Primary Care Management of Hepatitis B – Quick Reference (HBV-QR)

Introduction^{Footnote *}

Key Facts and Figures

• HBV is a vaccine-preventable disease that is highly infectious – far more so than either HIV or HCV.  It is transmitted through perinatal, percutaneous, or sexual exposure to an infected person's blood / body fluids; household contacts are also at risk of infection.
• Acute and chronic HBV infections are frequently asymptomatic or present with nonspecific symptoms; about two-thirds of chronically infected people are unaware of their status, and most will only be detected through proactive screening.
• Of those infected as adults, 5% will become chronically infected; in contrast, about 90% of infants infected at birth will develop chronic infection.Endnote 1
• Without intervention, 15%–40% of chronically infected people will go on to develop cirrhosis, end-stage liver disease, and/or HCC.

HBV is a notifiable disease in all provinces and territories in Canada. As such, it must be reported to the regional/local Medical Officer of Health.

Epidemiology of Acute and Chronic HBV in Canada

Acute HBV: Canada is a region of low endemicity; however, certain vulnerable populations are disproportionately affected. These include Aboriginal peoples, MSM, street-involved youth, and people who are or have been incarcerated.Endnote 2 Peak incidence is among those aged 30–39 years. The most commonly identified risk factors are high-risk sexual activities and injection drug use.

Canada has had universal HBV immunization programs in place since the mid-1990s. All provinces and territories have programs that target children aged 9–13 years, and some have also implemented a neonatal immunization program.^{Endnote 3} In addition, some provinces/territories provide coverage for high-risk individuals, but eligibility varies across jurisdictions (see Module 10).  Despite the success of these programs, there may be many who remain at risk of acquiring HBV.

Immunization contributes to disease control by interrupting disease transmission and decreasing the pool of susceptible people. It is essential to identify those at risk who would benefit from receiving the HBV vaccine.

Chronic HBV:  It is estimated that less than 1% of Canadians are chronically infected with HBV; in northern regions, serosurveys have documented the prevalence of chronic HBV at 3%–4%.Endnote 4, Endnote 5Although the number of studies is limited, data suggest that up to 70% of chronically infected Canadians are immigrants from regions of high endemicity. Screening immigrants from these regions will identify chronically infected individuals who can benefit from monitoring and medical management (secondary prevention); doing so will also permit vaccination of susceptible contacts, particularly infants and young children who are at risk of developing chronic infection (primary prevention).

There is an urgent need to screen, diagnose, and treat (where appropriate) chronic HBV infection so as to reduce associated morbidity and mortality and to prevent further transmission.

Module 1 – Who Should be Tested for HBV?

In low-risk populations, routine screening for chronic infection or immunity is not recommended. Testing to determine immune status and/or to detect chronic infection is indicated for those at risk of exposure; susceptible people should be immunized.

Clinicians should maintain a high index of suspicion for HBV as infection is frequently asymptomatic; 30% of infections have no identified risk factors.^{Endnote 6}

The decision to screen and the selection of tests should be based on a thorough review of the following:

• Self-reported HBV immunization history and/or documentation
• Results of previous testing
• Presence of risk factors for HBV infection

Who to Screen

Risk factors for HBV infection (current or past) – screen routinely at first visit:^{Endnote 3, Endnote 6, Endnote 7}

• Birth in a region with intermediate or high endemicity^{Footnote †}
• Infant of HBsAg-positive mother^{Footnote †}
• Exposure before 7 years of age (e.g., child's immediate and/or extended family immigrated from a region of intermediate/high endemicity and/or child visited such a region) ^{Footnote †}
• Family history of hepatitis B or hepatoma^{Footnote †}
• Exposure to HBsAg-positive person (e.g., percutaneous, sexual/household contact)^{Footnote ‡}
• High-risk sexual activities (e.g., unprotected sex, multiple sexual partners) ^{Footnote ‡}
• Substance use with sharing of equipment (e.g., injection/inhalation drug use) ^{Footnote ‡}
• Exposure to blood/blood products in endemic regions without routine precautions/screening^{Footnote †}
• Transfusion recipient / medical procedure in Canada before 1970^{Footnote †}
• Use of shared/contaminated materials or equipment (e.g., instruments/tools used for personal services procedures such as tattooing / piercing / body modifications, or any alternative health care that has the potential to break the skin) ^{Footnote ‡}
• Use of shared/contaminated medical devices (e.g., glucometers) ^{Footnote ‡}
• Occupational exposure to blood / body fluids^{Footnote ‡}
• Travel to / residence in a region of intermediate/high endemicity^{Footnote ‡}
• Incarceration^{Footnote ‡}
• Institutionalization (particularly in institutions for the developmentally challenged) ^{Footnote ‡}

Special clinical considerations – screen routinely:

• Pregnancy
• HIV or HCV infection
• Planned therapy with immunosuppressive/immunoregulatory agents
  (e.g., rituximab – increased risk of hepatic flares or reactivation of hepatitis B)
• Immunocompromised

Identification of any risk factor is an indication for screening.

Individuals born in regions with intermediate or high endemicity are at particular risk of having chronic HBV infection.

Where is your patient from?

Text equivalentPrevalence of HBV infection

Where is your patient from?

This is a figure of a map of the world within Module 1 that is meant to assist clinicians in determining whether a patient is from a country of low (less than 2 percent), intermediate (2 percent to 7 percent), or high (greater than or equal to 8 percent) prevalence of hepatitis B infection. Clinicians are advised that individuals born in regions with intermediate or high endemicity are at particular risk of having chronic hepatitis B infection and that screening populations at high risk of chronic infection is essential to identify anyone who can benefit from monitoring and treatment.

Most of North America has a low prevalence of HBV infection; however, Alaska and the northern-most strip of Canada have an intermediate prevalence of infection. South America is characterized by great regional variability. There are three main zones: a band of high endemicity that spans the northern region from coast to coast; Brazil and the northern coastline with an intermediate prevalence of infection; and south and southwestern South America which have a low prevalence of infection. Most of Western Europe has a low prevalence of hepatitis B infection. However, Greenland has a high prevalence and Spain and neighbouring countries have an intermediate prevalence. In general, Eastern Europe has an intermediate prevalence of infection. Sub-Saharan Africa has a high prevalence of infection, while North Africa is a region of intermediate prevalence. Most of the Middle East has an intermediate prevalence of, except Saudi Arabia, which has a high prevalence. Most of Russia and the Indian Subcontinent have an intermediate prevalence. Central Asia and South-East Asia have a high prevalence. Both Australia and New Zealand have a low prevalence. The figure was reproduced with permission from the New England Journal of Medicine, Volume 359, Issue 14, October 2008(8).

