does the clinical outcome of hepatitis c infection vary with the infecting hepatitis c virus type?

Does the clinical outcome of hepatitis C infection vary with theinfecting hepatitis C virus type?H. E. Harris,1 K. P. Eldridge,1 S. Harbour,2 G. Alexander,3 C.-G. Teo,2 M. E. Ramsay1 and TheHCV National Register Steering Group* 1Immunisation Department, Centre for Infections, Health Protection Agency, London;2Sexually Transmitted and Blood-Borne Virus Laboratory, Centre for Infections, Health Protection Agency, London; and 3Department of Medicine,

Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK

Received December 2005; accepted for publication March 2006

SUMMARY. Whether differences in the natural history of

hepatitis C virus (HCV) can be explained by differences in the

infecting HCV type is unknown. The aim of this study was to

investigate whether the HCV type might influence the clin-

ical outcome of infection. Study serum samples were

assembled from 749 individuals enrolled into the UK HCV

National Register from which data on clinical outcomes

were extracted. HCV-RNA-positive specimens were geno-

typed and HCV-RNA-negative specimens serotyped. Logistic

regression analysis was used to investigate the independent

effect of HCV type on viral clearance by comparing patients

who were HCV RNA negative (n ¼ 86) with those who were

HCV RNA positive (n ¼ 508). The same method was used to

investigate whether HCV type was associated with histo-

logical stage of liver disease. The prevalence of HCV type 1

among those who cleared infection was 69% and among

those who remained HCV RNA positive was 51%: Type 1

infections were more likely to be HCV RNA negative than

non-1 types (OR 0.47, 95% CI 0.29–0.78, P ¼ 0.003). Type

1 infections were also more likely to be associated with

histological stage scores above the median when compared

with non-1 types (OR 2.03, 95% CI 1.07–3.83, P ¼ 0.03).

In conclusion, HCV type 1 infection was more often HCV

RNA negative, suggesting that spontaneous clearance may

occur more commonly with this type. Among the RNA-

positive infections, type 1 infection may be more aggressive

than types 2/3.

Keywords: genotype, hepatitis C, liver disease, natural his-

tory, serotype.

INTRODUCTION

Hepatitis C virus (HCV) infection is a major cause of chronic

liver disease [1] that can lead to appreciable morbidity

including cirrhosis and hepatocellular carcinoma (HCC) [2].

HCV can be classified into several genotypes based on vari-

ations in the nucleotide sequence of its genome [3].

The infecting HCV type has been shown to be clinically

important because it predicts response to antiviral therapy,

with infection by type 1 being associated with the most

resistance to treatment [4]. There is no consensus, however,

as to whether differences in the clinical and histological

severity of liver disease can be explained by differences in the

infecting type. Several studies suggest genotype 1b to be

associated with more severe disease [5–7] but most have

found little or no influence of genotype on disease progres-

sion [8–11]. In many cases, the variable results can be

accounted for by possible biases in the study design. Such

biases result from failure to control for a number of

important confounding factors, like duration of infection and

age, or because subjects are selected from tertiary referral

centres where patients with more advanced disease are

concentrated. The duration of infection is an important

confounding factor in this context because the prevalence of

HCV genotypes is known to vary with time [12]. As a result,

cross-sectional studies that fail to control for duration of

infection might find a spurious association between genotype

and severity of disease because certain genotypes have per-

sisted longer. Age is also important as it can act as a sur-

rogate marker for disease duration when the date of infection

is unknown or poorly estimated.

Similar ambiguity surrounds the study of the role of HCV

genotypes in spontaneous viral clearance. Some studies

have found no association between the viral type and the

spontaneous clearance of HCV RNA, with host factors like

sex seeming to be more important [13,14], while other

*The members of the steering group are given in the Appendix.

Abbreviations: HCV, hepatitis C virus; HCC, hepatocellular

carcinoma.

Correspondence: Dr Helen E. Harris, Immunisation Department,

Centre for Infections, Health Protection Agency, 61 Colindale

Avenue, London NW9 5EQ, UK. E-mail: [email protected]

Journal of Viral Hepatitis, 2007, 14, 213–220 doi:10.1111/j.1365-2893.2006.00795.x

� 2006 The AuthorsJournal compilation � 2006 Blackwell Publishing Ltd

studies have suggested that infection by genotype 1 or 1b

might be less likely to clear spontaneously when compared

with infection by other genotypes [15–17].

