Akut C ve Kronik hepatit C`li hastanın güncel tedavisi

Akut C ve Kronik hepatit C`li hastanın güncel tedavisi

HCV’DE GÜNCEL
TEDAVİ
Dr Murat ALADAĞ
15 Haziran 2003
MALATYA
Dünyada HCV Sıklığı
WHO. Wkly Epidemiol Rec 2000; 75: 18-9.

Dünya’da prevalans % 3 (1)

Dünya ölçeğinde 130 - 210 milyon kişi Hepatit C ile infekte (1)

Türkiye’de prevalans % 0.5-1(2,3)
1) EASL Clinical Practice Guidelines: Management of hepatitis C virus infection, 2011
2) TKAD 2010
3) VHSD 2010
HCV infeksiyonunun doğal seyri
Primer
infeksiyon
Kronik
infeksiyon
Viral
Klirens
Kronik
Hepatit C
%75-85
Asemptomatik
%75
Siroz
%20
(20-30 yıl)
HCC
%1-4
(Sirozdan sonra
her yıl)
Semptomatik
%25
%15-25
Chen ve Morgan Int J Med Sci 2006
Akut HCV enfeksiyonu
HCV infeksiyonu %50-90 oranlarında
asemptomatik
 2-12 hafta içinde kuşkulu HCV bulaşı
 ALT seviyesinde en az 10 kat ve üzeri artış
 Total bilirubin seviyesindeki artış +/ Anti-HCV pozitif /negatif olabilir
 Anti- HCV negatif iken pozitifleşmesi
önemli.
-Hepatit C kesin tanısı serumda HCV RNA
pozitifliği…
 Akut

Akut HCV enfeksiyonu
Anti-HCV pozitif /negatif olabilir
(Anti- HCV negatif iken pozitifleşmesi önemli)


Hepatit C kesin tanısı için serumda HCV
RNA’nın pozitifliği gereklidir
Akut HCV tedavi
 Semptomatik olgularda tedavi için
 8-12 hafta beklenmeli
• spontan iyileşme oranı %15-25
 Tedavide
• Pegile IFN-alfa
• 12. haftada HCV RNA seviyesinde 2 log
azalma koşulu aranmaz
• Tedavi süresi en az 6 ay
(ribavirin kullanımı olgu bazında değerlendirilmeli)
AASLD 2004
7
Annual age-adjusted mortality rates from hepatitis B and hepatitis C virus and HIV infections listed as causes of death in the
United States between 1999 and 2007.Because a decedent can have multiple causes of death, a record listing more than 1 type of
inf...
Ly K N et al. Ann Intern Med 2012;156:271-278
©2012 by American College of Physicians
Time is critical

The average age of an HCV-infected patient is
approximately 55 yrs




Perhaps 40% have cirrhosis
10,000-15,000 die each year and is increasing
Only 25-30% of HCV patients have been
diagnosed
Only 11% have been treated
Objectives




Patterns of response
Predictors of response
Past therapies
Understanding the life cycle of HCV


Current treatments


Targets for anti-HCV drugs
Existing data
Future directions
Patterns of response
HCV RNA
NR (null responder)
Breakthrough
2 log↓
LVR
Relapse
RVR
eRVR
< 25 IU
cEVR
0
4
8
pEVR
12
24
36
Time (weeks)
48
72
Standart tedavi

