Efficacy and Tolerability of Telaprevir for Chronic Hepatitis Virus C Genotype 1 Infection: A Meta-Analysis

Background

Chronic hepatitis C virus (HCV) infection is one of the leading causes of hepatic cirrhosis and hepatocellular carcinoma, and HCV genotype 1 is the most prevalent genotype and is resistant to current standard therapy. We performed this meta-analysis to evaluate the efficacy and safety of telaprevir-based therapy for chronic HCV genotype 1 infection.

Methods

We included randomized controlled trials with no year or language restriction. All data were analyzed using a random-effects model by Review Manager v5.0. The primary outcome was the proportion of patients achieving sustained virologic response (SVR), and the secondary outcomes were HCV relapse rate, incidence of severe adverse events (SAEs), and discontinuation due to adverse events.

Results

The proportion of achieving SVR was significantly higher in the telaprevir group (odds ratio [OR] = 3.40 [1.92, 6.00], P<0.0001; I² = 87%) regardless of a patients’ previous treatment status. It was also significantly higher in the 24-week and 48-week treatment groups (OR = 4.52 [2.08, 9.81], P<0.001; I² = 85%, and OR = 4.05 [1.56, 10.56], P = 0.004; I² = 92%, respectively), while it was comparable in the 12-week treatment group (OR = 1.32 [0.63, 2.75], P = 0.46; I² = 35%). In addition, the HCV relapse rate was significantly reduced in the telaprevir group (OR = 0.28 [0.16, 0.49], P<0.001; I² = 76%). However, the incidence of SAE (OR = 1.56 [1.15, 2.10], P = 0.004; I² = 0%) and study discontinuation due to adverse events (OR = 2.24 [1.43, 3.50], P<0.001; I² = 37%) were significantly higher in the telaprevir group.

Conclusion

Despite its higher incidence of SAEs and discontinuation due to adverse events, telaprevir-based therapy can increase the proportion of achieving SVR in both previously treated and untreated chronic HCV-1 infected patients.     

Immune Activation Response in Chronic HIV-Infected Patients: Influence of Hepatitis C Virus Coinfection

Objectives

We have analyzed the parameters (bacterial translocation, immune activation and regulation, presence of HCV coinfection) which could be implicated in an inappropriate immune response from individuals with chronic HIV infection. The influence of them on the evolution of CD4+ T cell count has been investigated.

Patients and methods

Seventy HIV-infected patients [monoinfected by HIV (n = 20), HCV-coinfected (with (n = 25) and without (n = 25) liver cirrhosis)] and 25 healthy controls were included. Median duration of HIV infection was 20 years. HIV- and HCV-related parameters, as well as markers relative to bacterial translocation, monocyte and lymphocyte activation and regulation were considered as independent variables. Dependent variables were the increase of CD4+ T cell count during the follow-up (12 months).

Results

Increased values of bacterial translocation, measured by lipopolysaccharide-binding protein, monocyte and lymphocyte activation markers and T regulatory lymphocytes were detected in HIV-monoinfected and HIV/HCV coinfected patients. Serum sCD14 and IL-6 were increased in HIV/HCV-coinfected patients with liver cirrhosis in comparison with those with chronic hepatitis or HIV-monoinfected individuals. Time with undetectable HIV load was not related with these parameters. The presence of cirrhosis was negatively associated with a CD4+ T cell count increase.

Conclusion

In patients with a chronic HIV infection, a persistent increase of lipopolysaccharide-binding protein and monocyte and lymphocyte modifications are present. HCV-related cirrhosis is associated with more elevated serum concentrations of monocyte-derived markers. Cirrhosis influences the continued immune reconstitution of these patients.     

Eligibility and Safety of Triple Therapy for Hepatitis C: Lessons Learned from the First Experience in a Real World Setting

Background

HCV protease inhibitors (PIs) boceprevir and telaprevir in combination with PEG-Interferon alfa and Ribavirin (P/R) is the new standard of care in the treatment of chronic HCV genotype 1 (GT1) infection. However, not every HCV GT1 infected patient is eligible for P/R/PI therapy. Furthermore phase III studies did not necessarily reflect real world as patients with advanced liver disease or comorbidities were underrepresented. The aim of our study was to analyze the eligibility and safety of P/R/PI treatment in a real world setting of a tertiary referral center.

