Hepatitis C Virus Combination Therapy Research Articles

Glecaprevir and pibrentasvir combination therapy for hepatitis C virus-infected Japanese patients on hemodialysis

BackgroundIt remains unclear whether hepatitis C virus (HCV)-infected Japanese patients on hemodialysis (HD) have an altered viral response to glecaprevir (GLE) and pibrentasvir (PIB) combination therapy and whether this treatment is safe for this patient group. Therefore, we investigated the characteristics associated with virological response to GLE and PIB combination therapy for HCV in Japanese patients undergoing HD. This study aimed to evaluate the safety and efficacy of GLE and PIB combination therapy in HCV-infected Japanese patients on HD.MethodsThis multicenter, single-arm, open-label, and prospective study was conducted at four centers in Japan and enrolled Japanese patients with chronic HCV genotype 1b, 2a, and 2b infections. Enrolled patients received 300 mg GLE in combination with 120 mg PIB once daily for either 8 or 12 weeks. The primary endpoint of this trial was the rate of sustained virological response at 12 weeks after treatment (SVR12). Furthermore, pharmacological effects and adverse events associated with combination therapy were evaluated.ResultsA total of 18 HD patients with HCV infection were enrolled in this study. Of these patients, 17 (94.4%) achieved SVR12. Among patients receiving combination therapy for 8 weeks, only one experienced a virological relapse at week 12 after the end of treatment. Despite the absence of treatment-related deaths, adverse events were observed in 9 patients (50.0%) during treatment. The most frequent adverse event was pruritus, which occurred in 7 patients (38.9%).ConclusionsGLE and PIB combination therapy was effective and tolerable in Japanese HD patients with chronic HCV genotype 1b, 2a, and 2b infections.Trial registrationThis study was registered at the UMIN Clinical Trials Registry as UMIN000029781 (registered 21 November 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034026).

Discovery and preclinical development of dasabuvir for the treatment of hepatitis C infection

ABSTRACTIntroduction: Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality. Positively, the introduction of new directly-acting antivirals (DAAs) have led to dramatic improvements in response rates to antiviral therapy. Furthermore, newer generations of DAAs have demonstrated better safety profiles as well as efficacy than older generations. Current treatment recommendations are based on different combinations of DAAs. Current combination therapies rely on agents that target the different steps of viral replication by using different molecules from various DAAs families.Areas covered: In this review, the authors summarize data from of one of the recently developed NS5B polymerase inhibitors, dasabuvir, formerly known as ABT-333. Herein, the authors discuss the drug discovery data for dasabuvir including data from preclinical, toxicological resistance studies. The authors also review dasabuvir’s clinical efficacy across various clinical challenges, in addition to its limitations in clinical practice.Expert opinion: Dasabuvir represents an important medical advance when used as a combination therapy for HCV. Unfortunately, it does present limitations like low genotypic coverage and further research is still required to address some of the lingering issues

Virological response to daclatasvir and asunaprevir combination therapy for chronic hepatitis C virus genotype 1b infection in dialysis patients: a prospective, multicenter study

BackgroundThe introduction of direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection in patients undergoing hemodialysis (HD) has improved sustained virological response (SVR) rates. Our aim was to assess the characteristics of the virological response to daclatasvir (DCV) and asunaprevir (ASV) combination therapy for HCV in HD patients.MethodsA multicenter prospective study was conducted at eight centers in Japan. Patients on HD with chronic genotype 1b HCV infections were orally administered DCV and ASV for 24 weeks at doses of a 60-mg capsule once daily and a 100-mg tablet twice daily, respectively. The primary endpoint of this trial was the proportion of patients with a sustained virological response at 24 weeks after the treatment ended (SVR24). We also investigated the characteristics associated with the virological response to combination therapy.ResultsThirty patients were enrolled in this study, and the proportion that achieved an SVR24 after treatment was 83.3% (25/30). Virological failure was observed in 4 patients (13.3%). Two exhibited virological breakthrough at weeks 16 and 20 of drug administration, and viral relapse occurred in 2 patients at weeks 4 and 8 after the end of treatment. Virological failure was defined as HCV-RNA levels exceeding 5.5 log10 IU/mL, and resistance-associated variants (RAVs) NS5A-L31M/V and Y93H were not exhibited at baseline.ConclusionsDCV and ASV therapy for chronic HCV on HD was significantly effective. Most importantly, patients with the low viral loads undergoing HD demonstrated a higher response to combination therapy regardless of RAV.Trial registrationUMIN Clinical Trials Registry UMIN000016181