Reproduced with permission from NEJM 359:14 October 2008^{Endnote 8}

Screening populations at high risk of chronic HBV infection is essential to identify anyone who can benefit from monitoring and treatment.

Who to Test

In the absence of any identified risk factors, clinicians should test anyone who presents with any of the following:

• Clinical and laboratory findings suggestive of chronic liver disease:
  • Abnormal liver biochemistry is usually the only finding
  • Hepatomegaly, splenomegaly, and jaundice are late findings
  • Thrombocytopenia
• Signs and symptoms of acute hepatitis:
  • RUQ abdominal discomfort, fatigue, fever, nausea, vomiting, malaise, abnormal liver biochemistry, jaundice, dark urine
• Diagnosis of HCC
• Previous diagnosis of other liver disease

Module 2 – Approach to HBV Screening and Testing

Overview of HBV Serological Markers

Text equivalentAcute HBV with recovery, Acute HBV with recovery

Overview of HBV Serological Markers

There are two figures in this module that provide an overview of hepatitis B serological markers. The first figure is a line graph showing changes in serological markers for acute infection with spontaneous recovery ⁽⁹⁾ from 0 to 100 weeks after exposure. Hepatitis B surface antigen begins to rise just before 4 weeks after exposure, peaking at less than 12 weeks, after which, it falls to zero at 24 weeks. Hepatitis B e-antigen is present until just after the peak in hepatitis B surface antigen levels at 12 weeks. After this point, hepatitis B e-antigen disappears and hepatitis B e-antibody appears. Symptoms are present when hepatitis B surface antigen reaches its peak and during its decline. The IgM marker of the hepatitis B core antibody begins to rise around 6 weeks after exposure, peaks just before 16 weeks and then declines to zero at 32 weeks. Total hepatitis B core antibody also starts to rise around 6 weeks, then plateaus at about 20 weeks. Hepatitis B surface antibody begins to rise just before 32 weeks, peaks after 36 weeks and then declines.

Chronic Hepatitis B ⁽¹⁰⁾

The second figure is a line graph showing the changes in various hepatitis B serological markers, in the case of chronic hepatitis B infection, from the time of exposure to years later. In chronic infection, hepatitis B surface antigen begins to rise just before 4 weeks after exposure, plateaus at approximately 12 weeks and persists for years. Both the IgM marker of the hepatitis B core antibody and the total hepatitis B core antibody appear at approximately 6 weeks after exposure. The IgM marker peaks at approximately 16 weeks and then gradually declines to zero after 36 weeks, but in chronic hepatitis B infection, may reappear during hepatic flares of activity. The total hepatitis B core antibody plateau's just after 12 weeks and persists for years. In chronic infection, hepatitis B e-antigen rises at about 4 weeks after exposure and persists for years. In some chronically infected individuals the e-antibody may appear and replace the e-antigen after a period of many years.

Significance of HBV Serological Markers

HBsAg (surface antigen) indicates infection. Persistence of HBsAg for 6 months or more indicates chronic infection. However, up to 50% of people with extended chronic infection will eventually clear HBsAg. By contrast, those with resolving acute HBV will clear HBsAg several months after initial infection.

Anti-HBs (surface antibody) is a protective antibody produced with recovery from infection or in response to immunization. Over time, titre may decline to undetectable levels. Note: There is a gap of several weeks to months between the disappearance of HBsAg and the appearance of anti-HBs; during this period, anti-HBc total is detectable as a marker of HBV infection.

Anti-HBc IgM (core antibody - IgM) appears early in acute HBV infection and persists for about 6 months. It may also be seen in chronic infection during flares of activity, so clinical/epidemiological correlation is required for interpretation.

Anti-HBc total (total core antibody - IgM and IgG) is a marker of past exposure or current infection. IgG usually persists for life. In low prevalence populations, a finding of isolated anti-HBc may signify a false positive result.

HBeAg (e-antigen) is a marker of viral replication; its presence indicates high infectivity.  Implications for liver injury vary with stage of infection (see Module 7 for significance).

Anti-HBe (e-antibody) appears with recovery from acute infection. In chronic infection, the presence of anti-HBe is generally a marker of reduced viral replication, indicating a less infectious state. The implications for liver injury vary with stage of infection (see Module 7 for significance).

Approach to Test Selection

The choice of tests should be based on patient history and clinical presentation.

Screening to detect infection or determine immune status^{Footnote §} in asymptomatic patients at risk of acute or chronic infection:

• HBsAg, anti-HBs
• anti-HBc IgM – in case of recent known or suspected exposure

Baseline screening to assess need for PEP (i.e., immune status unknown and recent high-risk exposure):^{Footnote **}

• HBsAg, anti-HBs

Screening in patients with defined clinical conditions:

• Pregnancy (in the absence of identified risk factors)
  • HBsAg at first prenatal visit or at delivery if there is no documented result on file
• Before starting immunosuppressive therapy (e.g., prednisone, azathioprine, chemotherapy, infliximab, rituximab)
  • HBsAg (plus anti-HBc if to receive rituximab)
• Known HIV or HCV infection^{Endnote 3, Endnote 11}
  • HBsAg, anti-HBs, anti-HBc (total)  
• Immunocompromised
  • HBsAg, anti-HBc (total)

Pre-immunization screening of high-risk population:^{Footnote §}

• HBsAg, anti-HBs

Post-immunization screening^{Footnote §} for those with ongoing exposure or risk of exposure (e.g., HBV-positive sexual partner, injection drug use):

• anti-HBs

Testing to confirm diagnosis in patients with clinical or laboratory findings consistent with acute hepatitis:

• HBsAg, anti-HCV, anti-HAV IgM

If these are negative, test for:

• HEV, HCV-RNA
• Consider other infectious causes (e.g., CMV, EBV, HSV) or non-infectious causes (e.g., hepatotoxic drugs, autoimmune hepatitis, Wilson's disease, vascular causes, or other pre-existing chronic liver diseases)

Module 3 – Interpretation of HBV Diagnostic Test Results

HBV serological markers

HBV serological markers				Interpretation and recommended action
HBsAg	anti-HBs	anti-HBc (total)	anti-HBc IgM
Negative	NegativeTable 3 - Footnote *	Negative	N/A	Susceptible Vaccinate
Negative	PositiveTable 3 - Footnote *,Table 3 - Footnote †	Negative	N/A	Immune due to vaccination Counsel as outlined in Module 11
Negative	PositiveTable 3 - Footnote ‡	Positive	N/A	Immune due to previous infection Counsel as outlined in Module 11
Positive	Negative	Positive	PositiveTable 3 - Footnote §	Infected - acute infection Refer to Module 4 and counsel as outlined in Module 11
Positive	NegativeTable 3 - Footnote ‡	Positive	NegativeTable 3 - Footnote §	Infected – chronic infection Refer to Module 4 and counsel as outlined in Module 11
Negative	Negative	PositiveTable 3 - Footnote ||	Negative	Four possible interpretationsEndnote 12 See below and counsel as outlined in Module 11
Footnotes Footnote 1 About 5%–10% of people will not respond to the vaccine or else do not produce protective levels of antibody post-vaccination (i.e., ≥ 10 IU/ml). Return to footnote * referrer Footnote 2 Levels of anti-HBs may decline over time and become undetectable. Return to footnote † referrer Footnote 3 A small percentage of people with chronic infection will have both HBsAg and anti-HBs markers present. Return to footnote ‡ referrer Footnote * Since anti-HBc IgM can be detected in acute HBV, this test may be helpful when acute infection is suspected. It may also reappear in a flare of chronic infection. Return to footnote § referrer Footnote * On rare occasions, an isolated anti-HBc total will be the only detectable marker. Although there are four possible interpretations for this finding, it is more common in immunocompromised people and in those who are co-infected with HIV or HCV. In low prevalence populations this finding is most often a false positive result or due to lab error. Repeat test if lab error is suspected. Less frequently this finding may reflect resolving acute infection before the appearance of anti-HBs natural immunity with undetectable anti-HBs due to a decline in antibody titre over time Rarely, this finding may represent a chronic infection with undetectable HBsAg. Return to footnote || referrer

Text equivalentModule 3 – Interpretation of HBV Diagnostic Test Results

Module 3 – Interpretation of HBV Diagnostic Test Results

This table describes 6 possible interpretations of diagnostic test results and subsequent recommended actions for clinicians.

In the first scenario of this table, a patient should be considered to be susceptible to hepatitis B when: hepatitis B surface antigen results are negative; hepatitis B surface antibody results are negative; total hepatitis B core antibody results are negative; and the IgM marker of the hepatitis B core antibody is not available/or not done.

It's noted that approximately 5 percent to 10 percent of people will not respond to vaccine or else do not produce protective levels of antibody post-vaccination (that is, greater than or equal to 10 international units per millilitre).

The recommended action when a patient is considered to be susceptible to hepatitis B is to vaccinate.

In the second scenario of this table, a patient should be considered to be immune to hepatitis B due to vaccination when: hepatitis B surface antigen results are negative; hepatitis B surface antibody results are positive; total hepatitis B core antibody results are negative; and the IgM marker of the hepatitis B core antibody is not available/or not done. Regarding the hepatitis B surface antibody, clinicians are reminded that about 5 percent to 10 percent of people will not respond to the vaccine or else do not produce a protective level of antibody post-vaccination (that is, greater than or equal to 10 international units per millilitre). Note that in immune individuals, levels of hepatitis B surface antibody may decline over time and become undetectable.

The recommended action when the patient is considered immune due to vaccination is to provide education and counselling as per the recommendations in module 11.

In the third scenario of this table, a patient should be considered immune due to previous infection when: hepatitis B surface antigen results are negative; hepatitis B surface antibody results are positive; total hepatitis B core antibody results are positive; and the IgM marker of the hepatitis B core antibody is not available/or not done. Note that, a small percentage of people with chronic infection will have both hepatitis B surface antigen and hepatitis B surface antibody markers present.

The recommended action when the patient is considered immune due to previous infection is to provide education and counselling as per the recommendations in module 11.

In the fourth scenario of this table, a patient should be considered to have an acute infection when: hepatitis B surface antigen results are positive, hepatitis B surface antibody results are negative, total hepatitis B core antibody results are positive and the results of the IgM marker of the hepatitis B core antibody is positive. When an acute infection is suspected, ordering the IgM marker of the hepatitis B core antibody may be helpful; however this marker may also reappear in a flare of chronic infection.

The recommended action when the patient is considered to have an acute infection is for clinicians to refer to module 4 for guidance on the initial management of patients with hepatitis B surface antigen positive results and to provide education and counselling as outlined in module eleven.

In the fifth scenario of this table, a patient should be considered to have a chronic infection when: hepatitis B surface antigen results are positive; hepatitis B surface antibody results are negative, total hepatitis B core antibody results are positive ; and the results of the IgM marker of the hepatitis B core antibody is negative. Note that, a small percentage of people with chronic infection will have both hepatitis B surface antigen and hepatitis B surface antibody markers present; in addition, the IgM marker of the hepatitis B core antibody may reappear in a flare of chronic infection.

The recommended action when the patient is considered to have a chronic infection is for clinicians to refer to module 4 for guidance on the initial management of patients with hepatitis B surface antigen positive results and to provide education and counselling as outlined in module 11.

The final scenario of this table provides four possible interpretations for the rare occasion when an isolated total hepatitis B core antibody is the only detectable marker and hepatitis B surface antigen results are negative; hepatitis B surface antibody results are and the results of the IgM marker of the hepatitis B core antibody is also negative. The four possible interpretations for when an isolated total hepatitis B core antibody is the only detectable marker are that:

Firstly, that the finding of an isolated total hepatitis B core antibody is more common in immunocompromised people and in those who are co-infected with HIV or hepatitis C.

The recommended action is to provide education and counselling as outlined in module eleven.

Secondly, that the finding of an isolated total hepatitis B core antibody in low prevalence populations, is most often a false positive result or due to lab error.

The recommended action is for clinicians to repeat the test if lab error is suspected.

Less frequently, the third interpretation of a finding of an isolated total hepatitis B core antibody is that it may reflect either resolving acute infection before the appearance of hepatitis B surface antibody or natural immunity with undetectable hepatitis B surface antibody due to decline in antibody over time.

The recommended action is to provide counselling as outlined in Module 11

Finally, the fourth possible interpretation of a finding of an isolated total hepatitis B core antibody is that, rarely, it may represent a chronic infection with undetectable hepatitis B surface antigen.

