Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C

Of the 6 trials, 4 evaluated the effect of shortened treatment courses with peginterferon alfa plus ribavirin for people with HCV genotype 1 infections, while the other 2 trials evaluated the effect for people with genotype 2 or 3 infections. No trials assessed the effect of shortened treatment courses for people with genotype 4 infections. Five of the trials included people with a low viral load at the start of treatment. The comparator in all included studies was the same intervention for a standard duration of treatment. The dose of peginterferon alfa-2a was 180 micrograms per week and the dose of peginterferon alfa-2b was 1.5 micrograms per kg per week in all trials. All 6 RCTs reported sustained virological response rates as the primary outcome measure. A sustained virological response was defined as undetectable serum HCV RNA at the end of 24 weeks' follow-up in 4 trials, and as undetectable serum HCV RNA at the end of treatment and at the end of follow-up in the other 2 trials. In many of the trials the sustained virological response rates were presented for subgroups of people who had been randomised and who achieved a rapid virological response. It was not reported whether these subgroups were powered to detect a statistically significant difference between trial arms. A rapid virological response was defined as an undetectable serum concentration of HCV RNA (25 IU/ml or less) in 1 trial, serum HCV RNA negative (50 IU/ml or less) in 3 trials, serum HCV RNA of 600 IU/ml or less in 1 trial, and serum HCV RNA of 650 IU/ml or less in 1 trial, all at week 4 of treatment.

In people with a low viral load (800,000 IU/ml or less) who attained a rapid virological response up to and including week 4 of treatment, sustained virological response rates were comparable between the group that received 48 weeks (standard duration) of treatment (range 83% to 100%) and the group that received shortened treatment courses (range 84% to 96%), with no statistically significant differences between the groups. Regardless of HCV genotype, sustained virological response rates were similar across studies, with the exception of 1 trial that reported lower rates.

In 2 of the trials of peginterferon alfa-2a plus ribavirin, the ribavirin dose was varied according to body weight, which is no longer consistent with its marketing authorisation. The marketing authorisation specifies that ribavirin should be given as a fixed dose of 800 milligrams in people with HCV genotype 2 or 3, and both trials assessed the effectiveness of treatment only in people with HCV genotype 2 or 3 infections. The assessment group noted that if these 2 trials had been excluded on the basis of the variable ribavirin dosages, there would have been no evidence on the impact of shortened treatment durations in people with HCV genotype 2 or 3 infections.

Rapid virological response rates were comparable between the groups that received the standard duration of treatment and those that received shortened courses. However, there was a large range in reported rapid virological response rates between the studies, with rates in people with HCV genotype 2 or 3 infections generally being higher than those in people with genotype 1 infections.

The relapse rate in a subgroup of people with a low viral load and a rapid virological response was reported in 1 trial. Relapse was defined as the re-appearance of serum HCV RNA during the 24‑week follow-up period in people whose condition initially responded to treatment. The rates of relapse were low and were not statistically significantly different between the treatment arms (3.6% for 24 weeks of treatment versus 0% for 48 weeks of treatment; p=1.00). In contrast, in people with a high viral load at start of treatment and a rapid virological response later, shortening the duration of treatment was associated with a statistically significant higher rate of relapse (23.5% for 24 weeks versus 0% for 48 weeks; p=0.045).

Adverse events were presented for treatment groups as a whole, and not for the subgroup of people with a low viral load who had a rapid virological response. Overall, the frequency of adverse events did not differ statistically between treatment arms, although a lower incidence of adverse events was reported in 3 trials in people treated for a shorter duration with combination therapy. The most frequently occurring adverse events included influenza-like symptoms, insomnia, anorexia, dermatological symptoms and alopecia.

The cumulative incidence of serious adverse events ranged from 0% to 7% over the duration of the trials, and was not considered to be substantially different between treatment arms, although levels of statistical significance were lacking in most studies. One death was reported, which was a result of re-activation of pulmonary tuberculosis at week 36 of treatment in a person who was treated with peginterferon alfa-2a plus ribavirin. One trial reported that people receiving a shortened treatment regimen were less likely to discontinue their treatment than people receiving longer courses (3% versus 10%; p=0.045).

