Acute Hepatitis C, HIV
Conditions
Brief summary
The purpose of this study is to assess the rate of sustained virological response (SVR) 12 weeks after 8-week oral treatment with grazoprevir 100mg/elbasvir 50mg (MRK-combo) in patients with acute hepatitis C genotype1 or 4.
Detailed description
Increasing rates of acquisition of HCV in men who have sex with men (MSM) have been reported since 2001 in Western European countries and particularly in France. Observational studies have recently reported that HIV-infected gay and bisexual men with sexually transmitted hepatitis C have shown unexpectedly rapid liver disease progression in a relatively short period of time. It is therefore admitted that, in the absence of a spontaneous HCV clearance within 3 months of acute HCV infection, treatment should be initiated. Pegylated interferon in combination with weight-adapted ribavirin is still recommended as the treatment of choice for all HCV genotypes in an acute setting. For patients developing a rapid virologic response, treatment duration of 24 weeks is recommended. If antiviral therapy was initiated within 24 weeks after diagnosis, sustained virologic response rates of 60 to 80% have been observed at the price of a high side effects burden. However, short course therapies with new direct acting antivirals are likely to be safer and more efficient. But their efficacy in acute hepatitis C has still to be established. To date, US- and Europe- based trials are ongoing in this setting with the association of sofosbuvir and ribavirine, sofosbuvir / ledipasvir or sofosbuvir / simeprevir, for a duration of 4, 6, 8 or 12 weeks. Preliminary results are very diverse, with SVR12 ranging from 56% to 95%. MSD has been evaluating the efficacy and safety of a double drug combination (grazoprevir + elbasvir) in HIV-infected patients which exhibits paramount efficacy and excellent tolerance in a diverse range of genotypes, including 1 and 4 HCV strains, which are those mainly encountered in the French acute HCV epidemics in MSM. This association has the potential to be used for short treatment duration especially with regards to the fact that patients will have no fibrosis at the time of treatment initiation. This MRK-combo would therefore be an ideal candidate for treating acute hep C due to GT1 or 4 in a test and treat approach in high-risk population such as MSM.
Interventions
Once-daily, oral grazoprevir/elbasvir combination therapy at fixed-dose (100mg/50mg) for 8 weeks
Sponsors
Merck Sharp & Dohme LLC
Institut National de la Santé Et de la Recherche Médicale, France
Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult ≥18 years. 2. A recent acute HCV infection \[defined by (i) detectable HCV RNA within 6 months after a negative HCV RNA or HCV serology test OR (ii) detectable HCV RNA and acute clinical hepatitis within 5 months prior to screening visit (ALT ≥250 IU/L with normal ALT within the preceding 8 months OR ALT ≥500 IU/L with either no measured ALT or with abnormal ALT within the preceding 8 months)\] or reinfection \[defined by documented de novo infection after prior clearance post-treatment (defined by one negative HCV RNA ≥6 months after end of treatment) or spontaneously (defined by two negative HCV RNA a minimum of 6 months apart OR documented infection with a new viral strain, confirmed by phylogenetic or genotypic analysis)\] within 5 months prior screening OR (iii) patients having reported a risk factor for HCV contamination (traumatic sexual intercourse, intranasal, rectal or intravenous drug use) ≥6 months AND presenting a negative HCV RNA or HCV serology test within 12 months. 3. Infection with HCV genotype 1 or 4 (confirmed at screening visit or by using a previous biological test performed 1 to 4 weeks before week 0). 4. Plasma HCV-RNA ≥ 1000 IU/mL (confirmed at screening visit or by using a previous biological test performed 1 to 4 weeks before week 0). 5. Confirmed HIV infection (only for HIV co-infected patients). 6. Without HIV treatment or with an authorized stable HIV treatment for at least two weeks (only for HIV co-infected patients). 7. Body weight ≥40 kg and ≤125 kg. 8. Female patients with child-bearing potential and their heterosexual partners must use adequate contraception from the date of screening until 30 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 30 days after administration of the last dose of study drug. 9. Informed and signed consent. 10. Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle).
