HEPATITIS B Management
. Hepatitis B virus infection
3.1 Aetiology
Hepatitis B is an hepadna (DNA) virus. It is endemic
worldwide, apart from isolated communities, with very high carriage rates (up
to 20%) particularly in South and East Asia, but also in Southern Europe,
Central and South America,
Africa
and Eastern Europe. In the UK, HBV sero-prevalence varies from 0.010.04% in
blood donors and to >1% in PWID and MSM. In 2015 5090 HBV cases were
notified in England and Wales of which 457 were acute infections[52a]. There
are 8 distinct genotypes (A-H) which vary in geographical distribution, pathogenicity
and treatment susceptibility [53].
3.2 Transmission
•
Sexual transmission occurs in
unvaccinated/non-immune MSM and is associated with multiple partners,
unprotected anal sex and oro-anal sex
(“rimming”) [53, 54]. Transmission also occurs with heterosexual contact e.g.
18% infection rates for regular partners of patients with acute hepatitis B
[5256]. Sex workers are also at higher risk [57,58].
•
Other routes are: vertical (infected mother to
infant), parenteral (unscreened blood and blood products, injecting drug users
sharing needles, syringes and other ‘works’, occupational needlestick injuries,
non-sterile acupuncture and tattoo needles) [52-53, 59-62].
•
Sporadic infection occurs in people without
apparent risk factors, in institutions for learning difficulties and also in
children in countries of high background prevalence; in these cases the mode of
transmission is poorly understood [63,64].
3.3
Incubation period.
40-160 days [59]
3.4 Symptoms
•
Virtually all infants and children have
asymptomatic acute infection. Acute infection is also asymptomatic in 10-50% of
adults and is especially likely in those with HIV co-infection[24, 65-67].
•
Chronic carriers are usually asymptomatic but
may have fatigue or loss of appetite [66].
•
The prodromal and icteric phases are very
similar to hepatitis A, but may be more severe and prolonged [24].
3.5 Signs
• As
for hepatitis A in the acute phase.
• If
chronic infection occurs there are often no physical signs. After many years of
infection, depending on the severity and duration, there may be signs of
chronic liver disease including spider naevi, finger clubbing, jaundice and
hepatosplenomegaly, and in severe cases thin skin, bruising, ascites, liver
flap and encephalopathy [68-70].
3.6 Complications
Acute Infection
• ALF
occurs in less than 1% of symptomatic cases but carries a worse prognosis than
that caused by hepatitis A [26,27].
• Pregnancy
– there is an increased rate of miscarriage/premature labour in acute infection
[31]. There is a risk of vertical transmission (see above) [53,59] • Mortality
is less than 1% for acute cases [26].
Chronic infection
• Chronic
infection (>6 months) occurs in 5-10% of symptomatic cases but the rate is
higher in immunocompromised patients with HIV infection, chronic renal failure
or those receiving immunosuppressive drugs [52, 68, 69, 71, 72]. Profound
immunosuppression, for example in advanced HIV infection or in patients taking
immunosuppressive treatment can also reactivate hepatitis B [74]. A higher rate
of chronic infection is also found in patients at institutions for learning
disabilities [63]. Almost all (>90%) of infants born to infectious (HBeAg
+ve) mothers will become chronic carriers unless immunised immediately at birth
[59].
• There
are five phases of chronic infection or carriage ::
1. HBeAg-positive
chronic HBV infection, previously known as Immune Tolerant
(hepatitis B e antigen positive, high levels of HBV DNA, normal
aminotransferase levels, little or no necro-inflammation on liver biopsy),
2. HBeAg-positive
chronic hepatitis B previously known as Immune Active,
HBeAg-positive phase (hepatitis B e antigen positive, high but falling levels
of HBV DNA, raised aminotransferases, significant necro-inflammation and
progressive fibrosis),
3.HBeAg-negative chronic HBV infection,
previously known as Inactive hepatitis B carrier (typically HBeAg-negative, low
levels of HBV DNA and normal aminotransferases) and
4. HBeAg
negative chronic active hepatitis ( HBeAg –ve, detectable and fluctuating HBV
DNA, inflammation and progressive fibrosis, genetic sequencing might detect
mutations in the precore or core promotor mutationsregions of the viral
genome,).
