Despite the development of an effective vaccine, Hepatitis B virus (HBV) infection remains a major public health problem worldwide with a significant proportion of chronic HBV infected patients developing liver cirrhosis, liver failure, and primary hepatocellular carcinoma (HCC). Chronic hepatitis B is one of the 10 major causes of death worldwide. Although a number of antiviral agents against HBV are now available, proper selection of patients who would be ideal candidates for therapy is essential. The rationale for treatment is to reduce the risk of progressive chronic liver disease, transmission to others, and other long-term complications from chronic HBV such as hepatocellular carcinoma. The decision to commence treatment must balance the likelihood of a sustained treatment response, with the future risk of liver-related morbidity and mortality. Consideration of further factors, including patient age, concurrent illness, medication compliance, liver disease activity, likelihood of long-term benefit, and potential therapeutic risks such as side effects, must be included as part of a risk-benefit analysis. A large amount of new data have become available in recent years, suggesting that conventional criteria for treatment initiation based on existing disease progression do not necessarily correlate with the future risk of disease complications. This review summarizes the various factors which have to be considered before selecting the patient for treatment.
Keywords: Chronic hepatitis B, HBV DNA, Hepatitis B e antigen, Hepatitis B surface antigen
|How to cite this article:
Dhiman R K. Indications for treatment: Whom to treat and whom not to treat!. Hep B Annual 2010;7:28-44
The rationale for treatment is to reduce the risk of progressive chronic liver disease, transmission to others, and other long-term complications from chronic HBV such as hepatocellular carcinoma.
The decision to commence treatment must balance the likelihood of a sustained treatment response, with the future risk of liver-related morbidity and mortality. Consideration of further factors, including patient age, concurrent illness, medication compliance, liver disease activity, likelihood of long-term benefit, and potential therapeutic risks such as side effects, must be included as part of a risk-benefit analysis. A large amount of new data have become available in recent years, suggesting that conventional criteria for treatment initiation based on existing disease progression do not necessarily correlate with the future risk of disease complications.
| Natural History of Chronic HBV Infection
Acute hepatitis B develops 6 -12 weeks following exposure to the virus and is marked by serological and biochemical evidence of infection. HBV related symptoms are rare in the perinatal setting but relatively common in adult-acquired infection. Mortality from development of acute liver failure occurs in <1% of cases.
Acute HBV infection may have variable outcomes. Depending on the interactions among several virus and host-related variables, complete recovery with development of anti-HBV immunity may occur or it may evolve into chronic infection. Progression to chronic infection varies from >90% among perinatally exposed (and unvaccinated) infants, to 30% among children age under 5 years, to <5% for adults.
Using sensitive assays, HBV DNA can be detected in liver up to 10 years after 'recovery' from an acute HBV infection. This may account for chemo- and immunosuppressive therapy-induced reactivation of HBV replication in persons with serological markers of recovered HBV infection.
Progression to chronic HBV infection
CHB is defined as persistent detection of HBsAg for >6 months after initial exposure to the virus.
The natural history of CHB can be categorised into four potentially successive phases of variable duration classified by serum ALT, HBV DNA and HBeAg status.
Phase 1 - immune tolerance
The early phase of CHB is characterised by the presence in serum of hepatitis B e antigen (HBeAg), HBV DNA and normal ALT levels indicating a lack of host immune response against HBV infected hepatocytes. Spontaneous and treatment-induced HBeAg seroconversion is infrequent (<5% per year). The prognosis is generally favourable because of the absence of significant liver injury.
Phase 2 - immune clearance
The factors that lead to loss of immune tolerance and the development of an active host immune response against infected hepatocytes are unclear. The immune clearance phase is characterised by persistently or intermittently elevated ALT levels, fluctuating viral loads and moderate-to-high levels of liver inflammation and liver enzymes. Rapid progression of liver disease can occur.
In some patients the host immune response will result in seroconversion of HBeAg to anti-HBe accompanied by a state of nonreplicative infection, characterised by low or undetectable serum levels of HBV DNA and normal ALT levels. The annual rate of HBeAg seroconversion is estimated to be ≈5 to 15%. Following HBeAg seroconversion there is a relatively low risk of disease progression.
However, increasing viraemia and recurrent hepatitis after seroconversion indicate the emergence of the HBeAg-negative strain of the virus.
