Transcript Nove smjernice u liječenju hepatitisa C

Individualni pristup u liječenju
bolesnika s kroničnim C hepatitisom
Smjernice Hrvatske konsenzus konferencije 2009
Prof.dr.sc. Adriana Vince
Referentni Centar za dijagnostiku i liječenje
virusnih hepatitisa RH
Zagreb, 15.5.2009
Rezolucija o virusnom
hepatitisu
• 10.03.2009 Odbor za zdravstvo Hrvatskog
sabora jednoglasno je usvojio Rezoluciju o
virusnom hepatitisu, kojom se ističe
javnozdravstveni značaj virusnih hepatitisa i
obvezuje Ministarstvo zdravstva na donošenje
Akcijskog plana za borbu protiv virusnog
hepatitisa (prema Deklaraciji Europskog
parlamenta)
Hepatitis C Virus Infection
Natural History
Acute HCV
Resolved
15% (15%)
Chronic HCV
85% (85%)
Stable
80% (68%)
HCC, hepatocellular carcinoma
Cirrhosis
20% (17%)
Slowly
progressive
75% (13%)
HCC
Liver failure
25% (4%)
Putevi prijenosa HCV
• Perkutani put
• Intravensko uživanje opojnih droga
• Transfuzije krvi i krvnih pripravaka
• Dijagnostički i terapijski postupci ( hemodijaliza, instrumenti I
sl)
• Ubodni incidenti
• Permukozni
• Perinatalno
• Spolni put
• Ostale nedokazane mogućnosti: frizer, tatoo, kozmetičar,
pediker, body piercing
Broj genotipova HCV-a analiziranih u novodijagnosticiranih
bolesnika u Klinici za infektivne bolesti od 1996. do 2008.
Godina
Broj analiziranih
genotipova HCV-a
1996
215
1997
299
1998
262
1999
164
2000
170
2001
360
2002
262
2003
351
2004
481
2005
276
2006
252
2007
256
2008
217
HZZT
380-400
genotipizacija
godišnje
Distribucija genotipova HCV-a u bolesnika liječenih u
Referentnom centru za virusni hepatitis tijekom 2008. g.
Genotip HCV-a
Broj bolesnika
1a
24 (10.9%)
1b
76 (34.8%)
1
28 (12.8)
3a
78 (35.6%)
4
11 (5%)
2
2 (0.9%)
Ukupno
219
Dosadašnja terapija kroničnog
hepatitisa C
Učinak kombinirane terapije
• Pegilirani interferon
• Direktni antivirusni učinak
• Imunomodulatorni učinak
• Ribavirin
• Inhibira sintezu nukleinskih kiselina
• Imunomodulatorno djelovanje
• Eliminacija zaraženih hepatocita
Točke procjene virološkog odgovora
• EVR (Early virological response)-nedetektabilna
HCV RNA nakon 12 tj. th.
• ETR (End of treatment virological response)nedektabilna HCV RNA nakon završetka th
• SVR (Sustained virological response)nedektabilna HCV RNA 24 tjedna nakon
završetka terapije
• RVR (Rapid Virological Response)nedetektabilna HCV RNA nakon 4 tj. th.
Ciljevi terapije KHC
• Postizanje SVR-a
• - u 99 % slučajeva- trajna eradikacija virusa,
u većini slučajeva i “izliječenje”
• - zaustavlja se daljnje oštećenje jetrenog
parenhima
•
•
regresija stupnja fibroze
smanjuje se rizik za HCC
Histologic Progression of HCV
Monitored by Liver Biopsy
Inflammation Grade

Measure of severity and ongoing disease activity

0-4 (METAVIR)

Inflammation leads to scarring/fibrosis
No fibrosis
Fibrosis Stage

Amount of fibrous scar tissue

0-4 (METAVIR)

