Management of Hepatitis B infection in the community by Family Physicians: A Primer

Dr. Vinod Babu1, Dr. B. C. Rao2, Dr. Ramakrishna Prasad3

1
Hospitalist, Columbia Asia Hospital, Whitefield, Bangalore; 2Senior Family Medicine Specialist &
Mentor, Academy of Family Physicians of India, Karnataka; 3 Consultant Family Physician, Health Roots
Clinics & St. Philomena’s Hospital; Adjunct Assistant Professor of Family Medicine, University of
Pittsburgh School of Medicine, USA

Introduction
Hepatitis B is a common clinical problem encountered by family physicians in India. In India, there are
approximately 36 million individuals living with chronic hepatitis B virus (HBV) infection
(approximately 4% of the general population)1. The 2017 WHO Hepatitis report (Fig 1) reveals that
globally, there are nearly 300 million individuals living with chronic hepatitis B infection. Of these, 82%
remain undiagnosed. Among those diagnosed, 80% of patients in need of therapy are currently not on
therapy. And even among those on therapy, a very small number have achieved viral suppression2. These
challenges are further compounded by a lack of awareness of the burden, modes of transmission,
evaluation, and management among primary care clinicians.
In light of the enormous burden, it is imperative that family physicians manage these patients in
community settings where resources, access to required testing are limited.
This article has the following twin objectives:
1. Review current knowledge regarding the burden, diagnosis, and management of HBV infection
pertinent to family practice
2. Enable community based doctors with limited resources to recognize and manage HBV infected
individuals
Fig 1: Cascade of care for HBV infection, by WHO region, 2015. Source: WHO estimates, conducted
by the Center for Disease Analysis. See Annex 2.
Screening
Often Hepatitis B infection is detected by chance, particularly during testing pregnant women or when
patients are screened before a blood donation or a surgical procedure. It is advised that the following
groups be offered HBV screening:
 All pregnant women as a part of routine antenatal care
 All patients scheduled for surgical procedures
 Certain high risk groups like health care workers, HIV+ patients, family members of known HBV
infected patients, patients receiving dialysis, blood donors, injection drug users, jail inmates, and
commercial sex workers.
 All patients presenting with jaundice.

In the last few years, there has been a rise in the popularity of annual and periodic health checks. These
health checks often include tests and procedures supported by limited evidence. Given the burden of
undetected chronic Hepatitis B infection in our country, we feel that there is substantial merit in routinely
offering HBsAg screening to all persons presenting for a health check. Those with ongoing risk factors
may need periodic screening.
Fig. 2: Antigenic structure of HBV. Source: https://www.evaidya.com/Health-Articles/all-you-need-to-
know-about-hepatitis-b/. Accessed on 23/6/2017.

Tests used for hepatitis B detection can be confusing. Hence, a brief review of the structure (Fig 2) of the
HBV virus will be helpful. As shown in the figure, there is a protein envelope called Hepatitis B surface
antigen (HBsAg) and inside this envelope there is a circular antigen called the Hepatitis B core antigen
(HBcAg). HBeAg is another antigen associated with HBV. Inside the nucleocapsid (circle of core
antigen) sits the DNA genome with the polymerase. The clinical application of these antigens and their
corresponding antibodies is provided in the section on evaluation below.

Testing strategy

HBsAg testing is a rapid and inexpensive method to screen for Hepatitis B infection. Ideally, anti-
hepatitis B surface antibody (anti-HBs) titer and anti-hepatitis B core antibody (anti-HBc) should also be
done. However, it should be noted that while the anti-HBs titer and anti-HBc are of value, they are not
usually done at the time of screening in resource limited settings.

The interpretation of various serological patterns following screening are shown in Fig 3.
Fig 3: Interpretation of Hepatitis B serological test results. Source: CDC. Available at
https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf. Accessed on 23/6/2017.

Anti-HBc is the best marker of previous infection and alerts us to the possibility of situations where the
HBsAg might be negative but the HBV DNA level is detectable (this is called Occult hepatitis B), these
patients remain at risk of complications of chronic HBV infection.

