Recommendations
Who to treat
As a priority, all adults, adolescents and children with CHB
a and clinical evidence of compensated or decompensated cirrhosis
b (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 CHB
a who do not have clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), but are aged more than 30 years
c (in particular),
and have persistently abnormal ALT levels
d,e
and evidence of high-level HBV replication (HBV DNA >20 000 IU/mL
f), 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)
Existing recommendation for HBV/HIV-coinfected persons1
In HBV/HIV-coinfected individuals, ART should be initiated in all those with evidence of severe chronic liver disease
b, regardless of CD4 count; and in all those with a CD4 count ≤500 cells/mm
3, regardless of stage of liver disease. (
Strong 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
b (or based on APRI score ≤2 in adults),
and with persistently normal ALT levels
d,e
and low levels of HBV replication (HBV DNA <2000 IU/mL
f), 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.
- 1
Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Geneva, Switzerland: World Health Organization; 2013. These guidelines will be updated in 2015.
- a
Defined as persistence of hepatitis B surface antigen (HBsAg) for six months or more
- 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 aged 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 (based on greater sensitivity observed in hepatitis C for histological disease in the liver), though local laboratory normal ranges should be applied (1). 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, 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) (2).
Occasionally, extrahepatic manifestations of hepatitis B, including glomerulonephritis or vasculitis, may be indications for treatment.
BOX 5.1Key points in the initial assessment of persons with CHB prior to therapy
Assessment of the severity of liver disease should include a history, physical examination, including for the presence of hepatomegaly and splenomegaly, and measurement of ALT, AST, ALP and total bilirubin; full blood count, including platelet count and white cell count. ALT and platelet count measurements allow calculation of APRI for staging of liver disease. The synthetic function of the liver should be assessed with serum albumin and prothrombin time or international normalized ratio (INR). Patients should also be questioned about the presence of liver-related symptomsa, although it is recognized that even advanced disease may be asymptomatic.
Assessment of the level of viral replication: using quantification of serum HBV DNA (where HBV DNA testing is available) and HBeAg and anti-HBe serostatus.
Assessment for the presence of comorbidities: evaluation for the presence of other comorbidities, including coinfection with HIV, HCV or HDV, impaired glucose tolerance, dyslipidaemia, non-alcoholic fatty liver disease, alcoholic liver disease, iron overload and drug/toxin-induced injury. All persons with cirrhosis should be screened for the presence of HCC. A review of family history of HCC and medication history are also required.
Preventive measures: HBsAg screening with HBV vaccination of non-immune family members and sexual contacts, and other general measures to reduce HBV transmission (see also
Chapter 10.3: Prevention of hepatitis B transmission).
Counselling on lifestyle: assessment of alcohol consumption, and advice on lifestyle, including alcohol reduction (WHO ASSIST package (3) [Alcohol, Smoking and Substance Involvement Screening Test]), diet and physical activity. Consider also hepatitis A vaccination (see also
Chapter 10.3: Measures to reduce disease progression in persons with chronic hepatitis B).
Preparation for starting treatment: patients should be counselled about indications for treatment, including likely benefits and side-effects, the need for and willingness to commit to long-term treatment, and follow-up monitoring both on and off therapy; the importance of full adherence for treatment to be both effective and reduce the risk of drug resistance (and that abrupt cessation of treatment may precipitate acute liver failure); and cost implications.
Measurement of baseline renal functionb and assessment of baseline risk for renal dysfunctionc should be considered in all persons prior to initiation of antiviral therapy (see also
Chapter 9.2: Monitoring for tenofovir and entecavir toxicity).
- 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
Measurement of baseline renal function includes: serum creatinine levels, and calculation of estimated glomerular filtration rate (eGFR) using the Cockcroft–Gault (CG) or modification of diet in renal disease (MDRD) formulas. An online calculator is available at http://nephron.com/cgi-bin/CGSI.cgi. For children, the Schwartz or similar formula can be used: http://nephron.com/bedsidepedsnic.cgi.
CG formula: eGFR = (140 – age)×(wt in kg)×0.85 (if female)/(72×Cr in mg%)
MDRD formula: eGFR = 175×serum Cr–1.154×age–0.203×1.212 (if patient is Black)×0.742 (if female)
Estimation of GFR based on these formulas may underestimate the degree of renal dysfunction if muscle mass is lower than the age and sex standards, as is frequently the case in HIV-infected individuals (1).
- c
Factors associated with a higher risk of renal dysfunction include: decompensated cirrhosis, CrCl <50 mL/min, older age, body mass index (BMI) <18.5 kg/m2 (or body weight <50 kg), poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant use of nephrotoxic drugs or a boosted protease inhibitor (PI) for HIV, and solid organ transplantation.