Methods

All consecutive HCV GT1 infected patients who were referred to our hepatitis treatment unit between June and November 2011 were included. Patients were evaluated for P/R/PI according to their individual risk/benefit ratio based on 4 factors: Treatment-associated safety concerns, chance for SVR, treatment urgency and nonmedical patient related reasons. On treatment data were analyzed until week 12.

Results

208 patients were included (F3/F4 64%, mean platelet count 169/nl, 40% treatment-naïve). Treatment was not initiated in 103 patients most frequently due to safety concerns. 19 patients were treated in phase II/III trials or by local centers and a triple therapy concept was initiated at our unit in 86 patients. Hospitalization was required in 16 patients; one patient died due to a gastrointestinal infection possibly related to treatment. A platelet count of <110/nl was associated with hospitalization as well as treatment failure. Overall, 128 patients were either not eligible for therapy or experienced a treatment failure at week 12.

Conclusions

P/R/PI therapies are complex, time-consuming and sometimes dangerous in a real world setting, especially in patients with advanced liver disease. A careful patient selection plays a crucial role to improve safety of PI based therapies. A significant number of patients are not eligible for P/R/PI, emphasizing the need for alternative therapeutic options.     

Influence of Genes Suppressing Interferon Effects in Peripheral Blood Mononuclear Cells during Triple Antiviral Therapy for Chronic Hepatitis C

The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (IL28B) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-λs) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-λs were evaluated by real-time PCR. All 31 patients with a favorable IL28B genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for A20, SOCS1, and SOCS3, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as IRF1 were significantly higher at 8 h in patients with an unfavorable IL28B genotype than in those with a favorable one (P = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of IRF1 at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable IL28B genotype (P = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to IL28B genotypes, paralleling treatment efficacy.     

Feasibility of Telaprevir-Based Triple Therapy in Liver Transplant Patients with Hepatitis C Virus: SVR 24 Results

Management of recurrent Hepatitis C virus (HCV) infection following liver transplantation remains a major challenge. In non-transplanted HCV genotype 1 patients, the introduction of protease inhibitor-based regimens has significantly increased the rate of sustained virological response. In this follow-up study, on the first published cohort of post-liver transplant patients treated with telaprevir-based triple therapy, we investigated both efficacy and safety data in follow-up to 24 weeks (SVR 24) after end of treatment (EOT). SVR 24 efficacy and safety data from 9 liver transplant HCV patients being treated with telaprevir, pegylated interferon, and ribavirin, showed 5 of the transplanted patients accomplished the full duration of the 48 week triple therapy. Notable were the 4 patients found to be HCV RNA-negative at week 4, and 8 patients at week 12. Upon EOT, at week 48, 6 patients were HCV RNA-negative. Importantly, at follow-up (24 weeks after EOT), a favorable sustained virological response rate was observed in 5 of these patients with HCV RNA remaining negative, including in one patient who discontinued treatment prematurely. Due to side effects, 2 patients discontinued, 2 suffered from virological breakthrough after the telaprevir treatment phase, and 1 patient had a relapse after EOT. Two thirds of patients exhibited hematological side effects requiring ribavirin dose reductions, administration of erythropoetin, or even blood transfusions. This retrospective analysis provides evidence that - with respect to SVR 24 - liver transplant patients suffering from HCV genotype 1 recurrence may benefit from a telaprevir-based triple therapy as this new regimen showed acceptable antiviral efficacy in this small cohort of mostly pre-treated patients. Management of drug-drug interactions is challenging, but feasible. In part severe side effects are frequent during treatment and require therapeutic interventions.     

Liver Fibrosis,Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

Objective

To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism).

Patients and Methods

A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, −238 TNF-α and −592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count.

Results

Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of −238 TNF-α genotype GG was detected in patients with significant liver fibrosis.

Conclusions

In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a −238 TNF-α polymorphism in these patients.     

