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WHO Guidelines on Hepatitis B and C Testing. Geneva: World Health Organization; 2017 Feb.

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WHO Guidelines on Hepatitis B and C Testing.

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9DETECTION OF VIRAEMIC HBV INFECTION – to guide who to treat or not treat

9.1. Recommendation

Detection of HBV DNA – assessment for treatment
Adapted from existing guidance (WHO HBV 2015 guidelines6)
  • Directly following a positive HBsAg serological test, the use of quantitative or qualitative nucleic acid testing (NAT) for detection of HBV DNA is recommended as the preferred strategy and to guide who to treat or not treat.
    Strong recommendation, moderate/low quality of evidence
Algorithm of WHO recommendations on the management of persons with chronic hepatitis B infectiona.

Algorithm of WHO recommendations on the management of persons with chronic hepatitis B infectiona

NITs: non-invasive tests, ALT: alanine aminotransferase, APRI: aspartase aminotransferase-to-platelet ratio index

a Defined as persistence of hepatitis B surface antigen (HBsAg) for six months or more. The algorithm does not capture all potential scenarios, but the main categories for treatment or monitoring. Recommendations for settings without access to HBV DNA testing are provided in the relevant chapters.

b Clinical features of decompensated cirrhosis: portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy), coagulopathy, or liver insufficiency (jaundice). Other clinical features of advanced liver disease/cirrhosis may include: hepatomegaly, splenomegaly, pruritus, fatigue, arthralgia, palmar erythema, and oedema.

c The age cut-off of >30 years is not absolute, and some persons with CHB less than 30 years may also meet criteria for antiviral treatment.

d ALT levels fluctuate in persons with chronic hepatitis B and require longitudinal monitoring to determine the trend. Upper limits for normal ALT have been defined as below 30 U/L for men and 19 U/L for women, though local laboratory normal ranges should be applied. Persistently normal/abnormal may be defined as three ALT determinations below or above the upper limit of normal, made at unspecified intervals during a 6–12-month period or predefined intervals during 12-month period.

e Where HBV DNA testing is not available, treatment may be considered based on persistently abnormal ALT levels, but other common causes of persistently raised ALT levels such as impaired glucose tolerance, dyslipidaemia and fatty liver should be excluded.

f All persons with CHB should be monitored regularly for disease activity/progression and detection of HCC, and after stopping treatment for evidence of reactivation. More frequent monitoring maybe required in those with more advanced liver disease, during the first year of treatment or where adherence is a concern, and in those with abnormal ALT and HBV DNA levels >2000 IU/mL, not yet on treatment.

g Before initiation, assessment should be done of renal function (serum creatinine level, estimated glomerular filtration rate, urine dipsticks for proteinuria and glycosuria, and risk factors for renal dysfunction [decompensated cirrhosis, CrCl <50 mL/min, poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant nephrotoxic drugs, solid organ transplantation, older age, BMI <18.5 kg/m2 (or body weight <50 kg], concomitant use of nephrotoxic drugs or a boosted protease inhibitor [PI] for HIV). Monitoring should be more frequent in those at higher risk of renal dysfunction.

Existing recommendations on Who to treat and not treat (2015 WHO HBV guidelines)

Who to treat

  • As a priority, all adults, adolescents and children with CHBa and clinical evidence of compensated or decompensated cirrhosisb (or cirrhosis based on APRI score >2 in adults) should be treated, regardless of ALT levels, HBeAg status or HBV DNA levels. (Strong recommendation, moderate quality of evidence)
  • Treatment is recommended for adults with CHBa who do not have clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), but are aged more than 30 yearsc (in particular), and have persistently abnormal ALT levelsd,e and evidence of high-level HBV replication (HBV DNA >20 000 IU/mLf), regardless of HBeAg status. (Strong recommendation, moderate quality of evidence)
    ›

    Where HBV DNA testing is not available: treatment may be considered based on persistently abnormal ALT levels alonee, regardless of HBeAg status. (Conditional recommendation, low quality of evidence)