The aim of this study was to describe the prevalent gen-

otypes in a cohort of patients who acquired HCV infection at

a known date in the United Kingdom, and to investigate

whether there was any evidence to suggest that the natural

history of their infection varies with the infecting type. This

cohort of patients is well described [18–20] and offers a

unique opportunity to study the role of hepatitis C viral type

on the natural history of HCV infection.

METHODS

Study sample

Cases were eligible for inclusion in this study if they had been

enrolled in the UK HCV National Register [18] and had their

sera referred to the Registry for HCV genotyping (Fig. 1).

Most (90%) of these patients had been traced during the

National HCV Lookback Programme that was initiated by

the UK Department of Health to help find recipients of

potentially infected blood who had been transfused prior to

the introduction of routine testing of the blood supply for

HCV [21]. The remainder were infections that had been

identified during the course of the UK Blood Authority’s

routine donor testing programme [22] or who had acquired

their infections vertically. Their baseline characteristics are

summarized in Table 1. The precise date that individuals

acquired their infections is known either because the date of

the HCV-infected transfusion was known or because they

acquired their infections vertically or seroconverted for

antibodies to hepatitis C virus.

Serum collection and typing

In June 2000, requests for serum specimens that were col-

lected during the UK HCV Lookback Programme were sent to

laboratories throughout England, Northern Ireland and

Wales. Specimens were also requested from those HCV-

infected blood donors identified during routine donor

screening and enrolled into the HCV National Register. All

samples were referred to the Health Protection Agency’s

Hepatitis Reference Laboratory and stored at )80 �C. Each

specimen was tested for HCV RNA using a reverse tran-

scriptase nested PCR to amplify a segment in the 5¢-non-

coding region of the HCV genome [23]. Specimens found to

carry HCV RNA were genotyped using an assay based on

restriction fragment length polymorphisms of the amplified

cDNA [23]. Those samples found to be HCV RNA negative

were serotyped using the Murex 1-6 assay (Abbott Diag-

nostics, Berkshire).

Clinical outcomes

Data on clinical outcomes were collected using standardized

registry data collection forms at enrolment into the UK HCV

National Register (1998–2001) and again during routine

follow-ups in 2000–2002 and 2002–2004 [18]. Outcome

variables included physical signs and symptoms of liver

disease (including reports of liver tumours, varices, ascites,

splenomegaly, hepatomegaly and spider naevi), liver biopsy

results (classified as cirrhotic vs not cirrhotic) and response

to antiviral treatment (classified as no response, transient

response – PCR negative during treatment only, sustained

viral response and other response – PCR negative less than

6 months post-treatment).

Serotyping

Serotyping

Genotyping

753 patients with sera referred

749 tested for HCV RNA 4 insufficient volume for testing

444 HCV RNA Pos. 193 HCV RNA Neg.

Type n

1 2

1a 156

1a/b 6

1b 65

2a 17

2a/c 1

2b 54

3a 129

3b 1

4 5

5 6

6 2

112 HCV RNA Neg.[Known to have tested positive

at time of initial collection]

96

typed

97 unable

to type64

typed

48 unable

to type

Type n

1 31

2 10

3 17

Type n

Mixed 2

4 1

5 2

6 1

Type n

1 61

2 11

3 21

Type n

Mixed 1

4 2

Fig. 1 HCV RNA PCR and HCV typing

results for 753 patients.

� 2006 The AuthorsJournal compilation � 2006 Blackwell Publishing Ltd, Journal of Viral Hepatitis, 14, 213–220

214 H. E. Harris et al.

Mortality data were collected from death certification, and

deaths were considered �liver related� if there was any

mention of HCV or liver disease on the death certificate. By

reviewing the text of the death certificates, deaths were

further classified into those in which HCV-related liver dis-

ease was likely to have directly caused death. This included

certificates that mentioned HCC or outcomes of end-stage

liver disease (varices, ascites or hepatic encephalopathy) or

where liver disease was coded as the underlying and only

cause of death. In this analysis, death certificates in which

liver disease or hepatitis C were mentioned as contributory

factors only were excluded because they were considered to

have been influenced by knowledge of the patient’s HCV

status.

