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Natural history of chronic hepatitis B virus-related liver disease and its relationship to serum markers of viral replication
Journal of Hepatology, 1986;3 (Suppl. 2): $3-$8 Elsevier
$3
HEP 000168
Natural History of Chronic Hepatitis B Virus-Related Liver Disease and its Relationship to Serum Markers of Viral Replication
R o g e r Williams* a n d G . J . M . A l e x a n d e r The Liver Unit, King's College Hospital and School of Medicine and Dentistry, Denmark Hill, London SE5 8RX (U. K.)
Summary Our understanding of the process whereby replicating Hepatitis B virus is eradicated has been substantially modified by the development of highly sensitive assays of viral replication, such as the detection of H B V - D N A in serum. The implications of these developments on our therapeutic approach in terms of both timing and expectations is discussed.
Introduction Among those considerations that influenced the choice of November 1985 as the appropriate time to meet, was the anticipation that a considerable amount of new, up to date information would be available from the current clinical trials of antiviral agents from various parts of the world. This will almost certainly prove to be the case, although whether or not there is a more definite answer with respect to therapy will be a recurring theme of the next two days. Having the meeting now rather than 12 months ago, however, may have added some difficulties in our understanding of the process of seroconversion. The relationship between the HBeAg/anti-HBe sys-
tern and the change from the replicating to the non replicating stage is no longer as clear, as shown by a number of recent studies on the presence or absence of HBV-DNA in serum, an even more sensitive marker of viral replication. Many of the early studies on antiviral agents in hepatitis B-related chronic liver disease were reliant on the presence or absence of HBeAg as the marker of viral replication. More detailed appraisal of the sequence of events leading to seroconversion is crucial both with respect to an understanding of the natural history of chronic hepatitis B, with the attendant risks of cirrhosis and hepatoma, and to the possible role of antiviral therapy in terms of expectations and timing.
* To whom correspondenceshould be addressed. 0168-8278/86/$03.50© 1986Elsevier Science Publishe.,rs B.V. (Biomedical Division) .
$4 Prognosis Disease
of Hepatitis
B-Related
Chronic
Liver
COURSE OF CHRONIC PERSISTENT HEPATITIS (after Aldershville el al. [9])
There is considerable variation in the reported natural history of chronic hepatitis B from various parts of the world. Much of this may be related to the mode of, and age at, exposure which are so varied, as well as to racial differences and to referral patterns. Amongst the earliest markers of a poor prognosis identified were the presence of piecemeal necrosis and bridging necrosis-but in this context it is important to recognise that in these early studies, hepatitis B was just one cause of chronic hepatitis and the effect of aetiology may have been underestimated. Nevertheless, longitudinal studies have consistently shown a poor prognosis in patients with chronic active hepatitis, with a 5-year survival of about 72% while patients with bridging necrosis fare less well [i]. As can be seen clearly, a substantial proportion progress over a short period (Table 1). One further factor that has been shown recently to affect prognosis markedly is the presence of superinfection-particularly since many of those at risk of contracting H B V are exposed to a number of other microbial agents. Infection with the delta agent has been consistently shown to be associated with a poor prognosis [7]; recent evidence indicates that superinfection with H T L V - I I I attenuates disease activity [8]; non-A, non-B hepatitis too is likely to prove of importance in this respect. TABLE 1 PROGNOSIS OF CHRONIC ACTIVE HEPATITIS B
Dudley et al. [21 (U.K. 1982) Van Waes et al. [3] (Belgium 1974) Hadzyannis [41 (Greece 1974) De Groote et al. [51 (Belgium 1978) Lo et al. [6] (Taiwan 1985)
TABLE 2
No. of patients
Mean Profollow up gression (months) (%)
Death
25
23
5 (20)
3
22
38
10 (45)
I
37
32
--
3
17
87
12(70)
5
76
46
35(46)
15
(1)
(2) (3)
14 HBeAg + ve cases followed 38 months - 11 remained HBeAg + ve; 5 developed CAH or cirrhosis - 3 developed anti-HBe; 2 developed inactive liver disease 9 HBeAg-ve cases followed 47 months - 1 developed CAH 28 HBV-ve cases - 2 developed CAH or cirrhosis
The situation was less clear for chronic persistent hepatitis B. The rate of progression to C A H or cirrhosis is widely believed to be l o w - b u t many of the studies on which this belief is based have not looked separately at aetiology and the prognosis of hepatitis B-related CPH, particularly in the presence of H B e A g , may differ. The study p f Aldershville et al. [9] demonstrated clearly that the rate of progression in CPH was greater in those with H B V infection than in those with non-HBV infection and that the presence of H B e A g increased the risk (Table 2).
