Diagnosis, Management, and Treatment of Hepatitis C:

An Update
AASLD PRACTICE GUIDELINES

Zarka
R2,
AKUH
Today’s talk is about . .

• Hepatitis C virus
• Who to test
• How to test
• Response rates
• Why treat
• Treat with what
• Nonresponders and relapsers
• Special group of patients
 The hepatitis C virus (HCV)

• Leading cause of chronic liver disease. principal cause of death from

liver disease

• An estimated 180 million people are infected worldwide.

• In USA prevalence of HCV infection between the years 1999 and 2002
was 1.6%,

• Leading indication for liver transplan­tation in the U.S.

• Mortal­ity related to HCV infection (death from liver failure or

hepatocellular carcinoma) will continue to increase over the next two
decades.
 Purpose of this talk

• provide clinicians with evidence-based

approaches to the
– prevention,
– diagnosis,
– management of HCV infection.
 Who should be tested?
• Injection drug users (past or present) (90 %)

• Intranasal drug users who share paraphernalia

• Individuals who have received a blood or blood component

transfusion, organ transplant (before 1992) ( 10%).

• Unexplained elevations of the ALT/AST

• Those ever on hemodialysis

 Who should be tested?
• Children born to HCV-infected mothers

• Those with HIV

• Exposure to an infected sexual partner or multiple sexual

partners (1% to 5%)

• Exposure among health care workers to HCV­contaminated

blood and blood products (1% to 5%)

• Tattooing
 Measures to Avoid Transmission of HCV

• avoid sharing toothbrushes and dental or shaving

equipment

• stop using illicit drugs.

• not donate blood, body organs, other tissue or semen

• counseled that the risk of sexual transmission is low, and

that the infection itself is not a reason to change sexual
practices
 Laboratory Testing

• Two classes of assays are used in the diagnosis

and management of HCV infection:

– serologic assays that de­tect specific antibody to

hepatitis C virus (anti-HCV) ---- EIA, CIA, ELISA
– molecular assays that detect viral nucleic acid
(HCV PCR )
 Anti-HCV

• False positive results

– prevalence of hepatitis C is low.

• False negative results

– severe immunosuppression :HIV, solid organ
transplant recipients, hypo- or
aggammaglobulinemia
– patients on hemodialysis
 Genotyping Assays

• useful in
– epidemiological studies
– clinical management for pre­dicting the likelihood of response and
determining the optimal duration of therapy.

• HCV is classified into at least 6 major genotypes (genotypes 1

to 6)

• Genotype 1 (subtypes 1a and 1b) is the most com­mon in the

U.S
 Course of events

• After acute exposure,

– HCV RNA can be identified as early as 2 weeks

following exposure whereas
– anti-HCV is generally not detectable before 8-12
weeks.
Interpretation of HCV Assays
 Recommendation

• Patients suspected of having acute or chronic HCV infection should first be

tested for anti-HCV

• HCVRNA testing should be performed in:

– Patients with a positive anti-HCV test (Class I, Level B)
– Patients for whom antiviral treatment is being considered, using a sensitive quantitative
assay (Class I, Level A)
– Patients with unexplained liver disease whose anti-HCV test is negative and who are
immunocompromised or suspected of having acute HCV infection (Class I, Level B).

• HCV genotyping
– should be performed in all HCV-infected persons prior to interferon-based treat­ment in
order to plan for the dose and duration of therapy and to estimate the likelihood of
response
 3 primary reasons for performing
a liver biopsy:

•
• it provides helpful information on the current status of the
liver injury

• it identifies features useful in the decision to embark on

therapy

• it may reveal advanced fibrosis or cirrhosis that

necessitates surveillance for hepatocellular carcinoma
(HCC) and/or screening for varices.
 Justification for Treatment

• 55% to 85% of individuals who develop acute

hepatitis C will remain HCV-infected.
• Spontaneous resolution
– infected infants
– young women
•
• Progression to cirrhosis may be accelerated in
persons who are

– of older age
– obese
– immunosuppressed (e.g., HIV co-infected)
– consume > 50g of alcohol per day
 Risks

• Hepatic decompensation (30% over 10 years)

• Hepatocellular carcinoma (1% to 3% per

year).
• Infection with HCV can also cause extrahepatic
diseases including mixed cryoglobulinemia,
types II and III ( indication for treatment )
• The Optimal Treatment of Chronic HCV:

Peginterferon
Alfa and
Ribavirin
pegylated interferons

a
• Beneficial effects of ribavirin,
– an improvement in the ETR but, more importantly,
– a significant decrease in the relapse rate as
compared to peginterferon monotherapy
treatment.
 Optimal duration of treatment

• based on the viral geno­type

– genotype 1 for 48 weeks

– genotypes 2 and 3 24 weeks
– genotype 4 48 weeks
– genotype 5  insufficient data
– genotype 6 48 weeks
 Pretreatment Predictors of
Response

• useful for advising patients on their likelihood of an

SVR.

– the viral genotype : non-1 infection (mostly

genotype 2 and 3)

– pretreatment viral load : <600,000 IU/mL.

•
• Other less consistently reported baseline characteristics associated with a
favorable response include the

– doses of peginterferon (1.5 peg/kg/week versus 0.5 peg/kg/week) and

ribavirin (>10.6 mg/kg)
– Female gender
– age <40 years
– non–African-American race
– lower body weight (~75 kg)
– the absence of insulin resistance
– elevated ALT levels (three-fold higher than the upper limit of normal)
– absence of bridging fibrosis or cirrhosis on liver biopsy
…….
These terms ?!?!
• RVR
• EVR
• ETR
• SVR
• Breakthrough
• Relapse
• non-responders

-----
 Rapid virological response (RVR)

• HCV RNA negative at treatment week 4 by a

sensitive PCR-based quantitative assay
• May allow shortening of course for genotypes
2&3 and possibly genotype 1 with low viral
load
 Early virological response (EVR)

• ~ 2 log reduction in HCV RNA level compared

to baseline HCV RNA level (partial EVR) or HCV
RNA negative at treatment week 12 (complete
EVR)
 End-of-treatment response (ETR)

• HCV RNA negative by a sensitive test at the

end of 24 or 48 weeks of treatment
Sustained virological response (SVR)

• HCV RNA negative 24 weeks after

cessation of treatment
• Best predictor of a long-term response to
treatment
• A.k.a -- “virological cure”
 Breakthrough

• Reappearance of HCV RNA in serum while still

on therapy
 Relapse

• Reappearance of HCV RNA in serum after

therapy is discontinued
 Nonresponder

• Failure to clear HCV RNA from serum after 24

weeks of therapy
 Null responder

• Failure to decrease HCV RNA by < 2 logs after

24 week of therapy
 Partial responder

• Two log decrease in HCV RNA but still HCV

RNA positive at week 24
 Let’s memorize . .

• RVR --- PCR negative at wk 4

• EVR ---PCR negative at wk 12
• ETR --- PCR negative at end of treatment
• SVR --- PCR negative 24 wks after stopping
• Breakthrough– reappearance while on treatment
• Relapse--- reappearance after therapy stopped
• Nonresponder --- failure to clear HCV after 24
wks
• Achieving an RVR is highly predictive of
obtaining an SVR (independent of genotype and
regardless of the treatment regimen)

• However,RVR achieved in only

– 15% to 20% HCV genotype 1 infection
– 66%  HCV genotype 2 and 3 infections
• Because of the rapid clearance of virus from serum,
patients who achieve an RVR may be able to shorten
the duration of treatment

– HCV genotype 1 from 48 to 24 weeks

– HCV genotypes 2 and 3 

• may shorten treatment by weeks 12 and 16 if they had achieved
an RVR.
• However, patients should be informed of the higher relapse rate
associated with this strategy and be advised that re-treatment
with a 24 to 48 week course of therapy may be required
 Adverse Events

10% to 14% of patients had to discontinue therapy due to

an adverse event.

• influenza-like side effects such as fatigue, headache, fever

and rigors (>50% )

• psychiatric side effects (depression, irritability, and

insomnia), (22% to 31%)

• Lab abnormalities: neutropenia (ANC of 1500 mm3) (18% to

20%)
 Adverse Events ,
Ribavirin
• hemolytic anemia
• cleared by the kidney, the drug should be used with
extreme caution in patients with renal disease
• mild lymphopenia
• hyperuricemia
• itching
• rash
• cough
• nasal stuffiness
• fetal death and fetal abnormalities in animals
(strict contraceptive methods both during treatment and for a period of 6 months
thereafter)
Characteristics of Persons for Whom Therapy Is
Widely Accepted
• Age 18 years or older

• HCV RNA positive

• Liver biopsy chronic hepatitis with significant fibrosis (bridging fibrosis

or higher)

