Rethinking hepatitis C viral kinetics: Insights into host-virus interactions in ‘difficult-to-treat’ groups and implications for novel treatment approaches

Abstract

Hepatitis C virus (HCV) is a major cause of chronic liver disease, infecting 200 million persons worldwide [[1]McHutchison J.G. Understanding hepatitis C.Am J Manag Care. 2004; 10: S21-S29PubMed Google Scholar]. Without treatment, 20–30% will progress to cirrhosis over 20 years [[2]Consensus N.I.H. Statement on Management of Hepatitis C: 2002.Gastroenterology. 2002; 123: 2082-2099Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar]. Peginterferon-α (pegIFNα) with ribavirin is the best current therapy, but treatment outcomes remain suboptimal in HCV genotype 1-infected patients and in immunocompromised patients such as those with human immunodeficiency virus (HIV) coinfection or those experiencing post-transplant recurrent hepatitis C [3Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales Jr, F.L. 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, 4Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5871) Google Scholar, 5Hadziyannis S. Sette H. Morgan T. Balan V. Diago M. Marcellin P. et al.Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2738) Google Scholar, 6Torriani F.J. Rodriguez-Torres M. Rockstroh J.K. Lissen E. Gonzalez-Garcia J. Lazzarin A. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV patients.N Engl J Med. 2004; 351: 438-450Crossref PubMed Scopus (1186) Google Scholar, 7Chung R.T. Andersen J. Volberding P. Robbins G.K. Liu T. Sherman K.E. et al.Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.N Engl J Med. 2004; 351: 451Crossref PubMed Scopus (838) Google Scholar, 8Triantos C. Samonakis D. Stigliano R. Thalheimer U. Patch D. Burroughs A. Liver transplantation and hepatitis C virus: systematic review of antiviral therapy.Transplantation. 2005; 79: 261-268Crossref PubMed Scopus (40) Google Scholar]. Studies of HCV kinetics during antiviral therapy in these ‘difficult-to-treat’ groups may provide insight into viral-host interactions and assist in developing novel treatment approaches.Viral levels remain stable in chronic HCV infection, representing a dynamic equilibrium between viral production and clearance, with the host innate and adaptive immune systems maintaining this balance [[9]Nguyen T.T. Sedghi-Vaziri A. Wilkes L.B. Mondala T. Pockros P.J. Lindsay K.L. et al.Fluctuations in viral load (HCV RNA) are relatively insignificant in untreated patients with chronic HCV infection.J Viral Hepatitis. 1996; 3: 75-78Crossref PubMed Scopus (98) Google Scholar]. Neumann et al. first described a biphasic decline in viral load with IFN monotherapy [[10]Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. et al.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar]. The first phase decline is rapid, dose-dependent and occurs within the first 24–48 h of therapy. It is thought to reflect IFN's effect on the innate immune response and represents clearance (c) of HCV with its slope dependent on IFN's efficacy (ε) in blocking new virion production or release. A slower second phase decline begins between days 2–14 of treatment, is inversely correlated with the baseline viral load, and is thought to reflect the death of productively infected cells (δ). Large interpatient variations in the slope of this decline have been postulated to reflect differences in cellular immunity. More recently, Herman et al. described a triphasic decline in viral load in some patients on pegIFNα/ribavirin therapy which occurs between days 7–28 of treatment. This third phase has been attributed to a ribavirin-enhanced death of infected cells, possibly resulting from the restoration of a once suppressed cellular immune system upon decline of viremia below a certain threshold [11Hermann E. Lee J.H. Marinos G. Modi M. Zeuzem S. Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegIFN.Hepatology. 2003; 37: 1351-1358Crossref PubMed Scopus (226) Google Scholar, 12Bergmann C. Layden J.E. Levy-Drummer R.S. Layden T.J. Haagmans B.L. Neumann A.U. Clinical implications of a new tri-phasic model of hepatitis C viral kinetics during IFN-alfa therapy.Hepatology. 2001; 33: 345AGoogle Scholar].Based on the results of large randomized trials, the current practice recommendation is to consider discontinuing therapy in patients who do not experience a 100-fold or greater reduction in HCV viral load from baseline by treatment week 12, as these patients have no better than a 3% chance of achieving a sustained virologic response (SVR) [[2]Consensus N.I.H. Statement on Management of Hepatitis C: 2002.Gastroenterology. 