Relation of Liver Damage to Viral Replication
It has become increasingly clear that there is a close relationship between viral replication and histology. Three major studies [10-12] documented that the loss of H B e A g and the development of anti° HBe were associated with loss of hepatic inflammation, normalisation of biochemical indices and resolution of clinical symptoms. Persistence of hepatic inflammation and biochemical activity subsequent to seroconversion could be ~attributed in a proportion, as already mentioned, to the development of 6superinfection or other agents. It was also observed that at the time of seroconversion in many there was a period of increased inflammatory activity or 'hepatitis'. On the basis of these studies a model of chronic H B V infection shown in Fig. 1 was developed [4]. The development of anti-HBe was associated with reduced inflammation and hence a reduced risk of cirrhosis, but possibly at the expense of an increased
$5 PHASES
HDe Ag
*
Anl)-HEe
.
CAH
*
CHRONIC
*
.
CPH
OF
.
*
.
MINIMAL
HBV
.
*
.
.
INFECTION
.
.
.
(TRADITIONAL
.
~
.
*
.
*
.... I ....... I ,-C,,VE .......
LIVER
HEPATITIS
TABLE 3
VIEW)
.
SPONTANEOUS SEROCONVERSION RATES (HBeAg to anti-HBe)
.
*
*
+
INTEGRATION --
--
--
~
--
~
Interval
P.A.* rate
35% 51% 9.7% 44% 40%
-
17% 25% 2.5% 20%
SEASE
Liaw et al. [12] Norkranset al. [14] Hoofnagle et al. [10] Violaetal. [15] Realdi et al. [11] Schalm et al. [ 1 6 ] --
Rate Taiwan Scandinavia U.S.A. U.K. Italy Netherlands
2-7 yr 2 yr 44mo 2-7 yr 2 yr
* P.A. Rate = per annum rate
OF HSV-DNA
Fig. 1. The traditional view of HBeAg/anti-HBe seroconversion. An hepatitis-like illness, characterised by an elevation of the transaminases and lobular inflammation on the liver biopsy accompanies the loss of HBeAg and precedes the development of anti-HBe. This process may arise on a background of chronic active hepatitis, chronic persistent hepatitis or, rarely, minimal liver damage. chance of integration of H B V - D N A , with the potential for malignant transformatioi~. Liaw, in a large prospective study of 99 H B e A g positive patients, a t t e m p t e d to analyse the mechanism of H B e A g / a n t i - H B e seroconversion [12]. Just under a third of the patients d e v e l o p e d anti-HBe, a proportion of whom had been on corticosteroids throughout. Of those that had received no therapy, 65% d e v e l o p e d an 'hepatitis like illness', characterised by a m a r k e d elevation of serum aminotransferase and on liver biopsy by p r o m i n e n t lobular infiltration with m o n o n u c l e a r cells, that p r e c e d e d or coincided with seroconversion. In a small p r o p o r t i o n of cases, the hepatitis-like illness may be severe and associated with hepatic d e c o m p e n s a t i o n [13]. The r e p o r t e d rates for spontaneous seroconversion however vary widely (Table 3). The reasons for these discrepancies are not clear, but a n u m b e r of studies both of spontaneous seroconversion and that following antiviral therapy have retrospectively examined factors that might be relevant (Table 4). It is important to stress that none of these factors has been tested in prospective studies. O u r experience has been that the presence of elevated transaminases or Iobular inflammation or both is associated with subsequent seroconversion, in a g r e e m e n t with Liaw.
But does that mean that such patients should be offered antiviral therapy, since many will seroconvert spontaneously? By treating them with antiviral agents, do we j e o p a r d i s e their chances of a natural seroconversion or do we push the p r o p o r t i o n who eventually develop anti-HBe closer to 100%?
Serum HBV-DNA as Marker of Viral Replication i
In the past 12 months a n u m b e r of studies have emphasised that serum H B V - D N A is a considerably more sensitive index of viral replication than HB ' e ' status. I n d e e d it should be stressed that the presence of anti-HBe is simply a m a r k e r of lower viral replication, rather than absent viral replication. Thus for those with long-established anti-HBe, H B V - D N A is found in serum in 25% of South African blacks, 63% of Chinese and 40% of M e d i t e r r a n e a n patients [22-24]. The recent study of Chu is of particular interest in this respect [25]. H B V - D N A was found in TABLE 4 POSSIBLE FACTORS FAVOURING SEROCONVERSION RATES Chronic active hepatitis Female sex Male sex Homosexual activity Heterosexual activity Recent corticosteroid therapy
Realdi et al. (Italy 1980) [11] Scullard et al. (U.S.A. 1981) [17] Scullard et al. (U.S.A. 1981) [17] Chu et al. (Taiwan 1985) [19] Perrillo et al. (U.S.A. 1984) [20] Novick et al. (U.K. 1985) [21] Scullard et al. (U.S.A. 1981) [19]
$6 the sera of the majority of patients irrespective of the HB 'e' status but was present in significantly greater amounts in those with HBeAg than those with antiHBe. Strikingly, histological inflammation was rare in those in whom serum HBV-DNA was either high or absent; in the former, minimal liver damage was present and in the latter, inactive liver disease. In contrast in 76% of patients with low, but detectable, levels of serum HBV-DNA, chronic active or lobular hepatitis was present. These observations suggest that viral replication stimulates an immune mediated attack, the varied nature of which accounts in part for the wide spectrum of liver damage associated with HBeAg. A newer model of HBV has now evolved wherein chronic active or lobular hepatitis can be regarded as the histological expression of the process of clearance of HBV-replication and it is implied that the degree of liver damage will be related to the length and severity of that process. As in the case of HBeAg/anti-HBe seroconversion, it is not clear at present whether those with low levels of serum HBVDNA, i.e. those who may be undergoing spontaneous seroconversion, should or should not be treated (Fig. 2). A small number of reports indicate that loss of viral replication may not be permanent [25,26]. This is PHASES
OF CHRONIC
MINIMAL LIVER OAMAGE . . . . . . . . . . . . .
H~V-
DNA
HBV
iNFECTION
CHRONIC ACTIVE LOBULAR HEPAIITIS
(CURRENT
INACTIVE
LIVER
VIEW)
DISEASE
IN SERUM
J f _ ~ -- ~ ~ ---
INTEGRATION OF HSV-DNA
J TUMOUR
Fig. 2. The current view of HBeAg/anti-HBe seroconversion. In this model the process of clearing HBeAg is equated with chronic active hepatitis. The duration of the first two phases can vary markedly between individuals while the duration of seroconversion will determine the degree of chronic liver damage.
consistent with the principle that the presence of antiHBe is a crude index of loss of viral replication since most reports of reactivation have looked at antiHBe/HBeAg seroconversion. But some patients have apparently become positive for serum HBVDNA having previously been negative, although this has usually been associated with immunosuppression. The implications are that even serum HBVDNA may be a poor marker of the potential for viral replication and that complete clearance of HBV may not be a practical proposition in every patient.
Viral Integration An important aim of antiviral therapy must be to reduce the potential for hepatoma development. Paradoxically, one of the questions raised with respect to antiviral therapy has been the possibility that seroconversion from HBeAg to anti-l-iBe might increase the risk of malignant transformation by increasing the chances of integration. Only longitudinal studies can answer this question, but it would appear more likely that viral integration might occur at any time and that the period of exposure to virus rather than seroconversion is a more important factor. Adequate longitudinal data are not yet available regarding the timing of integration. Studies from Brechot's group [27] have shown that 18/20 HBsAg+, anti-HBe+ carriers had integrated sequences in the liver compared with 3/20 with HBeAg in serum, implying that integration occurs after a considerable period-yet the same group have demonstrated integrated sequences in patients with fulminant hepatitis B and when children, born to carrier mothers were analysed (i.e. those in whom the timing of infection could be accurately estimated), integrated sequences were found as early as 8 months of age. The role of HBV as a major determinant of malignant transformation has been questioned recently. In the study of Zaman et al. [28] male sex and the presence of cirrhosis were more important determinants than the presence of HBV. If cirrhosis is a major fac-
$7 PHASES
r,°o~m..t
OF CHRONIC
,1,
?,L
HeY-ONA
-
HBV
INFECTION
(CURRENT
VIEWI
?L
IN SEAUM
-
-
~ ~
~ ~
INTEGRATtON OF H S V - O N A
TUMOUR
Fig. 3. The timing of therapy. During the early phase when viral replication is high therapy may not be successful. Therapy during the phase of chronic active hepatitis may be too late to prevent cirrhosis or viral integration. The optimum time for therapy is at the earliest phase of chronic active hepatitis when immune mechanisms will contribute-but identification of this timepoint may prove elusive. tor then antiviral therapy might affect the incidence of h e p a t o m a by preventing progression to cirrhosis. If integration proves to be a m a j o r factor, then the likelihood of an effect of antiviral t h e r a p y on malignant transformation will d e p e n d on the timing of integration in relation to therapy.
Timing of Treatment
the objectives. The evidence that seroconversion from H B e A g ~o anti-HBe is accompanied by remission indicates that the primary objective should be prevention of progression to cirrhosis and the earlier that treatment is offered in the course of the disease the better. It is possible however, that t r e a t m e n t during the early phase (Fig. 3) when viral replication is high may be less successful than treatment at the stage when chronic active and/or lobular hepatitis is present and viral replication is low. Since C P H may progress, patients in the early phase should be considered for therapy. It could be argued that t r e a t m e n t during the phase of histological activity is unnecessary since seroconversion is likely to occur spontaneously. Against this are the observations that when seroconversion occurs following, or during therapy (with interferon in particular), the duration of the inflammatory process of seroconversion is curtailed although the degree of inflammation may be similar. Thus antiviral therapy during the active phase may limit the duration of the liver damage. Insufficient data concerning the timing of viral integration into host D N A are available at present to be certain whether antiviral therapy will have any effect, but since integration is likely to be a random event, then the earlier treatment is offered the more likely it is that integration will be prevented.
