Transcript L1_Viral Hepatitis

Viral Hepatitis: A Review
Ahmed Mayet, Pharm.D
Associate Professor; KSU
Introduction
Hepatitis A and E
• Fecal-oral transmission
Hepatitis B and C
• Blood and percutaneous transmission
Definition of Acute and Chronic Hepatitis
Acute hepatitis
• Sign and symptoms last less than 6 months and resolve
Chronic hepatitis
• Hepatocellular necrosis for more than 6 months or more
beyond the one set of acute illness
Hepatitis A Virus
HAV
Hepatitis A..
Case
• Mr. Al Shamrani is father of five children. One of his child is four
years old and attending a pre-school where most of the pupils are
of the same age. The school principle informed him that some of
the pupils are having hepatitis A in his school. He wants to
protect him and his wife from Hepatitis A infection. Next day they
went to clinic to test their hepatitis A status. Mr. Shamrani is
tested positive for Hepatitis A anti-IgG antibody while his wife
Mrs. Shamrani is tested negative for Hepatitis A anti-IgG and IgM
antibody. His son is tested positive for Hepatitis A anti-IgM
antibody
Hepatitis A..
Case
• Is Mr. Shamrani infected with Hepatitis A virus currently and he
may take immunoglobulin for Hepatitis A infection to protect him
from full blown hepatitis
or
• Mr. Shamrani is infected with Hepatitis A virus currently and he
may take vaccination for Hepatitis A infection to protect him from
full blown hepatitis
Hepatitis A..
Case
• Can we say that Mrs. Shamrani is not infected with Hepatitis A
virus and she does not need to take HAV IgG and vaccination
both immediately?
• What shall we do with her?
Hepatitis A..
Case
• What will you advise to his father for his four year old son?
• What about rest of the children should do?
Hepatitis A..
Hepatitis A
• Self limiting, mild and unrecognized
• No human asymptomatic carrier
• No chronicity
• Preventable either by vaccination or IG
• Children age 5-14 years  highest incidence and in lower
socioeconomic groups
• Fulminant is rare 0.1-1.0%
Hepatitis A..
Risk Factors
• Close contact with HAV
• Day care center
• Recent traveling history
• Raw shell-fish ingestion
Hepatitis A..
Clinical Manifestations
• Symptoms present within 1-2 wks before the onset of jaundice
• Symptoms include fatigue, weakness, anorexia, nausea, vomiting,
& abdominal pain
• Prodromal phase ALT > AST peak occur before the onset of
jaundice
• Serum bilirubin rarely > 10 mg/dl
Hepatitis A..
Diagnosis
• Two classes of anti-HAV are detectable: IgM & IgG.
• Detection of IgM consistent with acute HAV infection.
• IgG appears early in the convalescent phase and in individual
with past exposure give a life long immunity
Hepatitis A..
Hepatitis A
Hepatitis A..
Prevention
• Passive immunization, temporary protective antibody in the form
of IgG is administered
• Active immunization, a vaccine is administered to induce the
production of protective antibody
• Prophylaxis, can be administered before exposure (pre-exposure
prophylaxis) or after exposure (post-exposure prophylaxis)
Hepatitis A..
Pre & Post-Exposure Prophylaxis
• 0.02 ml/kg and 0.06 ml/kg of IgG administered I.M gives
protection for < 3 and < 5 months respectively
• Vaccination by at least 1 month before exposure to HAV don’t
require IgG  protective antibody titers are achieved in > 95% of
pts 1 month after vaccination
• IgG giving within 2 weeks of exposure to HAV is up to 90%
effective in preventing acute HAV infection
Hepatitis A..
Precautions
• IgG may interfere with the response to live attenuated vaccines
like MMR and varicella vaccines when administered as either
individual or combination vaccines
• MMR and varicella vaccines should be delayed for at least 3
months after administering IgG for HAV prophylaxis
• IgG should not be given within 2 weeks after the administering
MMR or varicella vaccine
Hepatitis A..
Vaccines
• Havrix (GSK) and Vaqta (Merck)
• Havrix contains a preservative (2-Phenoxyethanol)
• Vaqta is preservative free
• The immune response to each preparation has been rapid and
complete with > 94% in 1 month after vaccination, second dose
100% protection
Hepatitis A..
Pre-Exposure Prophylaxis
Doses Table: Recommended of Hepatitis A Vaccines
Product
Age (years)
Dose
Volume
(ml) IM
Schedule
(months)
Havrix
2-18
720 EL.U.
0.5
0,6-12
> 18
1440 EL.U.
1.0
0,6-12
2-17
25U
0.5
0,6-18
>17
50U
1.0
0,6
Vaqta
Hepatitis A..
ACIP recommends vaccination
• Travellers to high endemic area
• Children living in communities with high rates of hepatitis A
infection and periodic hepatitis A outbreaks. (higher
socioeconomic groups)
• Homosexual
• IV drug users
• Occupational risk for hepatitis A (e.g., health care workers)
• People with clotting factor disorders.
• People with chronic liver disease who are at an increased risk for
HAV
Advisory Committee on Immunization Practices (ACIP)
The underestimated risk of
hepatitis A and B: benefits of
an accelerated vaccination
schedule
Jay S. Keystone, Jody H, Hershey
International Journal of Infectious disease 2008, 12 (3-11)
PHCL 501
12 April 2016
20
Accelerated Vaccine
• The large numbers of travelers to endemic areas
are at high risk and the time needed to complete
the classical vaccination schedule are two major
points behind the idea of the accelerated vaccine
• Twinrix® is the approved vaccine to be used
among the accelerated schedule
PHCL 501
12 April 2016
21
Accelerated Vaccine
• Twinrix® is a combination of inactivated
hepatitis A and recombinant hepatitis B
• 1 ml dose contains 720 EL.U of Havrix® and 20
mcg of Engerix®
• Accelerated vaccine schedule is applied at 0, 7,
21 days and one last booster dose after 1 year
PHCL 501
12 April 2016
22
Accelerated Vaccine
Twinrix®
Havrix®
Time
N
S+ (%)
GMC
Time
N
S+ (%)
GMC
M1
211
100
845
M1
192
99
512
M2
206
99.5
780
M2
189
98.9
286
M3
206
100
628
M3
185
97.8
219
M12
183
96.2
374
M12
179
95
170
M13
183
100
9571
M13
179
100
5205
GMC: geometric mean concentration (mIU\ml) of anti-HAV concentrations
PHCL 501
12 April 2016
23
Accelerated Vaccine
Twinrix®
Engerix®
Time
N
S+ (%)
GMC
Time
N
S+ (%)
GMC
M1
211
82
65
M1
192
83.9
98
M2
206
85
53
M2
189
84.9
58
M3
206
95.2
183
M3
185
90.8
131
M12
183
94
209
M12
179
91.6
106
M13
183
100
26002
M13
179
100
29196
Nothdurft et All – Accelerated vaccination schedule provide protection against hepatitis A and B in last minute travelers – J Travel Med 2004; 11: 260-2
GMC: geometric mean concentration (mIU\ml) of anti-HBs concentrations
PHCL 501
12 April 2016
26
Conclusion
• large number of travelers to endemic areas can’t
identify their risk of HBV
• Accelerated vaccine has demonstrated suitable
immunogenicity for the last minute travelers
• Accelerated vaccine could be beneficial for
people less likely to contact health care systems
regularly
PHCL 501
12 April 2016
27
Hepatitis A Vaccine versus
Immune Globulin
for Postexposure Prophylaxis
John C. Victor, Ph.D., M.P.H., Arnold S. Monto, M.D., Tatiyana Y. Surdina,
M.D. , Saida Z. Suleimenova, M.D., Gilberto Vaughan, Ph.D., Omana V.
Nainan, Ph.D. , Michael O. Favorov, M.D., Ph.D., Harold S. Margolis,
M.D.,and Beth P. Bell, M.D.,M.P.H.
The New England Journal of Medicine,
October 25, 2007 Vol. 357 No. 17, 1685-94
Rejection of the null hypothesis
To show that
hepatitis A vaccine is not inferior to
immune globulin in
preventing clinical illness when
given to contacts of patients with hepatitis A
RESULTS :
Primary End Point
contacts with illness (HAV IgM-positive and elevated ALT)
Hepatitis A..
Case
• Mr. Al Shamrani is father of five children. One of his child is four
years old and attending a pre-school where most of the pupils are
of the same age. The school principle informed him that some of
the pupils are having hepatitis A in his school. He wants to
protect him and his wife from Hepatitis A infection. Next day they
went to clinic to test their hepatitis A status. Mr. Shamrani is
tested positive for Hepatitis A anti-IgG antibody while his wife
Mrs. Shamrani is tested negative for Hepatitis A anti-IgG and IgM
antibody. His son is tested positive for Hepatitis A anti-IgM
antibody.
Hepatitis A..
Case
• Is Mr. Shamrani infected with Hepatitis A virus currently and he
may take immunoglobulin for Hepatitis A infection to protect him
from full blown hepatitis.
or
• Mr. Shamrani is infected with Hepatitis A virus currently and he
may take vaccination for Hepatitis A infection to protect him from
full blown hepatitis
Hepatitis A..
Case
• Can we say that Mrs. Shamrani is not infected with Hepatitis A
virus and she does not need to take HAV IgG and vaccination
both immediately?
• What shall we do with her?
Hepatitis A..
