Clinical trial NCT01725542: Pilot Study to Assess the Efficacy of and Tolerance to a QUadruple Therapy to Treat HIV-HCV Coinfected Patients Previously Null Responders
Official title: Pilot Study to Assess the Efficacy and Tolerance to a QUadruple Therapy With Asunaprevir , Daclatasvir, Ribavirin and Pegylated Interferon Alpha-2a, in HIV-HCV Genotype 1 or 4 Coinfected Patients Previously Null Responders to a Standard Pegylated Interferon -Ribavirin Regimen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HCV-HIV Co-Infection
Keywords: HCV-HIV Co-Infection
Quadruple therapy
null responder to a standard Pegylated interferon/Ribavirin regimen
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Bristol-Myers Squibb
First posted: 2012-11-14
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: Evaluation of efficacy and tolerance to a QUadruple therapy with Asunaprevir , Daclatasvir, Ribavirin and pegylated Interferon alpha-2a, in HIV-HCV genotype 1 or 4 coinfected patients previously null responders to a standard Pegylated Interferon -Ribavirin regimen.

The proportion of patients presenting cirrhosis (defined by a METAVIR F4 score on liver biopsy and/or with hepatic impulse elastometry ≥ 15 kPa) will be limited to 50% of all of the patients included

Detailed description: The clinical trial is multi-center, national, Phase 2, open-label, single-arm.

Primary objective is to estimate the Sustained Virological Response rate (SVR) 12 weeks after 24 weeks of treatment with quadruple therapy combining Asunaprevir, Daclatasvir, Ribavirin and Pegylated Interferon alpha-2a in HIV-HCV genotype 1 or 4 coinfected patients previously null responders to a Pegylated Interferon -Ribavirin standard regimen.

Estimated enrolment is 65 patients during the enrolment period (9 months). The first 12 patients included will be on Raltegravir, Emtricitabine and Tenofovir and will participate to the pharmacological sub-study.

Schedule of assessments:

Evaluation of inclusion criteria: 4 to 8 weeks Anti-HCV treatment: 28 weeks (or shorter according to futility rules) Follow up: 24 weeks following the end of the treatment

Eligibility criteria: Inclusion Criteria:

* Adult ≥18 years with confirmed HIV-1 or 2 infection
* Infection with HCV genotype 1 or 4 only, confirmed and with detectable HCV-RNA ≥ 1000 IU/mL at screening.
* Null responders to a previous treatment with Peginterferon and Ribavirin, defined by a fall of less than 2 log10 IU/ml HCV-RNA from baseline to week 12.
* Stable antiretroviral treatment for \> 1 month at screening containing any of the following drugs: Raltegravir, Enfuvirtide, Tenofovir-Emtricitabine, Abacavir-Lamivudine.
* CD4 \> 200 /mm3 and \> 15% at screening
* HIV-RNA \< 400 copies/mL from ≥ 3 months at screening
* Any liver fibrosis stage,
* with the assessment of the presence or not of cirrhosis at screening:

  * previous liver biopsy exhibiting cirrhosis lesions (METAVIR F4), and/or
  * significant liver biopsy (cumulative length ≥ 15 mm and ≥ 6 portal spaces), within 18 months and after the end of last HCV treatment, and/or
  * significant and reliable liver stiffness assessment (Fibroscan®) within 6 months (at least 10 measures with IQR less then 25% of the mean value and a success rate of at least 80%)
* cirrhosis being defined as a METAVIR score F4 on liver biopsy and/or liver elastometry ≥ 15 kPa
* the proportion of patients with cirrhosis (METAVIR F4) is limited to 50% of all patients.
* Body weight ≥ 40 kg and ≤125 kg
* Male patients, female patients with child-bearing potential and their heterosexual partners must use adequate contraception from 1 month before initiation of treatment to 7 months following the end of treatment for men and to 4 months following the end of treatment for women.
* Informed and signed consent
* For participating patients, informed and signed consent for the pharmacokinetic sub-study
* Patients affiliated to the National Health Insurance or covered by Universal Medical Coverage
* For the first 12 patients included (who will participate to the pharmacological substudy): stable antiretroviral treatment for \> 1 month at screening, with Raltegravir+ Emtricitabine+ Tenofovir

