Not all primary care providers will be confident in prescribing antiviral therapy; however, as with other models of chronic disease delivery, increased expertise (including prescribing) will be essential for decreasing the incidence of HBV-related adverse outcomes, including cirrhosis and HCC.

Please note that guidelines for management of HBV infection continue to evolve. Clinicians are advised to refer frequently to the most recent recommendations from the European Association for the Study of the Liver (EASL) at:4 http://www.easl.eu/research/our-contributions/clinical-practice-guidelines

Treatment and monitoring

Acute HBV infection

Antiviral therapy is generally not necessary in patients with symptomatic acute HBV infection as >95% of adults will recover spontaneously.4-6 In a small number of cases (<1%), acute HBV can lead to fulminant liver failure, which can be recognised clinically by the presence of encephalopathy, abnormal prothrombin time and renal impairment. In such situations, specialist referral is warranted.7,8

Follow-up is required in all patients with acute HBV to document clearance of the infection. If hepatitis B surface antigen (HBsAg) persists for >6 months, they have progressed to chronic HBV.4

Chronic HBV infection

Goals of treatment

The treatment of chronic HBV infection is associated with several goals. These include:4,8

 

Improving survival and quality of life.

Achieving sustained suppression of viral replication.

Reducing the risk of progression to cirrhosis and HCC.

Prevention of HBV-associated extrahepatic manifestations.

These aims can be achieved in a significant proportion of patients with currently available therapies.8

Who and when to treat

Candidates for antiviral therapy, as recommended by the EASL Guidelines, are listed in Table 1. In general, the recommendations are based on the combination of three criteria:4

Serum HBV DNA levels,

Serum alanine aminotransferase (ALT) levels, and

Severity of liver disease.

Indications for treatment may also take into account the patient’s age, health status, risk of HBV transmission, family history of HCC or cirrhosis, and extrahepatic manifestations.

Table 1. Chronic HBV: indications for treatment4

*Defined by HBV DNA >2,000 IU/ml, ALT >ULN and/or at least moderate liver necroinflammation or fibrosis;

Defined by persistently normal ALT and high HBV DNA levels;
Even if typical treatment indications are not fulfilled.

HBeAg, hepatitis B envelope-antigen; HBV, hepatitis B virus, ALT, alanine aminotransferase; ULN, upper limit of normal; HCC, hepatocellular carcinoma.

Additional issues for clinicians to consider prior to treatment include:7,8

Disease severity (e.g. natural history, complications).

Potential treatment-related adverse effects.

The individual’s choice.

Anticipated duration of therapy.

Likelihood of response to therapy.

Likelihood of developing resistance.

Other factors (e.g., extrahepatic disease, immunosuppression, co-infection, etc.).

Likelihood of adherence to therapy regimens (non-adherence may result in significant flares in disease activity).

Individual’s life circumstance (e.g., considering starting a family – some agents are contraindicated in pregnancy).

Treatment options

The two main treatment options for chronic HBV are nucleos(t)ide analogues (NAs) or pegylated interferon (PegIFN) therapy. The characteristics of both medication classes are presented in Table 3.4

NA therapy usually consists of a once-daily oral treatment. NA therapies have a favourable safety profile and those with a high barrier to resistance, have a predictably high long-term efficacy leading to undetectable HBV DNA levels in the vast majority of compliant patients. However, unlike PegIFN, NAs do not induce a strong immune response and therefore, require long-term administration to prevent relapse.

Six NAs are approved in Europe for the treatment of chronic HBV. Lamivudine (LAM), adefovir dipivoxil (ADV) and telbivudine (TBV) have a low barrier against HBV resistance, while entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are classified as having a high barrier to HBV resistance. In some circumstances, ETV or TAF may be a more appropriate treatment choice than TDF (Table 2).4

Table 2. Indications for selecting ETV or TAF over TDF*

Age >60 years
Bone disease

Chronic steroid use or use of other medications that worsen bone density

History of fragility fracture

Osteoporosis

Renal alteration

 eGFR <60 ml/min/1.73 m2

Albuminuria >30 mg/24 h or moderate dipstick proteinuria

Low phosphate (<2.5 mg/dl)

Haemodialysis

*TAF should be preferred to ETV in patients with previous exposure to NAs;

ETV dose needs to be adjusted if eGFR <50 ml/min; no dose adjustment of TAF is required in adults or adolescents (aged ≥12 years and ≥35 kg body weight) with estimated CrCl ≥15 ml/min or in patients with CrCl <15 ml/min who are receiving haemodialysis.

PegIFN therapy consists of weekly subcutaneous injections usually given for 12 months. Treatment with PegIFN stimulates the immune system to eradicate the virus from infected hepatocytes.

The benefits of PegIFN can persist even after treatment, and relapse rates appear to be less than with non-PegIFN.9

The main disadvantages of PegIFN treatment is the high variability of response and its unfavourable safety profile making a significant number of patients ineligible or unwilling for this type of treatment.4

Table 3. Selected characteristics of PegIFN and NA therapy for chronic HBV4

Features PeqIFN therapy NA therapy
Route of administration Subcutaneous injections Oral
Treatment duration 48 weeks Long-term until HBsAg loss*
Tolerability Low High
Long-term safety concerns Very rarely persistence of on-treatment AEs Probably not
Contraindications Many§ None
Strategy Induction of a long-term immune control Inhibition of viral replication
Level of viral suppression Moderate Universally high
Risk of relapse after treatment cessation Low for those with sustained response 6—12 months after therapy Moderate if consolidation treatment provided after HBeAg seroconversion. High for HBeAg-negative disease
Early stopping rules Yes No
Risk of viral resistance No Minimal to none††

*Stopping NAs after some years might be considered in selected cases;

Psychiatric, neurological, endocrinological;

Uncertainties regarding kidney function, bone diseases for some NAs;

§Decompensated disease, comorbidities etc.;

Dose adjustments in people with eGFR <50 ml/min are required for some NAs;

Depending on baseline characteristics;

*Slowly increases with treatment time in HBeAg-positive persons (a plateau in serological responses has been observed beyond treatment Year 4), usually very low in HBeAg-negative persons;

††So far no TDF or TAF resistance development has been detected. 

AE, adverse event; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; NA, nucleos(t)ide analogue; PegIFN, pegylated interferon.

TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Treatment responses can be described in terms of virological and serological outcomes and can be estimated at several time points during and after therapy (Table 4).

Table 4. Definitions of response to treatment4

Responses NA therapy PegIFNα therapy

Virological
(on-treatment)

Response: HBV DNA <10 IU/ml

Primary non-response: <1 log10 decrease in HBV DNA after 3 months of therapy

Partial response: HBV DNA decreased by >1 log10 but still detectable after ≥12 months of therapy in compliant patients

Breakthrough: confirmed HBV DNA increase of >1 log10 above on-therapy nadir

Response: HBV DNA <2,000 IU/ml 

Virological
(off-treatment)

Sustained response: HBV DNA <2,000 IU/ml for ≥12 months after end of therapy
Serological

HBeAg loss and development of anti-HBe*

HBsAg loss and development of anti-HBs

*Only for HBeAg-positive persons.

The EASL Guidelines state that stopping ‘may’ be considered and it should only be considered in exceptional circumstances:

  • Stopping NAs should only be considered in a minority of patients at expert centres as non-specialist centres were not established to manage stopping therapy

  • Additional monitoring is essential and stopping therapy should not be something that is done routinely

Hepatitis B e antigen; HBsAg, hepatitis B surface antigen; NA, nucleos(t)ide analogue; PegIFN, pegylated interferon.

For treatment-naïve patients with chronic HBV infection, the current EASL Guidelines recommend the following:4

The long-term administration of a potent NA with high barrier to resistance is the treatment of choice regardless of the severity of liver disease.

  • NAs should be discontinued after confirmed HBsAg loss [± antibody to surface antigen (anti-HBs) seroconversion].
  • NAs can be discontinued in hepatitis B e antigen (HBeAg)-positive patients, without cirrhosis, who achieve stable HBeAg seroconversion and undetectable HBV DNA and complete ≥12 months of consolidation therapy. However, post-NA monitoring is warranted.
  • NAs may be discontinued in selected HBeAg-negative patients, without cirrhosis, who achieve long-term (e.g., ≥3 years) virological suppression, if close post-NA monitoring can be guaranteed.

PegIFN can be considered as an initial treatment option for patients with mild to moderate HBeAg-positive or -negative chronic HBV.

  • The standard duration of PegIFN therapy is 48 weeks.
  • Extension of PegIFN therapy beyond Week 48 may be beneficial in selected HBeAg-negative patients with chronic HBV.

Treatment failure with first-line NA therapy (demonstrated by persistent or recurrent viral replication on HBV viral load testing) is most commonly associated with poor adherence to treatment.

For primary care providers, providing support to patients on treatment is important; as is being aware of competing health priorities and potential barriers to taking medication.3

On-treatment monitoring

It is necessary to regularly monitor patients on therapy to record their adherence to the treatment, response to antiviral therapy with HBV DNA levels, adverse effects, and to facilitate early detection of antiviral resistance (Table 5).

Table 5: Recommended periodical monitoring in patients with chronic HBV treated with NA or PegIFN therapy4

NA therapy

PegIFN therapy

ALT: every 3–4 months 1st year; 6 months thereafter.

FBC/serum ALT levels: monthly

Serum HBV DNA: every 3–4 months 1st year; 6–12 months thereafter.

TSH: every 3 months

HBsAg: 12-month intervals if HBV DNA remains undetectable.

If clear HBsAg, test for anti-HBs.

Serum HBV DNA, HBsAg, HBeAg & anti-HBe: At 3, 6 and 12-months of treatment.

At 6- and 12-months post-treatment.

If undetectable HBV DNA (and negative HBeAg), check HBsAg at 12-month intervals.

If HBsAg-negative, test for anti-HBs.

Renal monitoring in people at risk of renal disease: every 3 months 1st year; 6 months thereafter, if no deterioration.

ALT, alanine aminotransferase; FBC, full blood count; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; NA, nucleos(t)ide analogue; PegIFN, pegylated interferon; TSH, thyroid stimulating hormone.

In the primary care setting, clinicians can utilise existing management systems to support the monitoring needs of patients with chronic HBV. Although every practice is different, existing systems may involve:

Recalls and use of appointment reminders.

Reminders in practice software.

Appointments made in advance.

Provision of pathology and ultrasound request forms in advance.

Utilisation of audit tools that work with practice software.

Surveillance for HCC

Long-term monitoring is recommended to detect reactivation of HBV infection and HCC.10 HCC is currently the main concern for patients diagnosed with chronic HBV and may develop even in individuals who have been effectively treated.11 For HCC identified at an early stage, curative treatment is available. Therefore, primary care providers play a significant role in surveillance for HCC.8

For patients undergoing treatment for chronic HBV:4

HCC surveillance is mandatory for all patients with cirrhosis or with moderate or high HCC risk at the onset of NA therapy.

HCC surveillance is recommended:

  • For all patients under effective long-term NA therapy.
  • For all patients with sustained responses after PegIFN therapy and high baseline HCC risk.

Other important co-factors, which increase the risk of HCC in patients living with chronic HBV infection include:12

  • cirrhosis;
  • co-infection with another hepatitis virus or the HIV virus;
  • high HBV DNA and/or HBsAg levels;
  • chronic excessive alcohol consumption;
  • older age;
  • male sex;
  • high HBV DNA levels;
  • diabetes or metabolic syndrome;
  • active smoking; and
  • family history of HCC.

At the time of writing, abdominal ultrasound is the most appropriate test, with acceptable diagnostic accuracy when used in the surveillance setting (sensitivity ranging from 58% to 89%; specificity greater than 90%).13 EASL guidelines on the management of HCC recommend that:10

Surveillance be performed by experienced personnel in all high-risk populations using abdominal ultrasound every 6 months.

Although alpha fetoprotein (AFP) is the most widely tested biomarker in HCC, it has suboptimal performance as a test for surveillance.

If the screening test is abnormal, computed tomography (CT) or contrast-magnetic resonance imaging (MRI) is recommended and referral to a multidisciplinary team for management is warranted.8

Education, support and lifestyle advice

Stigma and discrimination experienced within the health system can have a significant and negative impact on the health seeking behaviour of patients living with hepatitis.14 Therefore, it is important that primary care providers build trust and rapport with affected individuals and walk alongside them as a means of providing information, support and referral to additional services as required.

Education

Patients living with chronic HBV are commonly concerned about the risks of transmitting the infection to others including their children and family members.15 The primary care provider may take these opportunities to ensure that individuals understand the risks associated with sexual transmission, mother-to-child transmission, and blood-borne transmission.

Table 6. Protecting others from HBV.3

Ensure close contacts are vaccinated against HBV. Do not share needles, syringes or other equipment used to inject drugs.
Practice safer sex: use condoms and lubricant during vaginal, anal and oral sex. Do not donate blood, sperm, organs or body tissue.
Avoid blood-to-blood contact: do not share toothbrushes, razors or other personal items that may contain blood, including dry blood. Patients who are pregnant or planning to become pregnant should talk to their doctor about the necessary infant vaccinations.
Cover open wounds and clean blood spills with bleach. Do not allow other people to touch wounds or blood unless wearing gloves. Health-care workers who perform invasive procedures should seek expert medical advice, and expert occupational health and safety advice.

It is also important to be clear about activities that carry negligible risk (e.g. food sharing, touching, kissing, insect bites, swimming pools etc.) to dispel myths and prevent stigma, discrimination and sometimes self-imposed social isolation.3

Keep in mind that many patients leave a medical consult not understanding their condition, how to take medication or how to look after their health.

When providing education and support, consideration must be given to the individual’s level of health literacy and cultural understanding of the disease:16

Discussions should be conducted in a culturally appropriate and safe manner.

Consider the individual’s health beliefs about their illness and what it means to them.

Use plain language, addressing just 2 or 3 concepts at a time.

Written health information should be culturally appropriate.

Family members can be of great support but should not be used in place of an accredited interpreter. Interpreters are essential to ensure information is properly understood and there is an opportunity for patients to clarify information and ask questions.

For clinicians who work with a significant number of patients from a particular ethnic or cultural group, it can be useful to learn about relevant attitudes and practices prevalent in that group.

Lifestyle considerations

The possibility of lifestyle modification needs to be discussed with HBV-infected patients, particularly in relation to injecting drug use, cigarette smoking, alcohol consumption, diet, exercise and weight.

Patients with chronic HBV who inject drugs need support, advice and access to drug dependency treatment programs, in addition to ongoing care for their infection. Therefore, clinicians require knowledge of safe procedures and information about local services, such as needle and syringe programs and harm reduction information. There will be times when it is appropriate to discuss whether the patients wishes to reduce or cease drug use, and whether he or she would like a referral to an appropriate treatment service. However, it is important that the individual leads the discussion, rather than the clinician applying pressure.8

With regards to general lifestyle advice, there are a number of things patients with chronic HBV can do to reduce the risk of liver disease. Where appropriate, referral to specialist services such as dietitians and exercise physiologists can be considered to assist patients with their lifestyle modifications.

Strategies to reduce the risk of liver damage:3,8,17

Everyone with chronic HBV should be vaccinated against hepatitis A virus (HAV) unless they are known to be immune.

Alcohol should be avoided since it can worsen liver damage. All types of alcoholic beverages can be harmful to the liver. Patients with HBV can develop liver complications even with small amounts of alcohol.

If medication is prescribed for HBV, it is important that patients take it as directed. Treatment failure with HBV therapy is most commonly associated with poor adherence.

No specific diet has been shown to improve outcomes in people with HBV. The best advice is to eat a normal healthy and balanced diet and to maintain a normal weight.

Promote smoking cessation and minimise cannabis and other drug use.

Exercise is good for overall health and is encouraged, but it has no effect on the hepatitis B virus.

Patients should always check with their doctor or pharmacist before starting a new medication, regardless of whether it is prescribed or purchased over the counter.

No herbal treatment has demonstrated improved outcomes in patients with HBV, and some can cause serious liver toxicity.

