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13 September 2011
The ADVANCE trial (n = 1,095) found that in previously untreated patients with genotype 1 hepatitis C infection and a baseline hepatitis C virus RNA level of 800,000 IU/ml or more, the addition of oral telaprevir to standard therapy with peginterferon alfa-ribavirin was significantly more effective than standard treatment alone. A total of 75% of patients who received peginterferon alfa-ribavirin plus telaprevir for 12 weeks followed by peginterferon alfa-ribavirin for 12 or 36 weeks (depending on response) had a sustained virologic response, compared to 44% of patients on standard therapy for 48 weeks. Similarly, 69% of the group who received standard therapy plus telaprevir for 8 weeks followed by peginterferon alfa-ribavirin for 16 or 40 weeks had a sustained virologic response. A total of 58% of patients were eligible for the 24 weeks of total treatment duration.
Anaemia (defined as a haemoglobin level < 10 g/dl) occurred in 38% of patients who received telaprevir compared to 19% in the standard treatment group and rash occurred in 36% and 24%, respectively.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
The European Medicines Agency (EMA) has recently adopted a positive opinion, recommending the granting of a marketing authorisation for telaprevir (Incivo). It is indicated, in combination with peginterferon alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis) who are treatment‑naïve or who have previously been treated with interferon alfa alone or in combination with ribavirin, including prior relapsers, partial responders and null responders.
This published study will need to be taken into account by local decision-makers when managing the entry of new medicines and planning the commissioning of appropriate services. Publication of NICE guidance is anticipated in June 2012. The Scottish Medicines Consortium (SMC) telaprevir appraisals are also underway, with advice due potentially mid-December 2011.
The company has provided information that the telaprevir eight-week dosing schedule is not recommended as a treatment strategy and will not be part of the licence. However, factors to take into account are the number of patients who may be eligible for treatment, their baseline hepatitis C virus RNA level, the number of patients expected to be eligible for shorter response guided treatment durations and the incidence of anaemia, which may require reduction in dose of ribavirin or blood transfusion.
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 estimates that around 216,000 individuals in the UK are 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.
Telaprevir is an oral protease inhibitor. The EMA has recently adopted a positive opinion, recommending the granting of a marketing authorisation for telaprevir tablets (Incivo). Telaprevir, in combination with peginterferon alfa-ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis) who are treatment‑naïve or who have previously been treated with interferon alfa alone or in combination with ribavirin. Patients covered within this indication include relapsers, partial responders and null responders.
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. The T12PR group received peginterferon alfa-ribavirin and telaprevir for 12 weeks. The T8PR group received peginterferon alfa-ribavirin and telaprevir for 8 weeks, then placebo plus peginterferon alfa-ribavirin for 4 weeks. Patients in the telaprevir groups with an extended rapid virologic response received an additional 12 weeks of peginterferon alfa-ribavirin. Patients who had detectable HCV RNA at either week 4 or 12 received an additional 36 weeks of peginterferon alfa-ribavirin. A third group received placebo combined with standard therapy of peginterferon alfa-ribavirin for 12 weeks, followed by 36 weeks of peginterferon alfa-ribavirin. The primary endpoint was sustained virologic response.
The addition of telaprevir to standard therapy with peginterferon alfa-ribavirin was significantly more effective than standard therapy alone. A total of 271/363 patients (75%) in the T12PR group, 250/364 patients (69%) in the T8PR group and 158/361 patients (44%) on standard therapy had a sustained virologic response (p < 0.001 for both telaprevir doses versus standard therapy). A total of 58% of patients who received telaprevir were eligible to receive 24 weeks of treatment i.e. they had an extended rapid virologic response.
Overall, the incidence of adverse events and serious adverse events were similar in all three groups. However, gastro-intestinal disorders, rash and anaemia were more common in patients who received telaprevir. 37% of patients in the T12PR group and 35% of patients in the T8PR group experienced rash, compared to 24% in the standard therapy group. Anaemia, defined as a haemoglobin level of < 10 g/dl, was seen in 37% of the T12PR group, 39% of the T8PR group and 19% of the standard therapy group (p values not quoted).
How does this relate to other studies?
The use of telaprevir with standard treatment of peginterferon alfa-ribavirin in previously treated patients was compared to standard treatment alone in the REALIZE study. 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.
Another oral protease inhibitor, boceprevir(Victrelis), has recently been launched. It is licensed for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa-ribavirin, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy. A NICE appraisal is anticipated in May 2012. Data in previously untreated patients came from SPRINT-2 (n = 1,097), which found that 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. Further details can be found in a previous rapid review. A four-week lead-in period of peginterferon alfa-ribavirin was used in the boceprevir trial, but not in the ADVANCE trial with telaprevir.
So what?
As compared with peginterferon alfa-ribavirin therapy alone, the addition of telaprevir increased the rate of sustained virologic response among previously untreated adults infected with HCV genotype 1 and a high baseline HCV RNA level (> 800,000 IU/ml). Inclusion criteria for the ADVANCE 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, seronegativity for hepatitis B surface antigen, the absence of HIV and specified levels for neutrophil counts and haemoglobin levels. This may limit generalisation to patients seen in normal clinical practice.
In the ADVANCE study, the T12PR dosing schedule for TVR was found to demonstrate a better benefit: risk profile than the T8PR schedule. As a result of this finding, research around the T8PR dosing schedule was ceased; it is not recommended as a treatment strategy and is not part of the licence.
