* Alcohol consumption which may disturb the study participation according to the investigator
* Drug addiction which may disturb the study participation according to the investigator. Patients taking part to a substitution program with methadone or buprenorphine are allowed to be enrolled in the study.

Biological criteria:

• Haemoglobin \< 12 g/dL (female) or \< 13g/dL (male), Platelets \< 90 000/mm3, Neutrophil count \< 1500/mm3, Renal failure defined as creatinine clearance \< 50ml/min, Uncontrolled thyroid function, HbA1c ≥ 7% in case of diabetes

Criteria related to study drugs

* Contra-indication to Ribavirin, interferon treatment including psychiatric contra-indications.
* History of discontinuation for intolerance to anti-HCV treatment.Patients with a history of discontinuation for intolerance, especially anaemia or leuconeutropenia, and who were not treated with hematopoietic growth factor, are eligible
* Concomitant medication which may interfere with Boceprevir, atazanavir, ritonavir and raltegravir pharmacokinetic
* St.John's-wort consumption

Primary outcomes:
measure: Sustained Virologic Response
timeFrame: Week 72 or Week 96 (W72 or W96)
Secondary outcomes:
measure: HCV viral load
timeFrame: W4, W8, W12, W16, W28, W36 and at treatment completion at W48/72
measure: Predictive factors of Sustained virologic Response (SVR)
timeFrame: Baseline
measure: HIV virologic endpoints
timeFrame: W4, W8, W12, W16, W20, W24, W28, W32, W36, W40, W44, W48, W60, W72 and W84, W96 if treatment duration is 72 weeks
measure: Residual plasmatic concentration (Cres) of Ribavirin
timeFrame: W4 and W8
measure: Hepatic factors: liver fibrosis score
timeFrame: Screen, W4, W8, W16, W28, W48, W72, W96.
measure: Alcohol consumption
timeFrame: W4, W8, W16, W28, W48, W72, W96
measure: Evaluation of Pharmacokinetic parameters of anti-retroviral treatments
timeFrame: Day 0, W8
measure: Clinical and biological adverse events
timeFrame: Up to 24 weeks after treatment completion (W72 or W96)
measure: Number of participants classified by virologic failure type: non responder, relapser, null responder
timeFrame: W8, W12, W16, W28, W48, W72, W96
measure: ITPA gene polymorphism
timeFrame: Day 0
measure: CYP3A4 Polymorphism
timeFrame: W8
measure: Maximal Concentration (Cmax) of antiretroviral treatments
timeFrame: Day 0 and W8
measure: Area Under the Curve (AUC) of antiretrovirals
timeFrame: Day 0 and W8
measure: Insulin resistance
timeFrame: at W4, W8, W16, W28, W48, W72, W96
measure: Metabolic syndrome
timeFrame: W4, W8, W16, W28, W48, W72, W96
measure: Reasons and dates of treatment discontinuation
timeFrame: Up to W72
measure: Perceived symptoms
timeFrame: Day 0, W28, W48, W72, W96
measure: French AIDS questionnaire of compliance
timeFrame: W0, W28, W48, W72
measure: Tobacco consumption
timeFrame: W4, W8, W16, W28, W48, W72, W96
measure: Cannabis consumption
timeFrame: W4, W8, W16, W28, W48, W72, W96
measure: Intravenous/nasal drugs consumption
timeFrame: W4, W8, W16, W28, W48, W72, W96
measure: Residual Concentration (Cres) of atazanavir boosted or not by ritonavir
timeFrame: At screening day, at W48 and in the case of virological rebound
measure: Residual concentration (Cres) of ritonavir
timeFrame: At screening day, at W48 and in the case of virological rebound
Other outcomes:
Locations:
city: Marseille
country: France
facility: CHU Sainte Marguerite
Study officials:
affiliation: University Hospital, Marseille
name: Isabelle Poizot-Martin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rennes University Hospital
name: Eric Bellissant, MD, PhD
role: STUDY_CHAIR
References:
citation: Poizot-Martin I, Bellissant E, Garraffo R, Colson P, Piroth L, Solas C, Renault A, Bourliere M, Halfon P, Ghosn J, Alric L, Naqvi A, Carrieri P, Molina JM; ANRS HC27 BOCEPREVIH Study Group. Addition of boceprevir to PEG-interferon/ribavirin in HIV-HCV-Genotype-1-coinfected, treatment-experienced patients: efficacy, safety, and pharmacokinetics data from the ANRS HC27 study. HIV Clin Trials. 2016 Mar;17(2):63-71. doi: 10.1080/15284336.2015.1135553. Epub 2016 Feb 11.