IMPORTANT SUMMARY Article-Marty

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Seminars in Liver Disease

Recovery, Persistence, and Sequelae

in Hepatitis C Infection: A

Perspective on Long-term Outcome

Harvey J. Alter, MD and Leonard B. Seef, MD Department

of Transfusion Medicine, Warren Grant Magnuson Clinical

Center, and Section of Digestive Diseases and Nutrition,

NIDDK, NIH, Bethesda, land.

Abstract

Hepatitis C has emerged in recent years as the most common

basis for liver disease in the United States, having infected an

estimated 3.9 million people in this country and an estimated 170

million worldwide. Currently, it is the predominant reason for

undergoing liver transplantation. The disease it causes is

characterized by silent onset in most infected individuals, a high

rate of viral persistence, and the potential for development of

ever-worsening chronic liver disease, ranging from chronic

hepatitis to cirrhosis and occasionally to hepatocellular

carcinoma. Such progression, when it occurs, is also most

commonly a silent process that may take 20-40, and

occasionally even more, years to reach its end point. Because of

these characteristics, it has been exceedingly difficult to

accurately assess the natural history. Efforts to accomplish this

have consisted of retrospective, prospective, and cohort studies.

The most concerning data have derived from the retrospective

study approach, generally performed at tertiary referral centers.

Because these centers commonly attract persons with existing

chronic liver disease, they have tended to describe a high rate of

progression to cirrhosis and cancer. This " referral bias " is

avoided in the prospective and cohort study approach, and data

derived from these studies indicate a lower rate of progression

and a correspondingly higher rate of either recovery or minimal

liver disease. In this review, we briefly describe potential

mechanisms of viral persistence; present detailed information on

outcomes that have derived from retrospective, prospective, and

cohort studies, involving both adults and children; examine the

data regarding progression of fibrosis and of progression to

hepatocellular carcinoma; consider cofactors that might enhance

liver disease progression; and report the emerging data that

suggest that spontaneous viral clearance may be higher than is

currently believed. We conclude with the view that severe,

life-threatening, progressive liver disease clearly occurs in a

sizable minority (perhaps 30%) of chronically infected persons

but speculate that fibrosis progression is neither linear or

inevitable and hence that most hepatitis C virus carriers will have

either a stable nonprogressive course or such indolent

progression that they will die from an unrelated disease before

the severe sequelae of hepatitis C become manifest or will have a

sustained " curative " response to therapy. Although this view

provides reasonable hope to the hepatitis C virus-infected

individual, it does not deny the enormous burden this infection

presents as the result of its high prevalence and global

distribution. The sheer magnitude of the infected population will

result in a large number with severe life-threatening liver disease

even if the proportion of infected individuals that develop

progressive disease is relatively small. [sem Liver Disease

20(1):17-35,2000. © 2000 Thieme Medical Publishers, Inc.]

Introduction

As the chronic consequences of hepatitis C virus (HCV)

infection receive increased attention from patient advocate

groups, public health advisories, and the lay press and as patient

concern escalates, it is important to reexamine the natural history

of this infection and to place disease outcomes in proper

perspective. This is not an easy task because the disease process

is indolent and outcomes may not be known for many decades.

Thus, studies with 10-year or even 20-year follow-up that

provide definitive outcome assessments for most diseases may

not be adequate to fully assess the chronic sequelae of HCV

infection. At present, there are considerable data regarding

20-year outcomes in HCV infection, but with few exceptions,

extrapolations are required beyond that point. In addition to the

slow evolution of disease, a balanced perspective must take into

account variables such as the age at onset and cofactors,

particularly alcohol. Further, one must examine both the disease

burden for the infected individual and the disease burden for

society. Based on currently available data, it would appear that

the societal burden is considerable because of the high

prevalence of the infection, but for most HCV-infected

individuals, the infection has both low morbidity and low

mortality. The problem is that we cannot predict the 20-30% of

individuals who will sustain more dire outcomes.

In this review, we examine the evidence that HCV infection has

serious and sometimes mortal consequences and, paradoxically,

the evidence that this infection can be largely silent and

compatible with uncompromised longevity. Specifically, we

attempt to provide the framework within which the clinician can

address the most common concerns of the HCV-infected

individual, namely, " What is the likelihood that I will die of this

disease? " " How sick will I become? " " Can I be cured? "

The clinician cannot provide definitive answers to these questions

for the individual patient, but by presenting balanced data from

natural history studies and treatment options, the physician can

render a perspective that can reduce patient anxiety and offer

realistic hope that the hepatitis will not progress rapidly, may not

progress at all, may be compatible with a normal lifespan, and

may respond to therapy.

Historical Perspective

When first recognized, non-A, non-B hepatitis was regarded as

a relatively mild illness that generally lacked the typical clinical

manifestations of hepatitis A or B.[1] Speculation abounded as to

whether non-A, non-B was a distinct viral illness or a nonspecific

transaminitis related to postoperative events. The issue was

resolved when non-A, non-B hepatitis was linked to needlestick

injuries in health workers and, particularly, when human inocula

were shown to transmit non-A, non-B hepatitis to

chimpanzees.[2-5] Nonetheless, it required an additional 15 years

before this nebulous transmissible agent was identified as

HCV.[6]

The initial equanimity about the condition gave way to concern

when it became apparent that about 50% of those infected had

persistence of raised serum enzyme values even though most

continued to have no symptoms.[7] Subsequently, liver biopsies

established that the chronic asymptomatic hepatitis was

accompanied by moderate to marked fibrosis or cirrhosis in

about 20% of cases. Concern escalated when sporadic reports

began to appear linking hepatocellular carcinoma (HCC) to

previous episodes of non-A, non-B hepatitis.[8] The association

between non-A, non-B/HCV and both cirrhosis and HCC was

then confirmed in multiple studies.[9-12]

Later, epidemiologic studies of anti-HCV positive blood

donors[13] and patients with community-acquired hepatitis C[14]

revealed that 75-85% of HCV-infected individuals failed to

resolve their infection, and population surveys determined that

the prevalence of HCV infection in the United States was close

to 2.0%, suggesting that almost 4 million people were chronically

infected in the United States alone.[15]

Increasingly, the accrued evidence indicates that HCV infection,

despite its generally mild clinical presentation, is a problem of

considerable magnitude leading to persistent infection and

chronic hepatitis in most and to cirrhosis and end-stage liver

disease in some. Further, hepatitis C has now become the most

frequent reason for hepatologic consultation and the single

leading indication for hepatic transplantation, accounting for 30%

of such procedures in the United States.[16] Thus, from obscure

beginnings as a mild infection of unknown etiology, hepatitis C

has ascended to international eminence as a leading cause of

major liver disease. Nonetheless, the proportion of infected

patients who reach these well-publicized deleterious outcomes

remains poorly defined, and recent data suggest that such dire

outcomes are less frequent than commonly feared.

Mechanisms of Viral Perstence and the

Pathogenesis of Chronic Hepatitis

Although viral persistence is a fundamental prerequisite of

chronic hepatitis, the mechanisms of viral persistence and liver

injury may be distinct. It appears that the primary determinant of

persistence is the quasispecies nature of the virus. HCV, like

other RNA viruses, exists as a family of closely related but

immunologically distinct variants that have been termed the

quasispecies. More than 20 strains of HCV have been cloned

from a single patient at a single point in time, and this is an

underestimate of the total number of variants actually present.

Thus, even if the host mounts a neutralizing immune response to

the predominant HCV strain, any of the other variants already

present could escape the immune attack and replicate to become

the new predominant strain. By inoculating chimpanzees with

mixtures of known infectious inocula and human sera obtained at

various time points after the onset of infection, it has been shown

that humans develop neutralizing antibodies to HCV but that

these antibodies are highly strain specific and incapable of

preventing the emergence of viral variants that can maintain the

infection.[17]

Similar conclusions have been reached using in vitro systems that

measure the uptake or binding of HCV to cultured cells.[18,19]

Recently, Farci et al.[20] measured both the number of strain

variants (complexity) and the number and breadth of

nonsynonymous nucleic acid substitutions (diversity) that occur

during the first 16 weeks of HCV infection and showed that the

extent of viral diversity predicts whether HCV infection will

resolve or become chronic. It appears that in most

HCV-infected patients, the development of antibody exerts

immune pressure that drives the quasispecies and leads to an

increasingly complex population that can elude the immune

attack and result in viral persistence.

