Original article Chronic HBV infection outside treatment guidelines: is treatment needed?

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1 Antiviral Therapy 2013; 18: (doi: /IMP2325) Original article Chronic HBV infection outside treatment guidelines: is treatment needed? Alison A Evans 1,2 *, W Thomas London 2,3, Robert G Gish 4, Chari Cohen 1,2, Tim M Block 2,5 1 School of Public Health, Drexel University, Philadelphia, PA, USA 2 Hepatitis B Foundation, Doylestown, PA, USA 3 Fox Chase Cancer Center, Philadelphia, PA, USA 4 Division of Gastroenterology and Hepatology, University of California at San Diego, San Diego, CA, USA 5 Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA *Corresponding author Alison.Evans@drexel.edu Background: There are now seven antivirals approved for use in the management of chronic HBV infection in the US. Current professional guidelines recommend the use of antiviral treatment in only a distinct subset of the total HBV chronically infected population, estimated to be more than 350 million worldwide. The subset of chronically HBV-infected individuals for whom the antivirals have been demonstrated to produce desirable outcomes are those with abnormal liver enzymes and a viral load above a defined threshold, presumably identifying those at highest risk for development of cirrhosis and hepatocellular carcinoma. However, some individuals whose clinical features place them outside these guidelines, for whom treatment is not recommended, are also at significant risk for liver disease complications and liver-related death. Methods: In this report, we produce new estimates of the age-specific risks of liver-related death in people outside the current treatment guidelines using published data from multiple populations. Results: Our results indicate that the age-specific 10-year risks of liver-related mortality in these individuals range from 0.3 4% in the West to % in Asia. Conclusions: The magnitude of these risks and the estimated size of the global population that falls outside of current treatment guidelines have led us to consider whether medical interventions are also needed for these individuals, either with currently approved therapeutics or yet-to-be-discovered medications targeting new mechanisms of antiviral effect. Potential targets for development of new medications are discussed. Introduction People who are chronically infected with HBV are, compared with the general population, at considerably greater risk of morbidity and mortality due to liver disease as well as all-cause mortality [1,2]. However, the population with chronic HBV infection, that is, individuals who remain positive for the viral envelope protein particles (hepatitis B surface antigen [HBsAg]) in their blood for a period of 6 months or more, is clinically and virologically heterogeneous. The course of chronic HBV infection has been divided into several stages or phases that vary as a function of viraemia, other viral markers, liver enzymes and liver function tests, and histopathology. These phases include immune tolerant, inactive/asymptomatic hepatitis, and hepatitis B e antigen (HBeAg)-positive or -negative immune active/clearance hepatitis [3 5]. Globally, an estimated 25 30% of patients with chronic HBV infection will die of liver-related complications, including cirrhosis and hepatocellular carcinoma (HCC) [6]. The risk of disease progression and death from liver-related causes varies between clinical phases [3]. In large population studies, it is not always possible to clearly assign individuals to these phases because of the lack of key clinical or laboratory parameters and/or longitudinal measurements. It is from large population studies, however, that much of our understanding of the long-term consequences of chronic HBV infection comes [7 10]. There are now seven therapeutics that have been approved by governmental regulatory agencies in the US and in other countries for the management of chronic hepatitis B infection [11]. The drugs fall into 2013 International Medical Press (print) (online) 229

2 AA Evans et al. two categories, the interferons and the viral polymerase inhibitors. The American Association for the Study of Liver Diseases (AASLD) and other leading professional organizations have published guidelines for the medical management of people with chronic hepatitis B infection, including the selection of those who should be treated with the currently approved medications [12 17]. Not all people chronically infected with HBV have been shown to benefit from the available treatments, and not all are at equal need for intervention [4,18]. The current guidelines identify the clinical categories of people in whom these existing medications have been shown to be beneficial, with benefit generally defined as reduction in viral load and improvement of liver function tests and/or liver histopathology. A panel of Asian American physicians has also published a detailed set of guidelines, with recommendations for treatment incorporating other factors, such as family history of HCC and both platelet count and serum albumin [19,20]. In general, medical intervention has not been recommended for all HBsAg-positive individuals but reserved for those with elevated circulating viral DNA levels, who may be HBeAg-positive