Clinicians were asked to refer four unstained liver biopsy

sections to the Registry for scoring according to a stan-

dardized protocol. Two eminent, independent histopatholo-

gists, who were blinded to all clinical information, scored

liver biopsy specimens using the modified HAI system of

Ishak et al. [24]. Using this system, the grade (0–18) and

stage (0–6) of liver disease were uniformly scored across the

cohort [24].

Individuals were classified as having spontaneously

cleared hepatitis C virus infection if their baseline serum

specimen tested positive for HCV antibody but negative for

virus, and the individual had not undergone any prior

treatment for their infection.

Statistical analysis

The associations between genotype or serotype with the

clinical outcome variables were investigated using chi-

square, Kruskal–Wallis and median tests as appropriate.

Logistic regression was used to investigate the association

between the HCV type and the histological stage of liver

disease, and the viral clearance. All analyses were underta-

ken using SPSS (SPSS Inc., Chicago, IL, USA).

This study was approved by the North Thames Multi-

Centre Research Ethics Committee, London, UK.

RESULTS

Distribution of hepatitis C virus types

Of the 753 sera referred to the laboratory, 444 were found to

carry HCV RNA (Fig. 1). Among these, the most prevalent

HCV genotypes were 1 (52%), 3 (29%) and 2 (16%), with

smaller proportions of genotypes 4, 5 and 6 (Fig. 1.). Of the

305 specimens found to be HCV RNA negative, it was

possible to serotype 160 of them. Serotypes 1 (58%), 3 (24%)

and 2 (13%) were found to be the most common (Fig. 1).

One hundred and twelve of the 305 HCV-RNA-negative

specimens were known to have previously tested positive for

HCV RNA when they were initially collected during the HCV

Lookback Programme; HCV RNA in these is thought to have

degraded as a result of prolonged or inappropriate storage

between collection and archiving. Therefore, 556 individuals

(74%) were classified as �chronically infected�, with the

remainder (n ¼ 193 individuals) being HCV RNA negative

at baseline (26%; Fig. 1.). Of the 193 individuals who were

HCV RNA negative at baseline, 14 had received prior anti-

viral treatment and were excluded from analyses of viral

clearance. Individuals who were untreated and PCR negat-

ive at baseline (n ¼ 179) were more likely to be females

(v2 ¼ 9.38, P ¼ 0.002), to have HCV type 1 infections

(v2 ¼ 9.52, P ¼ 0.002) and to be born outside the United

Kingdom (v2 ¼ 7.05, P ¼ 0.03) when compared with those

who were chronically infected (n ¼ 556). Those who were

HCV RNA negative and untreated did not differ by duration

of infection, age at infection, ethnicity, mode of acquisition

or alcohol consumption from those who were chronically

infected (P ‡ 0.20 for all).

Table 1 Characteristics of the 749 eligible cases

Characteristics

Male/female (%) 51/49

Mean age at infection (range)

in years

41.6 (0.0–82.3)

Mean duration of infection (range)

in years

15.7 (7.6–40.6)

Country of birth (%)

UK 80.1

Non-UK 8.3

Not known 11.6

Ethnic group (%)

White 82.5

Non-white 6.0

Not known 11.5

Mode of acquisition (%)

Known transfusion 90.0

Others 10.0

Alcohol consumption* (%)

Nil 25.8

<21 units (#) or <14 units ($) 51.4

>21 units (#) or >14 units ($) 14.0

Not known 8.8

Other medical conditions reported (%)

No 25.6

Yes 62.5

Not known 11.9

Antiviral treatment for HCV (%)

Interferon and Ribavirin 11.6

Interferon monotherapy only 8.1

Not treated 80.2

*Highest reported alcohol consumption from four data col-

lection points (baseline, enrolment into the Register, follow-

up 1 and follow-up 2).


HCV type and outcome of infection 215

Association between hepatitis C virus type and clinicaloutcome

Analyses investigating clinical outcome vs HCV genotype

were restricted to the most prevalent types (1, 2 and 3 with a

total of 431 when the genotypes were grouped; 1a, 1b, 2b

and 3a with a total of 404 when the viral subtypes were

considered). Table 2 summarizes the associations between

hepatitis C viral type and (i) mortality, (ii) response to

treatment, (iii) signs and symptoms of liver disease, (iv)

reported liver biopsy results and (v) independently scored

liver biopsy results.

