Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II).

BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.

Efficacy and safety of continuous 4-year telbivudine treatment in patients with chronic hepatitis B.

In the phase-III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2-year treatment in HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine-treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2-year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per-protocol population. Amongst 293 HBeAg-positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg-negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off-treatment follow-up). The cumulative 4-year resistance rate was 10.6% for HBeAg-positive and 10.0% for HBeAg-negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m(2) (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg-positive and HBeAg-negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg-positive patients.

Clinical trial: individualized treatment duration for hepatitis C virus genotype 1 with peginterferon-alpha 2a plus ribavirin.

BACKGROUND: Individualized treatment regimens, taking into account the heterogeneity of patients with chronic hepatitis C, are needed to improve treatment outcomes. AIM: To investigate prospectively the period of undetectable viraemia required for a high rate of sustained virological response in patients with chronic hepatitis C genotype 1 and the relationship to early viral kinetics. METHODS: Forty-five chronic hepatitis C genotype 1 patients were given peginterferon-alpha 2a plus ribavirin. Viraemia and hepatocyte HCV-RNA levels were quantified using a TaqMan assay. Beyond the first time point of undetectable viraemia (<20 IU/mL) between baseline and treatment week 12, 32 of 45 (71%) patients were randomized to additional 12 weeks (G12); 24 weeks (G24) or 36 weeks therapy (G36). The remaining 13 patients received 48 weeks' treatment (G48). RESULTS: The sustained virological response rates were: G12--five of 11 (45%); G2 --eight of 10 (80%); G36--eight of 11 (73%); G48--four of 13 (31%). The anti-viral efficacy (epsilon) and treatment-induced loss of infected hepatocytes (Mdelta), were significantly higher in patients with early viral clearance. In G12, patients with sustained virological response had lower baseline viraemia than those who relapsed. CONCLUSIONS: Early viraemia clearance is a better marker than baseline viral load and differentiates chronic hepatitis C genotype 1 with high or low probability of sustained virological response. In patients with viraemia clearance within 12 weeks of starting peg-interferon/ribavirin therapy, an additional period of undetectable viraemia of minimum 24 weeks is required for high sustained virological response.

Distribution and characteristics of hepatitis B virus genotype C subgenotypes in China.

Genetic diversity within the same hepatitis B virus (HBV) genotype indicates the presence of several subgenotypes. We have found that genotype C is the most common in China, and this study aimed to determine the geographical distribution and characteristics of HBV-C subgenotypes in the country. A cohort of 534 patients with chronic HBV genotype C infection, collected across China, was analysed by nucleotide sequencing or polymerase chain reaction-restriction fragment length polymorphism. HBV-C1/Cs (n = 112, 21%) and HBV-C2/Ce (n = 397, 74%) were the most common HBV-C subgenotypes and showed different geographical distribution in China. No significant differences were found between patients infected with HBV-C1 and HBV-C2 when comparing liver function tests, hepatitis B e antigen positive rate and clinical manifestations. We identified two other types of HBV-C provisionally designated as HBV-CD1 and HBV-CD2, which have particular virological features and clustered in one geographic area. These two types of C/D hybrids have emerged through recombination with genotype D and encode serotype ayw2 hepatitis B surface antigen. In conclusion, there are at least four subtypes of HBV genotype C: subgenotypes C1, C2 and two types of C/D recombinants CD1 and CD2 in China, which have a distinct geographic distribution. Whether HBV-C subgenotypes differ in their impact on liver disease progression requires prospective studies.

Geographic distribution, virologic and clinical characteristics of hepatitis B virus genotypes in China.

