Interferon-Free Treatment Regimens for Hepatitis C: Are We There Yet?

Abstract

Podcast interview: www.gastro.org/gastropodcast. Also available on iTunes; See “Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection,” by Zuezem S, Asselah T, Angus P, et al, on page 2047.Combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) was the standard of care for chronic hepatitis C (CHC) for over a decade. Sustained virologic response (SVR) rates vary from 40% to 45% among patients with genotype 1 to 75% to 80% in patients with genotype 2 or 3 infection.1Ghany M.G. Strader D.B. Thomas D.L. et al.Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (2594) Google Scholar However, PEG-IFN and RBV treatment are associated with many side effects. In registration trials that enrolled highly selected patients, 13%–15% of patients discontinued treatment early and 25%–42% had dose reductions because of adverse events or laboratory abnormalities.1Ghany M.G. Strader D.B. Thomas D.L. et al.Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (2594) Google Scholar, 2Fried M.W. Shiffman M.L. Reddy K.R. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5859) Google Scholar, 3Manns M.P. McHutchison J.G. Gordon S.C. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5871) Google Scholar Because of the poor tolerability, many patients with CHC have elected not to pursue treatment or were not offered treatment. IFN and RBV are also contraindicated in many conditions, such as autoimmune diseases and severe/uncontrolled psychiatric illnesses.1Ghany M.G. Strader D.B. Thomas D.L. et al.Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (2594) Google Scholar Therefore, there is an urgent need for more efficacious and better tolerated therapy for CHC.Advances in the understanding of the hepatitis C virus (HCV) life cycle have led to the development of many promising direct-acting antiviral agents (DAA) in the last decade (Figure 1) .4Lindenbach B.D. Rice C.M. Unravelling hepatitis C virus replication from genome to function.Nature. 2005; 436: 933-938Crossref PubMed Scopus (672) Google Scholar, 5Schlutter J. Therapeutics: new drugs hit the target. Nature 474:S5–S7.Google Scholar Two DAAs—telaprevir and boceprevir—linear inhibitors of NS3/4A serine protease were approved for HCV treatment in the United States in May 2011. Although the approval of boceprevir and telaprevir represents a major breakthrough for the treatment of CHC with SVR rates of 67% and 73%, respectively, in treatment-naïve genotype 1 patients, both drugs require concomitant use of PEG-IFN and RBV to achieve SVR by preventing viral breakthroughs owing to drug resistance.6Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364:2405–2416.Google Scholar, 7Poordad F. McCone Jr, J. Bacon B.R. et al.Boceprevir for untreated chronic HCV genotype 1 infection.N Engl J Med. 2011; 364: 1195-1206Crossref PubMed Scopus (2240) Google Scholar Furthermore, both drugs need to be administered every 8 hours and are associated with additional adverse events.With the development of DAAs directed at multiple targets in the HCV life cycle (Figure 1), the obvious question is, “Are we ready for IFN-free treatment regimens?” Clinical trials involving telaprevir and boceprevir as monotherapy showed a rapid decline in plasma HCV RNA levels within the first day followed by virologic breakthrough as early as day 3.8Reesink H.W. Zeuzem S. Weegink C.J. et al.Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study.Gastroenterology. 2006; 131: 997-1002Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 9Susser S. Welsch C. Wang Y. et al.Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients.Hepatology. 2009; 50: 1709-1718Crossref PubMed Scopus (275) Google Scholar HCV circulates as quasispecies, a mixture of viruses with heterogeneous virus sequences. It has been estimated that preexisting drug resistance variants with 1, 2, 3, and even 4 mutations may be present in most HCV-infected patients, and account for the rapid development of drug resistance on exposure to DAAs. The emergence of clinically relevant, drug-resistant variants depends on several factors, such as the potency of the drug, the genetic barrier to resistance, and the replication fitness of the resistance variants.10Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology;53:1742–1751.Google Scholar, 11Sarrazin C. Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection.Gastroenterology. 2010; 138: 447-462Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar Based on modeling experiments, it has been suggested that an IFN-free regimen that can overcome the presence of variants with 4 drug-resistance mutations requires a combination of ≥3 DAAs with a low genetic barrier to resistance, namely, DAAs that select single amino acid resistant variants.12Rong L, Dahari H, Ribeiro RM, et al. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2:30ra32.Google Scholar Each of these drugs should have potent antiviral activity, possess nonoverlapping resistance profiles, and have limited or manageable drug interactions and minimal adverse events. Furthermore, these drugs should be at similar stages of clinical development so that they can be tested in combination.The first study of combination DAAs, the INFORM-1 study, involved a combination of an NS5B polymerase inhibitor (RG7128) and an NS3/4A inhibitor (danoprevir). This study enrolled treatment-naïve as well as treatment-experienced patients.13Gane E.J. Roberts S.K. Stedman C.A. et al.Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial.Lancet. 2010; 376: 1467-1475Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar At day 14, 13%–63% of treatment-naïve and 25% of null responders had undetectable HCV RNA (Table 1). None of the patients in any treatment arm experienced virologic breakthrough during the 14-day course of IFN-free regimen suggesting that the addition of RG7128, which has a high barrier to resistance, may have prevented the emergence of resistance to danoprevir.Table 1Clinical trials of combination of DAAs with and without PEG-IFN and RBVDAAs TestedPatient Population (N)Trial DesignPrimary EndpointVirologic Breakthrough13RG7128 (NS3/4A inhibitor)Danoprevir (NS5B inhibitor) for 14 daysG1 followed by 46 wksPEG-IFN+RBVTreatment naïve(B, C, D, G) (33)Non–null responder (8)Null-responder (8)Placebo (14)B–G: RG7128 (500–1000 mg) + Danoprevir (100–200 mg) × 14 daysE: RG7124 (1000 mg) + Danoprevir (600mg) × 14 daysF: RG7124 (1000 mg) + Danoprevir (900mg) × 14 daysPlacebo × 14 daysFollowed by PEG-IFN+RBV for a total of 48 weeksWk-2 VR (<15 IU/mL)B-G = 13%–63%E: 13%F: 25%Placebo: 0None up to day 1414BI201335 (NS3/4A inhibitor)BI207127 (NS5B inhibitor)RBVTreatment naïve (34)Group 1: BI207127 (400 mg) + BI201335+RBV × 4 wksGroup 2: BI207127 (600mg) + BI201335+RBV × 4 wksFollowed by BI201335+PEG-IFN+RBV for 24–48 wks based on achievement of extended rapid VRWk-4 VR (<25 IU/mL)Group 1: 73%Group 2: 100%Up to Wk 4Group 1: 20%Group 2: 0%16GS9256(NS3/4A inhibitor)Tegubovir (NS5B inhibitor)Treatment naïve (46)Group 1: GS9256 + tegobuvir × 4 wksGroup 2: GS9256 + tegobuvir + RBV × 4 wksGroup 3: GS9256 + tegobuvir + RBV + PEG-IFN × 4 wksFollowed by PEG-IFN + RBV for total of 48 wksWk-4 VR (<15 IU/mL)Group 1: 13%Group 2: 62%Group 3: 100%Up to Wk 4Group 1: 81%Group 2: 13%Group 3: 0%17PSI938 (NS5B purine nucleotide inhibitor)PSI7977 (NS5B pyrimidine nucleotide inhibitor)Treatment naïve (40)Group 1: PSI938 × 14 daysGroup 2: PSI938 × 7 days, PSI938 + PSI7977 × 8–14 daysGroup 3: PSI7797 × 7 days, PSI938 + PSI7977 × 8–14 daysGroup 4: PSI938 + PSI7977 × 14 daysWk-2 VR (<15 IU/mL)Group 1: 50%Group 2: 100%Group 3: 88%Group 4: 88%Up to wk 2None18BMS650032 (NS3/4A inhibitor)BMS790052 (NS5A inhibitor)Null responders (21)Group 1: BMS650032 + BMS790052 × 24 wksGroup 2: BMS650032 + BMS790052 + PEG-IFN + RBV × 24 wksSVR12 (<10 IU/mL)Group 1: 36%Group 2: 100%Up to wk 24Group 1: 55%Group 2: 0%PEG-IFN, pegylated interferon; RBV, ribavirin; VR, virologic response. Open table in a new tab These promising results have encouraged other studies of combination DAAs. The design and preliminary results of these trials are summarized in Table 1. All the studies reported to date enrolled patients with genotype 1 infection only. Results of 1 phase Ib trial of a combination of an NS3/4A protease inhibitor BI201335, an NS5B polymerase inhibitor BI207127, and RBV are published in the current issue of Gastroenterology.14Zuezem S. Asselah T. Angus P. et al.Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.Gastroenterology. 2011; 141: 2047-2055Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar In this study, the authors randomized 34 treatment-naïve CHC patients to either 400 or 600 mg TID BI207127, 120 mg once daily BI201335, and weight-based RBV for 4 weeks. All the patients were switched to triple therapy (BI201335 + PEG-IFN + RBV) from day 29 until week 24 or 48, depending on achievement of extended rapid virologic response. The primary endpoint was day 29 virologic response. All 5 genotype 1b but only 6 of 10 genotype 1a patients in the group that received low-dose protease inhibitor achieved day 29 virologic response (Table 1). One genotype 1a patient had virologic breakthrough on day 22, with variants resistant to both drugs (R155K in NS3 and P495L in NS5B) and another patient had an increase in HCV RNA of 0.7 log10 IU/mL from nadir, but sequencing could not be performed because of low HCV RNA level. Both patients had a