Book on hepatitis from page 204 to 223

Book on hepatitis from page 204 to 223

204  Hepatology 2012
Table 1. Relevant definitions for HCV treatment.
Abbreviation  Term  Description
SVR  Sustained Virological
Response
HCV RNA negative 6 months after the end of
therapy
SVR-12  Sustained Virological
Response
HCV RNA negative 12 weeks after the end of
therapy; FDA-accepted endpoint for future trials
RVR  Rapid Virological Response  HCV RNA negative after 4 weeks of therapy
eRVR (BOC)  Extended Rapid Virological
Response (for boceprevir)
HCV RNA negative (LLD not LLQ) between
week 8 and week 24 of BOC therapy: RGT
criterion for BOC
eRVR (TLV)  Extended Rapid Virological
Response (for telaprevir)
HCV RNA negative (LLD not LLQ) between
week 4 and week 12 of TLV therapy: RGT
criterion for TLV
EVR  Early Virological Response  HCV RNA decline ≥2 log10 at week 12
cEVR  Complete Early Virological
Response
HCV RNA negative at week 12
NR (BOC)  Nonresponse (boceprevir)  HCV RNA ≥100 IU/mL at week 12; or HCV
RNA positive at week 24; futility rule for BOC
NR (TLV)  Nonresponse (telaprevir)  HCV RNA ≥1000 IU/mL at week 4 or week 12;
or HCV RNA positive at week 12: Futility rule
for TLV
BT  Breakthrough  HCV RNA was LLD but increased to ≥100
IU/mL or increase of HCV RNA ≥ 1log10 during
therapy
RL  Relapse  HCV RNA negative at EOT and recurrence of
HCV RNA during the follow-up of 6 months.
PR  Partial Response  HCV RNA decline ≥2 log10 at week 12 but
positive at week 24 during PEG-IFN/RBV
NULR  Null response  HCV RNA decline <2 log10 at week 12 during
PEG-IFN/RBV
LI  Lead-In  4 weeks PEG-IFN/RBV before adding a PI
LLD, lower limit of detection (<10-15 IU/mL; here indicated as negative); LLQ, lower limit of
quantification; EOT, end of treatment; RGT, response-guided therapy
Standard Therapy of Chronic Hepatitis C Virus Infection  205
Figure 1. Development of chronic hepatitis C therapy. The sustained virologic response
rates have improved from around 5% with interferon monotherapy in the early 90s to >70%
today with triple therapy of PEG-IFN + ribavirin + PI.
Table 2. Approved drugs for the treatment of chronic hepatitis C (2011).
Medication  Dosing
Type I interferons  Subcutaneous injection
Pegylated Interferon α-2a
(Pegasys®)
180 µg once weekly
Pegylated Interferon α-2b (PEG-Intron®)
1.5 µg/kg once weekly
Interferon α-2a (Roferon®)  3 - 4.5 Mill I.U. three times weekly
Interferon α-2b (Intron A®)  3 Mill I.U. three times weekly
Consensus Interferon (Infergen®)  9 µg three times weekly
Ribavirin  Oral tablets or capsules
Ribavirin (Copegus®)  800 - 1200 mg daily (200 mg or 400 mg tablets)
Ribavirin (Rebetol®)  600 - 1400 mg daily (200 mg capsules or solution)
HCV protease inhibitors  Oral tablets or capsules
Boceprevir (Victrelis®)  800 mg (4 x 200 mg capsules) every 7-9 hours
Telaprevir (Incivek®, Incivo®)  750 mg (2 x 375 mg tablets) every 7-9 hours
206  Hepatology 2012
Predictors of treatment response
During the last decade, tailoring treatment duration and dosing according to
individual parameters associated with response have improved SVR. Predicting
SVR before the start of antiviral treatment helps in making treatment decisions.
Important baseline factors associated with SVR to PEG-IFN/RBV are the HCV
genotype, the degree of liver fibrosis and steatosis, baseline viral load, presence of
insulin resistance, age, gender, body mass index, ethnicity, and HIV co-infection
(Berg 2011, McHutchison 2009b). Many of these factors may have less relevance
for triple therapy, i.e., insulin resistance seems not to impact SVR to PEG-IFN/RBV/PI (Berg 2011, Serfaty 2010) whereas low-density lipoprotein (LDL) was
associated with SVR (at least for TLV) (Berg 2011).
On the other hand, new parameters seem to be more important such as HCV
subtype 1a and 1b. Patients with HCV G1a have a higher risk of developing
resistance during PI-based therapy compared to HCV G1b because HCV G1a
requires an exchange of only one nucleotide versus two for HCV G1b in position
155 to develop resistance (reviewed in Sarrazin and Zeuzem 2010b).
During treatment, the kinetics of the HCV RNA decline is a strong predictor of
response. HCV RNA measurements at week 4, 12 and 24 are important for a
response-guided treatment approach for PEG-IFN/RBV but also for the new triple
therapy including BOC and TLV. Definitions of response and futility rules are
summarized in Table 1. (Futility rules means that if at these time points, the viral
load threshold is exceeded or detected in serum, therapy should be stopped.)
Recently, genome-wide association studies have identified host genetic
polymorphisms (i.e., rs12979860, rs8099917) located on chromosome 19 located
upstream to the region coding for IL28B (or IFN λ3) associated with SVR to
treatment with PEG-IFN/RBV in HCV G1 patients (Ge 2009, Rauch 2010, Suppiah
2009, Tanaka 2009) but also to a lesser extent for HCV G2/3 (Mangia 2010c,
Sarrazin 2011b). Data on IL28B explain the different responses to PEG-IFN/RBV
between different ethnic groups, i.e., low SVR in African Americans and high SVR
in Asian patients. However, the negative predictive value is not strong enough to
recommend general testing (EASL 2011). Viral kinetics, especially response at
week 4, have a higher predictive value (Sarrazin 2011a) and the relevance of IL28B
as a predictive marker for the success of triple therapy with PEG-IFN/RBV/PI is
less significant (Jacobson 2011a, Pol 2011a, Poordad 2011a). However, IL28B
testing may be useful to determine the IFN responsiveness and the likelihood of
achieving RVR with PEG-IFN/RBV before starting triple therapy. It may be of
relevance to discuss treatment options with the individual patient (see below).
Additional predictive markers are being evaluated. For example, low serum levels
of interferon γ inducible protein 10 (IP 10) are associated with SVR and may
improve the predictive value for discrimination between SVR and nonresponse
(Darling 2011, Fattovich 2011).