pegINF ve ribavirin
48 hafta
Genotip 1,4,5,6
SVR %40-50
pegINF ve ribavirin
24 hafta
Genotip 2,3
>SVR %80
Virolojik kür
YENİ GELİŞME: DİREKT ETKİLİ ANTİVİRAL AJANLAR
Genotip 1 için yanıt süresine
göre tedavi
HVR
4.hafta
HCV RNA negatif
HCV RNA pozitif
(400.000 IU/ML)
24 hafta tedavi
EVR
12.hafta
negatif
2 log
azalma
Tedaviyi kes
48 hafta tedavi
24. hafta
2 log
azalma
negatif
48-72 hafta tedavi
pozitif
Tedaviyi kes
Genotip 1 için yanıt süresine göre tedavi
Genotip-1
HCV RNA
≥600 000 IU/ml
<600 000 IU/ml
4. Hafta HCV RNA
Pozitif
Negatif
12. Hafta HCV RNA
≥ 2 log azalma
24 hafta tedavi
24 hafta takip
< 2 log azalma
24. hafta PCR HCV RNA
Pozitif
Negatif
48 hafta tedavi
24 hafta
takip
Tedaviyi kes
(sirotikse idame?)
Manns MP, e tal. Gut 2006; 55: 1350-59.
Past HCV Therapy (2001-2010)
PegIFN + RVN
100
90
80
70
60
% SVR
50
40
30
20
10
0
RVR
cEVR
pEVR
GT 1 and 4
LVR
RVR
EVR
GT 2 and 3
Predictor of Response

Favorable









Genotype 2 and 3
HCV RNA < 400,000 IU/ml
Mild fibrosis (F0-F2)
Non-African American
Age < 40
IL28B CC
Adherence
RVR
cEVR

Unfavorable











Genotype 1
HCV RNA > 400,000 IU/ml
Advanced fibrosis (F3-F4)
African American
Age > 40
Steatosis
Insulin Resistance
Increased BMI
IL28B CT or TT
Dose reduction > 60%
Non-adherence
IL28-B POLYMORPHISM
IMPACT ON SVR
100
SVR (%)
80
60
40
20
0
TT
D Ge et al.
Nature 2009; 461:399-401.
TC
CC
IL28-B POLYMORPHISM AND SVR
IMPACT OF RACE AND ETHNICITY
100
Asians
SVR (%)
80
Caucasians
60
Hispanics
40
20
African Americans
0
30
40
50
60
70
80
IL28B CC HAPLOTYPE (%)
D Ge et al.
Nature 2009; 461:399-401.
90
100
IL28-B POLYMORPHISM
IMPACT OF RACE AND
RESPONSE
100
SVR (%)
RVR
80
No RVR
60
40
20
0
CC
Non-CC
Caucasian
A Thompson et al.
AASLD abstract 2009; LB5.
CC
Non-CC
African American
Outdated Strategies

Higher doses of PEG or RBV


Another kind of ribavirin (taribavirin)



Lower anemia rates
Similar SVR if dosed properly
Another kind of interferon


No real improvements on SVR
Consensus, albumin-interferon, continuous infusion
Longer duration


