14 July 2011
The SPRINT-2 trial (n=1,097) found that oral boceprevir given three times a day, plus standard therapy of peginterferon alfa-ribavirin, significantly increased rates of sustained virologic response compared to standard therapy in adult patients with treatment-naïve hepatitis C virus genotype 1 infection. Similar rates of sustained virologic response were seen in non-black patients when boceprevir was given for 24 weeks (67%) and 44 weeks (68%), as compared to standard therapy for 44 weeks (40%). Anaemia occurred in 49% of patients receiving boceprevir, of whom 43% received erythropoietin.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
The European Medicines Agency (EMA) has recently adopted a positive opinion, recommending the granting of a marketing authorisation for boceprevir (Victrelis®). It is indicated for the treatment of chronic hepatitis C genotype 1 infection, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy. Boceprevir 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 the first appraisal committee meeting planned for November 2011. Factors to take into account are the number of patients who may be eligible for treatment, similar sustained viral response at 24 and 44-weeks of boceprevir treatment and the incidence of anaemia, which may require actions including reduction in 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 SPRINT-2 note that rates of sustained virologic response to standard therapy are below 50% and can be less if patients have genotype 1 infection with advanced fibrosis or co-infection with HIV, for example.
Boceprevir is an oral serine protease inhibitor. The European Medicines Agency has recently adopted a positive opinion, recommending the granting of a marketing authorisation for boceprevir (Victrelis®). It is indicated for the treatment of chronic hepatitis C genotype 1 infection, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy. Boceprevir must be given in combination with peginterferon alfa and ribavirin to minimise viral resistance. A NICE technology appraisal is underway with the first appraisal committee meeting planned for November 2011.
Further information on the management of hepatitis can be found on NHS Evidence.
What does this study claim?
Previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups peginterferon alfa-2b plus ribavirin was administered for a four week lead-in period. Subsequently group 1 (standard therapy) received placebo plus peginterferon alfa-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon alfa-ribavirin for 24 weeks, and those with detectable HCV RNA levels between weeks 8 and 24 received placebo plus peginterferon alfa-ribavirin for an additional 20 weeks (response-guided therapy). Group 3 (fixed-duration therapy) received peginterferon alfa-ribavirin plus oral boceprevir for 44 weeks. Non-black and black patients were enrolled and analysed separately. The primary end point was sustained virologic response.
The addition of boceprevir to standard therapy with peginterferon alfa plus ribavirin was more effective than standard therapy alone. A total of 211/316 (67%) of the non-black cohort in group 2 (response-guided therapy), had a sustained virologic response compared to 125/311 patients (40%) in group 1 (standard therapy), P<0.001. 68% of group 3 (213/311) (fixed-duration therapy) also had this outcome, P<0.001 vs. group 1.
In the black cohort, 23% of group 1 (12/52) (standard therapy), and 42% of group 2 (22/52) (response-guided therapy), had a sustained virologic response (P=0.04). The results for group 3 (fixed-duration therapy) were 53% (29/55), P=0.004 vs. group 1.
Overall, the incidence of adverse events and serious adverse events were similar in all three groups. However, anaemia and dysgeusia (disordered sense of taste) were more common in patients who received boceprevir. In group 1, 29% of patients experienced anaemia compared to 49% in group 2 (P<0.001). Similarly, 49% of group 3 had anaemia (P<0.001 vs. group 1). Dysgeusia was reported by 18% of group 1, 37% of group 2 (P<0.001) and 43% 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 plus ribavirin in previously treated patients was compared to standard therapy alone in the HCV RESPOND-2 trial.
Another oral protease inhibitor, telaprevir, has been approved recently by the FDA, for patients who have either not received interferon-based drug therapy for their hepatitis C infection or who have not responded adequately to prior therapies. The drug is approved for use with interferon therapy made up of peginterferon alfa and ribavirin. Telaprevir is in licensing with the EMA and a NICE technology appraisal is in progress.
The results from the ADVANCE study in treatment-naïve patients and from the REALIZE study in previously treated patients have been published recently. The OPTIMIZE-HCV study to investigate different dosing regimens for telaprevir in treatment-naïve patients is on-going and is estimated to complete in October 2012.
