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Advancing Patient Care: Integrating New Data, part 3
 
 
  The American Journal of Gastroenterology
Volume 101 Page S32 - January 2006
 
Teresa L. Wright, M.D.1, Canan Avunduk, M.D., Ph.D.2, Jules L. Dienstag, M.D.3, James W. Freston, M.D., Ph.D.4, Ira M. Jacobson, M.D.5, H. Juergen Nord, M.D., F.A.C.G., F.A.C.P.6, andMorris Sherman, M.B., B.Ch., Ph.D., F.R.C.P.(C)7 1University of California, San Francisco, California; 2Tufts University Medical School, Boston, Massachusetts; 3Harvard Medical School, Boston, Massachusetts; 4University of Connecticut Health Center, Farmington, Connecticut; 5Weill Medical College of Cornell University, New York, New York; 6University of South Florida College of Medicine, Tampa, Florida; and 7University of Toronto and University Health Network, Toronto, Ontario, Canada
 
Physicians involved in the management of patients with chronic hepatitis B infection are frequently faced with complex clinical issues concerning the diagnosis, investigation, and treatment of patients. Guidelines exist within the literature that help with decision making; however, in practice individual nuances are often encountered necessitating decisions that go beyond the current guidelines. Following presentation of the available data, a panel of expert hepatologists and gastroenterologists sought to identify and solve challenges that are faced by clinicians in the daily management of patients with chronic hepatitis B infection. The following summary provides an overview of the outcome of these discussions. Because of the complexities of clinical management, the recommendations reflect the opinion of the majority; however, many recommendations were not unanimous. Furthermore, the recommendations that follow are limited to adult patients; the treatment of children was not discussed. A number of issues were identified, and statements concerning possible management strategies that could be applied were developed.
 
Note from Jules Levin: an important part of the discussion in this article revolves around when to commence HBV therapy, at what HBV DNA (viral load) level. Here is a link to recent research finding that the risk for liver cancer is increased with increasing HBV DNA, and that risk is associated with HBV DNA levels >10,000 c/ml and perhaps with lower levels. You may want to consider these study data in decision making regarding when to begin HBV therapy:
 
HBV DNA (viral load) Predicts Risk for Liver Cancer - (01/04/06)
 
INTRODUCTION
Hepatitis B infection affects a significant proportion of the global population, with an estimated 350 million carriers worldwide (1). Within the United States alone, 1.25 million individuals are infected with the hepatitis B virus, the highest prevalence occurring in Western Alaska (2). Chronic hepatitis B infection causes significant morbidity and mortality and presents clinicians with a number of management challenges.
 
Following the presentation of the data concerning epidemiology, screening, diagnosis, investigation, and management, a panel of expert hepatologists and gastroenterologists sought to apply this information to clinical situations faced by physicians who manage patients with chronic hepatitis B infection. Gaps in the available data were identified during the discussions, and consequently, the following statements are based on a combination of available data, clinical experience, and expert opinion. Due to the complexities of management, unanimity of all panel members was rarely achieved but the following summary reflects the majority opinion.
 
HBeAg-Positive Patients
Chronic hepatitis B infection (Fig. 1) is associated with an increased risk of cirrhosis, end-stage liver disease, and the development of hepatocellular carcinoma (3). The objective of therapy is to lessen the risk of complications of chronic infection by effectively suppressing viral replication and in turn reducing liver inflammation and fibrosis (4).
 
When to Commence Therapy
The point at which to commence therapy in HBeAg-positive patients is controversial. When considering individual patients, clinicians wish to reduce the risk of long-term morbidity while basing their decisions on available evidence. Patients with evidence of fibrosis greater than stage 1 on biopsy would be treated by the majority of the panel, particularly individuals with HBV DNA levels ≥105 copies/mL, with the aim of reducing the risk of progression of fibrosis. In those with none or minimal fibrosis on biopsy, the decision to treat is dependent on the level of viral replication and evidence of inflammation. Patients with serum HBV DNA levels ≥105 copies/mL or moderate or severe inflammation would be considered candidates for treatment even in the absence of fibrosis. Regular monitoring should be initiated in individuals with HBV DNA levels <105 copies/mL and no, or minimal inflammation on biopsy to enable assessment of changes in HBV DNA and/or ALT that might lead to repeat liver biopsy and initiation of therapy.
 