The recommended action is to consult a specialist for guidance and to provide counselling as outlined in Module 11

Module 4 – Initial Management of Patients with HBsAg-Positive Results

Text equivalentLaboratory reports HBsAg-positive result

Module 4 – Initial Management of Patients with HBsAg-Positive Results

This flow chart describes the role of the primary care provider and local public health in the initial management of patients with hepatitis B surface antigen-positive results. The laboratory reports the positive hepatitis B surface antigen result to both the primary care provider and the local public health department as per provincial/territorial legislation. From this point onward, there is ongoing communication for case management and follow-up between the primary care provider and local health department.

The primary care provider

• Advises patient of positive result
• Advises patient that hepatitis B is reportable to public health; reports to local public health department if not reported by laboratory staff
• Reviews history (including family history) and risk factors. The recommended action for clinicians is to refer to module 1 for a review of the risk factors for hepatitis B.
• Conducts physical assessment and follow-up testing
• Initiates contact investigation and follow-up where possible
• Screens contacts and vaccinates susceptible individuals. The recommended action is for clinicians to refer to module 2 to assist with decision making for test selection to screen contacts.
• Assesses need for/initiates post-exposure prophylaxis for contacts with acute exposures. The recommended action for clinicians is to refer to module 10 for guidance on prevention and vaccination.
• Provides education and counselling based on identified risk factors and provisional diagnosis. The recommended action is for clinicians to refer to module 11 for recommended education and counselling.
• In the case of suspected acute hepatitis B, the recommended action is to refer to module 5 for guidance on the natural history and management of acute hepatitis B.
• In the case of suspected chronic hepatitis B, the recommended action is to refer to module 6 for guidance on the initial evaluation of patients with confirmed chronic hepatitis B.

The local public health department as per provincial/territorial legislation

• Conducts source case investigation
• Assists with contact notification and follow-up. Note that all contacts should be located and offered vaccine plus or minus hepatitis B immunoglobulin if they do not show evidence of past exposure/immunity. The recommended action is for clinicians to refer to module 10 for guidance on prevention and vaccination.
• Vaccinates contacts through public health clinics or facilitates primary care providers' access to free vaccine
• Provides patient and health care provider educational materials. The recommended action is for clinicians to refer to module 11 for guidance on education and counselling.

Module 5 – Natural History and Management of Acute HBV

Incubation

The incubation period ranges from 45-180 days (average is 60-90 days).^{Endnote 1}

Signs and Symptoms

Whereas infants and children rarely have symptoms, 30%-50% of adults are symptomatic.Endnote 1 Symptoms tend to be insidious and can include fatigue, malaise, fever, nausea, vomiting, anorexia, rash, arthralgia, dark urine, and abdominal discomfort. Most will have elevated ALT/AST; a small proportion will develop acute icteric viral hepatitis.

A flare of chronic HBV may present like acute HBV, and should be included in the differential diagnosis.

Resolution Time and Clinical Course of Infection

The majority (95%) of immunocompetent adults will recover within 6 months and develop lifelong immunity; the remainder will be chronically infected. Immunocompromised adults are at a particular risk of developing chronic infection. The risk of developing chronic infection is also much higher for those who acquired the infection in infancy (70%-90%) or before 7 years of age (10%-30%).Endnote 3, Endnote 13, Endnote 14

Acute HBV does not require antiviral treatment. Management should focus on relief of symptoms, monitoring and prevention of hepatic complications, as well as counselling aimed at preventing transmission. Persistence of HBsAg for 6 months indicates chronic infection.

Baseline laboratory testing to assess liver function and screen for other infections:

• Bilirubin (total and direct), albumin, INR (PT), creatinine
• ALT, AST, ALP
• CBC
• anti-HBc IgM (if not already done)
• Testing for STIs, including HIV, and for HCV, where appropriate
• Repeat HBsAg at least 6 months after baseline, to confirm / rule out chronic infection. (Note: symptomatic patients may demonstrate seroconversion and recovery from acute infection at 3 months from baseline). See Module 6 for additional testing recommendations for those with confirmed chronic HBV

Acute HBV with Severe Presentation

Presentation of acute HBV as fulminant hepatitis is uncommon but can nevertheless be life threatening. Those most at risk include patients with pre-existing chronic liver disease of any etiology. Manifestations include fatigue, jaundice, altered mental status (encephalopathy), and abdominal swelling (ascites).

In patients with chronic HBV infection, spontaneous flares of disease or flares precipitated by withdrawal from immunosuppressive therapy can result in fulminant hepatitis. It is important to maintain a high index of suspicion and watch for signs of impending liver failure (see below).

Indications for urgent and immediate referral to a specialist:

• Worsening symptoms/signs of liver failure (e.g., encephalopathy)
• Laboratory tests indicating deteriorating liver function or liver failure
  • Elevated or rising INR
  • Elevated or rising bilirubin
  • Low or falling platelet count

Module 6 – Initial Evaluation of Confirmed Chronic HBV^{Endnote 2}

Baseline clinical evaluation includes:

• History, particularly risk factors for hepatitis acquisition, and family history of liver disease including HCC
• Physical examination to look for signs of liver failure (e.g., jaundice, ascites, encephalopathy)

Initial laboratory evaluation

• HBeAg/anti-HBe,^{Footnote *} quantitative HBV DNA (viral load)^{Footnote *}
• ALT,^{Footnote *Footnote †} AST, ALP, bilirubin (total and direct)
• CBC, albumin, INR (PT)^{Footnote ‡}
• Creatinine
• Anti-HAV (IgG) (vaccinate if negative)
• HIV-antibody testing, if not already done
• HCV-antibody testing, if not already done

Imaging

• Abdominal ultrasound

All patients with chronic HBV should be referred to a specialist at some point.

There are certain situations where referrals should be expedited.

Indications for urgent referral to a hepatologist:

• Signs of liver failure - acute or chronic
• Pregnant patients (HBV DNA detected during pregnancy)
• Imaging results suggestive of HCC

Indications for semi-urgent referral :

• Co-infection with HCV or HIV (refer to a hepatologist or an infectious disease specialist / primary care physician experienced in HIV and hepatitis care)
• Suspected cirrhosis^{Footnote ‡} (provide counselling as outlined in Module 11)

Module 7 – Natural History of Chronic HBV^{Endnote 15, Endnote 16}

The natural history and progression of chronic HBV is complex and non-linear, and varies from person to person. Familiarity with the natural history can help guide decisions related to treatment and monitoring.

