Hepatitis C virus infectionoru.diva-portal.org/smash/get/diva2:234612/FULLTEXT02.pdfViruset överfördes tidigare vid blod-transfusioner men sprids nu vanligen via injektionsmissbruk

Hepatitis C virus infection

Örebro Studies in Medicine 34

Ann-Sofi Duberg

Hepatitis C virus infectionA nationwide study of associated

morbidity and mortality

© Ann-Sofi Duberg, 2009

Title: Hepatitis C virus infection. A nationwide study of associated morbidity and mortality.

Publisher: Örebro University 2009www.publications.oru.se

Editor: Heinz [email protected]

Printer: intellecta infolog, Kållered 09/2009

issn 1652-4063 isbn 978-91-7668-681-2

ABSTRACT

Duberg, Ann-Sofi (2009). Hepatitis C virus infection. A nationwide study of associated morbidity and mortality. Örebro Studies in Medicine 34. Pp. 66.

The hepatitis C virus (HCV) was characterised in 1989. HCV was transmitted through transfusion of blood/blood products, but injection drug use is now the most common route of transmission. The infection is usually asymptomatic but becomes chronic in about 75%, and in 20 years 15-25% develops liver cirrhosis, with a risk for liver failure and liver cancer. HCV has also been associated with lymphoproliferative disorders.

The aim of this thesis was to study morbidity and mortality in a national, population-based cohort of HCV-infected individuals. The study population consisted of all persons with a diagnosed HCV-infection recorded in the national surveillance database. This file was linked to other national registers to obtain information of emigration, deaths, can-cers, and inpatient care. All personal identifiers were removed before analysis.

In Paper I the standardized incidence ratios (SIR) for Hodgkin’s and non-Hodgkin’s lymphoma (NHL), multiple myeloma, acute and chronic lymphatic leukaemia, and thy-roid cancer were studied. In the HCV-cohort (n: 27,150) there was a doubled risk for NHL and multiple myeloma in patients infected for more than 15 years, compared with the general population (age-, sex- and calendar-year specific incidence rates). The results strengthened these earlier controversial associations.

The SIR and also the absolute risk for primary liver cancer were estimated in Paper II. In the HCV-cohort (n: 36,126) the individuals infected for more than 25 years had a more than 40 times increased risk for liver cancer compared with the general population. The absolute risk of primary liver cancer was 7% within 40 years of HCV-infection.

Mortality and cause of death were studied in Paper III. The standardized mortality ra-tio (SMR) demonstrated a 5.8 times excess mortality in the HCV-cohort (n: 34,235) compared with the general population, and a 35.5 times excess mortality from liver dis-ease. Deaths from illicit drugs and external reasons were common in young adults.

Paper IV presents a study of inpatient care. The HCV-cohort (n: 43,000) was com-pared with a matched reference population (n: 215,000). Cox regression was used to estimate the likelihood, a hazard ratio, for admission to hospital, and frequencies and rates to estimate the total burden. In the HCV-cohort inpatient care was high and about 50% was psychiatric, often drug-related care. The likelihood for liver-related admissions was very high, and serious liver complications increased in the 2000s, indicating that HCV-associated liver disease will increase the next decade. In the 2000s, about 1000 individuals per year were treated with HCV-combination therapy.

To conclude, the risk for NHL and multiple myeloma was doubled, and liver- and drug-related morbidity and mortality was very high in the HCV-cohort. Serious liver complications increased in the 2000s and will probably increase the coming decade.

Keywords: HCV; hepatitis C; epidemiology; non-Hodgkin’s lymphoma; NHL; multiple myeloma; primary liver cancer; HCC; mortality; inpatient care; hospitalization

Ann-Sofi Duberg, Department of Infectious Diseases, Örebro University Hospital, SE-70185 Örebro, Sweden. E-mail: [email protected]

Populärvetenskaplig sammanfattning

Hepatit C viruset (HCV) upptäcktes 1989. Viruset överfördes tidigare vid blod-

transfusioner men sprids nu vanligen via injektionsmissbruk. Akut HCV-infektion

är oftast asymptomatisk men hos c:a 75% utvecklas en bestående infektion med

risk för kronisk leverinflammation, s.k. kronisk hepatit C. Efter 20 år med kro-

nisk hepatit C har 15-25% utvecklat skrumplever (cirrhos) med risk för sviktande

leverfunktion och levercancer. HCV har också förknippats med vissa andra sjuk-

domar, såsom bl.a. lymfkörtelcancer, men detta samband har varit omdiskuterat.

Syftet med denna avhandling var att studera sjuklighet och dödlighet hos alla

personer med diagnostiserad HCV-infektion i Sverige. Studiepopulationen häm-

tades från det nationella smittskyddsregistret och samkördes med andra nationel-

la register för information om emigration, död, cancer och sjukhusvård. Register-

filerna avidentifierades innan de analyserades.

I det första arbetet studerades risken för lymfkörtelcancer, s.k. non-Hodgkin’s

lymfom (NHL) och Hodgkin’s lymfom, akut och kronisk lymfatisk leukemi, mul-

tipelt myelom samt sköldkörtelcancer. Hos de 27150 HCV-infekterade fann man

en dubblerad risk för NHL och multipelt myelom hos dem som varit HCV-

infekterade mer än 15 år, jämfört med den allmänna befolkningen (korrigerat för

ålder, kön och år). Detta styrkte det tidigare omdebatterade sambandet.

I det andra arbetet studerades hur stor risken för levercancer var hos 36126

HCV-infekterade. Efter mer än 25 år med HCV-infektion var risken för levercan-

cer 40 gånger högre än i normalbefolkningen och den absoluta risken för att ut-

veckla levercancer var 7% under 40 års tid med HCV-infektion.

Död och dödsorsaker studerades i det tredje arbetet. Den totala dödligheten

var närmare sex gånger högre, och dödligheten i leversjukdom 36 ggr högre,

bland de 34235 HCV-infekterade än i normalbefolkningen. Drogmissbruk och

yttre orsaker (olyckor, självmord, m.m.) var vanliga dödsorsaker i yngre åldrar.

I det fjärde arbetet studerades sjukhusvård av HCV-infekterade (n: 43000) i

jämförelse med en matchad icke HCV-infekterad population (n: 215000). Den

statistiska metoden ”Cox regression” användes för att uppskatta sannolikheten

(hazard ratio) för att bli inlagd på sjukhus, och antalet inläggningar och vårdda-

gar för att uppskatta den totala sjukvårdsbelastningen. Slutenvård var c:a 6 ggr

vanligare bland de HCV-infekterade och c:a 50% var för psykiatriska, vanligen

drogassocierade tillstånd. Sannolikheten för leverrelaterad inläggning var mycket

hög, allvarliga leverkomplikationer ökade på 2000-talet och kommer troligen att

öka de närmaste åren, som ett resultat av stor smittspridning på 1970-talet. Un-

der 2000-talet behandlades årligen c:a 1000 patienter med HCV-läkemedel.

CONTENTS

ABBREVIATIONS............................................................................................ 11

LIST OF PAPERS.............................................................................................. 13

INTRODUCTION............................................................................................ 15

Historical aspects on hepatitis C virus (HCV) infection ................................. 15

HCV virology................................................................................................ 16

Diagnosis of HCV infection........................................................................... 17

Epidemiology and routes of transmission....................................................... 20

The natural course of HCV infection............................................................. 24

Extra-hepatic manifestations ......................................................................... 25

Mortality....................................................................................................... 26

Health care resource use ................................................................................ 26

Therapy for HCV infection............................................................................ 26

AIMS ................................................................................................................ 29

CONFIDENTIALITY AND ETHICS................................................................ 30

MATERIALS AND METHODS ....................................................................... 31

Study population ........................................................................................... 31

Linkage to other registers .............................................................................. 33

Modelling date of infection............................................................................ 34

Analyses ........................................................................................................ 35

RESULTS AND DISCUSSION.......................................................................... 39

HCV, non-Hodgkin’s lymphoma and multiple myeloma – Paper I................. 39

HCV and hepatocellular carcinoma – Paper II ............................................... 41

HCV and mortality – Paper III ...................................................................... 43

HCV and inpatient care – Paper IV ............................................................... 45

CONCLUSIONS............................................................................................... 49

ACKNOWLEDGEMENTS............................................................................... 51

REFERENCES .................................................................................................. 53

ORIGINAL PAPERS I–IV

Hepatitis C virus infection ann-sofi duberg I 11

ABBREVIATIONS

ALT alanine amino transferase

ALL acute lymphatic leukaemia

anti-HBs antibodies to hepatitis B surface antigen

anti-HCV antibodies to hepatitis C virus

ATC Anatomical Therapeutic Chemical Classification System

CI confidence interval

CLL chronic lymphatic leukaemia

DDD defined daily doses (dose per day of a drug)

DNA deoxyribonucleic acid

EIA enzyme immunoassay

HAV hepatitis A virus

HBsAg hepatitis B surface antigen

HBV hepatitis B virus

HCC hepatocellular carcinoma

HCV hepatitis C virus

HIV human immunodeficiency virus

HL Hodgkin’s lymphoma

HR hazard ratio

ICD International Statistical Classification of Diseases

IDU injection drug use

IU international units

MM multiple myeloma

NANBH non-A non-B hepatitis

NHL non-Hodgkin’s lymphoma

ORF open reading frame

peg-IFN pegylated interferon alfa

PCR polymerase chain reaction

PLC primary liver cancer

PLD liver-related principal discharge diagnoses

RIBA recombinant immunoblot assay

RNA ribonucleic acid

RVR rapid viral response

SIR standardized incidence ratio

SLC serious liver complications

SMI Swedish Institute for Infectious Disease Control

SMR standardized mortality ratio

12 I ann-sofi duberg Hepatitis C virus infection

STAT-C specifically targeted antiviral therapy for HCV

SVR sustained viral response

TC thyroid cancer

UTR untranslated region

WHO World Health Organisation


LIST OF PAPERS

This thesis is based on the following papers, which are referred to in the text by

their Roman numerals:

I Duberg AS, Nordström M, Törner A, Reichard O, Strauss R, Janzon R,

Bäck E, Ekdahl K. Non-Hodgkin’s lymphoma and other non-hepatic malig-

nancies in Swedish patients with hepatitis C virus infection. Hepatology

2005; 41:652-659.

II Strauss R*, Törner A*, Duberg AS*, Hultcrantz R, Ekdahl K. Hepatocellu-

lar carcinoma and other primary liver cancers in hepatitis C patients in Swe-

den – a low endemic country. J Viral Hepat. 2008; 15:531-537.

(*contributed equally to the article)

III Duberg AS, Törner A, Daviðsdóttir L, Aleman S, Blaxhult A, Svensson Å,

Hultcrantz R, Bäck E, Ekdahl K. Cause of death in individuals with chronic

HBV and/or HCV infection, a nationwide community-based register study. J

Viral Hepat. 2008; 15:538-550.

IV Duberg AS, Pettersson H, Aleman S, Blaxhult A, Daviðsdóttir L, Hultcrantz

R, Bäck E, Ekdahl K, Montgomery SM. The burden of hepatitis C in Swe-

den: a national study of inpatient care. Submitted.


INTRODUCTION

Historical aspects on hepatitis C virus (HCV) infection

When specific diagnostic tests for hepatitis A virus (HAV) and hepatitis B virus

(HBV) became available in the 1970s a post-transfusion hepatitis without sero-

logical markers of these viruses, non-A non-B hepatitis (NANBH), was recog-

nized 45. The NANBH also occurred sporadically within the community 7, 146, and

early studies of the natural history suggested a prolonged, asymptomatic course

with risk for chronic hepatitis and liver cirrhosis 94.

Searching for the NANBH agent for more than a decade finally resulted in the

characterization of the hepatitis C virus (HCV) in 1989 24. The subsequent devel-

opment of sensitive and specific diagnostic assays revealed that more than 90% of

NANBH was caused by HCV 31, 79. Furthermore, it was disclosed that chronic

HCV-infection was a global problem, estimated to affect about 170 million indi-

viduals, corresponding to a global prevalence of 3% 155.


HCV virology

The hepatitis C virus belongs to the Flaviviridae family, genus Hepacivirus. HCV

is a spherical, enveloped RNA virus, approximately 50 nm in diameter. The single

positive-strand RNA genome of approximately 9,500 nucleotides contains a large

translational open reading frame (ORF) flanked by highly conserved untranslated

regions (UTR) at both the 5’ and the 3’ termini 25 (Figure 1). The major open

reading frame encodes a large polyprotein of about 3,000 amino acids. The poly-

protein processing yields at least 10 different structural and non-structural pro-

teins: the core protein (C) which forms the viral nucleocapsid, two envelope gly-

coproteins (E1 and E2), the short membrane peptide p7 probably promoting as-

sembly and release of infectious virions, and six non-structural proteins (NS2,

NS3, NS4A, NS4B, NS5A and NS5B) involved in polyprotein processing and vi-

ral replication 111, 136.

Figure 1. Schematic diagram of the HCV-genome.

The HCV strains are classified into six major genotypes and an increasingly

number (>80) of subtypes or variants, designated by Arabic numerals for the

genotype and small letters for the subtype 130, 131. The genotypes differ from each

other by more than 30% at the nucleotide level, compared with 20% to 25%

between subtypes.

The understanding of the viral life cycle and the structural details of HCV have

been hampered by the lack of a satisfactory cell culture system. Only recently

were infectious HCV virions produced in cell cultures 65, 76 and studied by electron

microscopy 158. The virions isolated from cultured cells had a rather uniform di-

ameter of around 50 nm and a smooth or spike-less outer surface, thus very simi-

lar to other Flaviviridae such as dengue and West Nile virus.

Mathematical modelling of viral dynamics reveals high turnover rates of viral

production and clearance, approximately 1011 to 1013 virions per day, and an es-

timated half-life of a few hours for free virions 160.

C E1 E2 NS2 NS3 NS4B NS5A NS5B NS4A p7

5’ 3’


Diagnosis of HCV infection

Antibodies to hepatitis C virus

Diagnostic methods for HCV-infection became available in 1990. The detection

of specific antibodies in body fluids is based on the use of enzyme immunoassays

(EIAs) and recombinant immunoblot assays (RIBAs). In 1991 the first assays

were replaced by the more sensitive and specific second (and subsequently the

third) generation tests 1, 19. These tests are based on four recombinant HCV anti-

gens, c22-3, c100-3, 5-1-1, and c33c (representing the core, NS3, NS4, and NS5

sequences), to capture circulating antibodies.

In EIA the antigens are coated onto the wells of micro titre plates or micro

beads, adapted to automated devices. The presence of antibodies in the sample is

revealed by anti-antibodies with an enzyme that transform a substrate to a col-

oured compound. In RIBA the four antigens are attached as four separate bands

on a nitrocellulose strip and reactivity with two or more of the antigens are con-

sidered a positive test.

The currently used EIA and RIBA detect HCV-antibodies with a high sensitiv-

ity and specificity. However, patients with an acute HCV-infection can be nega-

tive as the serological window (HCV-RNA in plasma in the absence of antibod-

ies) can be 60 days on average 23. HCV antibodies usually appear 2–8 weeks after

the acute phase of infection (Figure 2). Exceptionally, patients with profound

immune-suppression such as HIV, agammaglobulinaemia, or in haemodialysis

could be negative for HCV-antibodies in spite of an HCV-RNA positive infection.

The antibody-tests do not allow distinguishing an acute or chronic infection from

a resolved infection. The specific antibodies persist for life in patients with a

chronic infection, but also persons with a resolved infection (spontaneously or by

treatment) usually have antibodies for many years or life-long. Thus, in these in-

dividuals HCV-RNA detection is required to discriminate a resolved infection

from a chronic.

The EIA is the mainstay in HCV-diagnostics, being cheap, easy to use, fully

automated, and well adapted for large volume testing. The RIBA, separating the

four antigens, has been used as a confirmation test, but is nowadays often re-

placed by RNA-tests.


Hepatitis C virus RNA detection and quantification

Assays for the detection of HCV-RNA are used to disclose viraemia. HCV-RNA

detection can be achieved using target amplification such as polymerase chain

reaction (PCR) or signal amplification such as the branched DNA assay 23. The

classical techniques for viral genome detection and quantification are now being

replaced by real-time PCR assays 21, 22, 63. These assays have a broad dynamic

range of quantification and are more sensitive than classical PCR, with lower lim-

its of detection of 10–15 IU/ml, and an upper range of quantification of 7–8 log10

IU/ml. Real-time PCR can be fully automated and has become the technique of

choice to detect and quantify HCV-RNA in clinical practice.

For quantification the preferred unit is international units per millilitre (IU/ml),

conversion factors can be used for the relationship between the IUs and the earlier

used non-standardized copies/ml 109.

HCV-RNA becomes detectable within 1–2 weeks after initiation of infection

(Figure 2). Detection and quantification of HCV-RNA is useful in clinical practice

to detect and confirm HCV-infection and to monitor the virological response to

antiviral therapy 82. However, in untreated patients the HCV-RNA level has no

prognostic value and monitoring with repeated analyses is not recommended.

Figure 2. The virological markers during chronic hepatitis C virus infection.


Hepatitis C virus genotype determination

The HCV genotype is determined through viral genome sequence analysis, gener-

ally based on direct sequencing or reverse hybridization. The reference method is

phylogenetic analysis of sequences generated after PCR amplification. Direct se-

quence analysis is the gold standard for genomic sequencing; however, it only

identifies viral variants representing at least 20–25% of the circulating viral popu-

lations, with a risk for overlooked dual infections. Reverse hybridization is more

sensitive to detect minor variants representing as few as 5% of the viral popula-

tion, and the new versions have improved the accuracy for the subtype determina-

tion 23. There is also a serological test for HCV-genotypes, detecting antibodies

against genotype-specific antigens. This test allows detection of the genotypes but

not the subtypes 110.

The geographic distribution of genotypes and subtypes varies. In the United

States, Japan, and the main part of Europe genotype 1b and 1a are predominant

followed by 2b and 3a. In Sweden genotype 3 is the predominant, followed by 1a

and 2 151. Genotype 4 is common in Africa and the Middle East 131.

Genotype identification is clinically important because of the varying resistance

to the currently recommended therapy for hepatitis C. The HCV genotype should

be determined before treatment, as it has an influence on the indication, dosing

and duration of treatment, and the virological monitoring procedure 82.


Epidemiology and routes of transmission

The global burden of hepatitis C virus infection

Hepatitis C virus infection is a global health problem, in the 1990s WHO esti-

mated the global prevalence to 3% 155, 156, more recent data suggested 2.2%, cor-

responding to 150 million individuals worldwide 59. An update is needed and the

work on estimating the global burden of disease is currently in progress 59, 84.

There is a large degree of geographic variability in the distribution; the highest

prevalence rates of HCV-antibodies are reported in Asia and Africa 127, in Egypt

the overall seroprevalence is around 15–20% as a result of parenteral antischisto-

somal therapy 51. Areas with lower prevalence include the Unites States, Japan,

Australia and Central Europe with reported rates of 1–2%, Southern Europe with

overall prevalence rates 2.5–3.5%, and Northern Europe <1%, with the lowest

rates in the United Kingdom and Scandinavia 6, 8, 10.

