Pharmacology Xagena

Hepatitis C - New direct acting antiviral therapy: combinations with and without Interferon

The challenge of new therapeutic agents and combinations is to improve virological response, shorten the length of therapy and offer treatment free of Interferon. New treatments will need to be evaluated by several markers: first, in terms of their improvements in efficacy beyond the new standard of polymerase inhibitor / Peg-Interferon / Ribavirin ( PI/PEG-IFN/RBV ) response; second, their reductions in side effects; third, improved treatment simplicity and pill burden; and finally cost for the individual and society.

There is the real potential to have Interferon free regimes available within several years with the consequent reduction in side effects and availability of treatment for IFN-intolerant individuals. However, there may remain a selective role for IFN since quadruple therapy with two DAAs plus PEG-IFN/RBV has been shown to improve outcomes for patients with multiple poor treatment response predictors ( such as previous treatment non-response, cirrhosis, genotype-1 infection and high HCV viral load ). In these difficult to treat individuals, the increase in efficacy may outweigh increases in complexity and toxicity.

Another area whether combination therapy is likely to improve in the next few years will be incremental changes in the current triple therapy PI/PEG-IFN/RBV as newer once daily protease inhibitors replace Boceprevir and Telaprevir.

Interferon-free therapy

Several studies have explored Interferon-free therapy combinations in different groups. Two agents, Sofosbuvir ( Sovaldi ) and Daclatasvir ( Daklinza ), are likely to be included in the first Interferon-free regimens.
A study of an NS5B polymerase ( Sofosbuvir ) with Ribavirin among treatment naïve, genotype-2/-3 patients treated 40 participants for 12 weeks, randomly assigned PEG-Interferon for different durations or not at all. All participants achieved an RVR ( rapid virological response ) and SVR ( sustained virological response ), regardless of PEG-Interferon administration.
Viral kinetics were no different in the IFN-free arm, and there were no cases of viral breakthrough, suggesting that the combination has a high barrier to resistance.

Sofosbuvir monotherapy for 12 weeks among 10 genotype-2/-3 patients resulted in an end-of-treatment response for all patients. However four relapsed within 4 weeks of stopping therapy, consistent with a need for RBV in IFN-free regimens.

Among harder to treat, genotype-1 null responders, Sofosbuvir plus Ribavirin for 12 weeks demonstrated a 100% end-of-treatment response ( n = 10 ). However nine out of 10 relapsed within 4 weeks of stopping treatment.
Previous null responders may require longer DAA therapy, the addition of other DAA agents, or might require PEG-Interferon.

Another phase II trial of treatment experienced, genotype-1, non-responders without cirrhosis studied Daclatasvir, an NS5A polymerase inhibitor, and Asunaprevir, an NS3 protease inhibitor, randomized to receive PEG-IFN/RBV versus no PEG-IFN/RBV. Amongst the IFN-free group ( n = 11 ), 4/11 of their non-responder population achieved an SVR, 1/11 relapsed after an undetectable HCV RNA at the end of treatment, while 6/11 had viral breakthrough on therapy.
When examining genotype-1 subtype, both genotype-1b infected patients achieved an SVR ( n = 2 ), while only 2/9 genotype-1a patients achieved an SVR.

Resistance mutations to both NS5A and NS3 agents occurred in patients with virological failure. It is unclear whether those mutations will affect subsequent therapy.
The same Interferon-free drug combination was used for 24 weeks in a small Japanese cohort ( n = 10 ) of HCV genotype-1b, IL28B favourable, treatment experienced null responders and was demonstrated to have a 100% SVR.

Quadruple therapy

In a phase II study of PEG-Interferon and Ribavirin in combination with Daclatasvir and Asunaprevir, very high SVR rates were achieved in a null responder population. Ten treatment experienced, genotype-1, non-responders without cirrhosis had undetectable HCV RNA on treatment. SVR response measured at 12, 24 and 48 weeks was 10/10, 9/10 and 9/10 respectively.
These results suggest that quadruple therapy may achieve very high SVR rates in patients who respond poorly to Interferon, a dramatic improvement on standard therapy which would have predicted less than 10% SVR. ( Xagena )

Doyle JS et al, Br J Clin Pharmacol 2013; 75: 931–943