Management of Extrahepatic Manifestations of Chronic Hepatitis C Mario U. Mondelli Department of Infectious Diseases, University of Pavia, Fondazione IRCCS Policlinico San Matteo Kasr Al-Aini International Post Graduate Course of Hepatology, Cairo University, 10-12 October 2009
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Management of Extrahepatic Manifestations of Chronic Hepatitis C
Mario U. Mondelli
Department of Infectious Diseases,University of Pavia, Fondazione IRCCS Policlinico San Matteo
Kasr Al-Aini International Post Graduate Course of Hepatology, Cairo University, 10-12 October 2009
Chronic Hepatitis C VirusExtrahepatic Manifestations
• Non organ-specific antibodies• Mixed cryoglobulinaemia (Types II & III):
1 minor serological finding ± compatible pathological findings– 2 minor symptoms + 2 serological findings ± compatible
pathological findings
Immune Manifestations of HCVPathogenesis
Monoclonal IgM RF
Cryoglobulin traps HCV
HCV evades theimmune response
Chronic B-cell stimulation by
HCV antigen (E2 ?)
Polyclonal IgG
Y
Y
Y
YGenetic and
environmentalfactors
Y Y
Y
YY
Y
Y
• Are specific viral protein sequence changes or recurrent amino acid motifs responsible for aberrant polyclonal B cell stimulation in chronic HCV infection ?
• Is polyclonal B cell activation a general feature of chronic HCV infection and what are the mechanisms responsible for initiation and maintenance of this phenomenon ?
Questions
HCV Sequence Changes Found in Cryoglobulinaemic patients
• Insertion at position 385 (HVR1) detected in 5 (24%) of 21 patients with cryoglobulinaemia and in none of controls (Gerotto et al., Blood 2001;98:2657-63).
• Two HVR1 positions (389 and 398) and 3 HVR2/CD81-binding site positions (474, 493, 497) associated with cryoglobulinaemia (Hofmann et al., Blood 2004;104:1228-9).
• No specific HVR1 motifs associated with cryoglobulinaemia (Rigolet et al., Leukemia 2005; 19:1070-1076)
AA Insertions within HVR1 in Patients with and without Cryoglobulins
Patient ID Insertion Position No. of clones with changes
Cryo + (6.2%) 117 (1b) TR 387 1/20
171 (1b) ?? ?? ??
28 (2a/c) GLSL
GLTL
404
404
9/11
1/11
169 (2a/c) ASSSM
SSPTA
SSPMA
384
385
385
8/12
3/12
1/12
193 (2a/c) GAG
GTV
385
385
9/10
1/10
Controls (9.1%) 17 (1b) GPG
ELG
385
385
4/12
2/12
191 (2a/c) ARY
TRQ
ARQ
TRR
*
385
385
385
385
6/11
1/11
3/11
1/11
183 (2a/c) RTV
RKT
RTA
384
384
384
2/10
1/10
Bianchettin G et al., J Virol 2007;81:4564-71 .
Weblogo of the Positions Highlighted by the PCA Analysis of 548 HVR1 Sequences.
The higher the letter, the higher the frequency of the amino acid in that position.
• Anti-HBs titers dropped precipitously after rituximab administration in vaccinated patients – Median titers 80 IU/mL before administration dropped to 38 IU/mL after
administration (P < .05)
• 3 of 20 patients with inactive HBV had detectable HBV DNA at Days 92, 146, 320 after 2-3 doses of rituximab
Metzler F, et al. AASLD 2008. Abstract 848.
25020015010050
10080604020
0 100 200 300
400
300
200
100
0
108
106
104
102
-200 0 200 400
30
20
10
00 500 1000
108
106
104
102
Patient 1 Patient 2 Patient 3
Ant
i-HB
s (I
U/m
L)S
erum
ALT
(U
/L)
HB
V D
NA
(IU
/mL)
1st r
ituxi
mab
dos
e
Days Days Days
Patients
Rituximab 250 mg/m2 2 one week apart (n = 36)
Wk 12interim analysis Wk 52
Phase 2 Single-Arm Study on Low-Dose Rituximab for Symptomatic, Refractory Mixed Cryoglobulinaemia
(AIFA Protocol FARM6KMZFY)
Follow-upRituximab 250 mg/mRituximab 250 mg/m22 2 2 one week apart one week apart (n = 16)(n = 16)
50% reduction in BVAS & cryocrit
Size of initial group 16 patientsSize of second group 36 patientsCriterion for stopping on a negative finding at 1st stage 5 or less respondersCriterion for positive finding at 2nd stage: 27 or more respondersSignificance level 0.03Expected number of patients under null hypothesis 46Power 0.85 (expected response rate 60 ± 15%)Expected number of patients under alternative hypothesis 50
(Fiorilli, Mondelli, Zignego, Pozzato, Co-PI’s)
5 or less responders5 or less respondersSTOPSTOP
BASELINE RITUXIMAB (after 2 infusions)
0.16
0.03 0.13 3.14
4 WEEKS 8 WEEKS 12 WEEKS
6.81
16 WEEKS
CD19 FITC
5.29
CD19 FITC CD19 FITC
% B
Lym
ph
ocy
tes
(CD
19+
)
Rituximab
Rituximab
Rituximab
Rituximab
#1 #2
#3 #4
Time (weeks)
B Lymphocyte Count after RITUXIMAB Treatment
Rituximab
• Excellent results on vasculitic ulcers and severe renal involvement.