or -negative, and who have biochemical or histopathological evidence of liver damage. Current evidence is consistent with the risk of developing HCC increasing with higher levels of circulating HBV viral DNA [9,21]. Moreover, reduction of the levels of circulating virus is the target of most of the approved medications and has been shown to lower HCC and liver failure risk [18,22,23]. Most studies generally agree that fewer than 50%, and possibly as few as 25%, of the total infected population would fall within the current treatment guidelines [24], depending on both the geographical area and the demographic characteristics of the populations. Complicating this is the fact that a large portion of the world s HBV-infected individuals are unaware that they are infected. In the US, approximately 70% (as many as 1.2 million of the million chronically infected individuals) are unaware of their infection status [24,25]. This proportion and total number is likely greater in areas of high HBV endemicity in Asia and sub-saharan Africa. Although the subset of people for whom most of the professional guidelines recommend intervention are those at the greatest risk of morbidity and mortality from liver disease, we wondered about the extent of risk to people with chronic HBV infection whose clinical profiles place them outside these guidelines. There have been a number of reports suggesting that people who are HBsAg-positive with moderate levels of circulating viral DNA remain at significant risk of death from liver disease compared with the general population [21,26 29]. Using the guidelines for treatment of chronic HBV infection as reference, in this paper, we examine the currently available information about the relative life-shortening risks of people with hepatitis B who fall outside these guidelines and consider the possibilities and rationale for their treatment with the currently available drugs. Moreover, because the currently approved drugs for the management of chronic HBV infection either target the viral polymerase or are interferons, we discuss the possibility for the need of the development of new drugs that employ other mechanisms. Methods Sources of data for estimates We have estimated the risk of liver-related mortality and/ or HCC in individuals chronically infected with HBV by using published data from non-clinic-based populations worldwide. For Asian populations, we have relied on the HCC nomograms published from the REVEAL study [30] as well as our own data from Haimen City (China) showing the ratio of HCC to other chronic liver disease deaths in HBsAg-positive adults [2,21]. The estimates presented here are for a composite population of males and females, with indeterminate family history and no self-reported alcohol consumption. Individuals with alanine aminotransferase (ALT) 45 IU/ml, whether HBeAg-positive or -negative, were considered candidates for treatment. Those with ALT<45 IU/ml were considered to be outside treatment guidelines because this was the cutoff in use at the time that most of these studies were conducted. To estimate risk for Western individuals outside the treatment guidelines, we used published rates from follow-up of infected individuals in healthy groups (blood donors or clinic patients) [10,31 33]. In these studies, information on transaminase levels or viral loads was not available, necessitating the assumption that the healthier individuals, identified as infected in these settings, were comparable to those outside of current guidelines. To estimate risk for Western patients within treatment guidelines, the data with mortality end points available in the literature was largely from clinical studies, mostly the untreated control groups from clinical trials [34 38]. Because of selection criteria in clinical trials, these individuals may experience more serious outcomes than treatment-eligible individuals in the general population. Indeed, we found that age-specific, liver-related mortality exceeded that seen in the Asian population studies for patients with similar characteristics. We, therefore, adjusted these rates downward, using a baseline at age 30 of 0.7% 10-year risk of liverrelated death, derived from the review of Fattovich et al. [39]. The slope of the increase in risk for 10-year age increases was estimated from the clinical populations and applied to this lower baseline International Medical Press

3 HBV outside treatment guidelines Table 1. Guidelines for consideration of treatment in the management of chronic hepatitis B from major professional organizations a HBeAg-positive c HBeAg-negative c Recommending group b HBV DNA IU/ml (genomes/ml) d ALT ( ULN) e HBV DNA IU/ml (genomes/ml) d ALT ( ULN) e References AASLD >20,000 (10 5 ) >2 >2,000 (10 4 ) >1 [13] US Panel >2,000 (10 4 ) >1 >2,000 (10 4 ) >1 [14,15] EASL >2,000 (10 4 ) >1 >2,000 (10 4 ) >1 [16] Asia-Pacific >20,000 (10 5 ) >2 >2,000 (10 4 ) >2 [17] a Levels of circulating viral DNA and alanine aminotransferase (ALT) at which the indicated organization, as described in the citation, recommend medical intervention with interferon or the orally available HBV polymerase inhibitors. b Organization or panel. c Serum hepatitis B e antigen (HBeAg) status. d Circulating levels of HBV DNA, as international units or viral