Hepatitis c management

8/8/2019 Hepatitis c management

1/86

Diagnosis, Management, and

Treatment of Hepatitis C:

An UpdateAASLD PRACTICE GUIDELINES

Zarka

R2,

AKUH


2/86

Todays 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


3/86


4/86

Purpose of this talk

provide clinicians with evidence-basedapproaches to the

prevention,

diagnosis,

management of HCV infection.


5/86

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


6/86

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 HCV-contaminatedblood and blood products (1% to 5%)

Tattooing


7/86

Measures to Avoid Transmission of

HCV

avoid sharing toothbrushes and dental or shavingequipment

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 changesexual practices


8/86

Laboratory Testing

Two classes of assays are used in the diagnosis

and management of HCV infection:

serologic assays that de-tect specific antibody to

hepatitis C virus (anti-HCV) ---- EIA, CIA, ELISA

molecular assays that detect viral nucleic acid

(HCV PCR )


9/86

Anti-HCV

False positive results

prevalence of hepatitis C is low.

False negative results

severe immunosuppression :HIV, solid organtransplant recipients, hypo- or

aggammaglobulinemia

patients on hemodialysis


10/86

Genotyping Assays

useful in epidemiological studies

clinical management for pre-dicting the likelihood ofresponse 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 com-monin the U.S


11/86

Course ofevents

After acute exposure,

HCV RNA can be identified as early as 2 weeks

following exposure whereas

anti-HCV is generally not detectable before 8-12weeks.


12/86

Interpretation of HCV Assays


13/86

Recommendation

Patients suspected of having acute or chronic HCV infection should firstbe tested for anti-HCV

HCVRNA testing should be performed in: Patients with apositive anti-HCV test(Class I, Level B)

Patients for whom antiviral treatment is being considered, using a sensitivequantitative assay (Class I, Level A)

Patients with unexplained liver disease whose anti-HCV test is negative andwho are immunocompromised or suspected of having acute HCV infection(Class I, Level B).

HCV genotyping should be performed in all HCV-infected personsprior to interferon-based

treat-ment in order to plan for the dose and duration of therapy and toestimate the likelihood of response


14/86

primary reasons for performing

a live

r 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.


15/86

Justification for Treatment

55% to 85% of individuals who develop acute

hepatitis C will remain HCV-infected. Spontaneous resolution

infected infants

young women


16/86

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


17/86

Risks

Hepatic decompensation (30% over 10 years)

Hepatocellular carcinoma (1% to 3% per

year).


18/86

Infection with HCV can also cause extrahepatic

diseases including mixed cryoglobulinemia,types II and III ( indication for treatment )


19/86

The Optimal Treatment of Chronic HCV:

PeginterferonAlfa and

Ribavirin


20/86


21/86

pegylatedinterferons

a

40-kd branchedPEG ,180

peg/week

12-kd PEG, 1.5peg/kg/week


22/86

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.


23/86

Optimal duration of treatment

based on the viral geno-type

genotype 1 for 48 weeks

genotypes 2 and 3 24 weeks

genotype 4 48 weeks

genotype 5 insufficient data

genotype 6 48 weeks


24/86

Pretreatment Predictors

of Response

useful for advising patients on their likelihood of anSVR.

the viral genotype : non-1 infection (mostlygenotype 2 and 3)

pretreatment viral load :


25/86

Other less consistently reported baseline characteristics associated with afavorable response include the

doses of peginterferon (1.5 peg/kg/week versus 0.5 peg/kg/week) andribavirin (>10.6 mg/kg)

Female gender age


26/86

These terms ?!?!

RVR

EVR

ETR

SVR

Breakthrough

Relapse

non-responders

-----


27/86

Rapid virological response (RVR)

HCV RNA negative at treatment week 4 by a

sensitiveP

CR-based quantitative assay May allow shortening of course for genotypes

2&3 and possibly genotype 1 with low viral

load


28/86

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)


29/86

End-of-treatment response (ETR)

HCV RNA negative by a sensitive test at the

end of 24 or 48 weeks of treatment


30/86

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


31/86

Breakthrough

Reappearance of HCV RNA in serum while stillon therapy


32/86

Relapse

Reappearance of HCV RNA in serum aftertherapy is discontinued


33/86

Nonresponder

Failure to clear HCV RNA from serum after 24weeks of therapy


34/86


35/86

Partial responder

Two log decrease in HCV RNA but still HCV

RNA positive at week 24


36/86

Lets 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


37/86


38/86

Achieving an RVR is highly predictive of

obtaining an SVR (independent of genotype andregardless of the treatment regimen)

However,RVR achieved in only

15% to 20% HCV genotype 1 infection

66% HCV genotype 2 and 3 infections


39/86

Because of the rapid clearance of virus from serum,patients who achieve an RVR may be able to shortenthe 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 rateassociated with this strategy and be advised that re-treatmentwith a 24 to 48 week course of therapy may be required


40/86

Adverse Events

10% to 14% of patients had to discontinue therapy due toan adverse event.

influenza-like side effects such as fatigue, headache, feverand rigors (>50% )

psychiatric side effects (depression, irritability, andinsomnia), (22% to 31%)

Lab abnormalities: neutropenia (ANC of 1500 mm3) (18% to20%)


41/86

Adverse Events ,

Ribavirin

hemolytic anemia

cleared by the kidney, the drug should be used withextreme 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 monthsthereafter)


42/86

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 3.4, plts 75,000 mm and no evidence of hepaticdecompensation (hepatic encephalopathy or ascites),

Acceptable hematological and biochemical indices (Hb 13 g/dL for menand 12 g/dL for women; ANC 1500 /mm3 and Cr


43/86

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 , heartfailure, significant IHD, poorly controlled DM, COPD

Age less than 2 years

Known hypersensitivity to drugs used to treat HCV


44/86

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 ofside effects anddepression. They should also be queried about

adherence to treatment.