There was no evidence of an association between viral

type and mortality, signs and symptoms of liver disease,

reported liver biopsy result or histological grade of disease

that was independently scored. A significant association was

observed between viral type and response to treatment, with

type 1 infection being associated with poorer response to

treatment than types 2 and 3. Type 1 infection was signifi-

cantly more likely to be associated with histological stage

scores above the median when compared with types 2 and 3.

Histological stage of liver disease was not associated with

alcohol consumption (v2 ¼ 0.96, P ¼ 0.81). The stage of

liver disease was scored according to Ishak on a scale of 0–6,

and the median stage score was 1. Logistic regression ana-

lysis with stages 0–1 vs stages 2–6 as the dependent variable

was undertaken, which showed an association between the

HCV type and the stage of liver disease (P ¼ 0.035). The

results of this analysis showed that types 2 and 3 were both

significantly different from type 1 (type 1 vs type 3; P ¼0.044 and type 1 vs type 2; P ¼ 0.029) but not from each

other (type 2 vs type 3; P ¼ 0.535), and so types 2 and 3

were grouped together to increase the power of the analysis.

After controlling for the potentially confounding effects of

sex, duration of infection, and age at infection and treat-

ment, genotype remained significantly associated with the

Table 2 Associations between HCV genotype and clinical outcomes

Factor level

Genotypes

Probability P (P)*1 2 3

Mortality

Alive 182/229 56/72 98/130 0.667 (0.836)

Dead 47/229 16/72 32/130

Died with mention of liver disease 6/47 4/16 9/32 0.211 (0.319)

Died, no mention 41/47 12/16 23/32

Died from liver disease 4/47 0/16 4/32 0.339 (0.460)

Died from other causes 43/47 16/16 28/32

Response to treatment

No response 24/56 1/16 8/36 0.003 (0.005)

Transient response 5/56 2/16 4/36

Sustained viral response 8/56 8/16 18/36

Others 19/56 5/16 6/36

Signs and symptoms of liver disease

No signs 152/187 54/62 92/118 0.329 (0.262)

Any signs 35/187 8/62 26/118

No signs 152/160 54/54 92/98 0.197 (0.330)

Serious signs 8/160 0/54 6/98

Reported liver biopsy result

Cirrhotic 9/120 2/44 8/73 0.445 (0.782)

Not cirrhotic 111/120 42/44 65/73

Independently scored liver biopsy

Ishak grade (0–18)

Mean rank (Kruskal–Wallis test) 90.25 82.23 85.19 0.684 (0.745)

Proportion > median (median test) 24/80 7/31 9/62 0.095 (0.152)

Proportion £ median 56/80 24/31 53/62

Ishak stage (0–6)

Mean rank (Kruskal–Wallis test) 93.46 79.03 82.65 0.246 (0.310)

Proportion > median (median test) 42/80 9/31 22/62 0.033 (0.049)

Proportion £ median 38/80 22/31 40/62

P* ¼ probability when tested vs genotypes 1a, 1b, 2b and 3a (not vs types 1, 2 and 3).



histological stage of liver disease (Table 3). Table 4 shows a

comparison of the subgroup of cases included in the multi-

variable analysis (those who had their liver biopsies referred

for independent scoring) with those who were excluded from

the analysis (because they had not had a biopsy referred for

independent scoring). Individuals were more likely to be

included in the analysis if they were younger, consumed

alcohol, had signs and symptoms of liver disease and were

known to have undergone treatment. Although alcohol

consumption was not associated with the stage of liver dis-

ease in the univariate analyses, the regression analysis was

repeated with alcohol being included in the model and

genotype remained independently associated with the stage

of liver disease (OR 1.99, 95% CI 1.05–3.78, P ¼ 0.035).

Association between hepatitis C virus serotypes and viralclearance

The 444 cases, whose HCV-RNA-positive samples had been

genotyped, were grouped with the 64 serotyped cases, who

were previously known to have tested positive for HCV RNA,

to give a total of 508 chronic infections (Fig. 1). These 508

cases were compared with the 86 cases of known serotype,

who were presumed to have spontaneously cleared virus

(although there were 96 patients with HCV-RNA-negative

specimens, 10 were excluded because they had received

prior antiviral treatment; Fig. 1). When serotypes 1, 2 and 3

were compared, type 1 was more likely to be associated with

clearance than 2 or 3 (v2 ¼ 8.46, df ¼ 2, P ¼ 0.015).

