Vaccination against hepatitis B virus among people who inject drugs - A 20year experience from a Swedish needle exchange program.

BACKGROUND: People who inject drugs (PWID) are at particular risk of hepatitis B virus (HBV) acquisition, but often have poor access or adherence to HBV vaccination. Vaccination against HBV has been offered at a major Swedish needle exchange program (NEP) since 1994. The aim of this study was to evaluate vaccine completion and response rates, and the effect of sequential booster doses to non-responders to the standard vaccination schedule. METHODS: PWID enrolled in the NEP 1994-2013, without serological markers for HBV at baseline (negative for HBsAg/anti-HBc/anti-HBs), were offered a three-dose standard intramuscular vaccination schedule (Engerix®-B, GSK, 20µg/mL, intended to be received at months 0, 1 and 6). Vaccination response was defined as protective levels of anti-HBs (⩾10mIU/mL). Up to three booster doses were then offered for non-responders, each followed by anti-HBs testing. RESULTS: HBV data was available for 2352 identifiable individuals at NEP enrolment, of whom 1516 (64.5%) had no markers for previous HBV exposure or vaccination. Vaccination was initiated for 1142 (75.3%) individuals and 898 (59.2%) completed the standard vaccination schedule. Post-vaccination anti-HBs levels were available from 800 individuals, with 598 (74.8%) responding to the basic vaccination schedule. After up to three booster doses a total of 676 (84.5%) individuals achieved protective anti-HBs levels. Non-response to vaccination was associated with higher age and anti-HCV positivity (p<0.001). Eighteen incident cases of HBV infection were observed among vaccine non-responders, as well as 30 cases among those who had not completed vaccination. CONCLUSION: We demonstrate the feasibility of including HBV vaccination in the services offered by a NEP, with completion of vaccination in a majority of HBV-susceptible PWID. The response to HBV vaccination among PWID was relatively low; however, the addition of up to three booster doses improved the response rate from 74.8 to 84.5%.

Dynamic tailoring of treatment durations improves efficiency of hepatitis C treatment with pegylated interferon and ribavirin.

The treatment durations for hepatitis C are guided by the analysis of hepatitis C virus (HCV) RNA in blood at certain time points. This multicentre, randomized open label trial evaluated the utility and performance of individualized treatment durations guided by viral decline rates in 103 patients with HCV genotype 1 infection. Pegylated interferon 2a and ribavirin were given as standard of care (SOC) for 24, 48 or 72 weeks or as dynamic treatment (DT) for 24-72 weeks. The DT duration was based on the time point when log HCV RNA would reach 0 log copies/mL, as estimated by the second-phase decline. The rate of sustained virologic response was 63% for SOC and 54% for DT, but this difference was not significant in multiple regression analysis taking predictive factors such as interleukin-28B genotypes, age and baseline viremia into account (P = 0.45). The mean required treatment time per cured patient was 51 weeks for DT as compared with 58 weeks for SOC (P = 0.22) when given per protocol (n = 95) and was significantly shorter (42 vs 51 weeks) among patients who achieved undetectable HCV RNA (P = 0.01). We conclude that DT was feasible and increased efficiency. The estimated time point for 0 log viral copies/mL is a new and quantitative response variable, which may be used as a complement to the qualitative variable rapid virologic response. The outcome parameter treatment weeks per cured patient could become a useful tool for comparing treatment efficiency also in the era of directly acting antivirals.

Minimal transmission of HIV despite persistently high transmission of hepatitis C virus in a Swedish needle exchange program.

