Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Abstract

Despite recent treatment advances, the majority of patients with chronic hepatitis C fail to respond to antiviral therapy. Although the genetic basis for this resistance is unknown, accumulated evidence suggests that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. Sequences within hepatitis C virus (HCV) envelope 1 and envelope 2 genes, inclusive of the hypervariable region 1, were analyzed in parallel with the level of viral replication in serial serum samples obtained from 23 patients who exhibited different patterns of response to therapy and from untreated controls. Our study provides evidence that although the viral diversity before treatment does not predict the response to treatment, the early emergence and dominance of a single viral variant distinguishes patients who will have a sustained therapeutic response from those who subsequently will experience a breakthrough or relapse. A dramatic reduction in genetic diversity leading to an increasingly homogeneous viral population was a consistent feature associated with viral clearance in sustained responders and was independent of HCV genotype. The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C.

HCV quasispecies evolution: association with progression to end-stage liver disease in hemophiliacs infected with HCV or HCV/HIV

“…Immune selection puts pressure on key antigen-recognition sites and drives the emergence of a closely related virus family that can be isolated from the serum of infected patients. Previous evaluation of viral population dynamics has provided critical insights into short-term outcomes including early spontaneous viral clearance, 6 interferon-associated viral clearance, 7,8 and HCV emergence following liver transplantation. 9,10 However, lack of suitable long-term longitudinal cohorts has limited study of the relationship between HCV quasispecies evolution and development of ESLD.…”

Hepatitis C virus quasispecies in HIV-infected women: Role of injecting drug use and highly active antiretroviral therapy (HAART)

“…A reduction in genetic diversity leading to an increasingly homogeneous viral population was also associated with viral clearance in patients undergoing therapy with interferon. 27 While in the above 2 settings lack of escape mutations is indicative of strong immune pressure leading to infection clearance, stability or reduction of quasispecies diversity and complexity in the natural course of chronic infection implies a weak immune response and may entail poor prognosis with respect to liver disease. 28,42,43 Similarly, narrowing of HVR1 complexity and diversity was associated with progressive liver disease in HCV/HIV coinfected hemophiliacs.…”

“…19,[21][22][23] HCV quasispecies heterogeneity and dynamics has been extensively studied in various settings, including in those with acute and chronic hepatitis C, those receiving anti-HCV therapy, and following liver transplantation for HCV-related liver disease. [24][25][26][27][28] However, despite the high frequency of HCV/HIV coinfection, HCV quasispecies have rarely been analyzed in HIV-positive patients. In the few studies that were published, the number of analyzed patients was small and the role of associated factors could not be properly analyzed.…”

Expression of hepatitis C virus hypervariable region 1 and its clinical significance

“…Like most RNA viruses, HCV circulates in the human host as a complex population of different but closely related viral variants, commonly referred to as quasispecies [25] . It has been suggested that a reduction in genetic diversity leading to an increasingly homogeneous viral population in the envelope genes, and especially in the HVR1 of the E2 gene, is likely to be the result of a more successful and balanced cellular and humoral immune response [26] , which can be observed in IFN therapy responders with viral clearance [27,28] . It was also reported that the broad reactivity of serum anti-HVR1 antibodies correlated with viral loads and response to IFN in genotype-1b-infected patients [10] .…”