Clinical trial NCT03572140: Safety of Sofosbuvir ,Daclatasvir in HCV Patients and RAVS in Resistent and Relapsed Cases
Official title: Safety of Sofosbuvir Plus Daclatasvir in Patients With Chronic Hepatitis c Virus and Assessment of Resistance Associated Variants in Resistant and Relapsed Cases
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: HCV
Keywords: HCV
Sofosbuvir
Safety
RAVs
Daclatasvir
Lead sponsor: Assiut University
Sponsor class: OTHER
First posted: 2018-06-28
Enrollment: 297
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Cases will be recruited from the viral hepatitis clinic, department of tropical medicine, Alrajhi Liver hospital, Assiut University. The lab. work will be done by researchers from Medical Microbiology and Immunology department, Faculty of Medicine, Assiut University-University of Cincinnat, USA and Clinical pathology department, Assiut University.

Brief summary: To identify side effects of Sofosbuvir/ Daclatasvir treatment regimen of chronic HCV GT-4 infection.

* To assess the occurrence and the prevalence of RAVs in patients with treatment failure and relapse after sofosbuvir and daclatasvir with assessment of their types .
* To examine the GT4 subtypes by phylogenetic analysis and baseline sequence variability among subtypes and their potential impact on treatment outcome and development of viral resistance in patients who received a regimen of Sofosbuvir/ Daclatasvir for treatment of chronic HCV GT-4.
* To assess the differences in patient demographics across GT4 subtypes.

Detailed description: Hepatitis C virus (HCV) chronically infects approximately 120-130 million individuals worldwide .Mortality related to HCV infection has been estimated at approximately 300,000 deaths per year..

Direct antiviral agents (DAAs) effectively eradicate HCV and rapidly improve residual liver functions. Current HCV eradication rates have exceeded 90% in a very short time .

Hepatitis C virus genotype 4 (GT4) is genetically diverse, with 17 confirmed subtypes, and comprises approximately 13% of infections worldwide \[3\]. In Egypt, GT4 accounts for approximately 90% of infections, with subtype 4a predominating .

Sofosbuvir and daclatasvir are generally well tolerated with only a few adverse effects reported.

Hepatitis C virus resistant associated variants (RAVs) are seen in most patients who do not achieve sustained virological response (SVR). These resistance-associated mutations depend on the class of direct-acting antiviral drugs used and also vary between hepatitis C virus genotypes and subtypes.

Donaldson et al performed an analysis on four phase III clinical trials in search of common RAVs against sofosbuvir, discovering L159F, C316N, and V321A were associated with virological failure. Interestingly, this study also verified S282R mutation as associating with failure.

NS5A RAVs can be very common, with Y93H detected in up to 15% of the population and L31M in up to 6.3%. Other RAVs tend to also be fairly common detected in approximately 0.3%-3.5% of the population

Eligibility criteria: Inclusion Criteria:

* Anti HCV positive patients either chronic HCV or liver cirrhosis. • Detectable HCV RNA by quantitative polymerase chain reaction (PCR) prior to treatment

Exclusion Criteria:

* Co-infection with hepatitis B virus .
* Presence of malignancy before treatment.
* End-stage liver disease (Child score more than 9).
* Major co-morbid disease e.g heart failure

Primary outcomes:
measure: relevance of HC RAVs to the outcomes of therapy with Sofosbuvir in treatment of egyptian patients infected with HCV genotype 4
timeFrame: baseline
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Assiut University
name: Ahlam Farghaly, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Assiut University
name: haidi ramadan, Lecturer
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ben Ari Z. [Chronic hepatitis C infection--eradication of the virus]. Harefuah. 2014 Jul;153(7):392-3, 433. Hebrew.
citation: Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, Lenzi M, Mazzella G, Verucchi G, Andreone P, Brillanti S. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol. 2016 Oct;65(4):727-733. doi: 10.1016/j.jhep.2016.06.015. Epub 2016 Jun 24.
citation: Reig M, Marino Z, Perello C, Inarrairaegui M, Ribeiro A, Lens S, Diaz A, Vilana R, Darnell A, Varela M, Sangro B, Calleja JL, Forns X, Bruix J. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016 Oct;65(4):719-726. doi: 10.1016/j.jhep.2016.04.008. Epub 2016 Apr 13.
citation: Kamal SM, Nasser IA. Hepatitis C genotype 4: What we know and what we don't yet know. Hepatology. 2008 Apr;47(4):1371-83. doi: 10.1002/hep.22127.
citation: Di Lello FA, Neukam K, Parra-Sanchez M, Plaza Z, Soriano V, Cifuentes C, Mira JA, Poveda E, Pineda JA. Hepatitis C virus genotype 4 in Southern and Central Spain does not originate from recent foreign migration waves. J Med Virol. 2013 Oct;85(10):1734-40. doi: 10.1002/jmv.23657. Epub 2013 Jul 16.
citation: Donaldson EF, Harrington PR, O'Rear JJ, Naeger LK. Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir. Hepatology. 2015 Jan;61(1):56-65. doi: 10.1002/hep.27375. Epub 2014 Nov 20.