As compared with peginterferon alfa-ribavirin therapy alone, the addition of boceprevir increased the rate of sustained viral response among previously untreated adults infected with HCV genotype 1. A low baseline HCV RNA level of 400,000 IU/ml or less in the trial was predictive of having a sustained virologic response (odds ratio of 3.9 [95% confidence interval 2.1 to 7.1], P<0.001).Inclusion criteria for the SPRINT-2 trial specified that patients had to have a liver biopsy with histology consistent with chronic hepatitis C infection and no other aetiology, genotype 1 only, baseline HCV RNA level of at least 10,000 IU/ml and no previous therapy for HCV infection. This may limit generalisation to patients seen in normal clinical practice.
Black patients respond less well to peginterferon alfa-ribavirin than do non-blacks. Although, the rates for sustained viral response are lower among black patients in this study than for non-black patients, the rates with boceprevir regimens are higher than for standard therapy. However, the number of patients in the black cohort was small (n=159), which may have affected the results.
The four week lead-in period with peginterferon alfa-ribavirin may lower HCV RNA levels before exposure to the protease inhibitor, thereby reducing the risk of viral breakthrough or resistance. In SPRINT-2, patients with a poor response at this stage were less likely to have a sustained viral response after boceprevir was added.
SPRINT-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 baseline HCV RNA level (< 400,000 or > 400,000 IU/ml) and HCV genotype 1 subtype (1a or 1b). If subtype was not known, patients were randomised in their HCV RNA stratum.
Patients: As response to treatment between black and non-black patients is known to be different, self-identified black and non-black patients were enrolled separately into two cohorts (black cohort n=159 and non-black n=938). Inclusion criteria included no previous treatment for HCV infection and HCV RNA level of at least 10,000 iu/ml. Exclusion criteria included HIV or hepatitis B infection, decompensated cirrhosis, renal insufficiency, and other causes of liver disease. Included patients had a mean age of 49 years and 60% were male. A total of 85% of patients had a baseline 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) were given on an open-label basis.
Each cohort of black and non-black patients were split into one of three groups. All groups started with a four-week lead-in period of peginterferon alfa plus ribavirin (weeks 0-4).
Group 1 (n=363) consisted of standard therapy: placebo capsules three times a day plus peginterferon alfa-ribavirin all for 44 weeks starting from week 5.
Group 2 (n=368), response-guided therapy, was peginterferon alfa-ribavirin plus boceprevir capsules 800mg three times a day for 24 weeks beginning at week 5. Treatment was considered complete if HCV RNA levels were undetectable from week 8 to the end of week 24. However, if levels were detectable from week 8 to the end of week 23, peginterferon alfa-ribavirin was continued with placebo from week 28 to the end of week 48.
Group 3 (n=366), the fixed-duration therapy group: peginterferon alfa plus ribavirin with oral boceprevir 800mg three times a day for 44 weeks beginning at week 5.
Study treatment was stopped if patients had a detectable HCV RNA level at week 24 (treatment failure). All patients were followed-up to the end of week 72.
Outcomes and results: The mean duration of treatment was 236 days (33.7 weeks) in group 1, 200 days (28.6 weeks) in group 2 and 261 days (37.3 weeks) in group 3. The primary efficacy analysis was based on all randomised, non-black patients who had received at least one dose of study medication. The primary end point was sustained virologic response, defined as undetectable HCV RNA levels for 24 weeks after the end of treatment. 40% of the non-black cohort in group 1 (125/311) and 67% of group 2 (211/316) had a sustained virologic response, P<0.001. 68% of group 3 also had this response (213/311), P<0.001 vs. group 1.
In the black cohort, 23% of group 1 (12/52) and 42% of group 2 (22/52) had a sustained virologic response (P=0.04). The results for group 3 were 53% (29/55), P=0.004 vs. group 1. When both cohorts were analysed together, 38% of group 1 and 63% of group 2 had a sustained virologic response (P<0.001). Group 3 results were 66% (P<0.001 vs. group 1).
P values were adjusted for pre-specified baseline stratification factors.
Overall, the incidence of adverse events (such as fatigue, headache and nausea), serious adverse events and discontinuations due to adverse events were similar in all three groups. However, dose reduction or initiation of haematopoietic growth factors was recommended to manage non-life threatening haematologic adverse events. 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 significantly more common in patients who received boceprevir. In group 1, 29% of patients experienced anaemia compared to 49% in each group receiving boceprevir (P<0.001 vs. group 1). Erythropoietin was required by 24% of the standard therapy group and 43% of patients who received boceprevir, P<0.001.
Dysgeusia was reported by 18% of group 1, 37% of group 2 (P<0.001) and 43% of group 3 (P<0.001 vs. group 1).
This study was sponsored by Schering-Plough (now part of MSD in the UK).
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