Stage 4 = cirrhosis

Indicates long-term disease progression
Cirrhosis
Brunt EM. Hepatology. 2000;31:241-246.
Factors Associated With SVR
•
•
•
•
•
•
•
•
•
Pretreatment or fixed
Genotype
HCV RNA level
Histology
Race
HIV coinfection
Steatosis
Body weight
Adherence
Dynamic factors
• Rapid virologic response
(HCV RNA negative at Wk 4)
• Early virologic response
• Partial (HCV RNA decline
of
> 2 logs at Wk 12)
• Complete (HCV RNA
negative at Wk 12)
Definitions of On-Treatment Response
Response
Definition
RVR
HCV RNA negative (< 50 IU/mL) at Wk 4
EVR
Complete
EVR
Partial
EVR
Non-EVR
HCV RNA positive at Wk 4 but negative at Wk 12
HCV RNA positive at WK 4 and 12 but  2 log10
IU/mL drop from baseline at Wk 12
< 2 log10 IU/mL drop from baseline at Wk 12
Virologic Responses
HCV RNA (log10 IU/mL)
8
7
PegIFN/RBV
6
5
EVR
2 log10 decline
4
3
2
1
Slow virologic response
RVR cEVR
Limit of detection
SVR
0
0 4 8 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
Suboptimal Virologic Responses
HCV RNA (log10 IU/mL)
8
7
PegIFN/RBV
6
Null
response
Partial
response
5
4
Relapse
Breakthrough
2 log10 decline
3
2
Limit of detection
1
0
0 4 8 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
Duration of Undetectability
106
Undetectable 44 wks
105
HCV RNA
Undetectable 36 wks
104
Undetectable
28 wks
103
102
101
UND
0
4
8
12
20
24
Wks of Treatment
//
48
Viral Kinetics and Outcome Importance of Rapid
Virologic Response
Virologic Response (%)
100
91 91
80
94
90
90
86
PegIFN
+ RBV (N = 453)
EOT response
SVR
72
60
60
48
43
40
20
13
2
0
HCV RNA Status
Wk 4
Wk 12
Wk 24
Neg
Neg
Neg
> 2 log
Neg
Neg
< 2 log
Neg
Neg
> 2 log
> 2 log
Neg
< 2 log
> 2 log
Neg
Any
Pos
Pos
Reprinted from Journal of Hepatology, 43, Ferenci P, et al, Predicting sustained virological responses in chronic hepatitis C patients treated with
peginterferon alfa-2a (40 KD)/ribavirin, 425-433, 2005
Molekularna dijagnostika
Da bismo točno mjerili virusnu kinetiku
moramo imati pouzdane testove za
mjerenje viremije
Clinical molecular assays for HCV RNA
quantification
•
Automated real-time PCR assays (qualitative and quantitative)
•
Examples of assays most widely used in Europe:
•
•
•
bDNA assay (quantitative)
•
•
Versant HCV RNA test (615-7 700 777 IU/ml, Simmens)
Classical RT-PCR assay (qualitative)
•
•
Cobas Ampliprep/TaqMan HCV RNA test (linear range 10-200 000 000 IU/ml)
Abbot RealTime HCV Assay (linear range 12-100 000 000 IU/ml)
Cobas Ampliprep/Cobas Amplicor HCV RNA (50 IU/ml, Roche)
Quantitative assay
•
Cobas Amplicor Monitor HCV test, konvencionalni PCR, 600-700 000 IU/ml
Analytical variability of HCV RNA assays used in clinical
diagnostics
Significant differences in HCV RNA viremia observed in wk4 and wk12
Between Versant bDNA and Roche TaqMan assay (p<0.001)
Halfon et al, J Med Virol, 2006
Analytical variability of HCV RNA assays
according to genotype
Significantly higher viremia measured by Abbott and Roche real-time PCR
Compared with bDNA for genotypes 1, 2 and 3
For genotype 4, viremia measured by Abbott and Versant were equivalent
but values for Roche PCR assays were lower
Caliendo et al, 2006
Nove spoznaje
• Virusna dinamika/kinetika najbitniji prediktor
za postizanje SVR-a
• Svi pacijenti s genotipom 2,3 nisu “easy to
treat”
• Svi pacijenti s genotipom 1,4 nisu “difficult to