Longitudinal Liver Stiffness Assessment in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy

Background/Aims

Liver stiffness (LS) measurement by means of transient elastography (TE) is accurate to predict fibrosis stage. The effect of antiviral treatment and virologic response on LS was assessed and compared with untreated patients with chronic hepatitis C (CHC).

Methods

TE was performed at baseline, and at weeks 24, 48, and 72 in 515 patients with CHC.

Results

323 treated (62.7%) and 192 untreated patients (37.3%) were assessed. LS experienced a significant decline in treated patients and remained stable in untreated patients at the end of study (P<0.0001). The decline was significant for patients with baseline LS ≥ 7.1 kPa (P<0.0001 and P 0.03, for LS ≥9.5 and ≥7.1 kPa vs lower values, respectively). Sustained virological responders and relapsers had a significant LS improvement whereas a trend was observed in nonresponders (mean percent change −16%, −10% and −2%, for SVR, RR and NR, respectively, P 0.03 for SVR vs NR). In multivariate analysis, high baseline LS (P<0.0001) and ALT levels, antiviral therapy and non-1 genotype were independent predictors of LS improvement.

Conclusions

LS decreases during and after antiviral treatment in patients with CHC. The decrease is significant in sustained responders and relapsers (particularly in those with high baseline LS) and suggests an improvement in liver damage.     

Hepatitis B,Hepatitis C and HIV-1 Coinfection in Two Informal Urban Settlements in Nairobi,Kenya

Background

HIV-1 and Hepatitis B and C viruses coinfection is common in Sub-Saharan Africa due to similar routes of transmission and high levels of poverty. Most studies on HIV-1 and Hepatitis B and C viruses have occurred in hospital settings and blood transfusion units. Data on Hepatitis B and C viruses and HIV-1 coinfection in informal urban settlements in Kenya are scanty, yet they could partly explain the disproportionately high morbidity and mortality associated with HIV-1 infections in these slums.

Objectives

The objective of this study was to determine the prevalence of HIV and Hepatitis B and C dual infection in urban slums in Nairobi.

Methods

Blood samples were collected from residents of Viwandani and Korogocho between 2006 and 2007. A structured questionnaire was used to obtain socio-demographic data from participants. Samples were screened for Hepatitis B surface antigen (HBsAg), anti-HCV and anti-HIV-1. Statistical analysis was done using STATA.

Results

Samples were successfully collected from 418 (32%) men and 890 (68%) females. The HIV-1, HBV and HCV prevalence was 20.4%, 13.3% and 0.76% respectively at the time of the study. Of the 268 (20.4%) HIV-1 positive participants, 56 (4.26%) had HBV while 6 (0.46%) had HCV. Of the 1041 HIV-1 negative participants, 117 (8.9%) had HBV while 4 (0.31%) had HCV. Only two people (0.15%) were co-infected with all the three viruses together.

Discussion

The odds of getting hepatitis infection were higher in HIV-1 participants (for HBV OR 2.08,p<0.005 and for HCV OR 5.93, p<0.005). HIV prevalence rates were similar in both informal settlements. HIV infection was highest in age group 35-39 years and among the divorced/separated or widowed. Prevalence of all viruses was highest in those who did not have any formal education.

Conclusion

The HIV prevalence in these informal settlements suggests a higher rate than what is observed nationally. The prevalence rates of HBV are significantly higher in the HIV-1 positive and negative populations. HCV as well as triple HIV-1, HBV and HCV coinfection are uncommon in Korogocho and Viwandani. This clearly indicates the need for HIV-1 control programmes and hepatitis B virus vaccination to be promoted through public awareness as preventive strategy.     

High Prevalence and High Incidence of Coinfection with Hepatitis B,Hepatitis C,and Syphilis and Low Rate of Effective Vaccination against Hepatitis B in HIV-Positive Men Who Have Sex with Men with Known Date of HIV Seroconversion in Germany

Objectives

Men who have sex with men (MSM) are at higher risk for coinfection with hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis than the general population. HIV infection and these coinfections accelerate disease progression reciprocally. This study evaluated the prevalence and incidence of these coinfections in HIV1-positive MSM in Germany.

