Mechanisms of Non-response to Hepatitis C Therapy
Mechanisms of Non-response to Hepatitis C Therapy
Understanding factors that may contribute to treatment failure in cirrhosis is necessary to implement strategies to overcome this challenge. Ideally strategies should address all factors that may ultimately lead to treatment failure (Table 1).
The first step is to eliminate IFN from all antiviral regimens given its poor safety and efficacy in patients with cirrhosis. While this aim may not be feasible everywhere initially, hopefully broader access to IFN-free DAA therapy will be feasible in the near future.
Increasing treatment duration and potentially adding more agents seem to improve the likelihood of treatment success in patients with cirrhosis. With first generation-PIs, 48 weeks of therapy was shown to result in better SVR rates than shorter response guided durations in patients with advanced fibrosis or cirrhosis. In a subanalysis of the ION2 study, 44 patients with cirrhosis were randomized to receive ledipasvir and sofosbuvir for either 12 or 24 weeks. The rate of SVR appeared significantly better in the 24-week arm (100%) compared to that in those who were treated for 12 weeks (82%) (P = 0.007). Similarly, using the combination of paritaprevir/r-ombitasvir/dasabuvir/ribavirin better SVR rates were seen in cirrhotic patients with genotype 1a infection treated for 24 weeks rather than 12 weeks. The benefit was greatest in those with genotype 1a infection and a prior null response. Prolonging therapy may improve DAA-exposure in hepatocytes in the presence of shunting. As virus is suppressed, there may also be partial recovery of the host immune response, which may aid in clearing virus.
In certain populations, longer therapy may not help if response to treatment reaches a plateau at which extending treatment will not improve SVR any further. Patients with genotype 3 infection and cirrhosis who have failed prior therapy fall into this category. The FUSION trial demonstrated that 16 weeks of sofosbuvir and ribavirin was more effective (61%) than 12 weeks of treatment (19%) in this population, however, further extension to 24 weeks (60%) did not increase the SVR rates further. The cause for this plateau is not clear but suggests that further lengthening of therapy is unlikely to be successful. The alternative to longer therapy is adding additional agents. In the genotype 3 treatment-experienced cirrhotic population, the re-inclusion of PEG-IFN with sofosbuvir and ribavirin increased SVR rates and allowed treatment to be shortened to just 12 weeks. Although helpful for compensated patients, this strategy would not be ideal for those with more advanced cirrhosis. Hopefully future DAAs, such as GS-5816, a pangenotypic NS5A inhibitor, will achieve high SVR rates in this difficult-to-cure population without the need for Peg-IFN. Initial results with sofosbuvir and GS-5816+ RBV for 12 weeks in genotype 3 treatment-experienced cirrhotics were very promising with 25 of 26 patients achieving SVR.
Particularly given the high costs of therapy, extending duration may not be the first choice if other alternatives are similarly effective. The data from the ION-2 trial suggested that treatment-experienced patients with cirrhosis required 24 weeks of SOF/LDV. However, only 22 patients with cirrhosis were included in each of the 4 study arms. In the larger SIRIUS trial reported by Bouleire and colleagues, 77 and 78 patients who had failed prior therapy and had cirrhosis were randomized to SOF/LDV for 24 weeks or SOF/LDV plus ribavirin for 12 weeks. The SVR rates were essentially identical at 96% and 97% respectively. Similarly, a pooled analysis of all treatment-experienced cirrhotics treated with this regimen showed that 12 weeks with ribavirin was equally effective to 24 weeks without. This important result highlights the dangers of poor trial design. Larger numbers of patients with cirrhosis should be included in all Phase 3 trials to ensure that safety, efficacy as well as the optimal regimen are clarified.
Patients with decompensated cirrhosis will continue to be challenging and extension of therapy may not matter. Patients with decompensated cirrhosis receiving LDV/SOF+RBV for 24 weeks demonstrated similar SVR rates to patients receiving the same regimen for 12 weeks (87% vs 89%) suggesting that in patients with advanced cirrhosis there are other factors contributing to treatment non-response that may not be overcome by prolonging therapy duration. IFN-containing regimens are clearly contraindicated in these patients but what will be required to increase the SVR rates remains unclear. Safety will continue to be a prime concern.
Based on the limited data derived from the small studies mentioned earlier, there are a number of other adjustments that could be made to improve the chances of treatment response. Further studies on antifibrotic agents may demonstrate value in treating HCV in patients with cirrhosis. TGF-β receptor inhibitors may be particularly attractive with the possibility to reduce fibrosis and improve innate immune function simultaneously. Aiming for higher serum albumin levels, improved nutrition status and appropriate management of vitamin D deficiency may also prove useful, however, as DAA therapies continue to improve, many of these minor adjustments are likely to become less and less relevant.
