Therapeutical strategies

The following strategies for prior genotype 1 non-responders
and relapsers can be distinguished:
1. Retreatment with PegIFN/RBV
2. Extended treatment duration for slow virological responders
3. Increasing PegIFN dose and longer treatment duration
4. Optimizing PegIFN and RBV dosing during retreatment
5. Maintenance therapy with low-dose of PegIFN
6. Triple-combination therapy
1. Retreatment with the previous regimen (PegIFN/RBV). In
the EPIC3 study, non-responders and relapsers to previous
therapy with interferon alfa (n=1203) or PegIFN alfa-2a/2b
(n=820) with or without RBV were retreated with PegIFN alfa-2b
(1.5μg/kg/week) and weight-based RBV (800-1400 mg/day) for
48 weeks (Poynard 2009). SVR was higher in prior relapsers
vs. non-responders (38% vs. 14%) and in patients who achieved
46 | Hepatitis C Treatment
an EVR (56%) during the second course of therapy (Poynard
2008; Poynard 2009).
2. Extended treatment duration for slow virological
responders. Slow virological responders are patients with ≥2
log10 decline in HCV RNA at treatment week 12, who achieve
undetectable HCV RNA between 12 and 24 weeks of therapy. In
this group, standard 48-week course of therapy has been
associated with a high rate of virological relapse after therapy.
Despite differences in study design (different criteria of
randomization to extended therapy, different doses of RBV),
several randomized controlled trials comparing 72 weeks to 48
weeks of treatment among slow virological responders have
shown consistently that prolonged therapy significantly
improves rates of SVR (44% vs. 28% [Sanchez-Tapias 2006]; 38%
vs. 18% [Pearlman 2007]), largely by decreasing the rate of
relapse (40% vs. 64% [Berg 2006]; 20% vs. 59% [Pearlman 2007]).
However, extending therapy has been associated with a
higher rate of AEs and premature discontinuation beyond 48
weeks of treatment, a finding that temper this approach in many
patients.
3. Increasing PegIFN dose and longer treatment duration.
Trials of intensified regimen with higher fixed-dose of PegIFN
and/or longer treatment duration have demonstrated only
modest increases in SVR in prior non-responders to
PegIFN/RBV. In the REPEAT trial (Jensen 2009) prior nonresponders
received PegIFN alfa-2a higher-dose induction
(360μg/week) for 12 weeks, followed by the usual 180μg/week
for a further 60 or 36 weeks (total duration 72 and 48 weeks,
respectively) with RBV 1000-1200 mg/day. The SVR rate was
higher for those treated for 72 weeks; no difference was found
between the induction and non-induction arms. This confirms
that retreatment of non-responders with extended therapy
may improve SVR rates, while induction therapy with higher
Antiviral therapy in non-responders, relapsers and special populations | 47
dose of PegIFN has no beneficial effect. Multiple logistic
regression analysis indicated that EVR at 12 weeks consistently
predicts SVR in retreated non-responders (Marcellin 2008).
4. Optimizing PegIFN and RBV dosing during retreatment.
When combined with PegIFN, RBV is critical to prevent
relapse after treatment cessation. A small prospective study on
10 patients with HCV genotype 1 infection and high baseline VL
(>800, 000 IU/ml) showed feasibility and high efficacy of
treatment with high RBV doses (Lindhal 2005). RBV was
calculated to achieve a steady-state concentration above 15
μmol/ml. Prophylactic and as-needed administration of
erythropoietin and blood transfusions were required in a single
patient. SVR was achieved in 9 of 10 patients without major
treatment regimen violation. RBV dosing at 13-15 mg/kg appears
to be the best balance between optimized efficacy and
intolerable hemolytic anemia that develops at high doses. SVR is
significantly diminished when RBV dose is below 11 mg/kg.