Antiviral resistance
The development of direct antiviral agents leads to the emerging problem of drug
resistance due to so-called resistant-associated amino acid variants (RAVs) of the
virus. Patients who received monotherapy with BOC or TLV develop resistance
Standard Therapy of Chronic Hepatitis C Virus Infection  207
within a few days (Sarrazin 2007). RAVs associated with resistance to BOC and
TLV are listed in Table 3. Due to their overlapping resistance profiles, one PI
cannot substitute the other in the case of viral breakthrough. Also, a combination of
the two PIs is not rationale. As mentioned above, combination with PEG-IFN/RBV
is mandatory for the usage of BOC or TLV and RAVs to BOC and TLV have not
been associated with less sensitivity to PEG-IFN/RBV (Kieffer 2007). Importantly,
if patients have a decreased PEG-IFN/RBV response, the risk of developing
significant RAVs is higher. Measures for the prevention of drug resistance are
adherence to the dose of the medications (most importantly to the PI) and
compliance with the futility rules (see below). If RAVs emerge, it is not completely
known for how long they persist and if this has any significant consequences for
future therapies. Some studies suggest that the majority of resistant variants revert to
wild type 1-2 years after the end of therapy (Sarrazin 2007, Sherman 2011b). At this
stage there is no rationale to routinely analyse HCV sequences either before therapy
or during treatment because it has no practical consequence. Dominant RAVs
before treatment have been documented (Kuntzen 2008) but the influence of
treatment response is not well characterised.
Table 3. Resistant-associated amino acid variants of HCV NS3 protease to
boceprevir and telaprevir (adapted from Sarrazin 2012).
V36A
/M
T54S
/A
V55A  Q80R
/K
R155K
/T/Q
A156S  A156T
/V
D168A
/E/G/H
/T/Y
V170A
/T
BOC  X  X  X    X  X  X    X
TLV  X  X      X  X  X
Treatment of HCV genotype 1
Treatment of naïve patients
Untreated patients with HCV genotype 1 (HCV G1) have various treatment options.
Triple therapy with PEG-IFN+RBV+PI increases the overall SVR by 25-31%
(Table 4). Many patients qualify for response-guided therapy (RGT) based on viral
kinetics. In 44-65% of patients with eRVR treatment duration can be reduced to 24-28 weeks (Figures 2A, 2B), some 4-6 times more than with PEG-IFN/RBV.
However, in patients with favourable predictors for SVR (low baseline HCV RNA,
IL28CC, no advanced fibrosis), dual therapy with PEG-IFN/RBV may still be an
option. In those patients, a lead-in of 4 weeks PEG-IFN/RBV can identify patients
with RVR who achieve high SVR without adding a PI. Patients with low viral load
at baseline who achieve RVR have demonstrated 78-100% SVR with 24 weeks
PEG-IFN/RBV dual therapy alone (Berg 2009, Ferenci 2008, Jensen 2006, Sarrazin
2011a, Zeuzem 2006) (Table 5). Not adding BOC or TLV will reduce costs and
adverse events, two factors that can lead to treatment discontinuation. The number
of patients who qualify for dual therapy may vary depending on the distribution of
IL28B polymorphisms. On the other hand, a lead-in therapy may identify patients
with a poor response to IFN with a high chance of developing resistance. Only 29-31% of patients who have <1 log10 reduction of HCV RNA after 4 weeks PEG-IFN/RBV go on to achieve SVR when they add BOC. Other negative predictors
208  Hepatology 2012
(HCV G1a, cirrhosis) together with the lead-in concept may increase the negative
predictive value of achieving SVR. In that case a wait-and-see strategy may be
considered. The 4-week lead-in strategy also proved useful in assessing compliance,
tolerability and safety before initiating the PI. The lead-in concept was developed in
the BOC studies with the hypothesis of reducing resistance and improving SVR
(Kwo 2010). However, the lead-in phase seems to have no significant effect on the
SVR or on the development of antiviral resistance (Kwo 2010, Zeuzem 2011).
Lead-in has also been evaluated for TLV but only in treatment-experienced patients
(Zeuzem 2011). It is recommended to discuss the lead-in option and the
consequences with the patient before initiation of treatment.
Table 4. Phase III studies with BOC or TLV treatment regimens in treatment naïve
patients with HCV genotype 1. Studies are no head-to-head studies and SVR between
different studies are difficult to compare because they had significant differences in
genetic and socioeconomic backgrounds.
Study  Dosing  eRVR, SVR
SPRINT-2
(Poordad 2011b)
N=938 nonblack
(NB)
N=159 black
*28 weeks if
eRVR BOC
a)  1.5 µg/kg PEG-IFN α-2b, 600-1400 mg
RBV 48 weeks
44 weeks Placebo (wk 4-48)
b)  1.5 µg/kg PEG-IFN α-2b, 600-1400 mg
RBV 28*-48 weeks
24 weeks 800 mg tid BOC (wk 4-28)
c)  1.5 µg/kg PEG-IFN α-2b, 600-1400 mg
RBV 48 weeks
44 weeks 800 mg tid BOC (wk 4-48)
a)  eRVR: 40/363 (11%) / NB: 12%
SVR: 137/363 (38%) / NB: 40%
b)  eRVR: 156/368 (42%) / NB: 45%
SVR: 233/368 (63%) / NB: 67%
c)  eRVR: 155/366 (42%) / NB: 44%
SVR: 242/366 (66%) / NB: 68%
ADVANCE
(Jacobson 2011b)
N=1088
*24 weeks if
eRVR TLV
a)  180 µg PEG-IFN α-2a, 1000-1200 mg
RBV 24*-48 weeks,
12 weeks 750 mg tid TLV (wk 0-12)
(T12PR)
b)  180 µg PEG-IFN α-2a, 1000-1200 mg
RBV 24*-48 weeks,
8 weeks 750 mg tid TLV, 4 weeks
Placebo (wk 0-12)
c)  180 µg PEG-IFN α-2a, 1000-1200 mg
RBV 48 weeks,
12 weeks Placebo (wk 0-12)
a)  eRVR: 210/363 (58%)
SVR: 271/363 (75%)**
b)  eRVR: 207/363 (57%)
SVR: 250/364 (69%)
c)  SVR: 158/361 (44%)
ILLUMINATE
(Sherman 2011a)
N=540
N=352 (65%)
eRVR
N=322
randomised
a)  eRVR: 180 µg PEG-IFN α-2a, 1000-1200 mg RBV 24 weeks, 12 weeks 750
mg tid TLV (wk 0-12)
b)  eRVR: 180 µg PEG-IFN α-2a, 1000-1200 mg RBV 48 weeks, 12 weeks 750
mg tid TLV (wk 0-12)
c)  no eRVR: 180 µg PEG-IFN α-2a, 1000-1200 mg RBV 48 weeks, 12 weeks 750
mg tid TLV (wk 0-12)
a)  SVR: 149/162 (92%)
b)  SVR: 140/160 (88%)
c)  SVR: 76/118 (64%)
** numbers from the published data are different from the numbers accepted by the FDA, i.e. 79% SVR for
telaprevir 12 weeks, PEG-IFN/RBV