Best for slow responders
Difficult to tolerate
Where are we now?
24
HCV Life Cycle and DAA
Targets
Receptor binding
and endocytosis
Transport
and release
Fusion and
uncoating
ER lumen
(+) RNA
LD
LD
Translation and
NS3/4 protease
polyprotein
inhibitors
processing
Membranous
web
Virion
assembly
LD
ER lumen
NS5A* inhibitors
*Role in HCV life cycle not well defined
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
NS5BRNA
polymerase
inhibitors
replication
Nucleoside/nucleotide
Nonnucleoside
HCV Polyprotein Processing
and Viral Protein Function
McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12
New Agents
Telaprevir
Protease inhibitor (NS3/NS4A)
Phase ¾
Boceprevir
Protease inhibitor (NS3/NS4A)
Phase 3/4
ITMN-191 (R7227)
Protease inhibitor (NS3/NS4A)
Phase 2
BI12202
Protease inhibitor (NS3/NS4A)
Phase 2
TMC435350
Protease inhibitor (NS3/NS4A)
Phase 2
MK7009
Protease inhibitor (NS3/NS4A)
Phase 2
R1728
Nucleoside Polymerase inhibitor (NS5B)
Phase 1
MK-0608
Nucleoside Polymerase inhibitor (NS5B)
Phase 1
GS9190
Non-nucleoside Polymerase inhibitor (NS5B)
Phase 1
Filibuvir (PF00868554)
Non-nucleoside Polymerase inhibitor (NS5B)
Phase 1/2
VCH-759
Non-nucleoside Polymerase inhibitor (NS5B)
Phase 1
BMS-790052
NS5A inhibitor
Phase 1
Nitozoxinide
Host-pathway
Phase 2
DEBIO-025
Cyclophilin inhibitor
Phase 2
NIM811
Cyclophilin inhibitor
Phase 1
CTS-1027
Matrix metalloproteinase inhibitor
Phase 1/2
Telaprevir in GT 1
ADVANCE and REALIZE trials
90
80
70
60
% SVR 50
T+P+R
P+R
40
30
20
10
0
Naïve
Relapser
Partial
Responder
Nul
Responder
Telaprevir
Genotype 1a vs. 1b
90
80
70
60
%SVR
50
1a
1b
40
30
20
10
0
Naïve (T12/PR48)
Relapser
Partial
Responder
Null Responder
Boceprevir in GT1
SPRINT 2 and RESPOND 2
80
70
60
50
%SVR 40
B+P+R
P+R
30
20
10
0
Naïve
Relapser
Partial
Responder
TREATMENT OF CHRONIC HCV
RESPONSE GUIDED THERAPY
It is essential that HCV RNA be monitored
at regular intervals and that the time the
patient becomes HCV RNA negative be
defined.
The sooner a patient becomes HCV RNA
undetectable during treatment the lower the
relapse rate and the shorter the course of
therapy.
The longer it takes for a patient to become
HCV RNA undetectable the longer they
must remain on treatment to limit relapse.
ADVANCE: Telaprevir with Response Guided
Therapy in naïve HCV-1
eRVR = HCV RNA(-) @W4,12: Yes 24W, No 48W
TPV 750 mg q8h; PEG-2a; WB RBV
100
P < 0.0001
SVR (%)
80
60
P <0.0001
75
69
44
40
20
0
PegIFN/RBV +
Placebo 48w
(n=361)
eRVR, %
Relapse, %
DC rash, T or Pl/all %
DC any AE,%
8
28
1/0
4
TPV 12w+
PegIFN/RBV
RGT (n=363)
58
9
7/1.4
7
TPV 8w+
PegIFN/RBV
RGT (n=364)
57
9
5/0.5
8
Jacobson I et al, NEJM 2011;364:2405-16
ILLUMINATE: Randomized trial of short vs.
long duration Rx after eRVR
Gt 1 naive
(N=540)
Peg2a /WB RBV/TPV x 12 wks
Randomize
+12 wks P/R
(n=162)
SVR
92%
met noninferiority criteria
 A truncated
PEG/RBV/TPV regimen
preserves high rates of
SVR following eRVR

Wk 4, 12 HCV RNA (-)
65.2% (n=352)
+36 wks P/R
(n=160)
SVR
87%
Sherman K et al, AASLD 2010; abstract LB-2
Response Guided Therapy with Boceprevir
non-cirrhotic
HCV RNA
Undetectable
< 100 IU/mL
Undetectable
Lead in
BOC + P + R
PR
0
4
8
Detectable
12
eRVR, stop at week 28
24
< 100 IU/mL
28
36
48
Undetectable
No RVR
BOC + P + R
PR
0
4
8
12
24
Stop
PR
28
If HCV RNA > 100 IU/mL
36
48
Response Guided Therapy with Telaprevir
non-cirrhotic naïve or experienced relapsers
HCV RNA
Undetectable
Undetectable
Undetectable
P+R
T+P+R
0
4
8
Detectable
12
24
< 1000 IU/mL
eRVR, stop at week 24
28
36
48
Undetectable
No RVR
T+P+R
0
4
8
PR
12
24
Stop
28
36
If HCV RNA >1000 IU/mL
48
Treatment of Null Responders and
Cirrhotics
HCV RNA
Undetectable
< 100 IU/mL
Undetectable
Non-cirrhotics stop week 36
Cirrhotics continue to week 48
Lead in
BOC + P + R
PR
0
4
8
12
24
36
48
HCV RNA
Undetectable
Undetectable
P+R
T+P+R
0
4
Undetectable
8
12
24
28
36
48
Adverse Events with DAA
Telaprevir
T/P/R
P/R
Pruritis
45-50%
28%
Nausea
40-43%
31%
56%
34%
Anemia
37-39%
19%
Diarrhea
28-32%
17%
11%
3%
Rash
Anorectal discomfort
Boceprevir
Anemia
50%
30%
35-43%
16%
Neutropenia
25%
19%
Nausea
46%
42%
Dysgeusia
Telaprevir Rash Summary