Case
• What will you advise to his father for his four year old son?
• What about rest of the children should do?
Hepatitis A..
Case
• Khalid is a pharmacy student who is planning to leave to Sudan
next week to do voluntary work for a year. His serology test is
positive for IgG anti-HAV and negative for IgM anti-HAV. He
wants to get prophylactic treatment before leaving the country and
asks you for your recommendation. What will you recommend?
a. start hepatitis A vaccine 1440 ELU now
b. immunoglobulin 0.02 ml/kg now
c. immunoglobulin 0.06 ml/kg now
d. does not need any treatment
Hepatitis A..
Case
• All of the following individual should be vaccinated against
hepatitis A except one statement is incorrect. Mark the incorrect
one:
a. travelers to high endemic area
b. military personnel
c. employees of child care center
d. children who live in poor countries
Hepatitis B Virus
HBV
Hepatitis B..
Case
• Zara is a 25-year-old woman who was recently diagnosed with
hepatitis B while undergoing a physical examination for
employment. She is otherwise healthy except for a history of
depression. Social history is insignificant. Her family history is
significant for mother with hepatitis B. Her grandmother died of
(HCC). She lives with her brother and sister, neither of whom
have been immunized against hepatitis B .Laboratory values are
significant for an elevated an AST 73 units/L and an ALTof 78
units/L. Her hepatitis serology are positive for HAV IgG, HBsAg,
anti-HBe, and anti-HBc IgG; negative for HBeAg; HBVDNA
concentration of 800,000 IU/ml; and undetectable HCVRNA. Her
other laboratory values are within normal limits. A liver biopsy
performed 2 weeks ago revealed chronic hepatitis B (CHB) with
minimal fibrosis.
Hepatitis B..
Case
1.
What is the most likely mode of transmission in her?
2.
Does Zara need treatment? Why?
3.
What is the best regimen for her?
4.
Why you have chosen this regimen?
5.
What is the best prophylaxis regimen for Zara’s brother and
sister?
Hepatitis B..
Case
• Zara mother has the following serology and laboratory values:
HBsAg-positive, anti- HBe-positive, ALTof 43 units/L,
HBVDNA of less than 2,000IU/ml, and a liver biopsy with no
inflammation or fibrosis.
6. What is the best regimen for Zara’s mother?
7. If Zara develops YMDD mutation while on lamivudine, what shall
we do?
Hepatitis B..
Hepatitis B
• HBV is responsible for 1-14% of CLD and more likely to develop
in infants compared to adults
• Common cause for primary HCC
• It is preventable disease
• Parenterally transmitted
• Heterosexuals contact (42%)
Hepatitis B..
Hepatitis B
• The HBsAg is essential for maintaining the HBV life
cycle
• HBeAg is a secreted product of the nucleocapsid core &
its presence means viral replication
Hepatitis B..
Acute HBV Infection with Recovery
Typical Serologic Course
HBeAg
anti-HBe
Symptoms
Titer
Total anti-HBc
HBsAg
IgM
anti-HBc
0 4 8 12 16 20 24 28 32 36
anti-HBs
52
Weeks after Exposure
Years
Hepatitis B..
Progression to Chronic HBV Infection
Typical Serologic Course
Acute
(6 months)
Chronic
(Yrs)
anti-HBe
HBeAg
HBsAg
Titer
Total anti-HBc
IgM anti-HBc
0 4 8 12 16 20 24 28 32 36
52
Weeks after Exposure
Years
Hepatitis B..
Definitions and Diagnostic Criteria
Diagnostic Criteria
Definitions
Chronic hepatitis B
Chronic necroinflammatory disease of
the liver caused by
persistent HBV infection
1. HBsAg positive > 6 months
2. Serum HBV DNA > 105 copies/ml
(20,000 IU/ml)
3. Persistent or intermittent elevation of
ALT/AST levels
4. Liver biopsy showing chronic hepatitis
(necroinflammatory ≥ score 4)
Hepatitis B..
Definitions and Diagnostic Criteria
Diagnostic Criteria
Chronic hepatitis B
a.
b.
HBeAg-positive
chronic hepatitis B
HBeAg-negative
chronic hepatitis B
Definitions
HBeAg positive, anti-HBe negative
HBeAg negative, anti-HBe positive
Hepatitis B..
Definitions and Diagnostic Criteria
Diagnostic Criteria
Definitions
Inactive HBsAg carrier
state
Persistent HBV infection
of the liver without
significant ongoing
necroinflammatory
disease
1.
2.
3.
4.
5.
HBsAg positive > 6 months
HBeAg negative, anti-HBe positive
Serum HBV DNA < 20,000 copies/ml
Persistently normal ALT/AST levels
Liver biopsy showing absence of
significant hepatitis
(necroinflammatory score < 4)
Hepatitis B..
Definitions and Diagnostic Criteria
Diagnostic Criteria
Definitions
Resolved hepatitis B
Previous HBV infection
without further
virological, biochemical,
or histological evidence
of active virus infection
or disease
1. Previous known history of acute or
chronic hepatitis B with the presence
of anti-HBs
2. HBsAg negative
3. Undetectable serum HBV DNA
4. Normal ALT levels
Hepatitis B..
Guide to Immunoprophylaxis After Exposure
Type of Exposure
Immunoprophylaxis
Perinatal
Sexual
Vaccination + HBIG
Vaccination ± HBIG
Household contact
Chronic carrier
Acute case, known exposure
Vaccination
HBIG ± vaccination
Inadvertent
(percutaneous/permucosal)
Vaccination ± HBIG
Hepatitis B..
Recommended vaccines dosage & schedule
Vaccine
Engerix-B
Age
group
Dose
Volume # Doses
Schedule
0–19
years
10µg
0.5 ml
3
Infants:
birth, 1–4,
6–18 mos. of
age
Alternative
for older
children: 0,
1–2, 4 mos.
20 years
& older
20µg
1.0 ml
3
0, 1, 6 mos.
(GlaxoSmithKlin)
Note For adult dialysis patients, the Engerix-B dose required is 40µg/2.0ml (use the adult 20µg/ml formulation)
on a schedule of 0, 1, 2, and 6 months
Hepatitis B..
Recommended vaccines dosage & schedule
Vaccine
Recombivax
HB
(Merck &
Co.)
Age
group
0–19
years
20 years
& older
Dose
Volume # Doses
Schedule
5µg
0.5 ml
3
Infants:
birth, 1–4,
6–18 mos. of
age
Alternative
for older
children: 0,
1–2, 4 mos.
10µg
1.0 ml
3
0, 1,6 mos.
Note For adult dialysis patients, the Recombivax HB, a special formulation for dialysis patients is available.
The dose is 40µg/1.0ml and it is given on a schedule of 0, 1, and 6 months
Hepatitis B..
Combinations using HAV and/or HBV
Vaccine
Age
group
Antigens used
Comvax
(Merck &
Co.)
6 weeks
thru 4
yrs.
Recombivax HB
(5µg)
+ PedvaxHib
Pediarix
(GlaxoSmithKlin)
6 weeks
thru 6
yrs.
18 years
& older
Twinrix
(GlaxoSmithKlin)
Volume
# Doses
Schedule
0.5 ml
3
2, 4,
12–15 mos.
of age
Engerix-B
(10µg),
Infanrix (DTaP),
and IPV
0.5 ml
3
2, 4, 6
mos. of age
Havrix (720
El.U.)
+
Engerix-B (20µg)
1.0 ml
3
0, 1,
6 mos.
Screening for HBV infection
Household
contacts
(Multiple) sexual
contacts
Born in
endemic area
Pregnant
women
HBV screening
HCV / HIV
infection
Injection
drug users
Correctional
facilities
Elevated ALT
Lok, Hepatology 2007
Hepatitis B..
•
Diagnostic Markers
Typical markers to diagnosis chronic HBV are:
1. Serology: HBsAg HBeAg anti-HBc
2. Virology: non-amplified hybridization assays (limit of
quantification of 105–106 copies/ml)
Note: Polymerase Chain Reaction (PCR) assays have lower limit
of detection (as low as 6-100 IU/ml)
3. Biochemistry: ALT
4. Histology: staging (necroinflammatory) and grading (fibrosis)
Primary Aims of HBV Treatment
No life-cycle
without HBsAg
Hepatitis B..
Primary Aims of Treatment
1. Reduce the HBV DNA level and maintain it at the lowest
Virological Response
possible levels
2. Seroconversion (loss of HBeAg and Gain of HBe antibody)
3. ALT level normalization
Biological
Response
4. Loss of HBsAg (resolution )
5. Histological improvement
Histological
Response
Hepatitis B..
Patients Stratum
• This algorithm include the following Patients:
1. HBeAg-Positive Patients
2. HbeAg-Negative Patients
3. Lamivudine-Resistant Patients
4. Patients with Cirrhosis
5. Patients Co-infected with HIV-HBV
6. Patients Co-infected HCV-HBV
7. Chemotherapy Patients
8. Pregnancy
Hepatitis B..
Approved HBV Therapies
• Five approved treatments for chronic HBV the US:
1. IFN alfa-2b or 2a
2. Lamivudine (Epivir-HBV)®
3. Adefovir Dipivoxil
4. Entecavir
5. Pegylated INF alfa-2a or 2b
Hepatitis B..
HBV Treatment Strategies
1. HBeAg-Positive Patients
Hepatitis B..
