Dutch Acute HCV in HIV Study (DAHHS-2): Grazoprevir/Elbasvir for Acute HCV

Study Overview
=================
Brief Summary
-----------------
New and recently EMA/FDA approved direct acting antiviral (DAA) combination therapies cure 95% or more of the patients chronically infected with HCV genotype 1 and 4. Grazoprevir (MK-5172) and elbasvir (MK-8742) combination therapy is such a, albeit not yet EMA/FDA approved combination DAA therapy. It is likely that the synergistic effect of the host's immune response and antiviral therapy when given during the first 6 months of HCV infection makes antiviral therapy during acute HCV infection more effective. In this study the investigators would like to document that treatment of acute HCV with grazoprevir (MK-5172), elbasvir (MK-8742) is effective and can ben shortened from 12 to 8 weeks for HCV genotype 1 and 4 infection without substantial loss in efficacy. Study design and intervention: Prospective open label interventional clinical trial in which 80 acute HCV genotype 1 or 4 patients co-infected with HIV will receive 8 weeks of grazoprevir and elbasvir (a once-daily combination tablet). Study population: 80 Adult HIV positive patients with an acute HCV genotype 1 or 4 infection from 10 HIV treatment centers in the Netherlands and Belgium will be included. Primary endpoint: Sustained viral response (SVR) 12 weeks after the end of therapy in ITT study population (=genotype 1 and 4).

Detailed Description
-----------------
Rationale: Over the last 2 years, the treatment of chronic HCV underwent an enormous change in a positive way. New and recently EMA approved direct acting antiviral (DAA) combination therapies cure as 95% or more of the patients chronically infected with HCV genotype 1 and 4. Grazoprevir (MK-5172) and elbasvir (MK-8742) combination therapy is such a combination DAA therapy. Two recent phase II and 1 phase III clinical trial showed that chronic HCV genotype 1 can be cured with 12 weeks of combination therapy with grazoprevir and elabsvir with a 97% cure in HIV-HCV co-infected patients in the phase III C-Edge co-infection study. However, none of these new HCV therapies have been well studied for the treatment of acute HCV and are therefore not registered for this indication. The only treatment approved for acute HCV is interferon. Interferon based therapy for the treatment of HCV has been shown to be much more effective when given during the acute phase of the HCV infection than at a time when the infection has become chronic. A likely explanation for this difference in success for acute versus chronic HCV therapy is a substantial immune response that is present during the acute phase of HCV infection, but becomes exhausted during chronic infection. This potent immune response is broadly targeted against various HCV epitopes and eradicates approximately 20% of HCV infections within the first 12 to 18 months of infection. However, spontaneous cure of HCV becomes very rare after the first 12 to 18 months of infection due to immune exhaustion. It is likely that the synergistic effect of the host's immune response and antiviral therapy when given during the first 6 months of HCV infection makes direct acting antiviral therapy during acute HCV infection more effective. Objectives: To document that treatment of acute HCV with grazoprevir (MK-5172), elbasvir (MK-8742) is effective. To show that, due to the host's immune response at the time of an acute HCV infection, the duration of therapy with grazoprevir (MK-5172) and elbasvir (MK-8742) for acute HCV genotype 1 and 4 infections can be shortened from 12 to 8 weeks without substantial loss in efficacy.

Official Title
-----------------
Grazoprevir (MK-5172)+ Elbasvir (MK-8742) for the Treatment of Acute Hepatitis C Genotype 1/4. The Dutch Acute HCV in HIV Study (DAHHS-2)

Conditions
-----------------
Acute Hepatitis C, Human Immunodeficiency Virus, Hepatitis C

Intervention / Treatment
-----------------
* Drug: Grazoprevir/Elbasvir 100mg/50mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV positive Acute HCV genotype 1 or 4 infection (≤26 weeks old at the baseline visit) Exclusion Criteria: Not on cART and a CD4 <500 at the time of screening Patients on cART for >6 months with a HIV viral load >400 copies Disallowed co-medication that cannot be stopped or replaced History of liver cirrhosis of any etiology. Inclusion of patients with a chronic well-controlled HBV (HBV-DNA <below the limit of detection) is allowed if fibroscan excludes >F1 fibrosis Protease inhibitor based and NNRTI based cART regimens are not allowed. Therefore, the inability to switch to a HAART regimen consisting of 2 nucleoside/tide reverse transcriptase inhibitors and an allowed third agent which can be raltegravir (Isentress®) 400mg BID, dolutegravir (Tivicay) 50mg QD or rilpivirine 25mg QD.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>Grazoprevir/elbasvir single tablet regimen (100/50mg) | Drug: Grazoprevir/Elbasvir 100mg/50mg<br>* Grazoprevir/Elbasvir 100mg/50mg<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SVR12 (Reinfection Not Considered Failure) | Sustained viral response (SVR) 12 weeks after the end of therapy in all patients who started treatment in which reinfections are not considered failure | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SVR12 (Reinfection Equals Failure) | Sustained viral response (SVR) 12 weeks after the end of therapy in all patients who started treatment in which reinfections are considered failure | week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Hepatitis C, Human Immunodeficiency virus, Grazoprevir, Elbasvir