copies/ml. e Circulating levels of ALT, expressed as an amount greater than the upper limit of normal (ULN). AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver. Because most non-clinical studies, particularly outside of the clinical setting and in Western populations, have not reported viral load status for their study patients, we could not take into account viral load variations or other viral factors, such as genotype or mutations in our risk estimates. We have also not accounted for the effect of comorbidities, such as HCV or HDV infection or excessive alcohol consumption, which may be important factors in increasing risk in some populations. Results Comparison of current treatment guidelines and numbers of individuals included Several professional organizations and leading publications have issued guidelines for the management of people with chronic hepatitis B infection. These include AASLD [13], the group referred to as the US Panel [14,15], the European Association for the Study of the Liver (EASL) [16] and the Asia Pacific Consensus Statement on the Management of Chronic HBV [17]. The guidelines all identify similar subsets of individuals with chronic hepatitis B infection, as summarized in Table 1. Generally, this includes those with a circulating viral load >10 4 viral copies/ml (>2,000 IU/ ml) and levels of ALT at least the upper limit of normal. It should be noted that the ranges of ALT values considered to be normal have been adjusted downward in recent years, with current recommendations now as low as 30 IU/ml for men and 19 IU/ml for women [40,41]. Individuals considered to be candidates for antiviral therapies are those at greatest risk for morbidity and mortality associated with HBV and also those in whom the antiviral therapies have been demonstrated to be effective in achieving key clinical end points, that is, reduction of viral load, clearance of HBeAg and reduction of biochemical or histological evidence of liver inflammation. To address the question of risk in those outside the treatment guidelines, we first put into context the size of this subgroup. Cohen et al. [24] recently considered the problem of awareness of infection and access to care for HBV-infected individuals in the US. Because most infected individuals (in the US and worldwide) are unaware of their infection status and many who are aware of their status do not access appropriate medical care, it has proved somewhat difficult to precisely estimate this number. For the US, Cohen et al. [24] estimated that 25 50% of the million chronically infected individuals fall within current treatment guidelines, whether or not they are aware of their infection status. That leaves approximately 700, million chronically infected individuals outside the treatment guidelines. In Asian populations, as much as 60% of chronically infected adults fall outside treatment guidelines [9,20,21], but because the prevalence of chronic HBV infection is high, the numbers of individuals outside the treatment guidelines in Asia may be substantially higher than in the West. Individuals with low active or inactive infection, as reflected by lower or undetectable viral load, and low transaminase levels, are excluded from treatment guidelines. Their risk of liver-related mortality or HCC is lower than those with more active disease, and they have already achieved the usual indicators of therapeutic success with current antivirals, that is, viral load and transaminase reduction. It is certainly true that many of these individuals have a benign course of disease and may spontaneously clear HBeAg or HBsAg over time. Those who do experience adverse outcomes may at some point enter the clinical categories for which current treatments have been deemed effective, opening a window of opportunity for treatment at that time. Nevertheless, we think it is important to consider the magnitude of risk in these populations. Risks of HCC or liver-related death in HBV-infected individuals not considered candidates for treatment Estimates Table 2 displays estimated range of 10-year cumulative liver-related death and/or HCC rates for HBV-infected populations within and outside treatment guidelines. Point estimates have been provided in a review by Fattovich et al. [39] at 0.1% for inactive carriers Antiviral Therapy

4 AA Evans et al. in the West and 1% for those in Asia. These estimates do not take into account the increasing risk with age, which is well-documented both in Western and Asian populations. Extrapolating from individual studies of Table 2. Risk of liver-related death over a 10-year period Estimated cumulative Population 10-year mortality, % References HBV-infected, within treatment guidelines Asian [2,21,30,39] Age 30 years Age 40 years 1 15 Age 50 years 3 40 Age 60 years 9 80 Western [34 39] Age 30 years 1 13 Age 40 years 8 23 Age 50 years Age 60 years HBV-infected, outside treatment guidelines Asian [2,21,30,39] Age 30 years Age 40 years Age 50 years 2 9 Age 60 years 5 20 Western [10,31 33,39] Age 30 years Age 40 years 1.5 Age 50 years 2.5 Age 60 years 4 Figure 1. Estimated cumulative 10-year risk of liver-related death or HCC by age among HBsAg-positive individuals Cumulative 10-year risk, % AT WT AnT WnT Age, years AT, Asian, within treatment guidelines; AnT, Asian, outside