Why most patients with hepatitis delta virus infection are seronegative for hepatitis B e antigen

IO6 ,,LPAT

wvn

Why most patients with hepatitis delta virus iniectkn seronegative for hepatitis B e antigen

are

A prospective controlled study :‘un-Fan

iiaw,

Jenn-Tang

Dong, King-Wah

Chiu, I-Shyan Sheen and Chia-Ming

Chu

1 iwr “,,i,, Chong Cung Me,nori!a,“orpi,*lInd c*vng Gun* Medico! c0nc.v **ipci. Taiwo” (Reccivcd BJa”“ary ,990) (Accepwd ZJ Augur tw,

A prospectwe age/sex matched cozirol and follow-up study was conducted to explore the reason(s) for the association of lhepatnia delta virus (HDV) infection with hepatitis B e antigen (HBeAg) negative hepatitis B surface antigen (HBsAg) carrier staw Over a 3.year period. B !otal of 110 patients (104 males and six females) with acute HDV superinfection were documented in our unit. Twenty-four (21.8%) of them were HBeAg positive at the onset of acute HDV infection. In the control study. 110 age- and sex-matched asymptomatlc HBrA8 carriers wi!h normal serum transaminase. es well as 110 age- and sex-matched patients with chronic type B hepatitis were randomly selected from the computer files of the same 3year period of entry. The prevalence of serun HBeAg in patients with HDV infection was similar to that of asymptomatic HBsAg carriers (2O.Y%). but significnntly lower than that of the patients with chronic type B hepatitis (72.7%). In a followup study of 16 HBeAg-positive patients with HDV infation, eight (50%) cleared HBeAg and three (16.8%) woconvcrtcd to arm-HBc within 3 months. The HBeAg clearance rate was signifacantly higher than for chronic type B hepatitis and asymptomatic carriers @ < 0.01). The results suggest that the low prevalence of serum HBeAg in HDV infection simply reflects the HBeAgianti-HBe status of the asymptomatic HBsAg carriers in the population under stody. Also in some patients HDV supermfection may itxlfauppress HBV and thus clear HBeAg.

Since the discovery of bcpatitis delta virus (HDV), it bar been well documented that patients with HDV infection usually exhibit a low level of hepatitis B virus (HBV) replicauon and are seeronegative for hepatitis B e antigen

none of these was a well controlled prospective study and many involved drug abusers that might complicate the situation. We therefore conducted a prospective age- and sex-matched case control and follow-up study in a non-ad-

(HBeAg) or seroporitive for its antibody (anti-HBe) (I-12). Previous studies suggest that direct or indirect

dict population

suppression of HBV by HDV may be responsible for this association (13-16). It has also been thought that antiHBe-positive hepatitis B surface anugen (HBsAg\ LXtiers are more s~osceptlb!r to HDV Infection (1,6,16,17) or that ano-HBe seropositivity reflects a later stage 01 chronic HBV infecrion which provides accumulated chances of acquiring HDV infection (11,14). However,

to explore this problem.

Materials and Methods From June 1985 to September 1988, a consecutive series of 110 patients with acute HDV superinfection was seen in our unit. They have already been included as part of a series of 164 patients described elsewhere (IS), and

formed were

the basis of this study not

included

HBVIHDV

The remammg

because

coinfection

two

patients

paoentr

hod

acute

and the other 52 were oatient\

fore June 1985 detected m ii retrospective

an;i-HD

br-

assay

on stored sera from patienta with chronic type B hepatms (19.20).

Thur.

these 110 patients rcprcwnt

senes of patiei-1: detected prospectwcly

.m unsclccted

river a period of

JO months after June 1985. when routine anti-HD became available in our unit. The dlagnws ruperinfection

was made if patients with clini~d

showed de nova seroconvers,on creasing tients).

testing

of acu!e HDV

titers of antibody

(53 pat,ents)

to HDV

hcpntm\ or hat

(;mti-HD)

I,,-

(57 pa-

Parients consisted of 1114mideb and SW. femnlc:.

The mean age was 34 years with a range between years.

Of \he

screening

110 patients,

Ih-hl

23 had been diagnoard

test as agmptonwic

HBsAg

carriers

years, and 12 pa1ic.m had had chronic liver dirrarer to acute HDV

infection.

prior to acute HIW

the former (one HBeAg and one negative HBeAg

positive

The

five anti-HBe positive)

The

positive

group*

(three

HBeAg

end six of the latter

and three anti-HBa

Results

stzxw

was known in seven of

positive.

for both)

prim:

HBeAg/anti.:fBe

superinfection

hy

for I-h

-#‘he re-

HBeAg xc

\tatur

of the stbdy gnmp

4111wn in Ti~hle

I

m pz~txnts with ixutc

w.ts \Ignificanlly

HDV

B hepabtis (p (

disease. and were serologically

defined as prevvx sly un-

tomam

recognized

carrwr~

P:ons of

rhc prcvalwcc

of the sewn

them admitted to drug or alcohol abuse or homosexual ac-

arymp,“mat,~~.

HBrAg

tivity. One patient was an operating

HBc status pour to their acute HDV

HBbAg

(3.21)

room nurse ,who hed

U.lMl).

HBQQ

recei\rd

perinfection

infection.

Twenty-four

positive, (9.1%)

76 (69.1%) were negative

acute HDV HD)

(21.8%) were

patients

anti-HBe

were

cxrters

and

type B hcpaniir

10

at the onset of

infection when serum antibody to HDV

patients

and 56 HBeAg-negative

had been regularly

followed

age- and srx-matched

up for at least 6

groups were randomly

anti-HD-negative

puter files of patients with chrome HBV entered the unit in the samo pc;iod. asymptomatic

HBsAg

lyconfirmed

mfeaion

The &her

serum trans-

during blood donation

or

were 1 LO clinicohistologrcal-

chronic type B bepattiis patrenrr who had not

recewed any iintivira,

or o’.,er

apeciric therapy.

tients in the controi groups were followed months.

who had

One group were II0

carriers with normal

aminase, detected inc’denally routine check-up.

control

selected from the Liver Unit com-

Their

HBeAgianti-HBe

All pa-

up for at least 6

srmus and subsequent

changes were compared with those of our study group. Hepatitis HBe

markers.

and anti-HD,

available

including were

radioimmunoassay

HBsAg.

HBeAg.

anti-

assayed using commercially kits (Ausria

!I.

HBe-RIA

recogmaxI,

to hut

infection

The prcva-

in patients woh acute HDV

iw

Gmilar to asymptnmzmc HB*Ag

but higher than patients

wth

chronic

(?S.S%_).

eigh. (iOc/)

cleared tiBcAg

(or a total of 72i

months. Two

(6S.Y+,)

previously

In B follow upstud:, of the prmenrs wrh itcute H3V faction.

(a&

was negative or positive at a very low titer. Six&n

HBeAg-positive

WF 69. I%,

HBrAg

positive

for both markers

but was ~.imilar !o ihat in asymp-

ciirrierr with known HB‘Agl;m,i-

lrncr of serum anti-HBe

transfusion 2 months prior to acute HDV

(2I.W)

carriers (p z IISI?). It was alro wnilar

experienced many needle pricks, and another palient had a blwd

of rerum

infectton

lower than in patients wth chrome type

maining 75 patients had no past history of hepatitis JT liver inapparent

z,nd (..rntrul

The prcvidcnce

of the I6 HBeAp-positive

fro,,, thor xrum

and rhree

I”-

p’&nts

(I8.WI wro-

IUN

convcrtcd tu .mti-HBc within 3 months after the “met of acute HDV infection. Scrcn HBeAg reappeared in two oflhr cighl p;~twnrrwith HHcAgclcarance. whde nooe of the 57 originally HRcP.g.:wgativc patients dcvelopcd NHV rcactiwl00” Of lbc R0 fiBcAp_positwe pnoents \wilh chrome type B hcpntitis. 12 (1S.IW) cleared their senot HBcAg and seroconvertcd to nnti-HBe withm 3 months of follow-up. while HBV rewtwation developed

and thst :1BeAg is po+ive

in 72.7 am! 20.9W. respective-

and asymp-

ly, in the tu” cwtwl groups (Table 1). it can be estimated that 26.h% of our patient* must bee” HRlAg positivc et the time of contracting HDV infection. If this is indeed the case. suppression of HBV with HBeAg clear~“ce or serocooversio” might have Wendy occurred in uo additional 5% of :he patients when they were first studied. These fiildings are consistent with the observation in another series of “co-addict patients (15), hut contradictory to that of a study involving mainly drug abusers (16). Since HBeAg clearance usually signals that HBV rcplicntion is dxreasiog or has cearrd (i9,22), these findings provide father support to !he suggestion that HDV soperinfection has B role in HBV clearance (14,15). Con-

Tbr results of the present prospective controlled study show that the prcvaleoce of serum HBeAg in our patients

ceivably, the prevalence of serum HBeAg will decrease further during the chronic phase of HDV infection. These observations arc consistent with the suggestion of Hadziyannis et al. (8) that HBV expression in chronic HDV infection reflects the virologic characteristics of the onderlying chronic HBV carrier Pate complicated by HDV superinfection.

in f”t.r of thesc patiunlr.

In mnt~dbt. unly mr of the 23 Hl)eAg.p”ritivc xymptomatic carriers cleared HBeAg ;mttl none suroconverted to aott-HBe within 6 months sfter ewry (Table The HBeAg clearance rate in patients c”ntr;rctmg ocutc HDV is stgnificnntly higher than the

I).

raie in patients with chronic type I3 hepatitis ,o”xmc CBrrlers ($7< 0.01).

wnh acute HDV superinfection IS as low as in anti-HDpostfive patients with chronic hepatitis From the same geographical area (IU-12). It is Itotable that the prevalence is similar to that of the sevc” ~symptomatic carriers whose HBcAgmnli-HBe status had been examined prior to acute HD\’ superinfection. as well as ordinary asymptomioic HBsAg carriers. It is much lower. however, than the prevalence in patients with chronic type B hepatitis with “a evidence of HDV infection fTable I). These results rupgest that the low prevalence of serum HBeAg in ox palients simply reflects the HBeAgianti-HBe status of the asymptomatic HBsAg carriers in a population at risk of HDV infection. Thb is further supported by the fact that the majority of our patients were previously inapparent or rccogmzed. but were asymptomatic HBsAg carriers prior to acute HDV infection. If anti-HBe-oositive carriers were morr susceptible to HDV superinfectton, as prewously suggested (l.h.lh.17). the prevalence oi serwt, HBeA@a”tl-HBe in patients with HDV infection should he lower/higher

than that of the control group of asymp-

tomatic HBrAg carriers 3ur results do not support this hypothesis. The resuhs of “or f”llo\wp study bavc also show” that HBeAg clearance occurs frcqucntly over a short time-penod followng acute HDV infection. It is noteworthy that the HBeAg clearance rate following HDV infection is signiflcantly hagher than that observed in the natural course of chronw HBV infection, particularly 1” asymptomatic HBqAg cerrxrs (Table I). Considering that 12 (10.9%) of the uhile 98 were asymptomatic HBsAg carriers prior to HDV intecri”“,

11”psuenrr haci ckanic lirerdkeare,

I YE

Recent studies on drug abusers in Taiwan (24 25) have show? tha: the prevalence of serum HBrAg in HBsAg carriers who have exposed to HDV infection (10.413.3%) in significantly lower tbam in the present study. The high HBeAg clearaoce rate following acute HDV infection in the present study rtwy explain the lower prevalence of serum HBeAg in the HBsAg carriers with remote HDV infection in those studies. In addition, the significantly higher HBeAg clearance rate in patients with HDV infection than io the control group of asymptomatic HBsAg carriers may also provide an explanation for the difference in HBeAg prevalence between their HBsAg carriers with and without remote HDV exposure (24). The data showing that the majority of our patients with acute HDV superinfection had bee” previously “orecognized asymptomatic HBsAg carriers and that only 12 (10.9%) of our pattents had had chronic liver disease prior to acute HDV infection, could suggest that HDV preferentially superinfects asymptomatic HBsAg carriers rather than patients with chronic liver disease. However, this is unlikely since in the present series the proportion of patients with chronic liver disease is even higher than the 5% or three of 60 HBsAg-positive adults observed in our previous survey study in the same geographical area (26). In conclusion, the results of the present study suggest that the association of HBeAg seronegative HBsAg carrier state with HDV infection simply reflects the HBeAgi anti-HBe status of asymptomatic HBsAg carriers in a particular population under study. HDV superinfection irsetf may also suppress HBV and thus clear HBeAg in some pEltietllS.

Arknowkdgemenb

This work war supported m part by grants from the National Science Counctl (NSC79M19-BISZ-07

and NSCXO-

0419.BlX24GJ)

and a grant from the Prosperous Fwn-

dation. Taper.

The authors thank the excellenr BWS~RICC

of Miss M H Tui manurcrq

during the study and preparation

of this