Antiviral therapy in non-responders, relapsers and special populations

More than 50% of genotype 1 and 20% of genotypes 2/3 HCVinfected
patients fail to achieve a sustained virologic response
(SVR) when treated with PegIFN/RBV. Non-sustained responders
to PegIFN/RBV comprise a heterogeneous group of patients
(non-responders, on-therapy and post-therapy relapsers)
defined by the time point when they achieved or not
undetectable viremia (see chapter 1). For these patients other
therapeutic options are clearly needed.
How to manage genotype 1 non-responders and
relapsers ?
Therapy selection: monitoring vs. retreatment
When considering further therapy for genotype 1 patients who
fail to achieve a sustained viral response (SVR) during the initial
standard-of-care (SoC) therapy, two important issues should be
considered:
– the exact classification of the initial response pattern (as
the response to subsequent therapy is strongly influenced
by the initial response),
44 | Hepatitis C Treatment
– the correctable factors of treatment failure during the
previous course of therapy.
Consistent with the change in HCV RNA during the previous
course of therapy, four different patterns of treatment failure
– with crucial implications for the regimen, duration and
likelihood of response to retreatment – can be distinguished:
1. Patients with less than 2 log10UI/ml decline in HCV RNA
from baseline to treatment week 12 are defined as nonresponders.
Within this group, null responders show a
minimal reduction in HCV RNA level (usually less than 1
log10UI/ml), being considered the most refractory group to
treatment with pegylated interferon alfa (PegIFN) and
ribavirin (RBV). SVR rates during retreatment rarely
surpass 15% in this population. Therefore, unless other
compelling reasons impose therapy in these patients (such
as control of extrahepatic manifestations or advanced liver
disease), the best option may be to closely monitor them
while waiting for triple therapy (PegIFN/RBV + a directacting
antiviral).
2. Patients with ≥2 log10UI/ml decline in HCV RNA from
baseline to treatment week 12, who remain HCV RNA
detectable at week 24 are partial virological responders.
3. Breakthrough is defined as detectable HCV RNA during
therapy, after an initial virologic response (HCV RNA
undetectable or ≥2 log10UI/ml decline at week 12).
4. In contrast to previous categories, relapsers are those who,
during therapy, achieved and maintained undetectable HCV
RNA (measured by a high sensitive assay), but HCV RNA
become again measurable during the first 6 months after the
end of therapy. Relapsers have the best chance of
achieving SVR during retreatment with PegIFN/RBV, with a
SVR rate of approximately 40%. Triple therapy with a
protease inhibitor further increase this rate.
Numerous host and virological factors strongly influence the
response to therapy. A complex constellation of fixed factors
related to virus, such as genotype 1 or high pre-therapeutic viral
Antiviral therapy in non-responders, relapsers and special populations | 45
load (VL) or to the patient, such as African-American or Hispanic
race, severity of liver fibrosis/cirrhosis, hepatic steatosis or
insulin resistance (IR), negatively impact the therapeutic
outcome during a subsequent course of treatment. On the
contrary, identifying correctable factors that may have
contributed to prior treatment failure can help the decision of
retreatment and subsequent management. The most common
correctable factors that can significantly diminish the rate of
SVR include:
Dose reduction, transient discontinuation or premature
interruption of therapy, due to side effects such as anemia,
neutropenia or depression. Close monitoring and judicious
interventions (modest dose reduction, use of growth factors,
prophylactic antidepressants) could minimize these factors.
Lack of adherence to the prescribed medication regimen.
Rigorous adherence should be stressed and monitored.