2002; 123: 2082-2099Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar]. A practical application of viral kinetics may be to predict which patients are unlikely to achieve SVR even earlier in the course of therapy. In the biphasic model by Neumann et al., a δ of <0.1/day estimated during the first two weeks of therapy correlated with viral undetectability at three months. In Herman's study, a more rapid third phase decay (Mδ>0.25/day) was strongly associated with virologic end-of-treatment response (ETR) and SVR. To obtain Mδ estimates, however, would still require frequent viral load measurements until weeks six to eight of therapy and may therefore be impractical for clinical application.Correlating viral kinetic data with T cell activity provides insight into the interactions between HCV and the host adaptive immune system during antiviral therapy. In this issue of the Journal, Tang et al. studied genotype 1 patients treated with pegIFNα/ribavirin and classified them as fast or slow responders according to the Mδ parameter described by Herman [[13]Tang K.H. Herrmann E. Cooksley H. Tatman N. Chokshi S. Williams R. et al.Relationship between early HCV kinetics and T-cell reactivity in chronic hepatitis C genotype 1 during peginterferon and ribavirin therapy.J Hepatol. 2005; 43: 776-782Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Despite similar baseline characteristics, fast responders exhibited greater antiviral efficacy (ε) and a higher rate of infected cell loss (δ) than slow responders. T cell reactivity increased more frequently in fast responders but only following a significant decrease in viremia. This finding is surprising, as other investigators have postulated that increased T cell reactivity preceded an exaggerated decline in viral load [[14]Kamal S.M. Fehr J. Roesler B. Peters T. Raseneck J.W. Peginterferon alone or with ribavirin enhances HCV-specific CD4+T-helper responses in patients with chronic hepatitis C.Gastroenterology. 2002; 123: 1070-1083Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar]. Consistent with these observations, another recent study found no relationship between a rapid second phase viral decline with a strong systemic antigen-specific T-cell response, supporting the notion that a mechanism other than cellular immunity contributes to the second phase decline [[15]Missale G. Pilli M. Zerbini A. Penna A. Orlandini A. Neumann A. et al.Analysis of peripheral HCV-specific T cell responses associated with rapid viral decline during peg-interferon-alfa-2a and ribavirin therapy (ditto-HCV project).J Hepatol. 2004; 40: S145-S146Abstract Full Text PDF Google Scholar].If a rapid lowering of viremia is a prerequisite for induction of an effective T cell response, the more intriguing question becomes why certain individuals have a better initial response to interferon. The answer may lie in differences in the ability of interferon-α to elicit a favorable innate immune response. HCV has been shown to disrupt the host innate immune response through the action of viral proteins. For instance, the HCV serine protease NS3-4A interferes with retinoic-acid inducible gene I (RIG-I) signaling to the interferon-β promoter, resulting in the inhibition of interferon regulatory factor 3 (IRF-3) [[16]Foy E. Li K. Sumpter R. Loo Y.M. Johnson C.L. Wang C. et al.Control of antiviral defenses through hepatitis C disruption of retinoic acid-inducible gene-1 signaling.Proc Natl Acad Sci USA. 2005; 102: 2986-2991Crossref PubMed Scopus (473) Google Scholar]. NS3-4A also cleaves Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) molecules, ablating Toll-like receptor signaling events that activate IRF-3 independent of RIG-I [[17]Li K. Foy E. Ferreon J.C. Nakamura M. Ferreon A.C.M. Ikeda M. et al.Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor adaptor protein TRIF.Proc Natl Acad Sci USA. 2005; 102: 2992-2997Crossref PubMed Scopus (911) Google Scholar]. When activated, IRF-3 induces the transcription of type I IFNs such as IFN-α. Type I IFNs in turn amplify the antiviral response by inducing hundreds of interferon-stimulated genes such as oligoadenylate synthase (OAS) and double-stranded RNA-activated protein kinase (PKR) to inhibit viral RNA and protein synthesis, respectively. Inhibition of type I IFNs also suppresses subsequent adaptive T cell responses required for elimination of virally infected cells. HCV core protein has also been shown to promote degradation of STAT1 resulting in disruption of the Jak-STAT kinase pathway responsible for interferon signal transduction [[18]Lin W. Choe W.H. Hiasa Y. Kamegaya Y. Blackard J.T. Schmidt E.V. et al.Hepatitis C virus expression suppresses interferon signaling by degrading STAT1.Gastroenterology. 2005; 128: 1034-1041Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. It is conceivable, then, that persons with an unfavorable initial response to IFN may benefit from an antiviral agent such as an NS3-4A inhibitor to lower initial viremia to levels that might permit resurgence of innate and, by extension, adaptive antiviral immunity. In other words, the viral block imposed on the host antiviral response pathway must be overcome in some patients to promote a cellular immune response that ultimately clears virus.It is interesting to compare T cell behavior in chronic HCV infection to that observed in hepatitis B virus (HBV) infection. T cell hyporesponsiveness in chronic HBV infection is likely secondary to the high viral burden and/or antigen load resulting in immune exhaustion and T-cell tolerance similar to what is observed in an experimental model [[19]Rocha B. Grandien A. Freitas A.A. Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance.J Exp Med. 1995; 181: 993-1003Crossref PubMed Scopus (194) Google Scholar]. Treatment with lamivudine causes a rapid enough decline in HBV levels to overcome peripheral T cell tolerance. However, restoration of T cell responsiveness is only transient, as prolonged viral suppression by lamivudine is accompanied by a decline in CD4+T cell reactivity and rebound of hepatitis B viremia [20Boni C. Penna A. Bertoletti A. Lamonaca V. Rapti I. Missale G. et al.Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B.J Hepatol. 2003; : 595-605Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 21Kalams S.A. Goulder P.J. Shea A.K. Jhones N.G. Trocha A.K. Ogg G.S. et al.Levels of human immunodeficiency virus type-1 specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy.J Virol. 1999; 73: 6721-6728PubMed Google Scholar, 22Lederman M.M. Connick E. Landay A. Kuritzkes D.R. Spritzler St, J. Clair M. et al.Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine and ritonavir: results of the AIDS Clinical Trials Group Protocol 315.J Infect Dis. 1998; 178: 70-79Crossref PubMed Scopus (374) Google Scholar].The situation appears to be somewhat different in chronic HCV infection. In the majority of patients who experience a significant increase in HCV-specific CD4+T cell responses after receiving pegIFN/ribavirin, achievement of a durable SVR occurs [[14]Kamal S.M. Fehr J. Roesler B. Peters T. Raseneck J.W. Peginterferon alone or with ribavirin enhances HCV-specific CD4+T-helper responses in patients with chronic hepatitis C.Gastroenterology. 2002; 123: 1070-1083Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar]. Therefore, the use of a novel antiviral agent may only be necessary until cellular responses are induced.HCV-related cirrhosis is the leading indication for liver transplantation[23Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 24Bizollon T. Ducerf C. Trepo C. Multimer D. Hepatitis C virus recurrence after liver transplantation.Gut. 1999; 44: 575-578Crossref PubMed Scopus (54) Google Scholar] but reinfection of the allograft is universal, with progression to cirrhosis occurring in 20% of patients over 5 years [[25]Gane E.J. Portmann B. Naoumov N.V. Smith H.M. Underhill J.A. Donaldson P.T. et al.Long-term outcome of hepatitis C infection after liver transplantation.N Engl J Med. 1996; 334: 815-820Crossref PubMed Scopus (943) Google Scholar]. HIV-infected patients have a high coinfection rate with HCV and experience a rapid progression to cirrhosis often within 10 years [[26]Feray C. Caccamo L. Alexander G.J. Ducot B. Gugenheim J. Casanovas T. et al.European collaborative study on factors influencing outcome after liver transplantation for hepatitis C European Concerted Action on Viral Hepatitis (EUROHEP) Group.Gastroenterology. 