In most subjects, the rash was mild-moderate
Severe rash in 4% resulting in discontinuation in
6% of subjects



Occurred early, usually first 4 weeks but can occur at any
time during TVR exposure
< 1% had Stevens Johnson Syndrome or DRESS
Treated with oral antihistamines, topical and/or
systemic steroids
No data available on effectiveness
 Systemic steroids are not recommended

Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee
/UCM252561.pdf. Accessed May 20, 2011.
Drug-Drug Interactions

Boceprevir
Strong inhibitor of CYP3A
 Partly metabolized by CYP3A


Telaprevir
Substrate of CYP3A
 Inhibitor of CYP3A

Important Safety Information
Contraindicated Drugs and Other Precautions
for Telaprevir
Contraindicated
Potential for
increased toxicity
from concomitant
medication
Not recommended
Alfuzosin
(UroXatral)
Methylergonavine
(Methergine)
Amiodarone
(Cordarone, Pacerone)
Midazolam oral*
(Versed)
Dihydroergotamine
(D.H.E. 45 and Migranal)
Pimozide
(Orap)
Ergonvine
(Ergonovine Maleate)
Propafenone
(Rythmol)
Ergotamine
(Ergomar)
Flecainide
(Tambocor)
Lovastatin
(Altocor, Altoprev, Mevacor)
Quinidine
(Quinaglute Dura-Tabs,
Quinidex Extentabs,
Cardioquin, Quinora)
Budesonide inhaled
(Pulmicort Flexhaler,
Pulmicort Respules)
Use with caution
Alprazolam*
(Niravam, Xanax)
Atorvastatin* (Lipitor)
Nifedipine
(Adalat, Afeditab CR,
Nifediac, Nifedical,
Procardia)
Bosentan (Tracleer)
Nisoldipine (Sular)
Clarithromycin (Biaxin)
Posaconazole (Noxafil)
Colchicine§ (Colcrys)
Sildenafil for ED (Viagra)
Desipramine (Norpramin)
Tadalafil for ED (Cialis)
Digoxin* (Lanoxin)
Telithromycin (Ketek)
Diltiazem
(Cardizem, Dilacor,
Tiazac)
Tenofovir* (Viread)
Amlodipine* (Norvasc)
Colchicine†
(Colcrys)
Cyclosporine*‡
(Atopica, Gengraf, Neoral,
Sandimmune,
Fluticasone inhaled
(Flovent)
Salmeterol
(Serevent)
Sildenafil for PAH
(Revatio)
Sirolimus‡
(Rapamune)
Simvastatin
(Zocor)
Tacrolimus*‡
(Prograf )
Triazolam
(Halcion)
Tadalafil for PAH
(Adcirca)
Erthromycin
(E.S.P., Eryzole, Pediazole,
Sulfimycin)
Felodopine (Plendil)
Voriconazole
(Vfend)
Nicardipine (Cardene)
Itraconazole (Sporanox)
*These interactions have been studied; †Impaired renal/hepatic function; ‡No clinical data are available regarding the treatment of
Ketoconazole*
organ transplant patients with TRADENAME in combination with peg-IFN/RBV. Therefore, the use of TRADENAME in organ
transplant
(Feoris, Nizoral)
patients is not recommended; §Normal renal/hepatic function.
Lidocaine (Xylocaine)
Trazadone
(Desyrel, Oleptro)
Vardenafil
(Levitra, Staxyn)
Verapamil
(Calan, Covera, Isoptin,
Verelan)
Warfarin
(Coumadin, Jantoven,
Marfarin)
Drugs that are contraindicated
Telaprevir and Boceprevir
Effect
St. Johns Wort
May reduce virologic response
Rifampicin
May reduce virologic response
Ergot drug class
Potential for ergot toxicity
Lovastatin, simvastatin
Potential for myopathy
Sildinafil (in Tx of pulmonary HTN) Potential for PDE5 associated AE
Midazolam (oral)
Prolonged sedation
Triazolam
Prolonged sedation
Boceprevir
Phenobarbitol, Phenetoin,
Carbamezepine
May reduce virologic response
Oral contraceptives
(Drosperinone)
Potential for hyperkalemia
Monitoring HCV RNA