5.1. Background
The natural history of chronic HBV infection is dynamic and complex, and progresses non-linearly through several recognizable phases that are of variable duration and not necessarily sequential (see also
Chapter 3.4
, Natural history of CHB and
Table 3.1). The spectrum of disease with CHB is diverse. In some people, CHB is inactive and does not lead to significant liver disease. In others (approximately 10–30%), it may cause progressive liver fibrosis, leading to cirrhosis with end-stage liver disease, and a markedly increased risk of hepatocellular carcinoma (HCC), usually many years after initial infection. Understanding the natural history and phases of chronic infection is important to inform decisions about who requires antiviral therapy, and when treatment can be deferred.
The objective of treatment is to prevent the adverse outcomes of CHB. The decision to initiate antiviral therapy is usually based on a combined assessment of the stage of liver disease (from clinical features, liver histology [where available], and increasingly on blood or ultrasound-based NITs), together with levels of serum ALT and HBV DNA. The decision to treat is usually clear in persons who present with life-threatening or advanced liver disease, such as acute liver failure, and compensated or decompensated cirrhosis and acute-on-chronic liver failure. In persons who have not yet progressed to cirrhosis, decisions are also based on ALT and HBV DNA levels. However, not all persons will have elevated 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 raised, with a much higher risk of progression of fibrosis. It is important that antiviral therapy is targeted to the active phases of CHB when the risks of disease progression (fibrosis) are greatest and, conversely, that persons with minimal fibrosis and low risk of CHB progression are identified, as they do not require antiviral therapy. Prospective studies have identified several predictors of progression of HBV-related liver disease, including the risk of cirrhosis and HCC, and likelihood of exacerbations of CHB. These include age, gender, serum ALT levels, viral factors (including ongoing HBV replication measured by serum HBV DNA level, HBV genotype and HBV pre-core and core promoter variants), a family history of HCC, as well as cofactors such as alcohol use, HIV infection and diabetes.
5.2. Summary of the evidence
Question: The purpose of the evidence review was twofold: (i) to determine what factors/tests among HBsAg-positive persons best identify individuals at the highest risk of progression, as well as those at very low risk of progression; and (ii) to determine what factors/tests best identify individuals with the greatest and least benefit from treatment, in those with and without access to HBV DNA testing. Potential baseline prognostic factors and stratification included: age (>40 or >30 vs <40 or <30 years); cirrhosis (compensated or decompensated)/fibrosis (METAVIR stages 1–3) vs no cirrhosis or fibrosis; ALT level (>2x or >5x ULN or >ULN) vs normal): and HBV DNA level (any positive or >2000 IU/mL or >20 000 IU/mL vs undetectable). Key outcomes were liver-related mortality and morbidity (fibrosis, cirrhosis, end-stage liver disease, HCC), and progression of liver disease (see
Web appendix 2: SRs5a and 5b).
Identifying individuals at highest and very low risk of progression
We reviewed a comprehensive body of evidence, including a systematic review (see
Web appendix 2: SR5a), which incorporated data from one previous systematic review (4) and 22 observational studies (four large population-based prospective cohort studies (5–14), 11 prospective cohort studies (15–25), seven retrospective cohort studies (26–32)). Of the 22 included primary studies, the majority were performed in Asia (6–9,11,17–19,22,24,32–37), four in Europe (23,26,28,29), two in North America (5,14) and one in the Middle/Near East (21). The populations analysed in these studies include HBeAg-positive, HBeAg-negative; and HIV-coinfected persons (see
Web appendix 2: SRs5a and 5b). A further systematic review (see
Web appendix 2: SR5b) of observational studies (17,18,20–23,35,39–43) identified thresholds of HBV DNA and ALT levels and age predictive of hepatitis reactivation among persons in different phases of CHB: HBeAg positive (immune-tolerant and immune-active) or HBeAg negative immune-escape.
Population-based studies and the REVEAL-HBV cohort
The Guidelines Development Group considered that the data from four large population-based prospective cohort studies conducted in Taiwan, China, Korea, and Alaska (5–7,37) provided the highest quality of evidence on predictors of progression (5–7,10,12,14). The REVEAL-HBV cohort, in particular – a large population-based prospective observational study of 23 820 participants, aged from 30 to 65 years, enrolled between 1991 and 1992 from seven townships in Taiwan provides the most comprehensive evidence based on high-quality data on patient-important outcomes of HCC, liver cirrhosis and liver-related deaths, and their association with gender, age, HBV DNA and ALT levels and thresholds, HBeAg positivity, family history, and combinations of these variables (8–10,12,13,15).