HBeAg-Positive Patients
HBeAg
Status
HBV
DNA
Positive
< 20000
IU/ml
ALT
Treatment Strategy
Normal No treatment
Monitor every 6–12 mo
Consider therapy in patients with
known significant
histological disease, even if low-level
replication
Hepatitis B..
HBeAg-Positive Patients
HBeAg
Status
HBV
DNA
Positive
≥ 20000
IU/ml
ALT
Treatment Strategy
Normal Consider biopsy; treat if disease
Low rate of HBeAg seroconversion
with IFN
If treated, lamivudine or entecavir
preferred (more potent HBV
Suppressive agents with fewer
side effects)
Hepatitis B..
HBeAg-Positive Patients
HBeAg
Status
HBV
DNA
Positive
≥ 20000
IU/ml
ALT
Treatment Strategy
Elevated Entecavir, lamivudine, or IFN are
first-line options
If “high” HBV DNA, Entecavir or
lamivudine preferred
Algorithm for HBeAg positive patients
HBeAg (+)
HBV DNA ≥20,000 IU/mL
(100,000 copies/mL)
HBV DNA <20,000 IU/mL
(100,000 copies/mL)
ALT normal
• No antiviral
treatment
• Monitor every 3-16
months
ALT <2 x ULN
• Monitor every 3-6 months
• Consider biopsy if:
- >40 years old
- ALT persistently 1-2 x ULN.
• Treatment indicated in case of
significant inflammation or fibrosis.
ALT ≥3 x ULN
• Start treatment
• Monitor ALT +
HBeAg every 1-3
months
• Liver biopsy
optional
Lok, Hepatology 2007
Hepatitis B..
Peginterferon α-2A and Lamivudine
Treated for 48 wks,
assessed wk 24 of
after treatment
PEGASYS
180 ug/wk
+ Placebo
(n=271)
PEGASYS
180 ug/wk
+ Lamivudine
100mg/d
(n=271)
Lamivudine
100mg/d
(n=272)
α-2a monotherapy is as effective as
HBeAg
combination
with32%
lamivudine 27%
and more effective
19%
seroconversion
(P<0.001)*
(P=0.023)*
than lamivudine monotherapy
in HBeAg-positive
34%
chronic HBV
HBV DNA
32%
22%
Primary
endpoints
Peginterferon
<100,000 copies/ml
* Compared with Lamivudine therapy
(P=0.012)*
(P=0.003)*
Marcellin et al, J Hepatol 2004
HBeAg relapse after discontinuation of therapy
100
Cumulative % relapse of HBeAg
90
80
70
60
LAM
50
40
IFN
30
20
IFN + LAM
10
0
0
26
52
78
104
130
156
Time (weeks)
Van Nunen, Gut 2003
Overview HBeAg seroconversion rates
Collation of currently available data:
30
not from head-to-head studies
using different assays
HBeAg seroconversion (%)
27%
24%
25
22%
21%
21%
20
18%
15
12%
10
5
n=271
n=266
n=458
n=176
PEG-IFN
α-2a1
PEG-IFN
α-2b2
Telbivudine3
Tenofovir4
n=354
n=355
n=171
0
1Lau,
Entecavir5 Lamivudine5 Adefovir6
NEJM 2005; 2Janssen, Lancet 2005; 3Lai, AASLD 2005; 4Heathcote, AASLD 2007; 5Chang, NEJM 2006;
6Marcellin, NEJM 2003
Hepatitis B..
Lamivudine
• Lamivudine (100mg po od)
• HBeAg seroconversion 17% 27% 40% 47% 50% at 1,2,3,4,5yrs
• Longer the treatment better the response
• High pretreatment ALT level the best predictor of response to
lamivudine treatment
• Seroconversion are durable after a median follow-up of 37 months
Hepatitis B..
Lamivudine
• Longer the treatment higher the MYDD mutation
• 14-32% 1yr, 69% 5yrs and ALT bounce back to pretreatment level
and rapid decompensation.
• Well tolerated
• HBsAg conversion is rare (no sufficient data)
• Excellent safely profile
• Reasonable price ( SR 300/month)
• Continue lamivudine atleast 6 months post seroconversion
Hepatitis B..
Adefovir
• 46% loss HBeAg; 23% seroconversion (52 weeks)
• No resistance mutation after 52 weeks of treatment
• HBsAg loss is rare (no sufficient data)
• Safety profile as similar to placebo
• Cost
SR 2,000 /month
• Durability of response after adefovir is no available
Hepatitis B..
Duration of Therapy and Monitoring
• Monitor lamivudine for resistance
• Treatment then should be continued for additional 6 months after
HBeAg seroconversion .
• Patient who fails to seroconvert (HBeAg+) should be treated
indefinitely*
• Patient who experience relapse should be retreated
• Adefovir should be added if patients who were intially treated
with Lamivudine in case of resistance
Hepatitis B..
HBV Treatment Strategies
2. HBeAg-Negative Patients
HBeAg Seroconversion
HBeAg positive with elevated ALT
4% - 20%
8% - 12% per year
Spontaneous HBeAg seroconversion
20% - 33%
67% - 80%
Inactive HBsAg
carrier state
HBeAg negative
chronic hepatitis
10% - 20%
Lok, Hepatology 2007
Serum HBV DNA in HBeAg(-) CHB
HBeAg-negative chronic
Inactive HBsAg carrier
hepatitis1
state1
• N=134
• N=62
• Median HBV DNA 2.8 x
• Median HBV DNA 3.3 x
106 (range 103 – 109) c/mL
103 (range <400 – 3 x 104)
c/mL
 95% of patients with HBeAg negative chronic hepatitis B has
HBV DNA >10,000 copies/mL (2,000IU/mL)1-4
1Manesis,
Am J Gastroenterol 2003; 2Zacharakis, J Med Virol 2005; 3Chu, Hepatology 2002; 4Yuen, Am J Gastroenterol 2004
Hepatitis B..
HBeAg-Negative Patients
• Therapy end-point is difficult to assess because HBeAg
seroconversion can not be determine
• HBV DNA suppression and ALT level normalization are the only
measures of response to therapy
• HBeAg negative patients tend to have lower serum HBV DNA
than HBeAg positive patient, but may still have considerable
disease
Hepatitis B..
HBeAg-Negative Patients
HBeAg
Status
HBV
DNA
Negative
< 2000
IU/ml
ALT
Treatment Strategy
Normal No treatment
Monitor every 6–12 months
Consider therapy in patients with
known significant histological
disease, replication
Hepatitis B..
HBeAg-Negative Patients
HBeAg
Status
HBV
DNA
Negative
≥2000
IU/ml
ALT
Treatment Strategy
Normal Consider biopsy; treat if justified
Low “efficacy” for antivirals and IFN
Hepatitis B..
HBeAg
Status
HBeAg-Negative Patients
HBV
DNA
ALT
Treatment Strategy
Negative ≥2000 Elevated lamivudine, entecavir, Adefovir etc
IU/ml
or IFN. All are first-line options
Long-term treatment required
Entecavir preferred (low rate of
resistance)
Algorithm for HBeAg negative patients
HBeAg (-)
HBV DNA ≥2,000 IU/mL
(10,000 copies/mL)
HBV DNA <2,000 IU/mL
(10,000 copies/mL)
ALT normal
ALT <2 x ULN
• No antiviral
treatment
• Monitor every 6-12
months
• Monitor every 3 months
• Consider biopsy if persistent
• Antiviral treatment in case of
significant inflammation or fibrosis
ALT ≥2 x ULN
• Antiviral treatment
if persistent
• Liver biopsy
optional
Lok, Hepatology 2007
Study Design
• Patients with HBeAg-negative CHB were
randomised using a 1:1:1 ratio (n=537)
EOT
48 weeks
Randomised
EOF
72 weeks
180 μg PEGASYS qw + oral placebo qd
24 week
follow-up
180 μg PEGASYS qw + 100 mg lamivudine qd
100 mg lamivudine qd
0
24
Study weeks
48
72
Marcellin et al. NEJM 2004;351:1206–17
Co-primary Endpoint - HBV DNA Response*
24 Weeks After End of Treatment (Week 72)
P=0.007
60
Patients (%)
P=0.849
40
43%
P=0.003
44%
29%
20
0
n=177
n=179
n=181
PEGASYS
+ placebo
PEGASYS
+ lamivudine
lamivudine
* HBV DNA response defined as <20,000 copies/mL
Marcellin et al. NEJM 2004;351:1206–17
PCR-undetectability in HBeAg(-) Patients
Collation of currently available data:
Undetectable HBV DNA (%)
100
92%
90%
not from head-to-head studies
using different DNA assays
undetectable HBV DNA 300–400 cp/mL
88%
80
71%
63%
60
51%
40
20
0
n=250
n=325
Tenofovir1
Entecavir2
1Marcellin,
n=222
n=224
Telbivudine3 Lamivudine3
n=177
n=123
PEG-IFN
-2a4
Adefovir5
AASLD 2007; 2Lai, NEJM 2006; 3Lai CL AASLD 2005; 4Marcellin, NEJM 2005; 5Hadziyannis, NEJM 2003
Hepatitis B..
Duration of Therapy and Monitoring
• Duration of therapy for IFN remains unclear
• Longer treatment duration (12 months) with INF appears more
beneficial in terms of sustained virological response
• Lamivudine and adefovir need to be administered for long term
• Entecavir or Adefovir preferred over Lamivudine due to YMDD
mutants
When to stop antiviral therapy?