Therefore, maximizing RBV dosing, particularly in overweight
patients, has the potential to improve SVR during the second
course of therapy. In a retrospective analysis of a large database
of patients treated with PegIFN/RBV, it has been demonstrated
that RBV dose reduction led to a stepwise decrease in SVR. The
cumulative dose of RBV below 60% is associated with an evident
decline in SVR (Reddy 2007). Thus, not only maximizing RBV
dosing, but also maintaining a cumulative RBV dose higher
than 80% of the overall dose, with or without erythropoietin,
improves SVR in previous non-responders and relapsers.
Other trials (Fried 2006) demonstrated improved SVR in patients
with body weight above 85 kg treated with higher dose of
PegIFN/RBV. Patients treated with PegIFN alfa-2a, 270 μg/week
and RBV 1600 mg/day, showed an SVR of 48% versus 28% in
those treated with standard dosing regimen (relapse rates 19%
vs. 40%). However, higher dose regimen was associated with an
increased rate of hematological AEs.
48 | Hepatitis C Treatment
5. Maintenance therapy with low-dose of PegIFN. Nonsustained
responders to SoC, with advanced fibrosis or cirrhosis,
have a high risk for disease progression and complications. Two
large multicentre trials have evaluated the benefits of
maintenance therapy with low-dose PegIFN in this group:
– the COPILOT study (Colchicine vs. PegIFN alfa-2b 0.5
μg/kg/week Long Term) (Afdhal 2008)
– the HALT-C study (Hepatitis C Antiviral Long-Term
Treatment Against Cirrhosis with PegIFN alfa-2a 90
μg/week) (Di Bisceglie 2008)
In the COPILOT study 555 patients with prior failure to
interferon-based therapy were randomized to receive either
PegIFN alfa-2b 0.5 μg/kg/week (n=286) or colchicine 0,6 mg twice
daily (n=269). No differences were observed between the two
groups with respect to progression of the CP score, development
of complications of portal hypertension or HCC.
The HALT-C trial was a prospective, randomized, controlled
study of long-term maintenance therapy with PegIFN alfa-2a 90
μg/week (n=517) or no treatment (n=533) for 3.5 years in
patients with chronic hepatitis C (CHC) and advanced fibrosis or
cirrhosis (Ishak score 3-6) who did not achieve SVR after
interferon-based therapy. By the end of the study period, there
was no difference between the control and treated groups in the
frequency of death, hepatic decompensation or development of
HCC. Overall, the COPILOT and HALT-C trials showed that
maintenance therapy with low-dose PegIFN alfa-2a or alfa-2b
does not reduce the rate of liver-related death, clinical
disease progression and complications over a period of up to 4
years.
6. Triple-combination therapy. Triple therapy combination of
PegIFN/RBV with a protease inhibitors (telaprevir or boceprevir)
in HCV genotype 1-experienced patients has been shown to
produce high rates of virological response in both prior relapsers
Antiviral therapy in non-responders, relapsers and special populations | 49
and, to a lesser extent, prior non-responders in phase III trials. A
detailed presentation of the newly aproved direct-acting
antivirals (DAAs) is given in chapter 4.
Prove-3 trial evaluated triple-combination therapy with
telaprevir in treatment-experienced patients (~60% nonresponders
and ~40% relapsers) (McHutchison 2010). Patients
were randomized on four treatment arms in order to assess the
impact of different durations of triple therapy, different total
treatment duration and the importance of RBV for this difficultto-
treat population. Prior relapsers treated with 24 weeks of
triple therapy followed by 24 weeks of PegIFN/RBV (total
duration of therapy 48 weeks) had a SVR rate of 76%, while prior
non-responders had lower rates of SVR (~40% ).
RESPOND-2 evaluated triple therapy combination with
boceprevir in non-responders and relapsers (Bacon 2011). The
results indicate that 75% of prior relapsers and 52% of prior nonresponders
treated with a fixed triple therapy boceprevir
regimen achieved SVR. In the response-guided arm, SVR was 69%
in prior relapsers and 40% in prior non-responders.
Curent available data clearly show that that triple therapies
including a protease inhibitor provide higher chance of SVR
for relapsers and non-responders. The benefits of these novel
treatment regimens for each individual patient must be weighed
against the side effects, costs and potential of developing viral
resistance