treatment guidelines; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; WT, Western, within treatment guidelines; WnT, Western, outside treatment guidelines. HBsAg-positive individuals in healthy populations, we arrived at the age-specific risks shown in Table 2, ranging from 0.3% to 4% in the West and 0.3% to 20% in Asia. In Figure 1, the age-specific curves are estimated for Asian and Western populations, within and outside treatment guidelines. These reinforce the importance of the acceleration of risk of liver disease complications with increasing age. The broad risk range also highlights that more study is needed because it is difficult to be precise about the degree of risk individuals in these clinical categories actually have. Despite this, our overall risk estimates are consistent with estimates used by Eckman et al. [42] in a recent cost-effectiveness analysis of HBV screening and with clinical findings reported by Tong et al. [43]. In that clinic-based prospective study, of the 369 HBsAgpositive individuals followed for approximately 5 years, 30 died from HCC. Significantly, 14 of these individuals who died from HCC would not have been recommended for antiviral therapy over the course of the study because their virological and ALT values placed them outside the AASLD guidelines. Other non-viral factors have also been consistently shown in studies to be important determinants of risk gender, family history of HCC, fluctuations in HBeAg status that may, taken together, be as strong as viral load as a predictor of adverse outcomes [3,8,19]. Particularly worth emphasizing is the substantially higher HCC risk in males versus females, seen in all HBV-infected populations, which can be threefold or higher [8,9,19,30]. Using the REVEAL nomograms, in fact, we would calculate identical 5 10-year risks for a female within the treatment guidelines and an HBeAg-negative male outside treatment guidelines with low viral load (<2,000 IU/ml), if the male had the additional risk factors of a family history of HCC, alcohol use and persistently high normal ALT. Discussion For comparison purposes, the risk of death from all liver-related causes is estimated to be approximately 0.1% per decade in the US [44,45]. World Health Organization estimates of liver-related mortality (HBV, HCV, HCC and cirrhosis) for the Americas and Europe together are 0.2% per decade and 0.3% per decade for Western and Southeastern Asia together [46]. The major professional organizations recommend medical intervention for people with chronic HBV infection with evidence of active viral replication and elevations of ALT. These treatment guidelines are appropriate in that they focus on the individuals more likely to achieve the desired clinical end points (that is, reduction of viral load, clearance of HBeAg, biochemical and histological improvement of liver inflammation), who International Medical Press

5 HBV outside treatment guidelines are also individuals known to be at high risk of liverrelated death or serious liver disease. In this paper, we suggest that treatment or other prevention options for HBV-infected individuals outside of current treatment guidelines should be actively explored. We present new age-specific risk estimates for liver-related deaths in chronically infected individuals in this clinical category in Asian and Western populations. We believe that effective treatment for this group probably necessitates the development of new therapeutic agents whose activity is not primarily directed at reduction of viral load. Although it is clear that those within the treatment guidelines in any population are at high risk of liverrelated death in the long term, the risk to those outside the guidelines is not negligible, particularly as they age. Even the lowest-risk group of HBV-infected individuals considered in our calculations, Western individuals outside the treatment guidelines, have a risk of liver-related death that greatly exceeds that of the general population and reaches levels seen in individuals with non-alcoholic fatty liver disease by age 50 [47 49]. Tong et al. [20] have advocated the treatment of Asian Americans otherwise outside the professional societies treatment guidelines (that is, HBeAg-negative, viral load <2,000 IU/ml and normal ALT) if they have low platelet counts, low serum albumin or a first degree relative with HCC. There are limitations to our conclusions because of the scarcity and limited comparability of datasets, especially in non-clinic-based populations. Nevertheless, we provide evidence that there are people with chronic hepatitis B infection who have levels of viral replication and liver damage that would place them outside the treatment guidelines but are at risk of death from liver disease that is comparable to other chronic diseases for which treatments are recommended. For those with chronic inactive HBV infection, gender, geography and age are all important factors that influence a person s risk of death from liver disease. In the case of Asian HBV-infected individuals, who are consistently found to be at higher risk for liver mortality than European or North Americans regardless of disease stage, some of this difference is attributable to the higher prevalence of genotypes B and C in Asia as well