Alanine aminotransferase (ALT) is monitored routinely in patients with chronic hepatitis B; however, ALT is primarily an indication of the degree of hepatic inflammation not the stage of fibrosis. Many panel members would consider therapy in patients with near-normal ALT levels if there is evidence of hepatic injury (particularly fibrosis) on biopsy, recognizing, however, that the established agents are less effective in achieving HBeAg seroconversion in this group.
 
Patients who are not actively treated should be monitored closely to assess the degree of disease and the need for treatment on a regular basis. The panel agreed that, if evidence emerges that patients with low HBV DNA levels and mild degrees of inflammation on biopsy are at risk for development of cirrhosis, end-stage liver disease, and hepatocellular carcinoma, treatment of such patients should be considered. Treatment would be highly recommended if therapy is demonstrated to reduce these life-threatening complications of HBV disease. Long-term trials (of at least 5-yr duration), however, would be necessary to demonstrate such benefits, and prospects for the ultimate availability of such data in the near future are limited. A recent study by Liaw and colleagues has provided data indicating that intervention with a nucleoside analog (lamivudine) reduces the incidence of complications in patients with compensated cirrhosis (5). Theoretically, treatment of disease at an earlier stage would also reduce the risk of complications of long-standing infection, although treatment of patients with mild disease may place these individuals at risk for the development of resistance, long before clinical benefits could be demonstrated.
 
Treatment Goals and When to Stop Therapy
 
Well-defined treatment objectives are required to assess the response to therapy in all patients. In HBeAg-positive patients viral suppression is one of the primary objectives of treatment. Seroconversion from HBeAg-positivity to anti-HBe-positivity is an important co-primary endpoint and has been the traditional endpoint used to define when antiviral therapy can be stopped with a good likelihood of durable response. The degree of viral suppression required is debated widely. There exists a small body of evidence that indicates that a correlation exists between the depth of viral suppression and disease outcome. Lower levels of HBV DNA are associated with higher rates of drug-induced HBeAg seroconversion and better histological outcomes (6, 7). Within the published literature, preliminary data indicate that a serum level of HBV DNA below 104 copies/mL is usually required to achieve a drug-induced seroconversion to anti-HBe, although seroconversion can occur at higher levels of HBV DNA, and conversely, not all patients suppressed to this degree will achieve seroconversion (8). The panel reached a consensus, concluding that the goals of therapy should be suppression of HBV DNA to low or undetectable levels (by PCR) and HBeAg seroconversion.
 
In interferon-treated patients, the standard is to treat for 16 wk in patients with HBeAg-positive disease (9). Following discontinuation of therapy, the rate of HBeAg seroconversion often increases with duration of follow-up. Treatment duration with peginterferon may be up to a year. In patients treated with nucleos(t)ide analogs, the duration of treatment attracted more controversy and discussion. Patients achieving low or undetectable serum HBV DNA levels by PCR, and HBeAg seroconversion to anti-HBe should continue nucleos(t)ide analogs for 6 to 12 months following the appearance of anti-HBe to increase the likelihood of a sustained response. At the end of this period, patients who remain anti-HBe-positive with low or undetectable serum HBV DNA levels are candidates for discontinuing therapy; however, regular monitoring should continue to identify any evidence of reactivation, anticipated in approximately 20% of such patients.
 
Therapy should be continued in patients with active replication who do not achieve HBeAg seroconversion. HBeAg seroconversion is a time-dependent event, with the rate increasing as a function of the duration of therapy (10). Two management options could be considered in patients achieving an incomplete viral response (e.g., HBV DNA >104 copies/mL, or persistence of HBeAg). Clinicians could consider continuing the current nucleos(t)ide agent (in the absence of drug resistance), or adding an agent, or switching to an alternative therapy. To date, however, evidence to support the latter strategy (adding or switching agents) is limited. With lamivudine and adefovir the rate of HBeAg seroconversion increases with the duration of therapy as long as resistance does not develop. With the introduction of novel, more potent nucleos(t)ide analogs, the option to switch between agents may become increasingly viable. Adding or switching therapy may be supported by future studies demonstrating that these interventions lead to an increase in viral suppression, reduced resistance, and/or increase the likelihood of HBeAg seroconversion.
 
