The recent approvals of the new medications for hepatitis C are expected to revolutionize treatment.
Boasting sustained viral response rates of up to 75% in treatment-naive
patients, telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir
(Victrelis, Merck) are being heralded within the infectious disease community,
but many clinicians are urging judicious use.
The FDA approved telaprevir in May, based on results of trials that
looked at the use of telaprevir 750 mg assigned three times daily for 12 weeks
combined with peginterferon and ribavirin. This medication increased sustained
virological response rates by 20% to 40% across a broad range of disease and
Rajesh T. Gandhi, MD, said resistance has
already been seen with boceprevir and telaprevir.
Photo courtesy of Rajesh T. Gandhi
The FDA also approved boceprevir in May for the treatment of chronic
hepatitis C virus genotype-1 infection combined with peginterferon alfa and
ribavirin in adult patients. That approval was based on data from the
HCV-Respond 2 trial and the SPRINT-2 trial, which suggested that the addition
of boceprevir to peginterferon-ribavirin treatment resulted in significantly
higher rates of sustained virologic response in patients previously treated and
patients with previously untreated HCV genotype-1 vs. pegylated interferon and
To further explore what these approvals mean, the editors at
Infectious Disease News interviewed experts on these medications and
their implications for treatment. It is our hope that, because there are
currently no head-to-head comparison trials of these medications, this story
can provide a snapshot of some of the differences between the medications.
IDN: What do the approvals of boceprevir and telaprevir mean in terms
of current practice for patients on standard therapies?
Rajesh T. Gandhi, MD, associate professor of medicine at
Massachusetts General Hospital: Approval of these two agents means that most
genotype HCV infection can now be treated with the
three-drug combination therapy of a protease inhibitor plus peginterferon plus
ribavirin. In addition, a substantial fraction of patients can be successfully
treated with 6 months of triple therapy rather than 1 year. This is a major
advance that promises to revolutionize HCV treatment.
Paul J. Pockros, MD, director of clinical research, Scripps
Translational Science Institute and head of the division of
gastroenterology/hepatology, Scripps Clinic, in La Jolla, Calif: We are on the
verge of a new era in HCV management, but there will be challenges in terms of
implementation, as is the case when all new medications are brought to market.
Practice requirements will likely increase as patient visits increase.
Laboratory tests will be needed before these medications are prescribed for
some patients, including genotype subtyping for G1 and IL28B polymorphism
testing for selected patients. Physicians will need to pay careful attention to
the subtype of G1 virus because the data show that both telaprevir and
boceprevir are less effective in G1a than G1b, mostly due to a higher rate of
viral breakthrough. Also, viral load testing will be needed frequently during
the first 24 weeks of therapy to comply with response-guided therapy guidelines
and early futility rules established for the two drugs.
Paul J. Pockros, MD
Debra Birnkrant, MD, director of the FDA’s antiviral
products division: Chronic hepatitis C is both a global and domestic problem,
with 170 million estimated to be infected worldwide and approximately 3 million
infected in the United States, according to FDA data. Of the 5.6 million
veterans in veterans’ health care in 2008, 2.6 million had a diagnosis of
chronic hepatitis C. Although the incidence of infection in the United States
is decreasing, chronic hepatitis C-related complications are increasing such as
psorosis and hepatocellular carcinoma. With the aging of the infected
population, more liver-related complications are expected in the next 10 to 20
years without the use of potent antiviral therapies.
IDN: What are the biggest differences reported to date between
boceprevir and telaprevir? What has been reported in terms of adverse events?
Gandhi: A 4-week lead-in period of peginterferon plus ribavirin
is given with boceprevir but not with telaprevir. In terms of adverse events,
in phase 2 and phase 3 clinical trials, 49% of patients in the boceprevir
groups had hemoglobin values less than 10 g/dL, compared with 28% of those in
the control groups, according to findings published in The New England
Journal of Medicine. Use of erythropoiesis-stimulating agents to treat
anemia was more frequent in the boceprevir groups (43%) than in the control
groups (24%). However, discontinuation of treatment was only about 1%.
Decreased neutrophil and platelet counts were more common in the boceprevir
groups, as was dysgeusia (35%-44% in boceprevir groups vs. 11%-16% in control
The main adverse effects of telaprevir that have been associated with
the medication include rash, anemia, nausea and other
gastrointestinal symptoms, and anorectal discomfort.
In clinical trials, rash developed in 56% of patients who received T+PR,
compared with 34% who received PR alone. Patients with mild to moderate rashes
may continue therapy with careful monitoring. Telaprevir should be stopped if a
rash progresses and becomes severe, or if systemic symptoms develop.
Pockros: Frequent physical examinations and laboratory testing
for anemia, rash, decreased hemoglobin and other adverse events will be needed
with both of the medications.
Birnkrant: Rash and pruritus were identified in phase 2 trials of
telaprevir and a monitoring and management plan was instituted for the phase 3
trials. There was also a dermatology expert panel that reviewed cases
retrospectively. Clinically and histologically, the rash seen with telaprevir
is comparable to that seen with pegylated interferon and ribavirin. It is
described as an exematous maculopapular and papular lichenoid rash. The rash
did not appear to be a drug-induced hypersensitivity type of rash. Less than 1%
of subjects experienced a suspected severe rash such as Stevens-Johnson and not
all occurred during telaprevir dosing period. The mechanism of rash was
investigated, but remains unknown, and there were no deaths related to rash.