It has been suggested that the spread of HCV in Southern and Central Europe

started during the last century as an epidemic of iatrogenic nature through the use

of unsafe injections, medical and surgical procedures, and transfusion of blood

products. This led to high prevalence in older individuals, followed, about 30

years later, of a still on-going IDU-related epidemic in younger people 38. Similar

patterns with high prevalence in older age groups were reported from other coun-

tries where iatrogenic spread has been important 6.

In Northern Europe HCV was mainly transmitted by IDU, resulting in an

overall prevalence between 0.1 and 1%, with the infected predominantly 30–49

years old. This indicated that the transmission occurred in the last 20–40 years

and primarily among young adults. A similar pattern was observed in the United

States, Australia, and other countries with similar HCV epidemiology 6, 10, 33, 34.

Blood transfusions used to be a leading cause of HCV-infection but the avail-

ability of diagnostic assays, the subsequent introduction of blood donor screening

and the rapid improvement of healthcare conditions have almost eliminated

transfusion-associated transmission in industrialized countries. However, noso-

comial outbreaks still occur 3, 152, and the iatrogenic spread continues in develop-

ing countries 115. In Western countries IDU has become the main transmission

mechanism of HCV, often acquired already the first year with IDU. The risk is

associated with the sharing of injection equipment as needles and syringes, but

also spoons, cottons, and other paraphernalia 38, 55, 91.

Transmission from an infected mother to the newborn has been estimated to

about 5%, with no protective effect of elective caesarean section delivery, how-

ever, there is no evidence of mother-to-infant transmission from breast-feeding 39,


98, 143. The risk for sexual transmission is low but evidence exists that this may

occur 2, 147.

Hepatitis C virus infection in Sweden

In Sweden (population 9 million) the seroprevalence was estimated to ≤0.5% in

the beginning of the 1990s when blood donor screening revealed that 0.2–0.5%

of blood donors, and 0.4% of a middle-aged urban population in Southern Swe-

den were anti-HCV positive 69, 108, 128. These studies probably included a healthier

part of the population and few injecting drug users, resulting in an underestima-

tion, but there are no recent population-based studies from Sweden.

Hepatitis C virus infection is a notifiable disease since 1990 when diagnostic

methods became available. All clinicians as well as laboratories are obliged to

report diagnosed HCV-infections, both positive HCV-antibody and/or HCV-

RNA analyses, to the Swedish Institute for Infectious Disease Control (SMI) 74, 132.

The notifications include information of epidemiological relevance. Individuals

with a resolved infection, spontaneously or by treatment, will still be in the regis-

ter.

Since 1990 about 45,000 HCV-infections have been notified. In a study of the

HCV-infected population notified 1990–2006 (43,000 individuals) the mortality

rates were high and 16% had died by the end of 2006 (Figure 3), leaving about

36,000 living, diagnosed HCV-infected individuals (paper IV). This could agree

with an overall prevalence rate of 0.5% (i.e. 45,000) with about 20% of the in-

fections undiagnosed.

Approximately 90% of the individuals notified with HCV-infection originate

from the Nordic countries, and 69% are men. More than 80% were born 1950

or later, 60% in the 1950s and 1960s 34. This resulted in an age-distribution

where 30–39 years were the predominant ages in the 1990s and 40–49 years in

the 2000s, with a rapid increase of age group 50–59 years (Figure 4). Conse-

quently, the HCV seroprevalence differs by age group, in year 2006 the living

HCV-notified population constituted about 0.4% of the Swedish population,

however, about 0.3% of age group 20–29 years, 0.5% of 30–39 years, 1.0% of

40–49 years, 0.7% of 50–59 years, 0.2% of 60–69 years, and <0.1% of 70+

years (results from the work with Paper IV).

According to the notifications to SMI the probable routes of transmission were

IDU in 65%, transfusion of blood/blood products 6%, sexual transmission 2%, a

few reports of mother-to-child, occupational, or nosocomial transmission, and

unknown or not stated in 26% 34.


In Sweden, NANBH existed but was rare in the 1950s; the large spread proba-

bly started in the mid 1960s and increased in the 1970s as a result of the increase

of IDU 146. In a Swedish study, analyses of stored frozen serum samples from pa-

tients with acute hepatitis in 1969–1972 revealed that 52% of the patients with

IDU were anti-HCV positive at that time 16. In more recent studies it was found

that about 90% of injecting drug users were anti-HCV positive by the age of 30,

and also short-term use was associated with a high risk of HCV-infection 85, 103, 153.

Since the introduction of blood donor screening in 1991 the risk for HCV-

transmission by blood transfusion is minimal. However, those who had blood

transfusions from the mid 1960s to 1992 were at risk for HCV-transmission. In

2007 the National Board of Health and Welfare recommended that everyone who

during childhood in the years 1965–1991 had received blood transfusions be-

cause of heart surgery, neonatal exchange transfusion, prematurity, or cancer

should be identified and HCV-tested 133. This national campaign has resulted in

an increase of diagnosed HCV-infections, the previously declining number of no-

tifications increased with about 400 in 2008 132.

Transmission through medical procedures have been reported also in Sweden,

in some of these the most likely route of transmission was contamination of saline

multidose vials, but also contaminated batches of immunoglobulin has been re-

ported 3, 4, 18, 80, 152, 154. Among those with unknown route of transmission there is

probably an overrepresentation of persons with a former IDU, supported by the

finding of a high proportion of inpatient care with psychiatric/drug-related diag-

noses in this group (Paper IV).

The HCV-epidemiology in Sweden, with the increase of individuals that have

been infected for 25-35 years, indicates that there would be an increase of HCV-

associated liver complications in the 2000s. This was verified in the study pre-

sented in Paper IV, but this increase has still not had any major impact on the

national rates of serious liver complications such as liver cancer. However, in

Sweden the inpatient care for ascites and liver failure has slowly increased 134.

This could be an effect of HCV, since in 2006 oesophageal varices, liver fail-

ure/encephalopathy, ascites, and primary liver cancer in HCV-infected individuals

constituted 15% of all admissions with these diagnoses in Sweden, in 2001 this

was 8% (Paper IV). Also the number of HCV-associated HCC has increased, in

the 2000s constituting 10% of the about 500 HCCs annually reported in Sweden

(Paper II and IV), but the national HCC incidence rates are still low, with a de-

creasing trend from the 1980s 134. However, 20-30% of all liver transplantations

in Sweden were performed in patients with HCV-infection 58, 121.


Figure 3. The annual number of HCV notifications, deaths/emigrations, and the resulting

annual observation time in person years as an approximation for individuals alive.

Figure 4. The age structure in the HCV-cohort over time, presented as person years (ap-

proximately equal to the number of individuals alive) by age group and calendar year.


The natural course of HCV infection

Already when NANBH was first described it was apparent that this hepatitis of-

ten persisted for a long time and that symptoms were mild, the diagnosis more

often based on elevated alanine aminotransferase (ALT) levels 31, 45, 93, 94.

After the initial exposure, the HCV-infection can be identified already within

7–10 days by detection of serum HCV-RNA 41. Some weeks later the liver-

associated serum enzymes such as ALT become elevated, the peak is often noted

about two months from infection date 23, 142 (Figure 2). Only about 20% of per-

sons with acute hepatitis C develop symptoms with jaundice, and the incubation

period is usually about 7 weeks 1, 5. Fulminant hepatitis is rare in hepatitis C 40, 89.

The HCV-specific antibodies appear on average 2-8 weeks after the acute phase

of infection, therefore HCV-RNA analysis is preferred for diagnosis of acute

HCV-infection.

Chronic HCV-infection is defined as persistence of HCV-RNA for 6 months or

more, but is often possible to predict earlier with stable HCV-RNA and fluctuat-

ing ALT levels 68. Progression to chronic HCV-infection occurs in about 75%.

However, in studies this differs between 50–85%, probably dependent on host

factors as age, race, immune status, and to some extent viral factors 1, 68, 77, 142. Pa-

tients who develop acute infection with jaundice and also children and young

women tend to have a higher rate of spontaneous clearance than others, and old

and immunosuppressed persons more often develop chronic infection.

Chronic infection usually remains asymptomatic for decades. However, some

studies have indicated that these patients have a reduced quality-of-life also in the

absence of liver cirrhosis. This could be related to the HCV-infection, but also to

the psychological impact of the knowledge of the infection, or a psychiatric con-

dition related to drug use 15, 28, 50.

Chronic hepatitis C progress to liver cirrhosis in 15–25% of the infected in 20

years. In early studies even higher rates were found, possibly an overestimation

due to referral bias in tertiary care centres 105, 144, 157. In general, lower rates have

been reported from community-based studies and in patients who were young at

date of infection 77, 119. There is little information regarding progression over peri-

ods longer than 30 years, but there is increasing evidence that disease progression

does not follow a linear path and that it is likely to increase as the infected person

ages 52, 113, 125, 141, 142. Co-factors as alcohol, obesity, and HBV or HIV co-infection

may worsen the prognosis 20, 60, 102, 150. In those who develop cirrhosis the progres-

sion of liver fibrosis begins and can be identified many years in advance 113, and

when cirrhosis is present the progression continues to end-stage liver disease in 2–

4% annually 43, 142. Also patients with cirrhosis have few signs and symptoms be-


fore culmination in end-stage liver disease with thrombocytopenia, prolonged

protrombinkomplex values, hypoalbuminemia, followed by ascites, oesophageal

varices, encephalopathy and/or HCC.

Liver biopsy is used for liver histology, to evaluate the grade of inflammation

and the stage of fibrosis 12, 73. To minimize the risk for sampling error a biopsy

longer than 25 mm is considered optimal. The biopsy is invasive with potential

adverse effects, therefore other non-invasive fibrosis markers have been studied,

however, liver biopsy is still considered the golden standard 13.

Hepatocellular carcinoma is a late complication, typically appearing after more

than 25 years with HCV infection, in patients with advanced cirrhosis. Clinical

findings could be worsening of symptoms and signs of cirrhosis and right-upper-

quadrant pain. Serum alfa-fetoprotein is sometimes elevated but ultrasound or

computed tomography could better reveal the tumour. It has been estimated that

1–4% of cirrhotic patients develop HCC annually, and among patients with

HCV-infection the total risk for developing HCC was estimated to 7% in 40

years or lifetime 30, 44, 137, 142.

The incidence and mortality rates of HCC have been reported to increase in

several developed countries 37, 75, 129. In contrast, the HCC incidence rates in Swe-

den have slowly decreased since the 1980s, and the last years there have been an

annual incidence of about 500 HCC 134. However, also in Sweden an increasing

proportion of all liver cancers occur in patients infected with HCV, and HCV-

associated liver disease is a major cause of liver transplantation 58, 121.

Extra-hepatic manifestations

HCV-infection has been associated with several extra-hepatic manifestations,

preferably immunological disorders. An association with essential mixed

cryoglobulinaemia has been established 87. Also, an association with malignant

non-Hodgkin’s lymphoma (NHL) has been suggested, though debated. A geo-

graphic variation was proposed as high HCV prevalence rates were found in

NHL patients in Italy, Japan and the United States, but not in Northern Europe 29,

48, 100, 101, 162. Later on several studies have found evidence for an association, with

an almost doubled risk for NHL in HCV-infected individuals, also in HCV low-

prevalence countries 35, 106, 122. Moreover, HCV has been associated with other

non-hepatic neoplasm as multiple myeloma (MM) and thyroid cancer (TC) 101.

Hepatitis C virus infection has also been linked to glomerulonephritis and end-

stage renal disease 145, and an association with several other disorders have been

proposed 47, 161.


Mortality

Early studies of mortality in HCV-infected individuals focused on mortality due

to liver disease, and were often performed in selected populations 126, 144. A few

community-based studies on mortality and causes of death were performed in

HCV low-endemic countries. These studies demonstrated a 3–6 times increased

all-cause mortality in HCV-infected individuals, and very high mortality rates

from liver disease and liver cancer compared with the general population 9, 36, 104.

However, the high proportion of IDU also influenced the mortality rates, with a

high excess mortality from drug-related and external reasons in younger age

groups, contributing to the high all-cause mortality rates (Paper III).

Health care resource use

Hepatitis C virus infection has been expected to cause an increasing demand on

the health care systems when the infected population ages. Several simulation

models of the future burden and temporal trends have found evidence for a rapid

increase in health care resource use 17, 61, 71, 138. In the United States, from 1994 to

2001, HCV liver-related hospitalizations were estimated to increase at average

annual rates exceeding 20% 61, and in England and Scotland models estimated a

rapid increase the next decade 71, 138.

In Sweden, 80% of the HCV-infected individuals are born in 1950 or later,

60% in the 1950s and 1960s, probably HCV-infected since the 1970s and early

1980s. They have now been infected for 25–35 years, some of them very likely at

risk for HCV-associated morbidity. This was the reason for the study of health

care resource use defined as inpatient care (Paper IV). This study verified an in-

crease of inpatient care from serious liver complications in the 2000s, with evi-

dence for a further increase the next decade.

Therapy for HCV infection

The main treatment goal in chronic hepatitis C is usually the prevention of liver

cirrhosis and HCC. Eradication of HCV improves liver histology and patient out-

come 105, 116, 148 and sustained viral response (SVR), defined as undetectable serum

HCV-RNA by a sensitive assay 24 weeks after the end of treatment, is the short-

term goal of antiviral therapy 82, 88.

The first report of antiviral treatment with interferon-alpha for NANBH was

published in 1986 70. It was followed by several studies of alpha-interferon treat-

ment for chronic hepatitis C; however, the outcome was poor as only about 20%

of the patients treated achieved a SVR 32, 112. Prolonged therapy resulted in higher


SVR 117, but in the late 1990s when interferon was combined with ribavirin the

SVR rate was approximately 40% 97, 114, 118. Since then, the standard interferon-

alpha has been modified to a pegylated interferon (peg-IFN) by adding a poly-

ethylenglykol molecule to increase the half-life and obtain a more efficient viral

suppression.

The current standard therapy is a combination of peg-IFN and ribavirin for 24

or 48 weeks 53, 62, 90. The dosing and duration of treatments are guided by the

HCV genotype, the HCV-RNA levels before treatment, and the viral kinetics dur-

ing treatment 82. Approximately 80% of patients infected with HCV genotype 2

or 3 achieve a SVR after 24 weeks of combination therapy. However, of those

infected with genotype 1 only 40–50% achieve a SVR after 48 weeks of therapy.

Treatment for 48 weeks is recommended also in patients infected with HCV

genotype 4.

A low baseline HCV-RNA is more often associated with a rapid viral response

(RVR) defined as undetectable HCV-RNA after 4 weeks treatment. In some pa-

tients with a RVR the duration of treatment can be shortened to 12 or 16 weeks

for genotype 2 and 3 27, 81, 82, and to 24 weeks for genotype 1 and 4. In a recent

trial, patients with HCV genotype 1 and 4 and RVR had a SVR of 80% 46. On

the contrary, patients with genotype 1 and a slow viral response (detectable

HCV-RNA at week 12 but undetectable HCV-RNA at week 24) benefit from

lengthening the treatment to 72 weeks. However, the SVR rates are still low, in a

recent study of slow responders treated for 72 weeks the SVR was 29% 14. Short-

ening the duration of therapy is associated with a lower SVR in patients older

than 50 years, or with high pre-treatment viral load, and/or cirrhosis. Other im-

portant factors for optimal treatment result are adherence to treatment and dose

maintenance 42, 140.

The unsatisfactory treatment results in HCV genotype 1 infections, and also

the substantial side effects of the currently recommended treatment, point to the

need for new treatment options. The development of new compounds under the

name of specifically targeted antiviral therapy for HCV (STAT-C), protease and

polymerase inhibitors, but also nucleoside and non-nucleoside analogues, is ongo-

ing. Promising results have been reported with two protease inhibitors that are

currently in phase III studies 67, 96. However, to reduce the risk for resistance to

the STAT-C drugs, the peg-IFN and ribavirin combination will probably be the

recommended treatment also in the near future, and when several STAT-C drugs

become available a combination of anti-virals will probably be used 11.


AIMS

The overall aim was to study hepatitis C virus (HCV) infection and associated

morbidity and mortality. The specific aims were to:

Study the association between HCV infection and non-Hodgkin’s lym-

phoma, Hodgkin’s lymphoma, acute and chronic lymphatic leukaemia,

multiple myeloma, and thyroid cancer in a large, population-based HCV-

infected cohort in Sweden (Paper I).

Study the association between HCV infection and primary liver cancer

(PLC), and to estimate the absolute risk for PLC, in all diagnosed HCV-

infected individuals in Sweden (Paper II).

Study mortality and cause of death in all individuals with diagnosed HCV,

chronic HBV, or combined HCV-HBV infections in Sweden (Paper III).

Examine the use of health care resources defined as inpatient care in all di-

agnosed HCV-infected individuals in Sweden, to demonstrate the total

burden, the temporal trends, and to assess the risk for inpatient care com-

pared with a non-infected population (Paper IV).


CONFIDENTIALITY AND ETHICS

The linkage between registers was possible using the personal identification num-

bers, all personal identifiers were then removed and the analyses were performed

on anonymous data.

The studies were approved by the Regional Ethical Boards in Örebro (Paper I)

and Stockholm (Paper I–IV).


MATERIALS AND METHODS

Study population

All four studies were register-based cohort studies and the study populations were

identified from the national surveillance database at the Swedish Institute for In-

fectious Disease Control (SMI) 132. Hepatitis C virus infection was classified as a

notifiable disease in 1990, when diagnostic methods became available, and since

then all clinicians as well as laboratories are obliged to report all diagnosed HCV-

infections to the SMI. Also hepatitis B virus (HBV) infection is, since 1969, a no-

tifiable disease. The notifications include information of epidemiological rele-

vance and are merged using the unique personal identification number issued to

all Swedish residents and used in all health care contacts 86.

The study populations in the four studies were identified from all HCV-

notifications, and in paper III also from the HBV-notifications, with the start in

1990. Statistics Sweden (Paper I and IV) or the National Tax Board (Paper II and

III) made a check up and excluded duplicates and notifications with incorrect per-

sonal identification number 135. The recruitment periods and the study popula-

tions were:

Paper I: All HCV-notifications 1990–2000 were identified, and the study

population consisted of 27,150 individuals notified for HCV-infection.

Paper II: The HCV-notifications 1990–2004 were identified. The 3,238

individuals notified for both HCV and acute or chronic HBV-infection

were excluded. Thus, the study population, the HCV-cohort, consisted of

36,126 individuals notified for HCV-infection but no HBV-infection.

Paper III: All HBV- and HCV-notifications 1990–2003 were identified.

The notifications for acute hepatitis B were excluded as the aim was to

study chronic hepatitis. The study population constituted three cohorts;

the HCV-cohort consisted of 34,235 individuals notified for HCV-

infection but no HBV-infection, the HBV-cohort of 9,517 individuals noti-

fied for chronic HBV but no HCV-infection, and the HBV-HCV cohort of

1,601 individuals with both HCV and chronic HBV-infection. HBV-

notifications before 1990 were not included, therefore some co-infected

with HBV-infection diagnosed before 1990 could be in the HCV-cohort.


