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PLoS One. 2017 May 18;12(5):e0177352. doi: 10.1371/journal.pone.0177352. eCollection 2017.

Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens.

Author information

1
Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
2
INSERM, Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France.
3
Tropical Diseases, Umberto I Hospital - "Sapienza" University, Rome, Italy.
4
Infectious Diseases, Sant'Andrea Hospital - "Sapienza" University, Rome, Italy.
5
Hepatology Unit, Polyclinic of Rome Tor Vergata, Rome, Italy.
6
Gastroenterology, "P. Giaccone" University Hospital, Palermo, Italy.
7
Infectious Diseases, Polyclinic of Rome Tor Vergata, Rome, Italy.
8
Clinic of Infectious Disease, Department of Health Sciences, San Paolo University Hospital, University of Milan, Milan, Italy.
9
Department of Biomedical, Metabolic and Neural Sciences, NOCSAE Baggiovara, Baggiovara, Modena, Italy.
10
Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
11
Infectious Diseases, AO Ospedale Niguarda Cà Granda, Milan, Italy.
12
Infectious Diseases, Ospedale di circolo di Busto Arsizio, Busto Arsizio, Varese, Italy.
13
Infectious Disease Unit, "Spirito Santo" General Hospital, Pescara, Italy.
14
Gastroenterology, Catholic University of Rome, Rome, Italy.
15
University of Genoa (DISSAL) Infectious Diseases Unit/AOU IRCCS San Martino-IST, Genoa, Italy.
16
1st Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy.
17
Istituto Nazionale di Genetica Molecolare (INGM) "Romeo ed Enrica Invernizzi", Milan, Italy.
18
Clinical Microbiology, Virology and Bioemergencies, ASST Fatebenefratelli Sacco, Milan, Italy.
19
School of Clinical Medicine, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa.

Abstract

BACKGROUND:

Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR.

STUDY DESIGN:

Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization.

RESULTS:

HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR.

CONCLUSIONS:

Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis.

PMID:
28545127
PMCID:
PMC5436665
DOI:
10.1371/journal.pone.0177352
[Indexed for MEDLINE]
Free PMC Article

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