treat”
• Response guided therapy (individualni
pristup)
Osnovni cilj individualiziranog pristupa
liječenju (response-guided therapy)
• Povećati postotak SVR-a, osobito u
populaciji G1 pacijenata
• Produljenjem liječenja (ovisno o virusnoj
kinetici)
• Povišenjem doze ribavirina
Meta-analysis of Response-Guided
Treatment for Hepatitis C
•
12 published RCTs from 2004-2008 comparing different durations of
pegIFN/RBV (N = 2399)
• 5 studies compared 48 vs 72 weeks of treatment for slow
responders with HCV GT 1 (n = 355)
• 7 studies compared 24 vs 12, 14, or 16 weeks of treatment for rapid
responders with HCV GT 2/3 (n = 2054)
• Studies grouped by fixed-dose (ie, 800 mg/day) or weight-based
RBV
• HCV GT 2/3 patient analysis also categorized by suboptimal short
therapy vs optimal short therapy
• Suboptimal short therapy: 12 or 14 weeks of treatment or fixeddose
RBV 800 mg/day administered (n = 1782)
• Optimal short therapy: 16 weeks of treatment and weight-based
RBV administered (n = 272)
Di Martino V, et al. AASLD 2008. Abstract 213.
Extended Genotype 1 HCV Peginterferon
alfa/ribavirin Treatment to 72 Weeks for Slow
Responders
Meta-analysis
• Slow virologic responders with genotype 1 HCV
• - Pooled estimate of SVR increase with 72 vs 48 weeks of
treatment: 12% (95% [CI]: 5% to 19%)
• - No benefit of extended treatment observed for patients who had
undetectable HCV RNA at Week 12
• 72 weeks of peginterferon alfa/weight-based ribavirin more effective
than 48 weeks for producing sustained virologic response (SVR) in
patients with genotype 1 HCV who had a slow virologic response to
treatment
Di Martino V, Richou C, Thévenot T, Sánchez-Tapias JM, Ferenci P. Modulations of peg-interferon plus ribavirin duration according to HCVgenotype and virologic response at W4 and W12: meta-analyses of RCTs with individual data. Program and abstracts of the 59th Annual
Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract
213.
POWeR Study
• SVR and EOT responses significantly higher in patients with
baseline mild to moderate fibrosis (F1-F2) compared with those
with baseline fibrosis or cirrhosis (F3-F4)
• Relapse rates also higher in F3-F4 patients vs F1-F2: 35% vs
18%, respectively (P = .0009)
• Virologic response by baseline HCV RNA (n = 651)
•
- Among patients with mild to moderate fibrosis (F1-F2) and
baseline HCV RNA assessment (n= 391), SVR rates
significantly higher for patients with low HCV RNA
•
- Among patients with bridging fibrosis or cirrhosis (F3-F4) and
baseline HCV RNA assessment (n = 260), no significant
difference in SVR rate by HCV RNA
Marotta P, Cooper C, Wong DK, et al. Impact of advanced fibrosis and cirrhosis on sustained virologic response of
HCV G1-infected patients: results of the Canadian POWeR program. Program and abstracts of the 59th Annual
Meeting of the American Association for the Study of Liver Diseases; October 31-November 4, 2008; San Francisco,
California. Abstract 1216.
ACCELERATE study
• Genotype 2/3, peginterferon alfa-2a
• Patients with RVR
•
-SVR (therapy for 24 weeks)- 85%
•
-SVR (therapy for 16 weeks)-79%
• Non-RVR patients
•
- SVR (therapy for 24 weeks)- 45%
• Longer duration of therapy (48 weeks) in non-RVR
patients may reduce relapse and lead to signifficantly
higher rates of SVR