Treatment regimens with boceprevir
Boceprevir (BOC) is a linear peptidomimetic ketoamide serine protease inhibitor
that binds reversibly to the HCV nonstructural 3 (NS3) active site. BOC results in a
significant decline of HCV RNA but given as monotherapy it leads to rapid
emergence of viral resistance (Sarrazin and Zeuzem 2010b). Thus, combination
with PEG-IFN/RBV is still necessary (Mederacke 2009). 800 mg BOC is given as
200 mg capsules every 7-9 hours together with food in combination with the
optimal dose of PEG-IFN/RBV (Table 2). In all Phase III trials BOC was added
Standard Therapy of Chronic Hepatitis C Virus Infection  209
after the 4-week lead-in period as described above. In SPRINT-2 (serine protease
inhibitor therapy 2), the Phase III study with 1097 treatment-naïve HCV G1
patients, safety and efficacy of two regimens of BOC added to PEG-IFN α-2b/RBV
after a 4-week lead-in with PEG-IFN/RBV were compared to PEG-IFN/RBV/placebo (Table 4) for 44 weeks. The two groups receiving BOC were
treated with an RGT concept or a fixed duration of BOC. Patients in the RGT group
received 24 weeks triple combination after the lead-in period. Treatment with PEG-IFN/RBV was continued through week 48 only if the criteria for eRVR were not
met (HCV RNA levels undetectable from week 8 through week 24). Patients in the
fixed therapy duration group received PEG-IFN/RBV/BOC for 44 weeks following
the 4-week lead-in phase. Based on published data for response rates being lower
for African-American patients, black and non-black patients were analysed as two
different pre-defined cohorts of the SPRINT-2 study. Overall, adding BOC to PEG-IFN/RBV could significantly improve SVR in previously untreated patients with
HCV genotype 1 leading to approval in 2011 (FDA: May; EMA: July). Non-black
patients achieved 27-28% higher SVR, black patients increased SVR by 19-30%.
Table 5. High SVR in naïve patients with HCV genotype 1 and low baseline viral
load treated with 24 weeks of PEG-IFN/RBV.
Study  Treatment  Subgroups
(fast responder)
Weeks  SVR
(Zeuzem
2006)
N=235
1.5 µg/kg PEG-IFN α-2b
800-1400 mg ribavirin
<600,000 IU/ml TW0
<600,000 IU/ml TW0 &
<29 IU/ml TW4 (RVR)
24
24
50%
89%
(Berg
2009)
N=433
1.5 µg/kg PEG-IFN α-2b
800-1400 mg ribavirin
<5.3 IU/ml TW4 (RVR)
<800,000 IU/ml TW0 &
<5.3 IU/ml TW4 (RVR)
18-24
18-24
80%
100%
(Sarrazin
2011a)
N=398
1.5 µg/kg PEG-IFN α-2b
800-1400 mg ribavirin
<800,000 IU/ml TW0 &
<5-10 IU/ml TW4 (RVR)
24 88%
(Jensen
2006)
N=216
180 µg PEG-IFN α-2a or
800 mg or 1000-1200 mg
ribavirin
<50 IU/ml TW4 (RVR)
>50 IU/ml TW4 (RVR)
24
24
89%
19%
(Ferenci
2008)
N=120
180 µg PEG-IFN α-2a or
1000-1200 mg ribavirin
<50 IU/ml TW4 (RVR)  24  74% ITT
79% PP
* SVR, sustained viral response; RVR, rapid virologic response.
The responsiveness to PEG-IFN/RBV is very important for the success of
treatment with BOC. This is emphasized by the fact that the HCV RNA decline at
week 4 is highly predictive of SVR. Patients with more than 1 log10 HCV RNA
decrease after the 4-week lead-in phase demonstrated an SVR of about 80% if
treated with BOC but only 28-38% responded if HCV RNA declined less than 1
log10. Thus, the lead-in phase can be valuable to predict the responsiveness to PEG-IFN/RBV for further individualization of therapy as discussed above (Figure 3).
Importantly, the overall SVR rates between the RGT group and the fixed 48-week
therapy group were comparable (Table 4). Patients achieving eRVR were eligible
210  Hepatology 2012
for a 28-week total therapy duration and almost all patients (96%) went on to
achieve SVR (Poordad 2011b). Of note, HCV RNA negative means below the limit
of detection (LLD) and not below limit of quantification (LLQ). This is important
because SVR is diminished in patients with LLQ at weeks 8-24 who were treated
for a shorter duration (Harrington 2011).
FDA and EMA have approved RGT for treatment naïve patients except for
patients with liver cirrhosis (Figure 2A) but the accepted treatment duration for
BOC-RGT is different to the study design of the Phase III study (32 vs 24 weeks
BOC for patients without eRVR) (Figure 2A). In addition, a retrospective analysis
led to the futility rule of HCV RNA >100 IU/mL at week 12. The predictive value
for nonresponse was 100%. BOC was initially combined with PEG-IFN α-2b.
Recently, a study in therapy-experienced patients including relapsers and partial
responders showed similar results with PEG-IFN α-2a/RBV (Flamm 2011). Thus,
both PEG-IFNs can be combined with BOC.
Treatment regimens with telaprevir
Telaprevir  (TLV) is also an orally administered reversible, selective,
peptidomimetic NS3/4A serine protease inhibitor, which leads to a significant
decline of HCV RNA although viral resistance emerges rapidly if given as
monotherapy (Sarrazin 2007). Thus, 750 mg TLV given as 375 mg tablets every 7-9
hours together with food (ideally >20 g fat) requires combination with optimal
PEG-IFN/RBV. Telaprevir was administered for a maximum of 12 weeks in the
Phase III trials; longer treatment duration is associated with increasing adverse
events (McHutchison 2010). Two large Phase III studies (ADVANCE and
ILLUMINATE) with a total of 1628 treatment-naïve HCV G1 patients showed that
PEG-IFN/RBV/TLV significantly improved SVR compared to PEG-IFN/RBV and
RGT is possible (Jacobson 2011b, Sherman 2011a). TLV was approved for the
treatment of HCV G1 in 2011 (FDA: May; EMA: September). In the ADVANCE
trial, 3 treatment groups were assessed for efficacy and safety  using  RGT in
treatment-naïve patients (Jacobson 2011b). 12 weeks of TLV versus 8 weeks of
TLV in combination with 24-48 weeks PEG-IFN/RBV were compared to 48 weeks
PEG-IFN/RBV dual therapy. Patients who achieved eRVR qualified for 24 weeks
of therapy (Table 4). SVR was significantly higher among those receiving TLV
compared to the placebo group; 12 weeks TLV resulted in the highest SVR (Table
4). In all treatment groups, more than 80% of patients who achieved eRVR had
SVR (89%, 83%, and 97%, respectively) (Jacobson 2011b).
