Is There any Loophole in the Roadmap Model?

High levels of HBV replication are associated with increased risk of cirrhosis, decompensation, hepatocellular carcinoma and liver related mortality. In addition, long-term studies of antiviral therapy for CHB have demonstrated that sustained suppression will prevent disease progression and complications. Professor Edward J. Gane from New Zealand Liver Transplant Unit, New Zealand, presented a report on the "Roadmap Concept".  He said that profound and sustained inhibition of viral replication was the most important goal of antiviral therapy in chronic hepatitis B. Multiple analyses of baseline factors and on-treatment responses have identified that the absolute HBV DNA level after 24 weeks of therapy as the best predictor of long-term efficacy. This on-treatment management algorithm where virologic responses at 24 weeks are used to identify those patients with suboptimal responses so that an appropriate change in therapy can be initiated in order to enhance long-term patient outcomes is called the "Roadmap Concept".
 
However, Professor Gane thought there were several potential loopholes in the practical application of this approach:

 (i) The Roadmap Concept is perhaps best suited to agents with medium or low genetic barrier to resistance such as lamivudine and telbivudine, where continued therapy in patients with suboptimal early viral suppression is associated with very high rate of resistance with subsequent virologic breakthrough and disease progression. In contrast, the 24 week serum HBV DNA level is a poor predictor for long-term efficacy in antiviral agents with high genetic barrier to resistance such as entecavir or tenofovir, which are both associated with extremely low rates of virologic breakthrough (0.8% after 5 years entecavir; 0% after 2 years tenofovir). For example, 79% of patients who remain PCR detectable after 24 weeks tenofovir will achieve PCR nondetectability by 76 weeks (Heathcote et al, EASL 2008), this is not however virologic breakthrough.

 (ii) There is a lack of evidence to support which is the best strategy for partial and inadequate responders to lamivudine or telbivudine. If the treatment is to be changed, which new agent should be used and should this be switched or added on to the original agent? Although the addition of a second agent should prevent emergence of resistance to either agent alone, there is no data to suggest that this will improve viral suppression over that achieved by switching to the second agent.

 (iii) This approach is unlikely to be suitable for previously treated patients because of the risk of accelerated emergence of resistance to subsequent agents.

 (iv) This approach is unlikely to be applicable with immunomodulatory therapies including standard and pegylated interferons.

 (v) Finally, there has been no pharmaco-economic modelling performed to determine whether the Road Map approach (initial therapy with an agent with low genetic barrier to resistance and intensifying therapy after 24 weeks if serum HBV DNA remains detectable) is more cost-effectiveness than starting with an agent with high genetic barrier to resistance and ignoring the 24 week serum HBV DNA level.

Professor Gane also stated that the most attractive application of the Road Map approach would be initial therapy in HBeAg positive CHB with an antiviral agent, which despite a low genetic barrier, achieves superior HBeAg seroconversion rates compared to other agents. Further studies are needed to determine whether telbivudine will be such an agent.