HBeAg-Negative Disease
 
In HBeAg-negative disease (Fig. 2), which occurs most commonly in genotypes B or D, a mutation in the precore or core promoter region reduces or negates the expression of HBeAg (11). Therefore, despite the presence of anti-HBe, viral replication can continue with detectable HBV DNA, elevated serum ALT, and liver disease progression. HBeAg-negative variants have been demonstrated in both acute and chronic HBV infections. The ratio of HBeAg-negative variants to wild-type virus often fluctuates during the course of the disease. Furthermore, this form of chronic hepatitis B may be associated with a fluctuating course characterized by flares and periods of inactivity (12). Patients with HBeAg-negative disease are typically older than those who are HBeAg-positive, suggesting that they may have been infected longer. This is consistent with the observation that HBeAg-negative disease is often associated with severe liver damage, including cirrhosis and end-stage liver disease. Patients with HBeAg-negative disease have lower levels of HBV DNA at baseline than do patients with HBeAg-positive disease, which likely explains why a greater proportion of HBeAg-negative patients become HBV DNA-negative by sensitive assays on therapy. However, relapse following discontinuation of treatment is common, and the need for indefinite therapy is high.
 
When to Commence Therapy
 
The point at which to commence therapy in HBeAg-negative individuals is debated widely. Patients with HBeAg-negative chronic hepatitis B normally have levels of serum DNA that are 10-fold lower than those found in HBeAg-positive patients, with fluctuations in ALT levels, both from normal to abnormal levels and within the normal range (12, 13). Infrequent monitoring can mislead the clinician into believing that the inflammatory processes are quiescent; however, in clinical experience, patients with HBeAg-negative chronic hepatitis often demonstrate more advanced liver disease at the time of diagnosis than that seen in patients with HBeAg-positive disease. Since some persons who enter the inactive hepatitis B phase after HBeAg seroconversion (anti-HBe-positive, HBV DNA <104 copies/mL and normal ALT) may develop HBeAg-negative chronic hepatitis B, all HBV-infected persons need regular follow-up with aminotransferase levels every 3 to 6 months. In individuals who demonstrate low HBV DNA levels and normal ALT for a number of years following seroconversion and who remain anti-HBe-positive, the frequency of monitoring may be decreased.
 
All patients with HBeAg-negative disease with HBV DNA levels >104 copies/mL and ALT levels above the upper limit of normal should be considered candidates for therapy, if liver biopsy shows moderate or severe inflammation or greater than stage 1 fibrosis. The suggested threshold HBV DNA level for HBeAg-negative patients is a log lower than that for HBeAg-positive individuals. In those in whom treatment is deferred (HBV DNA >104 copies/mL, mild inflammation, and minimal fibrosis on biopsy) monitoring of serum HBV DNA and ALT should be performed every 3 to 6 months to assess the pattern of disease activity. In addition, liver biopsy should perhaps be repeated at intervals to determine whether histological disease progression has occurred. Individuals who demonstrate progression of liver disease should be considered candidates for therapy.
 
Regular monitoring at 3- to 6-month intervals should be commenced in patients with serum HBV DNA levels ≦104 copies/mL. If HBV DNA levels rise to >104 copies/mL and ALT is above the upper limit of normal, biopsy should be considered to assess the level of histological disease and the need for therapeutic intervention.
 
Treatment Goals and When to Stop Therapy
 
In HBeAg-negative disease, the goal of therapy is to achieve maximal viral suppression (HBV DNA undetectable by PCR assay) and normalization of ALT. The aim of HBeAg seroconversion is not relevant to this population and, consequently, no clearly defined endpoint for stopping treatment exists. Patients treated for 48 wk in whom therapy is stopped have a high rate of relapse with oral agents such as adefovir and thus patients and providers should be committed to a long course of therapy (14). If HBsAg loss or seroconversion to anti-HBs is achieved (an endpoint that is attained in very few patients) therapy may be discontinued. Individuals who do not achieve HBsAg loss or seroconversion to anti-HBs and have stage 3 or 4 fibrosis on biopsy should continue therapy indefinitely. In those with lesser degrees of fibrosis, and persistent viral suppression after more than 1 yr of therapy, discontinuation of therapy may be considered; treatment duration in this group is very poorly defined and if treatment is stopped, these patients should be closely monitored for evidence of biochemical or virological relapse. Long-term viral suppression (HBV DNA levels below 1,000 copies/mL) is achievable in the majority (79%) of HBeAg-negative patients treated for prolonged duration with an agent such as adefovir that has a low likelihood of developing resistance (14).
 
