Feasibility, Tolerance and Efficacy of Interferon-free, Antiviral Treatment With Sofosbuvir + Ribavirin for the Treatment of Genotype 2 and Sofosbuvir/Ledipasvir for the Treatment of Genotype 1 and 4 Hepatitis C Virus-infected Patients in West and Central Africa

Study Overview
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Brief Summary
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Primary Objective: To evaluate the efficacy (sustained virological response 12 weeks after end-of-treatment [SVR12]) of 12-week course of an interferon-free regimen combining sofosbuvir and weight-dosed ribavirin (genotype 2), or sofosbuvir and ledipasvir (genotype 1 or 4) in treatment-naïve patients infected with HCV genotype 1, 2 or 4 in West and Central Africa Secondary Objectives: To estimate the study treatment SVR24 rate To evaluate the clinical and biological tolerance of study treatment To describe HCV kinetics under HCV treatment, and identify associated factors To describe the evolution of HIV disease under HCV treatment in HVC-HIV co-infected patients To describe the changes of liver fibrosis based on non-invasive tests between treatment initiation, week 24, and week 36 after treatment, and estimate its association with SVR12 or SVR24 To identify factors associated with SVR12 and SVR24 (including HIV status) To evaluate the performance of a nanodevice for rapid diagnosis of HCV viral load and genotypying and for assessing response to treatment (SVR12 and SVR24) Facilitate the detection and treatment of those infected with HCV by supporting national initiatives for access to strategies without interferon To set up a HCV clinical research network across French and English-speaking African countries, able to run large-scale comparative randomized clinical trials in a near future.

Detailed Description
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Study design Multicenter, phase IIb, non randomized, open-label trial involving 3 groups of HCV-mono infected or HCV-HIV co-infected patients: group G1 (patients infected with HCV genotype 1), group G2 (patients infected with HCV genotype 2), and group G4 (patients infected with HCV genotype 4). Number of Subjects A sample size of 40 patients per group will allow to demonstrate that the SVR12 is >70% (expected efficacy in difficult-to-treat patients, according to SPARE interim results), with the lower bound of the confidence interval being >50% (unacceptable efficacy). The overall sample size is 3x40=120 patients. Participating Countries 3 countries from West Africa (Senegal, Côte d'Ivoire) and Central Africa (Cameroon) Number of Sites 5 clinical sites: Côte d'Ivoire: Hepatology Departementat the Yopougon University Teaching Hospital, , Abidjan; and Blood Donors clinic (CMSDS) at the National Blood Bank (CNTS), Abidjan Senegal: CRCF (Centre Régional de Recherche et de Formation), and Fann University Teaching Hospital Cameroon: Clinique de la Cathédrale Duration of Recruitment : 6 months Duration of Treatment : 12 weeks Duration of follow-up : 36 weeks Anticipated Start Date / Anticipated End Date: November 2015 - October 2016 Target Population /Demographics : Patients >18 years, living with chronic hepatitis C genotype 1, 2 or 4, in West and Central Africa. In each genotype group approx. 50% of patients will be HCV-HIV co-infected, and 50% of patients will be mono-infected with HCV This study will enable us to assess the feasibility, tolerance and efficacy of such a strategy in resource-constrained settings with considerable treatment needs.

Official Title
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TAC (Treatment Africa Hepatitis C) : Feasibility, Tolerance and Efficacy of Interferon-free, Antiviral Treatment With Sofosbuvir + Ribavirin for the Treatment of Genotype 2 and Sofosbuvir/Ledipasvir for the Treatment of Genotype 1 and 4 Hepatitis C Virus-infected Patients in West and Central Africa

Conditions
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Hepatitis C, HIV Infection

Intervention / Treatment
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* Drug: Sofosbuvir
* Drug: Ribavirin
* Drug: Sofosbuvir
* Drug: Ledipasvir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥18 years Confirmed G1, G2 or G4 HCV infection Plasma HCV-RNA ≥1000 IU/mL No history of HCV treatment of any kind Willingness to use a birth control method (hormonal or intrauterine device for women, condoms for men), starting before HCV treatment initiation and continued until 4months (women) and 7 months (men) after end of treatment. Weight ≥40 kg and ≤125 kg For patients infected with HIV : Confirmed HIV-1 infection Stable HIV treatment for at least 8 weeks with two NRTIs (tenofovir or abacavir, and lamivudine or emtricitabine) and a third agent (raltegravir, lopinavir/ritonavir, atazanavir/ritonavir, darunavir/ritonavir, efavirenz, nevirapine) Current CD4+ lymphocytes count ≥100/mm3 Current plasma HIV-1 RNA <200 copies/mL Exclusion Criteria: For each patient: Cirrhosis classified Child-Pugh B or C Co-infection by the Hepatitis B virus Pregnant or breastfeeding ongoing History of transplantation of organs or tissues Progressive Cancer, including hepatocellular carcinoma Epilepsy Sickle Cell Disease A history of myocardial infarction or other severe heart disease Excessive consumption of alcohol or drug users, in the absence of substitution by methadone, a stable weaning for more than three months should be required Ongoing Participation in another clinical trial Contraindications to the Sofosbuvir as defined in the Summary of Product Characteristics At least one of the following laboratory abnormalities: Haemoglobin <10 g / 100 ml (woman) <11 g / 100 ml (man) Platelet count <50,000 / mm3 polymorphonuclear neutrophils rate <750 / mm3 Creatinine clearance <50ml / min For patients infected with HIV: Severe opportunistic infections in the last 6 months Poor adherence to antiretroviral treatment history Use of antiretroviral drugs other than those permitted in the test