The importance of antibody in driving viral diversity is further

illustrated in patients with agammaglobulinemia, in whom it has

been shown that in the absence of antibody the viral population

remains homogeneous (see Farci and Purcell in this issue).

Despite the correlation between viral diversity early in HCV

infection and the subsequent development of chronic hepatitis,[20]

it is clear that humoral immune pressure and escape variants are

not the only mechanisms determining persistent infection. Bukh et

al.[20a] showed in the chimpanzee model that two animals,

although infected with the identical full-length monotypic

infectious clone, nonetheless had diverse outcomes, with one

recovering and the other developing chronic infection. Other

speculative mechanisms for viral persistence include the potential

that HCV has mechanisms to decrease the effectiveness of

antiviral cytokines, to increase the resistance of infected cells to

cytotoxic T lymphocyte (CTL)-mediated killing, to infect

immunologically privileged sites, or to induce immunologic

tolerance.[21]

The net result of this host-virus interplay is that despite the

development of antibodies to proteins expressed along the entire

HCV genome, most patients are unable to eradicate the virus

and manifest persistent infection usually with evidence of chronic

liver disease. Further, the immune responses are so highly strain

specific that even patients or animals that recover from HCV are

susceptible to reinfection.[17,22]

Studies of cell-mediated immunity to HCV are just beginning to

emerge, and the role of cell-mediated immunity in viral clearance

and liver cell damage is still inconclusive but probably

fundamentally important. Of interest, studies of intrahepatic CTL

responses in chimpanzees have shown that viral variants can

escape the CTL response just as they escape the humoral

antibody response.[23] The influence of cell-mediated immunity on

viral persistence will be comprehensively reviewed by

Rehermann in the next issue of Seminars.

The mechanisms of cell death in HCV infection are not fully

elucidated. Clearly, liver cell damage is not solely due to viral

cytopathic effects because very high titers of virus within the liver

and in serum are compatible with minor cell damage. Similarly, it

is not clear that cytotoxic T cells are responsible because the

worst degrees of liver disease are often observed in patients who

are immunodeficient, particularly patients coinfected with human

immunodeficiency virus (HIV).[24] Liver cell damage is probably

a complex interplay of direct viral injury, cell mediated

cytotoxicity, cytokine effects, apoptotic events, and other

intracellular events that have not been elucidated.

Hepatitis C Outcome Based on Patients Refered

for Chronic Liver Disease

As might be expected, the most severe outcomes of HCV

infection have been observed in retrospective studies that assess

persons with already established chronic hepatitis and attempt to

define the rate of development of adverse sequelae by tracing the

chronic disease back in time to the moment of acute onset (Table

1).

Kiyosawa et al.[9] conducted a retrospective evaluation of 231

patients with chronic non-A, non-B hepatitis (96 with chronic

hepatitis, 81 with cirrhosis, and 54 with HCC) of whom

approximately 90% were HCV related and 30-50% had been

previously transfused. Serial liver biopsies in some documented

the sequential progression from stages of increasingly severe

inflammation and fibrosis to cirrhosis and, ultimately, to HCC.

When frequent serial biopsies were available, cirrhosis was

always found to precede HCC.

Similar data on clinical outcomes of transfusion- associated

hepatitis C came from a report by Tong et al.[10] These

investigators conducted a retrospective evaluation with

short-term follow-up of 131 individuals from a group of 213

patients with chronic hepatitis C referred to their hospital. All

131 selected individuals had received blood transfusion on a

single occasion. Initial liver biopsies in 101 patients revealed

chronic hepatitis in 21%, chronic active hepatitis in 23%,

cirrhosis in 51%, and HCC in 5%. Follow-up over a mean

duration of 3.9 years (range, 1-15 years) demonstrated that an

additional 7 patients (5%) developed HCC and 20 (15%) died,

8 from complications of cirrhosis, 11 from HCC, and 1 from

pneumonia.

Yano et al.[25] examined histologic progression in 70 noncirrhotic

patients who had 2-10 liver biopsies (mean, 3.9) obtained over

the course of 5-26 years of follow-up. During follow-up, 50%

developed cirrhosis, including all patients who had a high

histologic grade on a prior biopsy; the rapidity of progression

correlated directly with the histologic grade. This important study

clearly demonstrates the potentially serious nature of this chronic

infection, particularly among Japanese patients. However, again

this was a retrospective study of referred cases and had an

inherent selection bias. A small number of patients were selected

from a large patient base (70/2,000) without specific reasons

being offered for their selection.

Niederau et al.,[26] from Germany, conducted a follow-up study

of 838 HCV RNA positive patients referred to their tertiary-care

center for therapy. The duration of follow-up ranged from 6 to

122 months (median, 50.2 months). At study entry, 141

(16.8%) patients had cirrhosis, mostly classified as Childs' A

cirrhosis. A total of 62 patients (3.7%) died during the course of

the study, 18 from cirrhosis, 13 from HCC, and 31 from other

causes. Mortality was strongly related to the presence of

cirrhosis and estimated duration of infection. Importantly, among

the 696 patients without cirrhosis, mortality was no greater than

that of the general population regardless of duration of infection.

All patients who developed HCC either had cirrhosis at entry or

developed cirrhosis later.

These studies (Table 1) conducted by referral centers

unequivocally demonstrate the severe outcomes that can derive

from HCV infection. However, because of referral bias, such

studies do not assess the broad spectrum of outcomes that might

occur if the entire HCV-infected populations were fully

evaluated. Thus, referral-based studies do not determine the

proportion of patients who spontaneously recover from infection,

the proportion who have mild disease and do not seek medical

attention, or the proportion who die of intercurrent illnesses

before their HCV status can be assessed. Thus, by their very

design, such selective referral-based studies demonstrate only

the more severe outcomes of HCV infection and represent a

" worst-case " scenario. It is critically important to know that such

severe outcomes occur but equally important to realize that

retrospective studies provide incomplete information on the

frequency with which progressively severe liver disease occurs in

the entire universe of HCV-infected individuals.

Outcome Based on Long-Term Follow-up of

Acute Hepatitis C

The original indication that acute non-A, non-B hepatitis

progressed to chronic hepatitis in a large proportion of cases

emanated from the long-term follow-up of patients enrolled in

prospective studies of transfusion-associated hepatitis.[27-30]

These studies, originally designed to investigate the incidence and

causes of transfusion-associated hepatitis, were extended when it

was observed that many patients still had elevated alanine

aminotransferase (ALT) levels at the end of their designed

6-month follow-up (Table 1).

Patients originally enrolled in the NIH prospective

transfusion-associated hepatitis studies[31] were reassessed for

evidence of chronic liver disease by Di Bisceglie et al.[27]; 65

patients, 53 (82%) of whom had hepatitis C, were evaluated

1-24 years (mean, 9.7 years) after onset of acute non-A, non-B

transfusion-associated hepatitis. Forty-five of the 53 (65%)

developed chronic hepatitis, of whom 33 consented to liver

biopsy. The study described these 33 patients plus 6 others with

chronic non-A, non-B transfusion-associated hepatitis who were

not enrolled in the original prospective study. When initially

biopsied, 4 of 39 (10%) already had cirrhosis. Twenty of the 39

patients were rebiopsied at varying intervals, at which time 4

additional patients had histologic evidence of cirrhosis. Thus,

cirrhosis was found in 20% of the 39 patients biopsied, or

12.3% of the total 65 patients assessed; none had HCC. Eleven

patients died during follow-up, but only 2 from liver failure. Thus,

liver-related death occurred in 2 of 45 (4%) of those with

chronic hepatitis.