Genetic Variation in Interleukin-28B and Response to Peg-IFNα-2a/RBV Combination Therapy in Patients with Hepatitis C Virus Infection

Background: The hepatitis C virus (HCV) infection is one of the major causes of progressive liver diseases worldwide. Despite the new treatments for HCV infection, antiviral therapy with a combination of pegylated interferon-α 2a plus ribavirin (Peg-IFNα-2a/RBV) is still used in developing countries. Objectives: The aim of the current study was to determine the relationship between rs12979860 polymorphism in the interleukin 28B gene (IL28B) and response to Peg-IFNα-2a/RBV combination therapy in Azerbaijani patients with chronic HCV infection. Methods: A total of 72 Azerbaijani patients with established chronic HCV-1b took part in this cross-sectional study between January 2010 and September 2015. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) of the patients and the rs12979860 single nucleotide polymorphism was diagnosed by polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Results: The mean age of the patients was 36.9 ± 12.4 (range of 27 - 57 years) and 42 (58.3%) out of 72 were male. Concerning the IL28B polymorphism in rs12979860, the results indicated the presence of CC, CT, and TT genotypes in 24 (33.3%), 42 (58.3%), and 6 (8.3%) patients, respectively. There was a significant association between IL28B genotypes and response to HCV combination therapy with peg-IFNα-2a/RBV (P = 0.001). Conclusions: The results of this study indicate that the rs12979860 CC genotype of IL28B was associated with a response to Peg-IFNα-2a/RBV combination therapy in Azerbaijani patients with HCV-1b infection. Therefore, host genetics may be useful in predicting the response to hepatitis C treatment.

Chronic kidney disease: Treatment of hepatitis C virus infection in patients with CKD.

Treatment of hepatitis C virus (HCV) infection in patients with chronic kidney disease (CKD) can be challenging. Now, data from the phase III C-SURFER study show that grazoprevir and elbasvir — a new all-oral combination therapy for HCV — is safe and effective in patients with stage 4–5 CKD.

Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A.

It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.

Monitoring renal function during combination therapy with telaprevir in HIV/HCV co-infected patients with advanced/fibrosis cirrhosis.