I’ll now turn to anemia. The most problematic adverse effect of
ribavirin therapy is reversible hemolytic anemia. Telaprevir adds to the
frequency and severity of this toxicity. Anemia was seen in non-clinical
studies, so we knew we had to monitor for it in the clinical trials. It’s
highlighted in the warnings and precaution section of the label with
recommendations of how to deal with anemia such as measuring hemoglobin
baseline and every 4 weeks, utilizing ribavirin dose reduction to manage
anemia, and it’s important to note that Incivek should not be
dose-reduced, and if discontinued, then should not be restarted.
Regarding anorectal disorders, approximately 20% of patients receiving
telaprevir had an anorectal disorder compared to 5% on control. The most
commonly reported disorders in this category were hemorrhoids, anorectal
discomfort, and anal pruritus. The time to onset is approximately10 days. Less
than 1% were serious. Most were managed with topical agents. Again for this
adverse event, the mechanism is unknown and, in some, mostly remains bothersome
and rarely treatment limiting.
Adverse reactions seen in greater than or equal to more than 5% higher
frequency in telaprevir subjects compared with control were as follows: rash,
fatigue, pruritis, nausea, anemia, diarrhea, vomiting, hemorrhoids, anorectal
discomfort…or interference with taste.
Jeffrey Murray, MD, deputy director of the FDA’s antiviral
products division: Besides pregnancy warnings relating to the use of
boceprevir in combination with peginterferon and ribavirin, the major warnings
pertaining to Victrelis are hematologic adverse events. Boceprevir can
exacerbate anemia and neutropenia already seen with peginterferon and
ribavirin, and in fact, the number of transfusions and dosage reductions of
ribavirin were higher when Victrelis was added to a PR regimen compared to a PR
regimen alone. In addition to anemia and neutropenia, other clinical adverse
reactions are fatigue, nausea, headache and an unpleasant taste of the drug.
IDN: What are the potential drug interactions with both of these
Gandhi: Boceprevir is a strong inhibitor of CYP3A4/5 and should
not be administered with drugs that are highly affected by this pathway, such
as alfuzosin, carbamezepine, rifampin, simvastatin, phenytoin and oral
midazolam. Telaprevir inhibits CYP3A and should not be administered with drugs
that are highly affected by this pathway, including alfuzosin, rifampin,
HMG-CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin) and oral
IDN: What about patients with comorbidities? Can they take these
Gandhi: We need to know more about certain populations. For
example, these drugs are not yet approved for patients with HIV coinfection,
and trials of these agents in patients with HIV are ongoing. We also don’t
know how liver transplant patients with graft HCV reinfection should be treated
and how to treat patients with decompensated cirrhosis, in whom peginterferon
therapy is contraindicated.
Pockros: Drug developers face a conundrum in terms of testing new
classes of medications in patients with comorbidities. The possibilities with
the four major classes of drugs currently being developed include a PI/NPI,
PI/NS5a, PI/NNPI, NPI/NNPI, NPI/NS5a and a purine NPI plus pyrimadine NPI
together. Several issues need to be considered with each of these combinations:
dosing convenience; safety; adverse event profiles; resistance; and others. It
will be a long process.
IDN: Do you expect that we will see resistance with these medications?
Gandhi: Yes, there will definitely be resistance to these agents
in patients who do not achieve virologic suppression. Such resistance has
already been seen in clinical trials and reaffirms the importance of adherence
and close virologic monitoring.
IDN: As the recommended treatment regimens are fairly complex, do you
anticipate opportunities for misdosing?
Pockros: There is a lot of potential for misuse of these new
drugs for multiple reasons, not the least of which is the fact that both
medications are approved for three [times a day] dosing, which means a
considerable pill burden. Poor adverse event management, lack of understanding
of these medications’ use in treatment-experienced populations, and lack
of monitoring for resistance are all likely to complicate management, so
physicians must remain vigilant for all as they are prescribed. – by
For more information:
- Bacon BR. N Engl J Med. 2011;364:1207-1217.
- Poordad F. N Engl J Med. 2011;364:1195-1206.
Disclosures: Dr. Gandhi is an associate professor of medicine at
Massachusetts General Hospital. He reported no relevant financial disclosures.
Dr. Pockros is director of clinical research, Scripps Translational Science
Institute and head of the division of gastroenterology/hepatology, Scripps
Clinic, in La Jolla, Calif. He reports being a consultant and serving on
advisory boards for: Genentech, Vertex, Merck, Gilead, BMS, Abbott, Phenomix,
Tibotec, Pharmasset, Pfizer, Conatus, 3RT, Novartis, J&J, Achillion and
Regulus Therapeutics; and has grants/contracts with: Genentech, Vertex, Gilead,
BMS, Abbott, Quest, Conatus, Tibotec, Pfizer, GlobeImmune, Debio, Novartis,
Mochida, ZymoGenetics and HGS. Dr. Murray is deputy director of the FDA’s
antiviral products division. He reported no relevant financial disclosures. Dr.
Birnkrant is director of the FDA’s antiviral products division. She
reported no relevant financial disclosures.