Koretz et al.[28] followed 80 patients who had developed acute

transfusion-associated hepatitis approximately 16 years earlier,

64 (80%) of whom were HCV-infected based on enzyme

immunoassay (EIA). Fifty-five of the 80 (69%) had biochemical

evidence of chronic hepatitis. Liver biopsies were obtained in

only 10 patients and were based on clinical severity; 5 (50%)

had cirrhosis. Liver failure after 16 years of follow-up, primarily

the development of hypersplenism, developed in 22% of those

with chronic hepatitis C. Approximately one third of the cases

died during follow-up, but only one (1.3%) from liver disease

(HCC).

Mattson et al.[29] reported a 13-year follow-up of 39 of 61

patients who had developed acute transfusion-associated non-A,

non-B hepatitis. Serologic and molecular screening of archived

blood samples identified acute hepatitis C in 24. Follow-up

examination revealed that all 24 were still anti-HCV positive 13

years later and that 16 (66%) continued to have detectable HCV

RNA. Most of the patients in follow-up (79%) continued to

show abnormal serum enzyme levels whether or not HCV RNA

could be detected, whereas 21% seemed to have recovered.

Liver biopsies showed the presence of cirrhosis in 8%. One

patient (1.6%) died as a consequence of liver disease.

Tremolada et al.[30] reported a follow-up study (mean, 7.6 years)

among 135 patients with transfusion-associated non-A, non-B

hepatitis, most having undergone cardiac surgery. Almost all

cases were a consequence of HCV infection. Chronic hepatitis

evolved in 104 (77%). Thirteen percent had splenomegaly and

5%, esophageal varices. Sixty-five patients were biopsied and

21 (32.3%) were found to have cirrhosis. This represents a

cirrhosis frequency of 21% among those with chronic hepatitis

and 15.6% among all of those diagnosed with acute hepatitis C.

Among the 104 with chronic hepatitis, 5 (4.8%) died from liver

disease (3, bleeding; 1, liver failure; 1, HCC). Thus, 5 (3.7%) of

the original 135 HCV-infected group died as a consequence of

liver disease.

Less severe outcomes were noted in the follow-up of

community-acquired hepatitis C cases in the Center for Disease

Control and Prevention's Sentinel Counties Study.14 Among

130 identified hepatitis cases, 106 (82%) were diagnosed as

hepatitis C, of whom 62% advanced to chronic hepatitis. Liver

biopsies were performed in 30 of the 60 individuals with chronic

hepatitis; 10 (33%) had " chronic active hepatitis, " 1 of whom

also had cirrhosis; 13 (43%) had " chronic persistent hepatitis " ;

and 6 (20%) had chronic lobular hepatitis. Thus, cirrhosis was

found in only 1% of the 106 community-acquired hepatitis C

cases followed over this relatively short interval. No patient with

hepatitis C died over the course of the study.

Thus, these five prospective studies identified that progression

from acute to chronic hepatitis C was common, that during the

time periods of follow-up (approximately 4-16 years) cirrhosis,

when sought, was identified in between 1 and 20% of the cases,

that development of HCC was rare, and that liver-related

mortality was modest in frequency, ranging from 0 to 3.7%.

These prospective studies, which focus on entire populations

with an identified episode acute hepatitis C, provide a more

balanced portrait of hepatitis C outcomes than do the

retrospective studies that concentrate on patients with already

established chronic hepatitis. However, these prospective studies

also have their failings in that they were not initially designed to

study the chronic sequelae of hepatitis and had no mechanism for

systematic liver biopsies. Biopsies thus tended to be performed

on those who had the most severe biochemical abnormalities or

physical evidence of chronic liver disease, and thus biopsy data

are skewed to detect those with more severe liver disease.

These studies are also flawed in that the dramatic interplay

between hepatitis C and alcoholism was not established at the

time the studies were conducted and data on coexistent

alcoholism were sparse. Thus, these studies generally

underestimate the role of alcohol and attribute all outcomes to

the viral infection per se. Although this does not invalidate the

outcome data, it confounds the interpretation of the natural

history of uncomplicated hepatitis C infection. Finally, these

prospective studies do not provide data on long-term clinical

outcomes in control patients who did not develop hepatitis and

do not extend their follow-up into what may prove to be the

critical third and fourth decades of this infection.

Outcome Based on Cohorts Studied Long After a

Defined Parenteral Exposure

Four studies were designed to investigate the clinical and

histologic outcomes of HCV infection in cohorts infected 17-40

years earlier (Table 1). The unique feature of these studies is that

the HCV status of the subjects at or near the time of initial

exposure was known and that an attempt was made to recall all

known positives at least 15 years later. This design allows

assessment not only of those who developed chronic infection

and severe liver disease, but also those that cleared infection

and/or had benign outcomes. In essence, this study design has

some characteristics of a prospective study but allows long-term

follow-up that rarely can be achieved in prospective studies.

The " concurrent-prospective " approach is illustrated by the

collaborative Veterans Administration (VA) study of

transfusion-associated hepatitis conducted by Seeff et al.[32] This

study assessed long-term mortality after transfusion-associated

non-A, non-B hepatitis using data from five separate prospective

studies of transfusion-associated hepatitis performed between

1967 and 1980 (two VA studies[33,34]), an NIH study,[31] the

national Transfusion-Transmitted Viruses study,[35] and a study

conducted at the Walter Army Hospital.[36]

A total of 1,552 of the 6,438 persons who entered the original

studies were included in the follow-up study, 568 patients with

non-A, non-B hepatitis and 984 matched controls.[32] At

initiation of follow-up, an average of 18 years after transfusion,

all-cause mortality was 51% in both non-A, non-B hepatitis

cases and controls and was related primarily to the cardiac

diseases that necessitated the original open-heart surgery.

Liver-related mortality occurred in 3.3% of the non-A, non-B

cases and in 1.5% of controls (p = 0.). Cirrhosis as the cause of

liver death occurred in 1.9% of the non-A, non-B cases and

1.0% of the controls. In the first 18 years of study, death due to

HCC occurred in only one patient with non-A, non-B hepatitis

(0.2%) and in two control patients (0.2%). Medical records

could be examined for alcohol history in 28 of the 34 patients

with a liver-related cause of death; among these, 78% of cases

and 60% of controls were identified as heavy drinkers. Hence,

liver-related mortality was generally low and, when found,

strongly correlated with alcohol abuse.

In a follow-up report adding an additional 5 years of

evaluation,37 life-table analysis of all-cause mortality showed an

increase among the non-A, non-B hepatitis cases to 69.1% and

to 69.4% for the controls (p = 0.67). Liver-related death for the

entire cohort was 4.0% for the cases and 1.7% for the controls

(p = 0.009); for cases identified as HCV-related, liver-related

death was 2.7% for the cases and 1.5% among their controls (p

= 0.31) (Table 1). Thus, over the course of 23 years after

exposure, most deaths could be ascribed to the underlying

disease that initiated transfusion rather than to liver disease;

though the proportion who died of liver disease was small, there

was a trend toward increasing liver-related death among the

non-A, non-B hepatitis cases with increasing time from

exposure; the development of HCC was rare; and alcoholism

alone or in combination with chronic viral hepatitis appeared to

be the primary determinant of liver-related death. The number of

deaths in HCV-infected patients in the absence of alcohol was

extremely small.

In a separate analysis of this same multicenter cohort, long-term

morbidity was assessed by recalling living patients for whom an

archived blood sample was available for HCV testing.[38] Of the

146 living patients with a prior episode of transfusion-associated

hepatitis, 103 (71%) had detectable HCV markers in a sample

obtained during the course of their original hepatitis. An

assessment of the 103 HCV-related cases approximately 20

years after disease onset revealed that 74% were still HCV

RNA positive, 16% were HCV RNA negative on at least two

determinations but had persistent anti-HCV antibody, and 10%

had no residual markers of their HCV infection. One half of the

viremic patients had biochemical evidence of chronic hepatitis,

whereas the other half had normal serum enzymes. By protocol,

biopsies were restricted to those with abnormal ALT values.

Among these with persistent HCV RNA and ALT elevations,

30% had histologically defined cirrhosis. On the assumption that

cirrhosis would occur in no more than 5% of those with HCV

RNA and persistently normal ALT and in less than 1% in those

repeatedly HCV RNA negative, an extrapolation to the entire

group of HCV-related cases projected that less than 15% of

acute hepatitis C cases would develop cirrhosis in 20 years.

Combining the mortality and morbidity data from this large,

controlled, ,20-year follow-up study, it appeared that 25% of

patients had spontaneously recovered from their HCV infection

as evidenced by the loss of HCV RNA and in 10%, the

concomitant loss of HCV serologic markers; 75% had persistent

infection. Within the full cohort who developed acute hepatitis C,

3.5% subsequently died from liver disease and an additional

15% of living patients had cirrhosis. Thus, severe progressive

chronic liver disease occurred in 15-20% of transfusion-related

HCV-infected persons. The remaining 55% of the cohort had

stable generally asymptomatic chronic hepatitis. The ultimate

outcome of those with stable chronic liver disease over the first

two decades of infection will determine the true severity of

chronic hepatitis C. One can only speculate at present whether

the disease will be inexorably progressive over time or whether a

significant proportion of patients with chronic hepatitis C will, in

the absence of alcohol excess, maintain an indolent

nonprogressive infection that will have no impact on mortality

and minimal impact on morbidity. It is critical that such cohorts

continue in follow-up through the third and fourth decades of

their infection.

The high mortality unrelated to liver disease, the inclusion of

older patients, and the relatively restricted duration of follow-up

in these transfusion studies has detracted from their acceptance

as fully valid indicators of the natural history of hepatitis C

infection. Some of these concerns could be addressed

subsequently when it became possible to test a repository of

10,000 frozen sera that had been drawn from Air Force recruits

between 1948 and 1954.[39] Outcome data could be ascertained

in 8,568 of these individuals, all of whom were tested for

anti-HCV and, when positive, tested by a confirmatory

recombinant immunoblot (RIBA) assay and by polymerase chain

reaction (PCR) for HCV RNA.40 Outcome was determined

using VA and Medicare files and Social Security and National

Death Index tapes. Only 17 of 8,568 (0.2%) were confirmed to

be anti-HCV positive in the repository sample; 11 of the 17

(65%) were HCV RNA positive. The average age at initial

detection of HCV was 23 years. Over the almost 50-year

interval from the first detection of anti-HCV until outcome

tracing, mortality in the HCV-positive group (7/17, 41%) was

significantly higher than that in the negative group (26%), but only

one of the seven deaths was related to chronic liver disease. No

HCV-infected patient died of HCC compared with 9 of 8,557

(0.1%) HCC-related deaths in the large population that was

HCV negative in the repository sample. Although the sample size

was very small, this unique almost 50-year follow-up study of

HCV-positive individuals revealed only one death from liver

disease and no cases of HCC.

Milder outcomes are also observed in individuals whose HCV

infection is detected incidentally during donor screening or other

routine evaluation. In an NIH study of anti-HCV-positive blood

donors,[41] 15% appeared to have recovered from their HCV

infection based on the finding of RIBA-confirmed antibody but

repeatedly negative PCR determinations for HCV RNA. Of

those with persistent infection, peak ALT level exceeded two

times the upper limit of normal in only 16%, and clinical

symptoms were minimal. Liver biopsies were initially performed

on 60 patients.[42] In 20 donors with persistently normal ALT,

the mean histologic activity index (HAI) score was 5.4 and the

mean fibrosis score 0.3; the corresponding HAI and fibrosis

scores for donors with ALT levels between one and two times

the upper limit of normal were 7.7 and 0.6 and for those with

ALT levels more than twice normal, 9.0 and 1.2. Only one

patient had cirrhosis, that patient being in the high ALT group.

The number of biopsies in this population has now been

expanded to 94 (Ghany M, Hoofnagle J, Alter HJ, unpublished

data). No patients have severe inflammatory changes (HAI

15-18), 13% have stage 3 fibrosis, and 2% have cirrhosis after

an average duration of infection of 19 years based on a defined

parenteral exposure. Thus, this study of blood donors

corroborates the findings in the Seeff study,38 indicating that at

least 15% of HCV-infected individuals spontaneously recover

and that less than 15% have severe histologic lesions during the

first two decades of infection.

To determine the progression of histologic lesions over time,

repeat biopsies were obtained 5 years after the initial biopsy in

47 of 60 patients initially reported. Fibrosis progression over that

interval was minimal. The mean fibrosis score increased from 0.5

to 0.9 in 13 donors with normal ALT, remained constant in 19

with ALT levels one to two times the upper limit of normal, and

decreased from 1.4 to 0.8 in 15 donors with high ALT levels.

Overall, no patients developed severe inflammatory changes or

progressed to cirrhosis in the 5-year interval, which brought the

average follow-up time since exposure to 24 years.

Two very important outcome studies were derived from the

inadvertent administration of HCV-contaminated Rh immune

globulin. Kenny-Walsh et al.43 recently described clinical

outcomes 17 years after HCV infection that resulted from the

use of contaminated lots of anti-D immune globulin in Ireland in

1977. Eight batches of HCV-contaminated Rh immune globulin

were thought to have been administered. A national inquiry

organized tracing of recipients of these contaminated lots. Of

62,667 women who presented for screening, 704 were found to

be anti-HCV positive, of whom 390 (55%) were also HCV

RNA positive. Extensive evaluation was accomplished for 376

(96%) of those HCV RNA positive persons. Analysis revealed

that the mean age at exposure was 28 years, that all genotyped

as type 1, that about one third had at least one other hepatitis C

risk factor, and that 5% had a history of heavy alcoholism.

Serum ALT values were normal in 45%, slightly elevated (40-99

IU/mL) in 47%, and exceeded 100 IU/mL in 8%. The median

ALT concentration was 42 IU/mL. Liver biopsies were

performed on 363 of the 376 subjects enrolled in the recall

evaluation. No inflammation was found in 2%, grade 1-3

inflammation in 41%, grade 4-8 in 52%, and grade 9-18 in 4%.

Strikingly, 49% had no fibrosis, 34% showed periportal or

portal fibrosis (stage 1), 15% had portal to portal or portal to

central bridging (stage 3), and 2%, probable or definite cirrhosis

(stage 4). Two of the seven women with cirrhosis were also

heavy alcohol drinkers.

These results were quite similar to those of a study in Germany

that involved 152 women who also had received

HCV-contaminated Rh immune globulin44; approximately 15

years after exposure, none of these women had evidence of

chronic active hepatitis or cirrhosis. Although the duration of

follow-up in these two studies of contaminated Rh immune

globulin was only 15-17 years, it is striking that fewer than 2% of

HCV infected subjects had cirrhosis and less than 10% had

severe inflammation or fibrosis. The relatively benign outcome in

these studies may reflect the small size of the viral inoculum, the

young age at the time of infection, less rapid progression in

females, or simply insufficient duration of follow-up.

Nonetheless, these findings substantiate that of the other cohort

studies cited above and studies in children cited below, each of

which suggest that when the entire HCV-infected population is

followed, only a small percentage have severe outcomes during

the first two decades of infection. Indeed, in the Air Force study,

relatively benign outcomes were observed over five decades of

follow-up.

