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Aims: Hepatitis C virus (HCV) is a slowly progressive disease, often transmitted among people who inject drugs (PWID). Mortality in PWID is high, with an overrepresentation of drug-related causes. This study investigated the risk of death in patients with chronic hepatitis C virus (HCV) infection with or without illicit substance use disorder (ISUD). Methods: Patients with HCV were identified using the Swedish National Patient Registry according to the International Classification of Diseases -10 (ICD-10) code B18.2, with ≤5 matched comparators from the general population. Patients with ≥2 physician visits with ICD-10 codes F11, F12, F14, F15, F16, or F19 were considered to have ISUD. The underlying cause of death was analyzed for alcoholic liver disease, non-alcoholic liver disease, liver cancer, drug-related and external causes, non-liver cancers, or other causes. Mortality risks were assessed using the standardized mortality ratio (SMR) with 95% CIs and Cox regression analyses for cause-specific hazard ratios. Results: In total, 38,186 patients with HCV were included, with 31% meeting the ISUD definition. Non-alcoholic liver disease SMRs in patients with and without ISUD were 123.2 (95% CI, 103.7-145.2) and 69.4 (95% CI, 63.8-75.3), respectively. The significant independent factors associated with non-alcoholic liver disease mortality were older age, being unmarried, male sex, and having ISUD. Conclusions: The relative risks for non-alcoholic liver disease mortality were elevated for patients with ISUD. Having ISUD was a significant independent factor for non-alcoholic liver disease. Thus, patients with HCV with ISUD should be given HCV treatment to reduce the risk for liver disease.

Background and aims: Sharing of unsterile injection equipment contributes to transmission of hepatitis C virus (HCV), HIV and hepatitis B virus (HBV) among people who inject drugs (PWID) but is largely preventable through needle exchange programmes (NEP). Sweden has been one of the last countries in Europe to scale up access to NEP for PWID, who consequently have high prevalence rates of HCV and HIV. The aim of the study was to investigate demographic and drug-related determinants of injection risk behaviours, sharing of needle/syringe and paraphernalia, and patterns of change over time in subgroups of PWID participating in the Stockholm NEP. Methods: The Stockholm NEP started in 2013 as the first formal NEP in the region. A total of 2860 PWID were included in this prospective open cohort study. The association between demographic and drug-related determinants and injection risk behaviours were analysed at baseline and followed up at 6, 12, 24, 36 and 48 months post-enrolment. Results: The following factors were associated with high levels of injection risk behaviours at inclusion: female gender, homelessness, low education level, younger age, amphetamine use, not in opioid substitution therapy (OST), being HIV negative and being HCV positive. We found an overall significant decrease in injection risk behaviours over time among participants. Not previously investigated in depth, we found that subgroups of participants varied in degrees of injection risk behaviour reduction over time and that women decreased injection risk behaviours faster than men. Enrolment in OST, HIV positive and age <25 years at inclusion were not associated with a decrease in injection risk behaviours over time. Conclusions: In this prospective cohort study over 4 years, we found that NEP participation was associated with a significant decrease in injection risk behaviours.

Despite access to effective antiviral drugs and vaccines, hepatitis B virus (HBV) infection remains a major health issue worldwide. HBV is highly infectious and may cause chronic infection, progressive liver damage, hepatocellular cancer (HCC) and death. Early diagnosis, proper management and timing of treatment are crucial. The Swedish Reference group for Antiviral Treatment (RAV) here provides updated evidence-based guidelines for treatment and management of HBV infection which may be applicable also in other countries. Tenofovir alafenamide (TAF) has been introduced as a novel treatment option and new principles regarding indication and duration of treatment and characterization of hepatitis B have been gradually introduced which justifies an update of the previous guidelines from 2007. Updated guidelines on HCC surveillance in HBV-infected patients, treatment and prophylaxis for patients undergoing liver transplantation as well as management of pregnant women and children with HBV infection are also provided.

Background and aims: Sharing of unsterile injection equipment among people who inject drugs (PWID) is the major transmission-route for hepatitis C (HCV). HCV is highly prevalent in PWID in the Stockholm needle exchange programme (NEP). The frequency of advanced liver fibrosis among the participants is, however, unknown. Methods: From December 2016 to April 2018, all participants with chronic hepatitis C infection (CHC) were offered liver fibrosis evaluation at the Stockholm NEP, including liver stiffness measurement (LSM), a medical history and expanded blood tests to evaluate APRI and FIB-4 scores. Results: A total of 2037 individuals were enrolled of whom 964 (47.3%) had CHC. LSM was performed in 203 (21.1%) of eligible participants of whom 85% had mild fibrosis (LSM ≤9.4 kPa) and 15% advanced fibrosis (LSM ≥9.5 kPa). APRI >1 and FIB-4 > 3.25 only identified 30% of participants with advanced fibrosis. However, all 31(100%) participants with advanced fibrosis were detected when APRI >1 was combined with an age of ≥40 years and an injection drug use (IDU) duration of ≥15 years. Conclusions: We found that the diagnostic work-up for advanced fibrosis can be simplified with this combination of easily available factors. This allows identification of PWID in need of immediate HCV treatment to prevent further disease progression. Furthermore, LSM can be avoided among PWID with mild fibrosis, identified by age <40 years combined with IDU duration of <15 years and APRI score <1. This strategy enhances the HCV care cascade where LSM is not easily available, and will thus facilitate HCV treatment initiation.

Background: In both Russia and Sweden, the dominant hepatitis C virus (HCV) is genotype 1, but around one-third of patients have genotype 3 infection. For such countries, HCV genotype testing is recommended prior to therapy. An effective pangenotypic therapy may potentially eliminate the need for genotyping. In this study, we evaluated the efficacy and safety of sofosbuvir/velpatasvir for 12 weeks in patients from Russia and Sweden., Methods: In an open-label, single-arm phase-3 study, patients could have HCV genotype 1-6 infection and were treatment-naïve or interferon treatment-experienced. All patients received sofosbuvir/velpatasvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12)., Results: Of 122 patients screened, 119 were enrolled and treated. Overall, half (50%) were male, 18% had cirrhosis, and 24% had failed prior interferon-based therapy. In total, 66% of patients were infected with HCV genotype 1 (59% 1b and 7% 1a), 6% with genotype 2, and 29% with genotype 3. The overall SVR12 rate was 99% (118/119, 95% confidence interval 95-100%). One treatment-experienced patient infected with HCV genotype 3 experienced virologic relapse after completing treatment. The most common adverse events were headache (16%) and fatigue (7%). Serious adverse events were observed in four patients, but none were related to treatment. No patients discontinued treatment due to adverse events., Conclusion: Sofosbuvir/velpatasvir as a pangenotypic treatment for 12 weeks was highly effective in patients from Russia and Sweden infected with HCV genotypes 1, 2, or 3. Sofosbuvir/velpatasvir was safe and well-tolerated. Clinical trial number: ClinicalTrials.gov NCT02722837.

The major transmission route for hepatitis C virus (HCV) is through sharing of unsterile injection equipment among people who inject drugs (PWID). The WHO strategy for HCV elimination by 2030 proposes increased efforts to treat PWID populations that drive the HCV epidemic. Among participants in the Stockholm needle exchange programme (NEP), the HCV prevalence is 60%. We aimed to study HCV incidence, spontaneous HCV clearance rate, and predictors associated with new HCV infections and reinfections in NEP participants. All 2320 patients enrolled in the programme between 8 April 2013 and 23 September 2016 were tested for HCV at baseline, and responded to a questionnaire regarding sociodemographic data and injection risk behaviour. Tests for HCV were repeated at an interval of 3-6 months. The anti-HCV prevalence in the NEP participants at baseline was 77%, and the prevalence of HCV RNA was 57%. 24% of the anti-HCV positive were HCV RNA negative with a spontaneously cleared HCV infection. The overall HCV incidence rate was 22/100 PY. The HCV incidence rate in the HCV naive group was 26/100 PY, and in the spontaneously cleared group 19/100. Although there were no significant differences in becoming HCV infected between the two groups (31% vs 29%), the rate of spontaneous HCV clearance was significantly lower in the HCV naive group, 20% vs 44%, (P < 0.05). A high HCV incidence rate was noted among the PWID indicating that treatment needs to be scaled up in conjunction with harm reduction measures to achieve HCV elimination goals set by WHO. This includes high coverage needle exchange programmes and effective addiction treatment for substance users, including opiate substitution treatment., (© 2018 John Wiley & Sons Ltd.)

Background: Relapse of hepatitis C virus (HCV) infection after liver transplantation has been universal, and the fibrosis progression faster than in non-transplanted patients. Interferon (IFN)-free treatment with direct antiviral agents (DAA) has improved the treatment outcome dramatically. We here report on the outcome of IFN-free treatment for HCV relapse after liver transplantation in a real life setting in Sweden., Material: In total, 93 patients with a mean age of 60 years (range 32-80) with HCV relapse after liver transplantation were given sofosbuvir-based treatment in combination with a protease inhibitor (simeprevir) or a NS5A inhibitor (daclatasvir or ledipasvir) with or without addition of ribavirin (RBV), or sofosbuvir and RBV only. Treatment was generally given during 24 weeks for advanced fibrosis or cirrhosis cases and 12 weeks for mild fibrosis with fibrosis stage 2 or less. The distribution of genotype 1, 2, 3, 4 in our patients was 58, 7.5, 26.5 and 7.5%, respectively., Results: All recipients reached end-of-treatment response (ETR) with HCV RNA <15 IU/mL. Sustained viral response 12 weeks after treatment cessation (SVR12) was achieved in 91/93 (97.8%) recipients. The SVR12 rates for genotype 1, 2, 3 and 4 were the SVR12 rate were 96, 100, 100 and 100%, respectively (p = .04)., Conclusion: It is concluded that IFN-free treatment with DAAs for HCV relapse after liver transplantation is highly effective also in a real life setting and offers cure for most recipients.

Staphylococcus aureus is a leading cause of infective endocarditis. Little has been published on the outcome and epidemiology of S. aureus endocarditis (SAE) in the twenty-first century. Our aim was to evaluate the short-term and long-term outcome of SAE in Stockholm, Sweden, and assess its incidence over time. Patients treated for SAE from January 2004 through December 2013 were retrospectively identified at the Karolinska University Hospital. Clinical data were obtained from medical records and the diagnosis was verified according to the modified Duke criteria. Of 245 SAE cases, 152 (62%) were left-sided and 120 (49%) occurred in intravenous drug users. The calculated incidence in Stockholm County was 1.56/100 000 person-years, increasing from 1.28 in 2004-08 to 1.82/100 000 person-years in 2009-13 (p 0.002). In-hospital and 1-year mortality rates were 9.0% (22/245) and 19.5% (46/236), respectively. Age (OR 1.06 per year) and female sex (OR 3.0) were independently associated with in-hospital mortality in multivariate analysis. Involvement of the central nervous system (CNS) was observed in 30 (12%) patients, and valvular surgery was performed during hospitalization in 37 (15%). In left-sided endocarditis the strongest predictors for surgery were severe valvular insufficiency (OR 8.9), lower age (OR 1.07 per year) and no intravenous drug use (OR 10.7), and for CNS involvement lower age (OR 1.04 per year). In conclusion we noted low mortality, low CNS complication rate, and low valvular surgery frequency associated with SAE in our setting. The incidence was high and increased over time. The study provides an update on the outcome and epidemiology of SAE in the twenty-first century., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: Cirrhosis is a well-known risk factor for hepatocellular cancer, but the true risk in autoimmune hepatitis (AIH) is scarcely studied. Other cancers may arise after prolonged use of immune-modulating drugs. The aim of this study was to investigate the cancer risk in a large cohort of AIH patients., Material and Methods: Six hundred and thirty-four Swedish patients in a well-defined cohort were matched to the Cause of Death Registry and the Cancer Registry. Standard incidence ratios were calculated by relating the incidences in the cohort to an age-matched material from the Swedish background population., Results: A higher overall incidence of malignancies than the background population was found, counting from the date of diagnosis (standard incidence ratio (SIR) 2.08, 95% CI 1.68-2.55). The highest risk was found for hepatocellular carcinoma (HCC). We found 10 cases (4.0%) in 248 patients with cirrhosis, which gives an incidence rate of 0.3%. Standard incidence ratio for developing hepatobiliary cancer was 54.55 (95% CI 19.92-99.99). HCC only occurred in cirrhotic patients. There was also an increased risk for non-melanoma skin cancer (SIR 9.87, 95% CI 6.26-14.81)., Conclusion: A slightly enhanced risk for malignancies in general compared to the background population was found. The risk of hepatobiliary cancer was increased, but the annual risk over the observational period was well under the postulated 1.5% when surveillance in cirrhotic patients is considered to be cost-effective.

The IL28B genotype has been found to have a strong influence on spontaneous clearance of acute HCV both in HCV mono- and HIV/ the HCV co-infected patients. Spontaneous clearance of chronic HCV without HCV treatment is rare. Here, we report on three chronic HCV cases co-infected with HIV with spontaneous clearance of their HCV infection, all with the IL28B CC genotype. These cases were derived from a surveillance of the total HIV/HCV co-infected cohort in Sweden (n =4 66). The estimated frequency of spontaneous clearance of chronic HCV infection in our cohort was calculated to be 0.6-4.7%. Our cases lend some support to the initiation of ART prior to HCV treatment in HIV/HCV co-infected patients. Furthermore, HCV-RNA testing should be recommended immediately before initiation of HCV treatment, to find the subset of HIV/HCV co-infected patients with IL28B CC that may have cleared their chronic infection spontaneously., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: Autoimmune hepatitis (AIH) is a liver disease which, if untreated, may lead to liver cirrhosis and hepatic failure. Limited data exist regarding factors predicting the long-term outcome. The aims of this study were to investigate symptoms at presentation, prognostic features, management and treatment in relation to long-term outcome of AIH., Material and Methods: A cohort of 473 Swedish patients with AIH was characterized regarding initial symptoms and signs, factors predicting death and future need for liver transplantation. Survival and causes of death were retrieved from Swedish national registers., Results: At diagnosis, fatigue was a predominant symptom (69%), 47% of the patients were jaundiced and 30% had liver cirrhosis. Another 10% developed cirrhosis during follow-up. Markedly elevated alanine aminotransferase levels at presentation were correlated with a better outcome. A high international normalized ratio (INR) at diagnosis was the only risk factor predicting a need for later liver transplantation. Histological cirrhosis, decompensation and non-response to initial treatment were all factors that correlated with a worse outcome. Overall life expectancy was generally favourable. However, most deaths were liver-related, e.g. liver failure, shock and gastrointestinal bleeding., Conclusions: Cirrhosis at diagnosis, a non-response to initial immune-suppressive treatment or elevated INR values were associated with worse outcome and a need for later liver transplantation. In contrast, an acute hepatitis-like onset with intact synthetic capacity indicated a good response to treatment and favourable long-term prognosis. Lifetime maintenance therapy is most often required.

In a recent expert meeting, Swedish recommendations for the treatment of HCV infection were upgraded. The panel recommends vaccination against both hepatitis A and B in patients with HCV. Therapy for symptomatic acute HCV infection should be initiated if spontaneous resolution has not occurred within 12 weeks, whereas asymptomatic acute HCV should be treated upon detection. Patients with genotype 2/3 infection should generally be treated for 24 weeks. In patients with a very rapid viral response (vRVR), i.e. HCV RNA below 1000 IU/ml on d 7, treatment can be shortened to 12-16 weeks, provided that no dose reduction has been made. For genotype 1 patients with rapid viral response (RVR), 24 weeks treatment is recommended. For patients with a complete early viral response (cEVR), 48 weeks treatment is recommended, whereas 72 weeks treatment should be considered for patients with partial early viral response (pEVR). For patients with difficult-to-treat disease and with pronounced anaemia, erythropoietin can be used to maintain the ribavirin dose. In HCV-HIV coinfected patients, combination therapy for HCV should, if possible, be initiated before anti-retroviral therapy (ART) is indicated. For liver transplant patients pre-emptive therapy is not recommended; hence, treatment should be deferred until histological recurrence.

Objective: Autoimmune hepatitis (AIH) is a chronic liver disease, which if untreated can lead to cirrhosis and hepatic failure. The aim of the study was to investigate the incidence, prevalence, diagnostic tradition and clinical initial presentation of AIH., Material and Methods: Analyses were performed in 473 patients identified as having probable or definite AIH., Results: The incidence of AIH was 0.85/100,000 (95% CI 0.69-1.01) inhabitants, which is somewhat lower than reported previously. The point prevalence amounted to 10.7/100,000 (95% CI 8.8-13.1), and 76% of the cases were females. The age-related incidence curve was bimodal but men were found to have only one incidence peak in the late teens, whereas women had a peak after menopause. AIH was presented as a spectrum of clinical settings from detected "en passant" to acute liver failure. Almost 30% of patients already had liver cirrhosis at diagnosis. Autoantibodies indicative of AIH type 1 were found in 79% of cases. Other concomitant autoimmune diseases were frequently found (49%)., Conclusions: The incidence and prevalence figures confirm that AIH is a fairly uncommon disease in the Swedish population. Symptoms at presentation were unspecific, but almost half of the patients were jaundiced, with around 30% having liver cirrhosis. The majority of Swedish AIH patients had AIH type 1.

Hepatitis C virus (HCV)-induced cirrhosis is the major indication for liver transplantation globally, and an increasing indication for liver transplantation in Sweden. We have retrospectively examined the 120 patients transplanted for HCV cirrhosis from 1987 through 2005, including 11 who received more than one graft. The 1-, 3-, and 5-year postoperative survivals for all patients transplanted for HCV with or without hepatocellular cancer (HCC) were 77%, 66%, and 53%, respectively. HCV patients without HCC had a 1-, 3-, and 5-year survivals of 78%, 73%, and 61%, compared with 84%, 79% and 74%, respectively, for patients transplanted with chronic liver diseases without cancer or HCV. The number of patients with HCV cirrhosis transplanted in our center is increasing. Compared with patients transplanted for other chronic liver diseases, we experienced inferior results among patients with HCV cirrhosis.

Hepatitis E virus (HEV) infections are responsible for large waterborne outbreaks in developing countries. Sporadic cases in the developed world are mainly imported via immigrants and travellers from endemic areas. HEV has been suggested to be a zoonotic infection where pigs may be an important reservoir for the disease and specific swine strains of HEV have been identified which can infect also humans. The aim of this study was to analyse if Swedish pig farmers are more exposed to HEV than persons with other occupations. A total of 115 male pig farmers aged 40-60 y and 108 age- and geographically- matched control subjects were tested for IgG anti-HEV antibodies. No statistical difference in anti-HEV prevalence was noted between pig farmers (13.0%) and control subjects (9.3%). The prevalence of anti-HEV antibodies in the pig farmers and controls was higher than that previously reported among other populations in Europe (<1-9%). Further studies are needed to elucidate the routes for infection of indigenous HEV and if sub-clinical infections with pig associated HEV strains occur in Sweden.

Background: Genotype distribution of chronic hepatitis C in Sweden has shown a predominance of genotype non-1. With recent improvements in therapy, genotypes 2 and 3 infections can, according to consensus, be treated without histological assessment. The aim of this study was to evaluate the genotype distribution, histological stage and grade, and the percentage of patients fulfilling the histological treatment criteria., Method: A total of 323 patients with chronic hepatitis C were tested for genotype, histological findings and the percentage fulfilling the histological treatment criteria as stated by Swedish consensus; i.e. having fibrosis stage II or more, or fibrosis stage I with inflammation grade II or more., Results: The patients had a mean age of 45 years (range 16-71 years) and 62% were males. Genotypes were determined in 79% of patients and genotype 2b or 3a was found to predominate, comprising 56%. Former intravenous drug use was found to be the predominant mode of acquisition, noted in 60%. The mean disease duration was 21 years (range 3-40) after which time 14% of patients had developed cirrhosis (stage IV). In the total material, 77% fulfilled the histological treatment criteria, 76% and 86%, respectively, among genotype I and genotype non-1 (2b and 3a) patients., Conclusions: Genotype non-1 (2b or 3a) predominated among Swedish patients, 14% of whom developed cirrhosis after a mean follow-up time of 21 years. Furthermore, an absolute majority fulfilled the histological criteria used to judge patients' eligibility for antiviral therapy, supporting the recent Swedish consensus decision to treat genotypes 2 and 3 infected patients without a previous biopsy.

In Stockholm, Sweden, the majority of pregnant women positive for hepatitis B surface antigen (HBsAg) are hepatitis Be antigen (HBeAg) negative. Newborns to HBeAg positive mothers receive vaccination and hepatitis B immunoglobulin (HBIg). Newborns to HBeAg negative mothers receive vaccine and HBIg only if the mothers have elevated ALT levels. The aim of this study was to retrospectively evaluate ALT levels as a surrogate marker for HBV DNA levels in HBeAg negative carrier mothers. Altogether 8947 pregnant women were screened for HBV markers from 1999 to 2001 at the Virology Department, Karolinska Hospital. Among mothers screened 192 tested positive for HBsAg (2.2%). 13 of these samples could not be retrieved. Of the remaining 179 sera, 8 (4%) tested positive for HBeAg and 171 (95.5%) were HBeAg negative. Among the HBeAg negative mothers, 9 had HBV DNA levels > 10(5) copies/ml, and of these 7 had normal ALT levels indicating low sensitivity of an elevated ALT level as a surrogate marker for high HBV DNA level. Furthermore, no correlation was found between ALT and HBV DNA levels. Hence, it is concluded that the use of ALT as a surrogate marker for high viral replication in HBeAg negative mothers could be questioned.

The number of individuals with chronic hepatitis B in Sweden has increased, mainly due to new immigrant groups. A safe and effective hepatitis B vaccine exists which allows a flexible dosing schedule. Most countries in the world adheres to the WHO recommendations to include this vaccine in the childhood vaccination regimen. This has led to a substantial drop in morbidity and mortality from hepatitis B virus infections in high endemic regions such as Taiwan. Sweden should consider changing its vaccination policy, including the vaccination of high risk groups only, and consider vaccination of all infants.

Sera from 62 hepatitis C virus (HCV)-infected Swedish blood donors were tested by a nested polymerase chain reaction using primers targeting the 5'-noncoding region of the GB virus-C/hepatitis G (GBV-C/HGV) genome and an enzyme-linked immunosorbent assay that detects antibodies to the envelope protein E2 of GBV-C/HGV (anti-E2). Fourteen (22%) and 21 (34%) of the 62 blood donors were found to be GBV-C/HGV RNA and anti-E2 positive, respectively. None of the blood donors was positive for both GBV-C/HGV RNA and anti-E2. Thus, 35 of 62 (56%) HCV-infected donors had been exposed to GBV-C/HGV infection. At sequencing of the 14 GBV-C/HGV isolates, 12 were identified as subtype 2a and 2 as subtype 2b. One of 7 (14%) donors with mild liver disease such as steatosis and nonspecific reactive hepatitis had been exposed to GBV-C/HGV vs. 34 of 55 (62%) with chronic hepatitis with or without cirrhosis (P = 0.04). All other differences in histology were small between HCV and dual HCV GBV-C/HGV-infected donors. In conclusion, more than half of HCV-infected Swedish blood donors in this study were positive for either GBV-C/HGV RNA or anti-E2. GBV-C/HGV viremia and seropositivity were mutually exclusive.

The influence of different risk factors for viral hepatitis A, B and C, particularly if sexual contact with the indigenous population was related to an increased risk of having hepatitis B virus (HBV) markers, was assessed by multivariate analysis in a logistic regression model in a prospectively enrolled series of 563 adult Swedish expatriates. The most frequently reported recognised risk factors for the acquisition of viral hepatitis (as reported in a self-administered questionnaire) were having received an inoculation during medical or dental treatment, reported by 45% of all subjects, and having had sexual contact with the indigenous population, reported by 35%. Whilst the prevalences of hepatitis A virus (HAV) and hepatitis C virus (HCV) markers in these expatriates were of the same magnitude as previously reported in the general Swedish population, 8% and 0.3%, respectively, the prevalence of markers for a past or present HBV infection was about twice as high (5%). The presence of HBV markers was associated with being a health care professional or having received inoculations during medical or dental treatment in Africa. No significant association was found between having HBV markers and having had sexual contact with the indigenous population.

Sixty-two anti-HCV and HCV-RNA positive Swedish blood donors (44 men, 18 women; median age 34 years) were studied. HCV genotypes were correlated to parenteral risk factors, liver morphology, serum alanine aminotransferase (ALAT) levels and HCV antibody profile. Forty percent of the donors were infected with HCV genotype 1a, 10% with 1b, 21% with 2b, and 29% with 3a. Intravenous drug use (IVDU) was more common in donors with genotype 3a than in those with genotype 1a (p = 0.024), and prior blood transfusion more common in genotype 2b than in 3a (p = 0.012). Chronic active hepatitis with and without cirrhosis was found in 38% of donors infected with genotype 2b as compared to 8% of donors infected with 1a (p = 0.034). Forty percent of donors with genotype 1a had normal ALAT at the time of liver biopsy versus 11% with genotype 3a (p = 0.046). Antibodies to C33c and C22-3 were present in nearly all donors whereas reactivity to C100-3 and 5-1-1 was detected more often in donors with genotypes 1a and 1b as compared to donors with genotypes 2b and 3a. In conclusion, genotype 3a was correlated to IVDU or tattooing as parenteral risk factors for the acquisition of HCV infection, and genotype 2b to prior blood transfusion. Donors with genotypes 1a seemed to have less severe liver disease than those infected with genotypes 2b and 3a.

A total of 12 patients previously treated for acute hepatitis of unknown aetiology were retrospectively found to be anti-hepatitis E virus (HEV) IgG-positive. Four patients were anti-HEV IgM- and IgG-positive consistent with an acute HEV infection. All 4 had travelled to or were immigrants from HEV-endemic countries. One anti-HEV IgM-negative patient seroconverted from anti-HEV IgG-negative to positive and 3 from anti-HEV IgG-positive to negative in 2 consecutive serum samples. Of the remaining 4 patients without anti-HEV IgM, 3 had a history of recent travel to an HEV-endemic country. Most patients were young adults and all but 1 recovered from the hepatitis. One patient with a fulminant hepatitis was anti-HEV IgG-positive when tested 4 months after a journey to Turkey. She died from her fulminant hepatitis shortly after admission. All the other patients but 1 normalized their serum liver enzymes within 1-2 months after the onset of disease.

A polymerase chain reaction (PCR)-based assay using primers against the hepatitis C core gene has been described [Okamoto et al. (1992a): Journal of General Virology 73:673-679]. Within the two major HCV genotypes 1 and 2, the Okamoto system identifies two subtypes each (1a, 1b and 2a, 2b, respectively). Typing is achieved by a primary PCR with consensus primers followed by a nested PCR with type specific primers. The original assay was modified by addition of a parallel second PCR identifying the recently described major genotype 3. The assay also identifies in duplicate subtype 1b (type II by Okamoto), suggested to respond poorly to interferon. Reaction conditions were reviewed and melting temperatures of all typing primers equalised to increase strigency. The modified system functioned well and typing results were supported by partial core sequencing. The following distribution of genotypes was found in 53 hepatitis C virus (HCV) infected Swedish blood donors: genotype 1a (57%), 3 (19%), 1b (13%), and 2b (11%). In six recipients of HCV infected blood identified in a retrospective study, the recipient HCV genotype was identical to donor HCV genotype. Furthermore, in HCV positive couples identical genotype was observed when only one partner had an external risk factor; whereas genotypes were often diverse if both sex partners had parenteral risk factors. Finally, a cluster of hepatitis C cases in a haemodialysis unit was evaluated retrospectively. Eight patients had genotype 1b, two had mixed 1a and 1b, and one had type 1a. The modified HCV genotyping assay was of value in examining different epidemiological situations and can be expanded presumably to include future genotypes.

The prevalence of hepatitis C virus (HCV) markers was investigated among health care staff with a high rate of exposure to blood or needle-stick injuries. After screening sera in pools of 10 at a time and individual testing of all reactive pools, totally 6 of 880 (0.7%; 95% confidence interval, 0.25-14.8%) were positive for anti-HCV, a figure of the same order as that found among Swedish first-time blood donors. Among the seropositives, all of five evaluable had been exposed to blood and four of five to needle-stick injuries. Our data suggest that HCV, in addition to hepatitis B virus, may constitute an occupational hazard for health care workers in Stockholm, even though the risk appears to be low, and personal risk factors such as intravenous drug abuse or blood transfusion could not be ruled out as sources of the infection.

In order to study the importance of sexual transmission of hepatitis B virus (HBV) among intravenous drug abusers (IVDAs), and from IVDAs to others, we consecutively interviewed 171 IVDAs detained at the Stockholm Remand Prison during 4 months in 1990. Sexual histories revealed that 77% reported > or = 3 sexual partners during the last 3 years, 64% had had a sexual partner who did not inject drugs, and 61% reported a prior STD. The prevalence of HBV markers was 75%. In a multiple logistic regression analysis, a high risk for HBV markers was associated with an increasing duration of drug abuse, a high prevalence of hepatitis A markers, and an increasing number of drug injecting sexual partners during the last 3 years, indicating that sexual transmission, along with sharing of needles, may contribute to the high prevalence of HBV markers within this group. It is suggested that an adequate sexual history must be obtained from IVDAs with acute viral hepatitis in order to identify sexual partners who should be offered postexposure prophylaxis, and that non-immune IVDAs should be vaccinated against viral hepatitis A and B.

Seventy-three Swedish blood donors (52 men, 21 women; median age 36 years) repeatedly reactive for hepatitis C antibodies (anti-HCV C-100-3) were tested with a second-generation (2nd-gen) anti-HCV Elisa and a 4-band recombinant immunoblot assay (RIBA 2). These results were correlated to serum alanine aminotransferase (S-ALAT), liver morphology and viremia as detected by 'nested' polymerase chain reaction (PCR) based on primers from a 5'-noncoding sequence of the HCV genome. Thirty-five of 46 (76%) donors with positive 2nd-gen Elisa tests confirmed by RIBA 2 were PCR positive whereof 27 had histological findings compatible with chronic persistent hepatitis (CPH) and 7 had chronic active hepatitis (CAH). Ten of 56 (18%) 2nd-gen Elisa-positive donors were RIBA 2 negative (or indeterminate) and none of these had chronic hepatitis nor were PCR positive. Seventeen of 73 (23%) donors were 1st-gen Elisa positive but 2nd-gen Elisa negative. All of these were PCR negative and only 1 (6%) had chronic hepatitis (CPH). An elevated S-ALAT level (reference < 0.7 mu kat/l) was found in 26 2nd-gen Elisa and RIBA 2-positive donors of which 18 had CPH and 7 had CAH and all 25 were PCR positive. A normal S-ALAT level was found in 9 of 34 (26%) donors with chronic hepatitis (all had CPH) and positive PCR. We have found that blood donors with positive 2nd-gen anti-HCV Elisa tests confirmed by RIBA-2 and especially with a concomitant elevated S-ALAT are highly likely to be viremic as demonstrated by PCR and to have chronic hepatitis.

The prevalence of hepatitis B virus (HBV) markers and exposure to risks possibly associated with HBV transmission were investigated in 797 health care workers (HCW) from Stockholm. Altogether, 31/797 (3.9%) persons were positive for at least one HBV marker, 8.0, 7.9 and 6.4% respectively of children's nurses, laboratory assistants and psychiatric assistant nurses. A history of exposure to needle-stick injuries from any patient, was more often obtained from HCW with HBV markers than from HCW without such markers. The prevalence of HBV markers increased with age and duration of occupation in health care. Most HCW had been exposed to at least one occupational risk for HBV transmission early in their professional careers. Although the risk of acquiring HBV at present is low, the virus constitutes a potential occupational hazard for non-vaccinated HCW in Stockholm, a risk which may increase in the future since the number of chronic HBsAg carriers is increasing in Sweden.

