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 [
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 .
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
IFN)–ribavirin, both of which give better results than
IFN monotherapy [
]. 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 [
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 [
]. 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 .
We recently reported that NOSA positivity in children
negatively affects their response to IFN monotherapy [
along the same line, Wasmuth et al. [
] 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 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. [
], 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 [
]. LKM1-positive serum specimens were
tested by immunoblot assay (with use of human liver cytosol
as the antigen source, as described elsewhere [
]) 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 [
]. 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 [
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
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).
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
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
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
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 [
]. In adults and, as we have observed [
], 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 [
]. 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 [
]. This apparent
discrepancy may be explained by the different recruitment
criteria used: Cassani et al. [
] evaluated a series of consecutive
patients with overt liver disease, whereas Lenzi et al. [
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 [
]. The results of this study, however, are
not comparable with those of our previous report involving
pediatric patients [
] 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. [
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
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
]; 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 [
], 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. [
] 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. [
], 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
]. 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
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
]. 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 [
] 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.
Potential conflicts of interest. All authors: no conflicts.
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