Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning —Winston Churchill

These are extraordinary times in the history of hepatitis C virus (HCV) drug development. We waited 13 years between the approval of ribavirin (RBV) in 1998 and the approval of telaprevir and boceprevir in 2011. The trajectory of drug discovery and clinical trials has gone from exponential to warp speed since the European Association for the Study of the Liver (EASL) meeting in April 2011, and two articles are perfect examples of what has changed the world of hepatitis C: interferon (IFN)-free combination therapy and, in one of the trials, eradication of the virus.1, 2

The first demonstration in humans of IFN-free combination therapy with direct-acting antivirals (DAAs) was the INFORM-1 trial, the results of which were first presented at the EASL 2009 meeting and published in 2010.3 It showed that a nucleoside analogue polymerase inhibitor (now known as mericitabine) and a protease inhibitor (now known as danoprevir [presently boosted with ritonavir]) together without polyethylene glycol (PEG) or RBV could reduce HCV viral load by 5 × 1 log10 IU/mL in 14 days with no sign of resistant virus. This was the proof of principle that two DAAs by themselves could render HCV undetectable in most patients, without the use of PEG or RBV. This combination hit a snag with some danoprevir toxicity issues, and development has slowed. Those issues were successfully resolved with ritonavir boosting; the follow-up study to INFORM is now proceeding apace, and data will be forthcoming from that trial in 2012 or 2013.

The Zeuzem et al. study published in this issue of HEPATOLGY2 compared an all-oral combination of tegobuvir (a nonnucleoside polymerase inhibitor given twice daily) plus GS 9256 (an NS3 serine protease inhibitor) with and without RBV in two arms for 28 days, at which point they received PEG and RBV standard of care. The third arm used quadruple therapy with both DAAs plus PEG and RBV for 28 days and then PEG and RBV alone. All patients with viral rebound of >0.5 log10 from nadir or nonresponse defined as <2.0 log10 decline at day 5 received PEG and RBV immediately. Median maximal reductions in HCV RNA were −4.1 log10 IU/mL, −5.,1 log10 IU/mL, and −5.7 log10 IU/mL for the tegobuvir plus GS 9256, tegobuvir plus GS 9256 plus RBV, and tegobuvir, GS9256, PEG, and RBV arms, respectively. The results were quite instructive. Rapid virological response (RVR) for the two DAAs alone was 7%, for the two DAAs plus RBV 38%, and for the quadruple therapy arm 100%. The importance of RBV in preventing resistance is very clear with this combination and re-emphasizes the continuing value of using RBV in all oral regimens of DAAs. It also demonstrates the real, but weak antiviral activity of RBV.4

Why was this result so different from that of INFORM, in which virus was undetectable in virtually all patients at 14 days of dual therapy? The answer lies in the barrier to resistance.5 The nucleoside/nucleotide analogues in general have a very high barrier to resistance, and the INFORM study used the nucleoside mericitabine. The barrier to resistance for protease inhibitors is relatively low, and lower still for genotype 1a as opposed to genotype 1b, because the 1a virus only requires one mutation to generate resistance to protease inhibitors, whereas the 1b virus requires two. Most nonnucleoside polymerase inhibitors have a relatively low barrier to resistance. When you combine two DAAs with relatively low barriers to resistance, it is easy for the virus to produce the double mutants that are resistant to both drugs. RBV slows this down somewhat, but does not add enough antiviral activity to prevent resistance more than 60% of the time with tegobuvir and GS 9256.

There is one other factor involved in preventing resistance and that is the activity of the DAA. These extremely potent agents, which rapidly drop the viral load down to undetectable, also prevent resistance. A good example of this is the combination study of BI 201335 and BI 207127.6 This study compared two groups: BI201727 400 mg or 600 mg given thrice daily plus BI 201335 and RBV 1000-1200 mg for 4 weeks. In the 400-mg group, the RVR was 73% (with better response in genotype 1b than 1a, as one would expect with a protease inhibitor in the regimen). In the 600-mg group, the RVR was 100% and did not differ between genotype 1a and 1b. From these data, one can infer that the potency of either the protease inhibitor or the nonnucleoside polymerase inhibitor was different, because the same two classes of drugs, plus RBV, yielded a much higher RVR. To be fair, there was no arm without RBV in this study and, of course, it is hard to compare results between studies. The designs of both studies are elegant, simple, and easy to understand, and they advance the field enormously. Gilead is now aggressively addressing the issue of potency by adding a third DAA to tegobuvir and GS 9256 with and without RBV.7

The other study in this issue of Hepatology2 advances the field dramatically further. Not only does it move us from RVR without IFN to sustained virological response (SVR), but it does so in null responders! This represents a giant step toward the “Holy Grail” of HCV therapy: once-daily, oral IFN-free treatment.