When the analysis was repeated comparing type 1 with type

non-1 infections, type 1 infection was more likely to be

associated with RNA negativity than non-1 infection (v2 ¼9.52, df ¼ 1, P ¼ 0.002). When multivariable logistic

regression analysis was undertaken to examine whether the

effect of serotype was independent of the host factors, age

and sex, a statistically significant association remained

between viral serotype and viral clearance (OR 0.47, 95% CI

0.29–0.78, P ¼ 0.003). No significant independent effects of

age at infection or sex on viral clearance were found

(P > 0.30 for both). Individuals were more likely to be

included in the analysis of viral clearance if they were male

(P ¼ 0.003) and had undergone liver biopsy (P < 0.001).

HCV-RNA-negative samples were excluded from the analysis

Table 3 Multivariable logistic regression analysis with his-

tological stage of liver disease as the dependent variable

(Ishak scores 0–1 vs 2–6)

Factor

Odds

ratio 95% CI P-value

Genotype (1 vs non-1) 2.03 1.07–3.83 0.03

Sex (female vs male) 0.54 0.29–1.01 0.06

Treated (yes vs no) 2.74 0.91–8.26 0.07

Age at infection (years) 1.00 0.98–1.02 0.86

Duration of infection (years) 0.95 0.89–1.01 0.10

Table 4 Characteristics of the 176 individuals included in the analysis of histological stage of liver disease vs the 573

individuals whose data were excluded from the multivariable analysis

Characteristics

Included in the analysis

(n ¼ 176)

Excluded from the analysis

(n ¼ 573) P-value

Male [n (%)] 91/176 (51.7) 290/573 (50.6) 0.80

Mean age at infection in years (SD) 33.2 (18.0) 44.2 (21.4) <0.001

Mean duration of infection in years (SD) 16.0 (4.4) 15.5 (3.6) 0.14

UK born [n (%)] 149/176 (84.7) 451/573 (78.7) 0.08

White ethnicity [n (%)] 150/176 (85.2) 468/573 (81.7) 0.12

Transfusion acquired [n (%)] 156/176 (88.6) 522/573 (91.1) 0.33

Alcohol consumption* [n (%)] 0.008

Nil 39/176 (22.2) 154/573 (26.9)

<21 units (#) or <14 units ($) 101/176 (57.4) 284/573 (49.6)

>21 units (#) or >14 units ($) 30/176 (17.0) 75/573 (13.1)

Not known 6/176 (3.4) 60/573 (10.5)

Deceased [n (%)] 12/176 (6.8) 153/573 (26.7) <0.001

Biopsy result [n (%)] 0.11

Minimal change 19/176 (10.8) 20/142 (14.1)

Chronic hepatitis 143/176 (81.3) 101/142 (71.1)

Cirrhosis 13/176 (7.4) 17/142 (12.0)

Signs and symptoms of liver disease [n (%)] 42/176 (23.9) 63/459 (13.7) 0.008

Known to have undergone antiviral treatment [n (%)] 81/176 (46.0) 67/573 (11.7) <0.001

*Highest reported alcohol consumption from four data collection points (baseline, enrolment into the Register, follow-up 1 and

follow-up 2).



if they could not be typed (n ¼ 97) or had mixed infections

(n ¼ 1); those included were more likely to have undergone

liver biopsy (P ¼ 0.002) and more likely to have severe

disease (P ¼ 0.05). HCV-RNA-positive samples were exclu-

ded from the analysis if they could not be typed (n ¼ 48) or

had mixed infections (n ¼ 2); those included were more

likely to have chronic hepatitis on liver biopsy but less likely

to be cirrhotic (P ¼ 0.05).

DISCUSSION

The results of this study show that the most prevalent HCV

types among individuals in the United Kingdom, who

acquired their HCV infections on a known date, were 1a

(35%), 3a (29%), 1b (15%), 2b (12%) and 2a (4%), with

only small numbers (<5%) belonging to other genotypes.

This HCV type distribution is similar to that found by a

previous UK study that tested sera from haemophilia

patients, blood donors, injecting drug users, patients under

investigation for liver disease and attendees of antenatal and

genitourinary clinics [23].

There was no evidence of any differential mortality by the

infecting HCV type. Similarly, there was no evidence of any

relationship between type and reported signs and symptoms

of liver disease, or reported liver biopsy results. Liver biopsy

results in the UK HCV National Register are variably

reported because different scoring systems are used

throughout the country. Interobserver reliability between

different histopathologists is known to be poor [25,26], but

variation can be reduced when histological assessments are

undertaken by a small number of experienced liver patho-

logists according to a standardized scoring system. It was for

this reason that participating clinicians were asked to refer

liver biopsy specimens to the Registry for standardized

scoring. While the value of grading and staging a single

biopsy will always be limited by sampling variability, when

used as a research tool to assess a large number of biopsies,

sampling variability should be random and not biased in

relation to any prognostic factors. When the association

between stage of liver disease and HCV type was investigated

using these more reliable data, an association between the

HCV type and the stage of liver disease was observed.

Comparison of the results with previous studies is difficult

because a variety of different outcome measures have been

used, ranging from the development of liver complications

like cirrhosis [10,27], HCC [8,28,29] or decompensation [8],

to liver-related mortality [29] or survival [8]. Similarly, dif-

ferent investigators have examined different genotypes; some

looking at genotype 1b infections vs the rest [8,16], while

others have focused on selected genotypes that were preval-

ent in their particular study populations [10,27,29,30].

Nearly all of the previous studies have been conducted in

tertiary referral centres, where patients with advanced liver

disease are concentrated. Such studies tend to generate biased

results because the genotype distribution may differ from the

general infected population [31], with more aggressive gen-

otypes over-represented in hospital populations. The present

study does not suffer from this bias, as all individuals were

ascertained by virtue of exposure and not disease status.

Recruiting sufficiently large numbers of such individuals is

difficult because HCV-related disease is predominantly

asymptomatic in the early years of infection. In this context,

the UK HCV Lookback Programme provided a unique

opportunity to permit sufficiently large numbers of individu-

als to be recruited. Individuals recruited by this programme

are also unique because the precise date of their infection is

known. For most studies, the date of acquisition of infection is

usually unknown or at the best a crude estimate [32].

Because genotype distribution is also known to vary with time

[12,33,34], an accurate measure of duration of infection is

essential if investigators are to avoid finding a spurious

association between genotype and severity of disease because

of the longer persistence of certain genotypes. It is likely that a

variety of viral and host factors interact to influence the

development of HCV-related liver disease. If this is true, then

differences in recruitment method and study populations may

explain the differential roles of genotype, which have been

observed in the previous studies. Even in the present study, it

is unlikely that results are free from bias, as individuals who

had biopsies referred for independent scoring were more likely

to be younger, to drink alcohol and to have developed clinical

signs of liver disease than those who did not have biopsies

referred (Table 4). It was surprising to find no association

between alcohol consumption and histological stage of liver

disease. Alcohol consumption is known to be poorly reported

and recorded in medical settings [35,36], and the data on

alcohol consumption used in this study were collected by

clinicians during counselling sessions and during routine

outpatient clinic appointments [18]. As excessive alcohol

consumption is a known risk factor for progressive HCV-

related disease [37], the failure to find any effect of alcohol in

the present study is more likely to be the result of poor quality

data than an absence of an effect of alcohol on HCV-related

liver disease.

The best study design investigating the association

between viral type and clinical outcome may well be a

prospective longitudinal one. However, limited data are

available from these studies because HCV-related disease has

a relatively benign course in the early years of infection. An

insight into the course of HCV infection is offered by patients

undergoing liver transplant. Among such patients, reinfec-

tion of the graft is common. Recurrence of the disease usu-

ally occurs within 5 years [38,39], with the rate of

recurrence more frequently observed and liver disease pro-

gressing more rapidly in type-1-infected patients than in

those infected with other viral types [38,40]. This suggestion

of more aggressive disease in association with type 1 infec-

tion is in line with the findings of the present study.