The aim of this study was to examine the prevalence and incidence of HIV and hepatitis B and C (HBV and HCV) among injecting drug users in a Swedish needle exchange programme (NEP) and to identify risk factors for blood-borne transmission. A series of serum samples from NEP participants enrolled from 1997 to 2005 were tested for markers of HIV, HBV and HCV (including retrospective testing for HCV RNA in the last anti-HCV-negative sample from each anti-HCV seroconverter). Prevalence and incidence were correlated with self-reported baseline characteristics. Among 831 participants available for follow-up, one was HIV positive at baseline and two seroconverted to anti-HIV during the follow-up of 2433 HIV-negative person-years [incidence 0.08 per 100 person-years at risk (pyr); compared to 0.0 in a previous assessment of the same NEP covering 1990-1993]. The corresponding values for HBV were 3.4/100 pyr (1990-1993: 11.7) and for HCV 38.3/100 pyr (1990-1993: 27.3). HCV seroconversions occurred mostly during the first year after NEP enrolment. Of the 332 cases testing anti-HCV negative at enrolment, 37 were positive for HCV RNA in the same baseline sample (adjusted HCV incidence 31.5/100 pyr). HCV seroconversion during follow-up was significantly associated with mixed injection use of amphetamine and heroin, and a history of incarceration at baseline. In this NEP setting, HIV prevalence and incidence remained low and HBV incidence declined because of vaccination, but transmission of HCV was persistently high. HCV RNA testing in anti-HCV-negative NEP participants led to more accurate identification of timepoints for transmission.

Nosocomial hepatitis C in a thoracic surgery unit; retrospective findings generating a prospective study.

We describe the transmission of hepatitis C virus (HCV) to two patients from a thoracic surgeon who was unaware of his hepatitis C infection. By partial sequencing of the non-structural 5B gene and phylogenetic analysis, the viruses from both patients were found to be closely related to genotype 1a strain from the surgeon. Two further hepatitis C cases were found in relation to the thoracic clinic. Their HCV sequences were related to each other but were of genotype 2b and the source of infection was never revealed. To elucidate the magnitude of the problem, we conducted a prospective study for a period of 17 months in which patients who were about to undergo thoracic surgery were asked to participate. Blood samples were drawn prior to surgery and at least four months later. The postoperative samples were then screened for anti-HCV and, if positive, the initial sample was also analysed. The only two patients (0.4%) identified were confirmed anti-HCV positive before surgery, and none out of 456 evaluable cases seroconverted to anti-HCV during the observation period. Despite the retrospectively identified cases, nosocomial hepatitis C is rare in our thoracic unit. The study points out the risk of transmission of hepatitis C from infected personnel and reiterates the need for universal precautions.

Detection of hepatitis C core antigen in serum or plasma as a marker of hepatitis C viraemia in the serological window-phase.

A new immunoassay for the detection of hepatitis C core antigen (HCVcoreAg) in peripheral blood during serological window-phase was evaluated among healthy blood donors, commercially available hepatitis C virus (HCV) seroconversion panels and in-house specimens from individuals undergoing seroconversion. Among 1964 low-risk blood donor samples, seven samples were initially reactive but only one was repeat reactive. Reactivity of this specimen was not confirmable by neutralization with specific anti-HCV core antibody, and the sample was negative for HCV RNA by polymerase chain reaction (PCR). The specificity of the HCVcoreAg enzyme-linked immunosorbent assay (ELISA) was 99.95%. In seven commercially available HCV seroconversion panels, HCVcoreAg appeared 23-46 days earlier than anti-HCV antibody by third generation assay. Additional testing with specimens from patients undergoing anti-HCV seroconversion indicated that HCVcoreAg becomes undetectable by the present test format soon after the onset of antibody. This test may be considered as an alternative to nucleic amplification techniques (NAT) for blood donor HCV screening. Additional development of technology for detecting HCVcoreAg may be useful for patient diagnosis and therapy monitoring.

Detection and prevention of hepatitis C in dialysis patients and renal transplant recipients. A long-term follow up (1989-January 1997).