The assessment group did not identify any RCTs that compared treatment with peginterferon alfa (with or without ribavirin) with best supportive care for people whose hepatitis C had not responded to previous treatment or had responded but subsequently relapsed. The assessment group did identify a number of RCTs comparing treatment with peginterferon alfa (with or without ribavirin) with active treatment comparators (such as non-peginterferon alfa plus ribavirin), but these did not meet the inclusion criteria for the review (based on the decision problem) because they featured an active treatment comparator. However, the assessment group assumed in its economic model (see section 4.2) that the sustained virological response rates for people whose condition did not respond or responded but subsequently relapsed on peginterferon alfa therapy were those reported in the clinical trials that used an active comparator. The assessment group noted that these reported sustained virological response rates may not be representative of people with relapsed disease because the trial participants with HCV genotype 1 infections had less intensive initial treatment than what would be regarded as standard treatment.

The assessment group did not identify any RCTs that compared treatment with peginterferon alfa (with or without ribavirin) with best supportive care for people with HCV and HIV co-infection. A number of RCTs were identified that compared peginterferon alfa (with or without ribavirin) with active treatment comparators (such as non-peginterferon alfa plus ribavirin) for this subgroup, but these did not meet the inclusion criteria for the review because they featured an active treatment comparator. The assessment group noted that it is unlikely that any studies, whether randomised or not, would be available that include a non-active treatment arm, because withholding treatment would be unlikely to be considered ethical.

The collective evidence for combination therapy for both peginterferon alfa-2a and peginterferon alfa-2b suggests that there are no statistically significant differences in sustained virological response rates between people receiving shortened durations of treatment with peginterferon alfa plus ribavirin of 16 weeks (HCV genotype 2 or 3; peginterferon alfa-2a) or 24 weeks (HCV genotype 1; both peginterferon alfa-2a and alfa-2b) and people receiving the standard duration of treatment. Rates of relapse following a shortened course of treatment were reported to be low and not statistically significantly different from relapse rates after a standard course of treatment in people with a rapid virological response and low viral load. For people with a rapid virological response and a high viral load, shortening the duration of treatment may be associated with a higher rate of relapse. However, the assessment group noted that analyses of sustained virological responses in people with a low viral load at the start of treatment and a rapid virological response are likely to be underpowered because they were based on subgroups of the randomised participants, and therefore the results should be interpreted with caution. No RCTs were identified that compared peginterferon alfa (with or without ribavirin) with best supportive care for people who were re-treated after non-response or relapse of their condition, or for people with HCV and HIV co-infection.

The assessment group adapted a previously published model to undertake an independent economic assessment of shortened treatment durations with peginterferon alfa plus ribavirin, using clinical-effectiveness data from studies included in the systematic review. The economic model was structurally similar to those developed by the manufacturers, and used similar input parameters to model disease progression, health state costs and utility. The model consists of 9 health states representing stages of chronic liver disease and death.

The economic model contains 3 health states representing cure of chronic hepatitis C, which are differentiated by the stage of the disease before treatment, as this is expected to have an impact on the subsequent risk of progressive liver disease, post-treatment surveillance and health-related quality of life. The health states mild hepatitis C, moderate hepatitis C, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver transplant represent stages of progressive liver disease. People not exhibiting a sustained virological response are expected to have the same risk of disease progression as untreated people. These assumptions are all consistent with previous assessments and with other published economic evaluations of anti-viral treatment for chronic HCV infection. The model has a cycle length of 1 year and incorporates a half-cycle adjustment.

Baseline population data in the model were based on the results of a clinical audit undertaken at a London teaching hospital. New patients were taken to represent the population of people with HCV and HIV co-infection and the population eligible to receive shortened courses of combination therapy as applicable, and existing patients were taken to represent the population of people treated previously with peginterferon alfa and ribavirin. Patients were differentiated in terms of average age and distribution across stages of chronic liver disease (mild hepatitis C, moderate hepatitis C and compensated cirrhosis). The proportion of men in the baseline cohort was based on the assessment group's previous assessment. The majority of these assumptions do not affect response to treatment, but relate to the risk of all-cause mortality. The influence of the stage of chronic liver disease on response to treatment, and on the cost effectiveness of the intervention, was assessed in a sensitivity analysis.