The development of antiHBs and clearance of HBsAg occurs spontaneously in 0.5-2% of people with CHB each year in western countries. Clearance of HBsAg is most likely to occur in the year following HBeAg seroconversion and signifies resolution of the chronic infection.
Phase 3 - immune control
Individuals in this phase are characterised by persistent HBV infection without significant necroinflammatory disease.Immune control is associated with undetectable to low serum levels of HBV DNA, persistently normal liver enzymes and low risk of advanced disease. Individuals in this category need to be distinguished from those in the immune tolerant phase of infection who have high levels of serum HBV DNA [Figure 1]. The inactive replication phase may persist indefinitely; in which case the prognosis is generally favourable, especially if significant fibrogenesis has not occurred prior to an effective host immune response. Reactivation of HBV may occur spontaneously or as a result of immunosuppression.
Phase 4 - immune escape
Active HBeAg-negative disease is due to a mutant virus that does not secrete HBeAg (the 'precore or core-promoter mutant' strain) and causes recurrence of active liver disease. People can be infected with the HBeAg-negative virus following initial exposure or, more commonly, the viral mutation emerges late in the course of infection in those initially infected with wild type (HBeAg-positive) virus. The prevalence of HBeAg-negative hepatitis varies geographically; and is more common in Asia and the Mediterranean region. Infection with HBeAg-negative CHB is associated with a fluctuating course, progressive fibrosis and a poor prognosis.
Active disease is associated with either persistent ALT elevation or an erratic pattern of ALT changes with "flare-ups" resembling acute hepatitis B that can be severe or even fatal. Serum HBV DNA levels are usually lower than in HBeAg-positive patients, but generally higher than those seen in patients in the immune control phase. Few patients with HBeAg-negative CHB achieve a lasting remission.
HBeAg-negative CHB may escape clinical recognition and liver disease may have progressed to advanced stages of fibrosis, including cirrhosis and even HCC when reactivations are finally identified. Progression to cirrhosis of the liver has been estimated to occur in 8 -10% of people with HBeAg-negative CHB each year.
| Patients for whom Therapy is Indicated
Treatment is always an individual decision based on treating patients who are at risk for the development of cirrhosis and its consequences, liver failure and HCC. The decision to treat requires consideration of several factors which have been identified as indicating risk of adverse outcomes including HBV DNA, ALT levels, patient age, extent of histological fibrosis or inflammation and clinical or imaging evidence of cirrhosis [Table 1]. In addition to clinical parameters it is crucial to incorporate patients' wishes, anticipated compliance and consideration of any contra-indications to treatment.
Most patients require a long duration of treatment to derive continued clinical benefit. As treatment may be required for years, decades, or the duration of the patient's life, the decision to initiate treatment must balance the long-term benefits vs. the long-term risks. 
Patients should be considered for treatment when HBV DNA levels are above 2000 IU/ml (i.e., approximately 10,000 copies/ml) and/or the serum ALT levels are above the upper limit of normal (ULN) for the laboratory, and liver biopsy (or non-invasive markers when validated in HBV-infected patients) shows moderate to severe active necro-inflammation and/or fibrosis using a standardised scoring system (for example at least grade A2 or stage F2 by METAVIR scoring) (A1). Indications for treatment must also take into account age, health status, and availability of anti-viral agents in individual countries. 
EASL guidelines: The following special groups of patients should be considered
- Immunotolerant patients: Most patients under 30 years of age with persistently normal ALT levels and a high HBV DNA level (usually above 107 IU/ml), without any suspicion of liver disease and without a family history of HCC or cirrhosis do not require immediate liver biopsy or therapy. Follow up is mandatory (B1)
- Patients with mild CHB: Patients with slightly elevated ALT (less than 2 times ULN) and mild histological lesions (less than A2F2 with METAVIR scoring) may not require therapy. Follow-up is mandatory (B1)
- Patients with compensated cirrhosis and detectable HBV DNA may be considered for treatment even if ALT levels are normal and/or HBV DNA levels are below 2000 IU/ml (i.e., approximately 10,000 copies/ml) (B1)
- Patients with decompensated cirrhosis require urgent antiviral treatment. Rapid and profound viral suppression and efficacious prevention of resistance are particularly needed in this group. Significant clinical improvement can be associated with control of viral replication, but patients with very advanced liver disease may not always benefit if treated at this late stage and should be considered for liver transplantation (A1). 