Fibrosis Progression and Interval to Development

of Cirrhosis and HCC

Although retrospective studies do not provide the full spectrum

of outcomes, they do provide insight into the interval between the

presumed causative exposure and disease development. This is

generally achieved by tracing back to a single transfusion episode

or to a limited period of intravenous drug use. Both the

Kiyosawa study[9] and the Tong study[10] related histologic

diagnosis to the date of prior transfusion. In the Kiyosawa

study9 (Fig.1), transfusions had been received a mean of 10,

21.9, and 29 years earlier in patients with chronic hepatitis,

cirrhosis, and HCC, respectively. Among the 21 patients with

HCC, transfusions had been received as recently as 15 years

earlier and as remotely as 60 years earlier. In the Tong study,[10]

the mean interval from the date of transfusion to the diagnosis of

chronic hepatitis was 13.7 years, to cirrhosis, 20.6 years, and to

HCC, 28.3 years (Fig. 1). These two classic studies have led to

the useful approximations that the interval to development of

histologically recognized chronic hepatitis, cirrhosis, and HCC

are 10, 20, and 30 years, respectively.

Figure 1. (click image to zoom) The time course

of HCV-related disease in two retrospective

studies[9,10] that performed liver biopsies on

referred patients with a past history of blood

transfusion. The indicated duration of disease was

based on the interval from the time of transfusion

to the time of liver biopsy.

The rate of fibrosis progression to cirrhosis was evaluated in a

large multicenter histologic analysis conducted by Poynard et

al.[49] A total of 2,235 patients were recruited from three large

population-based studies performed in France. Fibrosis

progression was determined as a ratio between the fibrosis stage

(scale of 0-4 METAVIR units) and the estimated duration of

infection in years. The METAVIR scoring system incorporated

fibrosis staging and activity grading using carefully defined

parameters. Most data were derived from single biopsies,

although 70 patients had paired biopsy samples. The median rate

of fibrosis progression was 0.133 units/year. Thus, if fibrosis

progression were linear, it would require 7.5 years to progress

from one fibrosis stage to another and a median of 30 years to

progress from no fibrosis to cirrhosis. By incorporating other

variables in fibrosis progression, Poynard et al. estimated that the

development of cirrhosis would range from a median of 13 years

among men who were infected over the age of 40 and drank

more than 50 g of alcohol/day to a median of 42 years for

women infected under the age of 40 who did not drink. Because

the rate of fibrosis progression was not normally distributed, they

considered it likely that there are three separate populations with

regard to outcome: rapid fibrosers, intermediate fibrosers, and

slow fibrosers. These data prompted their view that about one

third of HCV- infected persons will advance to cirrhosis in less

than 20 years and that another one third would either never

develop cirrhosis or would do so over a span of at least 50

years. These estimates are very consistent with the progression

intervals defined by Tong et al.[10] and Kiyosawa et al.[9] and also

with the observations of the previously cited prospective studies

of transfusion-associated hepatitis.[27-30]

Outcome After the Development of Cirrhosis

An important and somewhat unexpected observation was that of

the long duration of survival even after the development of

cirrhosis. Fattovich et al.[50] conducted a retrospective follow-up

study of 384 patients with compensated HCV-related cirrhosis

to assess morbidity and mortality (Table 2). Fifty-one patients

(13.3%) died during follow-up, 17 from HCC, 16 from liver

failure, 6 from bleeding, and 15 from causes unrelated to

cirrhosis. Thus, 9% died from liver-related causes 9-124 months

(mean, 50 months) after study entry. Survival probability was

96% at 3 years, 91% at 5 years, and 79% at 10 years unless

decompensation ensued, in which case survival fell to 50% at

year 5. The annual mortality rate was 1.9% during the first 5

years. Multivariate analysis identified elevated bilirubin, physical

evidence of cirrhosis and portal hypertension, older age, and low

platelet count as independent risk factors for survival. Treatment

with interferon was not identified to be an independent

prognostic factor for survival.

HCC developed in 29 (8%) patients over periods of 7-134

months (mean, 48 months), the cumulative probability of its

occurrence being 4% at 3 years after recognition of cirrhosis,

7% at 5 years, and 14% at 10 years. The calculated yearly

incidence of HCC development was 1.4%. Among the remaining

355 patients, 65 (18%) developed evidence of decompensation

at a mean interval of 37 months. Overall, most patients with

documented cirrhosis in the Fattovich study survived for more

than 10 years without evidence of hepatic decompensation or

HCC.

A similar analysis was undertaken by Serfaty et al.[51] (Table 2).

Among 668 patients with HCV infection referred to a tertiary

care institution in Paris, 103 (15.4%) had cirrhosis. These

patients were followed for a median period of 40 months (range,

6-72 months). Fifty-nine of the 103 were treated with

interferon-a, six of whom developed normal ALT and three, a

sustained virologic response. Twenty-six (25%) of the 103

patients with cirrhosis developed hepatic complications,

consisting of HCC in 11 patients and hepatic decompensation

without HCC in 15. HCC developed in 3% after 2 years and

11.5% after 4 years for a calculated annual incidence of 3.3%.

The cumulative probability of decompensation without HCC at 2

and 4 years was 15% and 20%, respectively. Sixteen percent of

patients died in follow-up, all but one from hepatic causes (liver

failure, HCC, bleeding), and three patients underwent

transplantation. The annual incidence of death or transplantation

was 5.5%, and conversely, the cumulative probabilities of

survival were 96% at 2 years and 84% at 4 years. In contrast to

the Fattovich study,[50] interferon therapy was shown to reduce

the risk of hepatic decompensation and HCC in patients with

established cirrhosis.

HCV and HCC

Although the data for a causal relationship between HCV and

HCC are not as compelling as for HBV, they nonetheless

strongly suggest that HCV plays a major role in the evolution of

HCC, usually through the intermediary development of cirrhosis.

Although cirrhosis may not be an absolute prerequisite to the

evolution of HCC, it has been substantiated that HCC develops

in the setting of cirrhosis in at least 90% of cases. Because HCV

does not integrate into the host genome, it is commonly

speculated that malignant transformation is the byproduct of the

numerous mitotic events that accompany compensatory hepatic

regeneration in the face of progressive viral and

immune-mediated hepatocellular destruction and fibrosis. This is

clearly a simplistic explanation of complex extra- and intracellular

events, but it provides a common foundation for the development

of HCC in a variety of viral and nonviral diseases that affect the

liver.

Although an association between HCV and HCC has been

recognized throughout the world, the strongest evidence

emanates from Japan, where HCC is the leading cause of cancer

death in men. The association has been weaker in Western

counties, particularly the United States, and has been more

difficult to evaluate in areas such as China, Southeast Asia, and

sub-Saharan Africa where HBV is highly endemic and is the

leading cause of primary liver cell cancer.

One of the earliest clues to the relationship between HCV and

HCC came from the study of Kiyosawa et al.,[9] who performed

HCV serology on 54 HBsAg-negative patients with HCC; 94%

were shown to have antibody to HCV. Most convincing in this

study was the fact that serial biopsies were available from 21

patients who developed HCC at varying intervals after an

established episode of transfusion-associated non-A, non-B

hepatitis. In cases with frequent biopsies, the sequential

progression from acute hepatitis to chronic persistent hepatitis to

chronic active hepatitis to cirrhosis and then to HCC was well

documented. In those with less frequent biopsies, histologic

evidence of cirrhosis was documented before the onset of HCC

in 18 of 21 (86%). The transfusion event that was the presumed

source of HCV infection occurred 17-60 years earlier and most

commonly occurred more than 30 years before the diagnosis of

HCC.

A study of HCV seroprevalance among 105 HBV-negative

HCC cases was undertaken in five districts of Japan[52]; 76%

were found anti-HCV positive by first generation assays

compared with 1% of donors in these same districts. A history of

blood transfusion was found in 40% of the HCV-positive cases

compared with only 5% of those with HCC related to HBV or

of unknown cause. Hence, both transfusion and HCV infection

were strongly associated with the occurrence of HCC in this

population.

Also in Japan, Kato et al.[53] estimated the cumulative risk for

HCC development in patients with cirrhosis related to HCV,

HBV or a presumed non-ABC (cryptogenic) agent. Although

the diagnosis of HCC was initially made using imaging

techniques, most patients had histologic confirmation of the

cancerous lesion. Based on clinical diagnosis, the 5-year and

10-year cumulative incidence of HCC was 25% and 57%,

respectively. During follow-up of approximately 4 years, HCC

was recognized in 38% of patients in the HBV group, 44% in the

HCV group, and only 13% in the cryptogenic group. The

cumulative risk for HCC was slightly, but not significantly, higher

in HCV-infected patients compared with HBV-infected patients

with a yearly incidence of 7-14%.

A recent representative study from Japan is that of Yoshida et

al.[54] that focused on the effect of interferon in the prevention of

HCC. This was a multicenter retrospective cohort study of

2,890 patients with chronic hepatitis C who had undergone liver

biopsy since 1986; 2,400 (83%) were treated with interferon.

HCC developed in 89 interferon-treated patients (3.7%) and in

59 of 490 (12%) untreated patients. Among untreated patients,

the annual incidence of HCC increased with the degree of liver

fibrosis from 0.5% in those with stage 0 or stage 1 fibrosis to

7.9% in those with cirrhosis. The cumulative incidence of HCC

in treated patients was significantly (p < 0.001) less than that in

untreated subjects for those who had stage 2 or 3 fibrosis at the

time of enrollment. Overall, the risk of HCC during the follow-up

period of 4.3 years was significantly affected by both the initial

stage of fibrosis and treatment with interferon. In a multivariate

analysis, the adjusted risk ratio for the interferon-treated group

was 0.516 (p < 0.001) and 0.197 for the subset who had a

sustained virologic response to treatment. Thus, this very large

study confirms the progression from chronic hepatitis C to HCC,

relates progression to the stage of fibrosis, and demonstrates that

successful treatment with interferon can block both fibrosis

progression and malignant transformation.

Although most studies on the relationship of HCV to HCC have

derived from Japan, to various degrees there is confirmation of

this association throughout the world. In Italy, Colombo et al.[12]

found anti-HCV in 64 of 91 (70%) HBsAg-negative patients

with HCC and in 22 of 41 (54%) patients with HCC who were

HBsAg positive. Because the prevalence was similar in HBsAg-

positive and -negative cases and because all

anti-HCV-positive/HBsAg-negative cases were also anti-HBc

positive, it was difficult in this study to isolate the impact of HCV

in HCC causation. Nonetheless, the authors concluded that

HCV was an important factor in the development of HCC and

postulated that combined infection with HCV and HBV would

be more likely to result in serious outcomes. In contrast, Chen

and Chen,[55] who studied HCC in Taiwan, showed that patients

coinfected with HCV and HBV were on the average 10 years

older than HCC patients infected only with HBV. The authors

interpreted this observation to indicate that HCV did not

accelerate the occurrence of HCC among HBV carriers. In

another area of high HBV endemicity, Hadzyannis et al.[56]

studied 65 cases of HCC in Greece and compared

seroprevalance for HBV and HCV with that of age- and

sex-matched controls with benign conditions. In a logistic

regression model of HCC cases versus controls, the odds ratio

for cases being HBsAg positive was 18.8 (CI, 8.2-43.2) and for

being anti-HCV positive was 7.7 (CI, 1.7-35.1). In a study of

380 South African blacks with HCC, Kew et al.57 found

anti-HCV in 110 patients (29%) and in only 1 of 110 controls.

However, only 27 (7%) had anti-HCV in the absence of

markers for current or past HBV infection. Overall, in areas of

high HBV prevalence, it appears that HCV plays a causal role in

HCC pathogenesis, but the precise impact is difficult to ascertain

because of the more predominant and confounding role of HBV.

In contrast to Japan where HCC is a leading cause of cancer

death and where most cases appear related to HCV, in the

United States, HCC accounts for only 2% of cancer deaths and

the role of HCV in cancer causation is less well defined. Yu et

al.[58] studied 51 patients with HCC in Los Angeles County; 15

of 51 (29%) patients with HCC had anti-HCV and the relative

risk of HCC in those anti-HCV positive was 10.5. Based on

combined HCV and HBV markers, it was estimated that of the

51 cases, 9% were related to HCV alone, 20% to HBV alone,

and 18% to co-infection with HCV and HBV. Hence, most

cases had no identified viral etiology. Di Bisceglie et al.[59]

studied HCV prevalence in 99 consecutive cases of HCC and

compared that with 98 cases with other malignant tumors.

Anti-HCV was found in 13% of HCC patients and in 2% of

controls, and the relative risk of HCC for those anti-HCV

positive was 7.3. In this same study, 15% of cases were thought

related to HBV infection, and the relative risk for HBsAg

positive individuals was 17.3. Together, HCV and HBV

accounted for only 28% of HCC cases. Thus, in these U.S.

studies, HCV-infected patients have a definite increased risk of

developing HCC, but the proportion of HCC cases due solely to

HCV is low (13-17%). Most cases were unrelated to either

HCV or HBV, implicating other viral or nonviral etiologies.

Two other U.S. studies, both involving patients from the Miami

area, demonstrated a stronger association with HCC. Hassan et

al.[60] retrospectively studied 59 patients with HCC, 90% of

whom had biopsy-proven cirrhosis; 53% had anti-HCV by first

generation assays and none had other risk factors for HCC. A

high proportion (36%) of patients with HCC was negative for

both HCV and HBV markers. Liang et al.[61] performed a

molecular and serologic analysis of 112 patients with HCC

referred to the University of Miami. None of the patients had

nonviral risk factors for HCC and 95% had documented

cirrhosis. HBsAg was found in 21 (19%) patients. Of the 91

HBsAg negative HCC cases, 29 (32%) had isolated HBV DNA

in serum and/or liver and thus probably represent cryptic HBV

cases, 42 (46%) were anti-HCV positive, and an additional 8

(9%) were HCV RNA positive in the absence of anti-HCV;

13% had no identified viral marker. Thus, 50 of the 91 HBsAg

negative cases (55%) had serologic and/or molecular evidence

of HCV infection. In addition, HCV markers were found in 6 of

21 (29%) HBsAg positive cases. HCV RNA was amplified

from the liver tissue of seven of nine HBsAg negative cases;

three of these patients had no HCV markers in their serum.

This study provides the most compelling evidence that HCV

plays a prominent role in HCC pathogenesis in the United States

as well as in Japan. Indeed, it has been argued that the

differences in the incidence of HCV-related HCC in the United

States and Japan is a reflection of time rather than pathogenesis.

The average age of Japanese patients with HCC is 10-20 years

greater than U.S. patients, raising the possibility that the HCV

" endemic " began in Japan 10-20 years earlier than in the United

States and that decades from now the United States will

experience the same high rates of HCC as now seen in Japan.

Alternately, there may be genetic factors or environmental

cofactors present in Japan that either accelerate the progression

to cirrhosis, providing the backdrop for malignant transformation,

or that play a more direct oncogenic role. Only time will resolve

this issue.

Cofactors as Determinants of Severity

The outcomes of HCV infection vary so widely from patient to

patient that codeterminants of disease progression have long

been suspected. Differences in outcome could relate to viral

factors (viral load, viral genotype, multiplicity of quasispecies);

host factors (age at infection, duration of infection, gender,

immune deficiency, genetic susceptibility, co-infection with other

viruses such as HBV and HIV, comorbid conditions such as

hemochromatosis and iron overload); or external factors (chronic

alcoholism, diet, smoking, medicines, established hepatotoxins,

or undefined environmental contaminants).

Gordon et al.[62] studied whether the mode of HCV transmission

affected long-term outcomes (Table 1). They found that 19-20

years after acquiring hepatitis C, the cumulative risk of

developing cirrhosis in 215 patients who had been transfused

was 55% compared with 21% among 195 persons who had

been exposed through intravenous drug use (p = 0.001). The

authors concluded that the risk of liver failure was more closely

related to the mode of transmission than to other risk factors

evaluated, including age and duration of infection.