The influence of age, origin, and region of domicile on the prevalence of hepatitis B virus markers was investigated in a cross-sectional sample of young Swedish adults. Sera and demographic data were prospectively collected from 2,000 male conscripts and 2,000 pregnant women from urban and rural parts of Sweden during 1988-1989. A total of 10 of 4,000 (0.25%) were found to be hepatitis B surface antigen carriers, and 62 (1.6%) were positive for both anti-hepatitis B core antigen and anti-hepatitis B surface antigen, indicating a present or prior hepatitis B virus infection. Origin from a country with high hepatitis B virus endemicity and increasing age were factors associated with serologic signs of a present or prior hepatitis B virus infection, whereas region of domicile was not. In addition, seven individuals positive only for anti-hepatitis B core antigen (blocking greater than 70% in the test) and 39 positive only for anti-hepatitis B surface antigen (with a titer of greater than or equal to 10 international units/liter) were believed to have been exposed to hepatitis B virus. Altogether, these results indicated that 3% of young Swedes had encountered hepatitis B virus and that origin from a country with high hepatitis B virus endemicity was the factor that most strongly was associated with a present or past hepatitis B virus infection.

All clinical and serologically confirmed cases of sandfly fever among Swedish tourists during 1986-1989 were investigated. A total of 37 cases of Sicilian virus sandfly fever and 1 case of Naples virus sandfly fever were recorded from Cyprus. One case of Toscana virus infection was documented from Spain. The clinical and laboratory findings did not differ from those in previous reports, except for elevated aminotransferase levels. A questionnaire, that offered a possibility to estimate the number of cases that had not been reported, was sent to 713 tourists who had visited different hotels in Cyprus and Mallorca in September 1987. Serum samples from 95 of these tourists were tested for sandfly fever virus antibodies. These tests indicated that only some 20% of the real number of sandfly fever infections had been diagnosed. Both clinical cases and cases found by the questionnaire showed a focal distribution with an overrepresentation of certain hotels in Cyprus. The results were reported to the local health officers and possibly due to the measures undertaken hereafter the number of sandfly fever cases diagnosed have decreased.

The transmission of non-A, non-B hepatitis (NANB)/hepatitis C virus (HCV) was studied in patients undergoing open-heart surgery and related to the reception of blood products and hospitalization and surgery per se. Posttransfusion hepatitis NANB was noticed in 17/390 (4.4%) patients receiving heterologous blood and 8/16 tested became positive for anti-HCV (Ortho HCV ELISA), all within 5 months after onset of hepatitis. Among patients with normal ALAT before surgery and during follow-up, who had received heterologous blood, 1/50 seroconverted after 6 months. This patient probably had a subclinical HCV infection, or possibly a temporary non-specific anti-HCV reactivity with a maximum optical density/cut-off ratio (OD/CO) of 1.2, whereas all posttransfusion hepatitis C cases had OD/CO ratios greater than 4. No hepatitis occurred among the 92 non-transfused patients and no seroconversion was found in any of 62 non-transfused patients tested 6 months after the operation. It was concluded that (1) hospitalization and surgery per se does not seem to offer a risk of hepatitis NANB/C, and (2) seroconversion to for HCV occurs in only 50% of Swedish patients with acute posttransfusion NANB hepatitis.

The frequency and clinical features of acute hepatitis B virus (HBV) infection with and without a hepatitis D virus (HDV) co-infection was investigated retrospectively in the Stockholm region during two different time periods, September 1977-October 1978 and November 1984-October 1986. Totally, 31/229 (14%) patients with acute HBV infection had a HDV co-infection. No change in the frequency of co-infections, 12% and 15%, respectively, was observed between the 1970s and 1980s. Among the 31 HDV co-infected patients 74% were intravenous drug addicts. Totally 23/66 (35%) intravenous drug addicts with acute HBV infection had HDV co-infection. Clinically a biphasic rise of the serum levels of alanine aminotransferase and bilirubin was noted among 63% of the HDV co-infected patients but only among 8% of the solely HBV infected patients (p less than 0.001). A clinically more severe hepatitis was seen significantly more often among the HDV co-infected patients than among the solely HBV infected.

Possible routes for transmission of acute hepatitis B were studied retrospectively in 78 consecutive adult patients seen at the Department of Infectious Diseases, Roslagstull Hospital in Stockholm. Sexual transmission was found to be a major route of transmission, being more common than intravenous drug abuse. A single possible route of transmission was found in 66/78 (84%) patients. Eleven of the 78 patients (14%) had two possible routes, sexual contact being one. Overall sexual contact possibly accounted for 53% of all cases of hepatitis B, homosexual contact being responsible for only 10%. Cases reported earlier as being of unknown origin or associated with a recent visit abroad or to be 'social contact cases' are probably most often due to heterosexual transmission. Seven patients (9%) were heterosexually infected by persons who had been recently receiving medical care for hepatitis B. Seven sexually transmitted cases of acute clinical hepatitis B secondary to the patients studied were seen also. These findings show that sexual transmission, mainly heterosexual, is a major route for transmission of hepatitis B in a western society. They also emphasise the importance of taking an adequate sexual history as a prerequisite for providing effective prophylaxis for sexual partners of patients with acute hepatitis B.

