Clinical Impact of Non—Organ-Specific Autoantibodies on the Response to Combined Antiviral Treatment in Patients with Hepatitis C

Clinical Infectious Diseases, Feb 2005

Background. Hepatitis C virus (HCV)—related chronic hepatitis is frequently associated with non—organ-specific autoantibodies (NOSAs), but available data about the relationship between NOSA positivity and the effect of antiviral therapy in persons with hepatitis C are few and controversial. Our aim was to evaluate the impact of NOSA positivity on the outcome of combined antiviral therapy in HCV-positive patients.

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Clinical Impact of Non—Organ-Specific Autoantibodies on the Response to Combined Antiviral Treatment in Patients with Hepatitis C

Impact of NOSAs on Treatment for HCV • CID Clinical Impact of Non-Organ-Specific Autoantibodies on the Response to Combined Antiviral Treatment in Patients with Hepatitis C Paolo Muratori 0 Luigi Muratori 0 Marcello Guidi 0 Alessandro Granito 0 Micaela Susca 0 Marco Lenzi 0 Francesco B. Bianchi 0 0 Department of Internal Medicine , Cardioangiology, and Hepatology , Alma Mater Studiorum-University of Bologna , Policlinico Sant'Orsola-Malpighi, Bologna , Italy (See the editorial commentary by Bogdanos on pages 508-10) Background. Hepatitis C virus (HCV)-related chronic hepatitis is frequently associated with non-organspecific autoantibodies (NOSAs), but available data about the relationship between NOSA positivity and the effect of antiviral therapy in persons with hepatitis C are few and controversial. Our aim was to evaluate the impact of NOSA positivity on the outcome of combined antiviral therapy in HCV-positive patients. Methods. A total of 143 consecutive adult patients with hepatitis C were studied. Antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), and anti-liver/kidney microsomal antibody type 1 (LKM1) were detected by indirect immunofluorescence. All patients were treatment naive and received combined antiviral therapy (interferon [IFN]-ribavirin) after enrollment in the study. Patients were classified as nonresponders if HCV RNA was detectable after 6 months of therapy, as relapsers if abnormal transaminase levels and reactivation of HCV replication were observed after the end of treatment, and as long-term responders if transaminase levels were persistently normal and HCV RNA was undetectable 6 months after the end of treatment. Results. Thirty-seven patients (25%) were NOSA positive (SMA was detected in 19 patients, ANA in 10, ANA and SMA in 4, LKM1 in 3, and SMA and LKM1 in 1). The prevalence of long-term response was similar between NOSA-positive patients and NOSA-negative patients (48.6% vs. 56.6%; P p not significant). Compared with HCV genotype 1 (HCV-1), HCV genotypes other than 1 were more often associated with long-term response among NOSA-positive patients (93.3% vs. 30%; P p .0017). The overall rate of long-term response, irrespective of NOSA status, was 54.5%. Detection of HCV-1 and elevated g-glutamyl transpeptidase serum levels were independent negative prognostic factors of treatment response (P p .007 and P p .026, respectively). Conclusions. Combined antiviral treatment (IFN-ribavirin) is safe and effective in NOSA-positive patients with hepatitis C, even if long-term response is less likely in those infected with HCV-1. Immunological disorders have been frequently described in the course of hepatitis C virus (HCV)–related chronic hepatitis, and non–organ-specific autoantibodies (NOSAs) in particular are common examples of autoreactivity associated with HCV infection [ 1–4 ]. The pathogenesis and clinical significance of NOSAs in patients with chronic hepatitis C are still unclear. Recent data point to the interaction between the HVR1-E2 region of HCV and the B lymphocyte costimulation complex (tetraspanin CD81, CD19, and CD21) as a possible pathway for the production of NOSAs by means of the induction of B cell activation and spread [5]. In recent years, the therapeutic approach to HCV related chronic hepatitis has undergone remarkable improvement with the administration of combination treatment with IFN-ribavirin or pegylated IFN (PEG IFN)–ribavirin, both of which give better results than IFN monotherapy [ 6 ]. However, the best treatment option for NOSA-positive patients with HCV-related chronic hepatitis is still a controversial issue; clinical studies addressing treatment in the presence of NOSAs are few in number, have contradictory results, and are mainly limited to IFN monotherapy [ 7, 8 ]. In particular, patients