A limited body of evidence exists indicating that a finite period of treatment may result in a clinically acceptable off-treatment response (15, 16). Future studies may characterize the predictors of response in HBeAg-negative hepatitis and enable the clinician to identify suitable candidates for a predetermined period of treatment. The duration of therapy will likely be longer than required for HBeAg-positive patients.
 
The need for long-term therapy in this group requires an agent that is safe, well tolerated, and with a low or negligible rate of emergent resistance. Current guidelines state that lamivudine is probably not recommended as first-line therapy, because of resistance associated with long-term administration (9). Long-term data are available for adefovir demonstrating its efficacy in patients with HBeAg-negative disease (14), and entecavir is also expected to be an effective agent for long-term therapy in this group of patients (17). Recent data show that a 1-yr course of peginterferon alfa-2a produces a 17% chance of a maintained response (HBV DNA <400 copies/mL) 48 wk after the end of therapy (18).
 
FACTORS INFLUENCING MANAGEMENT DECISION
The Role of Liver Biopsy

Liver biopsies are frequently used as a management tool in patients with chronic liver disease and often provide important information; however, liver biopsies are associated with morbidity and occasionally, mortality. Minor complications include pain and occasional transient hypotension, while more serious complications of pneumothorax, hemothorax, hemobilia, and cardiac arrhythmias have been reported, though rarely (19). In the published literature, the mortality rate associated with liver biopsy ranges from 0% to 0.33% (19). Liver biopsy tends to be recommended if the histological results will influence subsequent management decisions. A list of examples is provided below; however, the list is not exhaustive. The potential benefits of the histological results obtained from a biopsy should be assessed in individual patients prior to undertaking the investigation.
 
1. In HBeAg-positive adult patients liver biopsy can be utilized to assess the level of inflammation and fibrosis, to provide an indication of the need for therapeutic intervention. Treatment should be considered in all patients with greater than stage 1 fibrosis on biopsy, and also in those with HBV DNA ≥105 copies/mL or moderate or severe inflammation.
 
2. In HBeAg-negative chronic hepatitis B, since therapy may be needed for an indefinite period of time, an advantage of liver biopsy is to identify those with mild disease in whom therapy may not be immediately necessary. Liver biopsy is recommended in adult patients with HBeAg-negative disease, HBV DNA level >104 copies/mL, and ALT above the upper limit of normal. Treatment should be considered if the biopsy shows moderate or severe liver inflammation or greater than stage 1 fibrosis.
 
3. Some members of the panel recommended following the AASLD Practice Guidelines regarding liver biopsy, which recommend liver biopsy in all persons with HBeAg-negative disease before initiation of therapy (9).
 
4. To assess the histological response to therapy in adult patients who have a submaximal response to a nucleos(t)ide analog without the development of resistance.
 
5. Adolescents and young adult patients with normal serum ALT levels should be monitored closely before a decision to perform liver biopsy is taken. Although the above list accentuates the group in which biopsy is felt to be most important in determining management decisions, some panelists favor biopsy in a broader spectrum of chronic HBsAg carriers with active viremia, such as those with HBeAg and ALT at least twice the upper limit of normal, regardless of level of HBV DNA.
 
Decision to Treat
A number of factors were discussed to determine whether they would influence a physician's decision to treat an individual with chronic hepatitis B infection. Serum HBV DNA level and ALT level were identified as important factors influencing the decision because they provide an indication of viral activity and the level of hepatic inflammation. Serum ALT measurements indicate the degree of hepatic inflammation; however, they do not reflect the extent of fibrosis (20). In the majority of individuals ALT levels provide a good reflection of current inflammatory activity, though some patients with ALT within the upper normal range may demonstrate significant histological disease on liver biopsy if HBV DNA levels are elevated (20). The results of a liver biopsy detailing the amount of inflammation and degree of fibrosis would be an important factor in the decision to undertake or continue treatment. In addition, a proportion of persons with elevated ALT levels can have other causes of aminotransferase abnormalities such as alcohol use, nonalcoholic liver disease (NAFLD), hepatitis C or D, or medication use that can either be the cause of the elevation or contribute, along with HBV, to the liver disease that is present. Preexisting illnesses, including infection with HIV or hepatitis C, would also influence the decision to commence therapy.
 