Overcoming Non-response in Cirrhosis
Understanding factors that may contribute to treatment failure in cirrhosis is necessary to implement strategies to overcome this challenge. Ideally strategies should address all factors that may ultimately lead to treatment failure (Table 1).
The first step is to eliminate IFN from all antiviral regimens given its poor safety and efficacy in patients with cirrhosis. While this aim may not be feasible everywhere initially, hopefully broader access to IFN-free DAA therapy will be feasible in the near future.
Increasing treatment duration and potentially adding more agents seem to improve the likelihood of treatment success in patients with cirrhosis. With first generation-PIs, 48 weeks of therapy was shown to result in better SVR rates than shorter response guided durations in patients with advanced fibrosis or cirrhosis. In a subanalysis of the ION2 study, 44 patients with cirrhosis were randomized to receive ledipasvir and sofosbuvir for either 12 or 24 weeks. The rate of SVR appeared significantly better in the 24-week arm (100%) compared to that in those who were treated for 12 weeks (82%) (P = 0.007). Similarly, using the combination of paritaprevir/r-ombitasvir/dasabuvir/ribavirin better SVR rates were seen in cirrhotic patients with genotype 1a infection treated for 24 weeks rather than 12 weeks. The benefit was greatest in those with genotype 1a infection and a prior null response. Prolonging therapy may improve DAA-exposure in hepatocytes in the presence of shunting. As virus is suppressed, there may also be partial recovery of the host immune response, which may aid in clearing virus.
In certain populations, longer therapy may not help if response to treatment reaches a plateau at which extending treatment will not improve SVR any further. Patients with genotype 3 infection and cirrhosis who have failed prior therapy fall into this category. The FUSION trial demonstrated that 16 weeks of sofosbuvir and ribavirin was more effective (61%) than 12 weeks of treatment (19%) in this population, however, further extension to 24 weeks (60%) did not increase the SVR rates further. The cause for this plateau is not clear but suggests that further lengthening of therapy is unlikely to be successful. The alternative to longer therapy is adding additional agents. In the genotype 3 treatment-experienced cirrhotic population, the re-inclusion of PEG-IFN with sofosbuvir and ribavirin increased SVR rates and allowed treatment to be shortened to just 12 weeks. Although helpful for compensated patients, this strategy would not be ideal for those with more advanced cirrhosis. Hopefully future DAAs, such as GS-5816, a pangenotypic NS5A inhibitor, will achieve high SVR rates in this difficult-to-cure population without the need for Peg-IFN. Initial results with sofosbuvir and GS-5816+ RBV for 12 weeks in genotype 3 treatment-experienced cirrhotics were very promising with 25 of 26 patients achieving SVR.
Particularly given the high costs of therapy, extending duration may not be the first choice if other alternatives are similarly effective. The data from the ION-2 trial suggested that treatment-experienced patients with cirrhosis required 24 weeks of SOF/LDV. However, only 22 patients with cirrhosis were included in each of the 4 study arms. In the larger SIRIUS trial reported by Bouleire and colleagues, 77 and 78 patients who had failed prior therapy and had cirrhosis were randomized to SOF/LDV for 24 weeks or SOF/LDV plus ribavirin for 12 weeks. The SVR rates were essentially identical at 96% and 97% respectively. Similarly, a pooled analysis of all treatment-experienced cirrhotics treated with this regimen showed that 12 weeks with ribavirin was equally effective to 24 weeks without. This important result highlights the dangers of poor trial design. Larger numbers of patients with cirrhosis should be included in all Phase 3 trials to ensure that safety, efficacy as well as the optimal regimen are clarified.
Patients with decompensated cirrhosis will continue to be challenging and extension of therapy may not matter. Patients with decompensated cirrhosis receiving LDV/SOF+RBV for 24 weeks demonstrated similar SVR rates to patients receiving the same regimen for 12 weeks (87% vs 89%) suggesting that in patients with advanced cirrhosis there are other factors contributing to treatment non-response that may not be overcome by prolonging therapy duration. IFN-containing regimens are clearly contraindicated in these patients but what will be required to increase the SVR rates remains unclear. Safety will continue to be a prime concern.
Based on the limited data derived from the small studies mentioned earlier, there are a number of other adjustments that could be made to improve the chances of treatment response. Further studies on antifibrotic agents may demonstrate value in treating HCV in patients with cirrhosis. TGF-β receptor inhibitors may be particularly attractive with the possibility to reduce fibrosis and improve innate immune function simultaneously. Aiming for higher serum albumin levels, improved nutrition status and appropriate management of vitamin D deficiency may also prove useful, however, as DAA therapies continue to improve, many of these minor adjustments are likely to become less and less relevant.