1999; 117: 619-625Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar]. In this issue of the Journal, Moreno et al. observed the patterns of virologic decline during pegIFNα/ribavirin therapy in these two groups of immunocompromised patients [[27]Moreno A. Bárcena R. García-Garzón S. Muriel A. Quereda C. Moreno L. et al.HCV clearance and treatment outcome in genotype 1 HCV-monoinfected, HIV-coinfected and liver transplanted patients on peg-IFN-α-2b/ribaririn.J Hepatol. 2005; 43: 783-790Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. The main findings include a lower rate of second phase HCV RNA decline among HIV-coinfected patients throughout therapy compared to monoinfected patients. In contrast, among liver transplant recipients, the initial slower decline in viral load was no longer evident after the second week of therapy.The results of Moreno et al. differ from published observations in several important aspects. First, patients with HIV coinfection did not have higher baseline HCV RNA levels compared to patients with HCV monoinfection as seen in other studies. Sherman et al., in a previous kinetic study, suggested that key HCV kinetic parameters did not differ between monoinfected and coinfected individuals but the latter took 28% longer to clear HCV because of higher baseline levels of viremia [[28]Sherman K.E. Shire N.J. Rouster S.D. Peters M.G. Koziel M.J. Chung R.T. et al.Viral kinetics in hepatitis C or hepatitis C/human immunodeficiency virus-infected patients.Gastroenterology. 2005; 128: 313-327Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar]. Secondly, it is puzzling that although Moreno's patients had lower baseline HCV viral load than those seen in other studies of HIV coinfected patients, these patients still suffered from diminished SVR rates. One possible explanation may lie in the lower CD4+T cell counts in their patients compared with other clinical trials [6Torriani F.J. Rodriguez-Torres M. Rockstroh J.K. Lissen E. Gonzalez-Garcia J. Lazzarin A. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV patients.N Engl J Med. 2004; 351: 438-450Crossref PubMed Scopus (1186) Google Scholar, 7Chung R.T. Andersen J. Volberding P. Robbins G.K. Liu T. Sherman K.E. et al.Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.N Engl J Med. 2004; 351: 451Crossref PubMed Scopus (838) Google Scholar]. It is conceivable that the lower CD4 count is associated with impaired host responses to IFN resulting in a slower second phase decline in HCV viremia. Lastly, viral load measurements were infrequent during the first two weeks of therapy. Therefore, no firm conclusions regarding differences in phase I kinetics or differences in the host innate and/or adaptive immune systems can be drawn.SVR rates of 12.5–36% with pegIFNα/ribavirin therapy have been reported in post-transplant recurrent hepatitis C, but most studies included small numbers of patients and few were randomized [8Triantos C. Samonakis D. Stigliano R. Thalheimer U. Patch D. Burroughs A. Liver transplantation and hepatitis C virus: systematic review of antiviral therapy.Transplantation. 2005; 79: 261-268Crossref PubMed Scopus (40) Google Scholar, 29Ross A.S. Bhan A.K. Pascual M. Thiim M. Benedictc Cosimi A. Chung R.T. Clin Transplant. 2004; 18: 166-173Crossref PubMed Scopus (89) Google Scholar]. Discontinuation rates ranged from 18–63% with dose reduction occurring in up to 88% of patients. Possible reasons for lower SVR rates include higher baseline viremia, bias toward selection of patients who previously failed antiviral therapy pretransplant, and difficulty reaching adequate antiviral doses because of cytopenias and renal insufficiency [[30]Feray C. Gigou M. Samuel D. Paradis V. Wilber J. David M.F. et al.The course of hepatitis C virus infection after liver transplantation.Hepatology. 1994; 20: 1137-1143PubMed Google Scholar]. Serial measurements of viral load by Moreno et al. demonstrated a slower viral decay at week 2 in transplant recipients but similar rates thereafter compared to HCV monoinfected patients. In conjunction with these findings, SVR rates between the two groups were surprisingly comparable. These impressive results may reflect dose preservation and lower levels of immunosuppression. Although no firm conclusions can be made regarding differences in viral kinetics, the results suggest that outcomes similar to those observed in immunocompetent patients may be achievable with maximal medication adherence. However, it remains to be seen whether this degree of dose preservation can be achieved in other transplant centers.In summary, viral kinetic studies can be helpful in understanding