who sporadically tested positive for both Impact of NOSAs on Treatment for HCV • CID 2005:40 (15 February) • 501 HCV and anti–liver kidney/microsomal type 1 antibody (LKM1) during IFN treatment developed a striking increase in transaminase levels that resolved after IFN therapy was stopped and immunosuppressive treatment was started [ 9–11 ]. On the other hand, results obtained with prednisone therapy in NOSApositive patients with hepatitis C were disappointing, with an increase in the alanine aminotransferase level [12]. We recently reported that NOSA positivity in children negatively affects their response to IFN monotherapy [ 13 ], and along the same line, Wasmuth et al. [ 14 ] reported that longterm response to combined antiviral treatment is less likely in NOSA-positive adults, compared with NOSA-negative adults. The aims of the present study were to evaluate retrospectively the impact of NOSA on the response to combined antiviral treatment in patients with HCV-related chronic hepatitis and to identify clinical, biochemical, or immunological features predictive of response to antiviral treatment in NOSA-positive patients. PATIENTS AND METHODS Study population. A total of 143 consecutive treatment-naive patients referred during 1999–2002 to the Department of Internal Medicine, Cardioangiology, and Hepatology (Policlinico Sant’Orsola-Malpighi; Bologna, Italy) were considered to be eligible for combined IFN-ribavirin treatment and were enrolled in this study. Criteria of eligibility were serum anti-HCV antibody and HCV RNA positivity, detection of abnormal alanine transaminase levels at least twice during the 6-month period before enrollment, chronic inflammation revealed by histological analysis of the liver, and the absence of contraindications to IFN-ribavirin therapy. Viral assays. Anti-HCV antibodies were tested by means of a third-generation enzyme immunoassay (Ortho HCV ELISA, version 3.0; Ortho-Clinical Diagnostics) according to the manufacturer’s instructions, and HCV RNA load was analyzed by nested PCR using primers derived from the highly conserved 5 noncoding region of the viral genome. Genotyping of isolates obtained from 106 (74.1%) of 143 HCV-infected patients was performed by PCR amplification of the core region of the HCV genome with specific antisense primers (HCV GenEti-K DEIA; Sorin Biomedica). Histological assessment. Liver biopsy specimens, which were available for 133 patients (93%), were evaluated by a single experienced liver pathologist, and inflammation activity was scored as mild, moderate, or severe. NOSA detection. The presence of antinuclear antibody (ANA), anti–smooth muscle antibody (SMA), anti-mitochondrial antibody (AMA), anti–liver/kidney microsomal antibody type 1 (LKM1), and anti–liver cytosol antibody type 1 (LC1) was assessed by means of indirect immunofluorescence on cryostat sections of rat liver, kidney, and stomach specimens at 502 • CID 2005:40 (15 February) • Muratori et al. serum dilutions of 1:40, which were titered to extinction. Indirect immunofluorescence of slides was performed by 2 investigators who were blinded to one another’s findings and to each patient’s clinical diagnosis. SMA reactivity was classified according to a report by Bottazzo et al. [ 15 ], in which the following 3 immunomorphological patterns on kidney sections were described: staining of small and/or medium-sized vessel walls only (SMA-V); staining of glomerular mesangial cells in addition to vessels (SMA-G); and staining of vessels, glomerular structures, and peritubular structures (SMA-T). To further characterize the pattern associated with ANA, all ANA-positive samples were retested by indirect immunofluorescence on human laryngeal carcinoma (HEp-2) cells (serum dilution, 1:100) in accordance with established criteria [ 16 ]. LKM1-positive serum specimens were tested by immunoblot assay (with use of human liver cytosol as the antigen source, as described elsewhere [ 17 ]) to assess the possible coexistence of LC1 positivity. Tests for detection of perinuclear antineutrophil cytoplasmic antibodies (pANCAs) were performed at a serum dilution of 1:20, as described elsewhere [ 18 ]. NOSAs were assessed in each patient at baseline and every 3 months thereafter during treatment, as well as 6 months after the end of treatment. The International Autoimmune Hepatitis Group score for the diagnosis of autoimmune hepatitis was calculated for each patient with at least 1 episode of autoantibody reactivity [ 19 ]. Treatment regimens and outcomes. A total of 56 (39.1%) of 143 patients received PEG–IFN-2b (PegIntron; ScheringPlough) (1.5 mg/kg per week) and ribavirin (12 mg/kg per day); the remaining 87 patients (60.9%) received recombinant IFN2b (Intron A; Schering-Plough) (5 MU 3 times/week) and ribavirin (12 mg/kg per day). The duration of treatment was 6 or 12 months, depending on the viral genotype: patients infected with HCV genotype 1 (HCV-1) received treatment for 12 months, whereas those infected with an HCV genotype other than 1 were treated for 6 months. The 37 patients for whom the HCV genotype was not determined received treatment for 12 months (30 patients received IFN-ribavirin, and 7 received PEGIFN–ribavirin). Patients were classified as nonresponders if HCV RNA was detectable after 6 months of therapy, as relapsers if abnormal alanine transaminase levels and reactivation of HCV replication were observed after the end of treatment, and as longterm responders if alanine transaminase levels were persistently normal and HCV RNA was undetectable 6 months after the end of treatment. Statistical analysis. The comparison of categorical variables was performed using x2 analysis and Fisher’s exact test, when applicable. The Mann-Whitney U test was used for comparison of continuous data. A P value of !.05 was considered to be statistically significant. Statistical analysis was performed NOTE. Data are median value (range), unless otherwise indicated. P values were determined by means of x2 analysis, Fisher’s exact test, and the Mann-Whitney U test. a Data are for 133 patients. b Data are for 106 patients. using GraphPad InStat, version 3.0a for Macintosh (GraphPad Software), and SPSS, version 11.0 for MacOSX (SPSS). RESULTS Immunological and biochemical features. Thirty-seven patients (25%) infected with HCV had detectable levels of NOSA at baseline or during combined antiviral treatment. SMA-V was present in 19 (13.3%) of 143 patients, ANA in 10 patients (7%), and LKM1 in 3 patients (2.1%); ANA and SMA-V were both detected in 4 patients (2.8%), and LKM1 and SMA-V were both found in 1 patient (0.7%). Twenty-five of the 37 patients had NOSAs detected at baseline, whereas 12 became NOSA positive during antiviral therapy (3 patients who received PEGIFN–ribavirin and 9 who received IFN-ribavirin). Of these 12 patients, SMA-V was detected in 8, ANA was detected in 3, and LKM1 was detected in 1. The overall prevalence of reactivity was 16.8% for SMA-V (median titer, 1:40; range, 1:40–1:160), 9.8% for ANA (median, 1:40; range, 1:40–1:80), and 2.8% for LKM1 (median, 1:40; range, 1:40–1:80). No patient had specimens reactive to AMA, LC1, or pANCA. Specimens from all but 1 of the ANApositive patients were associated with a speckled pattern on HEp-2 cells; the specimen from the other patient was associated with a diffuse pattern. No patient received the diagnosis of probable or definite autoimmune hepatitis on the basis of International Autoimmune Hepatitis Group score. At baseline, NOSA-positive patients had higher serum levels of g-glutamyl transpeptidase (g-GT), alkaline phosphatase, ferritin, g-globulin, and IgA, whereas there were no differences in virological features (e.g., viremia level and genotype distribution) between NOSA-positive and -negative patients (table 1). NOSA behavior during treatment and follow-up. Among the 25 patients who tested positive for NOSAs at baseline, auImpact of NOSAs on Treatment for HCV • CID 2005:40 (15 February) • 503 toreactivity status was unchanged during antiviral treatment and follow-up for 19, in 4 patients the titer increased (from 1: 40 to 1:80) during treatment (in 2, it returned to pretreatment levels during follow-up), in 1 the titer decreased (from 1:80 to 1:40) during treatment and follow-up, and 1 patient definitively lost autoantibody during antiviral therapy. Twelve patients developed NOSA during treatment (median, 6 months; range, 3–9 months). Six (50%) of these patients maintained the reactivity at the same titer (1:40) during followup; 2 (17%) had an increased titer (up to 1:80), which remained unaltered during follow-up; and 4 (33%) developed autoreactivities at a titer of 1:40 that disappeared during follow-up. The detailed kinetics of the NOSA profile is summarized in figure 1. Response to therapy. Given the same rate of long-term responders, relapsers, and nonresponders among NOSA-positive and -negative patients with the 2 treatment schedules used (i.e., IFN-ribavirin and PEG-IFN–ribavirin), all of the patients were considered to be a homogeneous group, even if they received different treatment regimens. Seventy-eight (54.5%) of 143 HCV-infected patients were