A 13-Day, Interferon-Free Regimen for Chronic Hepatitis C Genotype 1 Patients: Between Fear and Hope

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colonoscopy are needed to establish the benefits of colonoscopy for lesions at all sites. KARLEE J. AUSK University of Washington Seattle, Washington JASON A. DOMINITZ VA Puget Sound Health Care System University of Washington School of Medicine Seattle, Washington

Reply. We thank Ausk and Dominitz for their insightful

summary of and comment on our paper (Ann Intern Med 2011:154:22–30), and we agree with most of their conclusions. In particular, we agree that our study provides some evidence that colonoscopy offers significant benefit (in terms of protection from colorectal cancer [CRC]) in the proximal colon. To what extent the costs and risks of screening colonoscopy relative to sigmoidoscopy are justified cannot be judged based on our study alone, even though our study provides relevant data to inform careful, country-specific cost-effectiveness analyses required for such judgement (Gastrointest Endosc Clin N Am 2010;20:751–770), as well as evidence toward such justification. We also agree that randomized trials are the method of choice to ultimately establish efficacy of screening procedures. For screening colonoscopy, one such trial, the NORDICC study, aiming for inclusion of 66,000 participants, has recently been initiated in a number of European countries. However, results regarding primary endpoints, reduction of CRC incidence and mortality, will only be available 10 –15 years after completion of recruitment. By then, colonoscopy technology and training will hopefully and most likely have made further major progress, and results will again pertain to technology that will most likely be outdated. Furthermore, in the population of the United States and some European countries, colonoscopy and sigmoidoscopy are already now so widespread for both screening and diagnostic purposes, and prevalence of previous lower gastrointestinal endoscopy has become so high in the target population of screening (Gastrointestinal Endoscopy 2011;73:435– 443; Endoscopy 2010;42:546 –556) that randomized trials in those populations would most likely be strongly affected by contamination of the control group. Also, although randomized trials are able to assess screening efficacy under highly standardized trial conditions, they are insufficient to ultimately evaluate effectiveness of a colonoscopy screening program in routine practice. Finally, randomized trials are typically able to evaluate a single, specific screening option (such as one first-time colonoscopy at the age of 55– 65), and rarely permit comparative evaluation of different options, such as a different age at firsttime colonoscopy, or different screening or surveillance intervals. Therefore, although randomized trials undoubtedly have their merits, they can and should not replace carefully conducted observational studies that evaluate the effectiveness of colonoscopy in routine practice, and

that may help to inform recommendations and decisions on CRC screening offers. Such preliminary recommendations and decisions are clearly needed before the availability of results from recently commenced or future randomized trials on colonoscopy efficacy. HERMANN BRENNER Division of Clinical Epidemiology and Aging Research German Cancer Research Center JENNY CHANG–CLAUDE Unit of Genetic Epidemiology Division of Cancer Epidemiology MICHAEL HOFFMEISTER Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg, Germany

A 13-DAY, INTERFERON-FREE REGIMEN FOR CHRONIC HEPATITIS C GENOTYPE 1 PATIENTS: BETWEEN FEAR AND HOPE Gane EJ, Roberts SK, Stedman C, et al. (Auckland Clinical Studies, Auckland, New Zealand). Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir of chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, doubleblind, placebo controlled, dose escalation trial. Lancet 2010;376:1467–1475. The release of the 2 potent nonstructural 3/4A (NS3/ 4A) HCV protease inhibitors telaprevir and boceprevir make 2011 a key year for patients with hepatitis C virus (HCV) infection; these drugs should dramatically increase the currently attainable sustained virologic response (SVR) rates (Aliment Pharmacol Ther 2010;32:14 –28). Indeed a 30% increase in the SVR rates in HCV-1–naïve patients is expected after a 24- or 48-week course of pegylated interferon (PegIFN) plus ribavirin (Rbv) plus telaprevir or boceprevir (N Engl J Med 2009;360:1827– 1838; Lancet 2010;376:705–716). The same increase is also expected in HCV-1 patients with a previous treatment failure, especially in those with a previous posttreatment relapse, where the SVR rates are estimated in the 65%–70% range (N Engl J Med 2010;362:1292–1303). All in all, these 2 new drugs will constitute a major clinical breakthrough for the treatment of chronic HCV infection. This notwithstanding, because PegIFN and Rbv will remain as the backbones of this new triple therapy regimen, all the unpleasant side effects associated with these drugs will continue to hamper our patients, de facto limiting the enthusiasm of many patients for this new regimen and effectively reducing the applicability of this new regimen in the clinical practice. With this in mind, it is easy to understand why scientific efforts and commercial interests are focused on delivering an IFN- and possibly Rbvfree regimen. The randomized, double-blind, placebo-controlled, dose-escalation study by Gane et al (Lancet 2010; 376:1467–1475) is the first to provide scientific evidence