IntroductionTelaprevir (TVR) plus peg interferon (PEG-IFN) and ribavirin (RBV) substantially increase treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection but data about its safety in HIV patients with cirrhosis are lacking. Our purpose was to evaluate estimated Glomerular Filtration Rates (eGFR) variations during combination therapy in a difficult-to-treat HIV/HCV population with advanced fibrosis/cirrhosis through three different scores commonly used in clinical practice: CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), Modification of Diet in Renal Disease (MDRD) scores (that consider gender, ethnicity, age, serum creatinine level [SCL]) and MDRD 6 variable (that considers the previous parameters plus blood urea nitrogen and serum albumin). Second objective was to identify any association between creatinin clearance and haemoglobin (Hb) variation during combination therapy.Materials and MethodsWe conducted an observational retrospective study including 18 HIV/HCV patients attending our clinic who started combination therapy for HCV, including in the analysis the first 16 weeks of therapy. Treatment included TVR 1125 mg BID (twice a day) for 12 weeks, PEG-IFN α-2a 180 mcg QW and RBV daily dose according to body weight (800 mg in individuals <60 kg; 1000 mg in individuals 60–75 kg; 1200 mg in individuals >75 kg). Advanced fibrosis was defined as Metavir score=F3 or Ishak 3–4 and cirrhosis was defined as Metavir score F4 or Ishak 5–6 assessed by liver biopsy or transient elastography respectively. P per trend were assessed to evaluate any change of SCL and eGFR (according to different formulas). Multilevel linear regression analysis was performed to estimate factors associated with reduction of Hb.ResultsBaseline characteristics and HCV virological responses were collected. Figure 1 shows median SCL and eGFR trends across follow-up period: SCR p-per-trend was 0.28, for CKD-EPI was 0.50, for MDRD was 0.48, for MDRD-6 variables was 0.27. Hb trend was also assessed and a significant decrease of Hb across follow-up (p per trend <0.001) was noted. Multilevel regression analysis found an association between SCL and Hb change, after adjustment for age, sex, basal BMI, tenofovir exposure and proteinuria (assessed at baseline) as shown in Table 1. ConclusionsIn our experience, combination therapy with TPV in cirrhotic HIV-HCV patients did not significantly affect renal function. As expected, Hb levels decreased during treatment and it is likely related to RBV exposure. In multivariable analysis, reduction of Hb appeared to be related to SCL higher levels, thus suggesting even a mild decrease of renal function.

Association between IPTA gene polymorphisms and hematological abnormalities in hepatitis C virus-infected patients receiving combination therapy.

Background/AimsHematological abnormalities during hepatitis C virus (HCV) combination therapy with pegylated interferon α and ribavirin often necessitate dose reduction. Variants of the ITPA gene have been reported to protect against anemia during the early stages of HCV combination treatments but have also been associated with larger decreases in platelet counts. We aimed to identify the association between specific ITPA gene polymorphisms and hematological abnormalities in patients undergoing HCV combination therapy.MethodsIn this retrospective study, 175 patients treated with HCV combination therapy were enrolled at St. Martin De Porres Hospital in Taiwan between 2006 and 2012. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs1127354, rs6051702) were genotyped. We investigated the effect of ITPA gene variants on hematological abnormalities during the therapy.ResultsThe ITPA rs1127354 minor variants were significantly associated with protection against anemia at week 4 (p=1.86×10−6) and with more severe decreases in platelet counts during HCV combination therapy. SNP rs6051702 was not associated with the hemoglobin decline to >3 g/dL at week 4 in our study (p=0.055).ConclusionsThe ITPA SNP rs1127354 is a useful predictor of ribavirin-induced anemia in Taiwanese patients and may be related to more severe decreases in platelet counts during the early stage of HCV combination therapy.

Mutations in the NS5A gene of hepatitis C virus subtype 1b and response to peg-IFNα-2a/RBV combination therapy in Azerbaijani patients.

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease throughout the world. The presence of mutations in different regions of the HCV subtype 1b (HCV-1b) nonstructural 5A (NS5A) gene may be associated with response to interferon therapy. This study evaluated whether amino acid substitutions in the NS5A protein of HCV-1b correlated with response to pegylated interferon alfa-2a (peg-IFNα-2a) and ribavirin (RBV) combination therapy in Azerbaijani patients. From March 2010 to April 2014, a total of 34 chronically HCV-1b-infected Azerbaijani patients were enrolled in this prospective study. After extraction of RNA from plasma specimens, the entire sequences of the NS5A gene of HCV was amplified by reverse transcription nested polymerase chain reaction (RT-nested PCR), and the PCR products were sequenced subsequently. The data that were obtained revealed that there was no correlation between the response to HCV combination therapy and the number of mutations in the NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 regions of HCV. It also was found that changes from isoleucine to valine (I2252 V), aspartic acid to glutamic acid (D2257), arginine to lysine (R2269 K), and arginine to glycine in NS5A-PKRBD and from glycine to glutamic acid (G2379E) in the NS5A-V3 region were not associated with HCV treatment outcome. This study showed that genetic variability in the NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 regions is not a predictive factor of SVR, NR or relapse in HCV genotype1b treated with peg-IFNα-2a/RBV combination therapy.