45/86

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.


46/86

Retreatment of Persons Who

Failed to Respond to Previous

Treatment 20-50 % of patients treated will not achieve an

SVR

non-responsder

virological break-through

relapse

Poor compliance

The induction of antibodies to peginterferon (onlya minority)


47/86

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 respon ers to stan ar


48/86

non-respon ers to stan ar

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 previ-ously

received interferon monotherapy, (20% to 40%)

were lower among non-responders to the

combination of interferon and ribavirin, (8% to10%)

M i t


49/86

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

M i t


50/86

Maintenance(with peginterferon therapy)

HALT-C Trial

maintenance low dose peginterferon alfa-2a, 90 g

per week, is not indicated in patients withhepatitis C who have bridging fibrosis or cirrhosis

and who have not re-sponded to a standard

course of peginterferon and ribavi-rin therapy.


51/86

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.


52/86

relapsers tostandard IFN and

ribavirin

high dosepeginterferon

alfa-2b, 1.5 g/kg/week withfixed dose ribavirin 800 mg

daily

SVR 50 %

low dose

peginterferonalfa-2b, 1 peg/kg/week plus

weight-based ribavirin,1,000 to 1,200 mg daily.151

SVR 32 %


53/86

Lets take a picture break !!!


54/86


55/86


56/86


57/86


58/86


59/86


60/86


61/86


62/86


63/86

Lets get back to business . . .


64/86

Special Patient Groups

Treatment ofPersons with Normal Serum

Amino-transferase Values

Diagnosis and Treatment of HCV-Infected

Children.

Diagnosis, Natural History, and Treatment

ofPer-sons with HIV Coinfection

Treatment ofPatients with Kidney Disease

Treatment ofPersons with Compensated and

De- compensated Cirrhosis.


65/86

NormalSerum Amino-transferase

Values . .

Should we treat them?

Regardless of the serum ALT level, thedecision to initiate therapy with pegylated

interferon and ribavirin should be

individ-ualizedbased on the severity of liver

disease by liver biopsy

f h


66/86

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


67/86

CKD

Mild ,

GFR>60ml/min

same combination antiviraltherapy

Severe, no HD

reduced doses of bothpeginterferon (al-pha-2a,135 pg/week; alpha-2b, 1

pg/kg/week) and ribavirin(200-800 mg/day)

On HD

standard interferon (2a or2b) in a dose of3 mU t.i.w.or reduced dose pegylatedinterferon 2a, 135 ug/week

or 2b 1 ug/kg/week.Ribavirin can be used in

combination with interferonin a markedly reduced daily

dose


68/86

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 plusmethylprednisolone, or plasma exchange followed

by interferon-based treatment once the acute

process has subsided


69/86

Treatment is not recommended for patients

with chronic HCV infection who have

undergone kidney transplantation, unless

they develop fibrosing cholestatic hepatitis

Di i d T f HCV


70/86

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


71/86

Children more likely than infected adults to

spon-taneously clear the virus

have normal ALT

Children aged2-17 years who are infected

with HCV shouldbe consideredappropriate

candidates for treatment using the same

criteria as that usedfor adults

Diagnosis, Natural History, and


72/86

Diagnosis, Natural History, and

Treatment ofPer-sons 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 )


73/86

twofold increased risk of cirrhosis

likelihood of achieving an SVR (d/t higher HCV RNAlevels)

Initialtreatmentofhepatitis C in most HIV-

infectedpatients shouldbepeginterferon alfa plus ribavirin for 48 weeks (at

doses recommendedfor HCV mono-infectedpatients)


74/86

Ribavirin associated anemia is a greater

problem ( esp with AZT).

Ribavirin inhibits inosine-5-monophos-phate

dehydrogenase, an effect that potentiates

di-danosine (ddI) toxicity (lactic acidosis)

Treatment of Persons with


75/86

f

Compensated and De-

compensated Cirrhosis

Compensatedcir-rhosis (CTP classA), can be

treatedwith the standardregimenofpegylatedinterferon andribavirin (but willrequire close monitoringfor S/E)

Patients with HCV-relateddecompensatedcirrhosis shouldbe referredfor consideration

ofliver transplantation

Should Acute Hepatitis C be


76/86

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


77/86

Treatment of Persons with Acute

Hepatitis C

Ribavirin ??

No recommendation can be madefor 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).



78/86


Psychiatric Illnesses

Prevalence of chronic HCV infec-tion in

patients with mental or psychiatric diseases

8% to 31%

Neuropsychiatric side effects (associated with interferonand ribavirin )

Depression (21 -58 %)

suicidal ideation

mania

mood swings

relapse of drug or alcohol abuse.

reatment o ersons w t


79/86

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


80/86

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 infec-tion


81/86

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


82/86

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 treat-ment


83/86

All persons with chronic HCV infection who

lack antibodies to hepatitis A and B should be

offeredvaccination against these two viral

infections


84/86


85/86

Persons more likely to achieve an SVR from

retreatment included

genotype non-1 infec-tion,

who had lower baseline HCV RNA levels,

who had lesser fibrosis,

were of the Caucasian race,

prior treatment had consisted of interferonmono- therapy.


86/86

Documents

Hepatitis c management