Who not to treat but continue to monitor

  • Antiviral therapy is not recommended and can be deferred in persons without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), and with persistently normal ALT levelsd,e and low levels of HBV replication (HBV DNA <2000 IU/mLf), regardless of HBeAg status or age. (Strong recommendation, low quality of evidence)
    ›

    Where HBV DNA testing is not available: Treatment can be deferred in HBeAg-positive persons aged 30 years or less and persistently normal ALT levels. (Conditional recommendation, low quality of evidence)

  • Continued monitoring is necessary in all persons with CHB, but in particular those who do not currently meet the above-recommended criteria for who to treat or not treat, to determine if antiviral therapy may be indicated in the future to prevent progressive liver disease. These include:
    -

    persons without cirrhosis aged 30 years or less, with HBV DNA levels >20 000 IU/ mLe but persistently normal ALT;

    -

    HBeAg-negative persons without cirrhosis aged 30 years or less, with HBV DNA levels that fluctuate between 2000 and 20 000 IU/mL, or who have intermittently abnormal ALT levelsd,e;

    ›

    Where HBV DNA measurement is not available: persons without cirrhosis aged 30 years or less, with persistently normal or ALT levels, regardless of HBeAg status.

a

Clinical features of decompensated cirrhosis: portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy), coagulopathy, or liver insufficiency (jaundice). Other clinical features of advanced liver disease/cirrhosis may include: hepatomegaly, splenomegaly, pruritus, fatigue, arthralgia, palmar erythema and oedema.

b

Defined as persistence of hepatitis B surface antigen (HBsAg) for six months or more

c

The age cut-off of >30 years is not absolute, and some persons with CHB aged less than 30 years may also meet the criteria for antiviral treatment.

d

ALT levels fluctuate in persons with CHB and require longitudinal monitoring to determine the trend. Upper limits for normal ALT have been defined as below 30 U/L for men and 19 U/L for women (based on greater sensitivity observed in hepatitis B for histological disease in the liver), though local laboratory normal ranges should be applied. Persistently normal/abnormal may be defined as three ALT determinations below or above the upper limit of normal, made at unspecified intervals during a 6–12-month period or predefined intervals during a 12-month period.

e

Where HBV DNA testing is not available, other common causes of persistently raised ALT levels such as impaired glucose tolerance, dyslipidaemia and fatty liver should be excluded.

f

WHO has defined an international standard for expression of HBV DNA concentrations. Serum HBV DNA levels should be expressed in IU/mL to ensure comparability; the same assay should be used in the same patient to evaluate antiviral efficacy. All HBV DNA values in the recommendations are reported in IU/mL; values given as copies/mL were converted to IU/mL after dividing by a factor of 5 (10 000 copies/mL = 2000 IU/mL; 100 000 copies/mL = 20 000 IU/mL; 1 million copies/mL =200 000 IU/mL).

Occasionally, extrahepatic manifestations of hepatitis B, including glomerulonephritis or vasculitis, may be indications for treatment.

9.2. Background

The decision to initiate antiviral therapy is usually based on a combined assessment of the stage of liver disease (from clinical features, and now increasingly from blood or ultrasound-based NITs), together with levels of serum ALT and HBV DNA. Serum HBV DNA concentration quantified by real-time polymerase chain reaction (PCR) measures the extent of viral replication and correlates with disease progression (264–266). It is used to differentiate active HBeAg-negative disease from inactive chronic infection, and inform decisions on treatment and subsequent monitoring.

The objective of treatment is to prevent the adverse outcomes of CHB. The decision to treat is usually clear in persons who present with life-threatening or advanced liver disease, such as acute liver failure, compensated or decompensated cirrhosis, and acute-on-chronic liver failure. However, in persons who have not yet progressed to cirrhosis, it is important that antiviral therapy is targeted to the stage of CHB when the risk of disease progression (fibrosis) is greatest while those persons with minimal fibrosis and low risk of CHB progression that do not require antiviral therapy are identified. Decisions are generally based on ALT and HBV DNA levels. However, not all persons will have raised ALT and HBV DNA levels. For example, during the immune-tolerant phase of disease, there will be high levels of HBV DNA but low or normal levels of ALT, and little liver inflammation or progression of fibrosis. Later on, during the immune-active phase, HBV DNA levels will be low, but ALT levels will be raised, with a much higher risk of disease progression to fibrosis.