5. HBsAg-negative
phase also known as occult HBV infection (negative
Hep BsAg and positive anti-HBc +/- anti-HBs, normal ALT,
undetectable serum HBV DNA but HBV DNA (cccDNA) can be detected in the
liver)
Immunosuppression can lead to reactivation in these
patients.[79b]
|
Progression to
cirrhosis may occur during phases 2 and 4[67,68].Primary liver |
|
|
cancer may complicate
chronic HBV infection at any stage, but most commonly |
|
|
after
development of cirrhosis. |
|
• Concurrent
hepatitis C infection can be associated with more aggressive chronic hepatitis
with greater risk of cirrhosis and liver cancer [73-75].
• Concurrent
HIV infection increases the risk of progression to cirrhosis and death [72,
76].
• Acute
Hepatitis A co-infection can be severe in patients with HBV [77] • Concurrent
delta virus infection, or delta virus superinfectionis typically associated
with acute hepatitis and chronic hepatitis of increased severity, and may be
associated with more rapidly progressive fibrosis, cirrhosis and endstage liver
disease.
• Between
ten and fifty percent of chronic carriers will develop cirrhosis leading to
premature death in approximately 50% [68-70, 75]. 10% or more of cirrhotic patients will
progress to liver cancer.[68-70, 75].
3.7 Diagnosis (see also
Sexually Transmitted Infection Screening and Testing
Guidelines Hepatitis A, B and C)
3.7.1 Table: Hepatitis B serology [34, 67-70]
|
Stage of infection |
Surface antigen (HBsAg) |
‘e’ antigen (HBeAg) |
IgM anti-core antibody |
IgG anti-core antibody |
Hepatitis B virus DNA |
AntiHBe |
AntiHBs |
ALT |
|
Acute (early) |
+ |
+ |
+* |
+ |
+ |
- |
- |
|
|
Acute (resolving) |
+ |
- |
+ |
+ |
- |
+/- |
- |
|
|
Chronic (immune tolerant) |
+ |
+ |
- |
+ |
++ |
- |
- |
N** |
|
Chronic (immune active) |
+ |
+ |
- |
+ |
+ |
- |
- |
|
|
Chronic (eAg Neg.) |
+ |
- |
- |
+ |
+ |
+/- |
- |
|
|
Chronic (inactive carrier) |
+ |
- |
- |
+ |
- |
+ |
- |
N |
|
Resolved (immune) |
- |
- |
- |
+ |
- |
+/- |
+/- |
N |
|
Successful vaccination |
- |
- |
- |
- |
- |
- |
+ |
N |
*in very early infection the IgM and IgG anti-core can be
negative
** N=normal
3.7.2 Biochemistry
• Acute
infection: see hepatitis A (2.7.2)
• Chronic
infection - in most cases the only abnormality will be mildly elevated serum
aminotransferase levels; in many the liver enzymes will be normal.
3.8 Management
3.8.1 General Advice
•
Patients should be advised to avoid unprotected
sexual intercourse, including oro-analand oro-genital contact until they have
become non-infectious (loss of HBsAg) or their partners have been successfully
vaccinated (see below) (1D) [52,54,59].
•
Patients should be advised not to donate
organs/semen/blood until noninfectious (loss of HBsAg) (1B)[52,54,59].
•
Patients who are HBsAg+veshould be given a
detailed explanation of their condition with particular emphasis on the
implications for the health of themselves and their partner(s), routes of
transmission of infection (see below) (1C) [52-63].
•
Hepatitis B should be notified to the public
health authorities (the route of which depends on the country) (1D) [59]
3.8.2 Further Investigations
•
Screen for other STI in cases thought to have
been sexually acquired (1D)[54,55, 59].
•
In chronic infection, a liver imaging ultrasound
should be performed and in addition liver fibrosis should be assessed by either
a non-invasive technique (such as fibroscan) or with liver biopsy in selected
patients. (1B)[78,79].
3.8.3 Acute icteric hepatitis
• As
for hepatitis A.
• There
is evidence that anti-viral agents can prevent ALF, improve morbidity and
mortality in patients with severe acute infection (1A) [80,81].
3.8.4 Treatment of Chronic Infection
• Arrange
screening for hepatitis C, hepatitis D and hepatitis A immunity (1D).
• Vaccinate
against hepatitis A if non-immune (1D) [78,79]
• Refer
all HBsAg+ve patients to a specialist experienced in .the management of viral
hepatitis (1D) [78,79]
• The
decision to treat depends on pattern of disease, HBVDNA level, and presence or
absence of significant necro-inflammation and hepatic fibrosis. Treatment is usually given to adults with an
HBV DNA >2000 IU/ml with evidence of necro-inflammation and/or fibrosis
[78,79].
|
• Treatment
options are Tenofovir disoproxil fumarate (TDF) and tenofovir |
|
|
alafenamide
(TAF),entecavir or pegylated interferon (1A)[78,79, 79b]. |
|
Treatment responders have long-term benefits in terms of
reduced liver damage and decreased risk of liver cancer [82,83].
• All
patients should have an HIV test prior to starting HBV therapy because of the
similar risks of acquisition, the different treatment strategies required in HIV co-infection and the significant risk
of anti-retroviral resistant HIV developing if lamivudine, TDF, TAF or
entecavir are used as monotherapy (1A) [78,79, 79b]. • Lamivudine,
Emtricitabine, TDF and TAFwill suppress hepatitis B viral replication during
therapy of HIV [47, 87-90], and will prevent HBV-associated liver damage if
given as part of triple antiretroviral therapy. (1B)[47, 87-90].
• 
Lamivudine
and emtricitabine should only be given to HIV+ patients in combination with TDF
or TAF as part of HAART because of the rapid high rate of resistance that
occurs to these drugs if given as the only HBV-active agent (IA) [87-90].
Entecavir should not be used in HIV+ patients without adequately suppressed HIV
as it causes the M184V (lamivudine/emtricitabine) resistant mutation (47).
• Active
surveillance by a hepatologist of patients with significant fibrosis/cirrhosis
for hepatocellular carcinoma(HCC) with ultrasound and alphafeto protein is
recommended 6-12 monthly (1B) [78,91].
• In
the context of HBV, there is a high risk of HCC development in some groups of
non-cirrhotic patients. This includes African patients over the age of 20,
Asian males over 40, Asian females over 50, and patients with a family history
of HCC. HBV-infected patients meeting these criteria should be offered HCC
screening in the hepatology clinic [91].
3.8.5 Pregnancy and Breastfeeding
• In
the absence of intervention, vertical transmission occurs in 90% of pregnancies
where the mother is hepatitis B e antigen positive and in about 10% of surface
antigen positive, e antigen negative mothers. Most (>90%) infected infants
become chronic carriers [92].
• Infants
born to infectious mothers are vaccinated from birth. Hepatitis B specific
Immunoglobulin 200 i.u. IM is also given in certain situations where the mother
is highly infectious (1A) [59,78,92]. This reduces vertical transmission by
90%.
• Consider
Tenofovir monotherapy for pregnant women
with HBV DNA >107
IU/ml in the third trimester to reduce the risk of
transmission of HBV to the baby
(1A) [78]
• Hepatitis
B activity may increase immediately following pregnancy, but is seldom
associated with clinical consequences [78,93]
3.8.6 Sexual and Other Contacts
•
Partner notification should be performed and
documented and the outcome documented at subsequent followup. Contact tracing to include any sexual contact
(penetrative vaginal or anal sex or oro/anal sex) or needle sharing partners
during the period in which the index case is thought to have been infectious
(1D) [37,40].
•
In cases of chronic infection, trace contacts as
far back as any episode of jaundice or to the time when the infection is
thought to have been acquired although this may be impractical for periods of
longer than 3 years [40] (1D) • Arrange screening for hepatitis B of children
who have been born to infectious women if the child was not vaccinated at birth
(1C)[59,78].
•
For screening of other nonsexual partners who
may be at risk, discuss with the public health authorities (1C) [59,78].
•
Specific hepatitis B immunoglobulin 500 i.u.
intramuscularly (HBIG) may be administered to a non-immune contact after a
single unprotected sexual exposure or parenteral exposure/needlestick injury if
the donor is known to be infectious. This works best within 12 and ideally
within 48 hours and is of no use after seven days (IA) [59,78, 94, 95].
HBIG that is effective against HBV is in limited supply in
the UK and can only be obtained from Public Health England (England), NPHS
Microbiology Cardiff (Wales), Blood Transfusion Service (Scotland) or the
Northern Ireland Public Health Laboratory Belfast [59].
•
An accelerated course of recombinant vaccine
should be offered to those given HBIG plus all sexual and household contacts
(at 0, 7 and 21 days or 0,1, 2 months with a booster at 12 months in either
course) (1A) [59,61, 96-101].
Vaccination theoretically will provide some protection when
started within six weeks after the contacts first exposure (1B) [59].
•
Contacts who have previously been vaccinated and
achieved immunity can have a single booster dose, with no HBIG (1B)[95].
•
Contacts should themselves avoid sexual contact,
especially unprotected penetrative sex, until it is shown that infection has
not been acquired and it has been shown that vaccination has been successful
(anti-HBs titres >10i.u./l.) (1D) [59,61, 96-101].
•
The ultra-rapid vaccination schedule (0,1,3
weeks) leads to an anti-HBs antibody response in only 80% of recipients
4-12weeks after the third dose [96101].
This rises to 95% just prior to the 12 month booster dose.
It would be prudent to offer booster vaccinations of up to three further doses
to the 20% of sexual or household contacts without detectable antibodies 4-12
weeks after the primary course (1C), even though most would have eventually
developed an antibody response.
•
Protection from monovalent vaccines is believed
to persist for >20 years once immunity has been confirmed (1B)[102].
•
Patients with a chronic infection should be
advised of the need to disclose to new sexual partners, and partners encouraged
to be vaccinated (1D).
3.8.7 Follow-up.
•
Acute infection: as for hepatitis A. In view of
the possibility of chronic infection, serology should be repeated after 6
months even if the LFTs are normal [69,78]. • Chronic infection: If untreated,
patients should be regularly reviewed at intervals of one year or less, ideally
by a physician with expertise in this disease (1B) [69,78].
•
Immunity after recovery from infection (surface
antigen negative) is life-long in over 90%(1B) [69,78].
3.9 Screening and Primary Prevention (see also [107])
3.9.1
Screening
•
people from countries where hepatitis B is
endemic (outside of Western Europe, North America andAustralasia), needlestick
victims, heterosexuals with a large number (>10/year)
of partners and sexual partners of positive or high-risk patients (1A) [52-62].
For needlestick injury follow PHE guidelines [59].
•If non-immune, consider vaccination (see below) (1A)
[96-102].If found to be a chronic carrier,referthe patient to an expert in
hepatitis for long-term surveillance and to consider therapy (1A) [72,73,
78-86].
•
The screening tests of choice are anti-HBcore
antibody and/or the hepatitis B surface antigen (HBsAg) test with further
serology to assess the stage of infection and infectivity as appropriate (1B);
measure anti-HBs in those who have been vaccinated (1B)[97-102,108,109].
•
In those who are anti-HBc + and HBsAg –ve
measure anti-HBs and anti-HBe. If both are negative the anti-HBc may be a false
positive. In this case a single hepatitis B vaccine dose will induce anti-HBs
if there has been past natural HBV exposure (anamnestic response, measured 4
weeks after single dose of HBV vaccine). If anti-HBs is still negative after a
single booster, regard as non-immune and give a full course of vaccine
(1C).[110]
3.9.2. Figure: Flow chart for hepatitis B
screening using serum anti-HBc
________________________Anti-HBc___________________
Negative
Positive
No previous exposure to hepatitis B.
Test
for HBsAg
Consider hepatitis B vaccination
____________________
|
(or anti-HBs test if previously |
|
|
|
vaccinated) |
Positive |
Negative |
|
|
Acute orChronic |
Patient |
|
|
hepatitis B Carrier: |
naturally |
|
|
test for IgM anti-HBc |
immune to |
HBeAg/HBeAb hepatitis B
HBV-DNA
If
anti-HBs
-ve, give
Vaccine booster
3.9.3
Flow chart for hepatitis B screening using serum HBsAg
_________________________HBsAg____________________
Negative
Positive
anti-HBc
_________________________ Acute or Chronic
hepatitis B Carrier:
Negative Positive
test for IgM anti- HBc, HBeAg, HBeAb No previous exposure to Patient naturally (+/-HBV-DNA) hepatitis B. Do anti-HBs immune to test
if previously vaccinated hepatitis
B
If
Anti-HBe/s-ve,
give vaccine
booster
3.9.4
Primary prevention
• Discuss
safer sex and how to reduce the risk of catching this infection (1C)
• Vaccination
should be offered to non-immune patients in the above groups (1A) [59,
97-102,108,109] except those people born in countries of high endemicity but
not at continuing risk who are being screened primarily to detect chronic
carriage (1B)[78].
