403Although the recommended treatment for chronic HCV infection involves
PegIFN-α-2b or PegIFN-α-2a combined with ribavirin (RBV), the therapy cures
only ~40 % of those with HCV, and the response is even lower in African-American
populations. In addition to limited effi cacy, treatment is often poorly tolerated
because of side effects that prevent some patients from completing therapy. For these
reasons, identifi cation of a biomarker of response to treatment is a high priority.
Growing body of evidence shows that ethnicity plays a pivotal role in how
patients respond to treatment for HCV. A multicenter, open-label, nonrandomized,
prospective study (LATINO Study) has evaluated the effect of Latino ethnic back-
ground on the response to treatment with peginterferon alfa-2a (Pegasus®) and
ribavirin in patients infected with HCV genotype 1 who had not been treated previ-
ously (Rodriguez-Torres et al. 2009 ). The primary end point was a sustained viro-
logic response. The rate of sustained virologic response was higher among
non-Latino whites than among Latinos and absence of HCV RNA in serum was
more frequent in non-Latino whites throughout the treatment period. Poor response
rate across Hispanics of all nationalities indicates that strategies to improve the
sustained virologic response in Latinos are needed. A genetic polymorphism near
the IL28B gene, encoding IFN-lambda-3, has been reported to be associated with an
approximately twofold change in response to treatment, both among patients of
European ancestry and African-Americans (Ge et al. 2009 ). Almost 80 % of those
with the favorable response genotype eradicated the virus, while only about 30 %
with the less favorable response genotype did so. Because the genotype leading to
better response is in substantially greater frequency in European than African popu-
lations, this genetic polymorphism also explains approximately half of the differ-
ence in response rates between African-Americans and patients of European
ancestry. On the other hand, among African Americans who did carry the CC geno-
type, treatment response was 53.3 % − higher than the 33.3 % treatment response
observed among individuals of European descent who had the TT genotype. The
favorable C allele also tended to be found less frequently in those with chronic HCV
infections, suggesting a role in overall viral clearance. Unexpectedly though, the
authors reported that the C alleles actually appeared to be linked to higher rather
than lower baseline viral loads. More research is needed to determine whether the
newly identifi ed SNP is a biomarker for other important genetic changes or whether
the change itself directly infl uences treatment outcomes.
The measurement of viral RNA levels and genotyping may be used to optimize
individual patient treatment. Genotype non-1 and a low viral load are the most sig-
nifi cant pre-treatment indicators of sustained virologic response. The most reliable
predictor of a poor virologic response is continued seropositivity for viral RNA
during therapy.
The genomic sequences of independent HCV isolates differ by ~10 %, and to
study the effects of this variation on the response to therapy, amino acid covariance
within the full viral coding region of pretherapy HCV sequences were analyzed
from participants in the Viral Resistance to Antiviral Therapy of Chronic Hepatitis
C (Virahep-C) clinical study ( Aurora et al. 2009 ). Covarying positions were common
and linked together into networks that differed by response to therapy. There were
Personalized Management of Viral Infections