long-term responders, 18 (12.6%) were relapsers, and 47 (32.9%) were nonresponders. HCV strains with genotypes other than 1 were significantly more prevalent among long-term responders than among relapsers and nonresponders (80.9% vs. 30%; P ! .0001). In addition, the long-term responder group also had a lower median pretreatment g-GT level (34 MU/mL; range, 6– 313 MU/mL) than did the relapser and nonresponder groups (61 MU/mL; range, 10–323 MU/mL; P p .0041). The statistical significance of these 2 variables was maintained after stepwise logistic regression analysis (P p .007 and P p .026, respectively). A comparison between patients with normal versus abnormal gGT serum levels showed that long-term responders were significantly more likely than relapsers and nonresponders to have normal g-GT values (68.9% vs. 39.1%; P p .0004). The percentage of long-term responders, relapsers, and nonresponders was similar in both NOSA-positive patients and NOSA-negative patients; in particular, there were 18 (48.64%) of 37 long-term responders among NOSA-positive patients and 60 (56.60%) of 106 long-term responders among NOSA-negative patients (table 1). Within the group of NOSA-positive patients, those who achieved long-term response had lower viremia levels (2.7 vs. 11.1 Meq/mL; P p .06) and lower g-GT serum levels (50 vs. 90 IU/mL; P p .07) than nonresponders and relapsers, even if both parameters did not reach statistical significance (table 2). HCV-1 infection was more frequent among relapsers and nonresponders, compared with long-term responders (93% vs. 30%; P p .0017). Analysis of reactivities of the individual types of NOSAs indicated that ANA-positive patients—all of whom, of note, were infected with HCV-1— were less likely to be long-term responders than were SMApositive patients (30% vs. 68.4%), although this finding was not statistically significant (P p .06). Among the 4 LKM1positive patients, 1 was a long-term responder, and 3 were nonresponders. Five patients suspended the treatment schedule; 3 stopped after 4–6 weeks because of severe flulike syndrome (all were considered to be nonresponders), 1 stopped after 7 months because of acoustic nerve neuritis (HCV RNA reappeared, and the patient was therefore considered to be a relapser), and 1 stopped after 8 months because psoriasis had exacerbated (the patient was considered to be a long-term responder because he persistently tested negative for HCV RNA during followup). One of the 3 patients who suspended the antiviral treatment for flulike syndrome was SMA-V positive. In this study, the prevalence of NOSAs and the distribution of HCV genotypes did not differ from our previous observations in adult and pediatric patients with chronic hepatitis C [ 1, 3, 13 ]. In adults and, as we have observed [ 13 ], in children, SMA is the most frequently detected NOSA, whereas the LKM1 prevalence among adults with hepatitis C is lower than that among children with this disease [ 13, 20 ]. NOSA-positive patients were characterized by significantly higher serum levels of g-globulin, IgA, IgM, ferritin, alkaline phosphatase, and g-GT, although all parameters except g-GT level were within the normal range (table 1). Alanine transaminase levels, although higher in NOSA-positive patients, were not statistically significantly different from those in NOSA-negative patients; these findings differ from those we reported previously [ 1, 3 ]. This apparent discrepancy may be explained by the different recruitment criteria used: Cassani et al. [ 1 ] evaluated a series of consecutive patients with overt liver disease, whereas Lenzi et al. [ 3 ] analyzed the general population of a small town in northern Italy. The response to the combination therapy was similar in Impact of NOSAs on Treatment for HCV • CID 2005:40 (15 February) • 505 NOSA-positive patients and NOSA-negative patients; the low rate (30%) of long-term response among ANA-positive patients is likely to be ascribed to the predominance of HCV-1 in the ANA-positive subgroup. We have recently reported that NOSA positivity in children with hepatitis C seems to impair their response to IFN [ 13 ]. The results of this study, however, are not comparable with those of our previous report involving pediatric patients [ 1 ] for the following reasons: the therapeutic regimens differed (children received IFN monotherapy, whereas adults were treated with IFN-ribavirin), and there was a higher rate of LKM1 positivity in the pediatric series (11% for children vs. 2.7% for adults). It is of interest to mention that a recent report by Monti et al. [ 21 ] emphasizes the safety and efficacy of IFN-ribavirin therapy in HCV- and LKM1-positive patients, which is at variance with the occasional increases in alanine transaminase levels observed in LKM1-positive patients during IFN therapy (possibly due to latent autoimmune hepatitis triggered by IFN); in our study, only 1 of the 4 HCV- and LKM1-positive patients who received treatment was a long-term responder, but none had an increase of transaminases that required withdrawal of treatment. The low titer and the specificity of the autoreactivities detected in our series may explain, at least in part, our results: no patient had samples that showed the immunofluorescence pattern for SMA that is usually observed in type 1 autoimmune hepatitis [ 22 ]; similarly, the homogeneous ANA pattern, which is typical of type 1 autoimmune hepatitis, was detected only in 1 of 10 ANA-positive patients. As expected [ 23 ], the NOSA profile during treatment and follow-up was widely heterogeneous, without specific correlations to the outcome of therapy. Of interest, both patients for whom the NOSA titer developed and increased during treatment were nonresponder (one patient was LKM1 positive, and the other was SMA-V positive). Recently, Wasmuth et al. [ 14 ] studied the relevance of NOSA positivity among patients with hepatitis C who were treated with IFN-ribavirin. In their series, which involved a small number of AMA-positive patients and no LKM1-positive patients, they observed a rate of long-term response among NOSA-positive subjects that was lower than that observed in our study (43.8% vs. 54.5%). Differences in the number of cases studied as well as the fact that we found a higher rate of long-term response (irrespective of NOSA status) could account for the discrepancy observed in these 2 studies. Our results seem to agree with those recently reported by Stroffolini et al. [ 24 ], who analyzed a large series of HCVinfected patients to see whether the so-called autoimmune profile could affect the severity of the disease. They did not report adverse events that were associated with autoimmunity during or after the therapy or any difference in treatment response [ 24 ]. However, because the raw data on the outcome of treat506 • CID 2005:40 (15 February) • Muratori et al. ment are missing, a direct comparison with our findings is not possible. The overall rate of long-term response, irrespective of NOSA status, observed in this study was similar to results of randomized controlled trials involving IFN-ribavirin or PEG-IFN–ribavirin [ 25, 26 ]. In addition, HCV-1 infection and high g-GT level have been shown to be independent negative predictive factors of response. Although it is widely accepted that HCV1 is a negative predictive factor of treatment response, the negative prognostic significance of high serum g-GT levels has been reported only in a couple of studies [ 27, 28 ] and needs to be confirmed in a large series. In summary, our results demonstrate that combined IFNribavirin treatment is safe and effective in NOSA-positive patients with HCV-related chronic hepatitis for whom the diagnosis of probable or definite autoimmune hepatitis has been ruled out on the basis of their International Autoimmune Hepatitis Group score. With reference to the response to antiviral treatment, the presence of HCV-1 is the only negative predictive factor for NOSA-positive patients. HCV-1 infection and elevated serum levels of g-GT are independent negative predictive factors of response to antiviral treatment, irrespective of the patient’s NOSA status. Acknowledgments Potential conflicts of interest. All authors: no conflicts. 1. Cassani F , Cataleta M , Valentini P , et al. Serum autoantibodies in chronic hepatitis C: comparison with autoimmune hepatitis and impact on the disease profile . Hepatology 1997 ; 26 : 561 - 6 . 2. Clifford BD , Donahue D , Smith L , et al. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C . Hepatology 1995 ; 21 : 613 - 9 . 3. Lenzi M , Bellentani S , Saccoccio G , et al. Prevalence of non-organspecific autoantibodies and chronic liver disease in the general population: a nested case-control study of the Dionysos cohort . Gut 1999 ; 45 : 435 - 41 . 4. 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Muratori, Paolo, Muratori, Luigi, Guidi, Marcello, Granito, Alessandro, Susca, Micaela, Lenzi, Marco, Bianchi, Francesco B.. Clinical Impact of Non—Organ-Specific Autoantibodies on the Response to Combined Antiviral Treatment in Patients with Hepatitis C, Clinical Infectious Diseases, 2005, 501-507, DOI: 10.1086/427285