HIV-1 Infection Clinical Trial
— BocepreVIHOfficial 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
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.
Status | Completed |
Enrollment | 69 |
Est. completion date | May 2014 |
Est. primary completion date | May 2014 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years and older |
Eligibility |
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 |
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
France | CHU Sainte Marguerite | Marseille |
Lead Sponsor | Collaborator |
---|---|
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS) | Merck Sharp & Dohme Corp., Rennes University Hospital |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Sustained Virologic Response | HCV-RNA measured 24 weeks after the end of the HCV treatment (W72 or W96) | Week 72 or Week 96 (W72 or W96) | No |
Secondary | HCV viral load | HCV-RNA | W4, W8, W12, W16, W28, W36 and at treatment completion at W48/72 | No |
Secondary | 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 |
Baseline | No |
Secondary | HIV virologic endpoints | HIV-RNA CD4 and CD8 count |
W4, W8, W12, W16, W20, W24, W28, W32, W36, W40, W44, W48, W60, W72 and W84, W96 if treatment duration is 72 weeks | No |
Secondary | Residual plasmatic concentration (Cres) of Ribavirin | W4 and W8 | No | |
Secondary | 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). | Screen, W4, W8, W16, W28, W48, W72, W96. | No |
Secondary | Alcohol consumption | W4, W8, W16, W28, W48, W72, W96 | No | |
Secondary | 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. | Day 0, W8 | No |
Secondary | Clinical and biological adverse events | Up to 24 weeks after treatment completion (W72 or W96) | Yes | |
Secondary | 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 |
W8, W12, W16, W28, W48, W72, W96 | No |
Secondary | ITPA gene polymorphism | The relation between ITPA gene polymorphism and onset of haemolytic anaemia will be analysed. | Day 0 | No |
Secondary | 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. | W8 | No |
Secondary | 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. | Day 0 and W8 | No |
Secondary | 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. | Day 0 and W8 | No |
Secondary | 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). | at W4, W8, W16, W28, W48, W72, W96 | No |
Secondary | 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). | W4, W8, W16, W28, W48, W72, W96 | No |
Secondary | Reasons and dates of treatment discontinuation | Up to W72 | Yes | |
Secondary | Perceived symptoms | Perceived symptoms will be assessed on "AC24 French AIDS scale" | Day 0, W28, W48, W72, W96 | Yes |
Secondary | French AIDS questionnaire of compliance | W0, W28, W48, W72 | Yes | |
Secondary | Tobacco consumption | W4, W8, W16, W28, W48, W72, W96 | No | |
Secondary | Cannabis consumption | W4, W8, W16, W28, W48, W72, W96 | No | |
Secondary | Intravenous/nasal drugs consumption | W4, W8, W16, W28, W48, W72, W96 | No | |
Secondary | 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). | At screening day, at W48 and in the case of virological rebound | No |
Secondary | 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). | At screening day, at W48 and in the case of virological rebound | No |
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