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Disentangling the lifespans of hepatitis C virus‐infected cells and intracellular vRNA replication‐complexes during direct‐acting anti‐viral therapy
Author(s) -
Cardozo Erwing Fabian,
Ji Dong,
Lau George,
Schinazi Raymond F.,
Chen Guofeng,
Ribeiro Ruy M.,
Perelson Alan S.
Publication year - 2020
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.13229
Subject(s) - sofosbuvir , hepatitis c virus , viral load , boceprevir , virology , viral replication , set point , intracellular , medicine , hepacivirus , hepatitis c , population , virus , antiviral therapy , chronic hepatitis , immunology , biology , ribavirin , genetics , environmental health , control engineering , engineering
The decay rate of hepatitis C virus (HCV)‐infected cells during therapy has been used to determine the duration of treatment needed to attain a sustained virologic response, but with direct‐acting anti‐virals (DAA), this rate has been difficult to estimate. Here, we show that it is possible to estimate it, by simultaneously analysing the viral load and alanine aminotransferase (ALT) kinetics during combination DAA therapy. We modelled the HCV RNA and ALT serum kinetics in 26 patients with chronic HCV genotype 1b infection, under four different sofosbuvir‐based combination treatments. In all patients, ALT decayed exponentially to a set point in the normal range by 1‐3 weeks after initiation of therapy. The model indicates that the ALT decay rate during the first few weeks after initiation of therapy reflects the death rate of infected cells, with an estimated median half‐life of 2.5 days in this patient population. This information allows independent estimation of the rate of loss of intracellular replication complexes during therapy. Our model also predicts that the final ALT set point is not related to the release of ALT by dying HCV‐infected cells. Using ALT data, one can separately obtain information about the rate of ‘cure’ of HCV‐infected cells versus their rate of death, something not possible when analysing only HCV RNA data. This information can be used to compare the effects of different DAA combinations and to rationally evaluate their anti‐viral effects.