decrease in HCV RNA to <100 IU/mL after 10 days of BI201335, PEG-IFN, and RBV. All patients (8 genotype 1a and 8 genotype 1b) in the high-dose protease inhibitor group achieved day 29 virologic response. There were no serious adverse events or adverse event-related premature treatment discontinuations, but decreases in hemoglobin, increases in platelet count, and increases in total bilirubin (predominantly indirect) were observed.These results suggest that an IFN-free regimen comprising 2 DAAs (at the appropriate dose) plus RBV can achieve a very high rate of on-treatment virologic response for up to 4 weeks. However, this study does not address whether IFN-free combination DAAs will result in SVR. It also does not resolve the question of whether RBV contributed to the virologic response and whether RBV reduces relapse with IFN-free regimens. Furthermore, the safety of this combination treatment beyond 4 weeks remains to be determined. Finally, the presence of confirmed a dual drug-resistant variant in 1 patient and a persistent (<1 log) increase in HCV RNA after an initial decline in another patient is concerning, although not surprising, given that both drugs have a low barrier to resistance. Although it has been argued that HCV drug resistance variants are not archived and HCV drug resistance variants become undetectable at a median of 7 months after cessation of telaprevir,15Sullivan J.C. De Meyer S. Bartels D.J. et al.Evolution of treatment-emergent resistant variants in Telaprevir phase 3 clinical trials.J Hepatol. 2011; 54: s4Abstract Full Text PDF PubMed Google Scholar these data were based on population sequencing, which will not detect variants constituting <20% of the viral population and the real test, that is, response upon retreatment with DAA of the same class, has not been performed.Another study of combination DAAs involved an NS3 protease inhibitor (GS-9256) and a non-nucleoside NS5B polymerase inhibitor (tegobuvir) with or without PEG-IFN or RBV. The groups that received triple or quadruple therapy achieved higher rates of virologic response at week 4 compared with the group that received dual therapy (Table 1).16Zeuzem S. Buggisch P. Agarwal K. et al.Dual, triple and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PEGIFN/RBV for up to 28 days in treatment naive genotype 1 HCV subjects.Hepatology. 2010; 52: 400APubMed Google Scholar Thirteen of the 16 patients in the dual therapy group, 2 of 15 in the triple therapy group, and none of 15 in the quadruple therapy group experienced virologic breakthrough. Eleven of the patients in the dual therapy arm with breakthrough had variants resistant to both drugs.16Zeuzem S. Buggisch P. Agarwal K. et al.Dual, triple and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PEGIFN/RBV for up to 28 days in treatment naive genotype 1 HCV subjects.Hepatology. 2010; 52: 400APubMed Google Scholar These findings suggest that addition of RBV may accelerate viral clearance, thereby reducing the risk of resistance to DAAs, at least in the short term. The 4th study evaluated a combination of 2 nucleotide RNA-dependent RNA polymerase inhibitors, a purine (PSI-938) and a pyrimidine (PSI-7977) analog. It showed robust and consistent reduction in HCV RNA in the groups that received combination therapy as well as absence of virologic breakthrough up to week 2 (Table 1).17Lawitz E. Rodriguez-Torres M. et al.Once daily dual-nucleotide combination of PSI-938 and PSI-7977 provides 94% HCV RNA < LOD at day 14: first purine/pyrimidine clinical combination data (the NUCLEAR study).J Hepatol. 2011; 54: S543Abstract Full Text PDF Google ScholarCollectively, these studies showed that a 14- to 28-day course of the right combination of 2 DAAs dosed appropriately can result in a high rate of virologic response with a low rate of drug resistance, but the likelihood of SVR and risk of drug resistance with longer courses of IFN-free DAA only regimens were not addressed.To date, SVR data had been reported in only 1 study of combination DAAs. In this phase II study, genotype-1 null responders were randomized to receive a combination of an NS5A inhibitor (BMS790052) and an NS3 protease inhibitor (BMS650032) alone or together with PEG-IFN and RBV for 24 weeks.18Lok A.S. Gardiner D.F. Lawitz E. et al.Quadruple therapy with BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders.J Hepatol. 2011; 54: s536Abstract Full Text PDF Google Scholar All 11 patients in the dual therapy arm had a rapid decline in HCV RNA, with 7 achieving undetectable HCV RNA; however, 6 experienced virologic breakthrough and had variants resistant to both DAAs selected (Table 1). Although most of these patients responded to rescue therapy with addition of PEG-IFN and RBV, it is unclear if they will achieve SVR. Four of the 11 patients achieved SVR.12Rong L, Dahari H, Ribeiro RM, et al. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2:30ra32.Google Scholar Responses were more encouraging in the quadruple therapy arm with all 10 patients achieving SVR.12Rong L, Dahari H, Ribeiro RM, et al. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2:30ra32.Google Scholar These data showed that addition of 2 DAAs to PEG-IFN and RBV may result in a greater rate of SVR compared with 1 DAA in nonresponders to PEG-IFN and RBV.19Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med;364:2417–2428.Google Scholar More important, it provided proof of concept that SVR can be achieved with combination DAAs only.Similar to Zeuzem et al's study,14Zuezem S. Asselah T. Angus P. et al.Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.Gastroenterology. 2011; 141: 2047-2055Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar all patients with virologic breakthrough in Lok et al's study had genotype 1a infection.18Lok A.S. Gardiner D.F. Lawitz E. et al.Quadruple therapy with BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders.J Hepatol. 2011; 54: s536Abstract Full Text PDF Google Scholar Genotypes 1a and 1b HCV may differ in their susceptibility to DAAs. In addition, a larger number of nucleotide changes are required to create a clinically significant protease inhibitor resistance variant for genotype 1b (higher barrier to resistance) than for genotype 1a HCV.10Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology;53:1742–1751.Google Scholar, 11Sarrazin C. Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection.Gastroenterology. 2010; 138: 447-462Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar For example, 2 nucleotide changes are required to generate the resistance mutation R155K for 1b isolates (CGG→AAG), whereas only 1 nucleotide change is required for 1a isolates (AGG→AAG).19Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med;364:2417–2428.Google Scholar These data indicate that different strategies may be needed for genotype 1a and 1b infection in the era of combination DAAs.Eight years after the first clinical trial of DAA,20Lamarre D. Anderson P.C. Bailey M. et al.An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.Nature. 2003; 426: 186-189Crossref PubMed Scopus (845) Google Scholar development of direct-acting HCV treatments is now moving at a rapid pace with many products showing promising results. IFN-free regimens are no longer a dream, but a reality that may be available in the clinic in the next 5 years. It is possible that some of these regimens will also be RBV free. This will be good news for patients who wish to be treated but have to defer treatment because of contraindications to use of PEG-IFN or RBV, or out of concerns about their ability to tolerate these medications. However, caution must be taken in selecting which DAAs to combine and the appropriate dose and duration of therapy for each HCV genotype and subgenotype to prevent multidrug resistance. Podcast interview: www.gastro.org/gastropodcast. Also available on iTunes; See “Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection,” by Zuezem S, Asselah T, Angus P, et al, on page 2047. Podcast interview: www.gastro.org/gastropodcast. Also available on iTunes; See “Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection,” by Zuezem S, Asselah T, Angus P, et al, on page 2047. Podcast interview: www.gastro.org/gastropodcast. Also available on iTunes; See “Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection,” by Zuezem S, Asselah T, Angus P, et al, on page 2047. Combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) was the standard of care for chronic hepatitis C (CHC) for over a decade. Sustained virologic response (SVR) rates vary from 40% to 45% among patients with genotype 1 to 75% to 80% in patients with genotype 2 or 3 infection.1Ghany M.G. Strader D.B. Thomas D.L. et al.Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (2594) Google Scholar However, PEG-IFN and RBV treatment are associated with many side effects. In registration trials that enrolled highly selected patients, 13%–15% of patients discontinued treatment early and 25%–42% had dose reductions because of adverse events or laboratory abnormalities.1Ghany M.G. Strader D.B. Thomas D.L. et al.Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (2594) Google Scholar, 2Fried M.W. Shiffman M.L. Reddy K.R. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5859) Google Scholar, 3Manns M.P. McHutchison J.G. Gordon S.C. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5871) Google Scholar Because of the poor tolerability, many patients with CHC have elected not to pursue treatment or were not offered treatment. IFN and RBV are also contraindicated in many conditions, such as autoimmune diseases and severe/uncontrolled psychiatric illnesses.1Ghany M.G. Strader D.B. Thomas D.L. et al.Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (2594) Google Scholar Therefore, there is an urgent need for more efficacious and better tolerated therapy for CHC. Advances in the understanding of the hepatitis C virus (HCV) life cycle have led to the development of many promising direct-acting antiviral agents (DAA) in the last decade (Figure 1) .4Lindenbach B.D. Rice C.M. Unravelling hepatitis C virus replication from genome to function.Nature. 2005; 436: 933-938Crossref PubMed Scopus (672) Google Scholar, 5Schlutter J. Therapeutics: new drugs hit the target. Nature 474:S5–S7.Google Scholar Two DAAs—telaprevir and boceprevir—linear inhibitors of NS3/4A serine protease were approved for HCV treatment in the United States in May 2011. Although the approval of boceprevir and telaprevir represents a major breakthrough for the treatment of CHC with SVR rates of 67% and 73%, respectively, in treatment-naïve genotype 1 patients, both drugs require concomitant use of PEG-IFN and RBV to achieve SVR by preventing viral breakthroughs owing to drug resistance.6Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364:2405–2416.Google Scholar, 7Poordad F. McCone Jr, J. Bacon B.R. et al.Boceprevir for untreated chronic HCV genotype 1 infection.N Engl J Med. 2011; 364: 1195-1206Crossref PubMed Scopus (2240) Google Scholar Furthermore, both drugs need to be administered every 8 hours and are associated with additional adverse events. With the development of DAAs directed at multiple targets in the HCV life cycle (Figure 1), the obvious question is, “Are we ready for IFN-free treatment regimens?” Clinical trials involving telaprevir and boceprevir as monotherapy showed a rapid decline in plasma HCV RNA levels within the first day followed by virologic breakthrough as early as day 3.8Reesink H.W. Zeuzem S. Weegink C.J. et al.Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study.Gastroenterology. 2006; 131: 997-1002Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 9Susser S. Welsch C. Wang Y. et al.Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients.Hepatology. 2009; 50: 1709-1718Crossref PubMed Scopus (275) Google Scholar HCV circulates as quasispecies, a mixture of viruses with heterogeneous virus sequences. It has been estimated that preexisting drug resistance variants with 1, 2, 3, and even 4 mutations may be present in most HCV-infected patients, and account for the rapid development of drug resistance on exposure to DAAs. The emergence of clinically relevant, drug-resistant variants depends on several factors, such as the potency of the drug, the genetic barrier to resistance, and the replication fitness of the resistance variants.10Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology;53:1742–1751.Google Scholar, 11Sarrazin C. Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection.Gastroenterology. 2010; 138: 447-462Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar Based on modeling experiments, it has been suggested that an IFN-free regimen that can overcome the presence of variants with 4 drug-resistance mutations requires a combination of ≥3 DAAs with a low genetic barrier to resistance, namely, DAAs that select single amino acid resistant variants.12Rong L, Dahari H, Ribeiro RM, et al. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2:30ra32.Google Scholar Each of these drugs should have potent antiviral activity, possess nonoverlapping resistance profiles, and have limited or manageable drug interactions and minimal adverse events. Furthermore, these drugs should be at similar stages of clinical development so that they can be tested in combination. The first study of combination DAAs, the INFORM-1 study, involved a combination of an NS5B polymerase inhibitor (RG7128) and an NS3/4A inhibitor (danoprevir). This study enrolled treatment-naïve as well as treatment-experienced patients.13Gane E.J. Roberts S.K. Stedman C.A. et al.Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial.Lancet. 2010; 376: 1467-1475Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar At day 14, 13%–63% of treatment-naïve and 25% of null responders had undetectable HCV RNA (Table 1). None of the patients in any treatment arm experienced virologic breakthrough during the 14-day course of IFN-free regimen suggesting that the addition of RG7128, which has a high barrier to resistance, may have prevented the emergence of resistance to danoprevir. PEG-IFN, pegylated interferon; RBV, ribavirin; VR, virologic response. These promising results have encouraged other studies of combination DAAs. The design and preliminary results of these trials are summarized in Table 1. All the studies reported to date enrolled patients with genotype 1 infection only. Results of 1 phase Ib trial of a combination of an NS3/4A protease inhibitor BI201335, an NS5B polymerase inhibitor BI207127, and RBV are published in the current issue of Gastroenterology.14Zuezem S. Asselah T. Angus P. et al.Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.Gastroenterology. 2011; 141: 2047-2055Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar In this study, the authors randomized 34 treatment-naïve CHC patients to either 400 or 600 mg TID BI207127, 120 mg once daily BI201335, and weight-based RBV for 4 weeks. All the patients were switched to triple therapy (BI201335 + PEG-IFN + RBV) from day 29 until week 24 or 48, depending on achievement of extended rapid virologic response. The primary endpoint was day 29 virologic response. All 5 genotype 1b but only 6 of 10 genotype 1a patients in the group that received low-dose protease inhibitor achieved day 29 virologic response (Table 1). One genotype 1a patient had virologic breakthrough on day 22, with variants resistant to both drugs (R155K in NS3 and P495L in NS5B) and another patient had an increase in HCV RNA of 0.7 log10 IU/mL from nadir, but sequencing could not be performed because of low HCV RNA level. Both patients had a decrease in HCV RNA to <100 IU/mL after 10 days of BI201335, PEG-IFN, and RBV. All patients (8 genotype 1a and 8 genotype 1b) in the high-dose protease inhibitor group achieved day 29 virologic response. There were no serious adverse events or adverse event-related premature treatment discontinuations, but decreases in hemoglobin, increases in platelet count, and increases in total bilirubin (predominantly indirect) were observed. These results suggest that an IFN-free regimen comprising 2 DAAs (at the appropriate dose) plus RBV can achieve a very high rate of on-treatment virologic response for up to 4 weeks. However, this study does not address whether IFN-free combination DAAs will result in SVR. It also does not resolve the question of whether RBV contributed to the virologic response and whether RBV reduces relapse with IFN-free regimens. Furthermore, the safety of this combination treatment beyond 4 weeks remains to be determined. Finally, the presence of confirmed a dual drug-resistant variant in 1 patient and a persistent (<1 log) increase in HCV RNA after an initial decline in another patient is concerning, although not surprising, given that both drugs have a low barrier to resistance. Although it has been argued that HCV drug resistance variants are not archived and HCV drug resistance variants become undetectable at a median of 7 months after cessation of telaprevir,15Sullivan J.C. De Meyer S. Bartels D.J. et al.Evolution of treatment-emergent resistant variants in Telaprevir phase 3 clinical trials.J Hepatol. 2011; 54: s4Abstract Full Text PDF PubMed Google Scholar these data were based on population sequencing, which will not detect variants constituting <20% of the viral population and the real test, that is, response upon retreatment with DAA of the same class, has not been performed. Another study of combination DAAs involved an NS3 protease inhibitor (GS-9256) and a non-nucleoside NS5B polymerase inhibitor (tegobuvir) with or without PEG-IFN or RBV. The groups that received triple or quadruple therapy achieved higher rates of virologic response at week 4 compared with the group that received dual therapy (Table 1).16Zeuzem S. Buggisch P. Agarwal K. et al.Dual, triple and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PEGIFN/RBV for up to 28 days in treatment naive genotype 1 HCV subjects.Hepatology. 2010; 52: 400APubMed Google Scholar Thirteen of the 16 patients in the dual therapy group, 2 of 15 in the triple therapy group, and none of 15 in the quadruple therapy group experienced virologic breakthrough. Eleven of the patients in the dual therapy arm with breakthrough had variants resistant to both drugs.16Zeuzem S. Buggisch P. Agarwal K. et al.Dual, triple and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PEGIFN/RBV for up to 28 days in treatment naive genotype 1 HCV subjects.Hepatology. 2010; 52: 400APubMed Google Scholar These findings suggest that addition of RBV may accelerate viral clearance, thereby reducing the risk of resistance to DAAs, at least in the short term. The 4th study evaluated a combination of 2 nucleotide RNA-dependent RNA polymerase inhibitors, a purine (PSI-938) and a pyrimidine (PSI-7977) analog. It showed robust and consistent reduction in HCV RNA in the groups that received combination therapy as well as absence of virologic breakthrough up to week 2 (Table 1).17Lawitz E. Rodriguez-Torres M. et al.Once daily dual-nucleotide combination of PSI-938 and PSI-7977 provides 94% HCV RNA < LOD at day 14: first purine/pyrimidine clinical combination data (the NUCLEAR study).J Hepatol. 