as longer duration of infection due to acquisition in infancy or early childhood [3]. Other factors are likely involved as well, and studies in non-clinical populations often lack information on coinfections with HCV or HIV, alcohol consumption and other lifestyle factors. If subsets of those with inactive hepatitis and lowto-undetectable viral loads are to be considered for treatment to manage chronic hepatitis B, the question becomes how they should be treated. In a special case, inactive HBV carriers treated with immunosuppressive interventions for cancer and other conditions may see reactivation of HBV infection. Reports suggest the current polymerase inhibitors are effective in preventing reactivation of viral replication and liver inflammation in these individuals [50,51]. In addition, there are reports of the apparently beneficial use of polymerase inhibitors in patients with very low circulating viral loads following intervention for HCC [52,53]. In these cases, it is possible that HCC interventions (surgery and/or ablative techniques) may stimulate viral replication, making the appropriate target available for polymerase inhibitors. Outside of these special cases, how treatment with polymerase inhibitors might prevent progression in people with low-to-undetectable viral load is not clear but deserves consideration. Interferons have been shown to be ineffective in this population as well [54 56]. It is conceivable that polymerase inhibitors would have long-term benefits in individuals with very lowto-undetectable levels of viral DNA in their circulation because there may still be viral replication occurring at low levels in hepatocytes. Even a limited amount of viral replication with low levels of viraemia may be contributing to disease progression over long periods of time. Another possibility is that the low level of viraemia in some patients is the result of a post-replication step, and accumulation of replicated virions not entering free circulation contributes to disease. Both phenomena might be prevented by polymerase inhibition. There may be concerns, however, about the emergence of mutant viral strains under the selective pressure applied by polymerase inhibitors; therefore, other targets for therapy in this subpopulation should be considered as well. New approaches to immunomodulation, prevention or eradication of covalently closed circular DNA formation, interference with viral packaging and assembly or selective eradication of HBV-infected cells are avenues that may offer promise for all HBV-infected individuals, in addition to, or instead of, current therapies. It should be noted that although current antivirals have been shown to reduce the incidence of HCC in those within the treatment guidelines, reduction is still only in the range of approximately 50% [18,57], so there is a rationale for pursuing these new therapeutic strategies for those currently within treatment guidelines as well. We suggest that the time has come to consider the needs of the populations of HBV-infected individuals outside the treatment guidelines worldwide, both for use of existing therapies and for development of new ones. Although the risk in these groups is considerably lower than in those with more active disease and the estimated risks of liver-related death cover a broader range, it is clear that they are still at considerable risk for premature death due to HBV-related liver disease or HCC. We note that the broad range of risk of death from liver disease for individuals aged 40 and above who fall outside the Antiviral Therapy

6 AA Evans et al. treatment guidelines (0.7 9%) makes it all the more difficult to be confident about a decision not to intervene. This is a populous group, numbering approximately million people worldwide (25 50% of HBsAgpositive individuals), of whom as many as 1 2 million would be expected to die of liver disease in the next decade. In order to prevent these deaths, it is imperative that we have viable treatment options to offer for this population in the near future. Acknowledgements This study was funded in part by the Hepatitis B Foundation, the Commonwealth of Pennsylvania, and the National Cancer Institute of the United States (5R01CA and 5R01CA120206). Disclosure statement TMB has served as a consultant for Gilead Sciences, and Bristol Myers Squibb. RGG has served as a speaker, a consultant and an advisory board member for Gilead Sciences, Genentech/Roche and Bristol Myers Squibb, and has received research funding from Gilead Sciences, Genentech/Roche and Bristol Myers Squibb. These funds are directed to a research account at UCSD and are not personal income to RGG. CC owns 25 shares of Bristol Myers Squibb and 35 shares of Gilead Sciences. AAE and WTL declare no competing interests. References 1. Amin J, Law MG, Bartlett M, Kaldor JM, Dore GJ. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study. Lancet 2006; 368: Chen G, Lin W-Y, Shen FM, et al. Chronic HBV infection and mortality for non-liver causes: results from the Haimen City Cohort Study. Int J Epidemiol 2005; 34: McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009; 49:S45 S McMahon BJ. Selecting appropriate management strategies for chronic hepatitis B: who to treat. 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