For the outcome of HCC, the REVEAL-HBV cohort provides consistent evidence of a significantly increased risk of HCC associated with the following factors: male gender, age above 40 years, baseline HBV DNA more than 10 000 copies/mL (>2000 IU/mL), baseline ALT more than 45 U/L, HBeAg positivity, family history of HCC, as well as combinations of these factors (). A consistent and linear increase in the incidence of HCC with baseline HBV DNA >10 000 copies/mL (>2000 IU/mL) is also seen in HBeAg-negative persons, irrespective of the presence of cirrhosis or whether ALT levels were normal or abnormal (8,12). Five of the 11 other prospective cohort studies provided additional data on patient-important outcomes (16,21,23–25) and showed a consistently increased risk of liver-related outcomes with male gender, increasing age, and raised HBV DNA and ALT levels.
Outcome of cirrhosis/advanced fibrosis: HBV DNA levels not exceeding 20 000 IU/mL (i.e. 100 000 copies/mL) in persons with persistently normal serum ALT levels were associated with a low probability of advanced fibrosis in population-based prospective studies from Alaska (5,14) and Europe (44). Conversely, an HBV DNA level of >200 000 IU/mL (i.e. 1 million copies/mL) was significantly associated with histologically more advanced liver disease compared with <2000 IU/mL. The thresholds of 2000–20 000 and 20 000–200 000 IU/mL were not significantly associated with severe fibrosis (44). A cohort study from Taiwan (24) also showed that persistently normal ALT levels were associated with good long-term prognosis, and conversely, abnormal ALT levels of at least twice the ULN during follow up with an increased risk of cirrhosis.
Based on the systematic review (see
Web appendix 2: SR5b) of persons in different phases of CHB: Among HBeAg-positive personsa: age above 40 years, and ALT levels above 5 times ULN (compared to less than 2 times ULN) were significant independent predictors of future reactivation (in those who had undergone seroconversion from an HBeAg-positive to anti-HBe status) in one study (17). Among HBeAg-negative inactive carriersb (18,20–23,25): HBV DNA levels above a threshold ranging from 4200 to 20 000 IU/L were significant independent predictors of future active hepatitis; and an HBV DNA level above 20 000 IU/mL was predictive of current fibrosis among HBeAg-negative persons in the “immune-escape”c phase (23,38–40). There was conflicting or inconsistent evidence on thresholds for ALT and age.
Overall, the evidence from the population-based studies was rated as moderate to high quality for the outcomes of mortality and HCC, and low quality for liver cirrhosis or fibrosis (mainly due to imprecision as a result of a small number of events, and use of clinical criteria and/or ultrasound only without liver biopsy, which have a high specificity and low sensitivity for detecting cirrhosis). The quality of evidence from other studies ranged from low to moderate. There are caveats to the generalizability of the evidence. There were no data from cohorts in sub-Saharan Africa 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.
HBV/HIV coinfection
There are limited outcome data on HBV/HIV-coinfected persons based on one retrospective cohort study (45), and the majority were receiving ART. A baseline CD4+ cell count below 200 cells/mm3, an ALT elevation at baseline or during follow up, and cumulative time with detectable HIV RNA were associated with an increased risk of advanced liver disease. The evidence was rated as low quality, mainly due to the retrospective study design.
Treatment benefit in persons with advanced liver disease
A further systematic review (see
Web appendix 2:SR5c) considered four studies that examined the impact of treatment in persons with advanced liver disease (compensated and decompensated cirrhosis and different degrees of fibrosis) (46–49). There was a 55% reduction in the incidence of hepatic decompensation and risk of HCC with continuous lamivudine therapy (46). In an observational cohort study, entecavir-treated patients had a 50–70% reduced risk of all clinical outcomes, including HCC, liver-related and all-cause mortality, when compared with an historical cohort of untreated persons with cirrhosis (48). In the open-label extension of a tenofovir trial, there was a marked increase from baseline to year 5 in both the proportion with mild or no necroinflammation (8% to 80%) and with no or mild fibrosis (39% to 63%) among those who had a biopsy at baseline and five years (47). Overall, there is moderate- to low-quality evidence of a benefit of antiviral therapy in those with compensated or decompensated cirrhosis.
5.3. Rationale for the recommendations
Balance of benefits and harms
The Guidelines Development Group assessed the overall benefits and harms of initiating antiviral therapy at different stages of hepatitis B liver disease, balancing potential benefits on clinical outcomes with the requirement for long-term adherence to NA therapy, and the potential risks for developing drug resistance and toxicities. The Guidelines Development Group prioritized urgent initiation of antiviral therapy 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), regardless of ALT or HBV DNA levels. There were several reasons for this recommendation.
