Emerging Approaches for the Treatment of Hepatitis C Virus
Gap Analysis 1
Current Practice
Desired Practice
Physicians may not be sufficiently familiar with the
Physicians are knowledgeable of triple therapy
latest guidelines for chronic HCV treatment, including
involving direct-acting antiviral agents (DAAs) in
the initiation and optimization of triple therapy.
combination with the previous standard of care.
Resulting Gap
Physicians do not provide optimal care for patients based on a lack of familiarity of the latest guidelines for
treatment of HCV.
Learning Objective
Implement and optimize the current evidence-based components triple therapy including DAAs in the
treatment of chronic HCV.
Gap Analysis 2
Current Practice
Desired Practice
Physicians may not be knowledgeable of the
Physicians will be knowledgeable of the limitations of
limitations
triple therapy in certain populations.
of
triple
therapy in
certain
patient
populations.
Resulting Gap
Physicians are not sufficiently aware of appropriate treatment for patient populations that were
underrepresented in the phase 3 trials documenting the efficacy of triple therapy regimens.
Learning Objective
Diagnose and integrate the uncertainty of triple therapy regimens in certain patient populations.
Gap Analysis 3
Current Practice
Desired Practice
Clinicians may not be up to date on the issue of
Physicians will be knowledgeable of the risk of
resistant-associated
generating
variants
(RAVs)
after
administering triple therapy and of investigational
RAVs
and
of
emerging
therapeutic
treatments for hepatitis C.
drugs that may help overcome this resistance
Resulting Gap
Physicians may not be sufficiently familiar with the increasing risk of RAVs and other DAAs under
investigation and may fail to provide optimal ongoing treatment for patients
Learning Objective
Assess the risk for generation of RAVs with triple therapy and the utility of investigational DAAs in the
treatment of hepatitis C.
GAP 1: Physicians do not provide optimal care for patients based on a lack of familiarity of the latest
guidelines for treatment of HCV
Knowledge of the most recent guidelines for HCV subgenotype 1 treatment published in 2011 by the American
Association for the Study of Liver Diseases (AASLD) would aid in better management of chronic HCV. Per these
guidelines, patients with genotype 1 should receive triple therapy regimen that includes PEG-IFN, weight-based RBV,
and a protease inhibitor (boceprevir or telaprevir). Triple therapy has significantly improved SVR rates (70-80%)
compared with combination therapy consisting of PEG-IFN/RBV (40-50%). The patient’s prior treatment status is an
important factor to consider when administering triple therapy. Treatment-naïve patients, prior relapsers (patients
who had an undetectable viral load at the end of a prior attempt at treatment but did not achieve a SVR or a negative
HCV RNA 24 weeks after completing treatment), partial responders (patients who achieved a 2 log10 drop in HCV
RNA by week 12 of treatment but did not achieve an end of treatment response) and null responders (patients who
did not achieve a 2 log10 drop in HCV RNA by week 12 of treatment) are all candidates for triple therapy.7
Components of triple therapy
1.
Protease Inhibitors
Boceprevir and telaprevir mimic the carboxyl-terminal end of the NS3 protease and interfere with formation of the
HCV polyprotein resulting in inhibition of HCV replication.8 Boceprevir and telaprevir have demonstrated potent
inhibition of HCV genotype 1 replication and markedly improved SVR rates in treatment-naïve and treatmentexperienced patients in phase 3 trials.9-12 Telaprevir has also shown activity against HCV genotype 2 but not
genotype 3 in limited phase 2 testing.13 Although similar findings have been observed with boceprevir, neither drug
should be used to treat patients with genotype 2 or 3 HCV infections. Both boceprevir and telaprevir administered
without PEG-IFN and RBV result in the selection of resistance variants of HCV. However when used in combination
with PEG-IFN and RBV, lower resistance associated variants have been observed. 14 Telaprevir and boceprevir have
demonstrated similar efficacies in randomized trials. While telaprevir is effective in treatment-naïve patients,
relapsers, partial responders, and null responders; boceprevir is effective in treatment-naïve patients, relapsers,
partial responders, but it has not been studied in prior null responders. 7
2.
