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2 August 2011
The HCV RESPOND-2 trial (n=404) found that oral boceprevir given three times a day in addition to peginterferon alfa and ribavirin significantly increased rates of sustained virologic response compared to standard therapy in adult patients with previously treated hepatitis C virus genotype 1 infection. In the group given peginterferon alfa and ribavirin plus boceprevir for 44 weeks 66% of patients had a sustained virologic response compared to 21% in the peginterferon alfa and ribavirin group. Anaemia occurred in 45% of patients treated with boceprevir and erythropoietin was administered to 43% of boceprevir-treated patients.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
Boceprevir▼ (Victrelis®) has recently been licensed for the treatment of chronic hepatitis C genotype 1 infection, in adult patients with compensated liver disease who have failed previous therapy or are previously untreated. The drug must be given in combination with peginterferon alfa and ribavirin.
Local decision-making bodies may need to consider the managed introduction of boceprevir, bearing in mind that NICE guidance is underway with publication anticipated in May 2012. Factors to take into account are the number of patients who may be eligible for treatment, similar sustained viral response at 32 and 44-weeks of boceprevir therapy and the incidence of anaemia which may require actions including reduction in the dose of ribavirin, blood transfusion or off-label use of erythropoietin.
What is the background to this?
The blood-borne hepatitis C virus (HCV) predominately infects the cells of the liver. The virus is usually acquired through parenteral exposure to contaminated blood. Infected needles used for injecting drugs are the most common means of transmission. Six major genotypes of HCV are known, with genotype 1 being the most common in England and Wales. Genotype is a key predictor of the effectiveness of anti-viral treatment and people with genotype 1 have HCV that is the most resistant to treatment.
In approximately 80% of people who are infected, the virus is not cleared and they go on to develop chronic hepatitis C. The Health Protection Agency estimated in 2009 that around 185,000 individuals in the UK were chronically infected with hepatitis C. Standard therapy is with peginterferon alfa and ribavirin and information on the appropriate use of these drugs is available from NICE guidance. The authors of HCV RESPOND-2 note that rates of sustained virologic response in genotype 1 HCV are less than 50% with interferon and ribavirin.
Further information on the management of hepatitis can be found on NHS Evidence.
What does this study claim?
Patients with HCV genotype1 infection, who had had a non-response or a relapse following treatment with interferon, were randomised to one of three groups. All groups started with a four-week lead-in period of peginterferon alfa and ribavirin. Subsequently, group 1 (standard therapy) received placebo plus peginterferon alfa and ribavirin for 44 weeks. Group 2, response-guided therapy, received peginterferon alfa and ribavirin with boceprevir for 32 weeks beginning at week 5. Patients with undetectable HCV RNA levels at weeks 8 and 12 completed treatment at week 36, whereas those with a detectable level at week 8 but undetectable at week 12 received peginterferon alfa and ribavirin and placebo for an additional 12 weeks. Group 3 were given peginterferon alfa and ribavirin with boceprevir for 44 weeks beginning at week 5.
The primary end point was sustained virologic response. The addition of boceprevir to standard therapy with peginterferon alfa and ribavirin was more effective than standard therapy alone. The overall rates of sustained viral response being 21%, 59% and 66% in groups 1, 2 and 3 respectively (P<0.001 for each boceprevir group vs. standard therapy
Anaemia and dysgeusia (disordered sense of taste) were more common in patients who received boceprevir. In group 1 20% of patients experienced anaemia compared to 43% in group 2 (P<0.001). Similarly, 46% of group 3 had anaemia (P<0.001 vs. group 1). Erythropoietin was required by 21% of patients group 1, 41% of those in group 2 and 46% of group 3. Dysgeusia was reported by 11% of group 1, 43% of group 2 (P<0.001 vs. group 1) and 45% of group 3 (P<0.001 vs. group 1).
How does this relate to other studies?
The use of boceprevir with standard therapy of peginterferon alfa and ribavirin in untreated patients was compared to standard therapy alone in the SPRINT-2 trial and is the subject of a previous rapid review.
Telaprevir, another oral protease inhibitor, has recently been marketed in the US, is in licensing with the EMA and a NICE technology appraisal is in progress.
So what?
As compared with peginterferon alfa and ribavirin therapy alone, the addition of boceprevir increased the rate of sustained viral response among previously treated adults infected with HCV genotype 1. Results from a pre-specified subgroup analysis demonstrated an increase in rates of sustained viral response both in patients who had had a non-response to prior therapy and in patients who had had a relapse after prior therapy.
The four week lead-in period with peginterferon alfa and ribavirin may lower HCV RNA levels before exposure to the protease inhibitor, thereby reducing the risk of viral breakthrough or resistance but it adds other complexities. In HCV RESPOND-2, patients with a poor response at this stage were less likely to have a sustained viral response after boceprevir was added.