Immune Tolerant Phase

The immune tolerant phase is mainly seen in people infected at birth or in early childhood. During this phase, the body does not recognize the virus as foreign. HBeAg is present; HBV DNA levels are high; ALT levels are normal; and hepatic fibrosis is minimal or non-existent. Immune tolerant individuals may stay in this phase for up to 40 years or more before eventually progressing to the immune active phase.

HBeAg-positive Immune Active Chronic HBV Phase

Progression to the HBeAg-positive immune active chronic HBV phase occurs when the host immune system recognizes the virus as foreign. During this phase, ALT levels are elevated (sometimes only intermittently); HBV DNA levels are also elevated but not as high as in the immune tolerant phase; and mild to severe liver inflammation with/without fibrosis is found on biopsy. This phase can be prolonged, which may result in severe liver injury. Over 5-25 years, 90% of cases seroconvert to e-antibody-positive, which generally represents a transition to the inactive HBsAg phase.Endnote 15 Of these, approximately 4% are at risk of seroreversion (i.e., become HBeAg-positive again) with associated flares of activity.Endnote 14

HBeAg-negative Immune Active Chronic HBV Phase (anti-HBe positive)

Even after seroconversion to anti-HBe, approximately 20% of people remain in the immune active phase due to a mutant form of the virus. Their HBV DNA levels are elevated, although these are not as high as in the HBeAg-positive immune active phase, and ALT is elevated (this may be intermittent). Depending on the host immune response during this phase, liver injury may occur, increasing the risk of progression to cirrhosis and HCC.

Inactive HBsAg Phase

Most people enter the inactive HBsAg phase after they undergo seroconversion to anti-HBe. This phase is characterized by an HBeAg-negative status, normal ALT, and low levels of HBV DNA (often undetectable by PCR). Most individuals (70%-80%) remain in this inactive phase for life.

• An estimated 20% risk reactivating to the HBeAg-negative or returning to the HBeAg-positive immune active phase. They can have hepatitis flares over their lifetime, which in turn, can lead to cirrhosis or HCC. Either initiation of, or withdrawal from,immunosuppressive therapy may precipitate reactivation.
• Increasing ALT and HBV DNA levels are a sign of reactivation.^{Endnote 17}

HBsAg Clearance

Over many years, 50% of chronically infected individuals who are in the inactive phase will clear HBsAg; of those, most - but not all - will develop anti-HBs. During this phase, individuals who developed cirrhosis pre-clearance and those who do not develop anti-HBs are at increased risk of HCC.

• Reactivation (seroreversion to HBsAg-positive) is possible, although rare. Continued monitoring for reactivation is important for patients who remain anti-HBs negative and particularly for those who are receiving immunosuppressive therapy (e.g. rituximab).^{Endnote 2, Endnote 18}

Phases of Chronic HBV

Text equivalentPhases of Chronic HBVx

Phases of Chronic HBV

Within module 7 which outlines the natural history of chronic hepatitis B, there is a pictorial diagram. This diagram captures the four phases of chronic hepatitis B virus infection. It illustrates that the natural history and the progression of chronic hepatitis B is complex and non-linear, and varies from person to person. In general, transition from e-antigen positive to e-antigen negative (or e-antibody positive) is not always permanent hepatitis B e-antigen may transition back and forth between positive and negative. Active hepatitis, reactivation, and hepatitis flares increase the risk for cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B.

The diagram also illustrates the fluctuation of hepatitis B DNA and alanine aminotransferase levels during various phases of chronic hepatitis B and the impact these levels can have on histological activity and degrees of fibrosis that can occur in the transition between phases.

In the immune –tolerant phase, hepatitis B e-antigen is always present, the hepatitis B DNA levels are high and alanine aminotransferase levels are low. There is minimal histological activity and scant fibrosis in the liver.

During the immune-active chronic hepatitis B phase the patient can be either hepatitis B e-antigen-positive or –negative. In this phase the levels of hepatitis B DNA and alanine aminotransferase fluctuate. Histology shows active hepatitis and variable degrees of fibrosis, hence, treatment is appropriate.

During the inactive hepatitis B surface antigen phase, the hepatitis B e-antigen is negative and the e-antibody is positive. The hepatitis B DNA and alanine aminotransferase levels are both low. During the inactive phase, there is no histological activity but there may be moderate to severe fibrosis that takes time to resolve.

The diagram shows that there is a 20 percent risk of reactivation to the immune active chronic hepatitis B phase from the inactive hepatitis B surface antigen phase. If this occurs, there will be fluctuating hepatitis B DNA and alanine aminotransferase levels. Histologically, hepatic flares are possible over the lifetime and can result in progressive fibrosis. During reactivation, treatment is appropriate.

Module 8 – Long-term Management of Confirmed Chronic HBV^{Endnote 15}

The goal of managing chronic HBV is to prevent progression to cirrhosis, HCC, and liver decompensation by:

• Monitoring blood work regularly, regardless of phase
• Determining who requires or would benefit from antiviral therapy (see table below)
• Monitoring for portal hypertension and evidence of progression to cirrhosis or HCC
• Determining who would benefit from a liver biopsy to assess disease severity (ultrasound will detect most - but not all - cases of cirrhosis). ^{Footnote ††}

The following patients with chronic HBV should have lifelong screening for HCC at 6-month intervals using abdominal ultrasound:

• Any patient with cirrhosis
• Any patient with HIV or HCV co-infection
• People of African descent 20 years of age or older
• Men 40 years of age or older^{Endnote 2}
• Women 50 years of age or older^{Endnote 2}
• Any patient with a family history of hepatoma

Alpha-fetoprotein (AFP) is not an effective screening test for HCC and is not recommended for this purpose. It may be used, along with ultrasound with/without a CT scan, as a follow-up test to monitor patients undergoing treatment for HCC.

Suggested follow-up by phase of infection (as determined by serological and histological findings)

Suggested follow-up by phase of infection (as determined by serological and histological findings)

Phase	HBeAg	ALT (see Module 6 for ULN)	HBV DNA level		Histological activity and degree of fibrosis	Suggested follow-up
			IU/mL	log10 (IU/mL)
Immune tolerant	Positive	Normal	≥ 200,000	≥ 5.3 Usually > 7	Minimal activity and scant fibrosis Close to normal	Biopsy not indicated Monitor ALT q 6 months If ALT is elevated for 6 months and is not associated with a drop in HBV DNA, rule out other causes of liver disease and refer to a specialist as treatment may be indicated See Module 6 for urgent referral recommendations
HBeAg-positive immune active chronic HBV	Positive	Elevated, usually persistently	≥ 20,000	≥ 4.3	Active hepatitis with variable degrees of fibrosis	Treatment may be indicated to prevent severe liver injury Biopsy may be indicated Monitor ALT q 6 months If ALT remains elevated after 6 months of follow-up or if there is any evidence of liver failure, refer to / consult a specialist for treatment and monitoring recommendations See Module 6 for urgent referral recommendations
HBeAg-negative immune active chronic HBV (e-antibody positive)	Negative	Elevated, may fluctuate between normal and abnormal, and may flare intermittently	2,000 to ≥ 20,000	Can fluctuate between 3.3 and ≥ 4.3	Active hepatitis with variable degrees of fibrosis
Inactive HBsAg (e-antibody positive)	Negative	Normal	Often undetectable ≤ 2,000	≤ 3.3	No activity, but may have moderate to severe fibrosis that may resolve over time if the disease remains inactive	Biopsy not indicated Monitor ALT q 6 months If ALT > 1-2 times ULN, check HBV DNA level and rule out other causes of liver disease Check HBV DNA annually. If  elevated, refer back to the specialist
HBsAg clearance	Negative	Normal	Undetectable in serum; low levels may be present in the liver		No activity, but may already have fibrosis and/or cirrhosis that may slowly resolve	Biopsy not indicated Monitor ALT q 6 months Monitor q 6 months for development of anti-HBs; once detected, repeat × 1 HCC surveillance q 6 months is important in those who do not develop anti-HBs and in those who were cirrhotic pre-HBsAg clearance

Text equivalent Suggested follow-up by phase of infection (as determined by serological and histological findings)

Suggested follow-up by phase of infection (as determined by serological and histological findings)

This is a table within module 8, which outlines the long-term management of confirmed chronic hepatitis B.  It describes the suggested follow-up based on serological and histological findings in each phase of infection.

The first row of the table shows the serological findings and histological activity and degree of fibrosis during the immune tolerant phase.  During this phase, hepatitis B e-antigen is positive and alanine aminotransferase is normal; hepatitis B DNA levels are greater than or equal to 200,000 international units per millilitre. In base 10 logarithm, this translates to greater than or equal to 5.3 international units per millilitre; for most patients, the base 10 logarithm level is usually greater than 7 international units per millilitre. During the immune tolerant phase, there is minimal histological activity and scant fibrosis. The degree of fibrosis is close to normal, and biopsy is not indicated.

The suggested follow-up for patients in the immune tolerant phase is to monitor alanine aminotransferase every 6 months. If the alanine aminotransferase level s are elevated for 6 months and there's no associated drop in hepatitis B DNA, it is important to rule out other causes of liver disease and refer to a specialist, as treatment may be indicated. Refer to module 6 for interpretation of the upper limit of normal for alanine aminotransferase and for guidance on when urgent referral to a hepatologist is indicated. 

The second row of the table shows serological findings and histological activity and degree of fibrosis during the hepatitis e-antigen-positive, immune active chronic hepatitis B phase. During this phase,  hepatitis B e-antigen is positive and alanine aminotransferase is elevated, usually persistently; hepatitis B DNA levels are greater than or equal to 20,000 international units per millilitre. In base 10 logarithm, this translates to greater than or equal to 4.3 international units per millilitre. Histologically, there is active hepatitis with variable degrees of fibrosis. During the hepatitis e-antigen-positive, immune active chronic hepatitis B phase, treatment may be indicated to prevent severe liver injury. Clinicians are advised that biopsy may also be indicated.

The suggested follow-up for patients in the e-antigen-positive, immune active chronic hepatitis B phase is to monitor alanine aminotransferase every 6 months. If alanine aminotransferase remains elevated after 6 months of follow-up, or if there is any evidence of liver failure, the clinician is advised to refer to or consult a specialist for treatment and monitoring recommendations. Refer to module 6 for interpretation of the upper limit of normal for alanine aminotransferase and for guidance on when urgent referral to a hepatologist is indicated. 

The third row of the table shows serological findings and histological activity and degree of fibrosis during the hepatitis e-antigen-negative (or e-antibody positive), immune active chronic hepatitis B phase

During this phase, hepatitis B e-antigen is negative and alanine aminotransferase levels are elevated, though alanine aminotransferase levels may fluctuate between normal and abnormal and may flare intermittently; hepatitis B DNA levels range from 2000 to greater than or equal to 20,000 international units per millilitre. In base 10 logarithm, levels can fluctuate between 3.3 and greater than or equal to 4.3 international units per millilitre. Histologically, there is active hepatitis with variable degrees of fibrosis.  During the hepatitis e-antigen-negative (or e-antibody positive), immune active chronic hepatitis B phase, treatment may be indicated to prevent severe liver injury.  Biopsy may also be indicated.

The suggested follow-up for patients in the hepatitis e-antigen negative, or e-antibody positive, immune active chronic hepatitis B phase is to monitor alanine aminotransferase every 6 months. If alanine aminotransferase remains elevated after 6 months of follow-up, or if there is any evidence of liver failure, clinicians are advised to refer, or consult a specialist for treatment and monitoring recommendations. Refer to module 6 for interpretation of the upper limit of normal for alanine aminotransferase and for guidance on when urgent referral to a hepatologist is indicated. 

The fourth row of the table shows serological findings and histological activity and degree of fibrosis during the inactive hepatitis B surface antigen positive phase when e-antibody is positive. During this phase, hepatitis B e-antigen is negative and alanine aminotransferase is normal; DNA levels are often undetectable or less than or equal to 2000 international units per millilitre. In base 10 logarithm, this translates to less than or equal to 3.3 international units per millilitre. There is no histological activity, but there may be moderate to severe fibrosis that may resolve over time if the disease remains inactive. During this phase, biopsy is not indicated.

The suggested follow-up for patients in the inactive hepatitis B surface antigen-positive phase is to monitor alanine aminotransferase every 6 months. If alanine aminotransferase is greater than 1 to 2 times the upper limit of normal, clinicians are advised to check hepatitis B DNA levels and rule out other causes of liver disease. It is important to check the hepatitis B DNA level annually. If it is elevated, clinicians are advised to refer the patient back to the specialist.  

The fifth row in the table shows serological findings and histological activity and degree of fibrosis during the hepatitis B surface antigen clearance phase.

During this phase, hepatitis B e-antigen is negative and alanine aminotransferase is normal; DNA is undetectable in serum, but low levels may be present in the liver. There is no histological activity, but the patient may already have fibrosis and/or cirrhosis that may resolve slowly. During this phase, biopsy is not indicated.

The suggested follow-up for patients in the inactive hepatitis B surface antigen clearance phase is to monitor alanine aminotransferase every 6 months. The patient should also be monitored every six months for the development of hepatitis B surface antibody; once surface antibody is detected, repeat the test one time. Patients in the hepatitis B surface antigen clearance phase should undergo hepatocellular carcinoma surveillance every 6 months.  This is important in those who do not develop hepatitis B surface antibody and in those who were cirrhotic prior to hepatitis B surface antigen clearance.

Module 1 – Who Should be Tested for HBV?

In low-risk populations, routine screening for chronic infection or immunity is not recommended. Testing to determine immune status and/or to detect chronic infection is indicated for those at risk of exposure; susceptible people should be immunized.

Clinicians should maintain a high index of suspicion for HBV as infection is frequently asymptomatic; 30% of infections have no identified risk factors.^{Endnote 6}

The decision to screen and the selection of tests should be based on a thorough review of the following:

• Self-reported HBV immunization history and/or documentation
• Results of previous testing
• Presence of risk factors for HBV infection

Who to Screen

Risk factors for HBV infection (current or past) – screen routinely at first visit:^{Endnote 3, Endnote 6, Endnote 7}

• Birth in a region with intermediate or high endemicity^{Footnote †}
• Infant of HBsAg-positive mother^{Footnote †}
• Exposure before 7 years of age (e.g., child's immediate and/or extended family immigrated from a region of intermediate/high endemicity and/or child visited such a region) ^{Footnote †}
• Family history of hepatitis B or hepatoma^{Footnote †}
• Exposure to HBsAg-positive person (e.g., percutaneous, sexual/household contact)^{Footnote ‡}
• High-risk sexual activities (e.g., unprotected sex, multiple sexual partners) ^{Footnote ‡}
• Substance use with sharing of equipment (e.g., injection/inhalation drug use) ^{Footnote ‡}
• Exposure to blood/blood products in endemic regions without routine precautions/screening^{Footnote †}
• Transfusion recipient / medical procedure in Canada before 1970^{Footnote †}
• Use of shared/contaminated materials or equipment (e.g., instruments/tools used for personal services procedures such as tattooing / piercing / body modifications, or any alternative health care that has the potential to break the skin) ^{Footnote ‡}
• Use of shared/contaminated medical devices (e.g., glucometers) ^{Footnote ‡}
• Occupational exposure to blood / body fluids^{Footnote ‡}
• Travel to / residence in a region of intermediate/high endemicity^{Footnote ‡}
• Incarceration^{Footnote ‡}
• Institutionalization (particularly in institutions for the developmentally challenged) ^{Footnote ‡}

Special clinical considerations – screen routinely:

• Pregnancy
• HIV or HCV infection
• Planned therapy with immunosuppressive/immunoregulatory agents
  (e.g., rituximab – increased risk of hepatic flares or reactivation of hepatitis B)
• Immunocompromised

Module 9 – Treatment of Chronic HBV and Monitoring of Patients on Treatment

The goal of treating chronic HBV is to prevent disease progression and induce disease regression to minimize liver damage and its complications
(i.e., cirrhosis, liver failure, and HCC).

The current approved treatments for HBV are interferon injections (standard or pegylated interferon) or oral nucleoside/nucleotide analogues (entecavir, lamivudine, tenofovir). As oral antivirals are excreted by the kidney, dose adjustments are required in renal failure.

Not all patients with chronic HBV infection need to be treated. The decision to treat depends on several factors including age, serial ALT and HBV DNA levels, and severity of liver disease. Co-infection, particularly with HIV and HCV, needs to be considered when deciding on which medications to use.

Treatment should be initiated by a hepatologist or other physician with experience in the management of viral hepatitis.

The duration of therapy depends on the type of treatment. Interferon is used for up to 48 weeks; oral antiviral medication is used indefinitely or until the treatment endpoint is achieved (i.e., seroconversion from e-antigen-positive to e-antibody-positive OR loss of HBsAg with seroconversion to anti-HBs). Note: Treatment cannot be stopped in organ transplant recipients or infected individuals who require immunosuppressive therapy for another disorder.

All patients being treated for chronic HBV require laboratory monitoring of HBV DNA levels and liver biochemistry every 3 - 6 months. This is necessary both to assess response to treatment and to permit early detection of resistance to antiviral therapy.

In addition to close, ongoing monitoring of patients on treatment, certain patients require follow-up with a specialist. These include patients:

• who have been treated for HBV in the past
• with cirrhosis with/without liver failure
• co-infected with HIV or HCV
• with a history of renal failure (whether induced by or unrelated to antiviral therapy)
• who are pregnant

For in-depth information on the selection of patients for treatment and treatment options/regimens, refer to the Management of chronic hepatitis B: Canadian Association for the Study of the Liver consensus guidelines 2012.^{Endnote 2} These guidelines contain helpful information on selecting treatment regimens, and recommendations for on-treatment monitoring.

Module 10 – Prevention and Vaccination Checklist

The Public Health Agency of Canada website has information on risk eligibility criteria for publicly funded HBV vaccine^{Footnote ‡‡} and routine infant and childhood vaccination programs across Canada by jurisdiction.^{Footnote §§}

Contact your local public health department for guidance and information on obtaining publicly funded HBV vaccine.

• Review patient records for history of HBV immunization and adherence to vaccine schedule. See the Canadian Immunization Guide (CIG)^{Footnote ***} or your provincial/territorial immunization guidelines for recommended dosages and schedules.
  