Paper IV: All HCV-notifications 1990–2006 were identified. The HCV-

cohort consisted of 43,000 individuals notified for an HCV-infection, in-

cluding the 3,556 also notified for an acute or chronic HBV-infection. A

matched comparison-cohort consisting of 215,000 never HCV-notified

persons from the general population was identified by Statistics Sweden.

For each member of the HCV-cohort, five individuals were selected at

random from among those with the matching characteristics: birth-year,

sex, and county of residence on December 31st the year of HCV-

notification.

In the four studies the characteristics of the HCV-infected individuals were al-

most similar. About 80% were born after 1949, 69–70% were men, and ap-

proximately 90% originated from the Nordic countries (mostly Sweden). The

likely routes of HCV-transmission reported on the notifications were injection

drug use (IDU) in about 60%, transfusion of blood/blood products in 6%, sexual

2%, and unknown or not stated in approximately 30%.

In the HBV-cohort (Paper III) 85% were born in 1950 or later, 53% were men,

and >90% were immigrants with a probable HBV-transmission at birth (mother-

to-child) or early in life. In the HBV-HCV co-infected cohort 87% were born af-

ter 1949 and 78% were men, and the IDU transmission route constituted 67%.

Chronic HBV-infection is uncommon when HBV-infected as an adult, though it

seems as the HBV-HCV co-infected cohort consisted predominantly of injection

drug users probably infected as adults.

The HCV-cohort in Paper IV; the annual number of notifications, deaths and

emigrations, the annual observation time, and the age structure by calendar year,

was presented in Figure 3 and Figure 4 (see Epidemiology and routes of transmis-

sion). The age distribution over time demonstrated the fast growth of age groups

40–49 and 50–59 years during the last decade, a result of the HCV-epidemic in

the 1970s and early 1980s.


Linkage to other registers

The personal identification numbers 86 were used to link the notification datasets

to other national registers. Statistics Sweden (Paper I and IV) and the National

Tax Board (Paper II and III) added information on dates for emigration, immigra-

tion and deaths, country of birth and educational level (Paper IV). Statistics Swe-

den also identified the non-infected, matched comparison group for Paper IV 135.

The National Board of Health and Welfare added information from the Swed-

ish Hospital Discharge Register (Inpatient Register), Cancer Registry, Cause of

Death Register, and in Paper IV also the Prescription Register 134.

Since 1987 the Inpatient Register covers all inpatient care in Sweden, dropouts

are estimated to between one and two percent. Each in-hospital episode is re-

corded with (among other things) dates of admission and discharge, surgical pro-

cedures, and the discharge diagnoses with up to 8 medical conditions coded ac-

cording to the International Statistical Classification of Diseases (ICD). The ninth

revision (ICD-9) was used in 1987–1996 and the tenth revision (ICD-10) was

introduced in 1997. Validations revealed a correct ICD-code at the four-digit

level in 86% of all principle diagnoses 107.

All incident cancers in Sweden should be reported to the Cancer Registry both

by the clinician and pathologist/cytologist, and it has been estimated that more

than 95% of all tumours are reported and approximately 99% histologically or

cytologically verified 92. The cancers are coded according to the seventh revision

of ICD (ICD-7).

Swedish statistics on causes of deaths are among the oldest in the world, a na-

tionwide report system was first introduced in 1749. Since the 1940s the World

Health Organisation (WHO) is responsible for the international coordination. In

the Swedish Cause of Death Register the cause of death was coded according to

ICD-9 in 1987–1996 and ICD-10 was implemented in 1997. The underlying

cause of death is taken from the death certificate and is defined as the disease or

injury that initiated the chain of diseases that finally resulted in death.

The Prescription Register includes information regarding prescribed pharma-

ceuticals, the code according to the Anatomical Therapeutic Chemical Classifica-

tion System (ATC), the name, dose, size of package, cost, date of prescription and

dispatch, and since July 2005 the personal identification number of the customer.

Therefore the data on prescribed pharmaceuticals was of limited use and only in

Paper IV.


Modelling date of infection

Because of a mild or asymptomatic initial course the actual date for the primary

HCV-infection is seldom known, and the infection could remain undetected for

many years. The risk for HCV-related complications probably increases with time

and a model for date of infection was needed to make it possible to stratify ac-

cording to duration of infection (Paper I and II).

A model to approximate the date of infection was constructed based on birth

year, route of transmission, and available data on the HCV-epidemic in Sweden

indicating that HCV existed but was rare in the 1950s and that the spread of

HCV in Sweden started in the mid 1960s 16, 55, 103, 146, 153.

The same model was used for individuals infected through IDU, sexual, or un-

known routes of transmission. Persons born before 1930 were considered infected

in 1965; persons born in 1930 infected at the age of 35 years, linearly falling to

the age of 20 years when born in 1955; and when born in 1955 or later consid-

ered infected at the age of 20 years. If notified before the age of 20 years the age

at notification was used.

For those with transfusion-associated HCV infection (before blood donor

screening in 1991) the date of infection was approximated to 1980. When re-

ported route of transmission was mother-to-child or adopted child, the date of

birth was considered the date of infection, and when nosocomial or occupational

route of transmission the date of infection and notification was equalled.


Analyses

Paper I

The study period was 1990–2000. For each subject the observation time (ex-

pressed as person years) started at date of HCV-notification and ended at the first

date of any malignancy reported to the Cancer Registry, emigration, death, or

end of study, whichever occurred first.

To reduce the possibility that the HCV-infection was diagnosed as a result of

the cancer diagnosis only patients with the HCV-notification more than 3 months

before cancer diagnosis were included in the analyses.

All non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), chronic lym-

phatic leukaemia (CLL), acute lymphatic leukaemia (ALL), Hodgkin’s lymphoma

(HL), and thyroid cancer (TC) in the HCV-cohort were identified. Data were

stratified according to estimated duration of HCV-infection, less than 15 years

and 15 years or more, calculated according to the infection date model.

The risk for malignancy in the HCV-cohort compared with the general popula-

tion was expressed as a standardized incidence ratio (SIR), the ratio of the ob-

served number of malignancies compared with the expected number. The ex-

pected number was calculated using the age-, sex- and calendar year specific inci-

dence rates from the Cancer Registry.

Paper II

The study period was 1990–2004. For each subject the observation time started

at date of HCV-notification and ended at date of primary liver cancer (PLC) re-

ported to the Cancer Registry, emigration, death, or end of study, whichever

came first.

All PLC were identified, patients with PLC diagnosis the first 3 months after

HCV-notification were excluded, to reduce bias evolving from the possibility that

the HCV-infection was diagnosed as a result of liver cancer.

Time with HCV-infection was estimated according to the date of infection

model, and the cohort was divided in six strata: <10 years, 10–20, 20–25, 25–30,

30–35, and ≥35 years duration of HCV-infection.

The risk for PLC in the HCV-cohort compared with the general population

was expressed as SIR, the ratio between the observed and the expected numbers

calculated from the age-, sex-, and calendar year specific incidence rates from the

Cancer Registry and the observation time (person years) in the HCV-cohort.

The absolute risk of PLC within 40 years of HCV-infection was estimated with

the Kaplan-Meier method.


Paper III

The study period was 1990–2003. For each subject the observation time started

at date of HBV or HCV notification (first notification if co-infected) and ended at

death, emigration, or end of study, whichever occurred first.

All individuals who died less than 6 months after the hepatitis notification were

excluded from the analyses to reduce possible bias from HBV and/or HCV infec-

tions diagnosed as a result of the disease that led to death.

To categorize the causes of death, the ICD-codes were used to identify deaths

from the diagnoses forming the ICD-chapters, but also other diagnoses of inter-

est, i.e. liver-related, drug-related, external reasons, HIV, NHL, MM, and other

malignancies.

The mortality in the study population was compared with the mortality in the

general population by calculating standardized mortality ratios (SMR), the ob-

served number of deaths divided by the expected number of deaths. The mortality

rates for the general population were obtained from the Cause of Death Register.

For the calculation of the expected number of deaths the sex- and age-specific

mortality rates in the calendar year 1999 were used.

Paper IV

The study period was 1990–2006. For each subject the observation time (person

years) started at date of HCV-notification (same date for the five matched com-

parison individuals) and ended at date of death, emigration, or end of study,

whichever occurred first.

The risk for admission to hospital, a hazard ratio (HR), was estimated using

Cox regression to compare the HCV-cohort with the non-infected comparison-

cohort. The time from HCV-notification to first admission was used and the stud-

ied episodes were “all episodes”, “psychiatric care” (principal diagnoses, mostly

drug-related), “principal liver-diagnoses” and “all liver cancer” (principal and

non-principal diagnoses). To evaluate the effect of selection and surveillance bias

these analyses were also performed excluding all subjects who had been inpatients

the year before and/or the year after HCV-notification. The analyses were also

stratified by sex, period of notification, and age at notification, and adjusted by

age at notification, sex, HIV, and performed without the HBV-infected, and by

route of transmission.

The total burden was estimated by the frequency of admissions and days in

hospital, totally and by groups of diagnoses, and by sex, age groups, calendar

years, and annual rates per 1000 person years. The person years were an ap-

proximation for the number of individuals alive in the cohorts. The age- and sex-


adjusted rate ratios for admissions and hospital days were calculated. The

changes over time were also demonstrated by the differences in inpatient-care in

the years 1996, 2001 and 2006.

In all studies the ninety-five percent confidence intervals (CI) were calculated as-

suming a Poisson distribution.