Oral conditions associated with Hepatitis C virus infection

Hepatitis C virus (HCV) infection in more than 170 million chronically infected patients with no developed preventive vaccine is a globally important issue. In addition to expected hepatic manifestations, a number of extrahepatic manifestations, such as mixed cryoglobulinemia, glomerulonephritis, polyarteritis nodosa, rashes, renal disease, neuropathy, and lymphoma, have been reported following HCV infection, which are believed to be influenced by the virus or the host immune response. HCV combination therapy with pegylated interferon and ribavirin might be associated with side effects as well. The association of HCV with special oral conditions has also been reported recurrently; the mechanism of most of which remains unclear. This article reviews the association of HCV infection with some of the oral conditions such as oral health, Sjogren's syndrome, lichen planus and oral cancer.

Gene polymorphisms in chronic C virus hepatitis

Abstract The hepatitis C virus (HCV) is a major public health problem in the world. Current standard of treatment with pegylated interferonalpha (PegIFN) and ribavirin (RBV) achieves a sustained virological response in 40–50% of those infected with genotype 1. Host genotyping studies have the potential to identify genes and therefore pathogenic processes important in viral clearance, enabling a rational approach to design new drugs, and to identify patients who will most likely respond to current and new treatments. The polymorphisms in IL28B are highly predictive of response to PegIFN and RBV combination therapy for HCV genotype 1 infection. Possibly combined to other baseline features, such as the measurements of IP-10 and HLA-C as well as on-treatment viral kinetics, should allow for improved prediction of response to HCV combination therapy. Host genetics have significant role in spontaneous clearance of HCV. Genotyping of this polymorphism will aid clinical decision making for both current standard of care and potentially for the integration of other agents in the future, providing an opportunity for clinicians to individualize treatment regimens for hepatitis C patients.

IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV

The aim of this study was to investigate the utility of baseline plasma interferon-gamma inducible protein-10 (IP-10) levels in human immunodeficiency virus (HIV)-hepatitis C virus (HCV) co-infected patients. Baseline IP-10 was monitored during HCV combination therapy in 21 HIV-HCV co-infected patients (HCV genotype 1 (n = 16), 2 (n = 2), and 3 (n = 3)). Lower baseline IP-10 was significantly associated with a rapid decline in HCV RNA, in particular with the first phase reduction, and similar cut-off levels (< 150 and > 600 pg/ml) as in HCV mono-infected patients apply. In conclusion, baseline IP-10 < 150 pg/ml is predictive of a favourable viral response to HCV therapy in HIV-HCV co-infected patients, and may thus be useful in encouraging such difficult-to-treat patients to initiate therapy.

Evaluation of depression as a risk factor for treatment failure in chronic hepatitis C

The Major Depression Inventory (MDI) was used to estimate the value of routine medical interviews in diagnosing major depression among patients receiving peginterferon alfa-2a and ribavirin therapy for chronic hepatitis C virus (HCV) infection (n = 325). According to criteria from the MDI and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 19 patients (6%) had major depression at baseline. An additional 114 (37%) developed depression while on HCV combination therapy, with baseline MDI score and female sex independently predicting the emergence of major depression during treatment in a multivariate analysis. Only 36 (32%) of the 114 patients developing major depression according to MDI/DSM-IV criteria were correctly diagnosed during routine medical interviews. The emergence of major depression frequently led to premature discontinuation of peginterferon/ribavirin therapy, and an on-treatment MDI score increment exceeding 30 points (i.e., a validated marker of idiopathic DSM-IV major depression) was correlated with impaired outcome of HCV therapy (P = 0.02). This difference was even more pronounced among patients with an on-treatment increase in MDI score greater than 35 points (P = 0.003). We conclude that (1) depressive symptoms among patients undergoing HCV therapy are commonly overlooked by routine clinical interviews, (2) the emergence of depression compromises the outcome of HCV therapy, and (3) the MDI scale may be useful in identifying patients at risk for treatment-induced depression.