BACKGROUND: Hepatitis C is frequent problem in dialysis wards. DESIGN: A long time (1989-97) follow up of hepatitis C virus (HCV) infection in a Swedish nephrology unit was performed with anti-HCV screening, confirmatory antibody tests, viral RNA detection and molecular characterization. Case histories were reviewed with focus, onset of infection, liver morbidity and mortality. RESULTS: In October 1991, 10% (19 of 184) of the patients in the unit (haemodialysis-, peritoneal dialysis and transplanted patients) were verified or suspected HCV carriers, whilst the number at the end of 1996 was 8%, (13 of 157). Most patients were infected before 1991 but only in one case from a known HCV-infected blood donor. No new HCV infections associated with haemodialysis occurred during the study period. A total of 13 of 24 viremic patients had HCV genotype 2b, a pattern suggesting nosocomial transmission. This was further supported by phylogenetic analysis of HCV viral isolates in seven. HCV viremia was also common in patients with an incomplete anti-HCV antibody pattern as 8 of the 12 indeterminant sera were HCV-RNA positive. CONCLUSIONS: Awareness, prevention, identification of infected patients and donor testing limited transmission. Indeterminant recombinant immunoblot assays (RIBA)-results should be regarded with caution as a result of the relative immunodeficiency in uremic patients. Our data indicate nosocomial transmission in several patients.

A case-control study of transmission routes for GB virus C/hepatitis G virus in Swedish blood donors lacking markers for hepatitis C virus infection.

BACKGROUND AND OBJECTIVES: The transmission routes for GB virus-C (GBV-C)/hepatitis G virus (HGV) in blood donors unexposed to hepatitis C virus (HCV) are unknown. We performed a case-control study of risk factors for GBV-C/HGV exposure in blood donors. MATERIALS AND METHODS: After testing stored sera from 458 HCV-negative blood donors for GBV-C/HGV RNA and GBV-C/HGV E2 antibodies, 66 donors with GBV-C/HGV markers and 125 age- and gender-matched controls were interviewed regarding risk factors for viral transmission. RESULTS: Exposure to GBV-C/HGV was strongly associated with previous treatment for a sexually transmitted disease (odds ratio [OR] 4.6; 95% confidence interval [CI] 2.2-9.8), with multiple sexual partners (OR 2.9; 95% CI 1.4-5.7) and with a past history of endoscopy (OR 7.0; 95% CI 3.0-16.4). CONCLUSIONS: In blood donors with GBV-C/HGV markers, sexual contacts and medical procedures appear to be the main transmission routes.

GB virus C/hepatitis G virus infection in patients investigated for chronic liver disease and in the general population in southern Sweden.

Serum samples from patients referred for liver biopsy for investigation of suspected chronic liver disease (n = 286) and from healthy middle-aged volunteers (n = 445) were analyzed for markers of exposure to GB virus C/hepatitis G virus (GBV-C/HGV), hepatitis B virus and hepatitis C virus. GBV-C/HGV analyses included GBV-C/HGV PCR for detection of viremia and GBV-C/HGV enzyme-linked immunosorbent assay for anti-GBV-C/HGV E2 antibodies. Liver biopsies were re-evaluated by a hepatopathologist. GBV-C/HGV markers were detected in 97/286 (34%) patients (GBV-C/HGV RNA = 26; anti-GBV-C/HGV E2 antibodies = 74) compared to 86/445 (19%; p < 0.0001) controls (GBV-C/HGV RNA = 7, anti-GBB-C/HGV E2 antibodies = 79). A significantly higher proportion of GBV-C/HGV-exposed subjects in the patient group were viremic compared to controls (27% vs. 8.1%; p = 0.0015). GBV-C/HGV markers were more commonly found in patients with chronic hepatitis B and C. In patients with GBV-C/HGV viremia, a higher occurrence of bile duct degeneration was detected than in non-viremic patients. Markers of GBV-C/HGV infection were over-represented among patients investigated for chronic liver disease, and ongoing GBV-C/HGV viremia was more common in this group than in controls. Apart from a higher prevalence of bile duct degeneration in viremic patients, infection with GBV-C/HGV did not confer any specific histological characteristics.

Clinical spectrum of hepatitis C-related liver disease and response to treatment with interferon and ribavirin in haemophilia or von Willebrand disease.