Hepatitis B vaccination results in the production of anti-HBs antibodies, which are protective. However,
in a relatively high burden country like ours many people are already infected prior to vaccination.
Therefore it is advisable to test for HBsAg before administering the vaccine. If prior to vaccination,
HBsAg is noted to be positive, vaccination at that stage is of no benefit. The individual is already infected
and needs evaluation and treatment of hepatitis B infection.
An anti-HBs titer > 10 mIU/ml indicates lifelong immunity. It should be noted that among sero-
discordant couples (where one partner is HBsAg positive and the other is HBsAg negative), the
acquisition of an anti-HBs titer > 10 mIU/ml (either by vaccination or natural infection followed by
spontaneous clearance) in the HBsAg negative partner renders him or her immune to infection by the
positive partner. This is reassuring for patients and their partners.
Natural history of hepatitis B infection

As shown in Fig 4, Hepatitis B infection goes through the following phases (not necessarily sequentially):

Fig 4: The phases of chronic hepatitis B infection. Source: Public Health Agency of Canada. Available
at http://www.phac-aspc.gc.ca/publicat/hep/hbv-vhb/index-eng.php. Accessed on 23/6/2017.
Phase 1: initially there is the immune tolerant phase characterized by HBeAg positivity, high HBV viral
load, but normal ALT levels. Antiviral therapy is typically deferred during this phase. Most patients in
this phase are children or young adults who acquire the infection in their infancy.
Phase 2: In early adulthood, may individuals with chronic HBV infection transition to a phase
characterized by rising ALT levels indicative of inflammation in the liver. Their HBV DNA levels are
lower than during phase 1. While they are still HBeAg positive, this process might result in the loss of
HBeAg positivity and acquisition of anti-HBe antibody eventually. Antiviral therapy initiation is strongly
indicated if a patient is found to be in this phase.
Phase 3: This is one of two phases characterized by HBeAg negativity, normal ALT levels, and low to
undetectable HBV DNA levels. This phase used to be called the inactive carrier phase. Antibodies to HBe
(anti-HBe) is often present. While antiviral therapy is not indicated in this phase, it is important to
monitor them as they remain at risk of reactivation, progression to cirrhosis and liver failure, and liver
cancer.
Phase 4: This is also a HBeAg negative phase where the virus mutates and evades immune control
resulting in a relapse of inflammation characterized by elevated ALT and HBV DNA levels indicating
active. This underscores the importance of being vigilant in patients labeled “inactive carriers’.

Clinical evaluation

Illustrative case 1:
Mrs. Maya is a 43 y/o F, in excellent general health, who needs to travel to another country with her
family. As a requirement, she is asked to get a screening test for HIV, Hepatitis B, and Hepatitis C. Her
HBsAg returns positive.
A clinician when confronted with a positive HbsAg needs to ask the following questions:
1) Is this HBV mono-infection or co-infection? Since hepatitis B infection is acquired by the same
modes as HIV and HCV infection, and co-infection can have a significant impact on management
decisions-making, it is critical to test also for HIV and HCV infections.

2) Does the patient have ongoing (active) HBV infection? A common misconception among
many clinicians is that a positive HbsAg means a carrier status that is benign and can be left
alone. It needs to be realized that a positive HBsAg confirms active hepatitis B infection. The
implications of this are: a) that a patient may be undergoing progressive liver damage (indicated
by abnormal liver enzymes and other tests that are discussed later); and b) is infectious to his or
her contacts.

The risk of progression of liver disease and the risk of transmission of hepatitis B to others is best
predicted by the HBV DNA PCR level (HBV viral load). However, this test is often unavailable
or unaffordable to many patients in our context. In such situations, the HBeAg can be used as a
surrogate indicator of the viral load. Those with the presence of HBeAg are significantly more
likely to have high viral loads. Usually in the presence of HBeAg, anti-HBe is absent.