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that an oral combination therapy based on a nucleoside polymerase inhibitor (RG7128) and an NS3/4A protease inhibitor (danoprevir) can be safe and effective in HCV1–infected patients. The design of the study is quite complicated as 88 patients, most naïve but some with a previous failure to IFN-based therapies, were enrolled into 7 treatment cohorts and then randomly assigned to active treatment or placebo. Excluded from the study were patients co-infected with other viruses, those ⬎65 years of age, and those with cirrhosis. Because the doses of RG7128 and danoprevir were higher in each subsequent cohort, random allocation for each cohort was done after completion of treatment in the preceding cohort. Patients randomized to the active treatment group received RG7128 from 500 to 1000 mg twice daily plus danoprevir 100 mg every 8 hours to 900 mg twice daily, both given for 13 days. Afterward, patients transitioned to the current standard of care PegIFN and Rbv. The primary outcome of the study was the change in HCV RNA levels, measured with the COBAS TaqMan HCV Test (lower limit of quantification, 43 IU/mL; lower limit of detection, 15 IU/mL) from baseline to day 14. During the whole study drug treatment phase, patients remained in the research unit. Most of the enrolled patients were men (80%), white (90%), and infected with genotype 1a (79%), with a mean HCV RNA concentration of log10 6.4 IU/mL. The mean reductions in HCV RNA from baseline to day 14 (EOT) were about 5 log IU/mL for the cohorts with the highest dosing regimens; by stratifying patients based on HCV-1 subtype the HCV RNA mean reduction was similar among HCV-1a and HCV-1b patients (⫺4.8 log10 IU/mL vs ⫺5.1 log10 IU/mL). Overall, 55% of the patients had HCV RNA values at EOT below the lower limit of quantification, and in 27% HCV RNA was below the lower limit of detection. When looking only at the highest dose cohorts, the corresponding figures were 88% and 63% for treatment naïve patients and 50% and 25% for previous treatment failures. No evidence of treatment-emergent resistance to either compound was identified during the study, and 72 of the 73 patients receiving active treatment had a continuous decline in viral load. In the patient with an HCV RNA increase during treatment, no resistant variants were found by population sequence, whereas clonal analysis identified 1 clone (1/88) harboring a danoprevir-associated resistance mutation (F43S). The combination of the 2 drugs was generally well tolerated, with no treatmentrelated study withdrawals or dose reductions. The most common adverse events were headache, rash, and gastrointestinal disorders, in all cases occurring with similar frequency compared with the placebo group. Based on these promising findings, the authors conclude that the combination of RG7128 and danoprevir should be further developed and might be a viable IFN-free, all-oral regimen for patients with chronic HCV infection. Comment. It is estimated that roughly 4 million people in the United States and 10 million in Europe are chronically infected with HCV. Although both in Europe and