Our aim was to evaluate the severity of liver disease resulting from chronic hepatitis C in haemophilia or von Willebrand disease and the efficacy of 6 months treatment with interferon alpha and ribavirin. Fifty-five liver biopsies were performed in 43 patients without any bleeding complications, as seen with ultrasound immediately after the biopsy and 48 h thereafter. Histological changes were mild, with low scores for both inflammation and fibrosis, in spite of long exposure to blood products (mean 27 years). Two patients had compensated cirrhosis. Thirty-five out of 39 included patients completed study treatment. Hepatitis C virus (HCV)-RNA was negative in 77% (30/39) of patients at the end of treatment, and 36% (14/39) achieved a complete sustained response at follow-up 6 months after treatment. Treatment failure was more frequent in patients with virus genotype 1 compared with non-1 (P = 0.0003). The response rate correlated well with that of non-haemophilic patients. In summary: (1) liver biopsy was safe with our regimen; (2) liver disease in our patients was usually mild and had a slow progress; (3) only HCV genotype 1 predicted treatment failure; (4) our treatment results agreed with those from non-haemophilic patients.

Dynamic changes in hepatitis C virus genotypes and sequence patterns in plasma donors exposed to reinfection.

Sequential serum samples from four plasma donors (designated A, B, C, and D) at a Chinese blood bank with hepatitis C transmission problems were studied from 1994 to 1997. The samples were examined for antibodies to HCV, for HCV viremia by PCR and HCV genotyping. Co- and superinfections were studied by direct sequencing of the 5'-NCR, core, and HVR-1 regions, using low and high genotype-specific primers targeting the HVR-1, and by cloning of selected samples. Genotype changes occurred in all four donors: A (1b-2a-1b), B (1b-2a-2a/1b-1b), C (1b-2a), and D (1b/2a-1b). Donor D was married to donor B. The 1b isolates of donor A could not be sequenced in the HVR-1 due to low-level viremia. Two early 1b isolates from donors B and C showed high HVR-1 similarity. The later 1b isolates from B had changed significantly but were identical to the isolate from donor D. Spouses B and D also shared genotype 2a strains. The 2a isolates from donors A, B/D, and C differed by 8-10 nucleotides in the HVR-1. The frequent changes in genotype and the appearance of homologous isolates from different subjects indicate transmission at the blood bank. These four donors, all identified shortly after infection, developed very few mutations in the HVR-1 and few quasispecies during a period of 6-18 months. Highly specific primers proved to be superior to cloning for identification of minor virus populations. The results indicate nosocomial transmission of more than one strain at the blood bank studied.

[Probiotics restore the intestinal microflora. Modern life style has eradicated also the "good" bacteria]. / Probiotika återställer tarmens bakterieflora. Dagens levnadssätt har utrotat även de "goda" bakterierna.

Modern life style has lead to a reduced intake of beneficial bacteria. A healthy gastrointestinal microflora is vital to the immune system. Probiotic products could improve this balance.

Prevalence and clinical spectrum of chronic viral hepatitis in a middle-aged Swedish general urban population.

BACKGROUND: Although abundant data are available regarding the prevalence of chronic hepatitis B or C virus (HBV, HCV) among both blood donors and patients with liver diseases, corresponding data for the general population are scarce. Accordingly, this study was designed to investigate the prevalence and clinical spectrum of HBV and HCV in a general Swedish middle-aged urban population. METHODS: Demographic data and blood samples were collected from subjects enrolled in a prospective study of cancer development in the city of Malmö (population 250,000). The participation rate in the preliminary examination was 46.2%. From 12,445 individuals born between 1926 and 1945 and included in the study, a statistically representative subsample of 6103 persons was selected. Blood samples were available from 5533 of these. The mean age of the subjects in the series was 58.5 +/- 5.9 years, and 59% were women. The HBV markers used were anti-HBc and HBsAg. HCV antibodies were detected with a third generation anti-HCV ELISA, followed by immunoblotting (RIBA 3) if the test was positive. Immunoblot-reactive samples were analysed for HCV-RNA by polymerase chain reaction and genotyped. In all patients with signs of chronic HBV or HCV, epidemiological data were evaluated and liver biopsies obtained. RESULTS: Of the series as a whole (n = 5533), 4.2% (n = 211) tested positive for anti-HBc and 0.2% (n = 10) for HBsAg. RIBA 3 analysis showed 0.37% (18/5533) to be anti-HCV-positive, of whom 83% (15/18) were HCV-RNA-positive. Apart from two (both from HBsAg carriers) with normal histology, all liver biopsies manifested various degrees of inflammation and fibrosis. Among anti-HCV-positives, median grade was 6 and median stage 1 (Knodell score). CONCLUSION: The prevalence of both chronic HBV and HCV is low in the Swedish general urban middle-aged population. Nonetheless, the long-term effects on the population and the health care system may be significant.

