Boceprevir in HIV-HCV Coinfected Patients Who Have Failed to a Previous Therapy With Peg-Interferon/Ribavirin

ANRS, Emerging Infectious Diseases69 enrolled

Overview

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.

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

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Sustained Virologic Response

HCV-RNA measured 24 weeks after the end of the HCV treatment (W72 or W96)

Time frame: Week 72 or Week 96 (W72 or W96)

Secondary Outcomes

HCV viral load

HCV-RNA

Time frame: W4, W8, W12, W16, W28, W36 and at treatment completion at W48/72

Predictive factors of Sustained virologic Response (SVR)

* Sex * Age (\< vs ≥ 40 years) * Risk factor of HIV infection (drug consumer versus other risk factors) * Risk factor of HCV infection (drug consumer versus other risk factors) * Ethnic origin (Africano-American or Subsaharian-African or West Indies versus others) * CDC stade (C vs. A-B) * CD4 number (\< vs. ≥ 350/mm3) * HCV viral load (\< versus ≥ 800 000 UI/ml) * HCV genotype (1a versus 1b) * Cirrhosis (F4 versus no cirrhosis) * Alcohol, tobacco, cannabis, intravenous/nasal drugs consumption * IL28 gene polymorphism

Time frame: Baseline

HIV virologic endpoints

* HIV-RNA * CD4 and CD8 count

Time frame: W4, W8, W12, W16, W20, W24, W28, W32, W36, W40, W44, W48, W60, W72 and W84, W96 if treatment duration is 72 weeks

Residual plasmatic concentration (Cres) of Ribavirin

Time frame: W4 and W8

Hepatic factors: liver fibrosis score

Evolution of liver fibrosis between baseline and 24 weeks post-treatment, according to baseline value and Sustained Virologic Response (at W4, W8, W16, W28, W48/72 and 24 weeks post-treatment).

Time frame: Screen, W4, W8, W16, W28, W48, W72, W96.

Alcohol consumption

Time frame: W4, W8, W16, W28, W48, W72, W96

Evaluation of Pharmacokinetic parameters of anti-retroviral treatments

Pharmacokinetic parameters (Cres, Cmax, AUC) of anti-retroviral treatments before (baseline) and after (W8) the starting of Boceprevir combination in a sub-group of subjects and according to UGTA1 polymorphism.

Time frame: Day 0, W8

Clinical and biological adverse events

Time frame: Up to 24 weeks after treatment completion (W72 or W96)

Number of participants classified by virologic failure type: non responder, relapser, null responder

* Relapse patients: undetectable HCV RNA at the end of therapy, becoming detectable after treatment cessation. * Break-through patients: undetectable HCV-RNA at least once during treatment, becoming detectable before treatment cessation. * Non-responder patients: detectable HCV-RNA at W24, never achieved undetectable and HCV RNA drop ≥ 2 log at W12. * Null responder patients: HCV RNA drop \< 2 log at W12

Time frame: W8, W12, W16, W28, W48, W72, W96

ITPA gene polymorphism

The relation between ITPA gene polymorphism and onset of haemolytic anaemia will be analysed.

Time frame: Day 0

CYP3A4 Polymorphism

Evaluation of Pharmacokinetic parameters (Cres, Cmax, AUC) of Boceprevir at W8 in a sub-group of subjects, according to antiretroviral treatment and CYP3A4 polymorphism.

Time frame: W8

Maximal Concentration (Cmax) of antiretroviral treatments

Evaluation of Pharmacokinetic parameters (Cres, Cmax, AUC) of anti-retroviral treatments before (baseline) and after (W8) the starting of Boceprevir combination in a sub-group of subjects and according to UGTA1 polymorphism.

Time frame: Day 0 and W8

Area Under the Curve (AUC) of antiretrovirals

Evaluation of pharmacokinetic parameters (Cres, Cmax, AUC) of anti-retroviral treatments before (baseline) and after (W8) the starting of Boceprevir combination in a sub-group of subjects and according to UGTA1 polymorphism.

Time frame: Day 0 and W8

Insulin resistance

Evolution of insulin resistance between baseline and 24 weeks post-treatment according to baseline value and Sustained Virologic Response (at W4, W8, W16, W28, W48/72 and 24 weeks post-treatment).

Time frame: at W4, W8, W16, W28, W48, W72, W96

Metabolic syndrome

Evaluation of metabolic syndroms parameters according to baseline value and Sustained Virologic Response (at W4, W8, W16, W28, W48/72 and 24 weeks post-treatment).

Time frame: W4, W8, W16, W28, W48, W72, W96

Reasons and dates of treatment discontinuation

Time frame: Up to W72

Perceived symptoms

Perceived symptoms will be assessed on "AC24 French AIDS scale"

Time frame: Day 0, W28, W48, W72, W96

French AIDS questionnaire of compliance

Time frame: W0, W28, W48, W72

Tobacco consumption

Time frame: W4, W8, W16, W28, W48, W72, W96

Cannabis consumption

Time frame: W4, W8, W16, W28, W48, W72, W96

Intravenous/nasal drugs consumption

Time frame: W4, W8, W16, W28, W48, W72, W96

Residual Concentration (Cres) of atazanavir boosted or not by ritonavir

Measure of residual concentration of atazanavir for patients treated by atazanavir boosted or not by ritonavir at screening day, at W48 and in case of virological rebound (HIV and HCV).

Time frame: At screening day, at W48 and in the case of virological rebound

Residual concentration (Cres) of ritonavir

Measure of residual concentration of ritonavir for patients treated by atazanavir boosted by ritonavir at screening day, at W48 and in case of virological rebound (HIV and HCV).

Time frame: At screening day, at W48 and in the case of virological rebound

Boceprevir in HIV-HCV Coinfected Patients Who Have Failed to a Previous Therapy With Peg-Interferon/Ribavirin

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes