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"Predicting survival in hepatitis B" Should Targeted HBV DNA Suppression Be the Goal of Therapy?
 
 
  COMMENTARY
 
Gut Nov 2005
 
"..... prolonged and maximal suppression of HBV DNA to levels below the detection limit of PCR based assays may be necessary to reduce the risk of complications......
 
...........In conclusion, prolonged low level viraemia causing insidious and continual liver damage, as reflected by relatively mild elevations in ALT levels, is the most likely pathway leading to the development of complications for Asian patients with CHB. Long term antiviral therapy aiming at maximal suppression of HBV even after HBeAg seroconversion may be required for Asian patients."

 
M Sherman
University of Toronto and University Health Network, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada
 
Alanine aminotransferase (ALT) level alone is not an appropriate indication for therapy in chronic hepatitis B infection, and other criteria in addition to ALT must be used to determine eligibility for therapy
 
Predictors of survival in chronic hepatitis B infection are surprisingly not well described. Various studies have identified different factors that were associated with adverse outcomes. For example, Niederau and colleagues,1 in a cohort of European patients, identified lack of clearance of hepatitis B e antigen (HBeAg) as a predictor of decreased survival. Others have identified older age, presence of cirrhosis, and the persistence of alanine aminotransferase (ALT) elevations as adverse prognostic signs in an antibody to hepatitis B e antigen (anti-HBe) positive cohort.2 In patients undergoing a flare of hepatitis B activity, whether spontaneous or chemotherapy induced, the presence of jaundice is an ominous sign.3 None of these adverse predictive factors are unexpected. Clearly, jaundice, cirrhosis, older age, and elevated ALT are obvious adverse predictive factors but until recently we have not had the tools to predict, years in advance, the outcome of chronic hepatitis B infection. This is important because we would prefer to offer treatment only to those who are likely to develop complications of the disease, and not to those whose disease will become inactive without long term sequelae. Recently, new predictors of outcome have been identified. At last years American Association for Study of Liver Disease (AASLD) meeting and the recent European Association for Study of the Liver (EASL) meeting, new data were presented that contribute to this debate. In addition, the article by Yuen and colleagues4 in this issue of Gut also forces us to re-examine some of our assumptions about hepatitis B prognosis and therefore treatment (see page 1610, see article below).
 
To some extent our current management algorithms have been directed by the pharmaceutical industry because management algorithms tended to follow the design of clinical trials used to license products. For example, the initial registration trials with lamivudine lasted one year.5,6 However, it has since become clear that for most patients one year of therapy with lamivudine (or any nucleoside analogue) provides inadequate seroconversion rates in HBeAg positive patients. It is also clear that most anti-HBe positive patients require extended, perhaps lifelong, therapy. Trials in HBeAg positive subjects chose HBeAg seroconversion as an end point because historically, seroconversion to anti-HBe positive was considered to be associated with inactivation of disease, with lower levels of viral replication and less inflammation.6 It now seems that e antigen seroconversion may be an inappropriate end point for many patients. At best interferon treatment only induces e antigen seroconversion in 3035% of patients.7 The durability of this seroconversion is poor.8 The proportion of "sero-reverters" is even higher after seroconversion induced by one year of lamivudine therapy.8,9 Thus although randomised controlled studies have shown an increased seroconversion rate compared with controls in the short term, it is not clear that treatment induces more patients to undergo HBeAg seroconversion over the long term than would be expected without treatment.
 
Is it possible that treatment merely advances seroconversion by some uncertain period of time in those who are destined to seroconvert spontaneously at some future point? Perhaps therapy induced seroconversion merely advances spontaneous seroconversion by some years. An argument in favour of this hypothesis is that whether patients are treated with interferon or nucleoside analogues, those who have the highest likelihood of HBeAg seroconversion, namely those who have high ALT and low hepatitis B virus (HBV) DNA concentrations, are also those who have the highest likelihood of spontaneous seroconversion. Furthermore, Yuen and colleagues10 have observed matched cohorts of patients treated or not treated with interferon over an extended follow up period and have shown that beyond five years of follow up the proportion of treated patients who underwent seroconversion was the same as in the untreated group (that is, interferon therapy did not increase the overall number of patients undergoing seroconversion). It did however advance seroconversion by about five years. Nor did interferon therapy affect outcome. A study in children reached the same conclusion.11 Thus although in some populations treatment induced seroconversion appears to improve prognosis in the short term, it is not certain that treatment increases the overall number of patients undergoing e antigen seroconversions over the long term or improves the prognosis over the longer term.
 
Given the uncertainty about appropriate treatment end points, it is perhaps not surprising that the indications chosen for starting therapy have also been unsatisfactory. As the overall objective of treatment is to decrease inflammation, and hopefully thereby prevent all of the other complications of chronic hepatitis B, it seems logical to use an elevated ALT, a marker of hepatic inflammation, as an indication to start treatment. All of the registration trials have used this indication. All of the guidelines issued by various continental hepatology societies (AASLD, EASL, Asian Pacific Association for Study of the Liver)1214 supported the use of this indication. However, using elevated ALT as an indication for therapy means that only a small minority of all hepatitis B carriers will ever be treated, far fewer than the 2025% of hepatitis B carriers who will die of complications of their liver disease. Using ALT as an indication for therapy will leave many patients who are destined to develop cirrhosis or hepatocellular carcinoma (HCC) untreated. The study by Yuen and colleagues4 in this issue of Gut, together with conclusions from a large scale prospective study in Taiwan,15 supports the conclusion that ALT alone is not an appropriate indication for therapy. In the Yuen study, patients who had an ALT concentration in the upper range of normal had an increased mortality from HCC compared with those in whom ALT levels were less than <0.5x ULN. Paradoxically, the risk of HCC in patients with ALT levels that were higher than 2x ULN was lower than in patients with lower ALT levels. Yuen et al explain this anomaly by assuming that higher levels of ALT represent flares similar to acute hepatitis, which resolve without leaving significant permanent injury. However, there may also be some selection bias influencing these results, in that patients with ALT >2x ULN that persisted over time might have undergone therapy and been excluded from this study. Others might have been in the process of seroconverting and going into remission. Yuen and colleagues4 also showed that the HBeAg status and ALT on follow up did not correlate with the incidence of complications. When they analysed HBV DNA they found, as did Chu and colleagues,16 that HBV DNA below 105 copies/ml did not protect against the development of complications.
 
The REVEAL study is one of three similar large scale, long term, prospective, cohort studies of hepatitis B carriers, all of which provide new evidence about identifying patients at risk of a poor outcome. The studies were performed in a cohort in Philadelphia,17 a cohort in Haimen City China,18,19 and in a cohort from several townships in Taiwan.15,2022 Each cohort included more than 30004000 subjects who were recruited and followed for more than 10 years. The end points in all three were similar: incidence of HCC, cirrhosis, and death from liver disease. All three studies came to similar conclusions. The best predictor of an adverse outcome in a hepatitis B carrier was the HBV DNA concentration. The higher the HBV DNA the higher the incidence of an adverse outcome. Neither ALT15,22 nor e antigen status20 at recruitment was correlated with outcome. These results, together with the data of Yuen and colleagues,4 support the concept that patients with normal ALT levels can no longer be excluded from therapy, and that criteria other than the ALT must be used to determine eligibility for therapy.
 
How then can we distinguish between those hepatitis B carriers who need therapy and those who do not? Are there other markers of a poor prognosis that might be more useful? Liver biopsy showing fibrosis or cirrhosis may be one such marker but we cannot biopsy every hepatitis B carrier. Perhaps non-invasive measurements of fibrosis will help answer this question. However, if treatment is restricted to patients with advanced fibrosis the incidence of cancer might not fall a great deal. The only other logical marker is HBV DNA concentration. The three large cohort studies strongly suggest (but do not prove) that suppression of viral replication will decrease the incidence of adverse outcomes. There is other evidence to support this notion. Long term suppression of woodchuck hepatitis virus replication by entecavir leads to a reduction in the incidence of HCC.23 Suppression of viral replication in cirrhotic patients decreases the incidence of liver related adverse events (HCC and cirrhosis).24 (Whether suppression of HBV DNA before the onset of cirrhosis would have a similar effect is not known, and is unlikely to be studied, given the difficulty of maintaining a patient with active disease off therapy for an extended period of follow up.) Patients in whom viral replication is spontaneously suppressed early in the course of their disease are at a much lower risk of cirrhosis and HCC compared with those in whom viral replication persists.25,26 Finally, in the Taiwan cohort, patients in whom HBV DNA spontaneously improved had a lower incidence of adverse outcomes than those in whom HBV DNA levels remained high.27
 
This all suggests that a high HBV DNA concentration should be the prime indication for therapy. Several immediate questions arise. Firstly, at what point in the natural history is it appropriate to start treatment? This question cannot be answered at present and will have to await full publication of the cohort studies so that the relationship between HBV DNA, age at recruitment, and outcome can be evaluated. The next question is how low should the HBV DNA level be to have the highest likelihood of preventing complications of chronic HBV infection. In the three cohort studies, even HBV DNA concentrations <100 000 copies/ml were associated with a significant incidence of HCC, cirrhosis, and death from liver disease. Others have shown, in a small cohort, that all those with HCC had an HBV DNA concentration above 2x104.28 Until this level can be confirmed as "safe", it is probably wise to aim to suppress HBV DNA maximally, to undetectable levels, or if that is not possible, to below 104 copies/ml.
 
Until recently we have not had adequate tools to achieve optimal suppression of viral replication indefinitely. Interferon based therapy only induces permanent suppression in a small proportion of patients.5,29,30 There are as yet no long term studies on the durability of pegylated interferon response, but at best, only 3035% of HBeAg positive patients respond, leaving 6570% requiring additional treatment.31 Lamivudine cannot be used long term because of the development of resistance.32 The prospect of using adefovir long term is also fading, as up to 18% resistance rates at four years have been reported.33 Entecavir is the most potent nucleoside analogue to complete phase III testing and, so far, no resistance has been reported in the treatment of nave subjects.34 Tenofovir is more potent than adefovir35 but its HBV resistance profile and frequency of emergence of resistance remains unknown. However, it is inevitable that resistance will develop over time for both of these agents. There are as yet no data on the combined use of more than one nucleoside analogue, although this would seem to be a logical approach and perhaps the only approach that might provide long term viral suppression.
 
Given the above considerations, the time has come to abandon some of our old concepts about the management of hepatitis B. We should no longer rely on an elevated ALT to select patients for treatment. Patients with high viral loads and normal ALT levels are not good candidates for interferon and should probably only be treated with nucleos(t)ide analogues. Treatment should aim to suppress viral replication as much as possible. The target should be undetectable HBV DNA and if that is not possible, HBV DNA should not exceed 104 copies/ml. The availability of more potent drugs such as entecavir, telbivudine, and clevudine will make these targets feasible. To ensure long term suppression we have to prevent the emergence of resistance. It may be that if viral replication is suppressed deeply enough, even with monotherapy, resistance will be rare, but addition of a second agent that does not have cross reactive resistance might be necessary. Cost will be a huge issue once we contemplate long term therapy, which will have to be confronted head-on. I believe that we will have to bite the bullet and immediately undertake studies of combination therapy, or risk creating strains of virus that are resistant to everything.
 
SUMMARY
 
* ALT is a poor predictor of outcome and therefore cannot be used as the sole indication for therapy.
* HBeAg positivity is associated with a higher risk of adverse outcomes than anti-HBe positivity.
* HBV DNA concentration at recruitment and during follow up is the best predictor of an adverse outcome.
* The higher the HBV DNA concentration (above 104 copies/ml), the greater the mortality.
* Treatment should be aimed at suppressing HBV DNA maximally, to below 104, and preferably to below 103.
 
REFERENCES
 
1. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334:14227.[Abstract/Free Full Text]
 
2. Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol 2001;34:30613.[CrossRef][Medline]
 
3. Chan HL, Tsang SW, Hui Y, et al. The role of lamivudine and predictors of mortality in severe flare-up of chronic hepatitis B with jaundice. J Viral Hepat 2002;9:4248.[CrossRef][Medline]
 
4. Yuen M-F, Yuan H-J, Wong DK-H, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 2005;54:16104.
 
5. Schalm SW, Heathcote J, Cianciara J, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomized trial. Gut 2000;46:5628.[Abstract/Free Full Text]
 
6. Tassopoulos NC, Volpes R, Pastore G, et al. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology 1999;29:88996.[CrossRef][Medline]
 
7. Wong DK, Cheung AM, ORourke K, et al. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993;119:31223.[Abstract/Free Full Text]
 
8. van Nunen AB, Hansen BE, Suh DJ, et al. Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase. Gut 2003;52:4204.[Abstract/Free Full Text]
 
9. Song BC, Suh DJ, Lee HC, et al. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 2000;32:8036.[CrossRef][Medline]
 
10. Yuen MF, Hui CK, Cheng CC, et al. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology 2001;34:13945.[CrossRef][Medline]
 
11. Marx G, Martin SR, Chicoine JF, et al. Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins. J Infect Dis 2002;186:295301.[CrossRef][Medline]
 
12. Lok AS, McMahon BJ. Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: update of recommendations, Hepatology 2004;39:85761.[CrossRef][Medline]
 
13. de Franchis R, Hadengue A, Lau G, et al. EASL International Consensus Conference on Hepatitis B. 1314 September, 2002 Geneva, Switzerland. Consensus statement. J Hepatol 2003;39 (suppl 1) :P325.
 
14. Liaw YF, Leung N, Guan R, et al. Asian-Pacific Consensus Working Parties on Hepatitis B. Asian-Pacific consensus statement on the management of chronic hepatitis B: an update, J Gastroenterol Hepato 2003;18:23945.[CrossRef]
 
15. Iloeje UH, Yang HI, Su J, et al. Viral load is a strong predictor of hepatocellular carcinoma risk in people chronically infected with hepatitis B virus and with normal serum alanine aminotransferases. J Hepatol 2005;42 (suppl 2) :179. 16. Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 2002;36:140815.[CrossRef][Medline]
 
17. Evans AA, Fabre RE, Chen G, et al. Hepatitis B viral load is associated with the development of hepatocellular carcinoma. Hepatology 2004;40 (suppl 1) :602A.[CrossRef]
 
18. Chen G, Lin WY, Shen FM, et al. Viral load as a predictor of mortality from hepatocellular carcinoma and chronic liver disease in chronic hepatitis B infection. J Hepatol 2005;42 (suppl 2) :172.
 
19. Chen G, Lin W, Shen FM, et al. Viral load as a predictor of liver disease in chronic hepatitis B infection. Hepatology 2005;40 (suppl 1) :594A.
 
20. Chen CJ, Yang HI, Su J, et al. Viral load is a strong predictor of liver cirrhosis in people chronically infected with hepatitis B virus regardless of HBe antigen status. J Hepatol 2005;42 (suppl 2) :172.
 
21. Iloeje UH, Yang HI, Su J, et al. Serum hepatitis B virus DNA level predicts the incidence of liver cirrhosis in persons chronically infected with HBV. J Hepatol 2005;42 (suppl 2) :180.[Medline] 22. Iloeje UH, Yang HI, Su J, et al. Viral load, not serum ALT is the primary predictor of progression to cirrhosis in persons chronically infected with HBV. Results from a long term prospective study. J Hepatol 2005;42 (suppl 2) :180.
 
23. Colonno RJ, Genovesi EV, Medina I, et al. Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection. J Infect Dis 2001;184:123645.[CrossRef][Medline]
 
24. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:152131.[Abstract/Free Full Text]
 
25. De Franchis R, Meucci G, Vecchi M, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993;118:1914.[Abstract/Free Full Text]
 
26. Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002;35:15227.[CrossRef][Medline]
 
27. Chen CJ, Yang HI, Su J, et al. Elevated levels of serum hepatitis B virus DNA is an independent risk factor for hepatocellular carcinoma: A long term follow-up study in Taiwan. J Hepatol 2005;42 (suppl 2) :35.
 
28. Tang B, Kruger WD, Chen G, et al. Hepatitis B viremia is associated with increased risk of hepatocellular carcinoma in chronic carriers. J Med Virol 2004;72:3540.
 
29. Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol 2001;34:30613.
 
30. Brunetto MR, Oliveri F, Coco B, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J Hepatol 2002;36:26370.
 
31. Lau G, Piratvisuth T, Luo KX, et al. Peginterferon alpha 2a (40KD) (Pegasys) monotherapy and in combination with lamivudine is more effective than lamivudine monotherapy in HBeAg-positive chronic hepatitis B. Results from a large multinational study. Hepatology 2004;40 (suppl 2) :171A.
 
32. Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003;36:68796.
 
33. Locarnini S, Qi X, Arterburn S, et al. Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B. J Hepatol 2005;42 (suppl 2) :17.
 
34. Chang GG, Gish R, de Man R, et al. Entecavir is superior to lamivudine for the treatment of HBeAg (+) chronic hepatitis B: Results of phase III study ETV-022 in nucleoside nave patients. Hepatology 2004;40 (suppl 1) :193.
 
35. van Bommel F, Wunsche T, Mauss S, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 2004;40:14215.
 
"Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications"
 
Gut Nov 2005
 
......prolonged and maximal suppression of HBV DNA to levels below the detection limit of PCR based assays may be necessary to reduce the risk of complications.....
 
.......In conclusion, prolonged low level viraemia causing insidious and continual liver damage, as reflected by relatively mild elevations in ALT levels, is the most likely pathway leading to the development of complications for Asian patients with CHB. Long term antiviral therapy aiming at maximal suppression of HBV even after HBeAg seroconversion may be required for Asian patients.
 
M-F Yuen, H-J Yuan, D K-H Wong, J C-H Yuen, W-M Wong, A O-O Chan, B C-Y Wong, K-C Lai and C-L Lai
 
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
 
ABSTRACT
Background: Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria.
 
Aim: To determine risk factors for the development of complications in Asian CHB patients.
 
Patients and methods: A total of 3233 Chinese CHB patients (mean follow up 46.8 months) were monitored for liver biochemistry, viral serology, hepatitis B virus (HBV) DNA levels, acute exacerbation, hepatitis B e antigen (HBeAg) seroconversion, and development of cirrhotic complications and hepatocellular carcinoma.
 
Results: Median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years, respectively. Patients with alanine aminotransferase (ALT) levels of 0.51 times the upper limit of normal (ULN) and 12x ULN had an increased risk for the development of complications compared with patients with ALT levels <0.5x ULN (p<0.0001 for both). HBeAg/antibody to hepatitis B e antigen status, and number of episodes, duration, and peak ALT levels of acute exacerbations were not associated with an increased risk of complications. In patients with complications, 43.6% had HBV DNA levels less than 1.42x105 copies/ml. Male sex, stigmata of chronic liver disease, old age, low albumin, and high fetoprotein levels on presentation were independently associated with increased cumulative risk of complications. Male sex, presence of hepatitis symptoms, old age, low albumin level, and presence of complications on presentation were independently associated with shorter survival.
 
Conclusion: Prolonged low level viraemia causing insidious and continual liver damage, as reflected by ALT levels of 0.52x ULN, is the most likely pathway for the development of complications in Asian CHB patients.
 
INTRODUCTION
Chronic hepatitis B (CHB) virus infection affects more than 400 million people globally, of whom 75% are Asians1,2: 2540% of chronic CHB patients will develop complications of cirrhosis and hepatocellular carcinoma (HCC).3,4 Although there have been marked advances in the therapeutic options for CHB recently, indications for treatment remain controversial. Guidelines from the American Association for the Study of Liver Diseases, European Association of the Study of Liver, and Asian-Pacific Association of the Study of Liver suggest that treatment should only be given when there is persistent elevated alanine aminotransferase (ALT) levels >2 times normal and hepatitis B virus (HBV) DNA levels of >105 copies/ml for both hepatitis B e antigen (HBeAg) positive and negative patients.57 However, no study has proved that patients with values below these arbitrarily defined cut off levels are at a lower risk for the development of cirrhosis related complications or HCC. In fact, a recent study by Kim et al in the general population of Korea found that there was already an increased risk of mortality from liver disease in patients with ALT levels in the upper range of normal.8 It is essential that more evidence for establishing treatment criteria should be sought, especially as more potent and safe therapeutic agents will be available in the near future.9,10
 
The aim of the present large scale study was to examine the factors determining the development of cirrhosis related complications and survival in Asian CHB patients.
 
HBV DNA levels
HBV DNA levels were measured in 2332 patients. Of these, 112 had paired serum samples before and after HBeAg seroconversion. In addition, 525 HBeAg positive patients and 1695 anti-HBe positive patients had samples at the last follow up for HBV DNA assays. Details of HBV DNA levels measured by Digene Hybrid Capture assay are shown in table 4.
 
Median HBV DNA levels of the 1695 anti-HBe positive patients, as determined by the Cobas Amplicor HBV Monitor test, was 7250 copies/ml (range <2001.7x109). Only 386 patients (22.8%) had undetectable HBV DNA levels. HBV DNA levels were <103, >103104, >104105, and >105 copies/ml in 183 (10.8%), 320 (18.9%), 259 (15.3%), and 547 (32.3%) patients, respectively.
 
HBV DNA levels were measured in 110 patients with complications: 21 patients before the complications developed (range 0.28.25 months); nine at the time of the complications; and 80 after the complications developed (range 0.41193.5 months). Median HBV DNA level was 0.323x106 copies/ml (range <0.1421700x106 copies/ml). Forty eight patients (43.6%) had HBV DNA levels undetectable by the Digene Hybrid Capture assay. The Cobas Amplitor HBV Monitor test was performed in 45 of these patients. Thirteen (28.9%) patients had undetectable HBV DNA (that is, <200 copies/ml). HBV DNA levels (copies/ml) of the remaining 32 patients were as follows: <103 in two patients (4.4%); >103104 in 12 patients (26.7%); >104105 in 10 patients (22.2%); and >105 in eight patients (17.8%).
 
Independent factors associated with development of complications and poor survival Using the Cox proportional hazards model, male sex (p<0.0001), presence of stigmata of chronic liver disease (p = 0.045), increasing age (p<0.0001), low albumin level on presentation (p<0.0001), and high AFP level on presentation (p = 0.001) were found to be independent factors associated with a higher cumulative risk for the development of complications.
 
For survival analysis, male sex (p = 0.004), presence of hepatitis symptoms (p = 0.02), increasing age (p<0.0001), and low albumin level on presentation (p<0.0001) were found to be independent factors associated with a shorter actuarial survival. DISCUSSION
The present study was limited by the relatively short period of follow up even though 307 patients (10.0%) were followed up for more than 10 years. Another limitation of the study was the absence of histological assessment. However, the end points of our study, the development of cirrhosis related complications and HCC, are of great clinical and prognostic relevance.
 