RESULTS AND DISCUSSION

HCV, non-Hodgkin’s lymphoma and multiple myeloma – Paper I

After exclusion of the 464 individuals who had a cancer diagnosis before or

within 3 months after HCV-notification the observation time for the remaining

26,686 was 122,272 person years, 35,982 in the stratum with HCV-duration <15

years and 86,290 in the stratum ≥15 years with HCV-infection.

During follow-up, with the start 3 months after HCV-notification, there were

20 NHL, 7 MM, 4 CLL, 5 TC, 1 ALL, and 1 HL diagnosed in the HCV-cohort.

The risk of NHL was significantly increased in the stratum ≥15 years of HCV-

infection (SIR= 1.89; 95% CI: 1.10–3.03) and in the overall NHL group (SIR=

1.99; 95% CI: 1.21–3.07). However, when excluding 4 patients with HIV-

infection the SIR was 1.6 (95% CI: 0.91–2.59). The risk of MM was significantly

increased in the ≥15 year stratum (SIR= 2.54; 95% CI: 1.11–5.69).

Table 1. Standardized incidence ratios (SIR) for B-cell non-Hodgkin lymphoma, multiple

myeloma, chronic lymphatic leukaemia, and thyroid cancer in 26,686 HCV-infected. Diagnosis and Stratum

(duration of HCV-infection)

Observed

Expected* SIR 95% CI

B-cell non-Hodgkin’s lymphoma 0–14 years 3 1.08 2.78 0.57–8.11 >15 years 17 8.98 1.89 1.10–3.03 All 20 10.06 1.99 1.21–3.07 Chronic lymphatic leukaemia 0–14 years 0 0.09 - - >15 years 4 1.98 2.03 0.54–5.04 All 4 2.07 1.93 0.53–4.95 Multiple myeloma 0–14 years 0 0.13 - - >15 years 7 2.76 2.54 1.11–5.69 All 7 2.89 2.42 0.97–4.99 Thyroid cancer 0–14 years 0 0.75 - - >15 years 5 2.47 2.03 0.80–5.75 All 5 3.22 1.55 0.50–3.62

Analysis excluding patients with HIV-infection

B-cell non-Hodgkin’s lymphoma 0–14 years 2 1.07 1.86 0.12–6.75 >15 years 14 8.95 1.56 0.86–2.62 All 16 10.02 1.60 0.91–2.59 *The expected number of cases was calculated using age, sex and calendar year specific

incidence rates from the Swedish Cancer Registry.


The role of HCV as an etiological factor or cofactor in the pathogenesis of

NHL has been controversial. Earlier studies were often case-control studies with

diverging results 57 and geographical differences had been suggested, an increased

risk for NHL was reported from Italy, Japan, and the United States 29, 49, 100, 101, 162,

but not in HCV low-prevalence countries in Northern Europe 64, 95. In our study

we used a new approach and studied the incidence in the entire cohort of notified

HCV-infected individuals in Sweden, a country with low HCV prevalence. Fur-

thermore, other non-hepatic malignancies in which an association had earlier

been described (MM, TC) or with a theoretic background consistent with an as-

sociation were studied 101.

The study was complicated by the very mild initial course of HCV-infection,

the onset rarely identified. The chronic phase may last for decades without symp-

toms (and diagnosis) and also the virus was not discovered until 1989. The risk

for HCV-related complications might increase with time of infection, therefore

the model for date of infection and the stratification was performed. The SIR es-

timates were as high in the strata with shorter duration of HCV-infection, but the

numbers were small and no firm conclusions may be drawn.

Sometimes HCV-infection is diagnosed late and in the relation to other disease,

in this study demonstrated by the cluster of 14 NHL and 6 MM in close relation

to the HCV-notification (±3 months), therefore not included in the analysis.

These patients had probably been HCV-infected for many years and pointed to

the undiagnosed HCV-infections in society.

The results indicated an increased risk for B-cell NHL and MM in HCV-

infected in Sweden compared with the general population; the association with

NHL was still increased but not statistically significant when HIV-infected were

excluded. HIV-infection is a well-recognized risk factor for malignant lymphoma,

however, the NHL incidence has decreased since the introduction of highly active

antiretroviral therapy in 1996 78. Also organ transplantation with immune sup-

pressive therapy increases the risk for NHL 66, 159, however, in this study there

were no transplanted patients in the SIR analyses.

This study has been succeeded by studies supporting the findings of a low-

grade association between HCV and NHL but there are only few studies on the

association HCV and MM 26, 56, 122. The almost doubled risk for NHL was verified

in a recent study on methodology using the HCV-cohort in Sweden 1990–2006

(Törner A, et al. Submitted). This study supported the use of a 3 month time

window after HCV-notification but recommended the observation-time for all

subjects to start at that date, reducing the observation time with 6,500 person

years, resulting in lower number of expected, and a somewhat higher SIR.


HCV and hepatocellular carcinoma – Paper II

The study population contributed an observation time of 246,105 person years

and there were 234 patients (180 men, 54 women) with incident primary liver

cancer (PLC). Out of these cancers 219 (94%) were histologically verified; 211 as

HCC, eight as intrahepatic cholangiocellular cancers, and 15 were not histologi-

cally examined (most of them probably HCC). The mean time from HCV-

notification to PLC diagnosis was 5 years (range <1–13 years), and the mean es-

timated time from onset of HCV-infection to PLC diagnosis was 29 years (range

14–39 years). In the studied HCV-cohort another 120 PLC were diagnosed before

or less than three months after HCV-notification, and therefore not included in

the analyses in spite of an estimated onset of HCV-infection long before PLC di-

agnosis.

The risk for PLC in the HCV-cohort compared with the general population

was significantly increased in all strata with more than 10 years with HCV-

infection, the highest SIR in the stratum 25–30 years (SIR= 46; 95% CI: 36–56)

and 30–35 years with infection (SIR= 40; 95% CI: 31–51). The results were simi-

lar for men and women. The absolute risk of PLC within 40 years of infection

was 7% in the HCV-cohort.

Table 2. Standardized incidence ratios (SIR) for primary liver cancer in 36,126 individu-

als notified with HCV- but no HBV-infection.

Duration of

HCV-infection

Observation time

(person years)

Observed Expected* SIR 95% CI

<10 27,466 0 0.1 0 0–57

10-20 80,997 16 0.9 18 11–30

20-25 64,600 37 1.4 27 19–37

25-30 50,782 85 1.9 46 36–56

30-35 18,545 69 1.7 40 31–51

≥35 3,715 27 0.8 34 22–49

Total 246,105 234 6.7 35 31–40

*The expected number of cases was calculated using age, sex and calendar year specific

incidence rates from the Swedish Cancer Registry.

This study confirmed a very high risk for liver cancer in the HCV-cohort

(HBV-infected excluded) compared with the general population. Earlier studies

has estimated a progression to liver cirrhosis in about 20% of HCV-infected in

20-30 years, an annual incidence of HCC about 1–4% in cirrhotic patients, and

an estimated overall risk for HCC of 7% in all patients with chronic hepatitis C 30, 113, 144. However, most previous studies were performed in selected populations,


in tertiary care units, or in short follow-up periods 31, 77, 94, 149 and the high

chronicity rate and cirrhosis progression rate have been debated 52, 123, 124.

The here presented study used all HCV-notifications representing a population

based cohort as close as possible to all HCV-infected (HBV co-infected excluded)

in Sweden, however, the size of the undiagnosed cohort is not known. The pro-

portion of undiagnosed HCV-infections was high in the beginning of the 1990s

but has decreased with time, and at the end of study probably more than 75%

were diagnosed. The 120 PLC reported before or in close relation to the HCV-

notification (and not included in the analysis) have not been under observation

and represent HCV-infected who had been undiagnosed for a long time.

The SIR analysis was stratified according to estimated date of infection (see

modelling date of infection) to relate the cancer incidence to duration of infection.

An alternative could have been stratifying by age, but the model is probably more

relevant, being influenced both by age and HCV-epidemiology.

The stratification revealed that the highest relative risk for HCC was in pa-

tients who had been HCV-infected for more than 25 years, and the mean age at

PLC diagnosis was 60 years. Duration of HCV-infection in Sweden is highly re-

lated to age as the majority were infected already the first year with IDU, as very

young adults 55, 103. In the HCV-cohort the majority was born in the 1950s and

60s and infected in the 1970s and early 80s. In the general population PLC is a

disease of the elderly, the incidence rates increasing with age. In spite of that the

risk for PLC in the HCV-cohort compared with the general population increased

with duration of infection (and with higher age). This indicates that the incidence

of HCV associated PLC will increase when the HCV-cohort ages (the majority

still younger than 60 years) – if not prevented by more efficient treatments for

HCV 53, 90. In the 2000s about 10% of PLC in Sweden was in patients with a di-

agnosed HCV-infection, however, there is still no increase in the Swedish PLC

incidence rates that actually have decreased since the 1980s.

The SIR results were confirmed in a recent study of the methodology using the

HCV-cohort 1990–2006 (Törner A, et al. Submitted). This study also concluded

that to avoid bias when studying HCV and PLC the time window after HCV-

notification should be one year, however the predominant effect was the first

months, indicating that in the here presented study the SIR could be somewhat

too high due to selection bias, but also that the SIR could be a little too low as a

result of not excluding the first three months of observation time (resulting in a

lower number of expected PLC) for all individuals. However, none of these ad-

justments would have any major impact on the results.


HCV and mortality – Paper III

The mean observation times per subject in the HBV, HCV, and HBV-HCV co-

horts were 6.4, 6.3, and 7.9 years, constituting totally 60,697, 214,602, and

12,667 person years respectively. There were 425 (4.5%) deaths in the HBV-

cohort, 4651 (13.6%) in the HCV-cohort, and 209 (13.1%) in the co-infected

cohort. The most frequently reported underlying cause of death in the HBV-

cohort was neoplasm (38%), but external causes (e.g. injuries, intoxication, sui-

cide) were the predominant in the HCV and the co-infected cohort, 29% and

34% respectively.