To validate RGT, telaprevir 750 mg every 8 hours for 12 weeks was evaluated in
an open-label study (ILLUMINATE trial) to prospectively assess 24 vs 48 weeks of
treatment for HCV G1 patients who achieved eRVR. If HCV RNA levels were
undetectable at weeks 4 and 12, patients were randomly assigned to continue with
PEG-IFN/RBV for an additional 24 or 48 weeks. If eRVR was not attained, patients
received PEG-IFN/RBV for up to 48 weeks. Of the 540 subjects, 389 (72%)
achieved HCV RNA levels LLD at week 4 and 352 (65%) achieved eRVR. Patients
who achieved eRVR and were randomized to the 24-week cohort experienced 92%
SVR versus 88% who were treated for 48 weeks (Table 4) (Sherman 2011a).
Importantly, patients with liver cirrhosis showed higher relapse rates with shorter
treatment, therefore RGT for TLV has only been approved for naïve HCV G1
patients without liver cirrhosis. Also, retrospective analysis of the data showed that
Standard Therapy of Chronic Hepatitis C Virus Infection  211
early HCV RNA measurement at week 4 is predictive of nonresponse to TLV.
Patients with HCV RNA values >1000 IU/mL after 4 weeks PEG-IFN/RBV/TLV
did not achieve SVR. Therefore, therapy must be stopped.
Figure 2A. Treatment with BOC/PEG-IFN/RBV: Approved treatment algorithm for HCV G1
patients. *, RGT if eRVR (HCV RNA LLD week 8-24); #, EMA did not approve RGT for BOC
regimens in previously treated patients.
Figure 2B. Treatment with TLV/PEG-IFN/RBV: Approved treatment algorithm for HCV G1
patients. *RGT if eRVR (HCV RNA LLD week 4-12).
*** If patients have contraindications for BOC or TLV, dual therapy with PEG-IFN/RBV should
be given for 24-72 weeks according to the HCV RNA decline at week 4 and week 12 (Sarrazin,
Berg, Cornberg 2010 S3-Leitlinie). The treatment algorithm is similar to Figure 6.
212  Hepatology 2012
Figure 3. Suggestion to use the lead-in strategy for individualisation of treatment in
patients with HCV genotype 1. **The number of patients with low baseline HCV RNA and
RVR may vary between different countries due to IL28B differences.
Treatment of patients with prior antiviral treatment failure
As more patients have been treated, the size of the population of patients who have
failed to achieve SVR with PEG-IFN/RBV has expanded. Many nonresponder
patients have advanced liver disease and successful treatment may extend life
expectancy (Backus 2011,  Veldt 2007). Retreatment of patients with previous
treatment failure is one of the most important current topics in the treatment of
chronic hepatitis C.
Definition of treatment failure
Definition of response to or failure on antiviral therapy is very important when
considering retreating patients with chronic hepatitis C because the success of BOC-or TLV-based regimens depends on the IFN responsiveness. Patients may have been
treated with different treatment regimens and compliance during the previous
therapy was probably very varied. Most importantly, HCV RNA kinetics and the
response profile during the previous therapy have to be taken into account before
starting a new treatment. It is crucial to screen the patient’s records and check
treatment duration, drug dosing and HCV RNA of the previous therapy. Non-response is the failure of a patient to clear HCV RNA at any point during treatment.
Definitions used for trials assessing novel therapy approaches have generally
defined non-response as the failure to achieve EVR, which is ≥2 log10 reduction of
HCV RNA after 12 weeks. Classifications of non-response include null response,
partial response, relapse, and breakthrough (see Table 1, Figure 4).
Standard Therapy of Chronic Hepatitis C Virus Infection  213
Figure 4. Different scenarios of treatment failure to antiviral therapy in chronic hepatitis
C.
Retreatment of HCV G1 patients with relapse after PEG-IFN/RBV
Retreatment with PEG-IFN/RBV of relapse patients after IFN- or PEG-IFN-based
combination therapy with ribavirin resulted in an SVR of 24-34% (Bacon 2011,
Poynard 2009, Zeuzem 2011). Triple therapy with PEG-IFN/RBV/PI increases SVR
dramatically to 69-88% (Bacon 2011, Zeuzem 2011) (Table 6). Relapse patients are
the ideal patients for retreatment with a triple therapy regimen. Patients have already
proven to respond to PEG-IFN and RBV. Thus, the backbone to prevent PI
resistance is effective and a lead-in strategy may not be as important as in other
situations. Although RGT was not evaluated in the Phase III REALIZE trial with
TLV, a rollover study including relapse patients from Phase II studies has
demonstrated that shorter treatment is effective in patients with eRVR (Muir 2011).
Therefore, RGT is possible with BOC and TLV regimes (Figures 2A, 2B) if
cirrhosis is excluded (Ghany 2011, Sarrazin 2012). In contrast, BOC RGT has only
been approved by the FDA and not by the EMA because SVR was slightly lower in
the RESPOND-2 RGT group (Table 6).
Retreatment of HCV G1 patients with partial response to PEG-IFN/RBV
Patients who are partial responders (PR) to standard PEG-IFN/RBV combination
therapy have demonstrated SVRs ranging between 7% and 15% with a standard
PEG-IFN/RBV retreatment (Bacon 2011, Zeuzem 2011). Retreatment with triple
therapy increases SVR to 40%-59% (Bacon 2011, Zeuzem 2011) (Table 6). FDA
but not EMA approved RGT for BOC (Figures 2A, 2B). Treatment duration for
PEG-IFN/RBV/TLV is 48 weeks for all PR patients (Figure 2B). The 4-7-fold
increase justifies retreatment. However, SVR decreases significantly in patients with
cirrhosis (34% with TLV) and other negative response factors (Pol 2011b).
214  Hepatology 2012
Retreatment of HCV G1 patients with null response to PEG-IFN/RBV
Patients who are null responders (NULR) to standard PEG-IFN/RBV combination
therapy have demonstrated SVRs ranging between 5% and 16% with an optimised
PEG-IFN/RBV retreatment (Jensen 2009, Poynard 2009,  Zeuzem 2011).
Retreatment with PEG-IFN/RBV/PI did increase SVR more than 6-fold in the
REALIZE trial (Zeuzem 2011). However, overall SVR with triple therapy is limited
to 29-38% (Vierling 2011, Zeuzem 2011) (Table 6). If further negative predictive
factors are present, SVR decreases to 27% in HCV G1a patients and to 14% in
cirrhotic patients (not significantly different from PEG-IFN/RBV) (Figure 7A). This
may justify the lead-in concept to decide if treatment with a PI is beneficial. Patients
who do not acheive a 1 log10 decline of HCV RNA after 4 weeks demonstrate only
15% SVR (Zeuzem 2011). Futility rules are the same for treatment-experienced
patients as for treatment-naïve patients (Figures 2A, 2B).