Data on sustained virological response rates for the subgroup of people receiving shortened treatment courses were extracted by the assessment group from clinical trials included in the clinical effectiveness review. For the subgroups of people co-infected with HIV and HCV and of people whose hepatitis C did not respond to previous treatment or responded but subsequently relapsed, sustained virological response rates were taken from RCTs that included active comparators, which were not systematically reviewed by the assessment group. Data on sustained virological response rates were used in the model to estimate the probability of treatment-eligible people moving to the relevant state of a sustained virological response. Where applicable, early virological response rates were used to estimate the average duration of treatment and total drug acquisition costs for each anti-viral treatment strategy.

Shortening the duration of treatment with peginterferon alfa-2a plus ribavirin from 48 weeks to 24 weeks for people with HCV genotype 1, a baseline low viral load and a rapid virological response resulted in a reduction in total QALYs of between 0.08 and 0.14. This shortened treatment duration was also associated with a reduction in the total cost, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £34,510 to £64,880 per QALY). For people with HCV genotypes 2 and 3, a baseline low viral load and a rapid virological response, a shortened duration of treatment of 16 weeks with peginterferon alfa-2a plus ribavirin dominated the standard 24-week treatment duration. For the subgroup of people with HCV genotype 1, a baseline low viral load and a rapid virological response, a shortened duration of treatment of 24 weeks with peginterferon alfa-2b plus ribavirin dominated the standard 48‑week treatment duration.

The ICER for the subgroup of people who had been treated previously with peginterferon alfa-2b plus ribavirin or peginterferon monotherapy but whose hepatitis C did not respond to treatment, or responded initially to treatment but subsequently relapsed, was £23,912 per QALY gained (compared with best supportive care) for people with HCV genotypes 1 and 4. If an early stopping rule was applied, the ICER for people with genotypes 1 and 4 was reduced to £7681 per QALY gained. For people with genotypes 2 and 3, treatment with peginterferon alfa-2b plus ribavirin dominated best supportive care (with or without an early stopping rule). Re-treatment with peginterferon alfa-2a plus ribavirin of people whose hepatitis C did not respond to previous peginterferon therapy resulted in an ICER of £52,587 per QALY gained for people with HCV genotype 1 and £10,926 per QALY gained for people with other genotypes, each compared with best supportive care. If an early stopping rule was applied at 12 weeks for people re-treated with peginterferon alfa-2a plus ribavirin who did not show an early virological response at this time, the ICERs were reduced to £9,169 per QALY gained for people with HCV genotype 1 and £2,294 per QALY gained for people with other genotypes.

For people co-infected with HCV and HIV, treatment with peginterferon alfa-2a plus ribavirin resulted in an ICER of £7,941 per QALY gained for people with HCV genotypes 1 and 4 compared with best supportive care. Peginterferon alfa-2a plus ribavirin dominated best supportive care for people with genotypes 2 and 3. Treatment of people co-infected with HCV and HIV with peginterferon alfa-2b plus ribavirin resulted in an ICER of £11,806 per QALY gained for people with HCV genotypes 1 and 4 and an ICER of £2,161 per QALY gained for people with genotypes 2 and 3.

Cost-effectiveness analyses indicate that adopting a shortened duration of treatment with peginterferon alfa-2a plus ribavirin for people with HCV genotype 1 is associated with fewer QALYs, but also with lower treatment costs, resulting in ICERs ranging from £34,000 to £65,000 of savings per QALY lost. For people with genotypes 2 and 3, a shortened treatment course with peginterferon alfa-2a plus ribavirin dominates the standard treatment duration. Similarly, for people with HCV genotype 1, a shortened duration of treatment with peginterferon alfa-2b plus ribavirin dominates the standard treatment duration. The results submitted by the manufacturers and those reported by the assessment group also indicate that treatment with peginterferon alfa plus ribavirin for people who are eligible for re-treatment following previous non-response or relapse of their condition is associated with QALY gains and an increase in costs. If an early stopping rule was applied at 12 weeks, re-treatment with peginterferon alfa plus ribavirin was associated with ICERs below £10,000 per QALY gained for people with HCV genotypes 1 and 4. For people with HCV genotypes 2 and 3, re-treatment was associated with ICERs below £2,294 per QALY gained or dominated best supportive care. For people co-infected with HCV and HIV who were treated with peginterferon alfa plus ribavirin, either all ICERs were below £12,000 per QALY gained or treatment dominated best supportive care.