To reduce bias all individuals who died the first six months after notification

were excluded, this was 116 (27%), 744 (16%) and 21 (10%) in the HBV, HCV

and co-infected cohort, leaving 311, 3907, and 188 deaths respectively, for the

standardized mortality ratio (SMR) analyses.

The “all cause” mortality was significantly increased with SMR 2.3 in the

HBV, 5.8 in the HCV, and 8.5 in the HBV-HCV cohort. In the HCV and the co-

infected cohort there was a great excess risk for death from causes related to IDU,

e.g. HIV, psychiatric diagnoses (98% drug-related) and external reasons, com-

pared with the general population. However, liver-related mortality was highly

increased in all three cohorts. Some of the results are presented in Table 3.

Table 3. Cause of death in the HBV, HCV and HBV-HCV cohorts. The risk is expressed

as Standardized Mortality Ratio (SMR), the observed deaths / expected deaths.

HBV (311 deaths) HCV (3,907 deaths) HBV-HCV (188 deaths)

Diagnosis SMR* 95% CI SMR* 95% CI SMR* 95% CI

All cause 2.3 2.0-2.6 5.8 5.6-6.0 8.5 7.3-9.8

Infection 13.7 8.7-20.6 28.7 25.2-32.5 44.8 25.1-74.0

Neoplasm 2.8 2.3-3.3 2.8 2.6-3.1 3.9 2.5-5.9

Psychiatric 3.1 1.8-5.0 15.0 13.7-16.5 26.0 18.0-36.3

Circulatory 1.4 1.1-1.8 2.6 2.4-2.8 5.1 3.4-7.3

External reasons 1.7 1.2-2.4 12.4 11.7-13.1 11.4 8.8-14.6

Subgroups:

Viral hepatitis 78.9 46.8-124.7 133.0 114.3-153.9 168.6 84.2-301.7

Liver cancer 31.2 21.9-43.2 34.9 30.1-40.2 65.2 33.7-113.9

Liver disease 10.7 6.8-15.9 25.1 22.3-28.0 24.4 13.0-41.8

“Total, all liver” 21.7 17.1-27.0 35.5 32.9-38.3 46.2 31.5-62.3

HIV 11.4 2.4-33.2 41.2 31.4-53.2 23.7 2.9-85.5

Lung cancer 1.4 0.6-2.7 1.8 1.3-2.3 4.4 1.2-11.2

*SMR = observed/expected, the expected number of deaths were calculated using age

and sex specific mortality rates in the general population.


The SMR in relation to age disclosed excess “all cause” mortality at all ages. In

the HCV and HBV-HCV cohorts the greatest excess mortality was at age 15–35

years, then slowly declining, reflecting the high risk of death from psychiatric

(drug-related) and external reasons at younger ages in HCV-infected individuals.

The excess liver-related mortality increased with age, the maximum SMR was 26

at age 60-69 years in the HBV, and 42 at age 70 years in the HCV cohort.

Liver-related death was highly increased in all cohorts, though a little higher in

the HCV-infected than in the HBV-cohort, this could possibly be related to a

higher risk for alcohol induced liver damage in HCV-infected 20, 150, also there

could be a synergistic effect in HBV-HCV co-infection. However, also in the

2,154 individuals infected through transfusion of blood/blood products the SMR

analyses revealed an excess all cause mortality of 2.9 (95% CI: 2.6–3.2) and a

great excess “all liver-related” mortality of 29.2 (95% CI: 22.7–37.0) including

liver cancer 19.2 (95% CI: 11.7–29.6), but no increased mortality from psychiat-

ric disease indicating a low prevalence of drug abuse in this subgroup.

The HCV and the HBV-HCV co-infected cohort consisted of a large propor-

tion of active or former injection drug users, reflected in the high risk from life-

style related mortality in younger ages, consistent with earlier findings in drug

addicts 54, 99. This suggests that IDU is a larger threat than hepatitis C in young

drug addicts, with a greater need of drug preventive interventions than HCV

treatment. However, there is a high risk of HCV-related complications later in life

and treatment of the HCV-infection should be considered in patients without ac-

tive IDU.

In this study, HCV-infected (in contrast to the HBV-infected) had an excess

mortality from almost all diagnoses. This should be interpreted with the mind

that the SMRs represent mortality, not incidence of a disease, and it is possible

that some excess mortality represent treatment failure due to lack of co-operation

or bad adherence to therapy of an underlying disease. The increased risk to die

from congenital disease (mostly organic heart disease), genitourinary disease and

renal failure rather reflects the former risk of HCV-transmission through blood

transfusion and haemodialysis. Previous studies demonstrated an excess mortality

also from diagnoses not related to HCV in blood recipients, i.e. probably from

the underlying disease that required transfusion 108, 126.

More than 90% of the HBV-cohort was immigrants, predominantly from HBV

high-endemic countries, probably infected at birth or early childhood 83 and the

“all cause“ and the liver-related mortality in HBV-infected in Sweden were high,

very similar to the HBV associated mortality in a high-endemic country as Tai-

wan 72.


HCV and inpatient care – Paper IV

When studying the total burden and the temporal trends of HCV-associated inpa-

tient care the size and the age structure of the HCV-cohort have major impact

(Figure 3–4). The majority of the HCV-infected individuals in Sweden were born

in the 1950s and 60s, with an increase of individuals aged 40-59 years in the

2000s. During observation time 16% in the HCV-cohort and 3% in the matched

comparison-cohort died, resulting in a shorter mean observation time/subject in

the HCV-cohort than in the comparison group, 7.75 and 8.54 years, respectively.

In the HCV-cohort 72% and in the comparison group 34% had been inpa-

tients. The estimated likelihood, a hazard ratio (HR), for admission to hospital

was 4.03 (95% CI: 3.98–4.08) in the HCV- compared with the comparison- co-

hort. The HR for liver-related care was 77.52 (95% CI: 71.03–84.60) and liver

cancer care 40.74 (95% CI: 30.58–54.27). Age- and sex-adjustment did not

notably change the results.

The burden of inpatient care in the HCV-cohort was high, the age- and sex-

adjusted rate ratio for admissions was 5.91 (95% CI: 5.87–5.94) and for hospital

days 8.78 (95% CI: 8.76–8.80), when compared with the comparison-group.

Psychiatric (mostly drug-related) care constituted 45% of admissions and 62% of

hospital days in the HCV-cohort. As expected, inpatient care increased with the

growth of the cohorts, however, inpatient care/person decreased over time in the

HCV-cohort. This was partly a result of a decrease in psychiatric care (more

common in younger age groups) but also due to selection bias, the first years pa-

tients with pre-existing morbidity were more likely to be tested for HCV. Also,

hospital beds in Sweden decreased with 50% during the study period 120, this af-

fected both the HCV and the comparison-cohort, preferably the length of the

hospital stays, with a 60% decrease in hospital days but no change in admission

rates in the comparison group.

Inpatient care with liver-related (including HCV-infection) principal discharge

diagnoses (hepatitis A and B not included) were very common in the HCV-cohort

(6.4% of episodes) compared with the comparison cohort (0.6% of episodes), the

age-adjusted rate ratios were: admissions 70.05 (95% CI: 66.06–74.28) and hos-

pital days 47.73 (95% CI: 41.3–57.15). In the HCV-cohort diagnostic liver biop-

sies constituted 20% of the principal liver diagnosis (PLD) admissions but 1% of

the hospital days as the majority did not stay over night. Serious liver complica-

tions (SLC) defined as oesophageal varices, liver failure/encephalopathy, ascites,

cirrhosis, liver cancer, and liver transplantation constituted 42% of the PLD epi-

sodes and 63% of the hospital days. In the 2000s inpatient care from SLC increa-


Figure 5. The HCV and the comparison cohort, episodes with liver-related diagnoses at

discharge, the admission rates (/1000) by calendar year (with 95% confidence intervals).

Figure 6. The HCV and the comparison cohort, episodes with liver-related diagnoses at

discharge, the admission rates (/1000) by age group (with 95% confidence intervals).


sed, also per person, with a 74% increase in admission rates from 2001 to 2006

(Figure 5). Both PLD and SLC rates increased with age, and SLC were uncommon

before the age of 40 years with the highest rates in the 60–69 years age group

(Figure 6).

In the HCV-cohort the prescription register identified 1,611 individuals who

were prescribed combination therapy with pegylated alfa-interferon and ribavirin

during the last 18 months of the study. Based on these results and national data

on annual prescribed DDDs of ribavirin, an estimated 6,000 patients (about

1,000 annually) had been prescribed HCV-treatment in 6 years (2001–2006).

The first years of the study there was probably a selection of more sick indi-

viduals into the cohort with a high probability that asymptomatic individuals re-

mained undiagnosed. Initially the undiagnosed population was considerable, but

the last years of the study probably >75% of all HCV-infected individuals in Swe-

den were diagnosed, and the total burden defined as inpatient-care likely rather

correct (undiagnosed presumed to use less inpatient-care). The rates (inpatient-

care per person) decreased when a larger part of the HCV-cohort was diagnosed.

To evaluate the bias the likelihood for admission (expressed as HR) was esti-

mated excluding inpatients the year before and/or the first year after HCV-

notification. This reduced associations somewhat, suggesting some bias, however,

the magnitude of the associations remained substantial.