The timing of antivirai therapy will d e p e n d upon
References 1 Smith CI, Gregory PB. In: S. Cohen and RS Soloway (Eds.), Chronic Active Liver Disease. Churchill Livingstone, London, 1983: 73-80. 2 Dudley FJ, Scheur PJ, Sherlock S. Natural history of hepatitis associated antigen positive chronic liver disease. Lancet 1972; ii: 1388-1393. 3 Van Waes L, Segers J, Van Egmond J, et al. Chronic liver disease and hepatitis B antigen - - A prospective study. Br Med J 1974; III: 444-446. 4 Hadziyannis SJ. Chronic viral hepatitis. Clin Gastroenterol 1974; 3: 381-408. 5 De Groote J, Fevery J, Lepontre L. Long term follow up of chronic active hepatitis of moderate severity. Gut 1978; 19: 510-513. 6 Lo KJ, Tong MJ, Chien ML, et al. The natural history of hepatitis B surface antigen positive chronic liver disease in Taiwan. J lnf Dis 1982; 146: 205-210.
7 Rizzetto M, Verme G, Recchia S, et al. Chronic hepatitis in carriers of hepatitis B antigen with intrahepatic expression of the delta antigen. Ann Intern Med 1983; 98: 437-441. 8 Krogsgaard K, Lindhardt BO, Nielsen JO, et al. Hepatitis B virus replication and HTLV-III infection in male homosexual HBsAg carriers. J Hepatol 1985; 1: 270S (Abstract). 9 Aldershville J, Dietrichson O, Skinhoj P, et al. Chronic persistent hepatitis: serological classification and meaning of the hepatitis Be system. Hepatology 1982; 1: 243-246. 10 Hoofnagle JH, Dusheiko GM, Seef LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis Be antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981; 94: 744-748. 11 Realdi G, Alberti A, Rugge M, et al. Seroconversion from hepatitis Be antigen and anti-HBe in chronic hepatitis B virus infection. Gastroenterology 1980; 79: 195-199. 12 Liaw YF, Chu CM, Su IJ, Huang MJ, Lin DY, Chien CS. Clinical and histological events preceding hepatitis Be antigen seroconversion in chronic type B hepatitis. Gastroen-
$8 terology 1983; 84: 216-219. 13 Sheen IS, Liaw YF, Tai DI, Chu CM. Hepatic decompensation associated with hepatitis Be antigen clearance in chronic type B hepatitis. Gastroenterology 1985; 89: 732-735. 14 Norkrans G, Lindberg J, Frosner G, et al. Clearance of hepatitis Be antigen in chronic hepatitis B infection. Scand J Gastroenterol 1982; 17: 383-387. 15 Viola LA, Barrison IG, Coleman JC, Paradinas FJ, Murray-Lyon IM. The HBe antigen antibody-system and its relationship to clinical and laboratory findings in 100 chronic HBsAg carriers in Great Britain. J Med Virol 1981; 8: 169-175. 16 Schalm SW, Heijtink RA. Spontaneous disappearance of viral replication and liver cell inflammation in HBsAg-positire chronic active hepatitis: Results of a placebo vs. inteferon trial. Hepatology 1982; 2: 791-794. 17 Scullard GH, Pollard RB, Smith JL, et al. Antiviral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside. J Inf Dis 1981; 143: 772-783. 18 Chu CM, Liaw YF, Sheen IS, Lin DY, Huang MJ. Sex difference in chronic hepatitis B virus infection: an appraisal based on the status of hepatitis Be antigen and antibody. Hepatology 1983; 3: 947-950. 19 Scullard, GH, Smith CI, Merigan TC, Robinson W J, Gregory PB. Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B. Gastroenterology 1981; 81: 987-991. 20 PerriUo RP, Campbell CR, Sanders GE, Regenstein FG, Bodicky CJ. Spontaneous clearance and reactivation of hepatitis B virus infection among male homosexuals with
chronic type B hepatitis. Ann Int Med 1984; 100: 43-46. 21 Novick DM, Lok ASF, Thomas HC. Diminished responsiveness of homosexual men to antiviral therapy for HBsAg positive chronic liver disease. J. Hepatol 1985; 1: 29-35. 22 Chu CM, Karayiannis P, Fowler MJ, Monjardino J. Natural history of chronic hepatitis B virus infection in Taiwan: Studies of hepatitis B virus DNA in serum. Hepatology 1985; 5: 431-434. 23 Hadzyiannis SJ, Lieberman HM, Karvountzis GG, Shafritz DA. Analysis of liver disease, nuclear HBcAg viral replication and hepatitis B virus DNA in liver and serum of HBeAg vs. anti-HBe positive carriers of Hepatitis B virus. Hepatology 1983; 3: 656-662. 24 Lieberman, HM, Labrecque DR, Kew MC, et al. Detection of hepatitis B virus DNA directly in human serum by a simplified molecular hybridisation test: comparison to HBeAg/anti HBe status in HBsAg carriers. Hepatology 1983; 3: 285-291. 25 Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Int Med 1982; 96: 447-449. 26 Dusheiko G, Song E, Bowyer S, et al. Natural history of hepatitis B virus infection in renal transplant recipients - - A fifteen year follow up. Hepatology 1983; 3: 336-370. 27 Brechot C, Pourcel C, Hadchouel M, et al. State of hepatitis B virus DNA in liver disease. Hepatology 1982; 1: 27S-34S. 28 Zaman SN, Melia WM, Johnson RD, Portmann BC, Johnson PJ, Williams R. Risk factors in development of hepatocellular carcinoma in cirrhosis: prospective study of 613 patients. Lancet 1985; i: 1357-1360.