Table 6. Phase III studies with BOC or TLV treatment regimens in treatment-experienced patients infected with HCV genotype 1. Studies are not head-to-head and
SVR between studies are difficult to compare because they had significant differences in
genetic and socioeconomic backgrounds.
Study  Dosing  SVR
RESPOND-2
(Bacon 2011)
n=403
*36 weeks
if eRVR BOC
a)  1.5 µg/kg PEG-IFN α-2b, 600-1400 mg
RBV 48 weeks
44 weeks Placebo (wk 4-48)
b)  1.5 µg/kg PEG-IFN α-2b, 600-1400 mg
RBV 36*-48 weeks
32 weeks 800 mg tid BOC (wk 4-36)
c)  1.5 µg/kg PEG-IFN α-2b, 600-1400 mg
RBV 48 weeks
44 weeks 800 mg tid BOC (wk 4-48)
a)  REL: 29%  All: 21%
PR: 7%
b)  REL: 69%  All: 59%
PR: 40%
c)  REL: 75%  All: 66%
PR: 52%
(Flamm 2011)
n=201
a)  180 µg PEG-IFN α-2a, 1000-1200 mg
RBV 48 weeks
44 weeks Placebo (wk 4-48)
b)  180 µg PEG-IFN α-2a, 1000-1200 mg
RBV 48 weeks
44 weeks 800 mg tid BOC (wk 4-48)
a)  REL, PR: 21%
b)  REL, PR: 64%
PROVIDE
(Vierling 2011)
n=48
(42 available)
1.5 µg/kg PEG-IFN α-2b, 600-1400 mg
RBV 48 weeks
44 weeks 800 mg tid BOC (wk 4-48)
38% (16/42)
REALIZE
(Zeuzem 2011)
n=663
a)  180 µg PEG-IFN α-2a, 1000-1200 mg
RBV 48 weeks,
12 weeks Placebo (wk 0-12)
b)  180 µg PEG-IFN α-2a, 1000-1200 mg
RBV 48 weeks,
4 weeks Placebo (wk 0-4), 12 weeks 750
mg tid TLV (wk 4-16)
 Lead-in cohort
c)  180 µg PEG-IFN α-2a, 1000-1200 mg
RBV 48 weeks,
12 weeks 750 mg tid TLV (wk 0-12), 4
weeks Placebo (wk 12-16),
a)  REL: 24%
PR: 15%
NULR: 5%
b)  REL: 88%
PR: 54%
NULR: 33%
c)  REL: 83%
PR: 59%
NULR: 29%
Standard Therapy of Chronic Hepatitis C Virus Infection  215
PEG-IFN maintenance therapy
There has been much interest concerning the use of low-dose PEG-IFN maintenance
therapy in patients with a null response since data has suggested that IFN may halt
progression of liver disease (Nishiguchi 1995). There are two major published trials
that have analysed if maintenance treatment with IFN alters the natural course of
chronic hepatitis C. In the EPIC
3
trial, nonresponders to IFN/RBV with
compensated cirrhosis and no evidence of HCC received 0.5 µg/kg PEG-IFN α-2b
or no treatment for a maximum period of 5 years or until patients developed clinical
events (hepatic decompensation, HCC, death, or liver transplantation). The study
revealed no significant difference in time to first clinical event among patients who
received PEG-IFN compared with controls (Bruix 2011).
The HALT-C trial, a long-term maintenance study supported by the National
Institutes of Health evaluated a large cohort of chronic HCV-infected patients who
had failed previous IFN-based therapy and had METAVIR stage F2-F4. Patients
received 90 µg PEG-IFN α-2a maintenance treatment if they did not respond during
the first 20 weeks with standard therapy. Despite the fact that there were greater
reductions in viremia, decreases in alanine aminotransferase, and
necroinflammation in the patients who received PEG-IFN, none of the important
clinical outcomes (rates of death, decompensation, hepatocellular carcinoma, and
increase in fibrosis) were favourably affected by PEG-IFN therapy (Di Bisceglie
2008). In conclusion, long-term treatment with low-dose PEG-IFN cannot be
recommended (Sarrazin 2010a).
Treatment of HCV genotypes 2 and 3
Naïve patients
TLV shows antiviral efficacy against HCV G2 but is not effective against HCV G3
(Foster 2011). Data for BOC have only been presented in abstract form for 400 mg
TID in a small number of patients (Silva 2011). Importantly, both PIs are approved
only for the treatment of HCV G1. Thus, SOC for HCV G2/3 infection remains the
combination of PEG-IFN/RBV. Although a fixed duration of treatment (24 weeks)
has been advocated, the optimal results are likely to be achieved when the duration
of therapy is adjusted based on viral kinetics. Many studies have investigated the
reduction of treatment duration for HCV G2/3 to 16, 14, or even 12 weeks. Overall,
reducing the treatment duration to less than 24 weeks increases the number of
relapses (Andriulli 2008, Dalgard 2008, Mangia 2005, Manns 2011a, Shiffman
2007b). However, some HCV G2/3 patients may indeed be treatable for 12-16
weeks if certain prerequisites are fulfilled, especially the rapid virologic response
(RVR) by week 4 of therapy (Slavenburg 2009). Only patients with RVR have high
SVR rates after 16 weeks (Manns 2011a, von Wagner 2005), 14 weeks (Dalgard
2008), or even 12 weeks of therapy (Mangia 2005) (Table 7).
In addition to the RVR, the specific HCV genotype and the baseline viral load are
associated with response. Patients with HCV G2 respond better to PEG-IFN/RBV
therapy than those infected with HCV G3 (Zeuzem 2004b). Furthermore, the shorter
treatment schedules reveal that HCV G3 patients with low baseline viremia (<400-800,000 IU/ml) had a much better chance of responding than those with high viral
load (>400-800,000 IU/ml) (Shiffman 2007b,  von Wagner 2005). Patients with
216  Hepatology 2012
HCV G3 plus low viral load who achieve RVR can be treated for less than 24
weeks. However, reducing treatment duration is not recommended in patients with
advanced liver fibrosis or cirrhosis, insulin resistance, diabetes mellitus, hepatic
steatosis or BMI >30 kg/m
2
(Aghemo 2006,  Sarrazin 2010a, Sarrazin 2011).
Patients treated with a response-guided approach should be started on high-dose
ribavirin, which appears to increase the rate of RVR in patients with HCV G2/3
undergoing short treatment (Mangia 2010b).