Peginterferon therapy
• After a one-year course of therapy
• No head to head comparison of various treatment durations
Nucleos(t)ide analogue therapy
• HBeAg positive patients:
- HBeAg seroconversion during at least 6 months plus HBV
DNA undetectable by PCR assay
• HBeAg negative patients:
- Clearance of HBsAg
Lok, Hepatology 2007
Antiviral resistance
Primary treatment failure
Antiviral Drug
0.0
-1.0
<2 log
-2.0
-3.0
1.0
Log10 copies/mL HBV DNA
Log10 copies/mL HBV DNA
1.0
Virologic breakthrough
Antiviral Drug
0.0
-1.0
≥2 log
-2.0
-3.0
≥1 log
-4.0
-4.0
Time
Time
• Check compliance
• Perform genotypic analysis
• Check compliance
• Switch to alternative treatment
• Add second antiviral agent /
switch to another agent
Lok, Hepatology 2007
Choice of initial therapy (1)
Advantages and disadvantages of currently available antiviral agents:
Peginterferon
Nucleos(t)ide
analogues
Advantages:
Advantages:
- Finite duration of therapy
- Oral administration
- Durable treatment response - Negligible side-effects
- No drug resistance
- Potent inhibition of
replication
- HBsAg loss
Disadvantages:
- Subcutaneous
Disadvantages:
Hepatology 2006
- Indefinite therapyPerrillo,
in many
Choice of initial therapy (2)
Patient characteristics of interest when choosing antiviral therapy:
Peginterferon
Nucleos(t)ide
analogues
A/B
C/D
HBV DNA
≤109 copies/mL
>109 copies/mL
ALT
ALT >2 x ULN
ALT 1-2 x ULN
Severity of liver disease
Compensated
Compensated
Decompensated
HBV genotype
Adapted from: Perrillo, Hepatology 2006
Hepatitis B..
HBV Treatment Strategies
3. Patients with Cirrhosis
Patients with Cirrhosis (Compensated)
HBeAg
Status
HBV
DNA
Cirrhosis
Treatment Strategy
Positive ≥2000 Compensated Long-term treatment required
UL/ml
or
Entecavir or Adefovir is preferred
Negative
(low rate of resistance)
Combination adefovir plus
lamivudine has theoretical
advantage because of low
likelihood of resistance to either
virus
Hepatitis B..
Patients with Cirrhosis (Decompensated)
HBeAg
Status
HBV
DNA
Positive ≥ 200
or
IU/ml
Negative
Cirrhosis
Treatment Strategy
DeLong-term treatment required
compensated Entecavir or Adefovir is
preferred (low rate of resistance)
Combination adefovir plus
lamivudine has theoretical
advantage because of low
likelihood of resistance to either
virus
Hepatitis B..
HBV Treatment Strategies
4. Patients with Co-Infections
Hepatitis B..
HIV-HBV Co-infected Patients
• About 10% HIV- are co-infected with HBV
• Mortality 14-fold greater than either virus alone
• Do not treat HBV infection first in co-infected patient
• Resistant is high reaching 90% at 4 years lamivudine
Hepatitis B..
HIV-HBV Co-infected Patients
• Adefovir 10 mg/day is effective in lamivudine- resistant HBV
• Tenofovir is effective against both HIV and HBV
• Entecavir has no effect on HIV, does not promote HIV viral
resistance to the drug no effect on CD4 or HIV viral load
• If patient not requires HAART in near future or are on HAART no
include drug active against HBV, then use INF or adefovir or
entecavir
Hepatitis B..
HCV-HBV Co-infected Patients
• Patients with HBV DNA levels ≥ 103 copies/ml (200 IU/ml) and
undetectable HCV RNA should be treated for HBV infection
• Low HBV DNA levels and detectable HCV RNA should be
treated for 3 months with peginterferon and ribavirin in standard
doses
• If HBV DNA does not begin to respond or levels increase on
therapy lamivudine or adefovir can be added
Hepatitis B..
HBV Treatment Strategies
5. Pregnant Patients
Hepatitis B..
Pregnancy
• Efficacy and safety of lamivudine in late pregnancy for the
prevention of mother-child transmission of HBV; a multicentre,
randomized, double-blind, placebo-controlled study
Endpoint
LAM+VAC+HBIg PLA+VAC+HBIg
(Infants at Wk 52)
N=56
N=59
pvalue
HBsAg +ve
10 (18%)
23 (39%)
0.014
HBsAb +ve
47 (84%)
36 (61%)
0.008
HBV DNA +ve3
11 (20%)
27 (46%)
0.003
LAM, 100mg OD from wk 32 ± 2 wks of gestation until 4 wks postpartum; HBIg, 200IU, single dose within 24 hrs of
birth; VAC 0.5ml dose within 24hours of birth
Hepatitis B..
Approved Antiviral drugs
1. Lamivudine (Epivir-HBV)®
2. Adefovir Dipivoxil
3. Entecavir
4. Telbivudine
Interferon
•
•
•
•
•
Advantage of interferon
Finite duration of treatment
Absence of selection of resistant mutants
A more durable response
Disadvantage of interferon
Side effects from interferon
Cannot be used in decompensated disease
Interferon
Place in therapy
• Primarily treatment of young patients with well
compensated liver disease, who do not wish to be
on long-term treatment
• Planning to be pregnant within the next two to
three years, and in whom drug resistance may
limit their treatment options in the future
• An attractive option for patients with HBV
genotype A infection
Lamivudine
• It’s role is diminishing with the availability of
entecavir, telbivudine, and adefovir, that are
associated with lower rates of drug resistance.
• It may still have a role in patients coinfected with
HIV in whom lamivudine may be part of the
antiretroviral regimen.
• HBsAg patients (asymptomatic carrier) who
require short course of immunosuppressive
agents or chemotherapy.
Hepatitis B..
Lamivudine
• HBeAg seroconversion rate is 17% 27% 40% 47% 50%
at 1,2,3,4,5yrs.
• Seroconversion are durable.
• High pretreatment ALT level and lower HBV RNA are
the best predictor of response to lamivudine treatment.
• On average, lamivudine-resistance (YMDD) occurs 20%
and 70% after 1 and 4 year of treatment respectively.
N Engl J Med 1998 Jul 9;339(2):61-8
Adefovir
• Approved by FDA in 2002
• HBeAg seroconversion-12% and 48% in 1 and 5 years
respectively.
• In HBeAg –ve patients, 70% have maintained viral
suppression after 5 years of continued treatment.
• Resistant- HBV can emerge, but slower rate than
lamivudine resistance (28% in 5 years in HBeAg-ve pts)
• Resistance develop more rapidly (18% within 48 wks) in
patient who has lamivudine-resistant.
N Engl J Med 2003 Feb 27;348(9):808-16
Hepatology 2006 Jul;44(1):108-16
Adevovir
• The most important role of adefovir is in the
treatment of patients with lamivudine-resistant
HBV, preferably in combination.
• A good choice in HBeAg-ve patients and in
decompensated cirrhotic patients who will require
longer duration
• In telbivudine and entecavir-resistant HBV but
clinical data are scanty.
Entecavir
• A very potent antiviral activity and a low rate of drug
resistance.
• It has a more important role in primary treatment of
HBV than in patients with lamivudine-resistant HBV.
• A good choice in HBeAg-ve and in decompensated
cirrhotic patients who will require longer duration
• Resistance rate to entecavir is rare among nucleosidenaïve patients (1% in 3 years).
• Resistance rate to lamivudine refractory patients was
1%, 9%, and 19% during 1, 2, 3 years of treatment
respectively.
Gastroenterology. 2006 Jun;130(7):2039-49
Hepatology. 2006 Dec;44(6):1656-65
N Engl J Med. 2006 Mar 9;354(10):1001-10
N Engl J Med. 2006 Mar 9;354(10):1011-20
Telbivudine
• Approved in October 2006
• It appears to have slightly more potent antiviral
effects compared with lamivudine and adefovir
but it selects for the same resistant mutants as
lamivudine (4.5% over 1 yr) and it is more
expensive and its role as primary therapy is
limited.
Tenofovir
• Tenofovir has not approved for HBV.
• Highly effective against lamivudine-resistant HBV and
moderately effective against adefovir-resistant HBV.
• HBeAg seroconversion was documented in 36% of the
patients and HBsAg loss in 8% after 2 to 3 years.
• A recent study of 69 naïve patients, tenofovir showed
consistent suppression of HBV DNA and no signs of
viral resistance even after 5 years of treatment.
Hepatology 2006; 44(Suppl 1):549A
Hepatology. 2006 Aug;44(2):318-25
Responses of Approved Antiviral Therapies Among Treatment-naïve
Patients with HBeAg Positive Chronic Hepatitis B
INF alfa
(SD)
5MU qd
10MU
tiw
12-24 wk
Lamivdine
Adefovir Entecavir
100mg
qd
48-52 wk
10 mg
qd
48 wk
0.5 mg
qd
48 wk
Telbiv
udine
600mg
qd
52 wk
HBeAg
Seroconversion
18%
16-21%
12%
21%
22%
ALT
normalization
23%
41-71%
48%
68%
Durability
of
response
80-90%
50-80%
90%
69%
^Hybridization
77%
80%
Peg
INF
180ug
qw
48 wk
Peg
INF
+
Lam
48 wk
27-32% 24-27%
39%
46%
n/a
n/a
DNA assays lower limit of detection 20,000 IU/ml (100,000 copies/ml)
^ PCR assays lower limit of detection 50IU/ml ( 250 copies/ml)
*Responses rate at week 48/72
Hepatology 2007;45:507-39
Responses of Approved Antiviral Therapies Among Treatment-naïve
Patients with HBeAg Negative Chronic Hepatitis B
INF alfa
(SD)
5MU qd
10MU
tiw
12-24 wk
Lamivdine
100mg
qd
48-52 wk
Adefovir
10 mg
qd
48 wk
Entecavir
0.5 mg
qd
48 wk
Telbivud
600mg
qd
52 wk
Peg
INF
180ug
qw
48 wk
Peg INF
+
Lam
48 wk
HBV DNA^
(loss of)
60-70%
60-73%
51%
90%
88%
63%
87%
ALT
(normalizati
on)
60-70%
60-79%
72%
78%
74%
38%
49%
Durability
of
response
10-20%
<10%
5%
n/a
n/a
20%
20%
^Hybridization DNA assays lower limit of detection 20,000 IU/ml (100,000 copies/ml)
^ PCR assays lower limit of detection 50IU/ml ( 250 copies/ml) Hepatology 2007;45:507-39
How to manage HBV infection with
antivirals
• Choose antivirals that have the “highest genetic barrier
for resistance.”
• HBV DNA level should be checked after 24 weeks of
therapy.
• If HBV DNA fail to drop by <2log, then change to
another antiviral that does not target the same HBV
reproduction step to reduce resistance.
• If patient fails to response to IFNa, then retreated with
antiviral
• Don’t wait for clinical signs of drug resistance such as
elevated ALT before changing the antiviral treatment.
• Instead, HBV DNA should be closely monitored because
a continued elevated viral load or a surge in viral load is
the first indicator of drug-resistant HBV.
• Rescue therapy in virologic breakthrough patients.
• Antiviral-resistant HBV are often more virulent and lead
to liver damage faster than with non-resistant HBV.
• Antivirals treatment should be continued for additional 6
months after HBeAg seroconversion or HBV DNA
become undetectable.
• Add adefovir in lamivudine-resistant patient.
• Use tenofovir in multi-drugs resistant patient.
(lamivudine-adefovir-enticavir)
• Patient who experience relapse should be retreated.
Hepatitis B..
Case
• Zara is a 25-year-old woman who was recently diagnosed with
hepatitis B while undergoing a physical examination for
employment. She is otherwise healthy except for a history of
depression. Social history is insignificant. Her family history is
significant for mother with hepatitis B. Her grandmother died of
(HCC). She lives with her brother and sister, neither of whom
have been immunized against hepatitis B .Laboratory values are
significant for an elevated an AST 73 units/L and an ALTof 78
units/L. Her hepatitis serology are positive for HAV IgG, HBsAg,
anti-HBe, and anti-HBc IgG; negative for HBeAg; HBVDNA
concentration of 800,000 IU/ml; and undetectable HCVRNA. Her
other laboratory values are within normal limits. A liver biopsy
performed 2 weeks ago revealed chronic hepatitis B (CHB) with
minimal fibrosis
Hepatitis B..
Case
1.
What is the most likely mode of transmission in her?
2.
Does Zara need treatment? Why?
3.
What is the best regimen for her?
4.
Why you have chosen this regimen?
5.
What is the best prophylaxis regimen for Zara’s brother and
sister?
Hepatitis B..
Case
• Zara mother has the following serology and laboratory values:
HBsAg-positive, anti- HBe-positive, ALTof 43 units/L,
HBVDNA of less than 2,000IU/ml, and a liver biopsy with no
inflammation or fibrosis.
6. What is the best regimen for Zara’s mother?
7. If Zara develops YMDD mutation while on lamivudine, what shall
we do?
Hepatitis C Virus
HCV
Hepatitis C..
Case
• Ramzi (BMI 33) is a 50-year-old black male with hepatitis C. He
was treated in 2000 with (IFN)-a2b (Intron A) 3 mU 3 times/week
for 48 weeks, but he did not benefit from treatment. He was IV
drug user in his teens. Lab values include an HCVRNA level of
500,000 IU/ml, ALT of 74 units/L, AST of 53 units/L, total
bilirubin of 1.1 mg/dl, and albumin of 3.5 g/dl. He has genotype 4
disease. A liver biopsy in 2000 revealed mild disease with
moderate fibrosis. For the past 6 months, he has been retreated
with PEG-IFN-2a (Pegasys) 180 mcg/ml with ribavirin 600 mg
BID. He had an undetectable HCVRNA level at week 12 of
therapy. At this time, his LFTs are normal; however, he does have
an abnormal complete blood cell count panel: WBC = 2400
cells/mm3, ANC = 900 cells/mm3, Hgb = 8.9 g/dl, Hct = 26.6 %,
and Plt= 50,000 cells/mm3. He complains of fatigue and tied.
Hepatitis C..
Case
1.
Should he be treated for HCV infection?
2.
Is he receiving an appropriate drug regimen?
3.
How long does he need to be treated?
4.
Does he need dose adjustment?
5.
Would he be a good responder?
Hepatitis C..
Case
6.
What is sustain responder?
7.
What response rate would you expect?
8.
How do we access response? (3 parameters)
9.
For HCV genotype 2 or 3, what is the treatment
duration and response rate expected?
10. When is a good time to access an earlier response?
Hepatitis C..
Prevalence
• 170 million people are infected with Hepatitis virus
worldwide
• Global seroprevalence is around 3%
• 1.1% in Northern America to 20% in Egypt*
• HCV Prevalence among Saudi’s is estimated to be
between 1-3%**
Simmoonds P et al Hepatology 1995*; AlFaleh et al Hepatology 1991**
Hepatitis C..
Genotypes
• Six Genotypes 1-6 and subtype 1a,1b,2a,2b
• Type 1 is common in USA (75%)
• In Saudi Arabia
Genotype 4 prevalence: 62%
Genotype 1 prevalence: 24%
Genotype 2 and 3 prevalence: 13.4%
Al –Ahdal et al. SMJ 1998 Al- Faleh et al. J Viral Hepatitis1995 Osoba AO et al SMJ 2002.
Hepatitis C..
Risk Factors
• IV drug abuser (most common)
• Accidental needle sticks (2%)
• Multiple sex partners (5%)
• Vertical transmission (5%)
Hepatitis C..
Progression of Infection
HCV infection
10% to 15%
Acute infection
Recover
70%
Chronic hepatitis
10% to 15%
Liver cirrhosis
1% to 4% per year
HCC
Hepatitis C..
Serology Testing
Enzyme immunoassay
(high false positive)
Positive
RIBA for
Anti HCV
PCR HCV
Qualitative
Or
Quantitative
Hepatitis C..
Primary Prevention
1. Screening and testing
 Blood and Blood products
 Plasma
 Organ
 Tissue
 Semen donors
2. Instruments Sterilization
3. Education and Counseling
Hepatitis C..
Treatment Goal: NIH Recommendation
1. Virologic (HCV RNA concentration)
 undetectable (>100 copies/ml)
2. Biochemical
 Normalization of Alt
3. Histological (Liver Biopsy)
 2 points decrease in inflammatation (grading)
 1 point decrease in fibrosis (staging)
Hepatitis C..
Definition of Treatment Responses
• SVR = Sustained Veriological Response
SVR
Hepatitis C..
Definition of Treatment Responses
• IR = Intermediate Response
IR
Hepatitis C..
Definition of Treatment Responses
• TPR = Transient Partial Response
TPR
Hepatitis C..
Definition of Treatment Responses
• NS = No Response
NS
Hepatitis C..
Why Does HCV Treatment Fail?
Host factors
Virus
•
•
•
•
•
•
• Genotype
• Viral load
Race
Age
Gender
Fibrosis
Body weight
Insulin
resistance
• Active
substance
abuse
• Concomitant
disease
Reasons for
treatment failure
Treatment
• Poor adherence to therapy
• Side effects
• Use of a less than effective regimen
Hepatitis C..
Favorable SVR Responder
• Low HCV RNA load prior to Rx
• Low BMI
• Genotype 2 and 3 (75% to 85% response rate)
• Female gander
• Young age
Hepatitis C..
Poor Responder
• Genotype 1 ( 40% to 50%)
• Genotype 4 (50%)
• African American
• Male gander
• Old age
• Cirrhosis and bridging fibrosis
Hepatitis C..