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sofosbuvir+Ribavirin<br>Sofosbuvir 400mg QD (Sovaldi®) + Ribavirin weight-adjusted dosing (1000mg BID in patients < 75kg and 1200mg BID in patients ≥ 75kg) in treatment-naïve patients infected with HCV genotype 2 (12-week course) | Drug: Sofosbuvir<br>* Sofosbuvir 400mg QD (Sovaldi®) in treatment-naïve patients infected with HCV genotype 2 (12-week course)<br>* Other names: Sovaldi®;Drug: Ribavirin<br>* Ribavirin weight-adjusted dosing (1000mg BID in patients < 75kg and 1200mg BID in patients ≥ 75kg) in treatment-naïve patients infected with HCV genotype 2 (12-week course)<br>|
| Experimental: Sofosbuvir+Ledipasvir<br>Sofosbuvir/Ledipasvir 400mg/90mg (Harvoni®) in treatment-naïve patients infected with HCV genotype 1 or genotype 4 (12-week course) | Drug: Sofosbuvir<br>* Sofosbuvir/Ledipasvir 400mg/90mg (Harvoni®) in treatment-naïve patients infected with HCV genotype 1 or genotype 4 (12-week course)<br>* Other names: Harvoni®;Drug: Ledipasvir<br>* Sofosbuvir/Ledipasvir 400mg/90mg (Harvoni®) in treatment-naïve patients infected with HCV genotype 1 or genotype 4 (12-week course)<br>* Other names: Harvoni®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Viral Load Response (SVR) |  | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance | Grade 1, 2, 3 and 4 clinical or biological events (ACTG grading table), Adverse events-related HCV treatment discontinuation Adverse events-related ARV treatment modification | 36 weeks | 
| Viral kinetics as measured by SVR 24 and HCV-RNA | SVR 24 and HCV-RNA | W0, W2, W4, W12, W24, W36 | 
| HIV treatment clinical parameters | Number, nature and incidence of severe morbid events related to HIV, and clinical and biological events of grade 3 or 4 (ANRS scale) related to the ARV treatment | 36 weeks | 
| Liver fibrosis | Elastometry score and only for cirrhotic patients : Child-Pugh score | W0, W24 and W36 | 
| Adherence measured by number of remaining tablets at each visit based on the number of tablets should have been taken as a percentage of the total dose | Number of remaining tablets at each visit based on the number of tablets should have been taken as a percentage of the total dose | W4, W8, W12 | 
| Quality of life | proportion of people reporting symptoms in the scale of symptoms experienced (scale of side effects perception SF12) | 36 weeks | 
| Performance of an unit of nanotechnology | calculation of sensitivity / specificity / positive predictive value and negative of each of the steps that will be performed (genotype, viral load) compared to the reference measurement (PCR for viral load and sequencing to genotype). | 36 weeks | 
| Setting up the network: | number of network meetings that have taken place before the end of the trial, the number of training sessions (on site or online) and the numbers enrolled in the network active partners. The ultimate goal is the establishment of an e-learning platform that will be an ancillary project. | 36 weeks | 
| Integration Access initiatives evaluated by the number of patients off protocol that will have access to new anti-HCV treatment due to ACCESS programs of pharmaceutical companies conducting such programs in Sub-Saharan Africa | It will be evaluated by the number of patients off protocol that will have access to new anti-HCV treatment due to ACCESS programs of pharmaceutical companies conducting such programs in Sub-Saharan Africa | 36 weeks | 
| Biological events | Plasma HIV-RNA and CD4 count | W0, W24 and W36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Africa, Hepatitis C, HIV, Antiviral treatment, Adults, HCV genotype 1, HCV genotype 2, HCV genotype 4