In contrast, HCV G2/3 patients who do not achieve RVR (especially HCV G3 and
high viral load) may be treated for longer than 24 weeks (i.e., 36-48 weeks) (Figure
5). However, most data are retrospective (Willems 2007). A prospective study from
Italy showed a numerically significant benefit of 36 weeks versus 24 weeks (75%
vs. 62%) (Mangia 2010a). Further prospective studies investigating treatment
extension to 36 or 48 weeks are ongoing. Depending on the assay used to determine
RVR, around 25-30% of HCV G2/3 patients belong to this difficult-to-treat
population not achieving RVR (Table 8). Tailoring treatments individually for
patients with HCV G2/3 will reduce costs and side effects and further optimise the
response rates.
Figure 5. Recommendation for treatment of HCV genotypes 2 and 3. Sensitive HCV RNA
assays (limit of detection 12-15 IU/ml or 50 IU/ml) at weeks 4 and 12 may determine treatment
duration. Reducing treatment duration is not recommended in patients with liver cirrhosis,
insulin resistance, diabetes mellitus or hepatic steatosis.
Standard Therapy of Chronic Hepatitis C Virus Infection  217
Table 7. Response-guided therapy for patients with HCV genotypes 2 and 3.
Study  Treatment  Subgroups  Therapy
weeks
SVR*
(von Wagner
2005)
n=153
180 µg PEG-IFN α-2a
800-1200 mg ribavirin
>600 IU/ml TW4
<600 IU/ml TW4
24
24
36%
80%, 84% if HCV
RNA<800,000 IU/ml
<600 IU/ml TW4  16  82%, 93% if HCV
RNA<800,000 IU/ml
(Shiffman
2007b)
n=1469
180 µg PEG-IFN α-2a
800 mg ribavirin
All patients
All patients
<50IU/ml TW4 (RVR)
<50IU/ml TW4 (RVR)
<400,000IU/ml TW0
(LVL)
<400,000IU/ml TW0
(LVL)
24
16
24
16
24
16
70%
62%
85%
79%
81%
82%
(Mangia
2005)
n=283
1.0 µg PEG-IFN α-2b
1000-1200 mg ribavirin
Standard group 24 76%
Standard group 24 91% if TW4 HCV RNA
<50 IU/ml
>50 IU/ml TW4 (no RVR) 24 64%
<50 IU/ml TW4 (RVR)  12  85%
(Dalgard
2008)
n=428
1.5 µg PEG-IFN α-2b
800-1400 mg ribavirin
<50 IU/ml TW4 (RVR) 24 91% ITT, 93% with F24
HCV RNA test
<50 IU/ml TW4 (RVR)  14  81% ITT, 86% with F24
HCV RNA test
>50 IU/ml TW4 (no-RVR)  24  55% ITT, 59% with F24
HCV RNA test
(Manns
2011a)
n=682
1.0 µg PEG-IFN α-2b
1.5 µg PEG-IFN α-2b
800-1400 mg ribavirin
All patients 24 (1.5)67% ITT, 82% as treated
All patients 24 (1.0) 64% ITT, 80% as treated
All patients  16 (1.5) 57% ITT, 68% as treated
* SVR, sustained viral response; RVR, rapid virologic response; LVL, low baseline viral
load.
218  Hepatology 2012
Table 8. SVR of patients with HCV genotypes 2 or 3 not achieving RVR.
Study  Frequency of patients
without RVR
SVR without RVR
(24 wks therapy)
(von Wagner 2005)
180 µg PEG-IFN
α-2a 800-1200 mg ribavirin
7%
(HCV RNA >600 IU/ml TW4)
36%
(Shiffman 2007b)
180 µg PEG-IFN α-2a
800 mg ribavirin
36%
(HCV RNA >50 IU/ml TW4) (24 wk group)
45%
(Mangia 2005)
1.0 µg/kg PEG-IFN α-2b
1000-1200 mg ribavirin
36%-38%
(HCV RNA >50 IU/ml TW4)
48%-64%
(Dalgard 2004)
1.5 µg/kg PEG-IFN α-2b
800-1400 mg ribavirin
22%
(HCV RNA >50 IU/ml TW4/TW8)
56%
(Dalgard 2008)
1.5 µg/kg PEG-IFN α-2b
800-1400 mg ribavirin
29%
(HCV RNA >50 IU/ml TW4)
55%
Treatment of HCV G2/3 patients with prior antiviral
treatment failure
Patients with relapse after a short course of PEG-IFN/RBV show adequate SVR
after retreatment for 24 weeks (Mangia 2009). In patients with unfavourable
predictors,  longer treatment duration for 48 weeks is advisable  (EASL 2011).
Nonresponders can be retreated with an additional course of PEG-IFN/RBV. It is
important to optimise dose and duration of treatment. HCV G2 nonresponders may
benefit from retreatment with PEG-IFN/RBV/PI (so far only data for TLV). Triple
therapy is off-label but may be considered in difficult to treat HCV G2 patients with
an urgent treatment indication. Future DAAs will be pan-genotypic and therefore
also effective for HCV G3 (see Chapter 14). Nonresponder patients with mild
fibrosis may therefore wait for new treatment options, but  it is important to
understand that fibrosis progression is faster in patients with HCV G3 (Bochud
2009).
Treatment of HCV genotypes 4, 5, and 6
BOC and TLV have hardly been tested in patients with HCV G4, 5, or 6. Neither PI
is approved for the treatment of HCV G4, 5, or 6. Thus, SOC remains the
combination of PEG-IFN/RBV. In general, treatment duration of 48 weeks is
recommended based on the results of the large, randomized Phase III trials (Fried
2002, Hadziyannis 2004, Manns 2001). However, these trials included few patients
with HCV G4, 5, and 6 and further large, prospective randomized studies with RGT
are rare. Importantly, HCV G4, 5, and 6 are very common in areas where chronic
hepatitis C is highly prevalent. For example, HCV G4 is most prevalent in the
Middle East and Egypt where it accounts for >80% of all HCV cases
(approximately 34 million patients) (Khattab 2011). HCV G5 is most prevalent in
South Africa, and genotype 6 in Southeast Asia (Nguyen 2005). The available study
Standard Therapy of Chronic Hepatitis C Virus Infection  219
results, although limited, suggest that patients with HCV G4, 5 and 6 may show
different clinical courses and treatment outcomes. Ethnicity-related factors (i.e.,
IL28B, regional aspects) may contribute to these findings. Overall, data from
smaller studies suggest that HCV G4, 5 and 6 appear easier-to-treat compared to
HCV G1 but the optimal treatment duration is not clear (Antaki 2010, Nguyen
2005) (Table 9). Although some studies show SVR on the same order as for HCV
G2/3 patients, a fixed duration of 24 weeks of treatment as for HCV G2/3 is not
advisable, even for patients with HCV G6, which appears to show the best SVR
(Lam 2010, Nguyen 2008). RGT based on early viral kinetics should be possible.