Several findings from the present study have direct implications for criteria for the treatment of CHB in the future. Firstly, the risk of complications increased as ALT levels on presentation increased from >0.5x ULN to 2x ULN. In contrast, patients with ALT levels above 6x ULN had a significantly lower risk for the development of complications (fig 2). These findings were confirmed using median ALT levels of patients during subsequent follow up. Acute exacerbations and high ALT levels (for example, >2x ULN) probably signify acute injuries to the liver which may not lead to permanent damage. This is probably analogous to the situation in acute viral hepatitis. However, in patients with only mild elevation of ALT, including those with ALT levels in the upper range of normal, the immune attack on the liver might be more insidious and chronic, leading eventually to more severe and permanent damage.
 
In the study of Kim et al showing an increased risk of mortality from liver disease in patients with ALT levels in the upper range of normal, it was suggested that the normal range of serum aminotransferase concentrations should be lowered in populations in which liver disease are common.8 Even though the authors did not test their subjects for hepatitis B or C markers, their findings confirm ours. The present guidelines for treatment suggest that only patients with ALT levels >2x ULN should be treated.57 This would exclude patients with the highest risks for the development of complications from treatment.
 
Secondly, in the Asian population, disease activity continues to progress in a proportion of patients after HBeAg seroconversion. Median age for the development of complications in our patients was 57.2 years (table 2). Median age of HBeAg seroconversion was 35 years. More than two thirds of the patients were already anti-HBe positive when they developed complications. The cumulative risk for the development of complications was comparable between patients positive for HBeAg and for anti-HBe on presentation. A Taiwan study by Yang et al. claimed that HBeAg positivity was associated with an increased risk of HCC.12 HBeAg status of the patients in this study however was checked only at the time of enrolment whereas the development of HCC was observed during the subsequent 10 years of follow up. HBeAg/anti-HBe status at the time of development of HCC was not assessed. This study therefore can provide no clue as to the HBeAg status of patients at the time of HCC development. Another smaller Taiwan study found that although HBeAg seroconversion confers a favourable outcome in some patients, active hepatitis can occur after HBeAg seroconversion, leading to cirrhosis and HCC.13 McMahon et al, in their study, found that "seroconversion from HBeAg to anti-HBe, and even loss of hepatitis B surface antigen, did not protect patients from development of hepatocellular carcinoma".14 These latter two studies confirm the findings of the present study, that the majority of cirrhosis related complications and HCC develop after HBeAg seroconversion. The onset of cirrhosis occurs during the prolonged process of HBeAg seroconversion in Asian patients.15 Cirrhosis will continue to worsen or develop after HBeAg seroconversion.1618 Thus HBeAg seroconversion should only be regarded as a step towards viral suppression, and therapy may need to be continued after HBeAg seroconversion.
 
Thirdly, progression of cirrhosis is more likely to be related to the low level of viraemia in a large proportion of patients who are anti-HBe positive. In the current study, only 22.8% of anti-HBe patients had undetectable HBV DNA levels by the PCR based assay; 32.3% had more than 105 copies/ml. (That the wild-type virus is as likely to cause complications as the precore mutants have been analysed in a separate study19.)
 
Among the 56% of patients with complications in whom HBV DNA levels were undetectable by the Digene Hybrid Capture assay, over 70% had HBV DNA levels detectable by the Amplicor HBV Monitor test. Twenty nine per cent of patients had undetectable HBV DNA (that is, <200 copies/ml). This is evidence against the proposal that disease progression is unlikely once HBV DNA levels become less than 105 copies/ml.20 Our findings support the conclusion of Chu and colleagues21 that there is no cut off HBV DNA value for differentiating active from inactive disease in HBeAg negative patients. This implies that prolonged and maximal suppression of HBV DNA to levels below the detection limit of PCR based assays may be necessary to reduce the risk of complications.
 
In conclusion, prolonged low level viraemia causing insidious and continual liver damage, as reflected by relatively mild elevations in ALT levels, is the most likely pathway leading to the development of complications for Asian patients with CHB. Long term antiviral therapy aiming at maximal suppression of HBV even after HBeAg seroconversion may be required for Asian patients.
 
 
 
 
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