Package inserts for TVR and BOC specific
different time points during therapy.
TVR weeks 4, 12, and 24
 BOC weeks 8, 12 and 24



Different labs use different assays.
Different thresholds for using RGT.
TVR week 4 1000 IU/mL
 BOC week 8 100 IU/mL


Different thresholds for defining futility.
Stopping Rules
Telaprevir
Time point
HCV RNA
Action
Week 4 or 12
> 1000 IU/mL
Stop T/P/R
Week 24
Detectable
Stop P/R
Boceprevir
Time point
HCV RNA
Action
Week 8 or 12
> 100 IU/mL
Stop B/P/R
Week 24
Detectable
Stop P/R
İLAÇ REZİSTANSMONİTORİZASYONU



NS3/4A nın katalitik domaini-mutasyonlar
Cross rezistans var
Antiviral rezistan varyantlar: Bazal dönemde %7
BOC, %5 TVR. Ancak bu PI ile uzun dönem
sonuçları etkilemiyor. Bazal rezistans analizine gerek
yok




BOC: Naiv olgularda tedavi sırasında %16 olguda direnç.
İlk 4 hf lık Peginf+ribavirin ile HCV RNA 1 log dan az
düşme BOC için artmış direnç riskidir.
TVR: Naiv olguda %12 tedavi almış olguda %22
İnterferon yanıtsızlığı: PI’lerine direnç artar.
Genotip 1a>1b
ANTİVİRAL İLAÇ DİRENCİ
BİR PI/İLACA DİRENÇ VARSA
DİĞERİNE GEÇİLMEZ !
So, are we there yet?

Not yet, but we are getting there.
New
Combinations
New
DAAs
Genetic
tests
EMR
Peg
RVN
DAA
Resistance
Increasing Complexity
Of HCV Management
RGT
E-scribe
Cost
Compliance
Identifying Candidates For Triple
Therapy
Host factors
Treatment regimen
Age, gender, race obesity,
co-morbidities
Genetic factors
(IL28B and ITPA)
PEG-IFN
Ribavirin
DAA
Factors to Consider In
Treatment Decisions
Disease features
Fibrosis, steatosis,
co-infection
(HBV, HIV)
Viral factors
Genotype / Subtype
Quasispecies /
Resistance
Viral load
Conclusions




HCV is now more curable than ever.
Standard dose ribavirin and PEG interferon will
remain as backbone of therapy for now.
DAA
 ? Need for lead in phase to minimize development
of resistance and identify those with RVR that may
not need additional agents.
 Newer antiviral agents with few side effects
 Combining agents of different classes to avoid
interferon and/or ribavirin
Frequent HCV RNA testing.
The Future
0
10
PEG/RBV
PI+PEG+RBV
PI2+PEG+RBV
20
30
40
%
50
DAA1 + DAA2 + RBV
60
70
80
90
100
2011
2012
2013
2014
2015
2016
2017
2018
2019
Unanswered Questions






