Hepatitis B and C - Approach and Management : Updates 2018

RECENT ADVANCES IN DAIGNOSIS
AND MANAGEMENT OF HEPATITIS B
AND CHRONIC HEPATITIS C
CHAIR PERSON – Dr. KALINGA B E
STUDENT – Dr. ARATHY S

oHepatitis B is an infectious disease caused by the Hepatitis B virus
(HBV).
oIt is a major public health problem, causing chronic hepatitis, cirrhosis
of liver and hepatocellular carcinoma.
oHuman carcinogen—cause of up to 80% of hepatocellular
carcinomas.

• Appears in the blood about 6 weeks after infection and has usually
disappeared by 3 months after the clinical illness.
• Persistence for more than 6 months implies the development of a
carrier state or progression to chronicity
• A diagnosis of HBV infection can usually be made by detection of
HBsAg in serum

• An inverse correlation exists between the serum concentration of
HBsAg and the degree of liver cell damage.
• These suggest that, in hepatitis B, the degree of liver cell damage and
the clinical course are related to variations in the patient’s immune
response to HBV rather than to the amount of circulating HBsAg

• HBeAg has a signal peptide that binds it to the smooth endoplasmic
reticulum, the secretory apparatus of cell, leading to its secretion into
circulation.
• This secreted nucleocapsid protein is thus a reliable qualitative
marker of HBV replication and infectivity
• HBcAg, devoid of signal peptide is not secreted and incorporated into
nucleocapsid.

HBxAg
• Capable of transactivating the transcription of both viral and cellular
genes
• clinical association observed between the expression of HBxAg and
antibodies to it in patients with severe chronic hepatitis and
hepatocellular carcinoma
• The transactivating activity can enhance the transcription and
replication of other viruses besides HBV such as HIV.

Phase Liver histology
Immune Tolerant Minimal inflammation and fibrosis
Immune Clearance Moderate to severe inflammation or
fibrosis
Inactive Disease Minimal necroinflammation but variable
fibrosis
HBeAg-negative Chronic HBV Moderate to severe inflammation or
fibrosis

Evaluation of HBsAg +ve patients
• HISTORY
Symptoms and signs of liver disease
alcohol and metabolic risk factors
Family history of HCC
vaccination status

• Laboratory tests
complete blood count
s.bilirubin, AST, ALT, ALP
s.albumin, INR
AFP, GGT

SEROLOGY/ VIROLOGY
• HBsAg quantitative assay - The quantitative
electrochemiluminescence immunoassay determines the HBsAg
levels expressed in IU/mL
• widely used to monitor chronic Hepatitis B (CHB) patients response to
antiviral Therapy.

Antibodies to HBc
• In patients with hepatitis B surface antigenemia of unknown duration
testing for IgM anti-HBc may be useful to distinguish between acute
or recent infection (IgM anti-HBc-positive) and chronic HBV infection
• Specificity = 99.8% to 99.9%

HBeAg
• HBeAg correlates with ongoing viral synthesis and with infectivity
• Persistence for more than 10 weeks strongly suggests the
development of chronicity

Anti HBe
• Prognostic for resolution of infection
• The appearance of Anti-Hbe is strong evidence that the patient will
recover completely.

Anti HBs
• After immunization with hepatitis B vaccine, which consists of HBsAg
alone, anti-HBs is the only serologic marker to appear
• Anti-HBs >12mIu – Protective

Molecular Advances in Diagnosis of HBV
Infection
• Current HBV DNA assays make use of differing technologies and can
generally divided into i) signal amplification assays
ii) DNA amplification tests based on PCR
• HBV DNA detection based on PCR approach can detect as few as 10 2
– 10 3 Genome copies

HBV DNA
• the most sensitive index of viral replication.
• It is a good marker of the level of viraemia, can be correlated with
serum transaminase levels

NEEDLE LIVER BIOPSY
• ascertain the degree of necroinflammation and fibrosis
• help guide the decision to treat.
• the amount of replicating virus in the serum does not correlate with
the degree of histological activity

Non-Invasive Tests (NITs)
• APRI
• FIB-4
• transient elastography (FibroScan)

• In a meta-analysis of 40 studies, investigators concluded that an APRI
score greater than 1.0 had a sensitivity of 76% and specificity of 72%
for predicting cirrhosis

FIB-4 score <1.45 had a negative predictive value of 90% for
advanced fibrosis.
FIB-4 >3.25 would have a 97% specificity and a positive
predictive value of 65% for advanced fibrosis.
these individuals could potentially have avoided liver biopsy.

Fibroscan
• measure liver stiffness
• based on ultrasound technology.
• Transient elastography performed with FibroScan has been the most widely
evaluated.
• >90% accuracy for early Fibrosis and Cirrhosis.
• Cost in India – Rs.4000 to 5000/- per scan.

Screening for HCC
oPatients who are HBsAg positive with chronic hepatitis or cirrhosis,
especially if male and more than 45 years old, should be screened
regularly so that hepato-cellular carcinoma may be diagnosed early
when surgical resection may prove possible.
oSerum α-fetoprotein should be measured and ultrasound
examination performed at 6-monthly intervals.

• HBsAg seroclearance did not reduce therisk of HCC in patients with
Hepatitis B
• Hepatitis B patients who have indications for surveillance pre
seroclearance should continue getting surveillance post
seroclearance.
P pP Gounder, Bulkow, Snowball et al; Nested case control study:
Hepatocellular carcinoma risk after Hepatitis B surface antigen
seroclerance

ACUTE HEPATITIS B
• Supportive management
• Recovery in 99% cases
• Severe acute Hepatitis B – antiviral therapy with nucleoside analogue
duration – until 3 months after HBsAg seroconversion or
6months after HBeAg seroconversion

CHRONIC HEPATITIS B
• Interferons
• Nucleotide analogues
• Nucleoside analogues

INTERFERONS
• Interferon alpha was the first approved therapy for chronic Hepatitis
B.
Mechanisms – immunostimulatory
intrinsic antiviral activity
• Dosage – 5million units daily or
10million units thrice a week

Contraindications - psychiatric disease
neutropenia or thrombocytopenia
coronary artery disease
cardiac arrhythmia
decompensated cirrhosis
renal transplantation.

• Complications – flu like symptoms
marrow suppression
emotional lability
autoimmune reactions
alopecia, rashes, diarrhoea
numbness and tingling

PEGYLATED INTERFERONS
• Polyethylene glycol (PEG) is added to make interferon last longer in
the body
• Ease of administration
• Higher efficacy
• Better sustained response rate

NUCLEOSIDE/NUCLEOTIDE ANALOGUES
INHIBIT VIRAL DNA POLYMERASE ENZYME

LAMIVUDINE
• Clinical and laboratory side effects of lamivudine are negligible
• Emergence of resistance
• Long-term monotherapy with lamivudine is associated with
methionine to valine(M204V) or methionine-to-isoleucine
(M2041)mutations, primarily at amino acid 204 in the tyrosine-
methionine aspartate-aspartate (YMDD) motif of HBV DNA
polymerase

• lamivudine is no longer recommended as first-line therapy
• The drug is still used widely as first-line therapy in developing
countries

ADEFOVIR DIPIVOXIL
• effective against both wild-type and lamivudine-resistant HBV.
• primary treatment failure (<1 log decline in the serum HBV DNA level
at week 12) was observed in 30% of patients
• Adverse effect – nephrotoxicity
• Dose – 10mg/day

• No longer recommended as a first line therapy
• Used widely as primary therapy or in combination with lamivudine in
resistant cases.

TENOFOVIR
• More potent agent
• Dosage – 300mg/day
• Active against wild type HBV
lamivudine resistant HBV
slow or limited response to adefovir

• The 5-year safety and resistance profile are very favourable
• Replaced adefovir both as first line therapy for chronic Hepatitis B and
add on therapy for lamivudine resistant cases.

• Tenofovir monotherapy was as effective as tenofovir emtricitabine
combination and well tolerated in Lamivudine resistans chronic
hepatitis B patients for upto 240 weeks
Fung s, Kwan P, Fabri M et al; TDF versus TDF/FTC in Lamivudine
resistant Hepatitis B : a 5yr randomised study. J.Hepatology 2016
Aug18.

ENTECAVIR
• The most potent of the HBV antivirals
• High potency and high barrier to resistance renders it a first line drug
for patients with chronic Hepatits B
• Resistance to entecavir in lamivudine resistant chronic hepatitis B has
been recorded to increase progressively to 43% at 4 years.
• Entecavir is not as attractive a choice as adefovir or tenofovir for
patients with lamivudine resistant hepatitis B

EFFICACY OF ANTIVIRALS IN CHRONIC
HEPATITIS B

GUIDELINES
1. AASLD: American Association of Study of Liver Diseases
2. EASL: European Association for the Study of Liver
3. WHO: World Health Organization

TREATMENT RECOMMENDATIONS
• All adults, adolescents and children with CHB and clinical evidence of
compensated or decompensated cirrhosis should be treated,
regardless of ALT levels, HBeAg status or HBV DNA levels

• Treatment is recommended for adults with CHB who do not have
clinical evidence of cirrhosis but are aged more than 30 years have
persistently abnormal ALT levels with evidence of high-level HBV
replication (HBV DNA >20 000 IU/mL), regardless of HBeAg status

• Antiviral therapy is not recommended and can be deferred in persons
without clinical evidence of cirrhosis and with persistently normal ALT
levels and low levels of HBV replication (HBV DNA <2000 IU/mL),
regardless of HBeAg status or age

Continued monitoring is necessary
• persons without cirrhosis aged 30 years or less, with HBV DNA levels
>20 000 IU/ mL but persistently normal ALT
• HBeAg-negative persons without cirrhosis aged 30 years or less, with
HBV DNA levels that fluctuate between 2000 and 20 000 IU/mL, or
who have intermittently abnormal ALT levels

TREATMENT OF HEPATITIS B IN INDIA
• Guidelines recommend selection of drugs with high potency and low
risk of resistance
• Most guidelines advocate initial treatment with ETV, TDF or peg-IFN
• There is insufficient safety and efficacy data on antiviral agents in
India

• ETV has been associated with significantly higher rates of serological,
viral and biochemical improvement with no resistance
• ADV was found to be less potent though the frequency of resistance
mutations was low
• TDF and LdT were reported to reverse decompensation and improve
hepatic functional status with significant reduction in HBV DNA levels

• Though all approved agents are available in India, treatment with
guideline recommended first-line agents is a challenge, the major
hurdle being unaffordability due to high cost of therapy

DRUG COSTS [10 TABLETS]
ENTACAVIR 0.5mg 750 – 1500
ENTACAVIR 1mg 1500-3500
TENOFOVIR 400
LAMIVUDINE 80
ADEFOVIR 245

• ETV, LdT and TDF can be recommended in compliant patients who
can afford good treatment
• LAM/ADV combination may be advised for non-affording patients
with well compensated cirrhosis while LAM alone may be advised in
those with grade II fibrosis.

When to stop treatment?
• Lifelong NA therapy : All persons with clinical evidence of Cirrhosis.

• Discontinuation and careful long term follow up in :
oPersons without clinical evidence of cirrhosis
oEvidence of HBeAg loss and seroconversion to anti-HBe after
completion of atleast 1 year of treatment.
oIn association with persistently normal ALT levels and persistently
undetectable HBV DNA levels

LIVER TRANSPLANTATION
• Liver transplantation is currently a successful therapy for end-stage
chronic HBV-associated liver disease.
• The use of high dose HBIG ( Hepatitis B immunoglobulin ) peri-
operatively and post-operatively, combined with treatment of heptitis
B with entecavir or tenofovir are favored to prevent recurrent HBV
infection post-transplantation.

Special Groups : HBV-HIV coinfection
• treating for both HBV and HIV is recommended.
• Lamivudine, Emtricitabine and Tenofovir are all nucleoside analogs
with activity against both HIV and HBV
• Rate of HBV resistance to Lamivudine in HBV-HIV coinfection is almost
90% at 4 years, hence lamivudine should never be used as
monotherapy

• Entecavir has low-level activity against HIV and can result in selection
of HIV resistance
• Tenofovir and the combination of tenofovir and emtricitabine in one
pill are approved therapies for HIV and represent excellent choices for
treating HBV infection in HBV-HIV co-infected patients

PREGNANCY
• Tenofovir is effective in reducing mother to child transmission
Calvin Q Pan, Erhei Dai et al; Tenofovir to prevent Hepatitis B
transmission in mothers with high viral load, N Engl J Med 2016 June
16,; 2324-2334

CHB on Cytotoxic Chemotherapy
• Preemptive treatment with anti-virals for 6 months for inactive
Hepatitis B carriers prior to the initiation of chemotherapy has been
shown to reduce the risk of such reactivation.

PREVENTION & IMMUNOPROPHYLAXIS
• Hepatitis B immunoglobulin (HBIG) :
effective for passive immunization if given prophylactically or within
hours of infection.
It is indicated for sexual contacts of acute sufferers, babies born to
HBsAg-positive mothers and victims of parenteral exposure (needle
stick) to HBsAg-positive blood.

oIn healthy individuals the recombinant vaccine is given in a dose of
20μg (2 ml) intramuscularly, repeated at 1 month with a booster at 6
months.
oFor patients undergoing haemodialysis and for other
immunosuppressed patients, higher vaccine dosages (40μg) or an
increased number of doses are recommended(4 doses).

POST EXPOSURE PROPHYLAXIS
• 0.06ml/Kg HBIG plus first dose of Hepatitis B Vaccine and continue
vaccine course.

• Family – Flaviviridae
• Genus – Hepacivirus
• A small ( 50 nm ) virus ss RNA virus
• RNA sequence analysis into at least six major genotypes (Clades)
• There are 100 subtypes.

• HCV circulates in various forms in the serum of an infected host,
including
(1) virions that are bound to very-low-density and low-density
lipoproteins and appear to represent the infectious fraction,
(2) virions bound to immunoglobulins
(3) free virions.

• Chronic hepatitis develops in 50% to 90% of persons with acute HCV
infection.
• In the minority of patients in whom acute HCV resolves, an early and
multispecific T-cell response occurs.
• This response can be detected up to 20 years after resolution of
infection and may contribute to protection in case of subsequent
exposures to HCV.

ACUTE HEPATITIS C
• Acute hepatitis C is rarely seen in clinical practice
• nearly all cases are asymptomatic
• Even in symptomatic patients, however, most of the clinical symptoms
are nonspecific
• fatigue, nausea, abdominal pain, loss of appetite, mild fever, itching,
myalgia, Jaundice

• The rate of viral persistence after acute infection ranges from 45% to
more than 90%.
Age and gender
source of infection and size of inoculum
immune status of the host
patient’s race
• the rate of spontaneous clearance is higher in symptomatic patients
in whom jaundice develops during acute infection than in those who
remain asymptomatic

CHRONIC HEPATITIS C
• Chronic HCV infection has a variable course; in some patients disease
progression to cirrhosis is slow, while in others, progression is more
rapid

INVESTIGATIONS
Indirect Assays
• EIAs detect antibodies against different HCV antigens
• The third-generation EIAs detect antibodies against HCV core, NS3,
NS4, and NS5 antigens as early as 7 to 8 weeks after infection, with
sensitivity and specificity rates of 99%

• The presence of anti-HCV in high titer in serum (enzyme
immunoassay [EIA] ratio> 9) indicates exposure to the virus
• does not differentiate among acute, chronic, and resolved infection.
• Serologic assays are used initially for diagnosis.

Direct Assays
• Virologic assays are required for confirming infection, monitoring
response to treatment, and evaluating immunocompromised
patients.

• Quantitative assays
Real time PCR
Transcription meadiated amplification
• The advantages of these very sensitive tests include positivity within 1
to 3 weeks after acute infection and detection of low-level residual
infection during antiviral therapy
• Disadvantage – lack of comparability among different assays

• HCV core antigen assay - cheaper and faster alternative
Fully automated immunoassays

HCV GENOTYPING
• The most accurate method is PCR methodology and direct sequencing
of the NS5B or E1 region
• Reverse hybridization to genotype-specific probes
• restriction fragment length polymorphism analysis
• PCR amplification of the 5′ noncoding region of the HCV genome.

EASL Recommendations
• Anti-HCV antibodies are the first-line diagnostic test for HCV infection
• In the case of suspected acute hepatitis C or in immunocompromised
patients, HCV RNA testing should be part of the initial evaluation

• If anti-HCV antibodies are detected, HCV RNA should be determined
by a sensitive molecular method
• Anti-HCV-positive, HCV RNA negative individuals should be retested
for HCV RNA three months later to confirm true convalescence

TREATMENT
DRUGS
• INTERFERONS
• PEGYLATED INTERFERONS
• DIRECTLY ACTING ANTIVIRAL AGENTS

Ribavirin
• Guanosine analogue
• Side effect – RBC breakdown
birth defect in babies
Taribavirin [viramidine or ribamidine] - ribavirin derivative
less erythrocyte-trapping and better liver-targeting than
ribavirin.
phase III human trials

EASL Recommendations
• The goal of therapy is to cure HCV infection to prevent hepatic
cirrhosis, decompensation of cirrhosis, HCC, severe extra-hepatic
manifestations and death
• The endpoint of therapy is undetectable HCV RNA in a sensitive assay
(≤15 IU/ml) 12 weeks (SVR12) and 24 weeks (SVR24) after the end of
treatment

• In patients with advanced fibrosis and cirrhosis, HCV eradication
reduces the rate of decompensation and will reduce, albeit not
abolish, the risk of HCC. In these patients surveillance for HCC should
be continued
• In patients with decompensated cirrhosis, HCV eradication reduces
the need for liver transplantation. Whether HCV eradication impacts
mid- to long-term survival in these patients is unknown

• Treatment is indicated
All treatment-naive and treatment-experienced patients with
compensated and decompensated liver disease

Treatment should be prioritized
• Patients with significant fibrosis (F3) or cirrhosis (F4), including
decompensated cirrhosis
• Patients with HIV coinfection
• Patients with HBV coinfection
• Patients with an indication for liver transplantation

• Patients with HCV recurrence after liver transplantation
• Patients with clinically significant extra-hepatic manifestations
• Patients with debilitating fatigue
• Individuals at risk of transmitting HCV (active injection drug users,
men who have sex with men with high-risk sexual practices, women
of child-bearing age who wish to get pregnant, haemodialysis
patients, incarcerated individuals)

Treatment can be deferred
Patients with no or mild disease (F0-F1) and none of
the above-mentioned extrahepatic manifestations

Treatment is not recommended
Patients with limited life expectancy due to non-liver
related comorbidities

HCV genotype 1
• a combination of weekly PegIFN-α, daily weightbased ribavirin (1000
or 1200 mg in patients <75 kg or ≥75 kg, respectively), and daily
sofosbuvir (400 mg) 12 weeks

• combination of weekly PegIFN-α, daily weightbased ribavirin (1000 or
1200 mg in patients <75 kg or ≥75 kg, respectively), and daily
simeprevir (150 mg) for 12 weeks to be followed bg PegIFN and
ribavirin for 12weeks

IFN free regimens
• Sofosbuvir (400 mg) and ledipasvir (90 mg)
• sofosbuvir (400 mg) and simeprevir (150 mg)
• sofosbuvir (400 mg) and daclatasvir (60 mg)

• Duration - 12 weeks
• Patients with cirrhosis - with daily weight-based ribavirin
• If ribavirin contraindicated - combination for 24 weeks

• the fixed-dose combination of ombitasvir (12.5 mg), paritaprevir (75
mg) and ritonavir (50 mg) in one single tablet (two tablets once daily
with food), and dasabuvir (250 mg) (one tablet twice daily)

• 1a with cirrhosis – 24weeks with ribavirin
• 1a without cirrhosis – 12weeks with ribavirin
• 1b without cirrhosis – 12weeks without ribavirin
• 1b with cirrhosis – 12weeks with ribavirin

HCV genotype 2
• daily weight-based ribavirin (1000 or 1200 mg in patients <75 kg or
≥75 kg, respectively), and daily sofosbuvir (400 mg) for 12 weeks
• Cirrhosis or treatment experienced – 16-20 weeks

Cirrhotic and/or treatment-experienced
patients
• weekly PegIFN-α, daily weight-based ribavirin (1000 or 1200 mg in
patients <75 kg or ≥75 kg, respectively), and daily sofosbuvir (400 mg)
12 weeks
• an IFN-free combination of daily sofosbuvir (400 mg) and daily
daclatasvir (60 mg) for 12 weeks

HCV genotype 3
• weekly PegIFN-α, weightbased ribavirin (1000 or 1200 mg in patients
<75 kg or ≥75 kg, respectively), and sofosbuvir (400 mg) daily 12
Weeks
• weight-based ribavirin (1000 or 1200 mg in patients <75 kg or ≥75 kg,
respectively) sofosbuvir (400 mg) daily for 24 weeks
• sofosbuvir (400 mg) and daclatasvir (60 mg) daily for 12weeks

HCV genotype 4

HCV genotype 5 or 6

IFN free regimens for HCV genotype 4/5/6
• Sofosbuvir (400 mg) and ledipasvir (90 mg)
• sofosbuvir (400 mg) and simeprevir (150 mg)
• sofosbuvir (400 mg) and daclatasvir (60 mg)

Monitoring therapy
• PegIFN-α and ribavirin – Haematological parameters
• Sofusbuvir – Renal function tests
• Simprevir – rashes and indirect bilirubin

• A real-time PCR-based assay with a lower limit of detection of ≤15 IU/ml
should be used to monitor HCV RNA levels during and after therapy
• PegIFN-α, ribavirin and sofosbuvir - at baseline and at weeks 4, 12 (end of
treatment), and 12 or 24 weeks after the end of therapy
• PegIFN-α, ribavirin and simeprevir - at baseline, week 4, week 12, week 24
and 12 or 24 weeks after the end of therapy
• IFN-free regimen - at baseline, week 2 (assessment of adherence), week 4,
end of treatment and 12 or 24 weeks after the end of therapy

• Success of the treatment is assessed by SVR – defined as absence of
detectable HCV RNA in the serum six months following end of
treatment
• Relapsers: are defined as patients who achieved undetectable HCV
RNA at the end of treatment and subsequently relapsed and did not
achieve SVR

• With the triple combination of PegIFN-α, ribavirin and simeprevir,
treatment should be stopped if HCV RNA level is ≥25 IU/ml at
treatment week 4, week 12 or week 24
• An immediate switch to another IFN-containing DAA containing or to
an IFN-free regimen without a protease inhibitor should be
considered

HBV HCV COINFECTION
• Patients should be treated with the same regimens, following the
same rules as HCV monoinfected patients
• If HBV replicates at significant levels before, during or after HCV
clearance, concurrent HBV nucleoside/ nucleotide analogue therapy
is indicated

POST TRANSPLANT INFECTION
• All patients with post-transplant recurrence of HCV infection should
be considered for therapy
• an IFN-free regimen, for 12 or 24 weeks with ribavirin

In hemodialysis patients
• Haemodialysis patients should be considered for antiviral therapy
• an IFN-free, if possible ribavirin-free regimen, for 12 weeks in patients
without cirrhosis, for 24 weeks in patients with cirrhosis
• Sofosbuvir should not be administered to patients with an eGFR <30
ml/min/1.73 m2 or with end-stage renal disease

HCV HIV COINFECTION
• Regardless of genotype
• Weekly PEG IFN plus daily ribavirin
• Duration - 48 weeks

Hepatitis C in India
• According to current estimates more than 6 million people are
affected with Hepatitis C in India
• The predominant genotypes of HCV in India are genotype 3, followed
by genotype 1 and genotypes 4
• Until recently PEG IFN and ribavirin was the only treatment available
in India which costs around Rs.6000 per week

• Generic versions of sofosbuvir, ledipasvir and daclatasvir have now
become available in India, reducing the cost of therapy
• Combination therapy with ledipasvir and sofosbuvir or daclatasvir and
sofosbuvir with or without ribavirin is much more affordable than the
earlier treatment with PEG-IFNbased therapy

• Harvoni, the fixed-dose combination of ledipasvir-sofosbuvir of 90mg
and 400mg, respectively - Rs.25,000 for a bottle of 28 tablets.
• Sofusbuvir tablets – Rs 17000 for a bottle of 28 tablets
• Daclatasavir – Rs.3500 for 28 tablets
• Epclusa – sofusbuvir and velpatasavir

WHO organizes World Hepatitis day on 28 July
every year to increase awareness and
understanding of viral Hepatitis

REFERENCES
• Harrison’s Principles of Internal Medicine 19th Edition
• Sleisinger and Fordtran’s Gastrointestinal and liver diseases 10th
edition
• Diseases of liver and biliary system Sheila Sherlock 11th edition
• Pawlotsky et al, EASL Recommendations on Treatment of Hepatitis C
2015, Journal of Hepatology 2015 vol. 63 j 199–236
• WHO global guideline for Hepatitis B 2015

Hepatitis B and C - Approach and Management : Updates 2018

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