Exclusion criteria
1. Opportunistic infections (stage C), active or occurred within 6 months prior to baseline. 2. Primary HIV infection. 3. Co-infection with Hepatitis B virus (HBsAg-positive) without appropriate treatment (TDF or TAF) for at least 2 weeks. 4. Confirmed cirrhosis (before acute HCV diagnosis). 5. Any other causes of acute hepatitis. 6. Pregnant or breast-feeding women. 7. Liver transplant recipients. 8. Evolutive malignancy. 9. Patients with a history of non-adherence, who will be at risk of being unable to respect the study follow-up timetable. 10. Patients participating in another clinical trial (with an experimental treatment) or within an exclusion period of a previous clinical trial at screening. 11. Patients under legal gardianship or incarcerated. 12. Hemaglobulin \<10 g/dL (female) or \<11g/dL (male). 13. Platelet count \<50,000/mm3. 14. Neutrophil count \< 750/mm3. 15. Other antiretroviral drugs than those allowed in the study. 16. Contra-indications to grazoprevir and/or elbasvir or to any of the excipients listed in the summary of the product characteristics. 17. Contra-indicated treatment likely to interfere with the study drugs as listed in the summary of the product characteristics.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virological Response 12 Weeks Post-treatment (SVR12) | 12 weeks | Undetectable plasma HCV RNA (\<12 IU/mL) 12 weeks post-treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Virological Failure | 12 weeks | Number of patients harboring HCV (NS5A and NS3/4) resistance mutations 12 weeks post treatment |
| Treatment Adherence | 8 weeks | Number of patients missing study drug within the last four days during treatment |
| Number of Participants With Undetectable HIV RNA | 12 weeks | Number of participants with undetectable HIV RNA at 12 weeks post treatment (in HIV-positive co-infected patients) |
| CD4 Cell Count | 12 weeks | CD4+ T cell count at 12 weeks post treatment (in HIV-positive co-infected patients) |
| Incidence of HCV Re-infection | 48 weeks | Number of patients with positive HCV RNA 48-weeks post treatment. |
Countries
France
Participant flow
Recruitment details
Recruitment occurred between May 31, 2017 and August 20, 2019. Recruitment took place at 6 university hospitals in France (Paris, Lyon, and Nice). 33 individuals were assessed for eligibility and 3 did not meet inclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Grazoprevir/Elbasvir Once-daily, oral grazoprevir/elbasvir combination therapy at fixed-dose (100mg/50mg) for 8 weeks
Grazoprevir/Elbasvir: Once-daily, oral grazoprevir/elbasvir combination therapy at fixed-dose (100mg/50mg) for 8 weeks | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 12-week Post Treatment Follow-up | Death | 1 |
| 48-week Post Treatment Follow-up | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Grazoprevir/Elbasvir | — |
|---|---|---|
| Age, Continuous | 44 years | — |
| Co-infection with HIV | 28 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment France | 30 participants | — |
| Sex: Female, Male Female | 0 Participants | — |
| Sex: Female, Male Male | 30 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 30 |
| other Total, other adverse events | 23 / 30 |
| serious Total, serious adverse events | 2 / 30 |
Outcome results
Primary
Sustained Virological Response 12 Weeks Post-treatment (SVR12)
Undetectable plasma HCV RNA (\<12 IU/mL) 12 weeks post-treatment.
Time frame: 12 weeks
Population: Intent-to-treat analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Grazoprevir/Elbasvir | Sustained Virological Response 12 Weeks Post-treatment (SVR12) | 28 Participants |
Secondary
CD4 Cell Count
CD4+ T cell count at 12 weeks post treatment (in HIV-positive co-infected patients)
Time frame: 12 weeks
Population: Out of 28 HIV-positive individuals, 27 had available data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Grazoprevir/Elbasvir | CD4 Cell Count | 655 cells/mm^3 |
Secondary
Incidence of HCV Re-infection
Number of patients with positive HCV RNA 48-weeks post treatment.
Time frame: 48 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Grazoprevir/Elbasvir | Incidence of HCV Re-infection | With phylogentically different strain | 2 Participants |
| Grazoprevir/Elbasvir | Incidence of HCV Re-infection | With phylogentically similar strain | 1 Participants |
Secondary
Number of Participants With Undetectable HIV RNA
Number of participants with undetectable HIV RNA at 12 weeks post treatment (in HIV-positive co-infected patients)
Time frame: 12 weeks
Population: Out of 28 HIV-positive individuals, 27 had available data. All 27 participants analyzed had undetectable HIV RNA.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Grazoprevir/Elbasvir | Number of Participants With Undetectable HIV RNA | 27 Participants |
Secondary
Treatment Adherence
Number of patients missing study drug within the last four days during treatment
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Grazoprevir/Elbasvir | Treatment Adherence | 2 Participants |
Secondary
Virological Failure
Number of patients harboring HCV (NS5A and NS3/4) resistance mutations 12 weeks post treatment
Time frame: 12 weeks
Population: Intent-to-treat analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Grazoprevir/Elbasvir | Virological Failure | 1 Participants |