Drugs
• Before 1998 only Interferon α 2a or 2b 3 mU 3 times/wk for 48
weeks with SVR of 12% to 16%( genotype nonspecific)
• 1998 to 2001 Interferon α 2a or 2b plus Ribavirin for 48 wks SVR
of 35% to 45% (genotype nonspecific)
• After 2002 INH recommendation is Peginterferon α 2a or 2b plus
Ribavirin 48 wks SVR 55% genotype nonspecific and in
genotype 2 and 3 up to 75% to 85% and genotype 1 is 40% to
50%
Interferon/ribavirin has a dual mode of
action
HCV RNA
100%
Induction phase
Maintenance phase
0%
1st dose
Detection limit
14–28 Days
EOT
Ferenci P, et al. Viral Hep Rev 1999; 5: 229
Interferon/ribavirin has a dual mode of
action
HCV RNA
100%
Induction phase
Maintenance phase
0%
1st dose
Detection limit
14–28 Days
EOT
Ferenci P, et al. Viral Hep Rev 1999; 5: 229
Interferon/ribavirin has a dual mode of
action
HCV RNA
100%
Lymphocyte
Induction phase
Maintenance phase
0%
1st dose
Detection limit
14–28 Days
EOT
Ferenci P, et al. Viral Hep Rev 1999; 5: 229
Effect of interferon and ribavirin on HCV
infection dynamics
• Interferon (immune modulation, exact MOA
unknown):
– Mainly responsible for first phase viral decline
– Partially blocks virus production
• Ribavirin (nucleoside analogue, exact MOA
unknown):
– Mainly responsible for second phase decline
– Inhibition of de novo infection
– Reducing relapse in combination with interferon
Current recommendations for measurements of
treatment response: guiding treatment duration
slowRVR cEVR responder
EOTR
SVR
Follow-up
Genotype 1
Wk 4 Wk 12
RVR
Wk 24
Week 48
EOTR
SVR
Week 72
Follow-up
Genotype 2/3
Wk 4
Week 24
Week 48
EOTR = undetectable HCV RNA levels at end of treatment (EOT); SVR = undetectable HCV RNA levels at 24
weeks after completion of therapy (sustained virological response); EVR = undetectable HCV RNA or a
≥2 log10 drop (early virological response); RVR = HCV RNA negative (<50 IU/mL) at week 4 (rapid virological
response)
Hepatitis C..
Pegasys® (Peginterferon Alfa-2a)
• Adult Dose:
 Combination therapy with ribavirin: 180 mcg once/wk with
1000- 1200mg ribavirin
• Duration of therapy based on genotype:
 Genotype 1,4: Treat for 48 wks
 Genotype 2,3: Treat for 24 wks
Hepatitis C..
Pegasys® (Peginterferon Alfa-2a)
• Based on hematologic parameters:
 ANC <750/mm³: 135 mcg/wk.
 ANC <500/mm³: Suspend therapy until >1000/mm3 , then
restart at 90 mcg/wk and monitor
 Platelet count <50,000/mm³: 90 mcg/wk
 Platelet count <25,000/mm³: D/C therapy
ANC, Absolute Neutrophil Count
Hepatitis C..
Ribavirin (Dose)
• In combination with interferon alfa-2b:
 <75 kg: 400 mg AM, then 600 mg PM
 >75 kg: 600 mg AM, then 600 mg PM
Hepatitis C..
Dosage Adjustment
• Patient without cardiac history:
 Hgb <10 g/dL: Dec. to 600 mg/day
 Hgb <8.5 g/dL: Permanently D/C Tx
HCV RNA decrease (IU/mL)
Definitions of virological response at week 4
and week 12
RVR = undetectable HCV RNA at week 4
0
cEVR = no RVR but undetectable HCV RNA
at week 12
pEVR = no RVR and detectable HCV RNA,
but >2 log10 drop at week 12
>2 log10
EOTR
SVR
48
72
Undetectable
HCV RNA
(<50 IU/mL)
0
4
12
24
Weeks of therapy
RVR = rapid virological response; cEVR = complete early virological response;
pEVR = partial early virological response.
Time to response is a strong predictor of
achieving SVR
PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day; genotype 1
Virological response (%)
100
91
94
90
86
90
EOT
80
60
40
13
20
0 n=
Week 4
HCV
Week 12
RNA
status Week 24
33
Neg
Neg
Neg
93
≥2 log10 
Neg
Neg
20
21
30
<2 log10  ≥2 log10  <2 log10 
≥2 log10  ≥2 log10 
Neg
Neg
Neg
Neg
63
Any
Any
Pos
Ferenci P, et al. J Hepatol 2005: 43: 425
Time to response is a strong predictor of
achieving SVR
PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day; genotype 1
Virological response (%)
100
91
91
94
90
EOT
SVR
90
86
72
80
60
60
48
43
40
13
20
2
0 n=
Week 4
HCV
Week 12
RNA
status Week 24
33
Neg
Neg
Neg
93
≥2 log10 
Neg
Neg
20
21
30
<2 log10  ≥2 log10  <2 log10 
≥2 log10  ≥2 log10 
Neg
Neg
Neg
Neg
63
Any
Any
Pos
Ferenci P, et al. J Hepatol 2005: 43: 425
Predicting SVR in G 1 Patients with an RVR*
Predicting SVR in G 1 Patients with a cEVR*
Week 4 and 12 responses and corresponding
SVR rates in genotype 1
PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day for 48 weeks
N=569
SVR: 5%
SVR: 87%
No EVR
20%
SVR: 27%
pEVR
22%
RVR
16%
cEVR
42%
SVR: 68%
Marcellin P, et al. 58th AASLD 2007; Abstract 1308
Optimising outcomes in genotype 1/4
• Patients with a LVL who achieve an RVR may be
candidates for shorter treatment duration
Genotype 1 patients with an RVR can be
treated for 24 weeks
SVR (%)
PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day
100
90
80
70
60
50
40
30
20
10
0
88%
91%
84%
n=
33
56
24 weeks 48 weeks
Jensen et al.1
G1 = genotype 1
RVR = HCV RNA <50 IU/mL at week 4
68
24 weeks
Ferenci et al.2
1. Jensen D, et al. Hepatology 2006; 43: 954
2. Ferenci P, et al. 41st EASL 2006; Abstract 8
Very high SVR rates with 24 weeks’ therapy
in genotype 1 patients with an RVR and LVL
SVR (%)
PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day
100
90
80
70
60
50
40
30
20
10
0
93%
96%
Very few patients with
HVL achieve RVR. Of
these, 88% achieve SVR
with 48 weeks’
PEGASYS + COPEGUS
(SD)
n=
27
27
24 weeks
48 weeks
RVR = HCV RNA <50 IU/mL at week 4
LVL (low viral load) ≤800 000 IU/mL;
HVL (high viral load) >800 000 IU/mL
PEGASYS EU SPC, revised 2007
(based on: Jensen D, et al. Hepatology 2006; 43: 954)
Virological response pattern in genotype 1
and 4 patients
15%
27%
12%
RVR
RVR
EVR
58%
Genotype 1
EVR
46%
42%
Genotype 4
Ferenci P, et al. 58th AASLD 2007; Abstract 1301
High SVR rates with 48 weeks’ therapy in
genotype 1 patients with a cEVR
100
PEGASYS 180 g/wk plus ribavirin for 48 weeks
77
80
SVR (%)
65
73
67
Mean=67%
58
60
76
52
*cEVR =
detectable HCV
RNA at week 4 but
HCV RNA
<50 IU/mL
at week 12
40
20
n= 77/118
0
79/118
Study 1
2
Ribavirin 1000/1200
dose
mg/day
60/103
61/79
30/58
2
3
4
800
mg/day
65/88
5
38/50
6
600–1000
mg/day
Marcellin P, et al. 42nd EASL
2007; Abstract 613
1. Fried M, et al. N Engl J Med 2002; 347: 975 and Ferenci P, et al. J Hepatol 2005; 43: 425
2. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 3. Berg T, et al. Gastroenterology 2006; 130: 1086
4. Sánchez-Tapias JM, et al. Gastroenterology 2006; 131: 451
5. Bronowicki JP, et al. Gastroenterology 2006; 131: 1040 6. Sakai T, et al. 41st EASL 2006; Abstract 605
Optimising outcomes in genotype 1/4
• Patients with a LVL who achieve an RVR may be
candidates for shorter treatment duration
• Patients with a cEVR achieve high SVR rates
with 48 weeks’ therapy
• Slow responders who do not achieve HCV RNA
negativity by week 4 or 12 may be candidates for
treatment intensification (longer duration, higher
doses)
SVR (%)
No consistent improvement with 72 weeks’
therapy in G1 patients with a complete EVR
100
90
80
70
60
50
40
30
20
10
0
87%
77%
48 weeks
72 weeks
78%
70%
61%
52%
n=
79
87
Berg et al.
RBV 800 mg/day
58
74
TeraVic-4
800 mg/day
60
RBV
46
Ferenci et al.*
RBV 1000/1200 mg/day
Complete EVR = no RVR but HCV RNA <50 IU/mL at week 12
* Includes small number (<10%) of G4 patients
Sánchez-Tapias JM, et al. APASL 2007; Abstract 0-196
SVR (%)
Consistent improvement with 72 weeks’
therapy in G1 patients with a partial EVR
100
90
80
70
60
50
40
30
20
10
0
48 weeks
72 weeks
69%
52%
46%
44%
33%
16%
n=
46
46
31
25
25
16
Berg et al.