Of the viral factors, HCV genotypes 1a and 1b appear to be

associated with more severe disease and clearly are more

resistant to therapy.[63,64] In contrast, there has been no

reproducible relationship between viral load and disease

outcome.[65] Although a prospective study has shown that the

degree of diversity of the viral quasispecies during the first 4

months of HCV infection predicts whether the patient will

recover or develop chronic liver disease,[20] there is no apparent

relationship between viral diversity and disease outcome once

chronic infection is established.

Of host factors, age at the onset of infection appears to be an

important determinant of disease progression and severity. As

indicated above, infected children seem to have a more benign

outcome than infected adults. Also, the mildest outcomes in

adults have been observed in those infected under the age of 40,

as seen in the study of Air Force recruits[40] and the studies of

HCV- contaminated Rh immune globulin[43] described above.

Poynard et al.[49] assessed fibrosis progression in relation to nine

factors: age at biopsy, estimated duration of infection, sex, age at

infection, alcohol consumption, HCV genotype, hepatitis C

viremia, cause of infection, and histologic activity grade. Only

three factors were independently associated with fibrosis

progression: age at infection (older than 40 years), daily alcohol

consumption of 50 g or more, and male sex. Niederau et al.[26]

also performed a multivariate regression analysis of factors that

affected survival in HCV-infected individuals. Older age was a

significant independent variable in decreased survival, as was

cirrhosis, long disease duration, chronic alcoholism, and

intravenous drug abuse. Age, however, is a complex variable to

interpret. It is important to distinguish age at the onset of infection

from age at the time of diagnosis. Older age at the time of

diagnosis may simply reflect duration of infection, and it is clear

that for many patients, the longer the duration of infection, the

more severe the observed sequelae. In this respect, even though

those infected at a younger age appear to do better, they also

have a longer anticipated lifespan in which severe outcomes may

ultimately emerge. Finally, there is the complex issue of whether

there are elements of old age that will accelerate formerly stable

disease independent of the duration of infection. Basically, do

age-related changes in the host, such as depression of the

immune system, accelerate the course of the disease?

Unfortunately, it is difficult to design studies that clearly

distinguish the influence of disease duration from the influence of

age itself.

Hepatitis C progression appears to be more rapid in patients

with hypogammaglobulinemia, most of whom have been exposed

through contaminated lots of intravenous immunoglobulin. Rates

of progression to cirrhosis of 31% and 35% have been observed

within 10 years of exposure in two Swedish studies.[66,67] The

immunosuppression associated with HIV infection also appears

to influence outcome, though the data differ according to the

source of infection. In hemophiliacs, who were frequently

infected with both HCV and HIV before the viral inactivation of

clotting factor concentrates, those coinfected with HIV had more

severe histologic changes and higher liver related mortality than

those infected with HCV alone.[24,68-70] Although there is a

general correlation between low CD4 count, the level of HCV

viremia, and disease severity in these studies, the exact

mechanism by which HIV adversely influences the outcome of

HCV infection is not well elucidated. In intravenous drug abusers

co-infected with HIV and HCV, there is a clear inverse

relationship between CD4 count and the level of HCV RNA but

no consistent relationship between HIV infection and the severity

of coexistent hepatitis C.71

Genetic factors may also influence the outcome of HCV infection

through their effect on the immune response or other

susceptibility factors. Although specific human leukocyte antigen

alleles, particularly class II DR and DQ loci,[72,73] have been

associated with disease progression, there has been no

consistent genetic link to the outcome of HCV infection. Active

investigations continue in this area, particularly in search of

genetic links unrelated to HLA.

Of these potential cofactors, the relationship of alcohol to

disease severity is the most clearcut and has been consistently

demonstrated in multiple studies. In a unique study, designated

the Dionysios study, Bellentani et al.[74] attempted to determine

the extent and causes of chronic liver disease in the entire

population of two small Northern Italian towns. The study

enrolled 6,917 of 10,151 inhabitants (69%) and undertook

medical and epidemiologic histories, physical exams, and

serologic and biochemical testing. Among 1,211 patients

diagnosed with chronic liver disease, 58% were attributed to

alcohol abuse (>60 g/day), 16% to HCV infection, 3% to

alcohol plus HCV, and 7% to HBV. The remaining cases were

thought to be due to medications or other rare events. A different

pattern emerged when serious liver disease was evaluated.

Among 78 cases with cirrhosis, 28% were HCV related, 26%

alcohol related, 9% HBV related, and 11% due to combinations

of alcohol and virus; the remaining cases were hereditary or

cryptogenic. Important to this analysis, among HCV- or

HBV-infected patients who did not drink excessively, 11.5%

and 8.7%, respectively, developed cirrhosis or HCC. In

contrast, among HCV- or HBV-infected patients who drank

excessively, 31.2% developed cirrhosis or HCC (p < 0.001).

The role of alcohol in exacerbating viral infection was

dramatically demonstrated in a study by Corrao and Arico75

wherein they compared lifetime teetotalers with alcohol abusers

(175 g/day) according to HCV status (Fig. 2). Subjects who did

not drink and were HCV negative served as the reference

population. The relative risk for developing cirrhosis in alcohol

abusers who were not HCV infected was 15 and that for

persons HCV infected who did not drink was 9. In contrast, in

patients who were both HCV infected and abused alcohol, the

relative risk of developing cirrhosis was 147. These studies, and

others,[76-78] have led to the accepted conclusion that

HCV-infected patients should abstain from alcohol or limit their

intake to no more than one drink per day.

Figure 2. (click image to zoom) Comparison of

the risk of developing cirrhosis in relation to both

alcohol abuse and HCV status. Persons who do

not drink and are HCV negative are the referent

group. Abusing alcohol in the absence of HCV

imposes a 15-fold increased risk of cirrhosis. A

nine-fold increased risk was observed in persons

who were HCV-infected but abstained from

alcohol. A marked increased risk (147-fold) was

observed in patients who were HCV-infected and

drank excessively. Thus, the combined deleterious

effects of alcohol and HCV infection were

substantially more than additive.

Conclusions

There is an incontestable association between HCV infection and

the subsequent development of cirrhosis, HCC, and end-stage

liver disease. At present, 30% of liver transplants in the United

States are a consequence of underlying HCV-related cirrhosis.

These are somber associations that are well publicized and

create considerable fear in those diagnosed with hepatitis C,

even though most such individuals have a clinically silent

infection. It is important to provide this " silent majority " with a

balanced perspective that incorporates probabilities not only of

dire outcomes, but also long-term survival and successful

therapy. When these elements are balanced, the patient is not

only better informed but also generally relieved.

Although HCV infection is rarely encountered in the acute

stages, it is important to ascertain outcome in those who are

recognized during incipient infection. It has become increasingly

clear that at least 15% of HCV-infected individuals have a

spontaneous recovery, generally within the first year. The 15%

recovery rate, based on the absence of HCV RNA in sequential

samples and normalization of ALT, has been documented in

prospective studies7 and confirmed in population-based

screening.[41] This spontaneous recovery in HCV infection is as

unequivocal as is the progression to cirrhosis. Further, data now

suggest that spontaneous recovery rates may be even higher than

initially described. When cohorts known to have been HCV

infected from a defined exposure are recalled decades later, the

percent that maintain antibody but have lost HCV RNA has

ranged from 26% to 45% (Table 3). It is probable that on

average the recovery rate in acute HCV infection is closer to

20% than to the commonly cited 15%. The key issue then

becomes the clinical outcome in the 80% who develop persistent

HCV infection. There is an accumulating and consistent body of

evidence that during the first two decades of HCV infection,

fewer than 20% of patients followed prospectively from the time

of acute infection or recalled subsequent to a known exposure

have evidence of severe liver disease (Table 1). Indeed, in

persons infected as children and young adults, the proportion

with severe liver disease in the first two decades appears to be

less than 5%.

Thus, at the end of 20 years, approximately 80% of

HCV-infected individuals have either recovered, have stable

chronic hepatitis, or have died of an intercurrent illness. To

estimate the long-term outcome of HCV infection, attention must

focus on the majority of infected individuals who have apparent

stable or very slowly progressive liver disease. Figure 3 is

databased for the first 20 years, showing a less than 20%

incidence of severe disease during this interval, and then projects

a series of potential long-term outcomes. In projection I,

progression of liver disease is considered linear, advancing at a

constant pace so that after 60 years of HCV infection,

approximately 50% will have developed severe liver disease.

Projections II and III assume an acceleration of fibrosis after the

first 20 years of infection, in which case every HCV-infected

individual would ultimately develop severe liver disease if they

survived 40-60 years from the onset of infection. Projection IV

makes a very different assumption, namely that if severe disease

has not occurred in 20 years, it may never occur. The dilemma is

to decide where the truth lies in these assumptions that project

beyond our database? Conclusions drawn from these

projections are clearly speculative and tenuous, but worthy of

comment.

Figure 3. (click image to zoom) Projection of the

severe outcomes of HCV infection. The percent

with severe outcomes in the first two decades of

infection is based on a considerable body of

evidence (see text) and appears to be less than

20%. Curve I assumes that the development of

severe disease (fibrosis progression) will be linear

and that approximately 50% of infected

individuals will have severe outcomes 60 years

after the onset of infection. Curves II and III

assume that every HCV-infected individual will

develop severe liver disease if they do not die of

another illness in the 40-60 years that might be

required for this indolent progression. Curve IV

assumes that if severe disease has not developed

in 20 years, it generally will not occur. The relative

probabilities of these assumptions are discussed in

the text, and it is the author's speculation that the

" true " outcome will reside below curve I.

Is HCV-related liver disease linear in its progression as depicted

in curve I? The dramatically variable outcomes among

HCV-infected patients argues against linear progression as do

studies in blood donors,[42] blood recipients,[7,38] or unique

cohorts.[40] The large METAVIR analysis of fibrosis progression

by Poynard et al.[49] derives fibrosis units that assume a linearity

of progression. Nonetheless, the authors recognize that fibrosis

progression is neither linear nor normally distributed. They

considered the likelihood that there are three populations

consisting of rapid fibrosers, intermediate fibrosers, and slow

fibrosers (we would add a category of nonfibrosers). Based on

this, the investigators projected that about one third of

HCV-infected individuals would advance to cirrhosis in 20

years, that a third would advance more slowly, and that a third

would either never develop cirrhosis or require 50 or more years

to do so. When combined, this even distribution of diverse

outcomes could give the impression of a linearity that does not

indeed exist. It is of interest that the METAVIR projections are

not inconsistent with the ultimate outcome predicted by curve I

wherein 50% would develop severe disease in 60 years.

Is there reason to suspect that liver disease progression will

accelerate after the first 20 years due to increasing duration of

infection or age-related changes in the host environment?

Clearly, as indicated in this review, there is an established

relationship between disease duration and disease severity and

evidence that liver disease is more severe in the elderly.[9,49]

Increasing disease severity over time is indeed integral to the

assumptions of slope I (Fig. 3). In contrast, scenarios II and III

are predicated on acceleration, a distinct change in the slope of

the curve, at some point in time. Although this could occur, to

date, there has been no published evidence to support an

acceleration of fibrosis progression after any given number of

years of infection or any given age. Rather there are early data

that the liver disease can be nonprogressive for up to 50

years.[40] Overall, curve I appears more likely and more evidence

based than curves II or III.

Curve IV suggests that patients who have not demonstrated

progression to more intense inflammatory activity or fibrosis by

20 years may never do so. There is little published evidence to

support the flat trajectory depicted in curve IV, but anecdotally,

long-term follow-up of HCV-infected patients in NIH

prospective studies has demonstrated that some have late

spontaneous normalization of ALT levels and diminution in

anti-HCV reactivity despite the continued presence of HCV

RNA and others have persistently normal or near-normal ALT

with minimal histologic lesions in repeat biopsies obtained over

the course of two decades. More detailed studies are required to

determine if there is a true " burn-out " or complete long-term

stabilization of HCV-related liver disease, as also suggested in

the METAVIR analysis.[49] Based on the above considerations, it

is our speculation that in the absence of treatment, the natural

history of HCV infection will lie somewhere between curves I

and IV, perhaps closer to curve I. Successful treatment would,

of course, lower the slope as it improves outcome; highly

effective therapy would flatten the curve.

Clearly, these long-term projections are speculative, but it seems

reasonable, based on the data in this review, to conclude that of

100 persons acutely infected with HCV (Fig. 4), 20% (20

patients) will spontaneously recover and 80% (80 patients) with

develop persistent infection. Of the 80 persons with persistent

infection (chronic hepatitis C), based on the composite data

presented in this review, it would appear that up to 30% (24

patients) will have progressively severe liver disease culminating

in cirrhosis and/or HCC and another 30% (24 patients) will have

stable liver disease that will not progress to cirrhosis and its

serious sequelae whether or not treatment is given. The remaining

40% of those chronically infected (32 patients) will have a slowly

evolving infection whose outcome cannot be predicted (Fig. 4).

This results in 56 patients who are either highly likely to progress

to cirrhosis or who have a variable and unpredictable likelihood

of fibrosis progression. Of these 56 patients, approximately 35%

(20 patients) can be " cured " by existing combination therapy,[79]

leaving only 36 (36%) from this theoretic cohort of 100 acutely

infected individuals who will have progressive HCV-related liver

disease not responsive to therapy. In addition, the slow pace of

HCV progression will allow time for the development of

improved treatments that will further diminish long-term

morbidity and mortality.

Figure 4. (click image to zoom) Projected

outcome in a hypothetical cohort of 100

individuals with acute HCV infection. Existing

data (see text) suggests that 20% will

spontaneously resolve their acute infection.

Natural history studies suggest that of the residual

80 patients, 30% would manifest progressively

severe liver disease, 30% would have stable

chronic hepatitis that did not progress to cirrhosis,

and 40% would have a variable outcome that

might or might not eventuate in cirrhosis. The

natural history of HCV infection is now tempered

by therapeutic intervention. Because the ultimate

outcome in an individual patient cannot be

predicted accurately , most patients with chronic

hepatitis are now being treated. The figure

projects that of the 56 patients who might have

advanced to cirrhosis during the natural history of

their infection, 35% (20 patients) will be " cured "

by existing combination therapy. The figure

assumes that the 24 patients with stable chronic

hepatitis will do well whether or not they are

treated. Hence, of the total population of 100

acutely infected individuals, 64% will have a

favorable outcome either through spontaneous

recovery, an inherently stable chronic hepatitis, or

a sustained treatment response.

Although this perspective allows reasonable hope for the

individual HCV-infected patient, it is not intended to ignore the

large number of persons who may die or require liver

transplantation as a result of HCV infection. This individualized

perspective is also not intended to diminish the enormous global

impact of HCV infection engendered by the sheer magnitude of

the infected population. The absolute number of dire events on a

global scale is staggering even if the proportion that encounters

those events is encouragingly small.

Section 12 of 12

CONTENTS

Abstract &

Introduction

Historical

Perspective

Mechanisms of Viral

Perstence and the

Pathogenesis of

Chronic

Hepatitis

Hepatitis C Outcome

Based

on Patients Refered

for

Chronic Liver Disease

Outcome Based on

Long-Term Follow-up

of

Acute Hepatitis C

Outcome Based on

Cohorts

Studied Long After a

Defined

Parenteral Exposure

Outcome in Children

Fibrosis Progression

and

Interval to

Development of

Cirrhosis and HCC

Outcome After the

Development of

Cirrhosis

HCV and HCC

Cofactors as

Determinants of

Severity

Conclusions

References

SIDE BAR

Abbreviations

INTERACT

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