These persons are at a much higher risk of developing life-threatening complications of liver disease (death, acute liver failure, flares [i.e. ALT flare with jaundice and/or coagulopathy]/reactivation and HCC) than persons without cirrhosis, and so should be treated to prevent further clinical events and stabilize disease, even if the HBV DNA level is low or undetectable.
There is evidence that antiviral therapy can halve disease progression (including hepatic decompensation, HCC or liver-related death), and may also lead to regression of fibrosis and cirrhosis over the long term. Therefore, targeting treatment to persons with cirrhosis would also be an effective use of resources.
NA therapy can be safely administered even to those with decompensated cirrhosis.
In settings where liver transplantation is an option, suppression of HBV DNA will also decrease the risk of recurrence of hepatitis B post-liver transplantation.
Selection of thresholds of HBV DNA, ALT and age: In persons who have not progressed to cirrhosis (APRI score ≤2 in adults), the Guidelines Development Group recommended targeting treatment in this group 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 more than 30 years, regardless of HBeAg status. The recommended thresholds were derived from consistent evidence from large population-based cohort studies, which showed that those aged above 30 years, with persistently abnormal ALT levelsa and evidence of ongoing HBV replication (based on HBV DNA level over 20 000 IU/mL) are at an increased risk of HCC and liver cirrhosis. However, the Guidelines Development Group recognized that there were uncertainties in the specific thresholds of age, HBV DNA and serum ALT levels for identifying significant fibrosis and/or necroinflammation. The ALT level considered abnormal or normal will also vary according to local laboratory reference ranges, but the cut-off criteria for normal serum ALT levels have been lowered (<30 U/L for males and <19 U/L for females), based on studies that showed persons with CHB and fibrosis and inflammation on liver biopsy had ALT levels within the normal range (1). The evidence for age as a predictor of disease progression was also inconsistent. The threshold of >30 years was used as this takes into account that most reported evidence (supporting a higher age threshold of >40 years) was derived from populations in Asia and Europe, and there is a risk of HCC at a younger age in sub-Saharan African where there is a significant burden of CHB. The age threshold of 30 years is not categorical, and some persons with CHB aged 30 years or less will meet the criteria for antiviral therapy with persistently abnormal ALT and HBV DNA >20 000 IU/mL. Occasionally, extrahepatic manifestations of hepatitis B, including glomerulonephritis or vasculitis, may be indications for treatment.
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 important and is discussed further in Chapter 9.1.
In settings where HBV DNA testing is not available: The Guidelines Development Group recognized that it is difficult to identify cirrhosis or moderate fibrosis in persons who do not have clinically obvious stigmata of chronic liver disease and its complications. The very limited access to measurement of HBV DNA levels or ability to diagnose fibrosis in LMICs means that decisions to start therapy will be based on clinical features, use of NITs and serum ALT levels alone. In these settings, treatment decisions will be imprecise and may lead to either delayed initiation in persons with advanced liver disease, with possible worsening of disease, or premature treatment initiation in others. It is recognized that NITs, including APRI and transient elastography, have a low PPV for identifying persons with cirrhosis and identify less than 50% of those with cirrhosis. The Guidelines Development Group recognized that in settings where HBV DNA is not available, there is a need for simple criteria to guide who to treat and who not to treat in those without evidence of cirrhosis (based on clinical criteria or APRI score >2 in adults).
Overall, there was a very limited evidence base to guide recommendations in the absence of HBV DNA levels, and therefore two conditional recommendations were made 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 below 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. No specific recommendations were made for treatment indications in children, and the APRI score has not been evaluated in children.
These recommendations are consistent with existing guidance on the management of HBV/HIV-coinfected persons in the WHO 2013 consolidated ARV guidelines (50): to provide ART to all persons with evidence of severe liver disease, regardless of CD4 cell count; and initiate ART in all those with a CD4 count less than <500 cells/mm3 regardless of stage of liver disease. These guidelines will be updated in 2015.
Values and preferences
Antiviral therapy can be administered safely to persons with cirrhosis or advanced stages of liver disease, and is effective and generally safe. Baseline assessment and ongoing monitoring for renal dysfunction in persons on antivirals (tenofovir or entecavir) is discussed in Chapter 9.2.