$3
HEP 000168
Natural History of Chronic Hepatitis B Virus-Related Liver Disease and its Relationship to Serum Markers of Viral Replication
R o g e r Williams* a n d G . J . M . A l e x a n d e r The Liver Unit, King's College Hospital and School of Medicine and Dentistry, Denmark Hill, London SE5 8RX (U. K.)
Summary Our understanding of the process whereby replicating Hepatitis B virus is eradicated has been substantially modified by the development of highly sensitive assays of viral replication, such as the detection of H B V - D N A in serum. The implications of these developments on our therapeutic approach in terms of both timing and expectations is discussed.
Introduction Among those considerations that influenced the choice of November 1985 as the appropriate time to meet, was the anticipation that a considerable amount of new, up to date information would be available from the current clinical trials of antiviral agents from various parts of the world. This will almost certainly prove to be the case, although whether or not there is a more definite answer with respect to therapy will be a recurring theme of the next two days. Having the meeting now rather than 12 months ago, however, may have added some difficulties in our understanding of the process of seroconversion. The relationship between the HBeAg/anti-HBe sys-
tern and the change from the replicating to the non replicating stage is no longer as clear, as shown by a number of recent studies on the presence or absence of HBV-DNA in serum, an even more sensitive marker of viral replication. Many of the early studies on antiviral agents in hepatitis B-related chronic liver disease were reliant on the presence or absence of HBeAg as the marker of viral replication. More detailed appraisal of the sequence of events leading to seroconversion is crucial both with respect to an understanding of the natural history of chronic hepatitis B, with the attendant risks of cirrhosis and hepatoma, and to the possible role of antiviral therapy in terms of expectations and timing.
* To whom correspondenceshould be addressed. 0168-8278/86/$03.50© 1986Elsevier Science Publishe.,rs B.V. (Biomedical Division) .
$4 Prognosis Disease
of Hepatitis
B-Related
Chronic
Liver
COURSE OF CHRONIC PERSISTENT HEPATITIS (after Aldershville el al. [9])
There is considerable variation in the reported natural history of chronic hepatitis B from various parts of the world. Much of this may be related to the mode of, and age at, exposure which are so varied, as well as to racial differences and to referral patterns. Amongst the earliest markers of a poor prognosis identified were the presence of piecemeal necrosis and bridging necrosis-but in this context it is important to recognise that in these early studies, hepatitis B was just one cause of chronic hepatitis and the effect of aetiology may have been underestimated. Nevertheless, longitudinal studies have consistently shown a poor prognosis in patients with chronic active hepatitis, with a 5-year survival of about 72% while patients with bridging necrosis fare less well [i]. As can be seen clearly, a substantial proportion progress over a short period (Table 1). One further factor that has been shown recently to affect prognosis markedly is the presence of superinfection-particularly since many of those at risk of contracting H B V are exposed to a number of other microbial agents. Infection with the delta agent has been consistently shown to be associated with a poor prognosis [7]; recent evidence indicates that superinfection with H T L V - I I I attenuates disease activity [8]; non-A, non-B hepatitis too is likely to prove of importance in this respect. TABLE 1 PROGNOSIS OF CHRONIC ACTIVE HEPATITIS B
Dudley et al. [21 (U.K. 1982) Van Waes et al. [3] (Belgium 1974) Hadzyannis [41 (Greece 1974) De Groote et al. [51 (Belgium 1978) Lo et al. [6] (Taiwan 1985)
TABLE 2
No. of patients
Mean Profollow up gression (months) (%)
Death
25
23
5 (20)
3
22
38
10 (45)
I
37
32
--
3
17
87
12(70)
5
76
46
35(46)
15
(1)
(2) (3)
14 HBeAg + ve cases followed 38 months - 11 remained HBeAg + ve; 5 developed CAH or cirrhosis - 3 developed anti-HBe; 2 developed inactive liver disease 9 HBeAg-ve cases followed 47 months - 1 developed CAH 28 HBV-ve cases - 2 developed CAH or cirrhosis
The situation was less clear for chronic persistent hepatitis B. The rate of progression to C A H or cirrhosis is widely believed to be l o w - b u t many of the studies on which this belief is based have not looked separately at aetiology and the prognosis of hepatitis B-related CPH, particularly in the presence of H B e A g , may differ. The study p f Aldershville et al. [9] demonstrated clearly that the rate of progression in CPH was greater in those with H B V infection than in those with non-HBV infection and that the presence of H B e A g increased the risk (Table 2).
Relation of Liver Damage to Viral Replication
It has become increasingly clear that there is a close relationship between viral replication and histology. Three major studies [10-12] documented that the loss of H B e A g and the development of anti° HBe were associated with loss of hepatic inflammation, normalisation of biochemical indices and resolution of clinical symptoms. Persistence of hepatic inflammation and biochemical activity subsequent to seroconversion could be ~attributed in a proportion, as already mentioned, to the development of 6superinfection or other agents. It was also observed that at the time of seroconversion in many there was a period of increased inflammatory activity or 'hepatitis'. On the basis of these studies a model of chronic H B V infection shown in Fig. 1 was developed [4]. The development of anti-HBe was associated with reduced inflammation and hence a reduced risk of cirrhosis, but possibly at the expense of an increased
$5 PHASES
HDe Ag
*
Anl)-HEe
.
CAH
*
CHRONIC
*
.
CPH
OF
.
*
.
MINIMAL
HBV
.
*
.
.
INFECTION
.
.
.
(TRADITIONAL
.
~
.
*
.
*
.... I ....... I ,-C,,VE .......
LIVER
HEPATITIS
TABLE 3
VIEW)
.
SPONTANEOUS SEROCONVERSION RATES (HBeAg to anti-HBe)
.
*
*
+
INTEGRATION --
--
--
~
--
~
Interval
P.A.* rate
35% 51% 9.7% 44% 40%
-
17% 25% 2.5% 20%
SEASE
Liaw et al. [12] Norkranset al. [14] Hoofnagle et al. [10] Violaetal. [15] Realdi et al. [11] Schalm et al. [ 1 6 ] --
Rate Taiwan Scandinavia U.S.A. U.K. Italy Netherlands
2-7 yr 2 yr 44mo 2-7 yr 2 yr
* P.A. Rate = per annum rate
OF HSV-DNA
Fig. 1. The traditional view of HBeAg/anti-HBe seroconversion. An hepatitis-like illness, characterised by an elevation of the transaminases and lobular inflammation on the liver biopsy accompanies the loss of HBeAg and precedes the development of anti-HBe. This process may arise on a background of chronic active hepatitis, chronic persistent hepatitis or, rarely, minimal liver damage. chance of integration of H B V - D N A , with the potential for malignant transformatioi~. Liaw, in a large prospective study of 99 H B e A g positive patients, a t t e m p t e d to analyse the mechanism of H B e A g / a n t i - H B e seroconversion [12]. Just under a third of the patients d e v e l o p e d anti-HBe, a proportion of whom had been on corticosteroids throughout. Of those that had received no therapy, 65% d e v e l o p e d an 'hepatitis like illness', characterised by a m a r k e d elevation of serum aminotransferase and on liver biopsy by p r o m i n e n t lobular infiltration with m o n o n u c l e a r cells, that p r e c e d e d or coincided with seroconversion. In a small p r o p o r t i o n of cases, the hepatitis-like illness may be severe and associated with hepatic d e c o m p e n s a t i o n [13]. The r e p o r t e d rates for spontaneous seroconversion however vary widely (Table 3). The reasons for these discrepancies are not clear, but a n u m b e r of studies both of spontaneous seroconversion and that following antiviral therapy have retrospectively examined factors that might be relevant (Table 4). It is important to stress that none of these factors has been tested in prospective studies. O u r experience has been that the presence of elevated transaminases or Iobular inflammation or both is associated with subsequent seroconversion, in a g r e e m e n t with Liaw.
But does that mean that such patients should be offered antiviral therapy, since many will seroconvert spontaneously? By treating them with antiviral agents, do we j e o p a r d i s e their chances of a natural seroconversion or do we push the p r o p o r t i o n who eventually develop anti-HBe closer to 100%?