The world of HCV treatment changed forever in April of 2011 when the first IFN-free SVRs were presented using an NS5A inhibitor and a protease inhibitor, the same two drugs used in the Chayama et al. article.8 The 100% SVR with quadruple therapy was overshadowed by the all-oral double DAA combination (without RBV) that resulted in a 36% SVR. This was the long-awaited proof of principle that HCV could be eradicated without IFN. Notably, in the all-oral arm both of the genotype 1b patients achieved an SVR, but only 2/9 of the genotype 1a patients, demonstrating the differences in activity of protease inhibitors in genotypes 1a and 1b.

The Chayama et al. study in this issue7 examined the combination of the NS5A BMS-790052 60 mg qd (now called daclatasvir) and the protease inhibitor BMS-650032 600 mg (now called asunaprevir) in null responders, but only in genotype 1b, the most common genotype in Japan. Ten patients received both drugs for 24 weeks. Of the nine patients who completed the study, all achieved an SVR. HCV RNA remained undetectable in the patient who discontinued treatment after 2 weeks. This is truly a remarkable achievement in the field of HCV treatment. It is only partially applicable to genotype 1a patients around the world, but nonetheless brings us closer to what we seek in HCV therapy: all-oral, highly effective treatment. This publication marks a turning point in the HCV drug development world. It demonstrates that a protease and an NS5A inhibitor together can achieve an extremely high SVR in null responders, at least in genotype 1b. It is the second trial to show that an SVR is possible without either IFN or RBV in null responders.

In the patois of HCV drug development, we often speak of an all-oral regimen as the Holy Grail we all seek. In history that term has had many meanings, particularly in Arthurian legends beginning in the late 12th century. The meaning that comes closest, though, to what we really intend is found in Wolfram von Eschenbach's Parzival. He portrays the grail as a stone that prevents anyone who sees it from dying. The development of an oral regimen of DAAs that can produce SVR in a high proportion of patients is the grail that we seek. It will prolong life and prevent death from liver disease, just as the epidemic is reaching crisis proportions. The two studies in this issue of Hepatology bring us much closer to providing the answer to the epidemic.


  1. Top of page
  2. References
  • 1
    Chayama, K Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H, et al. Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 in HCV genotype 1b-infected null responders HEPATOLOGY 2012; 55: 742-748.
  • 2
    Zeuzem S, Bruggish P, Agarwal K, Marcellin P, Sereni D, Klinker H, et al. The protease inhibitor GS-9256 and non-nucleoside polymerase inhibitor tegobuvir alone, with RBV or peginterferon plus RBV in hepatitis. HEPATOLOGY 2012; 55: 749-758.
  • 3
    Gane E, Roberts S, Stedman C, Angus P, Ritchie B, Elston R, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomized, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010; 376: 1467-1475.
  • 4
    Thomas E, Feld J, Li Z, Hu Z, Fried MW, Liang TJ. Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis c virus cell culture models. HEPATOLOGY 2011; 53: 32-41.
  • 5
    Sarazin D, Zeuzem S. Resistance to direct acting antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138: 447-462.
  • 6
    Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Mullhaupt B, et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127 and ribavirin in patients with chronic HCV infection. Gastroenterology 2011; 141: 2047-2055.
  • 7
  • 8
    Lok A, Gardiner D, Lawitz E, Martorell C, Everson G, Ghalil R, et al. Quadruple therapy with BMS-790052 and BMS-650032 and peg-IFN/RBV for 24 weeks results in 100% SVR in HCV genotype 1 null responders J Hepatol 2012; 55:742748.
  • 9
    Paul E. It is indeed the cup, from “The Quest of the Saint Graal.” In: West M. Claire de Lune and Other Troubadour Romances. Music by Alfred Mereer. London: G.G. Harrap; 1913.