Viral genotype is of increasing interest to physicians involved in the management of patients with chronic hepatitis B. Studies indicating that genotype may influence the disease outcome and response to therapy are appearing in the literature; to date, however, the evidence is inconclusive and data that do exist suggest that viral genotype is more likely to influence response to interferon than response to antiviral agents (21-23). Currently, the evidence concerning the role of genotype on the natural history of chronic hepatitis B is insufficient to influence management strategies; however, as information evolves viral genotype may become an important consideration.
 
Choice of Therapy
At present five agents are licensed for the treatment of chronic hepatitis B infection (interferon alfa-2b, lamivudine, adefovir, entecavir, and peginterferon alfa-2a); moreover, new drugs are in different stages of clinical development. As the choice of therapies expands, the decisions concerning which agent to use may be influenced by a number of factors.
 
Gender and ethnicity should not influence the choice of therapy. In patients with high serum ALT levels and low serum HBV DNA levels, a short course of interferon may result in long-term benefit in those who are HBeAg-positive as well as in those who are HBeAg-negative; however, the HBeAg-positive patient with high ALT also responds to nucleos(t)ides. With oral antiviral agents, the likelihood of HBeAg seroconversion increases with higher baseline ALT levels being highest in those with ALT five times the upper limit of normal.
 
Disease severity will influence the choice of agent, particularly in patients with advanced stage liver disease. In this subpopulation, effective viral suppression is vital. Interferon or peginterferon in patients with decompensated cirrhosis should not be used since administration of interferon has been associated with a number of serious complications, including bacterial infections, bleeding varices, and worsening ascites (24-26). In contrast, the nucleos(t)ide analogs have been associated with improvement in markers of hepatic synthetic function with reduced complications of liver disease. The beneficial effect of the agent, however, is reduced if resistance develops (5, 27-30)
 
In patients with HBeAg-positive disease peginterferon has been suggested as an option to offer the patient a finite period of therapy (31). The predictors of response to this agent, however, have yet to be fully defined although peginterferon is superior to lamivudine in producing viral suppression and HBeAg loss following a 1-yr course of therapy (32). The relative efficacy of peginterferon compared to that of antiviral agents more potent than lamivudine remains to be determined. Treatment with conventional interferon or pegylated interferon occasionally results in loss of HBsAg at a higher rate than has been observed with oral agents. In a recent study by Lau and colleagues, treatment with peginterferon alfa-2a alone, or in combination with lamivudine, for 48 wk in HBeAg-positive patients resulted in HBsAg seroconversion in 16 patients (3%) after 24 wk of follow-up (32). Of note, only two therapies, peginterferon and entecavir, have achieved FDA approval through comparison with an active treatment arm (for both drugs, the comparison was with lamivudine) (17, 32, 33). Given that both peginterferon and entecavir were superior in efficacy to lamivudine for the treatment of HBeAg-positive and HBeAg-negative patients, lamivudine monotherapy should probably no longer be considered as a first-line agent for treatment for HBV disease (17, 32-34). Both entecavir and adefovir have activity in treatment of patients refractory to lamivudine and/or resistant to lamivudine, and both agents should be considered for this indication (35, 36).
 
COMBINATION THERAPY
Hepatitis B infection is a viral disease, and the aim of therapy should be to achieve maximal viral suppression with limited emergent resistance during long-term therapy. A number of studies have addressed the efficacy of combination therapy, both with interferon (conventional and pegylated) with a nucleoside analog and administration of two nucleos(t)ide analogs simultaneously (6, 32, 34, 35, 37, 38). To date, however, the results have been disappointing. All the recent studies of combination therapy, whether between two oral agents or peginterferon plus an oral agent, have failed to show additive efficacy, measured by viral suppression. However, combination therapy with peginterferon plus lamivudine or adefovir plus lamivudine reduces the development of resistance compared with monotherapy. Although the panel concluded that combination therapy might offer benefit in the future, they emphasized that data are at present limited and that additive viral suppression of two drugs over a single agent has not been shown.
 