Pegylated interferons (PEG-IFN)
The licensed pegylated interferons (PEG-IFNs) in the US are PEG-IFN-alfa-2b (Peg-Intron, Schering Plough Corp.,
Kenilworth, NJ) and PEG-IFN-alfa-2a (Pegasys, Hoffmann-La Roche, Nutley, NJ). While PEG-IFN-alfa-2b has a 12kd linear polyethylene glycol (PEG) covalently linked to the standard interferon alfa-2b molecule, PEG-IFN-alfa-2a
has a 40-kd branched PEG covalently linked to the standard interferon alfa-2a molecule. The doses of these PEGIFNs differ but both have antiviral and immunomodulatory properties. The linkage of PEG to the interferon molecules
enhances its half-life in the body.15
3.
Ribavirin (RBV)
RBV is a synthetic guanosine analogue previously used in the treatment of respiratory syncytial virus infection. While
the exact mode of action of RBV is unknown, combining RBV with interferon has demonstrated improvements in endof-treatment and SVR rates in HCV-infected patients.16
Specific guidelines for triple therapy
For treatment-naïve patients the recommended dose of boceprevir is 800 mg with food three times per day (every 7-9
hours) along with PEG-IFN and weight-based RBV for 24-44 weeks. This regimen is started after 4 weeks of lead-in
treatment with PEG-IFN and RBV alone. The recommended dose of telaprevir for treatment naïve patients is 750 mg
with food (not low-fat) three times per day (every 7-9 hours) along with PEG-IFN and weight-based RBV for 12 weeks
followed by an additional 12-36 weeks of PEG-IFN and RBV. Patients with virological relapse or partial responders of
combination therapy of PEG-IFN/RBV can be re-treated with triple therapy with boceprevir or telaprevir. Triple
therapy with telaprevir is also recommended for null-responders of combination therapy.7
Phase 3 trials with boceprevir and telaprevir have not only provided insights into the benefits of triple therapy but also
its associated limitations and toxicities. While both treatment-naïve and -experienced patients have benefited from
triple therapy administered for 48 weeks, half to two-thirds of treatment-naïve patients given boceprevir and telaprevir
can have reduced duration of treatment, without compromising efficacy. In treatment-experienced patients, prior
relapsers have shown the best response while less than one-third of prior null responders have demonstrated an
SVR. However, patients with advanced fibrosis or cirrhosis have shown lower rates of SVR. Both telaprevir and
boceprevir have adverse effects that need to be effectively managed. Therefore, physicians should be abreast of all
the optimization and management options associated with triple therapy. 17
Initiation of Triple Therapy
PEG-IFN and RBV remain the backbone of triple therapy and therefore, before initiating triple therapy,
contraindications for these agents must be considered. However, most patients with subgenotype 1 HCV are
potential candidates for triple therapy. Patients with milder disease (0-1 fibrosis) may also be administered triple
therapy regimens. Table 1 describes the dosing and monitoring guidelines for triple therapy. Healthcare professionals
should explain the importance of adherence to all the drugs in the triple therapy regimen and the potential barriers to
adherence should also be discussed before the initiation of triple therapy.
Table 1. Dosing and Monitoring Rules for Boceprevir and Telaprevir 17
Drug
Dosing
Duration of protease
inhibitor
HCV RNA monitoring Initial laboratory
monitoring
Boceprevir
200-mg
capsule
800 mg orally 3
times/d (every 7–9
hs) with food
Treatment naïve:
Baseline and wks 4, 8, CBC: baseline and wks 4, 6,
12, and 24 to assess
8, and 12
for RGT and futility
RGT: boceprevir dosed
wks 4–28
Non-RGT: boceprevir
dosed wks 4–36
Must be used in
conjunction with
PEG-IFN and RBV
Telaprevir
750 mg orally 3
375-mg tablet times/d (every 7–9
hs) with food
Must be used in
Treatment experienced: Assess for SVR 6 mos Serum electrolytes,
boceprevir dosed wks
after therapy is
creatinine, uric acid, LFTs,
4–36
completed
TSH: baseline and wks 2, 4,
8, and 12
All patients: telaprevir
dosed wks 0–12 for all
treatment regimens
Baseline and wks 4
and 12 to assess for
eRVR and futility
Assess for SVR 6 mos
CBC, serum electrolytes,
creatinine, uric acid, LFTs,
TSH: baseline and wks 2, 4,
8, and 12
Drug
Dosing
Duration of protease
inhibitor
conjunction with
PEG-IFN and RBV
HCV RNA monitoring Initial laboratory
monitoring
after therapy is
completed
CBC, complete blood count; eRVR, extended rapid virologic response; LFTs, liver function tests; RGT, responseguided therapy; TSH, thyroid-stimulating hormone.