variations in response among HCV-infected patients undergoing IFN-based treatment. The observation that lowering initial viral load may be necessary to elicit a strong adaptive immune response offers a potential rationale for early treatment with specific antiviral agents to decrease viral burden and derepress host antiviral immunity. Further kinetic studies in immunocompromised populations will be necessary, as current data are conflicting and remain unable to fully explain inferior treatment outcomes in these patients. Hepatitis C virus (HCV) is a major cause of chronic liver disease, infecting 200 million persons worldwide [[1]McHutchison J.G. Understanding hepatitis C.Am J Manag Care. 2004; 10: S21-S29PubMed Google Scholar]. Without treatment, 20–30% will progress to cirrhosis over 20 years [[2]Consensus N.I.H. Statement on Management of Hepatitis C: 2002.Gastroenterology. 2002; 123: 2082-2099Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar]. Peginterferon-α (pegIFNα) with ribavirin is the best current therapy, but treatment outcomes remain suboptimal in HCV genotype 1-infected patients and in immunocompromised patients such as those with human immunodeficiency virus (HIV) coinfection or those experiencing post-transplant recurrent hepatitis C [3Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales Jr, F.L. 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, 4Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5871) Google Scholar, 5Hadziyannis S. Sette H. Morgan T. Balan V. Diago M. Marcellin P. et al.Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2738) Google Scholar, 6Torriani F.J. Rodriguez-Torres M. Rockstroh J.K. Lissen E. Gonzalez-Garcia J. Lazzarin A. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV patients.N Engl J Med. 2004; 351: 438-450Crossref PubMed Scopus (1186) Google Scholar, 7Chung R.T. Andersen J. Volberding P. Robbins G.K. Liu T. Sherman K.E. et al.Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.N Engl J Med. 2004; 351: 451Crossref PubMed Scopus (838) Google Scholar, 8Triantos C. Samonakis D. Stigliano R. Thalheimer U. Patch D. Burroughs A. Liver transplantation and hepatitis C virus: systematic review of antiviral therapy.Transplantation. 2005; 79: 261-268Crossref PubMed Scopus (40) Google Scholar]. Studies of HCV kinetics during antiviral therapy in these ‘difficult-to-treat’ groups may provide insight into viral-host interactions and assist in developing novel treatment approaches. Viral levels remain stable in chronic HCV infection, representing a dynamic equilibrium between viral production and clearance, with the host innate and adaptive immune systems maintaining this balance [[9]Nguyen T.T. Sedghi-Vaziri A. Wilkes L.B. Mondala T. Pockros P.J. Lindsay K.L. et al.Fluctuations in viral load (HCV RNA) are relatively insignificant in untreated patients with chronic HCV infection.J Viral Hepatitis. 1996; 3: 75-78Crossref PubMed Scopus (98) Google Scholar]. Neumann et al. first described a biphasic decline in viral load with IFN monotherapy [[10]Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. et al.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar]. The first phase decline is rapid, dose-dependent and occurs within the first 24–48 h of therapy. It is thought to reflect IFN's effect on the innate immune response and represents clearance (c) of HCV with its slope dependent on IFN's efficacy (ε) in blocking new virion production or release. A slower second phase decline begins between days 2–14 of treatment, is inversely correlated with the baseline viral load, and is thought to reflect the death of productively infected cells (δ). Large interpatient variations in the slope of this decline have been postulated to reflect differences in cellular immunity. More recently, Herman et al. described a triphasic decline in viral load in some patients on pegIFNα/ribavirin therapy which occurs between days 7–28 of treatment. This third phase has been attributed to a ribavirin-enhanced death of infected cells, possibly resulting from the restoration of a once suppressed cellular immune system upon decline of viremia below a certain threshold [11Hermann E. Lee J.H. Marinos G. Modi M. Zeuzem S. Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegIFN.Hepatology. 2003; 37: 1351-1358Crossref PubMed Scopus (226) Google Scholar, 12Bergmann C. Layden J.E. Levy-Drummer R.S. Layden T.J. Haagmans B.L. Neumann A.U. Clinical implications of a new tri-phasic model of hepatitis C viral kinetics during IFN-alfa therapy.Hepatology. 