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the United States the incidence of new cases has been steadily declining, mainly as a consequence of screening for HCV in blood donors (Transfusion 2002;42:975–979), the prevalence of the infection is generally considered not to have changed much. One of the main reasons behind this paradox is the relatively small impact of antiviral therapy on the disease burden. Indeed, even if the achievement of an SVR has been shown to positively impact the natural history of the disease by reducing liver-related complications and improving patients’ survival, unfortunately, antiviral treatment is estimated to reach only a minority of all prevalent HCV cases (1%–16%; J Hepatol 2008;49:528 –536), with the most common reasons behind this being related to local health resources or lack of HCV infection diagnosis (J Hepatol 2008;49:528 –536; Hepatology 2009;50:1750 –1755). As a consequence, it is estimated that the health burden of HCV-related complications will continue to grow in the United States, with an estimated peak in cirrhotic cases in 2020 (Gastroenterology 2010;138:513–521). One of the many ways to positively impact these figures would be to increase the attainable SVR rates while also increasing the number of HCVinfected patients receiving treatment. As shown by Markov model analyses, if we had an hypothetical treatment regimen that achieves a 75% SVR rate and we could increase by 75% the number of patients treated, the reduction in liver-related deaths in 2030 would be 57% (Hepatology 2009;50:1750 –1755). Although the soon-tocome triple therapy regimen consisting of an NS3/4 protease inhibitor combined with PegIFN and Rbv will enable us to reach the first end point, it seems rather unlikely that it will provide a major boost in the number of treated patients. Indeed, expanding the patients access to these regimens will be limited by the contraindications to PegIFN and Rbv, which currently do play a major role in limiting the clinical applicability of this regimen (Ann Intern Med 2002;136:288 –292). Moreover, the side effect profile of these new regimens will be cumbersome, because not only will patients experience all the well-known side effects of PegIFN and Rbv, but also will require expert management for the development of symptoms directly likened to the new drugs such as skin rash, severe anemia, and gastrointestinal symptoms. Supporting this are the higher treatment discontinuation rates reported in the phase 2 studies of telaprevir- and boceprevir-based regimens compared with the standard of care treatment arm (15% vs 4% and 14% vs 8%, respectively; Expert Rev Anti Infect Ther 2011;9:151–160; Lancet 2010;376:705–716). The development of an IFN-free, and possibly also Rbvfree, regimen would therefore play a major role in broadening the access to treatment by increasing the number of eligible patients while also improving patients’ acceptability. Unfortunately, this goal cannot be reached by telaprevir or boceprevir monotherapy, because resistant viral strains are rapid to emerge owing to the low genetic barrier of the 2 drugs (Gastroenterology 2006;131:997– 1002; Hepatology 2009;50:1709 –1718). HCV is prone to the development of resistance to specific antiviral inhibi-

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tors owing to the quasispecies nature of the virus, its rapid dynamics, and the error-prone RNA-dependent RNA polymerase. For these reasons, persistent inhibition of HCV replication requires the combination of drugs inhibiting HCV by interaction with other targets (NS5B polymerase, NS5A or NS4B), possibly with a high genetic barrier, such as the NS5B polymerase nucleoside analogues (Gastroenterology 2010;138:447– 462). The combination of directly acting antivirals (DAA) tested by Gane et al meets these criteria as a potent NS3/4 Protease inhibitor (Danoprevir) was combined with a high genetic barrier nucleoside polymerase inhibitor (RG7128). This promising combination resulted in a significant HCV RNA decrease after 13 days of therapy (5 log10 IU/mL in the highest dosed treatment arms), that translated into a significant number of patients being HCV RNA undetectable. Although this is no small feat, we should not forget that HCV RNA undectability is not synonymous with HCV eradication, because this second end point requires elimination of infected hepatocytes and not just inhibition of viral replication. Whether this can be achieved by an IFN free regimen still remains to be proved; unfortunately, all patients in the Gane et al study were transitioned to PegIFN and Rbv at day 14. Although in theory a maintained viral suppression could lead to HCV clearance because the virus has no known genetic form of intracellular persistence, it is estimated that ⱖ3 different inhibitors without cross-resistance will be needed to clear the more complex quasispecies populations (Sci Transl Med 2010;2:30ra32). These concepts indirectly reinforce the role of PegIFN and/or Rbv as the ideal backbone of a DAA combination regimen. Supporting this are the data presented at the AASLD 2010 meeting of a Phase II study designed to compare 4 weeks of combination treatment with a protease inhibitor (GS9256) and an NS5B non-nucleoside polymerase inhibitor (tegobuvir) versus the same drugs plus Rbv or the same drugs plus PegIFN and Rbv in HCV-1 patients (Hepatology 2010;52[Suppl 1] [abstract LB-1]). In that study, the rates of HCV RNA undetectability after 4 weeks were 7%, 38%, and 100%, respectively, showing a clear-cut benefit for the quadruple therapy regimen while brilliantly highlighting the still puzzling antiviral effect of Rbv (Gastroenterology 2010;139:154 –162). Another small drawback of the Gane et al study is that the good tolerability of the IFN-free combination regimen and its optimal resistance profile need to be weighed against the fact that during the treatment phase all patients were required to stay at the research unit. Whether the same results can be achieved in clinical practice remains unknown. Indeed, one of the main issues with telaprevir and boceprevir relies on the fact that they are to be taken every 8 hours and preferably after a small meal (for telaprevir); although while on paper this does not sound like a big deal, in everyday life it can be quite impractical, if not unfeasible. Given that incorrect uptake of DAAs is one of the many reasons that can lead to the selection of viral resistants owing to impaired viral suppression, the clinical implications behind this are obvious. Of course, these issues cannot be assessed once the pa-

