Pilot Study to Assess Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-dose Combination in Treatment Experienced Subjects With Hepatitis C Virus (HCV) Genotype 1 - HIV Co-infection

Study Overview
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Brief Summary
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Aim of the study is to assess the efficacy and safety of 24 weeks of oral Sofosbuvir/Ledipasvir fixed-dose combination (FDC) in subjects with HCV genotype 1 infection and HIV co-infection, who have previously failed a NS3/4A protease inhibitor plus Pegylated interferon /ribavirin regimen or stopped prematurely their treatment for intolerance.

Official Title
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Pilot Study to Assess Efficacy and Safety of Sofosbuvir/Ledipasvir (GS-5885) Fixed-dose Combination in NS3/4A Protease Inhibitor-experienced Subjects With HCV Genotype 1 Infection and HIV Co-infection

Conditions
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HIV, Viral Hepatitis C

Intervention / Treatment
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* Drug: Sofosbuvir/Ledipasvir fixed dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV infection Infection with HCV genotype 1 only, confirmed at screen visit, with a HCV-RNA ≥ 1000 InternationalUnit(IU)/mL at screen visit Treatment-experienced subjects with: previous virological failure to tritherapy with Peginterferon/Ribavirin and protease inhibitor, or premature discontinuation of previous tritherapy with Peginterferon/Ribavirin and protease inhibitor due to intolerance to Peginterferon or protease inhibitor Anti-HCV treatment stopped for at least the last 3 months Patients on a stable (for more than 1 month) antiretroviral treatment consisting of an emtricitabine/tenofovir or lamivudine/tenofovir standard of care backbone plus efavirenz or raltegravir or rilpivirine or enfuvirtide. Alternative combinations of the above listed medications may be allowed. Dendritic cells 4 > 100/mm3 and > 15% at screen visit HIV-RNA < 50cp/ml for more than 3 months at screen visit Any liver fibrosis grade, with the assessment of the presence or not of cirrhosis at screening, cirrhosis being defined as a METAVIR score of F4 on the liver puncture biopsy and/or with hepatic impulse elastometry ≥ 14,5 kilopascal (kPa): Previous liver biopsy exhibiting cirrhosis lesions (METAVIR F4), and/or significant liver biopsy (cumulative length ≥ 15mm or ≥ 5 portal spaces), within the past 18 months and/or significant and reliable liver stiffness assessment (Fibroscan®) within the past 6 months (at least 10 measures with IQR less than 30% of the median value and a success rate of at least 70%). Female patients with child-bearing potential, and their heterosexual partners must use adequate contraception from the date of screening until 90 days after administration of the last dose of study drug. Male participants must agree to consistently and correctly use a condom, while their female partner must use adequate contraception from the date of screening until 90 days after administration of the last dose of study drug Body weight ≥40 kg and ≤125 kg Informed and signed consent for the main study and the Pharmacokinetic (PK ) sub-study (for the participating patients) Patients with Health insurance Non inclusion Criteria: Child-Pugh B or C cirrhosis or history of decompensated cirrhosis. Co-infection with Hepatitis B virus (HBV) (AgHBs +) with HBV DNA > 1000 UI/ml Pregnant or breast-feeding women Transplant recipients Opportunistic infections (stage C), active or occurred within 6 months prior to baseline Evolutive malignancy, including hepatocarcinoma which should be controlled prior to baseline Alcohol or drug consumption which may affect the study participation according to the investigator. Patients included in a programme of substitution with methadone or buprenorphine could be enrolled. The opinion of a consultant in addictology is recommended for patients presenting with current drug use or drug use during the previous year. Patients with a history of non-adherence, who will be at risk of being unable to respect the study follow-up timetable Patients participating in another clinical trial within 30 days prior to inclusion Hb < 10 g/dL (female) or < 11g/dL (male) Platelets < 50 000/mm3 Neutrophil count < 750/mm3 Renal failure defined as creatinin clearance (MDRD) < 60ml/min Other antiretroviral drugs than those allowed in the study Contra-indications to Sofosbuvir, Ledipasvir Contra-indicated treatment likely to interfere with the study drugs as listed in the protocol

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sofosbuvir/Ledipasvir<br>Non-cirrhotic patients will receive SOF/LDV Fixed Dose Combination (FDC) for 12 weeks. Cirrhotic patients will receive SOF/LDV Fixed Dose Combination (FDC) for 24 weeks. | Drug: Sofosbuvir/Ledipasvir fixed dose<br>* SOF 400 mg/LDV 90 mg FDC tablet administered orally once daily<br>* Other names: Ledipasvir is also known as GS-5885.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virologic response 12 weeks after discontinuation of therapy (SVR12), i.e. at week 36. |  | 12 weeks post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse clinical and biological events that occur during the treatment and up to 24 weeks after the end of the treatment |  | up to 24 weeks after the end of the treatment | 
| Number and causes of poor adherence and treatment interruptions |  | at 1,2,3,4,8,12,16, 20, 24 weeks during treatment, 4, 8,14,18,24 weeks after treatment discontinuationeeks after discontinuation of drugs | 
| SVR rate 24 weeks (i.e. W48) after the end of treatment and according to the HCV sub-type |  | Week 48 | 
| Number of patients with HCV resistance mutations to Sofosbuvir and/or Ledipasvir |  | from Day(D)0 to Week (W)24 | 
| HCV viral load |  | at Day 0, Week 1, 2, 4, 8, 12, 16, 20, week 24, and 4, 8, 12, 18 and 24 weeks after the end of the treatment | 
| Plasma HIV RNA levels |  | at Day 0, Week 4, 8, 12, 16, 20, 24, 36 and Week 48 | 
| Assess drug-drug interactions between HCV et HIV drugs | Describe pharmacokinetic parameters of HIV drugs at Day 0 and Week 4 Describe pharmacokinetic parameters of Sofosbuvir and Ledipasvir at Week 4 | Day 0 and Week 4 | 
| Patient's reported outcomes evaluation |  | Day 0, Week 12, Week 24 and Week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCV/HIV coinfection, HCV genotype 1