2001; 33: 345AGoogle Scholar]. Based on the results of large randomized trials, the current practice recommendation is to consider discontinuing therapy in patients who do not experience a 100-fold or greater reduction in HCV viral load from baseline by treatment week 12, as these patients have no better than a 3% chance of achieving a sustained virologic response (SVR) [[2]Consensus N.I.H. Statement on Management of Hepatitis C: 2002.Gastroenterology. 2002; 123: 2082-2099Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar]. A practical application of viral kinetics may be to predict which patients are unlikely to achieve SVR even earlier in the course of therapy. In the biphasic model by Neumann et al., a δ of <0.1/day estimated during the first two weeks of therapy correlated with viral undetectability at three months. In Herman's study, a more rapid third phase decay (Mδ>0.25/day) was strongly associated with virologic end-of-treatment response (ETR) and SVR. To obtain Mδ estimates, however, would still require frequent viral load measurements until weeks six to eight of therapy and may therefore be impractical for clinical application. Correlating viral kinetic data with T cell activity provides insight into the interactions between HCV and the host adaptive immune system during antiviral therapy. In this issue of the Journal, Tang et al. studied genotype 1 patients treated with pegIFNα/ribavirin and classified them as fast or slow responders according to the Mδ parameter described by Herman [[13]Tang K.H. Herrmann E. Cooksley H. Tatman N. Chokshi S. Williams R. et al.Relationship between early HCV kinetics and T-cell reactivity in chronic hepatitis C genotype 1 during peginterferon and ribavirin therapy.J Hepatol. 2005; 43: 776-782Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Despite similar baseline characteristics, fast responders exhibited greater antiviral efficacy (ε) and a higher rate of infected cell loss (δ) than slow responders. T cell reactivity increased more frequently in fast responders but only following a significant decrease in viremia. This finding is surprising, as other investigators have postulated that increased T cell reactivity preceded an exaggerated decline in viral load [[14]Kamal S.M. Fehr J. Roesler B. Peters T. Raseneck J.W. Peginterferon alone or with ribavirin enhances HCV-specific CD4+T-helper responses in patients with chronic hepatitis C.Gastroenterology. 2002; 123: 1070-1083Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar]. Consistent with these observations, another recent study found no relationship between a rapid second phase viral decline with a strong systemic antigen-specific T-cell response, supporting the notion that a mechanism other than cellular immunity contributes to the second phase decline [[15]Missale G. Pilli M. Zerbini A. Penna A. Orlandini A. Neumann A. et al.Analysis of peripheral HCV-specific T cell responses associated with rapid viral decline during peg-interferon-alfa-2a and ribavirin therapy (ditto-HCV project).J Hepatol. 2004; 40: S145-S146Abstract Full Text PDF Google Scholar]. If a rapid lowering of viremia is a prerequisite for induction of an effective T cell response, the more intriguing question becomes why certain individuals have a better initial response to interferon. The answer may lie in differences in the ability of interferon-α to elicit a favorable innate immune response. HCV has been shown to disrupt the host innate immune response through the action of viral proteins. For instance, the HCV serine protease NS3-4A interferes with retinoic-acid inducible gene I (RIG-I) signaling to the interferon-β promoter, resulting in the inhibition of interferon regulatory factor 3 (IRF-3) [[16]Foy E. Li K. Sumpter R. Loo Y.M. Johnson C.L. Wang C. et al.Control of antiviral defenses through hepatitis C disruption of retinoic acid-inducible gene-1 signaling.Proc Natl Acad Sci USA. 2005; 102: 2986-2991Crossref PubMed Scopus (473) Google Scholar]. NS3-4A also cleaves Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) molecules, ablating Toll-like receptor signaling events that activate IRF-3 independent of RIG-I [[17]Li K. Foy E. Ferreon J.C. Nakamura M. Ferreon A.C.M. Ikeda M. et al.Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor adaptor protein TRIF.Proc Natl Acad Sci USA. 2005; 102: 2992-2997Crossref PubMed Scopus (911) Google Scholar]. When activated, IRF-3 induces the transcription of type I IFNs such as IFN-α. Type I IFNs in turn amplify the antiviral response by inducing hundreds of interferon-stimulated genes such as oligoadenylate synthase (OAS) and double-stranded RNA-activated protein kinase (PKR) to inhibit viral RNA and protein synthesis, respectively. Inhibition of type I IFNs also suppresses subsequent adaptive T cell responses required for elimination of virally infected cells. HCV core protein has also been shown to promote degradation of STAT1 resulting in disruption of the Jak-STAT kinase pathway responsible for interferon signal transduction [[18]Lin W. Choe W.H. Hiasa Y. Kamegaya Y. Blackard J.T. Schmidt E.V. et al.Hepatitis C virus expression suppresses interferon signaling by degrading STAT1.Gastroenterology. 2005; 128: 1034-1041Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. It is conceivable, then, that persons with an unfavorable initial response to IFN may benefit from an antiviral agent such as an NS3-4A inhibitor to lower initial viremia to levels that might permit resurgence of innate and, by extension, adaptive antiviral immunity. In other words, the viral block imposed on the host antiviral response pathway must be overcome in some patients to promote a cellular immune response that ultimately clears virus. It is interesting to compare T cell behavior in chronic HCV infection to that observed in hepatitis B virus (HBV) infection. T cell hyporesponsiveness in chronic HBV infection is likely secondary to the high viral burden and/or antigen load resulting in immune exhaustion and T-cell tolerance similar to what is observed in an experimental model [[19]Rocha B. Grandien A. Freitas A.A. Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance.J Exp Med. 1995; 181: 993-1003Crossref PubMed Scopus (194) Google Scholar]. Treatment with lamivudine causes a rapid enough decline in HBV levels to overcome peripheral T cell tolerance. However, restoration of T cell responsiveness is only transient, as prolonged viral suppression by lamivudine is accompanied by a decline in CD4+T cell reactivity and rebound of hepatitis B viremia [20Boni C. Penna A. Bertoletti A. Lamonaca V. Rapti I. Missale G. et al.Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B.J Hepatol. 2003; : 595-605Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 21Kalams S.A. Goulder P.J. Shea A.K. Jhones N.G. Trocha A.K. Ogg G.S. et al.Levels of human immunodeficiency virus type-1 specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy.J Virol. 1999; 73: 6721-6728PubMed Google Scholar, 22Lederman M.M. Connick E. Landay A. Kuritzkes D.R. Spritzler St, J. Clair M. et al.Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine and ritonavir: results of the AIDS Clinical Trials Group Protocol 315.J Infect Dis. 1998; 178: 70-79Crossref PubMed Scopus (374) Google Scholar].The situation appears to be somewhat different in chronic HCV infection. In the majority of patients who experience a significant increase in HCV-specific CD4+T cell responses after receiving pegIFN/ribavirin, achievement of a durable SVR occurs [[14]Kamal S.M. Fehr J. Roesler B. Peters T. Raseneck J.W. Peginterferon alone or with ribavirin enhances HCV-specific CD4+T-helper responses in patients with chronic hepatitis C.Gastroenterology. 2002; 123: 1070-1083Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar]. Therefore, the use of a novel antiviral agent may only be necessary until cellular responses are induced. HCV-related cirrhosis is the leading indication for liver transplantation[23Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 24Bizollon T. Ducerf C. Trepo C. Multimer D. 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In this issue of the Journal, Moreno et al. observed the patterns of virologic decline during pegIFNα/ribavirin therapy in these two groups of immunocompromised patients [[27]Moreno A. Bárcena R. García-Garzón S. Muriel A. Quereda C. Moreno L. et al.HCV clearance and treatment outcome in genotype 1 HCV-monoinfected, HIV-coinfected and liver transplanted patients on peg-IFN-α-2b/ribaririn.J Hepatol. 