• The
vaccination schedule for both the monovalent and the combined hepatitis A+B
vaccines is outlined in Table 2. The ultra-rapid 0, 1,3 week regimen offers the
advantage of a higher completion rates and more rapid development of early
immunity. Test for response (anti-HBs >10i.u./l, ideally >100i.u./l) 4-12
weeks after the last dose (1A)[59, 97-102,108,109]. Only 80% of ultra-rapid
vaccine recipients will have detectable anti-HBs antibodies at this stage (see
‘Sexual and other contacts’ above). If someone is at high risk of acquiring
infection, and are in the 20% without an early antibody response, consider
further booster doses (1C). This should be as a repeat course (1C) with response
rates up to 100% [109-110].Alternatively, for those at lower risk, offer a
booster at 12 months by which time 95% would be anti-HBs positive [59,
97-102,108,109].
• Vaccines
with novel adjuvants (e.g. Fendrix ®) are effective for haemodialysis patients and
others who haven’t responded to conventional vaccine (1A)[112- 115].
HIV positive individuals
• HIV
positive patients show a reduced response rate to HBV vaccine and become
anti-HBs negative more quickly, although double dose vaccine increases the response
by 13% (1B)[47, 103-106, 111].
• Response
correlates with CD4 count if not on antiretroviral therapy (ART) but also with
viral load and ART use. [103-106]
Vaccine response improves if the CD4 count rises and the viral load is
undetectable on ART.
BHIVA recommends high dose vaccination (40μg Engerix or
HBvaxPro) or Fendrix 20mcg at 0,1,2,6 months. Only to use a single dose 0,1,3
week ultra rapid course if CD4 >500 and a rapid course is essential
Hep
BsAb levels should be measured 4-8 weeks after completion of the primary
course. If <10 three further vaccine doses should be given at monthly
intervals. Individuals with a HepBsAb
level of >10 <100 after the primary course should be given a booster dose
[115a]
3.9.5 Table: Vaccination Schedules for
Hepatitis B using monovalent vaccine or combined A+B vaccine [41-43, 59,
96-106].
|
Vaccine Schedule |
Advantages |
Disadvantages |
|
Ultra rapid 0,1,3 weeks, 12 months |
- Rapid immunity, - Short duration, - High antibody titres at 12 and 13 months - Better uptake |
-
Less evidence on HIV or other
immunecompromised patients -
Low antibody titres in the first year
(but current evidence suggests that protection is still adequate in the
immune-competent) |
|
Rapid 0,1,2,12 months |
-
Shorter time to early immunity than the 0,1,6 course -
High antibody titres at 12 and 13 months |
- Antibody titres lower than the 0,1,6
regimen in the first year |
|
Standard 0,1,6 months |
-
Higher antibody titres at 7 months than
the other two regimens although this may not be clinically important - Long
established regimen -
Most researched in HIV |
- Poor uptake of the 6 month dose in
the clinical setting |
• It
is probable that booster doses of vaccine are not required for at least fifteen
years in immunocompetent children and adults who have responded to an initial
vaccine course (1B) [102, 116-119] although in those vaccinated in infancy 10%
will be non-immune and show no immunological memory after 18 years [119].
HIV-positive and other immunocompromised patients will still need to be
monitored and given boosters when anti-HBs levels fall below 100 IU/L (1C) [87,
103-106,119].
• Evidence
suggests that if vaccine courses are not completed in immunocompetent patients,
the outstanding doses can be given 4 or more years later without the need to
restart a 3 dose course (1B) [ 120]. One or 2 doses of vaccine may provide
immunity in 40% and over 90% of immunocompetent patients respectively [120,
121].
3.10 Hepatitis D (Delta virus infection, HDV)
This is a small incomplete RNA virus that can only infect
individuals who have HBV. It is only found in patients with hepatitis B
(HBsAg+ve) infection. The main risk groups are: people who have acquired the
infection abroad, PWID and their sexual partners, sex workers and sporadically
in other groups [122]. Suspect HDV in an individual with hepatitis B infection
if the acute hepatitis is severe, if chronic hepatitis B carriers experience a
further attack of acute hepatitis or if the liver disease in chronic HBV is
rapidly progressive [24,26, 54, 69]. It is associated with a high rate of
fulminant hepatitis and progression to cirrhosis [24, 26, 73]. All hepatitis B positive patients should have
an anti-HDV test. Diagnosis is confirmed by a positive anti-HDV antibody and
HDVRNA test [34, 108]. Response to antiviral therapy is poor [123, 124]. Refer
to physician with experience in managing HBV/HDV co-infections for assessment
and treatment (IV,C).
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