Is sustained virological response a marker of treatment efficacy in patients with chronic hepatitis C viral infection with no response or relapse to previous antiviral intervention?

Abstract

Background: Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs.

Methods: We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality "wears off").

Results: The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR.

Conclusions: SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker.

Figure 1. Decision tree.

This figure shows the possible pathway followed by a patient with chronic hepatitis C infection, who does not respond to interferon monotherapy.

Figure 2. Probability that interferon retreatment is better at different sustained virological response (SVR) proportions in the interferon group (scenario 1).

The chart shows that the probability of interferon retreatment resulting in better life expectancy than no-intervention control group is always below 2% if the long-term mortality in the two groups continued at the same rates as the short-term mortality (scenario 1).

Figure 3. Probability that interferon retreatment is better at different sustained virological response (SVR) proportions in the interferon group (scenario 3).

The chart shows that the probability of the interferon retreatment group having a longer life expectancy than the no-intervention control group increases as the proportion of patients with SVR in the interferon retreatment group increases. This is only true if the patients with no SVR in the interferon retreatment group had long-term mortality at the same rates as the medium-term mortality in the control group (i.e., the increased mortality in the medium-term due to interferon retreatment wears off) while those in the SVR group had a long-term mortality at the same rate as the general population (scenario 3).

Figure 4. Probability that interferon retreatment is better at different odds ratio of long-term mortality in the no SVR group compared to the general population (scenario 3).

This chart shows that the probability that interferon retreatment results in longer life expectancy compared to the no-intervention control group increases as the odds ratio of long-term mortality in the no-SVR group increases compared to the general population.

Figure 5. Difference in life expectancy between the intervention groups at various proportions of sustained virological response (SVR) in the interferon retreatment group (scenario 3).

This chart shows that the interferon retreatment group had a longer life expectancy than the no-intervention control group if the proportion of patients who achieved SVR was 0.07 or above in the interferon retreatment group. This assumes that the patients with no SVR have a long-term mortality rate comparable to the medium-term mortality rate in the control group (i.e., the increased mortality in the medium-term due to treatment wears off) and those in the SVR group have a long-term mortality rate comparable to the general population (scenario 3).

Figure 6. Difference in life expectancy between the intervention groups at different odds ratios of long-term mortality rates in no sustained virological response (SVR) group (scenario 3).

This chart shows that the interferon retreatment group has a longer life expectancy than the no-intervention control group if the odds ratio of long-term mortality was 7.00 in the no SVR group compared to the general population. This also assumes that the patients in the SVR group had a long-term mortality rate similar to the general population (scenario 3).

Figure 7. Two-way sensitivity analysis.

The two-way sensitivity analysis of the odds ratios of long-term mortality in the no-SVR group compared to the general population versus the probability of SVR in the interferon group showed that in a 50 year old male, the interferon retreatment group had longer life expectancy than the no-intervention control group provided that the long-term mortality in the no-SVR group was higher than the general population. This assumes that the patients with no SVR have long-term mortality rate at the same rate as medium-term mortality in control group (i.e., the increased mortality in the medium-term due to treatment wears off), and if those in the SVR group had long-term mortality rates similar to the general population (scenario 3).