Resource considerations
The targeting of antiviral therapy to persons with cirrhosis or at highest risk of developing cirrhosis is the most cost–effective use of resources. Initial evaluation should include an assessment of the stage of liver disease based on NITs such as APRI, and the degree of liver necroinflammation based on liver enzymes and measurements of HBV DNA, as well as the presence of coinfection with HDV, HCV or HIV. The ability to assess all these predictors of disease progression, and especially HBV DNA levels, is severely constrained in LMICs. The measurements that are generally available in resource-limited settings are AST and platelet count (for calculation of APRI score). HBeAg serostatus and HBV DNA levels are much less readily available. It is also recognized that NITs, including APRI and transient elastography, have a low PPV for identifying persons with cirrhosis, and do not measure important necroinflammatory changes.
In general, the annual costs of treatment with generic tenofovir are relatively low, although a range of prices exists in LMICs (see
Chapter 12: Implementation considerations for programme managers). Long-term treatment with tenofovir (or entecavir) also requires clinical and laboratory infrastructure for monitoring the response to treatment with ALT and, where possible, HBV DNA levels, as well as renal toxicity. Access to HBV DNA testing is currently very limited in most LMICs, and is a major impediment to the effective management of CHB in these settings. (See also
Chapters 9.1: Monitoring for disease progression and
9.2: Monitoring for tenofovir and entecavir toxicity)
Research gaps
Conduct longitudinal cohort studies especially in sub-Saharan Africa, but also in underresearched populations, such as children, young adults, and pregnant women with CHB to determine prognostic criteria and indications for initiating or deferring treatment.
Conduct longitudinal studies to further evaluate different cut-offs for abnormal ALT in a range of settings and populations, as well as determine the prognostic significance of persistently normal ALT despite high HBV DNA levels in persons with CHB in sub-Saharan Africa and Asia.
Conduct comparative trials to assess the absolute and relative benefit of antiviral therapy for persons with different baseline HBV DNA levels in cohort studies with long-term follow up.
Assess long-term outcomes (morbidity and mortality) in HBV/HIV-coinfected persons, and impact of ART initiation at different CD4 cell count levels.
- a
High replicative phase of infection seen in the early stage among people infected at birth or in early childhood
- b
Low replicative phase of chronic hepatitis B characterized by HBeAg negativity, anti-HBe positivity, normal ALT and HBV DNA concentrations below 2000 IU/mL
- c
HBeAg-negative but anti-HBe-positive disease with variable levels of HBV replication and liver injury
- a
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, although local laboratory normal ranges should be applied. Persistently abnormal or normal may be defined as three ALT determinations above or below the upper limit of normal, made at unspecified intervals during a 6–12– month period or predefined intervals during a 12-month period.
Tables
TABLE 5.1REVEAL-HBV cohort: incidence of hepatocellular carcinoma (HCC) at 11.4 years according to HBV DNA level, HBeAg status and ALT level at study enrolment (8)
View in own window
| Participant characteristic | Incidence rate of HCC
(× 100 000 person-years) | Adjusted RR (95%CI) |
|---|
| Sex |
|---|
| Female | 178 | Reference |
| Male | 530 | 3.0 (2.0–4.5) |
| Age (years) |
|---|
| 30–39 | 111 | Reference |
| 40–49 | 399 | 3.6 (2.0–6.4) |
| 50–59 | 566 | 5.1 (2.0–8.9) |
| >60 | 901 | 8.3 (4.6–15.0) |
| Baseline HBV DNA (copies/mL)a |
|---|
| <300 | 108 | Referenceb |
| 300–9999 | 111 | NS |
| 10 000–99 999 | 297 | 2.7 (1.3–5.6) |
| 100 000–999 999 | 962 | 8.9 (4.6–17.5) |
| >1 million | 1152 | 10.7 (5.7–20.1) |
| Baseline ALT (U/L) |
|---|
| <45 | 337 | Reference |
| >45 | 1342 | 4.1 (2.8–6.0) |
| HBeAg serostatus |
|---|
| HBeAg-negative | 264 | Reference |
| HBeAg-positive | 1130 | 4.3 (3.2–5.9) |
RR relative risk, CI confidence interval
- a
1 IU/mL = 5.3 copies/mL; 2000 IU/mL = 10 000 copies/mL; 20 000 IU/mL = 100 000 copies/mL; 200 000 IU/mL = 1 000 000 copies/mL
- b
Cumulative per cent incidence of HCC at 11.4 years according to HBV DNA level: <300 copies/mL (undetectable) 1.3%; 300–9999 copies/mL 1.37%; 10 000–99 999 copies/mL 3.57%;100 000–999 999 copies/mL 12.17%; >1 million copies/mL 14.89%.