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tients in a study are strictly monitored for adherence and side effects in a clinical research unit. Further limiting the clinical applicability of the Gane et al study is the exclusion of patients with cirrhosis. Although this is a common practice for Phase I–II studies, owing to concerns on potentially serious adverse events and to the lack of pharmacokinetic data on patients with advanced disease, patients with cirrhosis represent the most treatment in need group, because an SVR has been shown to substantially improve survival through a reduction in the rate of liverrelated complications (Ann Intern Med 2007;147:677– 684; J Hepatol 2010;52:652– 657). Unfortunately, the effect of cirrhosis on the pharmacokinetic profiles of most DAAs is still poorly understood; in the Phase II–III studies of boceprevir and telaprevir, only a minority of patients with bridging fibrosis or cirrhosis were actually enrolled. Moreover, cirrhosis, especially in the decompensated stage, is associated with a higher rate of serious adverse events directly linked to IFN, such as life-threatening infections, reinforcing the concept that this patient’s category would be an ideal target for an IFN-free regimen (J Hepatol 2007;46:206 –212). All these issues do not really limit the insights provided by the INFORM-1 study results on future therapies for HCV-infected patients, as the study effectively opens the era of DAA combination treatment while tickling our mind with interesting concepts to ponder. Indeed, one cannot but wonder what the clinical impact of an all-oral, IFN-free regimen in patients on the liver transplantation waiting list might be, as in theory such a therapy could prevent recurrent hepatitis C that in a substantial number of patients leads to shortened survival of the liver graft (Hepatology 2000;32:852– 858). Even more groundbreaking would be the possibility to actually eradicate the virus in the category of patients who are currently contraindicated in IFN-based regimens such as those with a systemic autoimmune disease or those who received a solid organ transplant (Hepatology 2009; 49:1335–1374); however, before such a therapy can even be thought of, the potentially problematic drug– drug interactions between DAAs and immunosuppressive drugs need to be clarified. Another fascinating finding of the INFORM-1 study are the reduced rates of HCV RNA undetectability observed in previous null-responders to the standard of care treatment compared with naïve patients. This is quite surprising and suggests we might still be missing some pieces in our understanding of the complicated mechanisms behind inhibition of HCV replication. Indeed, it seems highly unlikely that the previous PegIFN and Rbv course might have selected for a resistant viral strain; a possible explanation would be that nonresponders resist the restoration of innate immunity brought about by NS3 Protease inhibitors, an often forgotten added benefit of this class of DAAs (Trends Mol Med 2010;16:277–286). HCV is able to directly evade innate immune actions through the direct inhibition of IRF-3 and nuclear factor-␬B; this is caused by the NS3/4 protease protein complex acting as an antagonist of IRF-3, inhibition of the NS3/4 protease

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in vitro has been shown to restore IRF-3 activation leading to IFN␣/␤ genes activation. Given that deregulated ISG activation is seen in patients with a treatment failure to PegIFN and Rbv, this pathway might, at least partially, explain the observed different treatment efficacy observed in the INFORM-1 study between previous treatment failures and naïve patients (Proc Natl Acad Sci U S A 2008; 105:7034 –7039). Although we do agree that this is a major speculation made by clinicians wandering into the scientific world, still it shows what an exciting moment it

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is for whoever is working in the hepatitis C virus field, a moment of fast-growing scientific and clinical progress that will finally lead us away from the empiric therapies we have used for decades. ALESSIO AGHEMO MASSIMO COLOMBO First Division of Gastroenterology Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Università degli Studi di Milano Milan, Italy