Exclusion Criteria:

* CHILD B and C cirrhosis, past history of decompensated cirrhosis. Patients with CHILD A cirrhosis must demonstrate the absence of significant oesophageal varices (Stages 2-3) on an upper gastrointestinal endoscopy ≤ 12 months
* Positive HBs antigenemia with HBV DNA \> 1000 IU/ml((if positive AgHBs with HBV DNA ≤ 1000 IU/mL, patient will be included provided it is treated with Ténofovir)
* Pregnant women, breast-feeding women
* Refusal of adequate contraception
* Contra-indication to Ribavirin, including hypersensitivity reaction to Ribavirin
* Contra-indication to Peginterferon, including psychiatric contra-indications. Patients with significant psychiatric past history, notably severe depression requiring hospitalization or suicide attempt, cannot be included unless they undergo a psychiatric evaluation and obtain a specific authorization for the use of interferon.
* Premature discontinuation (during the first six months) of a previous HCV treatment for toxicity. Patients who have stopped a previous treatment for severe anaemia or neutropenia can enter the study if erythropoietin or granulocyte growth factor had not been used during the previous treatment
* Previous HCV therapy including HCV NS3 protease inhibitor
* Severe pre-existing cardiac or pulmonary disease
* History of organ transplant
* Acute CDC stage C opportunistic infection occurring within the previouW6 months
* Any active malignant disease including hepatocellular carcinoma for which a specific assessment is required at screening
* Alcohol intake that may represent an obstacle for the participation of the subject in the study
* Substance abuse that may represent an obstacle for the participation of the subject in the study. Stabilized patients included in a substitution program can participate in the study
* Patients with previous observance problem unable to observe the study procedures
* Participation in another clinical trial within the previous 30 days
* Haemoglobin \< 90 g/L
* Platelets \< 50 000 /mm3
* Neutrophil count \< 750 /mm3
* Renal insufficiency defined by an estimated Glomerular Filtration Rate \< 50 mL/mn (MDRD equation)
* Absence of antiretroviral treatment or antiretroviral treatment different from the authorized combinations
* Associated medication likely to interfere with any of the study drugs such as CPY3A4 inducers (rifampin, Millepertuis)

Primary outcomes:
measure: HCV Sustained virological response rate
timeFrame: wk40
Secondary outcomes:
measure: Number of participants with adverse events as a measure of safety and tolerability
timeFrame: during throughout all the study
measure: Kinetics of HCV Virological response
timeFrame: wk4, wk5, wk6, wk8, wk12, wk16, wk20, wk24, wk28, wk32, wk40 and wk52
measure: Immunological and virological evolution of HIV infection
timeFrame: wk0, wk4, wk8, wk12,wk16, wk24, wk28, wk40 et wk52
measure: Evolution of cirrhosis (for cirrhotic patients)
timeFrame: wk12, wk28, wk40 and wk52
measure: Number of Participants with HIV and non HIV related clinical events
timeFrame: through the study
measure: Minimum Plasma Concentration (Cmin) of ribavirin
timeFrame: wk4 and wk8
measure: Pharmacokinetics of Antiretroviral drugs
timeFrame: wk0 and wk8
measure: Pharmacokinetics of Asunaprevir and Daclatasvir
timeFrame: wk8
Other outcomes:
Locations:
city: All the Regions of the Country (33 Centers)
country: France
Study officials:
affiliation: CHU Dijon
name: Lionel Piroth, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Piroth L, Paniez H, Taburet AM, Vincent C, Rosenthal E, Lacombe K, Billaud E, Rey D, Zucman D, Bailly F, Bronowicki JP, Simony M, Diallo A, Izopet J, Aboulker JP, Meyer L, Molina JM; ANRS HC30 QUADRIH Study Group. High Cure Rate With 24 Weeks of Daclatasvir-Based Quadruple Therapy in Treatment-Experienced, Null-Responder Patients With HIV/Hepatitis C Virus Genotype 1/4 Coinfection: The ANRS HC30 QUADRIH Study. Clin Infect Dis. 2015 Sep 1;61(5):817-25. doi: 10.1093/cid/civ381. Epub 2015 May 14.