Patients who achieve RVR are candidates for a short treatment regimen of 24 weeks
if they don’t have predictors of poor response (see above). Based on data for HCV
G1 (Berg 2006,  Sanchez-Tapias 2006), patients without RVR and/or partial
response may be considered for 72 weeks. This has been proposed for HCV G4 by
an international expert panel (Khattab 2011), but the evidence is limited. The
proposed algorithm is shown in Figure 6. We suggest treating HCV G5 and 6 also
according to this algorithm. Patients with treatment failure may be considered for
retreatment, especially if the previous therapy was suboptimal. It is important to
optimise dose and duration of treatment during retreatment.
Figure 6. Suggestion for treatment of HCV genotypes 4, 5, and 6. This algorithm was
initially proposed for HCV G4 (adapted Khattab 2011). Sensitive HCV RNA assays (limit of
detection 12-15 IU/ml or 50 IU/ml) at weeks 4 and 12 may determine treatment duration.
Reducing treatment duration is not recommended in patients with predictors of poor response
(liver cirrhosis, insulin resistance, diabetes mellitus or hepatic steatosis, high baseline viral load
>800,000 IU/mL).
220  Hepatology 2012
Table 9. Efficacy of antiviral treatment with PEG-IFN plus ribavirin in patients with
chronic hepatitis C infected with genotypes 4, 5, and 6. Selected trials.
Study  Treatment  HCV genotype/Duration  SVR
(Diago 2004)
n=49
180 µg PEG-IFN α-2a
800/1000/1200 mg ribavirin
G4  24 weeks
24 weeks
48 weeks
48 weeks
0% (if low RBV)
67% (if high RBV)
63% (if low RBV)
79% (if high RBV)
(Hasan 2004)
n=66
1.5µg/kg PEG-IFN α-2b
1000/1200 mg ribavirin
G4  48 weeks
48 weeks
48 weeks
68%
55% (if HVL)
86% (if LVL)
(Kamal 2005)
n=287
1.5µg/kg PEG-IFN α-2b
1000/1200 mg ribavirin
G4  24 weeks
36 weeks
48 weeks
29%
66%
69%
(Kamal 2007)
n=358
1.5µg/kg PEG-IFN α-2b
10.6 mg/kg ribavirin
RGT
G4  24 weeks RGT
36 weeks RGT
48 weeks RGT
48 weeks
86% (if RVR)
76% (if cEVR)
56% (if EVR)
58%
(Ferenci
2008)
n=66
180 µg PEG-IFN α-2a
1000/1200 mg ribavirin
RGT
G4  24 weeks RGT  87% (if RVR)
(Bonny 2006)
n=59
PEG-IFN α-2a or b
800-1200 mg ribavirin
G5  48 weeks  58%
(Lam 2010)
n=60
PEG-IFN α-2a
800-1200 mg ribavirin
G6  24 weeks
48 weeks
70%
79%
(Nguyen
2008)
n=35
PEG-IFN α-2a or b
800-1200 mg ribavirin
G6  24 weeks
48 weeks
39%
75%
RBV, ribavirin; LVL, low baseline viral load; HVL, high baseline viral load; RGT, response-guided therapy
Optimisation of HCV treatment
Adherence to therapy
Adherence to therapy is one of the most important factors associated with the
success of antiviral treatment (McHutchison 2002). The definition of adherence
used here is the “80/80 rule”, that is, patients who receive more than 80% of the
medication and are treated for more than 80% of the planned duration of treatment
are considered adherent. One of the first studies investigating the effect of
adherence in PEG-IFN/RBV treatment demonstrated that patients who fulfilled the
Standard Therapy of Chronic Hepatitis C Virus Infection  221
80/80 rule had a 63% SVR compared to 52% of those with less than 80% adherence
(McHutchison 2002). Another study showed that a cumulative ribavirin dose of
more than 60% is important to achieve an SVR (Reddy 2007). For the new triple
therapy, adherence to the PI becomes even more important as mentioned above. The
three-times-daily regimen necessitates highly motivated and compliant patients.
BOC and TLV have to be taken every 7-9 hours together with food. Reduction of
the PI or irregular intake bears the risk for rapid emergence of drug resistance. Dose
reduction of the PI is associated with significantly diminished SVR (Gordon 2011)
and is therefore not an option to manage side effects. An optimal management of
PEG-IFN/RBV side effects therefore is essential in order to optimise treatment
responses. In the case of anemia, dose reduction of ribavirin is possible and not
associated with impaired SVR to triple therapy (Roberts 2011). Another important
and new issue is drug interactions that can diminish the effectiveness of the PI or
induce toxicity of concomitant medications, which may lead to discontinuation of
all drugs. Knowledge about drug interactions is therefore important for the optimal
management of patients receiving PEG-IFN/RBV/PI.
Management of side effects and complications
Severe side effects may reduce adherence to therapy and may result in dose
modifications that result in a less-than-optimal response. IFN, ribavirin and the new
protease inhibitors induce side effects that have to be managed with the patient
(Table 10). The IFN-related side effects can be divided into IFN-induced bone
marrow suppression, flu-like symptoms, neuropsychiatric disorders, and
autoimmune syndromes. The main problem of ribavirin is hemolytic anemia.
Boceprevir and telaprevir are associated with additional side effects such as rash or
dysgeusia and additionally an increase of anemia (Table 10) (Jacobson 2011b,
Manns 2011b, Vertex 2011, Zeuzem 2011). Overall, side effects result in premature
withdrawals from therapy (5-17% during triple therapy depending on the duration of
therapy (Jacobson 2011b)) and additional patients require dose modifications during
treatment. The frequency of treatment discontinuations and dose modifications are
lower in recent studies, suggesting an improved understanding and management of
adverse events (Manns 2006). Similar developments are expected also for treatment
with PIs. For example, the reported cases of rash decreased from 60% in Phase II
(McHutchison 2009a) to 36% in the Phase III trial (Jacobson 2011b). However, the
frequency of adverse events that occurred in registration trials with carefully
selected patients may differ from general clinical practice, where patients with, e.g.,
history of psychiatric disorders or advanced liver disease are being treated. For
example, factors significantly associated with developing anemia on TVR were
older age and advanced fibrosis (Roberts 2011).
