HCV-RNA kinetics on-treatment do not predict sustained virologic response in HCV genotype 3 patients receiving sofosbuvir and ribavirin

Accepted Manuscript HCV-RNA Kinetics on-treatment do not predict sustained virologic response in HCV genotype 3 patients receiving sofosbuvir and ribavirin Elisabetta Degasperi, Stella De Nicola, Mariagrazia Rumi, Roberta D’Ambrosio PII: DOI: Reference:

S0168-8278(16)30344-0 http://dx.doi.org/10.1016/j.jhep.2016.06.031 JHEPAT 6196

To appear in:

Journal of Hepatology

Received Date: Accepted Date:

10 June 2016 12 June 2016

Please cite this article as: Degasperi, E., De Nicola, S., Rumi, M., D’Ambrosio, R., HCV-RNA Kinetics on-treatment do not predict sustained virologic response in HCV genotype 3 patients receiving sofosbuvir and ribavirin, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.06.031

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HCV-RNA KINETICS ON-TREATMENT DO NOT PREDICT SUSTAINED VIROLOGIC RESPONSE IN HCV GENOTYPE 3 PATIENTS RECEIVING SOFOSBUVIR AND RIBAVIRIN Elisabetta Degasperi1, Stella De Nicola1, Mariagrazia Rumi2 and Roberta D’Ambrosio1 1

A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and

Hepatology, Fondazione IRCCS CA’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. 2

Hepatology Unit, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy

Corresponding author: Elisabetta Degasperi, MD Division of Gastroenterology and Hepatology, A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS CA’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. Tel 39-0255035432 Fax 39-0250320410 E-mail: [email protected]

WORD COUNT: 689

KEYWORDS: IFN-Free, SVR, HCV, HCV-RNA, Sofosbuvir

LIST OF ABBREVIATIONS: Hepatitis C virus (HCV), Sustained virologic response (SVR), Sofosbuvir (SOF), Ribavirin (Rbv), CobasAmpliPrep/CobasTaqMan (CAP/CTM), Abbott Real Time HCV (ART), Direct-acting antivirals (DAAs), low limit detection/quantification (LOD)

Financial disclosure and Conflict of Interest: Authors have no financial disclosure to declare

Author’s Contributions: 1)

Elisabetta Degasperi: acquisition of data, analysis and interpretation of data, drafting the manuscript

2)

Stella De Nicola and Roberta D’Ambrosio: acquisition of data, analysis and interpretation of data

3)

Mariagrazia Rumi: critical revision of the manuscript for intellectual content, study supervision

To the Editor: We read with interest the paper by Maasoumy and colleagues, investigating the role of on-treatment viral kinetics during Sofosbuvir (SOF)-based antiviral regimens [1]. The authors analyzed samples from 298 HCV patients genotypes 1-5 receiving different SOF-containing regimens by using two HCV-RNA assays, CobasAmpliPrep/CobasTaqMan (CAP/CTM) and Abbott Real Time HCV (ART): they identified 45 IU/ml (CAP/CTM) and 60 IU/ml (ART) thresholds at week 2 to significantly predict sustained virologic response (SVR) in 33 HCV-3 patients treated with SOF + Ribavirin (Rbv). Indeed SVR was achieved in 100% of patients testing < 45 IU/ml (CAP/CTM) vs only 33% of patients with HCV-RNA ≥ 45 at week 2; when considering ART assay, the same figures were 100% SVR (< 60 IU/ml) vs 29% (≥ 60 IU/ml). The predictive value of these cut-offs remained significant also when restricting the analysis to the 19 patients with cirrhosis, only. Since HCV-3 has been identified as the difficult-to-treat genotype with the new direct-acting antivirals (DAAs), we think that identification of on-treatment predictors has relevant clinical importance in order to better refine treatment individualization and optimization in such patients, especially in patients with advanced fibrosis, as cirrhosis still has an impact in decreasing chances of SVR with DAAs [2]. Therefore we tried to externally validate the findings by Maasoumy and colleagues in 22 HCV-3 patients receiving SOF + Rbv for 24 weeks. Baseline and on-treatment HCV-RNA samples were tested according to ART assay, with a low limit detection/quantification (LOD) of 12 IU/mL. Males accounted for 55% of patient population and median age was 58 yearsold (range 41-66). 21 out of 22 patients (95%) had compensated cirrhosis at baseline, diagnosed either by liver biopsy or transient elastography above 12.5 KPa. At baseline, median HCV-RNA value was 5.79 Log10 (range 3.72-6.59 Log10). As expected with the high sensitive ART assay, at treatment week 2 only 6 (29%) patients dropped below the lower detection limit (LOD), 4 (19%) being undetectable and 2 (10%) also unquantifiable, while the remaining 15 (71%) patients were still quantifiable and for one patient HCV-RNA assessment at week 2 was not available. At week 4, 10/22 (45%) patients were HCV-RNA < 12 IU/ml, 6 (27%) undetectable and 4 (18%)

unquantifiable. At week 12, only one patient was still HCV-RNA quantifiable and 100% of patients achieved undetectability at week 24, that is the end-of-treatment response. Overall, 17 out of 22 patients (77%) achieved the SVR. When analyzing the on-treatment kinetics according to the proposed cut-off of 60 IU/ml in the 21 patients with available week 2 data, 11 patients (52%) tested HCV-RNA ≥ 60 IU/ml: 8 out of 11 (73%) achieved the SVR, compared to 8/10 (80%) patients with HCV-RNA < 60 IU/ml (p = 1.0). Interestingly, the single patient testing still HCV-RNA quantifiable at treatment week 12 achieved the SVR. Our findings do not confirm the 60 IU/ml threshold by ART at week 2 to predict SVR to SOF + Rbv regimen in HCV-3 patients. Unfortunately, we were not able to test samples with the other HCV-RNA assay, CAP/CTM, and to confirm these results also with the other suggested 45 IU/ml cut-off. Nevertheless, we think that our findings could be of additional importance as they were obtained in a cohort of patients with the highest prevalence of cirrhosis, where efficacy of SOF + Rbv should be suboptimal. We do not have clear explanations for the unexpected high SVR rates (77%) observed in our cohort compared to the literature reports for HCV-3 patients with advanced fibrosis [3], however we did not find significant differences with the cirrhotic patients in Maasoumy cohort according to baseline features. Although our results need to be replicated to larger cohorts, it has to be underlined that nowadays the SOF + Rbv regimen is no longer recommended in cirrhotic patients by EASL guidelines [4]; moreover Rbv full-dose administration in these patients in order to avoid adding a second DAA can still result in considerable side effects. Consequently, the development of new antiviral agents with pangenotypic efficacy suitable for Rbv-free regimens in HCV-3 patients could mitigate the clinical importance of viral kinetics during SOF + Rbv regimen in the near future.

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