Materials and Methods

As part of a nationwide, multicenter, prospective cohort study of HIV-infected MSM, plasma samples collected yearly were screened for HBsAg and antibodies to HBc, HBs, HCV, and syphilis. Samples with indications of active HBV or HCV infection were confirmed by polymerase chain reaction. Prevalence and incidence of each infection and incidence rates per study participant were calculated, and incidences over 4-year time intervals compared.

Results

This study screened 5,445 samples from 1,843 MSM. Median age at HIV seroconversion was 33 years. Prevalences of active, cleared, and occult HBV, and of active/cleared HCV were 1.7%, 27.1%, 0.2%, and 8.2%, respectively, and 47.5% had been effectively vaccinated against HBV. Prevalence of antibodies to Treponema pallidum and of triple or quadruple sexually transmitted infections (STIs) were 39.6% and 18.9%, respectively. Prevalence of STI, cleared HBV, HBV vaccination, and history of syphilis differed significantly among age groups. Incidences of HBV, HCV, and syphilis were 2.51, 1.54, and 4.06 per 100 person-years, respectively. Incidences of HCV and syphilis increased over time. HCV incidence was significantly higher in MSM coinfected with syphilis and living in Berlin, and syphilis incidence was significantly higher for MSM living in Berlin.

Discussion

Despite extensive HBV vaccination campaigns, fewer than 50% of screened MSM were effectively vaccinated, with a high proportion of HIV-positive MSM coinfected with HBV. High rates of STI coinfections in HIV-positive MSM and increasing incidences emphasize the need for better tailored campaigns for HBV vaccination and STI prevention.     

The Absence of Thyroid Disease in an Australian Hepatitis C Cohort Treated With Triple Combination Therapy: A Paradigm Shift

Objective: To assess the prevalence of thyroid disease in triple combination therapy with interferon (IFN)-α, ribavirin (RBV), and protease inhibitors (boceprevir and telaprevir) for the treatment of chronic hepatitis C virus (HCV) infection in an Australian hepatitis C cohort. Also, to compare with those who received dual RBV and IFN in the past.Methods: A preliminary, retrospective, and nested case control study of thyroid disease in patients who underwent triple combination therapy for chronic HCV infection compared with dual therapy at a major tertiary referral hospital center. Fifty-nine patients were treated with such therapy at the Hunter New England Area Hepatitis C Treatment Center. Of these, 38 were treated with boceprevir and 21 with telaprevir. All had genotype 1 HCV infection. The main outcome measures included (1) the prevalence of thyroid disease (TD), including hyperthyroidism and hypothyroidism, and (2) thyroid outcome comparison with patients who had received dual therapy.Results: There was no case of TD detected for the entire duration of therapy with triple anti-HCV therapy. There was a significant absence of TD in the protease inhibitor–treated group.Conclusion: No case of TD was detected during the treatment of HCV patients with protease inhibitor–based triple therapy. The reasons for this are unclear. Larger studies are necessary to confirm this finding.Abbreviations: CV = coefficient of variation fT₃ = free triiodothyronine fT₄ = free thyroxine HCV = hepatitis C virus IFN-α = interferon-alpha PI = protease inhibitor RBV = ribavirin TD = thyroid disease TSH = thyroid-stimulating hormone TTX = thyrotoxicosis     

Interferon-Based Therapy Decreases Risks of Hepatocellular Carcinoma and Complications of Cirrhosis in Chronic Hepatitis C Patients

Background

Interferon-based therapy (IBT) has been the standard of care for hepatitis C virus (HCV) infection. However, conflicting results exist regarding the effects of IBT on risk of developing hepatocellular carcinoma (HCC) and cirrhosis-associated complications, and most included highly selected patients.