| Acute Liver Failure (ALF)
Acute hepatitis B progresses to liver failure with the need of liver transplantation in about 1% of cases. Liver transplantation is currently the only therapeutic option to prevent death, which would occur otherwise in approximately 70% of patients.  Although HBV-induced liver failure is a major issue, the underlying pathophysiological mechanisms are still unknown. In adults, acute HBV infection, mainly due to sexual transmission, is followed by high viral replication rates leading to hepatocyte death and in some cases ultimately to ALF. The rationale of treating HBV-induced ALF is to eliminate or significantly suppress HBV replication, so as to reduce cell death and restore liver function. 
Currently, the kind of therapy, and time of onset, in patients with HBV infection remains controversial. For example, while Kumar et al.  found treatment with lamivudine in acute hepatitis B to be ineffective, Tillmann et al.  showed that patients with imminent ALF due to acute hepatitis B benefitted from such treatment, and that lamivudine treatment was safe in this setting. However, with the emergence of new, effective antiviral drugs with a higher barrier to resistance, lamivudine is no longer recommended as a first-line treatment for chronic hepatitis B because of the high rates of drug resistance. In contrast, entecavir has a higher genetic barrier to resistance and has proven as an effective and safe treatment for chronic hepatitis, which prompted us to evaluate this virostatic agent in a series of patients with HBV-dependent ALF.
| Decompensated Cirrhosis
Chronic HBV may lead to decompensated liver disease; characterized by ascites, hepatic encephalopathy, variceal bleeding, hepatocellular carcinoma (HCC) and liver failure.  Patients with compensated or decompensated cirrhosis, who are infected with HBV, receive entecavir for persistent clearance of HBV DNA detectable by the real-time polymerase chain reaction and normalization of aspartate aminotransferase as well as ALT levels. Combined lamivudine plus adefovir therapy are indicated for patients in whom HBV mutants resistant to lamivudine or entecavir have developed. Guidelines for maintaining liver function, for preventing the development of HCC, include liver supportive therapy with glycyrrhizin and UDCA, either alone or in combination [Table 2]. 
Guidelines for treatment of type B cirrhosis
Decompensated: reversal to compensation and prevention of HCC
- Eradication of HBV and normalization of ALT/AST (compensated and decompensated cirrhosis).
- Combined lamivudine and adefovir (for patients with HBV mutants resistant to lamivudine or entecavir).
- Maintenance of liver function (improvement of ALT/AST and albumin) for preventing HCC
- Liver supportive therapy such as SNMC or UDCA
- Branched chain amino acids (Livact)
- Supplementation with nutrients (for stabilizing liver function in decompensated cirrhosis).
| Severe Hepatitis Flare
Acute flares in chronic hepatitis B are common and may be caused by a number of identifiable and potentially treatable factors. The common link for many of these exacerbation episodes is a change in the immunologic response to hepatitis B virus (HBV), and this may have no identifiable cause or be triggered by an increase in viral replication or genotypic change. It is important to keep in mind the clinical situations in which patients are at increased risk of reactivated infection and secondary exacerbations.  During treatment with IFN and after withdrawal of lamivudine therapy, flares of inflammatory activity are a well known phenomenon in CHB patients. Flares can be life threatening but have also been associated with virological response.  The predictors of flares in chronic HBV infection are 1) male, 2) Age > 20, 3) HBeAg +ve 4) Base line ALT > 200. 
Guidelines for treatment of severe hepatitis flare
- Particular care should be paid to these patients, as flares due to antiviral response, antiviral resistance or after cessation of treatment can lead to severe decompensation. 
- Antiviral treatment should not be delayed for patients with hepatic decompensation due to severe hepatitis flare.
Life-Threatening HBV-Related Liver Disease (AASLD/NIH) [Table 3].