Given the current therapeutic options available, the use of combination therapy with two nucleos(t)ide analogs may be beneficial in patients with advanced decompensated cirrhosis, in whom the development of resistance could lead to further decompensation and even death. Combination therapy may reduce the risk of resistance through potent viral suppression and reciprocal activity of different agents against resistant variants (e.g., lamivudine against adefovir-resistant variants and adefovir against lamivudine-resistant variants); however, the panel was not unanimous in recommending combination therapy in patients with advanced disease.
 
With the availability of novel agents the potential remains that new, more efficacious combinations will be identified in future studies.
 
NOVEL THERAPIES
As novel agents are developed for the treatment of chronic hepatitis B infection, the ideal agent should be potent, safe, well tolerated, and associated with a low level of resistance. Studies published and presented recently indicate that a number of new therapies may meet these needs (tenofovir, telbivudine) (6, 39, 40).
 
FUTURE DIRECTIONS FOR RESEARCH
During the course of the discussion, a number of areas requiring additional research were identified, as outlined below. The list is not exhaustive and represents the opinions of the panel members.
 
Determination of the appropriate level of HBV DNA above which patients are at risk for complications of liver disease and in whom therapy should be considered. The current society guidelines (AASLD, EASL, and APASL) recommend therapy in patients with a serum HBV DNA level >105 copies/mL (9, 41, 42). The AASLD guidelines also consider therapy in patients with moderate or severe inflammation on biopsy (9). The HBV DNA threshold of 105 copies/mL was agreed upon by an NIH consensus meeting, because, at the time, 105 copies/mL was the lower limit of detection of HBV DNA by the then-available testing methods (43). With the development of PCR-based assays, however, the level of DNA detectable is now as low as 400 copies/mL. Level of HBV DNA may correlate with risk of complications of liver disease, including the development of cirrhosis or hepatocellular carcinoma (44, 45). Evidence suggests that inflammation and fibrosis can occur in some patients with HBV DNA levels between 104 and 105 copies/mL, particularly in those with HBeAg-negative chronic hepatitis in which the level of DNA is generally lower (12). The panel concluded that a study should be performed to investigate the most appropriate level of HBV DNA above which therapy should be commenced to guide future management strategies.
 
Development of hepatic injury in patients with normal ALT levels. An ALT level of two times the upper limit of normal is often presented as the threshold above which therapy should be considered; however, ALT levels are indicators of inflammation, not the degree of hepatic fibrosis. Whereas patients with normal ALT levels tend, generally, to have minimal-to-mild histologic necroinflammatory activity, substantial injury can be demonstrated occasionally in patients with normal or near-normal ALT levels (20). The panel concluded that studies addressing the histologic findings in patients with persistently normal ALT, and the impact of treatment in patients with normal ALT versus no treatment would be helpful.
 
Impact of long-term therapy on the natural history of the disease. Evidence is becoming available concerning the impact of long-term therapy on outcomes. The recently published study by Liaw and colleagues has indicated that nucleoside therapy in patients with cirrhosis associated with chronic hepatitis B infection can significantly reduce the risk of clinical complications and death from liver disease (5). The data are still limited, however, and restricted to a subgroup of patients with advanced disease. To date, no studies have addressed the impact of long-term therapy in patients with mild disease. Early, effective, and sustained viral suppression might reduce the necroinflammatory response to the virus and, consequently, could reduce the risk of development of cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Long-term therapy, however, would introduce an increased risk of resistance and raise cost-benefit issues. While the panel concluded that a long-term randomized prospective study to determine the benefit of treating mild disease earlier would be difficult to conduct, in part because of considerations in giving patients placebo for prolonged periods, data from case-control or retrospective studies would be potentially useful for developing future recommendations.
 
Predictors of response to therapy in HBeAg-negative disease. Limited data are available supporting the use of finite periods of therapy in patients with HBeAg-negative disease. At present, indefinite therapy is likely necessary, because relapse after treatment cessation is high, and the rate of sustained response off-treatment is low. Establishing the predictors of response to therapy may enable certain patients to be identified who would benefit from finite periods of treatment.
 
CONCLUSIONS
Chronic hepatitis B infection remains a significant cause of morbidity within the United States. Clinicians regularly face challenges in the management of patients with this disease who fall outside the established guidelines for treatment. Further investigations are required to establish the data needed for the practice guidelines to evolve. In the absence of data, clinical expertise and judgment may influence management strategies. The development of novel agents offers exciting opportunities for the future.
 
 
 
 
 
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