IFN side effects
The effect of IFN on bone marrow results in decreased granulocytes and
thrombocytes during treatment. These are usually moderate if normal counts are
initially present. However, dose modifications are necessary, especially in patients
with initially low counts (Manns 2006). This limits the use of IFN in patients with
advanced liver cirrhosis who often have low platelets and are also more vulnerable
to infections. Therapeutic concepts in order to raise platelet levels safely would have
222  Hepatology 2012
a significant effect on the effective management of patients, especially those with
advanced liver disease.
A promising novel agent is the oral thrombopoietin receptor agonist eltrombopag
that has been tested in patients with chronic hepatitis C and liver cirrhosis
(McHutchison 2007). Eltrombopag was able to increase platelet levels in 75-95% of
patients depending on the dose, and antiviral therapy was then initiated. Twelve
weeks of antiviral therapy were then taken by 36-65% of patients receiving 30-75
mg of eltrombopag vs only 6% of patients in the placebo group (McHutchison
2007). A recent Phase III study including patients with platelets <75 K/µl has shown
that eltrombopag pretreatment for 9 weeks and later combination with PEG-IFN/RBV could significantly increase SVR in comparison to eltrombopag
pretreatment and later PEG-IFN/RBV/placebo (Afdhal 2011). Neutropenia is
another of the most common reasons for dose modification.
Granulocyte macrophage colony stimulating factor (GM-CSF, Filgrastim) could
potentially be used to stabilize neutrophil counts during IFN therapy (Shiffman
1998, Younossi 2008). While administration of GM-CSF may enable patients to
remain on treatment, a systematic review documented only weak evidence that this
improves the likelihood of SVR compared to dose reduction (Tandon 2011). The
economic evaluation was inconclusive, therefore further cost-benefit analyses and
trials are required to recommend routine use of these agents. However, IFN-induced
neutropenia is generally not associated with a significant increased risk for bacterial
infections (Soza 2002).
Flu-like symptoms usually occur during the first weeks of treatment and severity
declines over time. These symptoms include fever, chills, headache, arthralgia, and
myalgia. Antipyretic drugs such as paracetamol can help to prevent or reduce these
side effects (Manns 2006).
Neuropsychiatric side effects such as irritability, severe fatigue, and apathy are
frequent (>50%) and pose a great problem for many patients and their family
members. Severe depression can occur and suicide has been reported (Janssen
1994). Psychiatric care and the use of antidepressants, especially serotonin uptake
inhibitors (SSRIs) may help reduce IFN-induced depression and consequently
improve adherence to hepatitis C therapy. A double-blind placebo-controlled study
in 100 patients with chronic hepatitis C was terminated prematurely due to
significant superiority of SSRIs over placebo in terms of decreasing scores on the
Hospital Anxiety and Depression Scale (HADS). All SSRI-treated patients were
able to complete IFN treatment (Kraus 2008). SSRI treatment is highly effective in
HCV patients during IFN-based therapies, when starting early after the onset of
clinically relevant depression. Of note, citalopram should no longer be used at doses
greater than 40 mg per day because it can cause prolongation of the QT interval on
the electrocardiogram. This may be of relevance during triple therapy.
IFN has immunomodulatory properties, and treatment can induce autoimmune
phenomena (Wesche 2001). The most frequent problem is the development of
autoimmune thyroiditis. In most cases thyroiditis starts with hyperthyroidism that
later turns into hypothyroidism. Autoimmune thyroiditis has been reported in up to
20% of patients during IFN-based therapies (Costelloe 2010). However, only a few
patients develop thyroid disease that requires ongoing therapy (Costelloe 2010, Tran
2011). Patients with preexisting thyroid antibodies may have a higher risk and it is
Standard Therapy of Chronic Hepatitis C Virus Infection  223
possible that hepatitis C itself may be a cause of autoimmune thyroiditis (Ganne-Carrie 2000).
Other autoimmune diseases can also be aggravated by IFN therapy (e.g., diabetes
or autoimmune hepatitis). Patients with documented HCV infection may get worse
during IFN treatment if an underlying autoimmune hepatitis is present. This has
been observed particularly in LKM antibody-positive individuals. These patients
require careful monitoring if IFN is considered as first-line treatment. However, IFN
therapy seems to be safe in most HCV/anti-LKM-1-positive patients (Dalekos 1999,
Todros 1995).
Ribavirin side effects
The main side effect of ribavirin is hemolytic anemia that frequently results in
ribavirin dose reduction or even discontinuation, which may significantly affect the
SVR with PEG-IFN/RBV alone (Reddy 2007). Treatment with erythropoietin
(EPO) can reverse ribavirin-associated anemia and allow full adherence to ribavirin
therapy (Afdhal 2004). Although the use of EPO can reduce the incidence and
severity of ribavirin induced anemia, there is limited evidence that EPO has an
effect on SVR. A prospective, randomized, controlled trial has evaluated the effect
of EPO on SVR. Patients receiving PEG-IFN α-2b plus 13.3 mg/kg/day ribavirin
were compared to patients receiving PEG-IFN α-2b, 13.3 mg/kg/day ribavirin and
40,000 U/week EPO. Although there were significantly fewer ribavirin dose
reductions in those patients who received EPO, no improvement in SVR  was
shown. A third group received a higher starting dose of 15.2 mg/kg/day in
combination with EPO and they did show a significantly higher SVR but there was
no control group in this trial (Shiffman 2007a).  A placebo-  controlled trial
investigated the use of 30,000 U/week EPO or placebo in addition  to PEG-IFN/RBV when hemoglobin reduced to ≤12 g/dL in men and ≤11 g/dL in women.
SVR was not significantly improved with EPO. Overall, EPO may improve quality
of life, and in some individuals it may also improve the chance of achieving an SVR
(in those requiring high doses of RBV). However, EPO use is off-label. Alternative
ribavirin-like drugs with less toxicity and/or higher antiviral efficacy have failed
(Benhamou 2009, Marcellin 2010). Drug monitoring of ribavirin could be an option
to optimise the ribavirin dose without losing efficacy (Svensson 2000). The
pharmacokinetics of ribavirin suggests that not only body weight but also renal
function (glomerular filtration rate) should be considered when selecting the
ribavirin dose (Bruchfeld 2002). Importantly, RBV is considered as teratogenic and
therefore contraindicated during and 6 months after pregnancy. Effective birth
control measures are necessary (Sarrazin 2010a).
Protease inhibitor side effects
Both BOC and TLV were associated with more frequent and severe anemia.
Approximately 1-1.5 g/dL additional decrease of hemoglobin can be expected. The
different treatment duration of both drugs results in different grades and duration of
anemia.  In the BOC trials, approximately 50% of patients receiving BOC
experienced anemia, compared to 29% of participants who did not receive the drug
(Poordad 2011b). Of note, treatment with EPO was allowed in the BOC trials.
Participants in the TLV trial were not permitted to receive EPO and anemia rates
were 36% and 17% for patients who did or did not receive the drug, respectively