The significance of hepatitis B virus (HBV) genotypes for the heterogeneity of chronic HBV infection and severity of liver disease is not well understood. The aim of this study was to determine the distribution and virologic characteristics of HBV genotypes in China and possible association with the diversity of liver disease. The study includes 1096 chronic HBV carriers from nine provinces in China. We collected clinical and laboratory data and analysed the HBV strains in sera by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and nucleotide sequencing techniques. The most common HBV genotypes were B (41%) and C (53%), while genotypes A and D were also found. A North-South divide was identified in genotype B and C distribution - genotype C was predominant in northern China, while genotype B was more prevalent in southern provinces. Patients with genotype B were younger than those with genotype C, and had a lower prevalence of HBeAg - 65%vs 72%, respectively (P = 0.03). However, the severity of liver disease did not differ significantly between patients infected with genotype B or C - neither when comparing liver function tests (1024 patients), nor hepatic inflammation and fibrosis (264 patients). Amongst 47 patients with genotype D (by PCR-RFLP), 37 (79%) were infected with a new subtype (designated Dc), having a recombination fragment from genotype C precore/core region. This is the first large-scale HBV genotype study from China and convincing documentation of the North-to-South gradient of genotypes C vs B in this country. HBV DNA recombination over the surface and precore/core genes increases the diversity of HBV strains and may have diagnostic and clinical implications.

[New views on immunopathology of viral hepatitis B and C]. / Nové pohledy na imunopatologii virových hepatitid B a C.

The interaction of non-cythopatic, hepatotropic viruses of hepatitis B and C with the host's immune system plays a critical role in determining the viral clearance and it contributes to the liver damage. The initial line of defence is antigen non-specific and is mediated by natural killer cells and macrophages. Simultaneously, virus-specific immunity is induced by professional antigen presenting cells that process and present viral antigens to T and B lymphocytes in the regional lymph nodes. Thereafter, viral specific T helper cells are activated and these cells initiate the anti-viral immune responses of B and CTL lymphocytes. Early, multispecific T cell responses are associated with viral clearance, whereas the imbalance of viral specific Th1 and Th2 lymphocytes plays a crucial role in the viral persistence. The imbalance of viral specific Th1 and Th2 lymphocytes leads to inadequate activation of antigen specific CTL cells. After recognition of viral antigens, T helper lymphocytes are differentiated to Th1 and Th2 cells according to the type of secreted cytokines. Th1 cells produce cytokines: interleukin-2, IFN-gamma, TNF-alpha, which are responsible for effective activation of CTL cells. In contrast, interleukin-4, interleukin-5 and interleukin-10 are secreted by Th2 cells, which are involved in activation of B lymphocytes and in production of neutralizing antibodies. These finding suggests that the viral clearance is associated with the early development and adequate mounting of the anti-viral multispecific immune responses of T helper and cytotoxic T lymphocytes.

Non-cytolytic inhibition of hepatitis B virus replication in human hepatocytes.

BACKGROUND/AIMS: Interferon-gamma (IFN-gamma) has been shown to abolish hepatitis B virus (HBV) gene expression and replication in HBV transgenic mice without destroying infected hepatocytes. We investigated the characteristics of IFN-gamma induced non-cytolytic inhibition of viral replication in human HBV infection. METHODS: We used an in vitro model where lymphocytes from 15 HBsAg positive patients were co-cultured with transfected hepatocytes supporting HBV replication. The effector and target cells were separated by a membrane, which allowed transfer of soluble factors only, to determine whether IFN-gamma produced from antigen-specific CD4+ T cells or mitogen stimulated lymphocytes inhibits HBV replication. RESULTS: IFN-gamma produced following lymphocyte stimulation reduced cytoplasmic HBV DNA in the target cells. The degree of HBV DNA reduction correlated with the level of IFN-gamma in the supernatants. Further investigations using naturally infected human hepatocytes confirmed that recombinant IFN-gamma reduces HBV DNA and HBV RNA in these cells as well, in parallel with the induction of cellular interferon-responsive genes. This antiviral effect was without significant cytotoxicity and was more pronounced in hepatocytes from patients with low HBV replication. CONCLUSIONS: These results provide direct evidence that IFN-gamma can inhibit both HBV transcription and replication in human hepatocytes without cell lysis.

Interferon plus amantadine versus interferon alone in the treatment of naïve patients with chronic hepatitis C: a UK multicentre study.

BACKGROUND/AIMS: The antiviral agent amantadine may have activity against the hepatitis C virus. To determine whether the combination of interferon-alpha plus amantadine was more effective than interferon monotherapy we conducted a multicentre clinical trial in untreated patients with chronic hepatitis C infection. METHODS: We performed a pilot study in two centres (36 patients) to determine the number needed for a statistically significant clinical trial and then conducted a multicentre, randomized controlled clinical trial involving 14 centres and 143 patients. RESULTS: There was no significant difference in sustained response rates in patients receiving interferon and amantadine compared to those receiving interferon alone. The on treatment response rate at 3 months was 65% on combination vs. 49% on interferon alone (P = 0.05) while the sustained response was 18 and 15%, respectively. CONCLUSIONS: Combination therapy with interferon plus amantadine does not lead to a significant increase in sustained response rates when compared to interferon monotherapy.