We found that type 1 infection was more likely to be RNA

negative than non-1 infection, suggesting that viral clear-



ance is more common with this type of infection. Other

cross-sectional studies have failed to show any association

between viral clearance and viral type, showing host factors,

like sex, to be more important [13,14]. In the present study,

the association between viral clearance and viral type was

independent of age and sex. It is possible that the relatively

small sample sizes of the previous studies (154 in one [14]

and 345 in another [13]) might explain why no significant

associations were found. Other studies of individuals with

acute HCV who were followed prospectively have shown

genotype 1b to be associated with failure to clear sponta-

neously [15,16]. In the absence of early postinfection sera

specimens, cross-sectional studies like the present one are

only able to compare the types of individuals who have

cleared infection, and cannot inform on differential clear-

ance that might be associated with certain viral subtypes

[15,16]. If patients with genotype 1b infection were less

likely to clear than those with type 1a infection, then this

association might be masked when the two subtypes are

grouped together. In our study, around 70% of the type 1

infections were type 1a.

In the present study, patients were more likely to have their

data included in the analysis of viral clearance if they were

male or had undergone liver biopsy. The principal reason for

exclusion from the analysis was failure to type the specimen,

which occurred in 50% of the HCV-RNA-negative specimens

(Fig. 1). The individuals with HCV-RNA-negative specimens

who were included in the analysis were more likely to have

undergone liver biopsy and to have more severe histopatho-

logical disease. In contrast, only 9% of patients whose sera

were HCV RNA positive failed to type and were excluded from

the analysis (Fig. 1). The HCV-RNA-seropositive patients

included in the analysis were marginally more likely to have

severe histopathological disease. If individuals who have

undergone liver biopsy or who have a more severe histo-

pathological disease were more likely to carry higher viral

loads, it is possible that a bias would be introduced if there was

an association between HCV type 1 infection and high viral

load. The higher proportion of untyped specimens in the

RNA-negative group (50%) when compared with the

RNA-positive-infected group (9%) might then have resulted

in type 1 infection being over-represented in the former

group. However, there is no firm evidence to show that HCV

type 1 is associated with a higher viral load than HCV type

non-1 [41].

In summary, the results of this study suggest that HCV

type 1 infection is more likely to be associated with spon-

taneous clearance than non-1 infection. Among infections

that do not clear spontaneously, type 1 infection is associ-

ated with greater aggressiveness than type 2 or 3 infections,

with type 1 infection being independently associated with

more advanced stages of liver disease. If genotype differences

determine disease outcome, they are likely to constitute only

one factor among a whole variety of complex host–virus

interactions that modify the course of HCV-related disease.

ACKNOWLEDGEMENTS

We are grateful to all the clinicians and research nurses who

have supported this national project by enrolling their

patients and to the regional laboratories for referring their

sera to the archive. We also thank Nick Andrews for his

advice on the statistical analyses and all laboratory staff at

the Sexually Transmitted and Blood-Borne Virus Laboratory

who have helped with the hepatitis C testing. This research

was funded by the UK Department of Health. None of the

authors have any financial or other conflicts of interest. All

views and any errors are the responsibility of the authors

alone.

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APPENDIX

The UK HCV National Register Steering Group:

Dr Graeme Alexander (Senior Lecturer and Consultant

Hepatologist, Addenbrooke’s Hospital, Cambridge), Mr Brian

Gunson (Lay Representative, Non-Executive Director, St Al-

bans and Harpenden Primary Care Trust, Hertfordshire), Dr

Helen Harris (Research Associate, Health Protection Agency,

London), Dr Julia Heptonstall (Consultant Microbiologist,

Health Protection Agency, London), Dr Patricia Hewitt (Lead

Consultant, National Blood Service, London), Prof. Giorgina

Mieli-Vergani (Consultant Paediatric Hepatologist and

Director of Paediatric Liver Services, King’s College Hospital,

London), Dr Hugh Nicholas (Senior Medical Officer, UK

Department of Health, London), Prof. Bernard Portmann

(Consultant Histopathologist, Institute of Liver Studies,

King’s College Hospital, London), Dr Mary Ramsay (Con-

sultant Epidemiologist, Health Protection Agency, London)

and Dr Angela Robinson (Medical Director, National Blood

Authority, Watford).



does the clinical outcome of hepatitis c infection vary with the infecting hepatitis c virus type?

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