Continuing evidence to support the role of early kinetic monitoring in predicting sustained viral response for HIV/HCV co-infected patients

Background Hepatitis C virus (HCV) is a major cause of chronic liver disease and requirement for liver transplantation. Shared acquisition risk factors mean that HIV co-infection is common. Co-infection has been shown to lead to faster progression of liver fibrosis. Combination therapy for HCV with pegylated interferon-alpha and ribavirin (pegIFN/ RBV) results in comparable sustained virological response (SVR) rates for HIV/HCV co-infected patients vs. HCV mono-infected patients. Monitoring early viral kinetics, specifically baseline HCV viral load and week 4 HCV PCR can allow tailoring of treatment duration for specific patients and give prognostic information regarding primary treatment success.

Early Virologic Failure in HIV-Coinfected Hepatitis C Patients Treated With the Peginterferon-Ribavirin Combination

Early Virologic Failure in HIV-Coinfected Hepatitis C Patients Treated With the Peginterferon-Ribavirin Combination

Management of Hematologic and Neuropsychiatric Side Effects in Treatment of Chronic HCV Infection

An estimated 4 million persons are infected with hepatitis C, making it the most common chronic viral infection in the United States. Combination antiviral therapy with pegylated interferon alpha 2a (α-2a) or alpha 2b (α-2b) with ribavirin (RBV) (combination therapy) has become the mainstay of current hepatitis C virus (HCV) therapy. Control of treatment-related side effects is crucial to successful completion of combination therapy. This article outlines these therapies and reviews the literature detailing appropriate strategies for symptom management of the most common hematologic and neuropsychiatric side effects experienced with combination therapy for HCV. An estimated 4 million persons are infected with hepatitis C, making it the most common chronic viral infection in the United States. Combination antiviral therapy with pegylated interferon alpha 2a (α-2a) or alpha 2b (α-2b) with ribavirin (RBV) (combination therapy) has become the mainstay of current hepatitis C virus (HCV) therapy. Control of treatment-related side effects is crucial to successful completion of combination therapy. This article outlines these therapies and reviews the literature detailing appropriate strategies for symptom management of the most common hematologic and neuropsychiatric side effects experienced with combination therapy for HCV.

Cost-effectiveness of hematologic growth factors for anemia occurring during hepatitis C combination therapy

In hepatitis C virus (HCV)-infected patients who develop anemia during combination therapy, erythropoietic growth factors maintain higher drug treatment levels compared to ribavirin dose reduction, which may lead to an increase in treatment response rates. This study estimated the cost-effectiveness of growth factor therapy in maintaining anemic HCV-infected patients on target drug levels during combination therapy. A decision analysis using a Markov model was developed with 7 health states: Sustained viral response, chronic HCV, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Data sources included population-based studies of growth factor therapy, previously published estimates of costs and natural history of hepatitis C, and recent prospective studies. Our reference case was a 45-year-old Caucasian man with HCV infection (genotype 1, 2, or 3) who developed anemia while undergoing combination therapy with ribavirin and pegylated interferon. We compared growth factor injections (darbepoetin alpha or epoetin alpha) during combination therapy with standard ribavirin dose reduction. Compared to a ribavirin dose reduction strategy, the cost of darbepoetin per additional quality-adjusted life-year was 34,793 dollars for genotype 1 and 33,832 dollars for genotypes 2 or 3 versus 60,600 dollars and 64,311 dollars for epoetin. For all genotypes, the results were sensitive to changes in the cure rates of HCV therapy, the utility of chronic HCV, the costs of growth factors, and the age at which therapy is begun. In conclusion, use of erythropoietic growth factors, specifically darbepoetin, for patients with anemia occurring during HCV combination therapy appears to be cost-effective for genotypes 1, 2, or 3.