TT virus infection in patients with primary hypogammaglobulinaemia: natural history and relationship to liver disease in the immunocompromised host.

BACKGROUND: TT virus (TTV) is a recently discovered human DNA virus with worldwide distribution, but with no clear disease association. The possibility of an enhanced TTV virulence in patients with immunodeficiencies has not yet been investigated but is of particular interest because other viruses have been demonstrated to cause severe and rapid liver disease in such patients. Here we analysed the characteristics of TTV infection in a large cohort of patients with primary hypogammaglobulinaemia (PHG) and whether TTV has a role in the frequently observed cryptogenic liver disease in these patients. METHODS: 83 Norwegian patients with PHG (serum immunoglobulin G < 2 g/L), receiving substitution treatment with immunoglobulins, were followed regularly for median 10.2 years (range 2-30). TTV DNA was sought in serum samples and three immunoglobulin preparations by polymerase chain reaction; TTV DNA quantitation, DNA sequencing and phylogenetic analysis were performed in selected samples. RESULTS: TTV DNA was detected in 27 of 83 (32.5%) patients and was not associated with a particular type of PHG. The prevalence of TTV infection was dependent on intravenous immunoglobulin administration, duration of therapy and patient's age. TTV DNA was found in two of three currently used immunoglobulin preparations. In the longitudinal study, whether TTV was cleared or newly acquired had no impact on liver function tests and no particular TTV strain was found in patients with more severe liver disease. CONCLUSIONS: TTV infection is common in patients with PHG. Treatment with immunoglobulins has a role in the transmission of TTV in these patients. However, we found no evidence of TTV-induced liver disease in this group of immunocompromised patients.

Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation.

BACKGROUND/AIMS: The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment. METHODS: Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver. RESULTS: Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function. CONCLUSIONS: Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis.

Novel immunoassay for the detection of hepatitis B surface 'escape' mutants and its application in liver transplant recipients.

Hepatitis B virus (HBV) strains with mutations in the surface gene are responsible for the failure of prophylaxis with hepatitis B immunoglobulin (HBIG) in a proportion of patients transplanted for HBsAg positive cirrhosis. So far, the emergence and evolution of these 'surface antibody escape' mutants have been studied by DNA sequencing. In this study the use of an immunoassay is described for diagnosis and characterisation of HBV recurrence after liver transplantation (OLT), based on a monoclonal antibody able to recognise both wild-type and mutant HBsAg. Pre- and post-transplant samples from 22 patients transplanted for HBsAg positive cirrhosis were studied: Group A: 12 patients who reinfected the graft despite receiving HBIG; Group B: 6 patients with no HBV recurrence with continuous HBIG; Group C: 4 patients with HBV recurrence without prophylaxis. By running the new assay in parallel with an immunoassay that is susceptible to HBsAg mutants, 4 of 12 cases were identified in Group A with HBV recurrence due to surface antibody escape mutants, whereas in 8 patients this was due to the wild-type HBV. The results from the immunoassays were confirmed in all cases by HBV DNA sequencing. The surface gene mutations in the 4 patients affected codons 144 and 145 and in one of these 4 patients HBV strains with mutations in both codons were detected before and after transplantation. The epitope recognised by the new monoclonal antibody that reacts with both wild-type and mutant HBsAg seems to remain stable in the HBIG-induced HBV mutants. This serological approach allows rapid and cost-effective screening for HBsAg escape mutants in the liver transplant setting and may be helpful in the selection of appropriate prophylaxis.

The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with persistent HBV infection were studied: one without liver inflammation and HBV replication, the other with liver inflammation and a high level of HBV replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circulating reservoir of CD8(+) cells able to expand after specific virus recognition that was not detectable in highly viremic patients with liver inflammation. These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.