Shiffman et al. HCV patients with genotype 2 and 3 who do not achieve a Rapid Virological
Response (RVR) with peginterferon alfa-2a (Pegasys) and ribavirin (Copegus) are not easy to
treat: An analysis of non-RVR patients from the ACCELERATE study. Hepatology 2007:46(Suppl
1):Abstract 164.
Lowered RBV Exposure as a Predictor of
Relapse Following PegIFN/RBV
• Reduced cumulative RBV exposure independently and
significantly predicted relapse rates
• Individuals receiving 50% of RBV target dose more than twice as
likely to relapse
• Risk of relapse increased gradually with amount of dose reduction
Cumulative RBV Exposure
OR for
Relapse
(95% CI)
P Value
1.2 (1.0-1.3)
1.4 (1.0-1.8)
2.1 (1.1-4.2)
.0257
.0257
.0257
Model 1: decrease from target
dose
• 10%
• 20%
• 50%
Reddy R, et al. AASLD 2008. Abstract 1283.
Dosadašnje smjernice za
liječenje kroničnog hepatitisa
C u RH
Liječenje kroničnog hepatitisa CHZZO
(dopuna 27.05.2008.)
• bolesnici u dobi do 65 godina koji apstiniraju od i.v. droga i alkohola
najmanje 12 mjeseci uz potvrdu liječnika specijalista koji liječe bolesnika i
koji zadovoljavaju slijedeće kriterije:
• a. virološki kriteriji: anti HCVpozitivan; HCV RNA (PCR) pozitivan;
• viremija dulje od 6 mjeseci;
• b.biokemijski kriteriji: 2x povišen ALT u dva uzastopna laboratorijska nalaza,
bez obzira na stupanj fibroze; normalan ALT sa stupnjem fibroze većim od
F2;
• c. histološki kriteriji: dokaz kronične upale, odnosno verifikacija stupnja
aktivnosti i stadija fibroze (osim kod kontraindikacija za biopsiju jetre);
• d. bolesnici prethodno liječeni konvencionalnim interferonom, koji imaju
dokazani relaps bolesti pozitivnim nalazom HCV RNA (PCR metodom) u
serumu;
• e. isključiti bolesnike s prisutnim kontraindikacijama za terapiju pegiliranim
interferonom.
Genotip 1
• Pegilirani interferon alfa-2b 1.5 mcg/kg
1xtjedno uz ribavirin/TT u trajanju 48 tjedna
• Pegilirani interferon alfa-2a 180 mcg 1xtjedno
uz ribavirin/TT u trajanju 48 tjedna
• Uz određivanje EVR-a kod osoba s viremijom>600
000 IU/ml
• Uz određivanje RVR-a kod osoba s niskom
viremijom<600 000 IU/ml seruma
Genotip 2 i 3
• Pegilirani interferon alfa-2b 1.5 mcg/kg
1xtjedno uz ribavirin u trajanju 24 tjedna
• Pegilirani interferon alfa-2a 180 mcg 1xtjedno
uz ribavirin u trajanju 24 tjedna
Genotip 4,5,6
• Pegilirani IFN-alfa-2a ili alfa-2b+ribavirin u
trajanju od 48 tjedana
• Odrediti EVR (12. tj.)
• - ako je HCV RNA neg. ili pad viremije 2 log
- nastavak th
•
-ako je HCV RNA poz. - prekid th
Rezultati liječenja pegiliranim
interferonom od 2003.-2008. godine
Demographic and histological profile of
patients with chronic hepatitis C (GT1) at
baseline
Number of patients (M/F)
200 (125/75)
Age (years)
43.5 (23-65)
Body weight (kg)
Female:Male ratio
63.7 (48-120)