Regular screening for liver cancer is recommended (e.g., every 6 months), particularly for older individuals, those with cirrhosis, and patients with a family history of liver cancer.

Psychosocial support

Patients living with HBV come from a diverse mix of cultures, sexualities, social situations and genders. It is important that a comprehensive psychosocial assessment, including a screen for mental health issues, be conducted during the initial consultation and opportunistically thereafter. The need for assistance from other services may arise at any point during the management continuum and primary care providers need to have a low threshold for referral to specialist agencies.3

Referral to counselling or support services may be indicated in a variety of situations:3

The presence of a mental illness such as depression, anxiety, mood disorders or post-traumatic stress disorder.

Patients with little supportive and/or trusting relationships will be isolated and vulnerable.

Individual cultural and linguistic diversity.

Issues related to drug and alcohol dependence.

Financial and employment status and stability.

Housing affordability and stability.

Issues around pregnancy and parenthood for men and women.

Emotional, family and relationship issues or concerns about disclosure.

Social, emotional and educational support is available through a variety of organisations and it is important that all patients with HBV infection be made aware of counselling and support groups, telephone helplines, and community organisations.

Hepatitis B

HBV

A comprehensive summary of currently available knowledge on HBV is provided here – information that reiterates the key role of primary care clinicians in screening, diagnosis and management of people living with HBV.

The burden of HBV

HBV

Understanding the epidemiology and natural history of HBV helps primary care providers to target screening practices towards individuals at greatest risk of infection, and to identify potential candidates for treatment.

Prevention and diagnosis

HBV

Testing people from priority populations is an opportunity to diagnose, intervene, prevent illness and death, and to test and vaccinate contacts if required.

Expert insights

HBV

Case-based discussions, expert insights and evidence-based updates on managing patients living with chronic HBV.

References

  1. Wallace J, et al. Managing chronic hepatitis B – the role of the GP. Aust Fam Physician 2012;41:893-8.
  2. MacLachlan J, Cowie B. Chronic hepatitis B. What’s new? Aust Fam Physician 2013;42:448-51.
  3. Australian Society for HIV Medicine (ASHM). HIV, viral hepatitis and STIs: a guide for primary care providers. 2014.
  4. European Association for the Study of the Liver (EASL). EASL 2017 Clinical practice guidelines on the management of hepatitis B virus infection. Available at: http://www.easl.eu/research/our-contributions/clinical-practice-guidelines (accessed November 2018).
  5. Terrault NA, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-99.
  6. British Association for Sexual Health and HIV (BASHH). 2017 interim update of the 2015 BASHH National Guidelines for the Management of the Viral Hepatitides. Available at: https://www.bashh.org/guidelines (accessed November 2018).
  7. Bell SJ and Nguyen T. The management of hepatitis B. Australian Prescriber 2009;32:99-104.
  8. Matthews G, Robotin M. eds. B Positive – All you wanted to know about hepatitis B: a guide for primary care providers. ASHM, 2008.
  9. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–2.
  10. European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2018;69:182–236.
  11. Varbobitis I, Papatheodoridis GV. The assessment of hepatocellular carcinoma risk in patients with chronic hepatitis B under antiviral therapy. Clin Mol Hepatol 2016;22:319–326.
  12. Fattovich G, et al. Natural history of chronic hepatitis B: Special emphasis on disease progression and prognostic factor. J Hepatol 2008;48:335-52.
  13. Bolondi L. Screening for hepatocellular carcinoma in cirrhosis. J Hepatol 2003;39:1076–1084.
  14. WHO guidelines on hepatitis B and C testing. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO.
  15. Valery PC, et al. Systematic review: unmet supportive care needs in people diagnosed with chronic liver disease. BMJ Open 2015;5:e007451.
  16. ASHM. Hepatitis C: Your crucial roles as a primary healthcare nurse. 2015. Available at: https://www.ashm.org.au/products/product/1-921850-24-8 (accessed Dec 2018).
  17. Patient education: Hepatitis B (Beyond the Basics). Available at: https://www.uptodate.com/contents/hepatitis-b-beyond-the-basics (accessed November 2018).

LID/IHQ/18-12//1048c(1) Date of preparation: August 2019