Nonresponders and relapsers

Using on-treatment viral kinetics, the following categories of
treatment failure can be defined:
– virologic breakthrough: HCV RNA reappearance while still
on treatment
– virologic relapse: undetectable HCV RNA at the end of
therapy, but HCV RNA reappearance after completion of
therapy
– nonresponse: failure to achieve undetectable HCV RNA
throughout treatment
Further detailing of the nonresponse category have been made
based on the observation that SVR rates are significantly higher
if more than 1 log10 reduction was registered at week 12 (Zeuzem
2011):
– null responders – patients with <2 log10 decrease in HCV
RNA level by week 12, who never reach undetectable levels
throughout the course of treatment
– partial responders – patients with >2 log10 decrease by
week 12, despite remaining detectable during treatment
All HCV-infected individuals who fail to respond or who relapse
have a series of pre-treatment and on-treatment fixed factors
(genotypes 1/4, advanced fibrosis, older age, race and genetic
background- risk alleles at IL28B gene (CT or particularly TT)
or/and correctable factors (patient adherence, AEs associated
with therapy) that contribute to the therapy failure (Missiha
2008). Overcoming these obstacles substantially increase the
chances for success, as will be shown in detail in chapter 3.
Moreover, failure to eradicate HCV infection does not mean that
the patient is non-responsive to therapy, as most patients
28 | Hepatitis C Treatment
improve biochemically and histologically. Therapeutic options
for these individuals include (AISF 2009):
– Retreatment with current SoC; the use of higher doses
and/or extended duration of treatment, maintenance
therapy with PegIFN – described in detail in chapter 3.
– The use of newly developed direct-acting antivirals (DAA) –
described in detail in chapter 4.
The overall objectives of new therapeutic strategies are to
prevent complications of end-stage liver disease and death from
HCV infection. In this respect, patients with compensated
cirrhosis are candidate for (re)treatment in order to prevent
decompensation. For patients with decompensated disease the
aim of treatment is to improve survival, while waiting for liver
transplant. The benefits and challenges posed by these
approaches are detailed in chapter 5.
Outlook
The management of patients with CHC is complex and
challenging, due to the potential AEs of antiviral therapies and
common co-morbidities often found in this group of patients.
Studies have shown that a multidisciplinary team-based
management approach can improve treatment outcomes in a
cost-effective manner.
Early treatment involves providing SoC therapy to all patients
with mild disease, some of whom will never progress to the
moderate to severe stage. This approach is associated with
increased costs per quality-adjusted lifeyears (QALY) gains.
Moreover, drug costs and excess costs for monitoring patients
are all incurred in the first year of the strategy, rather than at a
future date determined by the rate of disease progression
(Hartwell 2011).
In contrast, the watchful waiting strategy involves providing
antiviral treatment only to those patients with disease
progression. This is mostly based on the fact that although
antiviral therapy prevents complications and decreases the
overall severity and duration of the illness, its long-term benefit
Antiviral Therapy: The Basics | 29
on the morbidity and mortality associated with chronic infection
is poorly quantified.
The best choice for treatment initiation is made on a case by
case basis. Individulised decisions are based on a thorough pretreatment
assessment of the virus, host and other associated
factors that contribute to treatment failure. Response-guided
therapy has demonstrated significant advantages compared to
the watchful waiting strategy.
The decision regarding retreatment of patients with advanced
liver diseases depends on clinical factors like expected
progression of diseases, degree of inflammation/fibrosis,
coinfection with HIV or/and HBV, co-morbidities (autoimmune
diseases, heart and renal failure). Furthermore, modified
regimens, with currently available medications, novel modified
IFNs and RBV or combinations with direct-acting antivirals
(DAAs), are developed. A more active and highly individualized
therapeutic strategy is a priority for nonresponders to current
SoC.