TeraVic-4
Ferenci et al.*
RBV 800 mg/day
RBV 800 mg/day
RBV 1000/1200 mg/day
partial EVR = no RVR and >2 log10 drop but
HCV RNA >50 IU/mL at week 12
* Includes small number (<10%) of G4 patients
Sánchez-Tapias JM, et al. APASL 2007; Abstract 0-196
Extending treatment duration: summary
• Genotype 1 patients with a partial EVR (no RVR
and detectable HCV RNA but >2 log10 drop at
week 12) gain considerable benefit from
extension of therapy from 48 to 72 weeks
• The proportion of genotype 1 patients that benefit
from extended therapy is small but significant
• These results need to be confirmed in randomised
trials
Optimising outcomes in
genotype 1/4: conclusion
• Patients with a LVL who achieve an RVR may be
candidates for shorter treatment duration
• Patients with a cEVR achieve high SVR rates
with 48 weeks’ therapy
• Slow responders who do not achieve HCV RNA
negativity by week 4 or 12, but achieve a pEVR
may be candidates for treatment intensification
(longer duration, higher doses)
RVR is a strong predictor
of SVR in genotype 2/3
PEGASYS 180 g/wk plus COPEGUS 800 mg/day for 24 weeks
SVR: 49%
SVR: 94%
(105/215)
RVR, LVL:
24%
(141/150)
SVR: 90%
No RVR: 34%
(370/410)
SVR: 88%
(229/260)
RVR, HVL: 42%
<50 IU/mL at week 4 (RVR) and LVL (≤800 000 IU/mL)
HCV RNA response:
<50 IU/mL at week 4 (RVR) and HVL (>800 000 IU/mL)
>50 IU/mL at week 4 (No RVR)
Data from ACCELERATE. Roche data on file
Shortening treatment duration in
genotype 2/3 patients: ACCELERATE
Screening
132 centres; n=1469
PEGASYS
180 g/week
plus COPEGUS
800 mg/day
Follow-up
Treatment duration
blinded until week 16
PEGASYS
180 g/week
plus COPEGUS
800 mg/day
Follow-up
0 ------------------ 16 ---- 24 ----------------- 40 ----- 48
Weeks
Randomisation to 16 or 24 weeks’ treatment
Shiffman M, et al. N Engl J Med 2007; 357: 124
ACCELERATE: 24 weeks is more effective
than 16 weeks in genotype 2/3 patients
PEGASYS 180 g/wk plus COPEGUS 800 mg/day
100
90
SVR (%)
80
70
76%
65%
60
50
40
30
20
10
n=679
n=630
16 weeks
24 weeks
0
Standard analysis
Shiffman M, et al. N Engl J Med 2007; 357: 124
High SVR rates with shorter duration in G2/3
patients with an RVR
PEGASYS + COPEGUS
100%
SVR
80%
RVR: YES
67%
60%
40%
(871/1291)
82%
90%
378/461
370/410
16 weeks
24 weeks
20%
All patients
(n=1291)
0%
100%
SVR
80%
RVR: NO
60%
33%
40%
16 weeks
24 weeks
(420/1291)
20%
49%
27%
0%
Standard analysis
RVR = HCV RNA <50 IU/mL at week 4
55/205
105/215
Shiffman M, et al. 41st EASL 2006; Abstract 734
Very high SVR rates with shorter duration in
G2/3 patients with an RVR and LVL
16 weeks PEGASYS plus COPEGUS
24 weeks PEGASYS plus COPEGUS
100
90%
95%
92%
88%
84%
78%
SVR (%)
80
60
40
20
n=123 n=101
n=43
n=49
n=295 n=260
0
≤400 000 IU/mL
Standard analysis
400–800 000 IU/mL
>800 000 IU/mL
Shiffman M, et al. 57th AASLD 2006; Abstract 340
Optimising outcomes in genotype 2/3
• Patients with a LVL who achieve an RVR may be
candidates for shorter treatment duration
• Slow responders who do not achieve HCV RNA
negativity by week 4 may be considered
for treatment intensification (longer duration,
higher doses)
Optimising outcomes in
genotype 2/3: conclusion
• Patients with an RVR achieve high SVR rates >90%
– Patients with an RVR and a low baseline viral load
achieve very high rates of SVR with a shorter
duration
• Patients without an RVR achieved an SVR of 49%
with 24 weeks
– The possibility of improving SVR in non-RVR
patients by intensifying treatment (longer
duration/higher RBV doses) will be explored in a
prospective trial (NCORE 2/3 study; N=400)
Non-responders
• Combination therapy with pegylated interferon (IFN)
plus ribavirin (RBV) has led to a substantial increase in
SVR rates when compared to conventional IFN/RBV
combination therapy1
• Despite this, up to half of all patients treated with
pegylated interferon alfa-2b (12KD) plus RBV fail to
achieve an SVR2,3
• Initial retreatment studies have suggested a benefit of
induction doses and a prolonged duration of treatment in
4,5
previous non-responders to IFN/RBV
1. Strader D, et al. Hepatology 2004; 39: 1147
2. Manns M, et al. Lancet 2001; 358: 958
3. Jacobson I, et al. Hepatology 2007; 46: 971
4. Diago M, et al. Aliment Pharmacol Ther 2007; 26: 1131
5. Tong, M, et al. J Viral Hepat 1998; 5: 323
Treatment intensification in non-responders
Treatment intensification
Increase treatment
duration
Increase PEGASYS
dose
Fixed-dose induction: high PEGASYS
dose for 12 weeks followed by 180 g/wk
for 48 or 72 weeks
Spanish high-dose induction pilot trial
Non-responders to interferon plus ribavirin
270 g
PEGASYS 180 g/wk
Follow-up
+ COPEGUS 1000/1200 mg/day
360 g
n=72
PEGASYS 180 g/wk
Follow-up
+ COPEGUS 1000/1200mg/day
PEGASYS 180 g/wk
Follow-up
+ COPEGUS 1000/1200mg/day
0
Randomisation
12
24
36
48
Study week
60
72
Diago M, et al. Aliment Pharmacol Ther 2007; 26: 1131
Virological response (%)
Increasing SVR rates with increasing
PEGASYS dose
50
45
40
35
30
25
20
15
10
5
0
Non-responders to interferon plus ribavirin
38%
30%
18%
PEGASYS
PEGASYS
PEGASYS
360 g/week +
180 g/week +
270 g/week +
COPEGUS (n=28) COPEGUS (n=20) COPEGUS (n=24)
Diago M, et al. Aliment Pharmacol Ther 2007; 26: 1131
No increase in AEs with increasing
PEGASYS dose
PEGASYS
PEGASYS
PEGASYS
180 g/week + 270 g/week + 360 g/week +
COPEGUS
COPEGUS
COPEGUS
(n=28)
(n=20)
(n=24)
Adverse events
Serious adverse
events
Adverse events
leading to
withdrawal
27 (96%)
20 (100%)
24 (100%)
3 (11%)
1 (5%)
1 (4%)
3 (11%)
0 (0)
1 (4%)
Diago M, et al. Aliment Pharmacol Ther 2007; 26: 1131
REPEAT study design
A
360 µg
PEGASYS
180 µg
plus COPEGUS 1000/1200 mg
PEGASYS
B
360 µg
180 µg
plus COPEGUS 1000/1200 mg
Follow-up
Follow-up
R
PEGASYS
180 µg
plus COPEGUS 1000/1200 mg
C
PEGASYS
180 µg
plus COPEGUS 1000/1200 mg
D
0
12
24
36
Follow-up
Follow-up
48
Study weeks
R Randomisation (105 centres, 2:1:1:2, n=950)
60
72
84
96
Marcellin P, et al. AASLD 2005; Abstract
Study endpoints
• Primary endpoint:
– Compare the efficacy of 72 weeks of PEGASYS plus
COPEGUS with high-dose induction versus the standard doses
of the same combination given for 48 weeks
• Secondary endpoints:
– Compare the efficacy of high-dose induction with
standard dose
– Compare the efficacy of 72 weeks of treatment with
48 weeks of treatment
– Evaluate the safety of PEGASYS plus COPEGUS combination
therapy given for 48 and 72 weeks, including high-dose
induction regimens
Baseline characteristics
PEGASYS plus COPEGUS 1000/1200 mg/day
Males (%)
Caucasian (%)
Mean age, years
Mean weight, kg
Genotype 1 (%)
Cirrhosis (F3/F4) (%)
Mean HCV RNA (log10 IU/mL)
HCV RNA >800 000 IU/mL (%)
Mean Peg-IFN α-2b (12KD) start
dose (µg/kg/wk)*
Mean RBV start dose (mg/day)
360/180 µg/week
180 µg/week
72 weeks 48 weeks 72 weeks 48 weeks
A (n=317) B (n=156) C (n=156) D (n=313)
64
60
69
68
88
90
88
90
48.1
48.8
49.4
48.5
81.5
81.1
81.2
80.9
91
91
91
91
25
29
30
28
6.4
6.4
6.4
6.4
77
83
82
74
1.491
1.476
1.470
1.485
1019.5
1019.6
1024.5
1019.8
*Dose based on injected volumes of different vial strengths, according to label
Primary comparison:
72 week induction vs. 48 week non-induction
p=0.006, Odds ratio 2.0 (95% CI 1.21, 3.31)
20%
16%
SVR
14%
9%
10%
7%
52/317
11/156
22/156
27/313
360/180 µg
72 weeks
(A)
360/180 µg
48 weeks
(B)
180 µg
72 weeks
(C)
180 µg
48 weeks
(D)
0%
Jensen D, et al. 58th AASLD; Abstract LB4
Pooled induction vs. non-induction
20%
p=0.92, Odds ratio 0.98 (95% CI 0.63, 1.51)
SVR
13%
10%
10%
63/473
49/469
360/180 µg
48 and 72 weeks
(A+B)
180 µg
48 and 72 weeks
(C+D)
0%
Pooled 72 weeks vs. 48 weeks
p=0.0006, Odds ratio 2.22 (95% CI 1.40, 3.52)
20%
SVR
16%
10%
8%
74/473
38/469
72 weeks
(360/180 µg
and 180 µg)
(A+C)
48 weeks
(360/180 µg
and 180 µg)
(B+D)
0%
Predictors of response
Multiple Logistic Regression
P-value
Treatment duration (72 vs. 48 wks)
0.0002
Induction dose (360 vs. 180 µg/wk)
0.8881
Genotype (1 vs. non-1)
0.0219
Cirrhotic vs. non-cirrhotic
0.0032
Age (in 10 years)
0.0161
Weight (in 10 kg)
0.0009
HCV RNA >1.5 MIU/mL
vs. ≤1.5 MIU/mL
0.0004
0.25
0.5
1
Worse
2
Better
Odds ratio (95% CI)
4
Virologic response over time
PEGASYS plus COPEGUS 1000/1200mg/day
360/180 µg/wk
180 µg/wk
72 weeks
A (n=317)
48 weeks
B (n=156)
72 weeks
C (n=156)
48 weeks
D (n=313)
Week 12
24%
14%
16%
11%
EoT *
31%
33%
31%
28%
SVR
16%
7%
14%
9%
Virologic response over time
PEGASYS plus COPEGUS 1000/1200mg/day
360/180 µg/wk
72 weeks
A (n=317)
Week 12
EVR
62%
24%
EVR
58%
180 µg/wk
48 weeks
B (n=156)
14%
72 weeks
C (n=156)
EVR
49%
16%
48 weeks
D (n=313)
EVR
42%
11%
EoT *
31%
33%
31%
28%
SVR
16%
7%
14%
9%
Virologic response over time
PEGASYS plus COPEGUS 1000/1200mg/day
360/180 µg/wk
72 weeks
A (n=317)
Week 12
EVR
62%
24%
EVR
58%
180 µg/wk
48 weeks
B (n=156)
14%
72 weeks
C (n=156)
EVR
49%
16%
48 weeks
D (n=313)
EVR
42%
11%
EoT *
31%
33%
31%
28%
SVR
16%
7%
14%
9%
Virologic response over time
PEGASYS plus COPEGUS 1000/1200mg/day
360/180 µg/wk
72 weeks
A (n=317)
Week 12
EVR
62%
EoT *
SVR
24%
48 weeks
B (n=156)
EVR
58%
31%
Relapse
49%
16%
180 µg/wk
14%
72 weeks
C (n=156)
EVR
49%
33%
Relapse
78%
7%
16%
48 weeks
D (n=313)
EVR
42%
31%
Relapse
59%
14%
11%
28%
Relapse
67%
9%
Hepatitis C..