Management and Treatment of Hepatitis C Virus Infection in HIV-Infected Adults: Recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office1

Nearly 40% of human immunodeficiency virus- (HIV-) infected veterans on highly active antiretroviral therapy (HAART) in the United States are coinfected with hepatitis C virus (HCV). With the increased survival due to declining opportunistic infections as a result of HAART, HCV-associated liver disease has become a leading cause of death in HIV-infected individuals. HCV infection has been shown to lead to rapid progression of HCV-related liver disease in HIV infection. Results from recent clinical trials in HIV/HCV-coinfected patients show improved response rates using pegylated formulations of interferon plus ribavirin when compared to standard interferon plus ribavirin. However, the treatment of HCV in HIV/HCV-coinfected patients can be complicated by the hepatotoxic and myelosuppressive effects of HIV therapy and HIV infection itself. Prior to initiating HCV therapy, HIV therapy should be optimized by improving immune suppression and avoiding specific antiretroviral drugs that may cause hepatotoxicity and myelosuppression. In the event of treatment-related neutropenia or anemia during HCV therapy, the use of growth factors should be considered to maximize sustained virologic response to HCV therapy. In HIV/HCV-coinfected patients with end-stage liver disease, liver transplantation is being investigated and shows promise as a potential therapeutic option. With the recent advances in the treatment of HCV in HIV/HCV-coinfected individuals, all HIV/HCV-coinfected patients eligible for HCV treatment should be evaluated for HCV combination therapy with careful consideration of their HIV disease.

Management of hepatitis C in HIV-infected patients

As the survival of HIV-infected patients has been lengthening over the past 10 years as a consequence of effective antiretroviral therapy, hepatitis C virus (HCV) coinfection has emerged as a major cause of morbidity and mortality in this population. HCV/HIV coinfection is associated with accelerated progression of liver disease, untoward effects on the immunologic and virologic response to antiretroviral medications, and possibly with a more aggressive course of HIV disease. The results of major trials of combination therapy for HCV in coinfected patients have clearly established the combination of pegylated interferon-alpha with ribavirin as the treatment of choice in this population. However, the effectiveness and tolerability of this regimen remains suboptimal, particularly in patients with genotype 1 HCV infection. This paper reviews the impact of HCV coinfection in HIV-infected patients, outlines current concepts on management and antiviral treatment, and discusses some of the newer agents, currently in the therapeutic pipeline, that are directed against novel molecular targets.

The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection

Hepatitis C virus (HCV) readily sets up a persistent infection and is a major cause of liver disease worldwide. Interferon alfa and ribavirin therapy lead to sustained clearance of virus in 31% to 64% of patients with type 1 and non–type 1 genotypes, respectively. It is not clear to what extent these drugs act directly to reduce HCV replication, or indirectly via host immune responses, and what evoked immune responses are associated with clinical outcome. We have examined prospectively 15 patients with chronic HCV infection before, during, and after combination therapy. Quantitative assays for HCV antigen–specific CD4+ and CD8+ T-cell responses, and flow cytometric assays for analysis of the phenotype of T cells, in addition to viral sequencing of core protein, were performed throughout the treatment and follow-up period over 18 months. We found enhancement of proliferative T-cell responses during therapy. Proliferative responses are strikingly heterogeneous in terms of specificity, kinetics, and magnitude. Proliferative responses are often not associated with interferon-γ release. T-cell responses are rarely sustained irrespective of treatment outcome and this is not due to the evolution of new immune escape variants. T-cell responses tend to peak late in the course of treatment. In conclusion, combination therapy for HCV has a transient effect on host virus–specific T cells in the blood. Induction of sustained T-cell responses may require additional immune modulation later in therapy. (H EPATOLOGY 2002;36:743-754.)