Evolution of the NS3 and NS5B Regions of the Hepatitis C Virus During Disease Recurrence After Liver Transplantation

Abstract

In patients with hepatitis C virus (HCV)-related cirrhosis, infection recurrence is universal after liver transplantation (LT). The relevance of host and virusrelated factors on the outcome of hepatitis C recurrence is poorly understood. This study analyzed the relationship between the genetic evolution of the NonStructural (NS)3 protease and NS5B polymerase regions of HCV and the severity of hepatitis C recurrence. Thirty-three patients were classified as having mild (n = 16) or severe recurrence (n = 17), according to the degree of fibrosis in liver biopsies obtained 1 year after transplantation. Viral load and consensus sequences of the NS3 and NS5B domains were determined in a pre-LT and in four post-LT sequential serum samples. At week 12 after LT, viremia was significantly higher in patients with severe recurrence. NS3 and NS5b regions evolved independently after LT. The genetic evolution of NS3 domain was not related to the severity of the recurrence. However, the diversification in the NS5B region later than 12 weeks after LT was greater in patients with mild than in those with severe recurrence, suggesting a stronger immune pressure in the first group. These observations highlight the complex interplay between viral evolution and clinical outcomes in the LT setting.

Unexpected Maintenance of Hepatitis C Viral Diversity following Liver Transplantation

“…In contrast, some evidence suggests that posttransplant viral dynamics are more complex than a simple population bottleneck; for example, the dominant variant at 7 days posttransplant does not persist in later samples in all cases (2,42), and the minor variant pretransplant can become dominant (14). An observed bottleneck could be explained by a founder effect of colonization of the new liver, or result from methodological limitations such as consensus sequencing (28) or single-strand conformation polymorphisms (2,32) and the use of summary statistics (9,32,37,41), which fail to elucidate evolutionary relationships or structure (39,44); grouping results from multiple patients rendering data interpretation difficult (9,27,32,41,42); and temporally restric-tive sampling schemes that limit investigation of long-term evolutionary trends (8,9,16,37).…”

Antiviral Treatment for Hepatitis C Virus Infection after Liver Transplantation

“…Other studies [52, 53] have also demonstrated that individuals with a high level of replication in the perioperative period develop more fibrosis in the allograft 1 year after transplantation. When the graft develops fibrotic or cirrhotic changes, the patient prognosis is dismal.…”

Hepatic Transplant and HCV: A New Playground for an Old Virus

“…Surprisingly, longitudinal analysis of HCV T‐cell epitope evolution after liver transplantation has demonstrated that epitope sequences remained largely conserved (47,48; Figure 1). In cases where mutational changes after transplant have been documented, increased genetic diversity was correlated with less severe disease (49,50). Many of these analyses have focused on few or individual targeted epitopes, therefore additional studies may be required before a proper understanding of immune escape posttransplant can be acquired.…”