• Compensated liver disease (total serum bilirubin <1.5 g/dL; INR 1.5;
albumin >3.4, plts 75,000 mm and no evidence of hepatic
decompensation (hepatic encephalopathy or ascites),

• Acceptable hematological and biochemical indices (Hb 13 g/dL for men

and 12 g/dL for women; ANC 1500 /mm3 and Cr <1.5 mg/dL, and

• Willing to be treated and to adhere to treatment requirements, and

• No contraindications
 Characteristics of Persons for Whom
Therapy Is Currently Contraindicated
• Major uncontrolled depressive illness

• Solid organ transplant (renal, heart, or lung)

• Autoimmune hepatitis or other autoimmune condition

• Untreated thyroid disease

• Pregnant or unwilling to comply with adequate contraception

• Severe concurrent medical disease : severe HTN , heart

failure, significant IHD, poorly controlled DM, COPD

• Age less than 2 years

• Known hypersensitivity to drugs used to treat HCV
• A reasonable schedule would be
– monthly visits during the first 12 weeks of
treatment
– followed by visits at 8 to 12 week intervals
thereafter until the end of therapy.
• At each visit the patient should be questioned
regarding the presence of side effects and
depression. They should also be queried about
adherence to treatment.
 Laboratory monitoring

• CBC ,Cr and ALT levels, and HCV RNA

– weeks 4, 12, 24,
– 4 to 12 week intervals thereafter,
– the end of treatment,
– 24 weeks after stopping treatment.
• TFTs
– Q 12 weeks while on treatment.
 Retreatment of Persons Who
Failed to Respond to Previous
Treatment
• 20-50 % of patients treated will not achieve an
SVR
– non-responsder
– virological break­through
– relapse
– Poor compliance
– The induction of antibodies to peginterferon (only a
minority)
 Non-Responders
• Approximately thirty percent of patients
• Options for non-responders to pegylated
interferon and ribavirin---- limited.
• Retreatment with the same regimen --- SVR in
fewer than 5% of patients and --cannot be
recommended.
 non-responders to standard
interferon either with or without
ribavirin
• retreatment with peginterferon alfa-2a or 2b
has been evaluated in three
• The SVR rates
– higher among patients who had previ­ously
received interferon monotherapy, (20% to 40%)
– were lower among non-responders to the
combination of interferon and ribavirin, (8% to
10%)
 Maintenance
(with peginterferon therapy)

• Goal
– delaying or preventing progression to cirrhosis
and/or hepatic decompensation
– currently being assessed in two ongoing and one
completed randomized trials in the U.S. and
Europe
 Maintenance
(with peginterferon therapy)

• HALT-C Trial
– maintenance low dose peginterferon alfa-2a, 90 g
per week, is not indicated in patients with
hepatitis C who have bridging fibrosis or cirrhosis
and who have not re­sponded to a standard course
of peginterferon and ribavi­rin therapy.
 Relapsers
• . In the majority of instances, virological
relapse occurs within the first 12 weeks and
late relapse, beyond 24 weeks, is extremely
uncommon.
• likely to respond to the same regimen given a
second time but will still experience an
unacceptable rate of relapse.
• . Data on retreatment of relapsers to
peginterferon and ribavirin have not been
published.
 relapsers to standard IFN and
ribavirin

high dose peginterferon low dose peginterferon

alfa-2b, 1.5 g/kg/week with fixed dose ribavirin 800 alfa-2b, 1 peg/kg/week plus weight-based ribavirin,
mg daily 1,000 to 1,200 mg daily.151
Let’s take a picture break
……!!!
• Let’s get back to business . . .
 Special Patient Groups
• Treatment of Persons with Normal Serum
Amino­transferase Values
• Diagnosis and Treatment of HCV-Infected
Children.
• Diagnosis, Natural History, and Treatment
ofPer­sons with HIV Coinfection
• Treatment ofPatients with Kidney Disease
• Treatment of Persons with Compensated and
De- compensated Cirrhosis.
 Normal Serum Amino­transferase
Values . .
Should we treat them?

• Regardless of the serum ALT level, the

decision to initiate therapy with pegylated
interferon and ribavirin should be individ­
ualized based on the severity of liver disease
by liver biopsy
 Treatment of Patients with
Kidney Disease
• Hepatitis C affects the kidney in at least two
ways

– CKD who undergo hemodialysis are at high risk of

acquiring HCV infection

– essential mixed (type II) cryoglobulinemia

 CKD

Mild , GFR Severe, no HD On HD

>60ml/min
 Cryoglobulinaemia
• Mild to moderate proteinuria 
– standard interferon or reduced doses of pegylated
interferon alfa and ribavirin
• Proteinuria with evidence of progressive
kidney disease or an acute flare of
cryoglobulinemia
– rituximab, cyclophosphamide plus
methylprednisolone, or plasma exchange followed
by interferon-based treatment once the acute
process has subsided
• Treatment is not recommended for patients
with chronic HCV infection who have
undergone kidney transplantation, unless
they develop fibrosing cholestatic hepatitis
 Diagnosis and Treatment of HCV-
Infected Children
• Risk of perinatal HCV transmission 4% to
6%, (2- to 3-fold higher for mothers with HIV/HCV co-
infection)

• Breastfeeding not prohibited

• When to test ?
– Anti- HCV --- until 18 months
– HCV RNA testing --- 6 months
• Children more likely than infected adults to
– spon­taneously clear the virus
– have normal ALT

• Children aged 2-17 years who are infected

with HCV should be considered appropriate
candidates for treatment using the same
criteria as that used for adults
 Diagnosis, Natural History, and
Treatment ofPer­sons with HIV
Coinfection
• 25% of HIV-infected persons in the Western
world have chronic HCV infection.
• approximately 6% of HIV-positive persons fail
to develop HCV antibodies( therefore, HCV
RNA should be assessed )
• twofold increased risk of cirrhosis

• likelihood of achieving an SVR (d/t higher HCV RNA

levels)

• Initial treatment of hepatitis C in most HIV-

infected patients should be
– peginterferon alfa plus ribavirin for 48 weeks (at
doses recommendedfor HCV mono-infected patients)
• Ribavirin associated anemia is a greater
problem ( esp with AZT).

• Ribavirin inhibits inosine-5-monophos­phate

dehydrogenase, an effect that potentiates di­
danosine (ddI) toxicity (lactic acidosis)
 Treatment of Persons with
Compensated and De-
compensated Cirrhosis
• Compensated cir­rhosis (CTP class A), can be
treated with the standard regimen
ofpegylated interferon and ribavirin (but will
require close monitoring for S/E)

• Patients with HCV-related decompensated

cirrhosis should be referred for consideration
of liver transplantation
 Should Acute Hepatitis C be
treated??
• Response rates
– >> acute vs. chronic HCV infection (SVR s of 83-
100%)
• Treatment can be delayed for 8 to 12 weeks

• standard interferon monotherapy=

peginterferon
• Duration :
– reasonable to treat for at least 12 weeks, and 24
weeks may be considered
 Treatment of Persons with Acute
Hepatitis C
• Ribavirin ??

– No recommendation can be made for or against

the addition of ribavirin and the decision will
therefore need to be considered on a case-by-
case basis (Class IIa, Level C).
 Treatment of Persons with
Psychiatric Illnesses
• Prevalence of chronic HCV infec­tion in patients
with mental or psychiatric diseases 8% to
31%
• Neuropsychiatric side effects (associated with interferon
and ribavirin )
– Depression (21 -58 %)
– suicidal ideation
– mania
– mood swings
– relapse of drug or alcohol abuse.
 Treatment of Persons with
Psychiatric Illnesses
• Available evidence is that interferon and
ribavirin can be safely administered provided
there is
– comprehensive pretreatment psychiatric assessment
– risk benefit analysis is conducted
– there are provisions for ongoing follow-up of
neuropsychiatric symptoms during antiviral therapy by a
multidisciplinary team
 Psychiatric patients and HCV
– They can achieve SVR rates that are similar to patients
without psychiatric disorders.

– Most psychotropic agents are thought to be safe for use in

the management of patients with chronic HCV infec­tion
 Alcohol and HCV

• Strong association between the use of excess

alcohol (>50 gms )
– development or progression of liver fibrosis and
even the development of HCC.
– increase HCV RNA replication
– interfere with response to treatment
 Obesity and HCV
• Obesity (BMI >25 kg/m2) and its associated
NAFLD are believed to play a role in the

– progression of fibrosis in HCV-infected individuals

– response to treat­ment
All persons with chronic HCV infection who
lack antibodies to hepatitis A and B should be
offered vaccination against these two viral
infections
• Persons more likely to achieve an SVR from
retreatment included
– genotype non-1 infec­tion,
– who had lower baseline HCV RNA levels,
– who had lesser fibrosis,
– were of the Caucasian race,
– prior treatment had consisted of interferon
mono- therapy.