Immunopathogenesis of hepatitis B virus recurrence after liver transplantation.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation is associated with inflammatory graft changes, despite immunosuppression and donor/recipient HLA mismatch. We investigated whether immune mechanisms are involved in the pathogenesis of hepatitis B after liver transplantation. METHODS: The virus-specific T helper (Th) cell response, activation of Th1/Th2 subpopulations, donor/recipient HLA, and expression of tumor necrosis factor (TNF)-alpha/TNF receptors were determined in 28 patients who underwent transplantation for HBV-related cirrhosis (17 with HBV recurrence and 11 without recurrence) in comparison to 30 nontransplant patients with chronic hepatitis B. RESULTS: Orthotopic liver transplantation recipients with HBV recurrence showed significant hepatitis B core antigen-specific T-cell proliferation, comparable to nontransplant patients, which was not present in transplant recipients without recurrence. In addition, hepatic and serum interleukin (IL)-2, interferon-gamma, and TNF-alpha were enhanced, without changes in IL-4 and IL-10. Phenotypically, hepatic infiltrates in allografts with HBV recurrence were comprised of CD4+ lymphocytes and macrophages with a correlation between interferon-gamma- and TNF-alpha-producing cells and the degree of necroinflammatory activity. There was a marked up-regulation of both TNF-alpha receptors, significantly greater than in nontransplant patients. CONCLUSIONS: These findings suggest that despite immunosuppression, HLA class I-independent immune mechanisms have a significant pathogenic role in liver damage associated with HBV recurrence after liver transplantation.

Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C.

BACKGROUND & AIMS: The role of virus-specific T-helper lymphocyte reactivity in determining the therapeutic response in chronic hepatitis C virus (HCV) infection is not fully understood. METHODS: We studied CD4(+) T lymphocyte proliferation together with interferon (IFN)-gamma and interleukin (IL)-10 production from peripheral blood mononuclear cells in response to 4 HCV antigens (core, NS3, NS4, and NS5) in 25 patients with chronic hepatitis C undergoing antiviral therapy with IFN alone or in combination with ribavirin, prospectively, before, during, and after treatment. RESULTS: HCV-specific T-cell reactivity was uncommon at baseline but increased markedly during antiviral therapy, peaking around treatment weeks 4-8. Resolution of hepatitis C viremia was significantly more likely in patients who developed HCV-specific T-cell proliferation with increased IFN-gamma production. The main difference in T-cell reactivity of patients treated with IFN plus ribavirin was a significantly lower production of IL-10, whereas lymphocyte proliferation was similar to that in patients receiving IFN monotherapy. CONCLUSIONS: Treatment-induced control of hepatitis C viremia is associated with the development of HCV-specific T-cell responses with enhanced IFN-gamma and low IL-10 production. The greater efficacy of combination therapy with IFN-alpha plus ribavirin may be related to its ability to suppress HCV-specific IL-10 production.

Evolution of wild-type and precore mutant HBV infection after liver transplantation.

Recurrence of hepatitis B virus (HBV) infection after liver transplantation is associated with varying degree of graft damage. The aim of the study was to investigate longitudinally the changes of wild-type and precore A1896HBV mutant viral populations after reinfection and their impact on liver graft damage. The wild-type HBV and A1896HBV strains were quantitated before and serially after orthotopic liver transplantation (OLT) in 14 hepatitis B surface antigen (HBsAg)-positive liver graft recipients (4 hepatitis B e antigen [HBeAg]+; 10 anti-HBe+). Before OLT, the wild-type precore HBV was present in all 4 HBeAg-positive patients and in 2/10 anti-HBe-positive patients; a mixed virus population was present in 6 patients; and A1896HBV mutant alone in 2 patients. After OLT, A1896HBV mutant appeared and gradually accumulated in 5/6 patients who had the wild-type HBV before OLT and 1 of these patients seroconverted from HBeAg to anti-HBe 52 months after transplantation. A mixed HBV population was present continuously in 6 patients before and after OLT. Of the 2 patients with A1896HBV only pre-OLT, the wild type appeared in one patient and the other patient retained persistently the A1896HBV mutant. There was no relationship between liver graft histology and the type of viral population at reinfection or at the end of follow up. Changes in the HBV population occur during follow up of recurrent hepatitis B in liver transplant recipients with frequent accumulation of precore A1896HBV mutants, but the type of viral population does not determine the severity of hepatitis B in the graft.

Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP).

Interferon alfa (IFN-alpha) is the primary treatment for chronic hepatitis B. The standard duration of IFN-alpha therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-alpha treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in which all patients were treated with a standard regimen of 10 million units IFN-alpha 3 times per week over 16 weeks. Patients who were still HBeAg-positive after 16 weeks of therapy were randomized to prolongation of the identical regimen up to 32 weeks (prolonged therapy) or discontinuation of treatment (standard therapy). Among the 162 patients who entered the study, 27 (17%) were HBeAg-negative after the first 16 weeks of treatment, and 118 were randomized to standard or prolonged therapy. After randomization, a response (HBeAg seroconversion and sustained hepatitis B virus [HBV]-DNA negativity) was observed in 7 of the 57 (12%) patients assigned to standard therapy versus 17 of the 61 (28%) patients assigned to prolonged therapy (P =.04). A low level of viral replication after 16 weeks of treatment, as indicated by serum HBV-DNA values under 10 pg/mL, was found to be the only independent predictor of response (52% vs. 0%; P <.001) during prolonged therapy. The prolonged IFN-alpha schedule was well tolerated in the large majority of patients. In chronic hepatitis B, prolongation of IFN-alpha therapy up to 32 weeks is superior to a standard course of 16 weeks. Those patients who exhibit a low level of viral replication at the end of the standard regimen benefit most from prolonged treatment.

Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia.

BACKGROUND/AIMS: Most patients infected with hepatitis C virus (HCV) develop chronic infection and persistent viraemia. The immune mechanisms responsible for resolution of viraemia remain poorly understood. HCV specific humoral and cellular immune responses in patients with and without viraemia were investigated. METHODS: In vitro T helper (TH) lymphocyte responses to structural and non-structural HCV proteins were determined by means of proliferative response and cytokine production in 35 anti-HCV positive/HCV RNA negative patients and in 31 patients with chronic HCV infection and persistent viraemia. Humoral responses were determined by measuring HCV specific antibody quantity and specificity. RESULTS: A TH response to two or more HCV proteins was present in 18 of 35 patients with serological viral clearance compared with just one of 31 viraemic patients (p = 0.00001). HCV specific interferon-gamma production was increased only in the former group. In contrast, the antibody levels were significantly lower and directed at fewer HCV antigens in patients with undetectable HCV RNA. CONCLUSIONS: Patients without viraemia after HCV infection frequently have strong TH lymphocyte responses of the TH1 type to multiple HCV antigens many years after the onset of infection, whereas antibody responses are less marked. These results suggest that control of HCV replication may depend on effective TH lymphocyte activation.

Antibodies to hepatitis C virus envelope proteins correlate with hepatitis C viraemia after liver transplantation.

BACKGROUND: Liver transplant recipients for hepatitis C virus (HCV)-related cirrhosis usually remain anti-HCV-seropositive after transplantation. The aim of this study was to characterize, longitudinally, the profile of HCV-specific antibodies and cryoglobulins in liver transplant recipients with recurrent HCV infection. METHODS: Serial serum samples were collected prospectively before, at 1 month after, and at 12 months after transplantation for HCV cirrhosis in 30 patients infected with genotype 1. The antibodies against HCV envelope proteins (E1 and E2) were quantitated by enzyme-linked immunosorbent assay and antibodies against core, E2/hypervariable region I (HVRI), NS3, NS4, and NS5A antigens by a line immunoassay. Sera were also tested for cryoglobulins. RESULTS: The titer of each anti-HCV antibody had fallen at 1 month after transplantation (P<0.05) with the exception of anti-E1 levels, which had risen in 16 patients with acute hepatitis C at that time (P=0.01). Anti-E1 and anti-E2 titers, but not antibodies against other HCV antigens, increased to pre-transplantation levels or higher at 12 months, which correlated with serum HCV RNA levels. Cryoglobulinemia was present in nine patients after transplantation (30%) and was associated with lower anti-E1 levels (P=0.04) and more severe graft damage. CONCLUSIONS: The early increase in antibodies to HCV envelope proteins in correlation with viremia suggests that the envelope-specific humoral immune response may be directly stimulated by HCV replication. Anti-E1 levels may be a useful marker in monitoring patients with recurrent HCV infection.