1.7:1
Risk factors
transfusions
43.86%
parenteral
15.79%
sporadic
7.02%
IVDU
33.33%
Time since exposure (ys)
20.05
Liver biopsy
fibrosis/stage
3.3 (1.074)
HAI
8.3 ( 3.035)
Baseline serum HCV-RNA
< 600,000 IU/mL
> 600,000 IU/ml
24.88%
75.12%
Sustained viral response
genotip 1,4
93% EVR
80% ETR
7%
20%
56% SVR
200
pacijenata
44%
Patients with SVR vs non-responders
Factor (mean)/
response
SVR
Non-responders
p
Age (years)
45.28
44.41
NS
Body weight
(kg)
60.14
70.6
NS
Fibrosis
3.15
4.1
S
1304630
NS
Viremia (IU/ml) 4758012.8
Glavni prediktor relapsa
u naših bolesnika s G1,3
Stadij fibroze
4 (ISHAK)
Nove smjernice za liječenje kroničnog hepatitisa
C u naivnih bolesnika
Hrvatska konsenzus konferencija,
studeni 2008
Referentni Centar za dijagnostiku i iječenje
virusnih hepatitisa
Referentni Centar za kronične bolesti jetre RH
Indikacije za liječenje
• Dob bolesnika- liječenje bolesnika starijih od
65 godina prema “kondiciji” bolesnika
• Biokemijski kriterij- povišen ALT u 2
uzastopna lab. nalaza, bez obzira na stupanj
fibroze
• Histološki kriteriji- liječenje bolesnika s
dokazom fibroze
Individulni pristup
• Uzima u obzir
•
•
•
•
Genotip
Viremiju
Stadij fibroze
Virusnu kinetiku (RVR, EVR)
Terapija kroničnog hepatitisa
C
• pegilirani interferon alfa-2b (Pegintron) 1.5
mcg/kg s.c. jednom tjedno
• pegilirani interferon alfa-2a (Pegasys) 180
mcg s.c. jednom tjedno
• ribavirin 800-1200 mg (ovisno o tjelesnoj
masi (11-15mg/kg TT) p.o. svakodnevno
Genotip 1, Visoka viremija
(>600 000 IU)
Fibroza 1-6
cEVR postignut
Th kroz
48 tj.
pEVR
EVR nije postignut
Viremija u
24. tjednu
PCR neg
Th kroz
72 tj.
Prekid th
PCR poz
Prekid th
Genotip 1, Niska viremija
(<600 000 IU)
Fibroza 1-4
RVR
postignut
Th kroz 24 tj.
RVR nije
postignut
Postupak za
visoku
viremiju
Fibroza 5,6
Postupak kao kod visoke
viremije
Genotip 4,5,6
EVR postignut
Th kroz 48 tj.
EVR nije postignut
Prekid th
Genotip 2,3 Niska viremija
(<600 000 IU)
Fibroza 1-4
RVR postignut
RVR nije postignut
Th kroz 16 tj
Th kroz 24 tj.
Fibroza 5,6
Th kroz od 48 tjedana (ako HCV
RNK negativna nakon 24 tj)
Genotip 2,3, Visoka viremija
(>600 000 IU)
Fibroza 1-4
Fibroza 5,6
Viremija u
24. tjednu
Th kroz 24 tj.
PCR neg.
Th kroz 48 tj.
PCR poz.
Prekid th
Zaključak
• Potrebne promjene u indikacijama za
liječenje kroničnog hepatitisa C
• Nove preporuke za liječenje bolesnika s KHC
•
- genotip 1 uz visoku fibrozu/cirozu
•
- genotip 1- “slow responderi”
•
- genotip 2/3 uz visoku fibrozu/cirozu
•
-genotip 2/3-RVR, skraćenje th kod niske
viremije
Svi naši suradnici:
Ivan Kurelac
Snježana Židovec Lepej
Davorka Dušek
Vjeran Čajić
Jelena Budimir
Ankica Rukavina
Matija Ćorić
Marica Trogrlić
Mario Rubil
Vesna Misir
Mira Turk
Jozefina Stunja
Sanja Naglić
Nena Bolkovec
Dunja Kovačić
Martina Šarić