Serum HBV-DNA as Marker of Viral Replication i
In the past 12 months a n u m b e r of studies have emphasised that serum H B V - D N A is a considerably more sensitive index of viral replication than HB ' e ' status. I n d e e d it should be stressed that the presence of anti-HBe is simply a m a r k e r of lower viral replication, rather than absent viral replication. Thus for those with long-established anti-HBe, H B V - D N A is found in serum in 25% of South African blacks, 63% of Chinese and 40% of M e d i t e r r a n e a n patients [22-24]. The recent study of Chu is of particular interest in this respect [25]. H B V - D N A was found in TABLE 4 POSSIBLE FACTORS FAVOURING SEROCONVERSION RATES Chronic active hepatitis Female sex Male sex Homosexual activity Heterosexual activity Recent corticosteroid therapy
Realdi et al. (Italy 1980) [11] Scullard et al. (U.S.A. 1981) [17] Scullard et al. (U.S.A. 1981) [17] Chu et al. (Taiwan 1985) [19] Perrillo et al. (U.S.A. 1984) [20] Novick et al. (U.K. 1985) [21] Scullard et al. (U.S.A. 1981) [19]
$6 the sera of the majority of patients irrespective of the HB 'e' status but was present in significantly greater amounts in those with HBeAg than those with antiHBe. Strikingly, histological inflammation was rare in those in whom serum HBV-DNA was either high or absent; in the former, minimal liver damage was present and in the latter, inactive liver disease. In contrast in 76% of patients with low, but detectable, levels of serum HBV-DNA, chronic active or lobular hepatitis was present. These observations suggest that viral replication stimulates an immune mediated attack, the varied nature of which accounts in part for the wide spectrum of liver damage associated with HBeAg. A newer model of HBV has now evolved wherein chronic active or lobular hepatitis can be regarded as the histological expression of the process of clearance of HBV-replication and it is implied that the degree of liver damage will be related to the length and severity of that process. As in the case of HBeAg/anti-HBe seroconversion, it is not clear at present whether those with low levels of serum HBVDNA, i.e. those who may be undergoing spontaneous seroconversion, should or should not be treated (Fig. 2). A small number of reports indicate that loss of viral replication may not be permanent [25,26]. This is PHASES
OF CHRONIC
MINIMAL LIVER OAMAGE . . . . . . . . . . . . .
H~V-
DNA
HBV
iNFECTION
CHRONIC ACTIVE LOBULAR HEPAIITIS
(CURRENT
INACTIVE
LIVER
VIEW)
DISEASE
IN SERUM
J f _ ~ -- ~ ~ ---
INTEGRATION OF HSV-DNA
J TUMOUR
Fig. 2. The current view of HBeAg/anti-HBe seroconversion. In this model the process of clearing HBeAg is equated with chronic active hepatitis. The duration of the first two phases can vary markedly between individuals while the duration of seroconversion will determine the degree of chronic liver damage.
consistent with the principle that the presence of antiHBe is a crude index of loss of viral replication since most reports of reactivation have looked at antiHBe/HBeAg seroconversion. But some patients have apparently become positive for serum HBVDNA having previously been negative, although this has usually been associated with immunosuppression. The implications are that even serum HBVDNA may be a poor marker of the potential for viral replication and that complete clearance of HBV may not be a practical proposition in every patient.
Viral Integration An important aim of antiviral therapy must be to reduce the potential for hepatoma development. Paradoxically, one of the questions raised with respect to antiviral therapy has been the possibility that seroconversion from HBeAg to anti-l-iBe might increase the risk of malignant transformation by increasing the chances of integration. Only longitudinal studies can answer this question, but it would appear more likely that viral integration might occur at any time and that the period of exposure to virus rather than seroconversion is a more important factor. Adequate longitudinal data are not yet available regarding the timing of integration. Studies from Brechot's group [27] have shown that 18/20 HBsAg+, anti-HBe+ carriers had integrated sequences in the liver compared with 3/20 with HBeAg in serum, implying that integration occurs after a considerable period-yet the same group have demonstrated integrated sequences in patients with fulminant hepatitis B and when children, born to carrier mothers were analysed (i.e. those in whom the timing of infection could be accurately estimated), integrated sequences were found as early as 8 months of age. The role of HBV as a major determinant of malignant transformation has been questioned recently. In the study of Zaman et al. [28] male sex and the presence of cirrhosis were more important determinants than the presence of HBV. If cirrhosis is a major fac-
$7 PHASES
r,°o~m..t
OF CHRONIC
,1,
?,L
HeY-ONA
-
HBV
INFECTION
(CURRENT
VIEWI
?L
IN SEAUM
-
-
~ ~
~ ~
INTEGRATtON OF H S V - O N A
TUMOUR
Fig. 3. The timing of therapy. During the early phase when viral replication is high therapy may not be successful. Therapy during the phase of chronic active hepatitis may be too late to prevent cirrhosis or viral integration. The optimum time for therapy is at the earliest phase of chronic active hepatitis when immune mechanisms will contribute-but identification of this timepoint may prove elusive. tor then antiviral therapy might affect the incidence of h e p a t o m a by preventing progression to cirrhosis. If integration proves to be a m a j o r factor, then the likelihood of an effect of antiviral t h e r a p y on malignant transformation will d e p e n d on the timing of integration in relation to therapy.