• No effect on peripheral neuropathy
Clinical, Immunological, and Virological Efficacy of Rituximab ± PEG-IFN2b and Ribavirin
Clinical Team:• Serena Ludovisi• Giuseppe Michelone • Marco Zaramella
Area di Ricerca Infettivologica Fondazione IRCCS Policlinico San Matteo and
University of Pavia
Collaborators:• Franco Negro, Dept.of Gastroenterology, University of Geneva• Anna Tramontano, Dept. of Biochemistry, University of Rome La Sapienza• Milvia Casato, Dept. of Medicine, University of Rome La Sapienza• Giampaolo Merlini, Centre for Amyloidosis, University of Pavia
Chronic Hepatitis C Virus Autoantibodies (cont’d)
• No relationship between presence of autoantibodies and
– Severity of chronic HCV
– HCV genotype
• Correlation between rheumatoid factor titre and
– Cryoglobulinaemia
– But not symptomatic cryoglobulinaemia
• Circulating autoantibodies from autoimmune disorders may result in
– False positive anti-HCV
HCV Prevalence and Crude and Adjusted O.R. in Patients with B-NHL vs. Controls
Total # HCV+ % HCV+ Crude O.R. (95% C.I.)
Adjusted O.R. (95% C.I.)
Controls 396 22 5.6 1 1
Patients with B-NHL
400 70 17.5 3.6 (2.2-6.0) 3.1 (1.8-5.2)
Mele A, et al. Blood. 2003;102:996-999
ANTI-THYROID ANTIBODIES IN PATIENTS WITH VIRAL CHRONIC HEPATITIS
(Preziati et al, 1995)
CH-HCV (n=78)
positiveTiter (KU/l)
CH-HBV (n=49)
positiveTiter (KU/l)
36%(17 – 1190)
0
16%(57 – 836)
10%(64 – 282)
TPO-Ab Tg-Ab
Anti-Thyroid AutoAb
Extrahepatic Effects of HCVPorphyria Cutanea Tarda
2 case series3 uncontrolled series280 patientsAlcohol: 36%-77%
Fargion (1992)
De Castro (1993)
Criber (1995)
Stolzel (1995)
Kondo (1997)
0
20406080100
PCT
0 5 10 15 20
Control
Combined meta-analysis of 7 studies: OR 274.78, CI 104.12-725.13
(Gisbert et al., J Hepatol 2003;39:620-7.)
CharacteristicHCV
Sialadenitis
Primary
Sjögren’s Syndrome
SS-A, SS-B Negative Positive
Lymphocytic capillaritis
Mild
Pericapillary
Mostly CD8 cells
Severe
Periductal
Mostly CD4 cells
Sicca syndrome:• Xerophthalmia• Xerostomia
Absent
8%-36%
Present
Present
Extrahepatic Effects of HCVLymphocytic Sialadenitis
Nagao Y, et al. J Gastroenterol Hepatol. 2004;19:1101-1113.
Extrahepatic Effects of HCVLichen Planus
• Occurs in < 1% of the general population• 10%-30% of patients with chronic HCV• Appearance
– Flat topped, violaceous, pruritic papules– Throughout body – Oral mucosa
• Histology– Dense infiltration of dermis with T lymphocytes
Meta-Analysis of Case-Control Studies Comparing the Prevalence of HCV Infection in Patients with PCT and in Healthy Controls.
Gisbert et al., J Hepatol 2003;39:620-7.
Extrahepatic Effects of HCVB-Cell Lymphoma
8 case series1754 pts evaluated
Ferri (1994)
Mazzaro (1996)
Silvestri (1996)
Izumi (1996)
McColl (1996)
Zignego (1997)
DeRosa (1997)
Zuckerman (1997)
0102030
B Cell Lymphoma
0 10 20 30
Controls
Three Signals Are Required to Activate Human Naïve B Cells