9.3. Rationale for the recommendations on HBV DNA measurement (WHO 2015 HBV guidelines)

The Guidelines Development Group recognized that access to HBV DNA measurement remains limited in LMICs. In the 2015 HBV guidelines (6), a strong recommendation was made for use of HBV DNA NAT (quantitative or qualitative) as the most important assay to guide decisions about who to treat or not treat. This was based on low/moderate-quality evidence from 22 observational studies (including four large population-based prospective cohort studies) to identify individuals with the highest and lowest risk of progression (i.e. cirrhosis and HCC) (Web appendix 2: SRs 5a and 5b – WHO HBV guidelines 2015, http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1&ua=1). There are caveats to the generalizability of the evidence. The majority of the studies were from Asia, and there were no data from cohorts in SSA or Latin America, and the data from the REVEAL study may not apply to those with adult-acquired HBV infection, those aged <30 or >65 years, and those infected with HBV genotypes non-B or C. There were also no studies in pregnant women, children or adolescents with CHB.

Balance of benefits and harms

Who to treat

In the 2015 HBV guidelines, it was recommended that antiviral therapy be prioritized for those with life-threatening liver disease (decompensated cirrhosis) and compensated cirrhosis, identified either clinically or using NITs (APRI score based on the single high cut-off >2 for cirrhosis in adults, or FibroScan®), regardless of ALT or HBV DNA levels. In persons who had not progressed to cirrhosis (APRI score ≤2 in adults), it was recommended to target treatment to those at highest risk of disease progression based on the detection of persistently abnormal ALT and HBV DNA levels >20 000 IU/mL (especially in those aged >30 years, regardless of HBeAg status). The recommended thresholds were derived from consistent evidence from large population-based cohort studies of increased risk of HCC and liver cirrhosis above these thresholds. It was recognized that there were uncertainties in the specific thresholds of age, HBV DNA and serum ALT levels for identifying significant fibrosis and/or necroinflammation.

Who not to treat

Conversely, treatment was not recommended in persons with minimal liver disease or fibrosis, and at low risk of progression to cirrhosis and HCC on the basis of persistently normal ALT levels and low levels of HBV replication (<2000 IU/mL), and an APRI score ≤2, as the potential harms of long-term antiviral therapy outweigh the benefits. Long-term monitoring of these persons is required.

In settings where HBV DNA testing is not available

The current limited access to HBV DNA testing in many LMICs is a significant impediment to the effective management of CHB in these settings, and this means that decisions to start treatment will be based on clinical features and serum ALT levels alone.

Overall, there was a very limited evidence base to guide recommendations in the absence of HBV DNA levels, and two conditional recommendations were made in the 2015 WHO HBV guidelines based mainly on expert opinion. First, treatment should be initiated in persons with persistently abnormal ALT levels (regardless of HBeAg status), but where other common causes of persistently abnormal ALT such as impaired glucose tolerance, dyslipidaemia and fatty liver have been excluded. Conversely, treatment was not recommended in HBeAg-negative persons without cirrhosis aged less than 30 years with persistently normal ALT levels. It was recognized that there are several other categories of persons with CHB who do not meet the criteria for initiating or not initiating treatment, who would also require continued monitoring and observation.

9.4. Implementation considerations

  • Access to HBV DNA testing is currently very limited in most LMICs, and is a significant impediment to the effective management of CHB in these settings.
  • Serum HBV DNA levels should be expressed in IU/mL to ensure comparability; values given as copies/mL can be converted to IU/mL by dividing by a factor of 5 to approximate the conversion used in the most commonly used assays (i.e. 10 000 copies/mL = 2000 IU/mL; 100 000 copies/mL = 20 000 IU/mL; 1 million copies/mL = 200 000 IU/mL).
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