3) What is the extent of liver disease (fibrosis stage, cirrhosis, hepatocellular carcinoma)? From
a clinical perspective, this is of immense significance. Clinically the two main sequelae, namely,
advanced fibrosis/cirrhosis and hepatocellular carcinoma (HCC) need to be determined. This can
be done using clinical examination, simple non-invasive tests such as liver functions, platelet
count (suggestive of hypersplenism), and abdominal ultrasound.

History of jaundice, hematemesis, abdominal distension, easy bruisability, piles, etc. could
represent stigmata of chronic liver disease. Additionally, it is advisable to obtain details pertinent
to past history of liver disease, h/o Blood transfusion, surgery or dental procedure, history/o
Hepatitis B screening during pregnancy, sexual history including multiple exposures, partner’s
serological status, lifestyle habits (alcohol, smoking, drug abuse) & occupation, h/o Hepatitis B
vaccination

Physicial examination findings such a hepatomegaly, and/or splenomegaly, ascites, multiple

spider nevi, palmar erythema, testicular atrophy, thinning of hair, and gynecomastia, bruises and
bruisability and evidence of hepatic encephalopathy are well established features of chronic liver
disease.
 A meta-analysis by Udell et al. that reviewed 86 studies found that certain physical examination
findings and simple laboratory tests significantly increase the likelihood of cirrhosis. Particularly
valuable are the presence of ascites (Likelihood Ratio (LR) 7.2; 95% CI, 2.9-12), a platelet count
less than 1.6 lakh/μL (LR, 6.3; 95% CI, 4.3-8.3), and spider nevi (LR, 4.3; 95% CI 2.4-6.2) are
the most frequently studied, reliable, and informative results3. It is important to realize that the
overall impression of the clinician alone has not been shown to be accurate as compared to a
combination of clinical and laboratory findings. Furthermore, abdominal ultrasound examination
misses cirrhosis in up to 50% of cases.

Certain simple and non-invasive scores such as the AST-to-platelet-ratio-index (APRI) and
Fibrosis-4 score have also been validated to predict the degree to liver fibrosis. While only
moderately accurate, given their simplicity, low cost, non-invasive technique, and utility in the
setting of high pretest probability, they are valuable alternatives to other more invasive or
expensive tests such as liver biopsy or fibroscan (transient elastography).

APRI scores higher than 1 are an indicator of cirrhosis to a sensitivity of 76%.

Example calculation:

Let’s return to the case of Mrs. Maya. Her AST value is 71 (the upper limit of the reference range
per the laboratory is noted to be 41) and her platelet count of 90,000/microliter (90 X 109/L). The
computed APRI value is calculated as follows: 71/41 = 1.775; 1.775/90 = 0.0198 X 100 = 1.98.
An APRI score of nearly 2 indicates that Mrs. Maya has already developed liver cirrhosis.
Note: The calculator can be found at http://www.hepatitisc.uw.edu/page/clinical-calculators/apri

4) Does this patient need be on antiviral therapy? The decision to initiate or defer antiviral
therapy depends on several factors but the two most important are ALT level and HBV DNA
PCR level. However, since the test for HBV viral level is often not available or affordable to
patients in resource limited settings, a practical approach that relies primarily on clinical
assessment of degree of liver damage and simple calculations like the APRI score need to be
relied upon.

On a priority basis, the WHO recommends that any individual (regardless of age) with HBsAg
positivity and clinical evidence of cirrhosis (clinically or on ultrasound) or an APRI score more
than 2 should be treated. Additionally, adults older than 30 years of age with persistently
abnormal ALT levels even in the absence of cirrhosis may be considered for initiation of antiviral
therapy in our setting.