Methods

This 8-year cohort study was based on the Longitudinal Health Insurance Database 2000 (LHID 2000) consisting of 1,000,000 beneficiaries randomly selected from all Taiwan National Health Insurance enrollees in 2000 (>23.7 million). Patients with newly detected HCV infections (n = 11,264) were classified based on treatment and clinical outcomes. IBTs were defined as regimens that included interferon- alfa, pegylated interferon- alfa -2a, or pegylated interferon- alfa -2b for at least 3 months. The Cox proportional hazards models were used to estimate the hazard ratio (HR) and associated confidence interval (CI) of HCC and cirrhosis-associated complications for IBT.

Results

The 8-year incidence rate for HCC was 3.9% among patients who received IBT and 5.6% among those who did not. The HCC-free survival rate was significantly higher among patients receiving IBT during the 8-year period than their counterpart (adjusted HR, 0.50; 95% CI, 0.31–0.81; P = .004). Similarly, the event-free survival rates for esophageal variceal bleeding (adjusted HR, 0.45; 95% CI, 0.22–0.91; P = .026), hepatic encephalopathy (adjusted HR, 0.38; 95% CI, 0.21–0.69; P = .001), ascites (adjusted HR, 0.28; 95% CI, 0.14–0.57; P<.001), and cirrhosis (adjusted HR, 0.63; 95% CI, 0.44–0.91; P = .013) were significantly higher among patients who received IBT than those who did not, after adjustment for associated factors.

Conclusion

Treatment with interferon may reduce the 8-year risk of HCC and cirrhosis-associated complications in patients with chronic HCV infection.     

Oxidative Status in Chronic Hepatitis C: The Influence of Antiviral Therapy and Prognostic Value of Serum Hydroperoxide Assay

The effect of α-interferon (α-IFN) and ribavirin (RBV) treatment on oxidative status in chronic hepatitis C (CHC) is unknown.

Aim: To study the time course of oxidative status in patients with CHC during α-IFN and RBV administration, and to evaluate the role of oxidative status in order to predict the therapeutic response.

Patients and methods: Fifty one patients with CHC were studied. All received a combination of α-IFN and RBV for 6 or 12 months in relation to the type of response. The hydroperoxides concentration in serum test samples by D-ROM test was measured in all of the patients before therapy. In 27 patients, hydroperoxides were also measured during the treatment and during the 12 subsequent months.

Results: Cross-sectional analysis demonstrates that patients with a successive long-term response had a lower basal serum hydroperoxide concentration than non-responders (280±40.8 vs 337±83 CARR Units, p<0.05). This resulted to be an independent factor predictive of long-term response in the multi-varied analysis. Longitudinal observation on 27 patients showed that the mean hydroperoxide concentration decreased significantly during treatment (T⁰ 329±79.2 vs T¹² 272±34.5 CARR Units) and that the decrease in the mean values was mainly due to variations in the relapsers group.

Conclusions: Normal basal hydroperoxide concentration helps to predict long-term response to combination therapy. The D-ROM test may be used for screening patients before treatment.     

Thyroid Function Outcomes after Pegylated Interferon-α and Ribavirin Therapy - For Chronic Hepatitis C

ObjectiveTo assess the frequency of new thyroid disease, in patients who did not develop thyroid disease during treatment with interferon-a in combination with ribavirin for hepatitis C, during the 6-month period after the end of therapy.MethodsA prospective study was performed in 190 patients who underwent a combination of interferon-a and ribavirin therapy for hepatitis C infection during the 36-month period between 2006 and 2008. Thyroid function tests were performed at the completion of treatment and at 4, 12, and 24 weeks of follow-up.ResultsDuring the 6 months after the completion of interferon-a and ribavirin therapy in the 190 study patients with hepatitis C infection, there were 2 cases of thyroid disease. One patient had the typical biphasic thyroiditis, and the other had primary hypothyroidism. Thus, the prevalence of thyroid disease in this setting was 2 of 190 patients (1.0%).ConclusionThe majority (99%) of patients had normal thyroid outcomes at 6-month follow-up. Only 1 patient had symptoms. This finding is reassuring and eliminates the need for ongoing thyroid surveillance during this time and probably longer. In the absence of symptoms, only a single thyroid-stimulating hormone measurement at 6-month review is recommended. (Endocr Pract. 2010;16:934-939)     

Prediction of Week 4 Virological Response in Hepatitis C for Making Decision on Triple Therapy: The Optim Study

Background

Virological response to peginterferon + ribavirin (P+R) at week 4 can predict sustained virological response (SVR). While patients with rapid virological response (RVR) do not require triple therapy, patients with a decline <1log₁₀ IU/ml HCVRNA (D1L) should have treatment discontinued due to low SVR rate.