Spanish high-dose induction pilot trial:
(re-treatment of non-repsonders)
Virological response (%)
50
46%
SVR**
38%
40
35%
30%
30
21%
20
EVR*
270ug/wk x 12 wks
360ug/wk x 12 wks
18%
10
0
PEGASYS®
180 g/week +
ribavirin (n=28)
48 wks
PEGASYS®
PEGASYS®
360 g/week +
270 g/week +
ribavirin (n=20) ribavirin (n=24)
12+60 wks
12+60 wks
* EVR: HCV RNA <50 IU/mL at week 12
** SVR: HCV RNA <50 IU/mL 24 weeks post-treatment
Diago M, et al. 55th AASLD 2004; Abstract 522
Hepatitis C..
Comparing with earlier studies on Genotype 4 VRS
Type of INF
Our Shobokshi Et Hassan et al*
al*
study
Kuwait
KSA
N = 44
Esmat et al*
Egypt
Peg-INF
Ribavirin
SVR
(72wk)
42.9%
50%
Fix dose
Ribavirin
800mg
61%
40%
Weight-base Weight-based
Ribavirn dose Ribavirn dose
1000-1200mg 800-1000mg
Reg-INF
Ribavirin
SVR
(72wk)
32.3%
30%
Fix dose
Ribavin
800mg
39%
Ribavirn dose
Weight-based
800-1000mg
Annual Meeting of the American Association for the Study of Liver Diseases Oct 2003*
Hepatitis C..
Important Notes
• Anemia is a common side effect that begins soon after the
initiation of peginterferon/ribavirin in the treatment of hepatitis C
virus (HCV) infection
•
Negative impact QOL and is the most common reason for
reducing the dose and temporarily or permanently discontinuing
ribavirin
• Dose modifications have been shown to reduce the efficacy of
treatment
American Journal of Gastroenterology; Apr2007, Vol. 102 Issue 4, p880-889,
Significantly faster viral decay with
addition of ribavirin to pegylated interferon
PEGASYS 180g/wk (n=17)
Viral load (log10 IU/mL)
6
PEGASYS 180g/wk
plus COPEGUS
1000/1200 mg/day (n=10)
5
4
3
Limit of
detection
2
1
0
7
14
21
28
42
56
Days
Herrmann E, et al. Hepatology 2003; 37: 1351
Increase in SVR by prevention of relapse with
addition of ribavirin
48 weeks’ treatment;
all patients
100
90
PEGASYS 180 g/wk
PEGASYS 180 g/wk +
COPEGUS 1000/1200 mg/day
Patients (%)
80
69%
70
60
59%
56%
51%
50
40
29%
30
19%
20
10
n= 224
453
224
453
132
313
0
ETR
ETR = end-of-treatment response
SVR
Relapse
Fried M, et al. NEJM 2002; 347: 975
Increased SVR rate with higher ribavirin
starting dose in clinical trials
100
48 weeks’ PEGASYS 180 g/wk + COPEGUS;
genotype 1
90
80
SVR (%)
70
60
52%
50
41%
40
p=0.005 for
standard
versus low
dose (24 and
48 week data
combined)
30
20
10
n=
250
271
COPEGUS
800 mg/day
COPEGUS
1000/1200 mg/day
0
Hadziyannis S, et al. Ann Intern Med 2004; 140: 346
Dose-dependent increase in SVR with
ribavirin dose >10 mg/kg/day
Genotype 1: PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day
Observed values
Probability of SVR
1.0
Median
0.8
95% pointwise
confidence
intervals
0.6
0.4
0.2
0.0
5
10
15
20
25
COPEGUS dose (mg/kg)
Snoeck E, et al. Br J Clin Pharmacol 2006; 62: 699
Dose-dependent increase in anaemia with
ribavirin dose >15 mg/kg/day
Incidence of haemoglobin <10 g/dL
All patients: PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day
Observed values
1.0
Median
0.8
95% pointwise
confidence
intervals
0.6
0.4
0.2
0.0
5
10
15
20
25
COPEGUS dose (mg/kg)
Snoeck E, et al. Br J Clin Pharmacol 2006; 62: 699
Intensified ribavirin dose improves SVR in
‘difficult-to-cure’ patients
PEGASYS + COPEGUS; Treatment-naive,
genotype 1, high viral load, weight >85 kg
80
70
SVR (%)
60
47%
50
40
28%
30
32%
36%
20
10
0
n=
46
47
47
47
180 g +
COPEGUS
1200 mg
180 g +
COPEGUS
1600 mg
270 g +
COPEGUS
1200 mg
270 g +
COPEGUS
1600 mg
VR = HCV RNA <50 IU/mL
ITT; Missing = failure
Fried M, et al. 57th AASLD 2006; Abstract 3350
Hepatitis C..
Important Notes
• Erythropoietin can improve anemia caused by peginterferon and
ribavirin therapy and is more effective than dose reduction at
improving QOL during treatment
• A new ribavirin analog, viramidine, is expected to be associated
with a lower incidence of anemia and, if proven effective, may
eventually be substituted for ribavirin
American Journal of Gastroenterology; Apr2007, Vol. 102 Issue 4, p880-889,
Hepatitis C..
Case
• Ramzi (BMI 33) is a 50-year-old black male with hepatitis C. He
was treated in 2000 with (IFN)-a2b (Intron A) 3 mU 3 times/week
for 48 weeks, but he did not benefit from treatment. He was IV
drug user in his teens. Lab values include an HCVRNA level of
500,000 IU/ml, ALT of 74 units/L, AST of 53 units/L, total
bilirubin of 1.1 mg/dl, and albumin of 3.5 g/dl. He has genotype 4
disease. A liver biopsy in 2000 revealed mild disease with
moderate fibrosis. For the past 6 months, he has been retreated
with PEG-IFN-2a (Pegasys) 180 mcg/ml with ribavirin 600 mg
BID. He had an undetectable HCVRNA level at week 12 of
therapy. At this time, his LFTs are normal; however, he does have
an abnormal complete blood cell count panel: WBC = 2400
cells/mm3, ANC = 900 cells/mm3, Hgb = 8.9 g/dl, Hct = 26.6 %,
and Plt= 50,000 cells/mm3. He complains of fatigue and tied.
Hepatitis C..
Case
1.
Should he be treated for HCV infection?
2.
Is he receiving an appropriate drug regimen?
3.
How long does he need to be treated?
4.
Does he need dose adjustment?
5.
Would he be a good responder?
Hepatitis C..
Case
6.
What is sustain responder?
7.
What response rate would you expect?
8.
How do we access response? (3 parameters)
9.
For HCV genotype 2 or 3, what is the treatment
duration and response rate expected?
10. When is a good time to access an earlier response?