*Lack of data to support which cutoff HBV DNA level for initiating treatment.
| Patients for whom Therapy nay be Indicated
Most trials of anti-HBV therapies conducted for drug approval purposes have enrolled patients who have chronic HBV with high HBV DNA levels and signs of liver inflammation as reflected by elevated ALT levels or histology. The decision to treat is affected by knowledge about the natural history of these patients in the absence of therapy. An elevated ALT level indicates active liver inflammation and is considered a predictor of likelihood of disease progression. Patients in the immune active phase (sometimes referred to as immune clearance) may be treatment candidates after consideration of various prognostic factors. The immune active phase is defined by the presence of elevated HBV DNA levels, with or without HBeAg, and evidence of active inflammation (ALT level elevation or active inflammation on liver histology). The available randomized, controlled trials (RCTs) provide evidence that selected patients treated with anti-HBV therapy have decreases in HBV DNA levels and improvement in ALT levels. The onset of complications from chronic HBV generally increases in patients around age 40 years. Younger HBeAg-positive patients may undergo spontaneous HBeAg seroconversion; therefore, it is reasonable to monitor this group without therapy unless evidence of progressive liver disease is found. If spontaneous seroconversion does not occur by the late 30s or early 40s and active inflammation is present, as reflected by ALT level elevation or inflammation or fibrosis on liver biopsy, therapy may be indicated. Patients in the reactivation phase of chronic HBV infection, defined as having elevated HBV DNA levels and evidence of liver inflammation, usually should be treated. In general, these patients have evidence of liver inflammation in association with lower HBV DNA levels compared with the HBeAg-positive patients. Therefore, a lower threshold of HBV DNA levels in the presence of liver inflammation might justify therapy. Several prognostic factors for disease progression may be considered in the decision to treat, including male sex, genotype (genotype C), a family history of hepatocellular carcinoma, and ongoing alcohol abuse. Co-infection with HIV, HCV, or hepatitis D virus increases the risk for adverse clinical outcomes. If the HIV infection requires treatment, then hepatitis B also should be treated. Combination therapy with nucleoside or nucleotide analogues is required to avoid the emergence of resistance and to provide optimal reduction in the replication of both viruses.
The antiviral therapies must be selected in view of the potential for cross-resistance. If HIV is not treated, then the decision to treat the HBV infection with therapy that targets HBV replication should follow guidelines for HBV monoinfection, except a lower threshold for HBV DNA might trigger treatment. Some information suggests that a normal ALT level in co-infected patients does not exclude the presence of active liver inflammation. 
| Patients for whom Therapy is not Indicated
Certain patients have a lower risk for adverse clinical outcomes. These patients may be identified through various clinical features (such as younger age) and absence of indicators of hepatic inflammation. Younger patients in the immune-tolerant phase, those in the inactive carrier phase, and those who have latent HBV infection do not meet the criteria for therapy. Therapy is not recommended for patients who are in the immune-tolerant phase, which includes the presence of HBsAg, high HBV DNA levels, normal ALT levels, and liver histology with mild or minimal inflammation and fibrosis. Typically, such patients have not been included in prospective randomized, controlled trials (RCTs). As mentioned, retrospective data suggest that some patients who have baseline ALT levels in the normal range may, rarely, have adverse outcomes. Also, ALT values can vary over time. Serial monitoring of ALT levels may help identify those persons who have ALT levels that are persistently in the normal range and who thus have a favourable prognosis. Careful surveillance is reasonable for such patients.
Therapy is also not recommended for patients who are in the inactive carrier or low replicative phase, defined by the presence of HBsAg, low HBV DNA levels, normal ALT levels, and liver histology with mild or minimal inflammation and fibrosis. The presence of latent HBV infection, defined as detection of HBV DNA in the absence of HBsAg, is not an indication for therapy. Treatment may not be indicated in patients for whom concurrent serious medical conditions preclude expectation of improved outcomes with therapy. This is because the risk for death from the coexisting medical condition is high and complications from HBV-associated liver disease are therefore unlikely to contribute to morbidity and mortality. Anti-HBV therapy will be most effective in those patients who follow the prescribed regimen for therapy. Thus, patients who are non-adherent to a prescribed anti-HBV regimen are unlikely to benefit from therapy. 
| Other Considerations in Therapy
Patients undergoing immunosuppressive treatment or chemotherapy, even for short-term courses, should be screened for HBsAg, anti-HBc, and anti-HBs (and HBV DNA if HBsAg is already positive) because of the high risk of viral reactivation with hepatic flares. In HBV naïve patients (all serum markers negative), vaccination should be given prior to immunosuppressive treatment.