  Note: If a recommended HBV immunization schedule has been interrupted, it is not necessary to restart the series: the missed dose should be given at the earliest opportunity and the schedule completed as per the recommendations. ^{Endnote 19}
• Assess patient risk factors for HBV infection in those with no immunization history. (See Module 1 for risk factors and, if identified, screen as per Module 2).
  Offer vaccine to those without serological evidence of immunity.^{Footnote ‡‡},^{Footnote §§}
• Discuss immunization for infants and children under 7 years of age who may be at high risk of exposure (e.g., frequent contact with an HBV-positive person and/or travel to an endemic country). ^{Footnote ††},^{Footnote §§}
• Assess immune response post-immunization in previous non-responders to the vaccine who are at risk of repeated exposure or at increased risk of adverse outcomes if they were to acquire HBV infection. Otherwise, assessment of immune response is not generally recommended. See the CIG^{Footnote ***} or your provincial/territorial immunization guidelines for who should be tested and the recommended follow-up for non-responders.
• Routinely screen all pregnant women for HBsAg. If negative and at risk of exposure, offer vaccine; HBV vaccine is not contraindicated in pregnancy. ^{Footnote ‡‡} ,Footnote §§ If positive, refer to a specialist for assessment before the third trimester of pregnancy. HBV DNA levels ≥106 IU/mL are an indication to initiate treatment during the last 3 months of pregnancy. Treatment can be discontinued early in the postpartum period once the child has received HBIg and the HBV vaccine series.
• Ensure follow-up for infants exposed to HBV at birth.
  All infants born to HBsAg-positive mothers should receive HBIg and the initial dose of HBV vaccine within 12 hours of birth, followed by a second and third dose of the vaccine at 1 and 6 months of age. Ideally, this should be discussed during prenatal visits.
  
  Post-vaccination serological testing should be done as early as 9 months of age, but no sooner than 1 month after the last dose of vaccine is administered. Testing should take place no more than 4 months after the final dose of vaccine is administered.^{Endnote 20}
  
• Testing for both HBsAg and anti-HBs is required to assess outcomes.
  Post-vaccination testing will help to identify:
  • Susceptible infants, who should be revaccinated and retested
  • Infected infants, who should be referred to a specialist for continuing medical care
• Routinely screen for HBV infection and immunity (HBsAg and anti-HBs) in all individuals who are immunocompromised / immunosuppressed, are co-infected with HIV or HCV, or have chronic liver or kidney disease. Also screen those who will be undergoing immunosuppressive therapy including anti-tumour necrosis factor drugs and rituximab).(See Module 2).

Module 10 – Prevention and Vaccination Checklist

Immune status	Recommended action
Susceptible	Vaccinate
Susceptible and recently exposed	See the CIGFootnote *** or your provincial immunization guidelines for PEP recommendations
HBsAg-positive	Refer to a specialist
Immune	No action required

Text equivalentModule 10 – Prevention and Vaccination Checklist

Module 10 – Prevention and Vaccination Checklist

Module 11 – Patient Education and Counselling

Specific Guidance for All Patients to Reduce the Risk of Transmission

• Inform HCPs (e.g., dentist, physician, nurse) and other providers of personal services whose care involves piercing of the skin (e.g., acupuncturist, tattoo artist) of your infection.
• Do not donate blood, organs, semen, or tissues.
• Do not share personal hygiene materials / sharp instruments (e.g., razors, nail clippers, toothbrushes, glucometers).
• Safely dispose of articles contaminated with blood (e.g., feminine hygiene products, dental floss, bandages, needles, broken glass).
• Cover all cuts and sores.
• Clean up blood spills with diluted household bleach (9 parts water to 1 part bleach). Leave the solution on the surface for 10 minutes before wiping it away. If others must clean up blood spills, they should wear protective gloves and wash their hands thoroughly after removing them.
• Ensure sexual partner(s), household members, and drug use partner(s) are tested and immunized if susceptible. Hepatitis B vaccine is free for susceptible contacts.^{Footnote †††}
• Use condoms with all sexual partners until testing shows they are immune.^{Footnote †††}
• Do not share any equipment used to prepare, inject, or inhale drugs (e.g., syringes/needles, spoons, drug solutions, water, wash filters, cookers, pipes, straws, devices for snorting drugs).^{Footnote †††}

Pregnant Women and Infants

• If you are pregnant or considering pregnancy, consult your HCP for advice on reducing the risk of mother-to-child transmission. Pregnant women need to be assessed before their third trimester to see if treatment is indicated.
• Infants born to HBV-positive women require PEP including HBIg and HBV vaccine to reduce the risk of mother-to-child transmission. See Module 10 for prevention, vaccination, and follow-up recommendations for infants exposed to HBV at birth.

For Patients with Acute HBV

• Acute hepatitis B does not require anti-viral treatment.
• A follow-up blood test is required 6 months later to determine if the infection has resolved.

For Patients with Chronic HBV

Reducing the risk of liver damage (fibrosis progression)

• Have liver enzymes monitored every 6-12 months.
• Reduce or eliminate alcohol.
• Stop smoking, as it increases the risk of liver cancer.
• You may drink coffee; 3 or more cups per day may reduce the risk of liver cancer.Endnote 21
• Maintain a healthy weight.
• Get vaccinated against hepatitis A if you are not already immune - talk to your HCP or contact your local public health department.
• Stick to your medication schedule and your regular lab testing and follow-up visits.
• Tell your HCP before starting any immunosuppressive therapy.

About medications for patients with cirrhosis

• Avoid aminoglycosides (a type of antibiotic), benzodiazepines, and narcotics including codeine (even in cough syrup).
• Whenever possible, avoid ASA or NSAIDs. Acetaminophen, oral contraceptive pills, and statins are safe to use.
• Do not drink alcohol.
• Treat any infection immediately.
• If you require surgery, discuss it with your specialist first.
• If you have black stools, call your specialist immediately or go to the ER.
• Tell your HCP(s) about any complementary/alternative therapies or over the counter supplements including herbal remedies that you are taking.
• Follow your HCP's advice on how frequently you require abdominal ultrasounds.

Living well with HBV

• Stay actively involved in your care plan. It is provided by your HCP to monitor and follow-up on your infection.
• Access accurate and up-to-date information on HBV; examples of credible sources include the specialist's office, your family doctor, public health departments, and the Canadian Liver Foundation.
• Enjoy physical activities. There are no restrictions on working out or sports, including contact sports.
• Eat a healthy diet. See Canada's Food Guide,^{Footnote ‡‡‡} which is also available for First Nations / Inuit / Métis.^{Footnote §§§} The US Department of Agriculture also has a variety of ethnic/cultural food pyramids.
• Allow children to go to school or daycare and to play with other children.
• Kissing or sharing food/utensils pose no risk for transmission.

References