In the subgroup infected through transfusion of blood/blood products the HR

estimates for liver care and liver cancer care was equally high, but the HR for

psychiatric care was much lower, compared with those infected through other

routes of transmission. This indicated that there was a high risk for liver disease

also in the absence of drug abuse. The HR for psychiatric (mostly drug-related)

care was almost as high when route of infection was IDU, sexual, unknown, or

tattoos, indicating that IDU probably was common in all these groups.

Liver-related care, especially from SLC, increased in the 2000s. The SLC ad-

mission rates by age group were stable over time, demonstrating that the increase

in SLC was an effect of the growth of the older age groups, resulting from the

spread of HCV in the 1970s and early 80s, and the large group of individuals

infected for 25–35 years. In the coming decade age group 60–69 years will about

four-double and inpatient care from SLC will likely more than double if not pre-

vented by treatments 53, 90. The last six years of the study approximately 1000 pa-

tients annually were treated with combination therapy curing about 50% of the

patients treated. If treated before serious liver damage this could prevent compli-

cations 10–20 years later, however, as the patients with cirrhosis have a lower

treatment response rate 139, and also when successfully treated will be at higher


risk for HCC, the treatments given until 2006 will not be enough to prevent an

increase in liver complications the next 10 years.

The fast increase in HCV liver-related hospitalizations estimated in the United

States 1994-2001 61 was not confirmed in the Swedish HCV-cohort. However, in

the next 10 years there could be a faster increase, also consistent with the predic-

tions from England and Scotland 71, 138.

In spite of very high rates of SLC in the HCV-cohort these episodes were too

few to significantly influence the national rates 134. However, the Swedish admis-

sion and hospital day rates for ascites and liver failure have slowly increased, pos-

sibly related to HCV. In 2006 oesophageal varices, liver failure/encephalopathy,

ascites and primary liver cancer care in the HCV-cohort constituted 15% of all

admissions with these diagnoses in Sweden, in 2001 this was 8%. The HCV-

cohort liver cancers in 2006 constituted 10% of all liver cancers in Sweden, but

the HCC incidence rates in Sweden have slowly decreased since the 1980s.

This study of the HCV-cohort in Sweden confirmed a high demand for inpa-

tient care, with a considerable proportion psychiatric care for drug-related condi-

tions in younger age groups, and a very high demand for liver-related care in all

ages. Inpatient care from serious liver complications increased in the 2000s, and

will probably increase the next decade as a result of the HCV-epidemic in the

1970s.


CONCLUSIONS

This thesis includes register-based cohort studies of morbidity and mortality in all

diagnosed and notified HCV-infected individuals in Sweden and can be summa-

rized with the following conclusions:

A low-grade association between B-cell non-Hodgkin lymphoma and HCV

was supported.

An association between Multiple Myeloma and HCV was found.

The risk for primary liver cancer was 40–45 times increased after more

than 25 years with HCV-infection, compared with the general population.

The absolute risk for primary liver cancer was 7% within 40 years of

HCV-infection.

All-cause mortality was significantly increased in the three cohorts of

HBV, HCV, and HBV-HCV co-infected.

Liver-related mortality was highly increased in the HBV, HCV, and HBV-

HCV cohorts, especially after the age of 50 years.

The HCV and HBV-HCV cohorts were similar with a high risk for life-

style-related mortality in young adults.

The total burden of inpatient care was high in the HCV-cohort and about

half of the episodes were from psychiatric, drug-related conditions, espe-

cially in younger ages.

Inpatient care from serious liver complications in HCV-infected individu-

als started to increase in the 2000s, and will probably increase the next

decade, as a result of the HCV-epidemic in the 1970s.


ACKNOWLEDGEMENTS

The work with this thesis has occupied my thoughts for a long time by now, and I

wish to express my sincere gratitude and appreciation to all who have supported

me and made this work possible. In particular I wish to thank:

Erik Bäck, my supervisor, for always being enthusiastic and supportive, and for

your pioneer ideas when planning the first paper – the spark that set it all off, and

also for, already in 1988, encouraging my interest in viral hepatitis.

Karl Ekdahl, assistant supervisor, for the collaboration with SMI, your interest,

and your excellent support and instructions in manuscript writing.

Rolf Hultcrantz, assistant supervisor, for sharing your knowledge in hepatol-

ogy, and for always stressing the simple but important questions.

Anders Blaxhult, assistant supervisor, for the collaboration with SMI, and your

valuable comments.

Anna Törner for your enthusiasm, ideas, and statistical knowledge, and for

your special engagement in the mortality study, enabling this thesis.

Marie Nordström for excellent collaboration regarding the first study, and for

encouraging me to continue this work.

Scott M Montgomery for sharing your knowledge in epidemiology and answer-

ing my numerous questions.

Helena Pettersson for your hard work with the register files for paper IV.

Ragnhild Janzon for supplying data from the National Surveillance database.

All other co-authors for support and advice and for the collaboration in our

study group, hopefully to be continued.

Margareta Landin for important End-Note assistance.

Jan Källman, head of the department, and all my colleagues at the Department

of Infectious Diseases for giving me time to carry out this project, for support and

patience, and for your nice company during working days.

The Research Committee of Örebro County Council for financial support, and

Roche Sweden for the Roche scholarship in 2009.

Family and friends for brighten up my spare time, and for playing golf with my

husband while I was working with this thesis. My parents Ulla and Bert who al-

ways have supported me. My children (and IT-support) Karl, Jens, and Erik with

Guro and little Jacob, you are always in my mind…

Last but not least, Hans – the man in my life, thank you for encouraging and

supporting me.


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Publications in the seriesÖrebro Studies in Medicine

1. Bergemalm, Per-Olof (2004). Audiologic and cognitive long-term sequelae from closed head injury.

2. Jansson, Kjell (2004). Intraperitoneal Microdialysis.Technique and Results.

3. Windahl, Torgny (2004). Clinical aspects of laser treatment of lichen sclerosus and squamous cell carcinoma of the penis.

4. Carlsson, Per-Inge (2004). Hearing impairment and deafness.Genetic and environmental factors – interactions – consequences.A clinical audiological approach.

5. Wågsäter, Dick (2005). CXCL16 and CD137 in Atherosclerosis.

6. Jatta, Ken (2006). Infl ammation in Atherosclerosis.

7. Dreifaldt, Ann Charlotte (2006). Epidemiological Aspects onMalignant Diseases in Childhood.

8. Jurstrand, Margaretha (2006). Detection of Chlamydia trachomatis and Mycoplasma genitalium by genetic and serological methods.

9. Norén, Torbjörn (2006). Clostridium diffi cile, epidemiology and antibiotic resistance.

10. Anderzén Carlsson, Agneta (2007). Children with Cancer – Focusing on their Fear and on how their Fear is Handled.

11. Ocaya, Pauline (2007). Retinoid metabolism and signalling invascular smooth muscle cells.

12. Nilsson, Andreas (2008). Physical activity assessed by accelerometry in children.

13. Eliasson, Henrik (2008). Tularemia – epidemiological, clinical and diagnostic aspects.

14. Walldén, Jakob (2008). The infl uence of opioids on gastric function: experimental and clinical studies.

15. Andrén, Ove (2008). Natural history and prognostic factors inlocalized prostate cancer.

16. Svantesson, Mia (2008). Postpone death? Nurse-physicianperspectives and ethics rounds.

Avh_Ann-Sofi Duberg_K200809.indd 135 2009-08-20 09.48

17. Björk, Tabita (2008). Measuring Eating Disorder Outcome – Defi nitions, dropouts and patients’ perspectives.

18. Ahlsson, Anders (2008). Atrial Fibrillation in Cardiac Surgery.

19. Parihar, Vishal Singh (2008). Human Listeriosis – Sources and Routes.

20. Berglund, Carolina (2008). Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus. Epidemiological aspects of MRSA and the dissemination in the community and in hospitals.

21. Nilsagård, Ylva (2008). Walking ability, balance and accidental falls in persons with Multiple Sclerosis.

22. Johansson, Ann-Christin (2008). Psychosocial factors in patientswith lumbar disc herniation: Enhancing postoperative outcome by the identifi cation of predictive factors and optimised physiotherapy.

23. Larsson, Matz (2008). Secondary exposure to inhaled tobacco products.

24. Hahn-Strömberg, Victoria (2008). Cell adhesion proteins in different invasive patterns of colon carcinoma: A morphometric and molecular genetic study.

25. Böttiger, Anna (2008). Genetic Variation in the Folate Receptor- and Methylenetetrahydrofolate Reductase Genes as Determinants of Plasma Homocysteine Concentrations.

26. Andersson, Gunnel (2009). Urinary incontinence. Prevalence, treatment seeking behaviour, experiences and perceptions among persons with and without urinary leakage.

27. Elfström, Peter (2009). Associated disorders in celiac disease.

28. Skårberg, Kurt (2009). Anabolic-androgenic steroid users in treatment: Social background, drug use patterns and criminality.

29. de Man Lapidoth, Joakim (2009). Binge Eating and Obesity Treatment – Prevalence, Measurement and Long-term Outcome.

30. Vumma, Ravi (2009). Functional Characterization of Tyrosineand Tryptophan Transport in Fibroblasts from Healthy Controls, Patients with Schizophrenia and Bipolar Disorder.

31. Jacobsson, Susanne (2009). Characterisation of Neisseria meningitidis from a virulence and immunogenic perspective that includes variations in novel vaccine antigens.


32. Allvin, Renée (2009). Postoperative Recovery. Development of a Multi-Dimensional Questionnaire for Assessment of Recovery.

33. Hagnelius, Nils-Olof (2009). Vascular Mechanisms in Dementia with Special Reference to Folate and Fibrinolysis.

34. Duberg, Ann-Sofi (2009). Hepatitis C virus infection. A nationwide study of assiciated morbidity and morality.



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