Six hundred and fifteen Swedish soldiers (X = 24.9 years) serving with the UN forces in Cyprus were tested for antibody against hepatitis A (anti-HAV) before and after six months' service. Before the service, a high susceptibility to hepatitis A was found, as only 2.3% (14/615) had anti-HAV. In comparison, the prevalence of anti-HAV among 124 native Cypriots (X = 23.9 years) was 97% (120/124), which showed Cyprus to be a region where hepatitis A is endemic. The soliders were given immunoglobulin (IG) prophylaxis (2 ml of 16.5% IG) against hepatitis A very third month. The incidence of subclinical seroconversion against hepatitis A among the Swedish soliders was 0.2% (1/615). It was concluded that the IG-prophylaxis scheme used seems to be highly effective and probably completely prevents even subclinical seroconversion against hepatitis A in non-immune persons in regions where hepatitis A is endemic.

This study was performed to investigate the efficiency of 5 ml of 16.5% immunoglobulin (Ig) with an antibody titer against hepatitis A (anti-HAV) of 1:4000, using the HAVAB RIA technique, as pre-infection prophylaxis in 610 Swedish UN soldiers stationed in Sinai for 6 months. Sera were collected from 553 of these soldiers before, during, and after their service and were tested by the HAVAB technique for anti-HAV. Only 13 of 553 (2.4%) were immune before their service. During the first 5 months in Sinai, only one subclinical case of hepatitis A occurred among the men. Thereafter, two subclinical and four clinical cases occurred, although one of the subclinical cases and the four clinical ones did not occur until after the 6-month period. Thus, the Ig prophylaxis scheme used seems to offer almost complete passive protection for 5 months.

Sera collected in 1968 from persons selected on a statistical basis as being a representative sample of the Swedish population, were tested for antibody against hepatitis A (anti-HAV). The prevalence of anti-HAV increased with age from 4% (3/83) among 15-19 year olds (born between 1948 and 1952) to 87% (68/78) among 60-69 year olds (born between 1898 and 1907), and was furthermore higher in cities than in rural areas for corresponding age groups.

The prevalence, epidemiology and consequences of delta infection were analysed in 60 patients attending the Roslagstull Hospital for Infectious Diseases, Stockholm, Sweden, between 1972 and 1982. All of the patients had biopsy-documented chronic hepatitis B. Using radioimmunoassay techniques, sera from all patients were tested for antibodies to hepatitis A virus, for hepatitis B surface antigen and the corresponding antibody, for antibodies to hepatitis B core antigen, for hepatitis B e antigen and the corresponding antibody and for antibodies to delta antigen. All 60 patients underwent a liver biopsy which was repeated in 28 patients. 32% of the patients (19/60) were found to be anti-delta positive. The majority of the anti-delta positive patients were either immigrants from non-European countries or addicts (both 9/19 or 47%). Infections with delta agent were found to have already occurred in the Stockholm region in the early 1970s. During the study period, four of the patients developed clinical and laboratory signs of acute hepatitis in association with a delta infection. Among the anti-delta positive patients, 63% (12/19) were classified as having chronic active hepatitis, with or without cirrhosis, as against 39% (16/41) of the anti-delta negative patients. Histological progression to cirrhosis was observed in two of the four anti-delta positive patients with initial chronic active or chronic persistent hepatitis.

In 1979-1980, a distinct outbreak of hepatitis A occurred among homosexual men in Stockholm, Sweden, city and county area. The epidemic comprised 145 known cases. It began in December 1979 and progressed in waves during the following 10 months, with three distinct peaks separated by about six-week intervals. Actually, the incidence of hepatitis A in the Stockholm area showed a fivefold increase during 1980 as compared to the previous year. Clinical serologic, and social characteristics were studied more closely in 98 of the 145 homosexual men. Verification of hepatitis A was made by a solid-phase radioimmunoassay technique for detection of antibody to hepatitis A virus of the immunoglobulin M class. In addition, 64% of the men showed findings consistent with a prior hepatitis B (antibody to hepatitis B core antigen and/or antibody to hepatitis B surface antigen) and 34% were Treponema pallidum immobilization-positive from a prior or concomitant syphilis. Employment in risk professionals was common; thus, 19% worked in restaurants or otherwise handled food and 20% were engaged in medical care as compared to the 1% occupied in either branch of work among the general population in Sweden. Sexual habits with multiple partners and oral-anal sexual contacts were judged to be of major importance in the spread of this epidemic. Some spread of hepatitis A to the general population probably occurred due to the risk occupations of many homosexual men.

An epidemiologic study covering about 1/3 of the adult Swedish population showed an annual incidence of chronic active hepatitis (CAH) of 1.6 per 100,000. At least 45% had a viral cause of their CAH, the proportion being distinctly higher in large cities than in rural ones. Drugs, alcohol, and metabolic disorders were rarely identified as etiologic factors. The prevalence of ulcerative colitis and gluten enteropathy was remarkably high in idiopathic CAH. Compared with antibody-negative patients with idiopathic CAH, antibody-positive patients showed higher rates of the female sex, IgG increase, anti-HBs negativity, compliance with the Mayo criteria for treatment, and absence of previous episode of jaundice. Furthermore, in autoantibody-negative idiopathic CAH the prevalence of anti-HBs antibodies was at least three times greater than in the Swedish population, suggesting a viral cause of some forms of idiopathic CAH, a suggestion supported by the clinical pattern of the disease.