Timing of Treatment
the objectives. The evidence that seroconversion from H B e A g ~o anti-HBe is accompanied by remission indicates that the primary objective should be prevention of progression to cirrhosis and the earlier that treatment is offered in the course of the disease the better. It is possible however, that t r e a t m e n t during the early phase (Fig. 3) when viral replication is high may be less successful than treatment at the stage when chronic active and/or lobular hepatitis is present and viral replication is low. Since C P H may progress, patients in the early phase should be considered for therapy. It could be argued that t r e a t m e n t during the phase of histological activity is unnecessary since seroconversion is likely to occur spontaneously. Against this are the observations that when seroconversion occurs following, or during therapy (with interferon in particular), the duration of the inflammatory process of seroconversion is curtailed although the degree of inflammation may be similar. Thus antiviral therapy during the active phase may limit the duration of the liver damage. Insufficient data concerning the timing of viral integration into host D N A are available at present to be certain whether antiviral therapy will have any effect, but since integration is likely to be a random event, then the earlier treatment is offered the more likely it is that integration will be prevented.
The timing of antivirai therapy will d e p e n d upon
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$8 terology 1983; 84: 216-219. 13 Sheen IS, Liaw YF, Tai DI, Chu CM. Hepatic decompensation associated with hepatitis Be antigen clearance in chronic type B hepatitis. Gastroenterology 1985; 89: 732-735. 14 Norkrans G, Lindberg J, Frosner G, et al. Clearance of hepatitis Be antigen in chronic hepatitis B infection. Scand J Gastroenterol 1982; 17: 383-387. 15 Viola LA, Barrison IG, Coleman JC, Paradinas FJ, Murray-Lyon IM. The HBe antigen antibody-system and its relationship to clinical and laboratory findings in 100 chronic HBsAg carriers in Great Britain. J Med Virol 1981; 8: 169-175. 16 Schalm SW, Heijtink RA. Spontaneous disappearance of viral replication and liver cell inflammation in HBsAg-positire chronic active hepatitis: Results of a placebo vs. inteferon trial. Hepatology 1982; 2: 791-794. 17 Scullard GH, Pollard RB, Smith JL, et al. Antiviral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside. J Inf Dis 1981; 143: 772-783. 18 Chu CM, Liaw YF, Sheen IS, Lin DY, Huang MJ. Sex difference in chronic hepatitis B virus infection: an appraisal based on the status of hepatitis Be antigen and antibody. Hepatology 1983; 3: 947-950. 19 Scullard, GH, Smith CI, Merigan TC, Robinson W J, Gregory PB. Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B. Gastroenterology 1981; 81: 987-991. 20 PerriUo RP, Campbell CR, Sanders GE, Regenstein FG, Bodicky CJ. Spontaneous clearance and reactivation of hepatitis B virus infection among male homosexuals with
chronic type B hepatitis. Ann Int Med 1984; 100: 43-46. 21 Novick DM, Lok ASF, Thomas HC. Diminished responsiveness of homosexual men to antiviral therapy for HBsAg positive chronic liver disease. J. Hepatol 1985; 1: 29-35. 22 Chu CM, Karayiannis P, Fowler MJ, Monjardino J. Natural history of chronic hepatitis B virus infection in Taiwan: Studies of hepatitis B virus DNA in serum. Hepatology 1985; 5: 431-434. 23 Hadzyiannis SJ, Lieberman HM, Karvountzis GG, Shafritz DA. Analysis of liver disease, nuclear HBcAg viral replication and hepatitis B virus DNA in liver and serum of HBeAg vs. anti-HBe positive carriers of Hepatitis B virus. Hepatology 1983; 3: 656-662. 24 Lieberman, HM, Labrecque DR, Kew MC, et al. Detection of hepatitis B virus DNA directly in human serum by a simplified molecular hybridisation test: comparison to HBeAg/anti HBe status in HBsAg carriers. Hepatology 1983; 3: 285-291. 25 Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Int Med 1982; 96: 447-449. 26 Dusheiko G, Song E, Bowyer S, et al. Natural history of hepatitis B virus infection in renal transplant recipients - - A fifteen year follow up. Hepatology 1983; 3: 336-370. 27 Brechot C, Pourcel C, Hadchouel M, et al. State of hepatitis B virus DNA in liver disease. Hepatology 1982; 1: 27S-34S. 28 Zaman SN, Melia WM, Johnson RD, Portmann BC, Johnson PJ, Williams R. Risk factors in development of hepatocellular carcinoma in cirrhosis: prospective study of 613 patients. Lancet 1985; i: 1357-1360.