HBsAg-positive patients (inactive carriers) should be tested for HBV DNA levels and treated with lamivudine, probably the best candidate because due to its low price and negligible side effects.
This pre-emptive therapy should be maintained for up to 12 months after cessation of immune suppression or chemotherapy. Anti-HBc positive carriers (HBsAg negative ± anti-HBs, past infection) should only be closely followed without pre-emptive anti-HBV treatment. HBV viraemia and ALT levels should be tested bimonthly and in case of HBV DNA reactivation (even without ALT elevation) a potent nucleos(t)ide analogue (NUC) should be urgently added to avoid hepatic flares. 
Health care workers
EASL guidelines suggest that healthcare workers, especially those involved in invasive procedures, should be treated with a potent NUC, if HBV viraemia ≥2000 IU/ml. Undetectable HBV DNA is a requirement to minimise the risk of HBV transmission to patients.
Telbivudine and tenofovir are characterised by the FDA as category B drugs, whereas lamivudine, adefovir and entecavir are listed as category C. Antiviral treatment is to be avoided until the third trimester of pregnancy. Studies show that in patients with high viraemia lamivudine reduces the risk of intra-uterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIG and HBV vaccination.
The majority of children presents with CHB in an immune tolerant phase and should not be treated. Only conventional interferon-a, lamivudine and adefovir have been evaluated for safety and efficacy, which are comparable to adults. 
The most important predictors of cirrhosis or hepatocellular carcinoma in persons who have chronic HBV are persistently elevated HBV DNA and ALT levels in blood. Other risk factors include HBV genotype C infection, male sex, older age, family history of hepatocellular carcinoma, and co-infection with HCV or HIV. The major goals of anti-HBV therapy are to prevent the development of progressive disease, specifically cirrhosis and liver failure, as well as hepatocellular carcinoma development and subsequent death. To date, no RCTs of anti-HBV therapies have demonstrated a beneficial impact on overall mortality, liver-specific mortality, or development of hepatocellular carcinoma.
The most important research needs include representative prospective cohort studies to define the natural history of the disease and large RCTs of monotherapy and combined therapies, including placebo-controlled trials, that measure the effects on clinical health outcomes. Screening will facilitate the provision of medical and public health services for infected patients and their families and provide public health data on the burden of disease in immigrant populations.
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Conflict of interest
There are no conflicts of interest.
Ahn SH. Chronic hepatitis B: whom to treat and for how long? Propositions, challenges, and future directions. Hepatol Int. 2010 Feb 20;4(1):386-395.
Gastroenterological Society of Australia. October 2008.
European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227-242.
Tillmann HL, Hadem J, Leifeld L, Zachou K, Canbay A, Eisenbach C, Graziadei I, Encke J, Schmidt H, Vogel W, Schneider A, Spengler U, Gerken G, Dalekos GN, Wedemeyer H, Manns MP: Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006; 13: 256-263.
Christoph Jochum et al
. Hepatitis B-Associated Acute Liver Failure: Immediate Treatment with Entecavir Inhibits Hepatitis B Virus Replication and Potentially Its Sequelae: Digestion 2009;80:235-240.
Kumar M, Satapathy S, Monga R, Das K, Hissar S, Pande C, Sharma BC, Sarin SK: A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 2007; 45:97-101.
Muneer, B et al
. Entecavir Therapy in a Hepatitis B-Related Decompensated Cirrhotic Patient. Southern Medical Journal: November 2008 - Volume 101 - Issue 11 - pp. 1173-1176.
Hiromitsu K et al
. Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in Japan. Hepatology Research 2010; 40: 1-7.
Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120:1009-1022
H J Flink et al
. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon α-2b therapy. Gut 2005;54:1604-1609.
Amarapurkar DN. Flares on and off therapy during chronic HBV infection: Pathogenesis, significance and management. Hep B Annual 2008;5:12-22.
The EASL Jury / Journal of Hepatology 39 (2003) S3-S25.
National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis B. Ann Intern Med. 2009;150:104-110.
The new EASL guidelines for the management of chronic hepatitis B infection adapted for Swiss physicians. S W I S S M E D W K LY 2 010 ; 1 4 0 ( 11 - 12 ): 154-159.
Prof. R K Dhiman
Department of Hepatology, PGIMER, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]