2005; 43: 783-790Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. The main findings include a lower rate of second phase HCV RNA decline among HIV-coinfected patients throughout therapy compared to monoinfected patients. In contrast, among liver transplant recipients, the initial slower decline in viral load was no longer evident after the second week of therapy. The results of Moreno et al. differ from published observations in several important aspects. First, patients with HIV coinfection did not have higher baseline HCV RNA levels compared to patients with HCV monoinfection as seen in other studies. Sherman et al., in a previous kinetic study, suggested that key HCV kinetic parameters did not differ between monoinfected and coinfected individuals but the latter took 28% longer to clear HCV because of higher baseline levels of viremia [[28]Sherman K.E. Shire N.J. Rouster S.D. Peters M.G. Koziel M.J. Chung R.T. et al.Viral kinetics in hepatitis C or hepatitis C/human immunodeficiency virus-infected patients.Gastroenterology. 2005; 128: 313-327Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar]. Secondly, it is puzzling that although Moreno's patients had lower baseline HCV viral load than those seen in other studies of HIV coinfected patients, these patients still suffered from diminished SVR rates. One possible explanation may lie in the lower CD4+T cell counts in their patients compared with other clinical trials [6Torriani F.J. Rodriguez-Torres M. Rockstroh J.K. Lissen E. Gonzalez-Garcia J. Lazzarin A. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV patients.N Engl J Med. 2004; 351: 438-450Crossref PubMed Scopus (1186) Google Scholar, 7Chung R.T. Andersen J. Volberding P. Robbins G.K. Liu T. Sherman K.E. et al.Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.N Engl J Med. 2004; 351: 451Crossref PubMed Scopus (838) Google Scholar]. It is conceivable that the lower CD4 count is associated with impaired host responses to IFN resulting in a slower second phase decline in HCV viremia. Lastly, viral load measurements were infrequent during the first two weeks of therapy. Therefore, no firm conclusions regarding differences in phase I kinetics or differences in the host innate and/or adaptive immune systems can be drawn. SVR rates of 12.5–36% with pegIFNα/ribavirin therapy have been reported in post-transplant recurrent hepatitis C, but most studies included small numbers of patients and few were randomized [8Triantos C. Samonakis D. Stigliano R. Thalheimer U. Patch D. Burroughs A. Liver transplantation and hepatitis C virus: systematic review of antiviral therapy.Transplantation. 2005; 79: 261-268Crossref PubMed Scopus (40) Google Scholar, 29Ross A.S. Bhan A.K. Pascual M. Thiim M. Benedictc Cosimi A. Chung R.T. Clin Transplant. 2004; 18: 166-173Crossref PubMed Scopus (89) Google Scholar]. Discontinuation rates ranged from 18–63% with dose reduction occurring in up to 88% of patients. Possible reasons for lower SVR rates include higher baseline viremia, bias toward selection of patients who previously failed antiviral therapy pretransplant, and difficulty reaching adequate antiviral doses because of cytopenias and renal insufficiency [[30]Feray C. Gigou M. Samuel D. Paradis V. Wilber J. David M.F. et al.The course of hepatitis C virus infection after liver transplantation.Hepatology. 1994; 20: 1137-1143PubMed Google Scholar]. Serial measurements of viral load by Moreno et al. demonstrated a slower viral decay at week 2 in transplant recipients but similar rates thereafter compared to HCV monoinfected patients. In conjunction with these findings, SVR rates between the two groups were surprisingly comparable. These impressive results may reflect dose preservation and lower levels of immunosuppression. Although no firm conclusions can be made regarding differences in viral kinetics, the results suggest that outcomes similar to those observed in immunocompetent patients may be achievable with maximal medication adherence. However, it remains to be seen whether this degree of dose preservation can be achieved in other transplant centers. In summary, viral kinetic studies can be helpful in understanding variations in response among HCV-infected patients undergoing IFN-based treatment. The observation that lowering initial viral load may be necessary to elicit a strong adaptive immune response offers a potential rationale for early treatment with specific antiviral agents to decrease viral burden and derepress host antiviral immunity. Further kinetic studies in immunocompromised populations will be necessary, as current data are conflicting and remain unable to fully explain inferior treatment outcomes in these patients.