How does IL28B testing fit in with DAA
therapy?
Do we still need to biopsy all patients?
Will DAA ever be used for GT 2 and 3?
Does it make a difference what Peg is used?
When will interferon free regimens really be
here?
Will we ever have a HCV vaccine?
SONUÇ OLARAK






HCV’nin yeni standart tedavisi olarak düşünülen
proteaz inbitörleri her vakada kullanılacak kadar;
Çok yüksek etkinlikte, yan etkisiz, tedaviye uyumu kolay
ve ucuz değildir.
Gelecek tedavileri riske atacak direnç problemleri
vardır.
Tedavide seçici olunmalıdır.
Uyum çok önemli
Hem BOC hem de TVR tedavisinde öncü tedavi
uygulaması yararlı olabilir.
53
İNÖNÜ ÜNİVERSİTESİ
DENEYİMİ-AKUT HCV







Toplam 16 hasta
Tanı rastlantısal olarak veya diabet ve diğer
hastalıkları inceleme esnasında konuldu
Tedaviye 4 hastada klasik interferon
12 hastada PEG-INF başlandı
Tüm olgularda tedavi sonu cevap alındı
3 ayda ve 6 ayda negatif
Tedavi sonu 6ay SVR %100
İNÖNÜ ÜNİVERSİTESİ
DENEYİMİ-Kronik HCV

Klasik ikili tedavi
Tedavi sonu cevap (ERV)
 SVR
 1. yılda nüks
 2. yılda nüks
 3. yılda nüks

%80
%60
%10
%20
%27
İNÖNÜ ÜNİVERSİTESİ DENEYİMİKr HCV Yüksek doz Ribavirin
Olgu sayısı
32
 Yaş ortalaması
42 (18-65)
 HCV-RNA
320 (75-1600.000)
 RVR
23 (%71.8)
 12. hafta RNA Negatif
29 (%90.62)
 24. hafta RNA Negatif
30 (%93.75)
 SVR
29 (%90.62
 Sadece 2 olguda HCV-RNA>400.000 idi
 Tedavinin 3. Ayından sonra cevap veren bir olguda
tedavi kesilmesindne sonra nüks olduğu görüldü.

İNÖNÜ ÜNİVERSİTESİ
DENEYİMİ-Tx olguları







Toplam 1034 Tx olgumuzun %6.9’ u HCV
T x sonrası HCV tedavisi 1. yılın sonunda
başlandı
Toplam 10 Tx olgusuna tedavi verildi.
Tedavi sonu cevap oranı %80
Kalıcı cevap oranı (SVR) %70
Kan transfüzyonu normal hastalardan daha fazla
gerekli oldu
Halen tedavisi devam eden 2 olgu var
İNÖNÜ ÜNİVERSİTESİ
DENEYİMİ-DAA deneyimi






16 sirotik olgu alındı
Yaş aralığı 53-74
4 hafta HCV-RNA negatifliği %100
12 hafta tamamlayan 9 olgu HCVRNA neg %100
7 olgu tedavi devam ediyor
En sık yan etki -Anal ağrı
-Ağızda tat bozukluğu
-Ciltte kaşıntı ve lezyonlar
-Bir olguda pnömoni
-Anemi, trombositopeni
İNÖNÜ ÜNİVERSİTESİ
DENEYİMİ-DAA deneyimi
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Kan transfüzyonu ihtiyacı çok fazla oldu
Bir olguda diş çekimi öncesi trombosit 30.000 olduğu
için trombosit aferezi verildi
Cilt lezyonları steroidli krem ve güneş koruyucu lar
ve antihistaminiklerle tedavi edildi.
Tedavi bıraktırılmasını gerektiren yan etki olmadı
Bir hasta tedavinin 17 haftasında devam etmek
istemedi ve bıraktığında HCV-RNA negatif idi.
İNÖNÜ ÜNİVERSİTESİ
DENEYİMİ-DAA deneyimi
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