Evaluation of Drug Interactions
Like other common medications, boceprevir and telaprevir are metabolized via the cytochrome p450 pathway. In
addition, boceprevir and telaprevir inhibit and/or serve as substrates for p-glycoprotein. Therefore, boceprevir and
telaprevir administration could alter efficacy and/or toxicities of drugs that are metabolized by the same pathway or
vice versa. Hence, several drugs are contraindicated for use with boceprevir and telaprevir and a review of
medications used by patients must be conducted to avoid potentially harmful drug interactions. Additionally, careful
monitoring of therapeutic dose and efficacy of all drugs administered to the patients should be performed. Boceprevir
and telaprevir could also affect systemic hormonal therapies and metabolism of cholesterol-lowering agents (statins)
and antidepressant medications such as escitalopram. Product information brochures for boceprevir and telaprevir
and on-line resources (such as www.hcvadvocate.org and www.hep-druginteractions.org) would be useful in
assisting clinicians with the management of drug interactions.17,18
Monitoring response to treatment
For telaprevir, patients must be monitored for HCV RNA levels at weeks 4 and 12 after treatment initiation. Patients
with an SVR at weeks 4 and 12 can be considered for 24 weeks of total therapy and only need an additional 12
weeks of treatment with PEG-IFN and RBV. In the absence of an SVR at weeks 4 and 12, 48 weeks of the
recommended triple therapy regimen for telaprevir must be followed. Partial and null responders are also
recommended a total of 48 weeks of therapy. In contrast to telaprevir, triple therapy including boceprevir follows a
different routine, wherein boceprevir is administered after 4 weeks of lead-in combination therapy with PEG-IFN and
RBV and then triple therapy is continued through at least week 28. Treatment naïve patients demonstrating an SVR
at weeks 8 and 24 can discontinue treatment at week 28. However, patients with detectable levels of HCV RNA at
week 8 but undetectable levels at week 24 should continue treatment through week 48. Prior partial responders and
relapsers who have undetectable levels of HCV RNA at both 8 and 24 week time points can continue triple therapy
until week 36. Prior partial responders and relapsers showing detectable HCV RNA at week 8 but not at week 24
should follow guidelines for boceprevir triple therapy through week 48. Since strict adherence to the treatment
guidelines is essential for optimal outcome, regular clinic visits should be encouraged to monitor adherence. Assays
for HCV RNA vary in accuracy and sensitivity of detection.19 Therefore, ensuring that the HCV RNA assay matches
the accuracy and detection levels of the assays from the clinical trials would be of importance.17,20,21
Adverse event management
For successful triple therapy outcomes, physicians administering triple therapy should not only be knowledgeable of
the reported adverse events but also be prepared for the management of those adverse events. For telaprevir triple
therapy regimens, rash (56%), anemia (36%), and anorectal complaints (29% in aggregate) were some of the
significant adverse events.11,12,22 Boceprevir triple therapy adverse events were anemia (45%–50%) and dysgeusia
(35%–44%).9,10
Anemia: Anemia should be regularly monitored (every 2 weeks) and can be managed by reducing the dose of RBV in
both telaprevir and boceprevir regimens. Reduction in the dose of RBV is indicated when hemoglobin decreases by
1.5 g/dL within a 2-week period.23 Severe (persistently ≤10 g/dL), symptomatic, or progressive anemia even upon
reduction of RBV dose can be managed by administration of growth factors such as epoeitin-α.24 Notably, doses of
protease inhibitors should not be reduced.
Rash: Mild to moderate rashes can be managed by administration of oral antihistamine and a topical corticosteroid
with triple therapy. However, in case of severe rash, telaprevir therapy should be stopped, but treatment with PEGIFN and RBV can be continued. Serious cutaneous adverse reactions, such as Stevens–Johnson syndrome or drug
rash with eosinophillia and systemic symptoms, such as fever or edema (also known as DRESS), although rare
require urgent medical evaluation and cessation of all treatment. 21
Gastrointestinal Adverse Effects: Telaprevir therapy has been associated with hemorrhoids, anal pruritis, anorectal
discomfort and anal burning which can be managed with topical corticosteroids, analgesics, over-the-counter
hemorrhoid preparations and antidiarrheal agents. 21 Boceprevir was associated with dysgeusia (altered taste
sensations or unpleasant taste in the mouth) but significant weight loss from dysgeusia was not observed in the
phase 3 trials.20