Aim

To develop a tool to predict first 4 weeks’ viral response in patients with hepatitis C genotype 1&4 treated with P+R.

Methods

In this prospective and multicenter study, HCV mono-infected (n=538) and HCV/HIV co-infected (n=186) patients were included. To develop and validate a prognostic tool to detect RVR and D1L, we segregated the patients as an estimation cohort (to construct the model) and a validation cohort (to validate the model).

Results

D1L was reached in 509 (80.2%) and RVR in 148 (22.5%) patients. Multivariate analyses demonstrated that HIV co-infection, Forns’ index, LVL, IL28B-CC and Genotype-1 were independently related to RVR as well as D1L. Diagnostic accuracy (AUROC) for D1L was: 0.81 (95%CI: 0.76 — 0.86) in the estimation cohort and 0.71 (95%CI: 0.62 — 0.79) in the validation cohort; RVR prediction: AUROC 0.83 (95%CI: 0.78 — 0.88) in the estimation cohort and 0.82 (95%CI: 0.76 — 0.88) in the validation cohort. Cost-analysis of standard 48-week treatment indicated a saving of 30.3% if the prognostic tool is implemented.

Conclusions

The combination of genetic (IL28B polymorphism) and viral genotype together with viral load, HIV co-infection and fibrosis stage defined a tool able to predict RVR and D1L at week 4. Using this tool would be a cost-saving strategy compared to universal triple therapy for hepatitis C.     

Comparison of Immune Restoration in Early versus Late Alpha Interferon Therapy against Hepatitis C Virus

Early alpha interferon (IFN-α) therapy against hepatitis C virus (HCV) rescues polyfunctional, virus-specific memory CD8⁺ T cells, but whether immune restoration is possible during late therapy remains controversial. We compared immune restoration of HCV-specific memory T cells in patients who cleared HCV infection spontaneously and following early or late IFN therapy. Multifunctional CD4⁺ and CD8⁺ memory T cells were detected in spontaneous resolvers and in individuals treated early following an acute infection. In contrast, limited responses were detected in patients treated during chronic infection, and the phenotype of HCV-specific cells was influenced by autologous viral sequences. Our data suggest that irreversible damage to the HCV-specific memory T-cell response is associated with chronic HCV infection.The majority of acute hepatitis C virus (HCV) infections become chronic, with persistent viremia and serious liver complications (12). Alpha interferon (IFN-α)-based therapy is the only approved treatment for chronic HCV; its success rate ranges from 40 to 90% depending on the infecting genotype (9, 18). The success of therapy is characterized by a sustained virological response (SVR), defined as undetectable HCV RNA in plasma at 6 months after termination of therapy. SVR rates are greatly enhanced if therapy is started between 3 and 6 months following acute HCV infection, but the underlying mechanisms are not well understood (27, 28). We have demonstrated that early interferon therapy for HCV can rescue and select for long-lived polyfunctional CD8⁺ memory T cells (1). Treatment-induced memory T cells were similar in phenotype and function to natural memory T cells generated following spontaneously resolved infection. They expressed high levels of CD127 and Bcl-2 (CD127^hi, Bcl-2^hi) and low levels of PD1 (PD1^lo) and were polyfunctional in nature (1). However, restoration of HCV-specific memory CD4⁺ T cells has not been examined. Furthermore, whether immune restoration is possible following the late initiation of therapy during the chronic phase remains controversial. Kamal et al. demonstrated that SVR is associated with a recovery in HCV-specific CD4⁺ T-cell responses (13). In contrast, Barnes et al. and Rahman et al. demonstrated that the induction of HCV-specific immunity during therapy does not correlate with outcomes (2, 21).