2011; 54: S543Abstract Full Text PDF Google Scholar Collectively, these studies showed that a 14- to 28-day course of the right combination of 2 DAAs dosed appropriately can result in a high rate of virologic response with a low rate of drug resistance, but the likelihood of SVR and risk of drug resistance with longer courses of IFN-free DAA only regimens were not addressed. To date, SVR data had been reported in only 1 study of combination DAAs. In this phase II study, genotype-1 null responders were randomized to receive a combination of an NS5A inhibitor (BMS790052) and an NS3 protease inhibitor (BMS650032) alone or together with PEG-IFN and RBV for 24 weeks.18Lok A.S. Gardiner D.F. Lawitz E. et al.Quadruple therapy with BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders.J Hepatol. 2011; 54: s536Abstract Full Text PDF Google Scholar All 11 patients in the dual therapy arm had a rapid decline in HCV RNA, with 7 achieving undetectable HCV RNA; however, 6 experienced virologic breakthrough and had variants resistant to both DAAs selected (Table 1). Although most of these patients responded to rescue therapy with addition of PEG-IFN and RBV, it is unclear if they will achieve SVR. Four of the 11 patients achieved SVR.12Rong L, Dahari H, Ribeiro RM, et al. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2:30ra32.Google Scholar Responses were more encouraging in the quadruple therapy arm with all 10 patients achieving SVR.12Rong L, Dahari H, Ribeiro RM, et al. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2:30ra32.Google Scholar These data showed that addition of 2 DAAs to PEG-IFN and RBV may result in a greater rate of SVR compared with 1 DAA in nonresponders to PEG-IFN and RBV.19Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med;364:2417–2428.Google Scholar More important, it provided proof of concept that SVR can be achieved with combination DAAs only. Similar to Zeuzem et al's study,14Zuezem S. Asselah T. Angus P. et al.Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.Gastroenterology. 2011; 141: 2047-2055Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar all patients with virologic breakthrough in Lok et al's study had genotype 1a infection.18Lok A.S. Gardiner D.F. Lawitz E. et al.Quadruple therapy with BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders.J Hepatol. 2011; 54: s536Abstract Full Text PDF Google Scholar Genotypes 1a and 1b HCV may differ in their susceptibility to DAAs. In addition, a larger number of nucleotide changes are required to create a clinically significant protease inhibitor resistance variant for genotype 1b (higher barrier to resistance) than for genotype 1a HCV.10Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology;53:1742–1751.Google Scholar, 11Sarrazin C. Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection.Gastroenterology. 2010; 138: 447-462Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar For example, 2 nucleotide changes are required to generate the resistance mutation R155K for 1b isolates (CGG→AAG), whereas only 1 nucleotide change is required for 1a isolates (AGG→AAG).19Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med;364:2417–2428.Google Scholar These data indicate that different strategies may be needed for genotype 1a and 1b infection in the era of combination DAAs. Eight years after the first clinical trial of DAA,20Lamarre D. Anderson P.C. Bailey M. et al.An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.Nature. 2003; 426: 186-189Crossref PubMed Scopus (845) Google Scholar development of direct-acting HCV treatments is now moving at a rapid pace with many products showing promising results. IFN-free regimens are no longer a dream, but a reality that may be available in the clinic in the next 5 years. It is possible that some of these regimens will also be RBV free. This will be good news for patients who wish to be treated but have to defer treatment because of contraindications to use of PEG-IFN or RBV, or out of concerns about their ability to tolerate these medications. However, caution must be taken in selecting which DAAs to combine and the appropriate dose and duration of therapy for each HCV genotype and subgenotype to prevent multidrug resistance. Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127, and Ribavirin in Patients With Chronic HCV InfectionGastroenterologyVol. 141Issue 6PreviewTherapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin. Full-Text PDF