In terms of treatment options, it is important for family physicians to recognize that tenofovir (a
medicine used in the management of HIV infection) or entecavir are two medications which are
tablets taken once daily are highly effective, have negligible side effects, and pose a minimal risk
of hepatitis B drug resistance.
 Fig 5: The ECHO (Extension for Community Healthcare Outcomes) Model’s Learning
Loop. Source: Agency for Health Care Research (AHRQ). Available at
https://www.ahrq.gov/cpi/about/impact/index.html. Accessed on 23/6/2017)

With some basic knowledge and experience, family physicians are well positioned to manage
chronic Hepatitis B infection (including antiviral therapy) in their own practices. Help from a
gastroenterologist may be sought for patients with cirrhosis or liver failure. In this regard, the
development of online or app based networks of primary care providers connected with clinical
mentorship from experienced HBV treatment providers using a model such as the ECHO
(Extension for Community Healthcare Outcomes) program might be a transformational approach
to building HBV treatment capacity in our country. Fig 5 shows an ECHO model developed at
the University of New Mexico. In India, this model has been utilized to tackle hepatitis C virus
infections in Punjab4.

5) What monitoring does the patient need? In all patients who are HBsAg positive, monitoring liver
function tests, blood counts, alfa fetoprotein levels and liver ultrasound are advisable every 6-12
months. In our setting, from a practical perspective, ALT levels and APRI score monitoring
might be more feasible.

Illustrative case 2:
A 24 year old female, in good general health, finds out that she is 6 weeks pregnant. This is her first
pregnancy. During her antenatal visit, HBsAg is found to be positive. She does not have any symptoms.
Examination is normal, and all other tests including transaminases and platelet count are within the
expected range. As her family physician, what would you advise her?
This is a common scenario family physicians are confronted with in our country. The management of
hepatitis B in pregnant women in addition to the steps outlined above, involves the unique consideration
of reducing the risk of mother to child transmission of hepatitis B virus. Standard practice is to give all
newborns of HBsAg positive mothers, hepatitis B vaccine and Hepatitis B Immunoglobulin (HBIg)
within 12 hours of birth. This is called immunoprophylaxis. However, if the HBV DNA level is more
than 200,000 copies/ml, there is a 10-30% risk of HBV transmission to the baby despite timely
immunoprophylaxis5,6.

Antiviral therapy during the third trimester with tenofovir reduces this risk substantially. As a result,
family physicians should ideally check the HBV DNA level during pregnancy and initiate tenofovir in the
third trimester themselves or in consultation with another experienced HBV treatment provider. In
settings where HBV DNA PCR is not available, in our opinion, it may be acceptable to test for HBeAg
and start HBeAg positive mothers on tenofovir in the third trimester.

Conclusion

Hepatitis B infection is a major public health problem in India. Family physicians are best placed to
screen, diagnose, evaluate, and manage hepatitis B infection in the vast majority of patients. This article is
written with the aim of providing a review of the current knowledge of HBV infection pertinent to family
practice and enabling community based doctors with limited resources to recognize and manage HBV
infected individuals.
References:
1) Makroo RN, Hegde V, Chowdhry M et al. Seroprevalence of infectious markers & their
trends in blood donors in a hospital based blood bank in north India. Indian J Med Res. 2015
Sep;142(3):317-22.
2) WHO Global Hepatitis Report, 2017. Available at
http://apps.who.int/iris/bitstream/10665/255016/1/9789241565455-eng.pdf?ua=1. Accessed on
23/6/1017.
3) Udell JA, Wang CS, Tinmouth J. et al. Does this patient with liver disease have cirrhosis?
JAMA. 2012 Feb 22; 307(8):832-42.
4) Dhiman RK, Satsangi S, Grover GS. Tackling the Hepatitis C Disease Burden in Punjab, India. J
Clin Exp Hepatol. 2016 Sep;6(3):224-232.
5) Chamroonkul N, Piratvisuth T. Hepatitis B During Pregnancy in Endemic Areas: Screening,
Treatment, and Prevention of Mother-to-Child Transmission. Paediatr Drugs. 2017
Jun;19(3):173-181.
6) Jaffe A, Brown RS Jr. A Review of Antiviral Use for the Treatment of Chronic Hepatitis B Virus
Infection in Pregnant Women. Gastroenterol Hepatol (N Y). 2017 Mar;13(3):154-163.