The primary endpoint in this report of the ADVANCE study is a disease-oriented outcome, sustained virologic response. However, the trial did include outcomes related to quality of life, fatigue and productivity, but these have not been reported yet.
The authors of ADVANCE note that rates of sustained virologic response to standard therapy are around 40–50% in patients with genotype 1 infection who had received no previous therapy. Most patients require at least 48 weeks of treatment. The ADVANCE trial showed that shorter courses can be effective when telaprevir is added to standard therapy. Potential concerns with triple therapy include the increasing complexity of treatment regimens, a possible increased risk of anaemia and the potential need for a reduction in the dose of ribavirin or the use of a blood transfusion.
The telaprevir regimens were associated with a higher incidence of skin reactions than standard therapy. The majority of skin reactions were mild to moderate and did not lead to discontinuation of the drug. In those cases where telaprevir was stopped the rash was reversible after discontinuation. One case of Stevens-Johnson syndrome occurred. In the US, where telaprevir is already on the market, the prescribing information notes that serious skin reactions, including Stevens-Johnson syndrome have been reported rarely in trials and provides advice on patient care in such situations.
Design: Phase III, randomised, double-blind, placebo-controlled trial. Randomisation was stratified according to baseline HCV RNA level (< 800,000 or > 800,000 IU/ml) and HCV genotype 1 subtype (1a, 1b or unknown).
Patients: Previously untreated adults with chronic hepatitis C genotype 1 infection as confirmed by a liver biopsy within one year before screening. Patients with compensated liver cirrhosis were eligible. Included patients had a median age of 49 years. Exclusion criteria included liver disease due to other causes, decompensated liver disease, low haemoglobin levels, HIV and hepatocellular carcinoma.
Intervention and comparison: Peginterferon alfa-2a was given subcutaneously at a dose of 180 microgram per week. Oral ribavirin was taken as 1000 mg or 1200 mg daily, depending on body weight. Oral telaprevir was taken as 750 mg every 8 hours. Total treatment duration was either 24 or 48 weeks. Patients were randomised to one of three groups as follows:
Standard therapy (n = 361) consisting of peginterferon alfa-ribavirin plus placebo for 12 weeks then peginterferon alfa-ribavirin for 36 weeks.
T12PR (n = 363) consisting of peginterferon alfa-ribavirin and telaprevir for 12 weeks or the T8PR group (n = 364) consisting of peginterferon alfa-ribavirin and telaprevir for 8 weeks, then placebo plus peginterferon alfa-ribavirin for 4 weeks. If patients in the telaprevir groups had an extended rapid virologic response (defined as undetectable HCV RNA at weeks 4 and 12) they received an additional 12 weeks of peginterferon alfa-ribavirin. If patients had a detectable HCV RNA level at either week 4 or 12 they received an additional 36 weeks of peginterferon alfa-ribavirin.
Patients who did not have an adequate response, defined as patients given telaprevir whose HCV RNA levels were greater than 1000 IU/ml at week 4, stopped telaprevir but continued with peginterferon alfa-ribavirin. Any patient who had less than 2 log10 reduction from baseline to week 12 in HCV RNA stopped treatment. Treatment also stopped if HCV RNA was detectable at anytime between weeks 24 and 40.
Outcomes and results: Analyses were based on 1,088 patients who took at least one dose of study drug out of a total of 1,095 randomised patients. The primary outcome was the proportion of patients with undetectable HCV RNA levels 24 weeks after the last planned dose of study drug (sustained virologic response). Sustained virologic response was seen in 271/363 patients (75%) in the T12PR group, 250/364 patients (69%) in the T8PR group and 158/361 patients (44%) in the control group, P<0.001 for both doses versus standard treatment. A total of 58% of patients receiving telaprevir were eligible to receive 24 weeks of treatment as compared with 8% of those on standard therapy. Relapse was reported in 9% of the telaprevir groups compared to 28% of the standard treatment group (no p value given).
Patients with high baseline viral load (> 800,000 IU/ml) had better rates of sustained virologic response in the telaprevir groups than standard therapy; 74% in the T12 PR group, 66% in the T8PR group and 36% for standard therapy (p value not stated). Patients with a lower viral load did not benefit from the addition of telaprevir.
Gastro-intestinal adverse events were more common in patients who received telaprevir. Nausea was experienced by 43% of the T12PR group and 40% of those in T8PR compared with 31% of those receiving standard therapy. A total of 37% of the T12PR group and 35% of the T8PR group experienced rash compared with 24% of the standard therapy group. The rash was classified as serious in five patients receiving telaprevir. A total of 7% of patients in the T12PR regime discontinued telaprevir owing to rash. The rashes resolved with the discontinuation of the drug. One case of Stevens-Johnson syndrome was seen about 11 weeks after the last dose of telaprevir. Anaemia was seen in 37% of the T12PR group, 39% of the T8PR group and 19% of the control group. Anaemia during the trial was managed with dose reduction of ribavirin. If ribavirin was stopped due to anaemia, telaprevir or placebo was also stopped. The use of erthyropoietin was not allowed. A total of 5% of patients in the telaprevir groups received blood transfusions compared to 2% of patients on standard therapy. Anaemia was one of the reasons patients discontinued treatment. This occurred in 1% of the T12PR group, 3% of the T8PR group and less than 1% of those in the control group.
Sponsorship
This study was sponsored by Vertex Pharmaceuticals and Tibotec.
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