As in SPRINT-2, HCV RESPOND-2 used a disease-oriented outcome, sustained virologic response. It did not include patient-oriented outcomes such as improvement in symptoms, mortality or quality of life.
Potential concerns about adding protease inhibitors to standard therapy include the complexity of treatment regimens, the risk of anaemia and potential need for a reduction in the dose of ribavirin or off-label treatment with erythropoietin.
Design: Phase III, randomised, double-blind, placebo-controlled trial with concealed allocation. Randomisation was stratified according to previous response to treatment (non-response or relapse) and HCV genotype 1 subtype (1a or 1b). If subtype could not be classified, patients were randomly assigned to a group.
Patients: Previously treated adults with HCV infection genotype 1 were studied. Patients were classified as having a relapse or non-response after at least 12 weeks of interferon therapy. The study excluded patients in whom 12 weeks of the prior therapy resulted in a reduction in the HCV RNA level of less than 2 log10 IU/ml. Other exclusion criteria included HIV or hepatitis B infection, decompensated liver disease, or other causes of clinically significant liver disease. Included patients had a mean age of 53 years, 67% were male and 13% black. A total of 88% of patients had a high baseline viral load (HCV RNA level of more than 800,000 IU/ml).
Intervention and comparison: Subcutaneous peginterferon alfa-2b (1.5 microgram/kg weekly) plus oral ribavirin (600 to 1400mg daily in divided doses according to body weight) was given on an open-label basis.
All groups started with a four-week lead-in period of peginterferon and ribavirin (weeks 0 to 4).
Group 1 (n=80) consisted of standard therapy: placebo capsules three times a day plus peginterferon alfa and ribavirin all for 44 weeks beginning at week 5.
Group 2 (n=162), response-guided therapy, was peginterferon alfa and ribavirin with boceprevir capsules 800mg three times a day for 32 weeks beginning at week 5. Patients with undetectable HCV RNA levels at weeks 8 and 12 completed treatment at week 36. However, those with a detectable level at week 8 but undetectable at week 12 received peginterferon alfa and ribavirin and placebo for an additional 12 weeks.
Group 3 (n=161) was peginterferon alfa and ribavirin with oral boceprevir 800mg three times a day for 44 weeks beginning at week 5.
Patients in the above groups were followed up to the end of week 72.
The trial protocol included a stopping rule i.e. patients who failed to achieve an undetectable HCV RNA level at week 12 stopped all treatment, but were followed-up to the end of week 72.
Outcomes and results: Due to not achieving undetectable HCV RNA levels by treatment week 12, 61% of patients in the standard therapy group (control) stopped therapy, compared to 22% in group 2 and 18% in group 3. Consequently, the median duration of exposure to study drugs was considerably shorter in the control group than in the boceprevir groups: 104 days (14.9 weeks) compared to 252 days (36.0 weeks) in group 2 and 336 days (48.0 weeks) in group 3. The primary efficacy analysis was based on all patients who had received at least one dose of study medication. Only one patient of the 404 randomised did not receive any study medication and was not included in the final analyses. The primary end point was sustained virologic response, defined as an undetectable plasma HCV RNA level at week 24 of the follow-up period. 21% of patients in group 1 (17/80) and 59% of group 2 (95/162) had a sustained virologic response, P<0.001. 66% of group 3 (107/161) also had this response, P<0.001 vs. group 1.
P values were adjusted for pre-specified baseline stratification factors.
In a pre-specified subgroup analysis the rates of sustained virologic response among patients with prior relapse were 29% in group1, versus 69% and 75% in group 2 and 3, respectively. In patients with a prior non-response the corresponding rates were 7% vs. 40% and 52%. No P values or CIs stated for this data in the published paper.
At the discretion of the treating physician, a recommendation to decrease the ribavirin dose or the addition of erythropoietin in patients with a drop in haemoglobin levels to <10 g/dl was part of the protocol. Erythropoietin was to be discontinued once haemoglobin levels reached >12 g/dl. Anaemia was more common in patients who received boceprevir: in group 1, 20% of patients experienced anaemia compared to 43% of group 2 and 46% of group 3 (both P<0.001 vs. group 1). Erythropoietin was required by 21% of group 1, 41% of group 2 and 46% of group 3. Dysgeusia was reported by 11% of group 1, 43% of group 2 (P<0.001) and 45% of group 3 (P<0.001 vs. group 1).
Rash and dry skin were also more common in patients who received boceprevir. Although few patients discontinued treatment due to adverse events, dose modification due to adverse events was more common in patients who received boceprevir: 14% of group 1, 29% in group 2 (P=0.01 vs. group 1) and 33% in group 3 (P=0.002 vs. group 1).
Sponsorship
This study was sponsored by Schering-Plough (now part of MSD in the UK).
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