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.

Perinatal infection with hepatitis C virus (HCV) is characterized by a wide range of alanine aminotransferase (ALT) levels. The mechanisms responsible for this variability are unknown. We examined whether the evolution of the HCV quasispecies was associated with different ALT profiles in perinatally infected children. Sequences within HCV envelope 1 and 2 genes, inclusive of the hypervariable region 1, the viral load, and the nascent humoral immunity were analyzed in serial serum samples from 12 perinatally infected children prospectively followed for a median of 53 months. These patients were selected to represent two different ALT patterns during the first year of life: 6 had high levels (maximum values ranging from 4.2 to 30 times the normal upper limit), and 6 had normal or slightly elevated levels (<2 times the normal upper limit). Two patterns of viral evolution were identified according to the ALT profiles. Biochemical evidence of hepatic injury was invariably associated with a mono-or oligoclonal viral population, whereas mild or no liver damage correlated with the early emergence of a heterogeneous viral quasispecies. Consistent with selective immune pressure, amino acid changes occurred almost exclusively within the hypervariable region 1 and were temporally associated with antibody seroconversion; at this time, the difference in genetic diversity between the two groups was highly significant (P ‫؍‬ 0.002). The two patterns of viral evolution persisted over time and did not correlate with viral load or genotype. Our study demonstrates that, in perinatally infected children, the evolution of HCV quasispecies correlates with hepatic injury.perinatal hepatitis C virus infection ͉ genetic variability ͉ alanine aminotransferase levels M aternal-infant transmission is the dominant route for acquisition of hepatitis C virus (HCV) infection in children in developed countries, with an estimated transmission rate of Ϸ5% (1-3). Age and mode of infection are assumed to influence the progression of HCV disease in adults, but limited data are available on the natural history of perinatally acquired HCV infection (4, 5). Recent studies suggest that 80% of these children develop chronic infection (6-8), a rate similar to that documented in adults (9) but higher than that reported in children with posttransfusion HCV infection (10). Persistent HCV infection in infants and children is associated with minimal or mild liver damage and very rarely with advanced liver disease (5,(11)(12)(13)(14). However, perinatal HCV infection is associated with a wide range of aminotransferase levels during the first year of life (5, 7). Whereas some infants reach serum concentrations of alanine aminotransferase (ALT) compatible with acute hepatitis, others show normal or slightly elevated levels (5, 7). The mechanisms responsible for the different ALT profiles seen in perinatal HCV infection are unknown but are likely the result of a complex interplay between viral factors and host immunity. One of the most effective strategies enacted ...