Continued transmission of hepatitis B and C viruses, but no transmission of human immunodeficiency virus among intravenous drug users participating in a syringe/needle exchange program.

The virological efficacy of a syringe/needle exchange program was evaluated in a cohort incidence study. Of 698 intravenous drug users (IVDUs) initially recruited, 15 (2.1%) were HIV-positive at baseline. Adequate follow-up was possible in 515 (74%) and showed no new cases of HIV infection during a median of 31 months. Most IVDUs had been previously exposed to HBV (anti-HBc-positive 70.1%) and HCV (anti-HCV-positive 90.7%). Of those 159 IVDUs negative at baseline for anti-HBc and/or anti-HCV, 56 (35%) seroconverted to one or both viruses during follow-up, corresponding to 11.7 seroconversions/100 y at risk for HBV and 26.3 seroconversions/100 y for HCV. Multiple logistic regression analysis showed hepatitis seroconversion to correlate with imprisonment during the study (OR 2.2; 95% CI 1.04-4.74), absence of drug-free periods (OR 5.7; CI 1.44-22.3) and frequent syringe/needle exchanges (OR 1.31; CI 1.02-1.7). The absence of HIV spread was probably partly due to the low prevalence of HIV-infected IVDUs in the city. Despite free syringes and needles, both HBV and HCV continued to spread at high rates. Nevertheless, syringe/needle exchange programs, coupled with monitoring of serostatus provide good surveillance and are valuable for further assessment of remaining risks.

Gene variation of 5'-NCR and core region in serum samples collected from patients with HCV infection.

OBJECTIVE: To study the variation of HCV 5'-NCR and core gene in serial sera collected from patients with HCV infection. METHODS: Serial sera were collected from 4 plasma-donors with HCV infection. 5'-NCR and core gene were amplified, sequenced and analyzed using software. RESULTS: All the sequences obtained from the serial sera of patients with HCV infection were 1b and 2a subtypes. The variation of 5'-NCR only related to the genotype, and not associated with patients and time of serum collection. However, the sequences of core gene were not identical in HCV strains isolated from different patients. The sequences of those two regions of the same genotype isolated from the same patient did not change with time. CONCLUSION: 5'-NCR is more conserved than the core region and the genotype is the major cause of gene variation. No change in sequences of those two regions is found at the different points of time.

Assessment of liver disease and biochemical and immunological markers in Swedish blood donors with isolated GB virus C/hepatitis G virus viremia.

OBJECTIVE: To investigate signs of liver disease, and biochemical and immunological markers in blood donors with isolated GBV-C/HGV viremia. METHODS: Eighteen donors with isolated GBV-C/HGV viremia were followed up 3-5 years after initial identification. Testing for GBV-C/HGV RNA, GBV-C/HGV-E2 antibodies and a range of biochemical and immunological tests was performed. Thirteen donors consented to liver biopsy. RESULTS: Twelve donors remained GBV-C/HGV viremic at follow-up. Five donors had developed E2 antibodies. Liver biopsies revealed mild portal inflammatory lesions in 6/11 individuals with persistent viremia, and steatosis in 10/13 biopsied donors. CONCLUSION: Steatosis and mild portal inflammatory lesions were found in liver biopsies from several blood donors with isolated GBV-C/HGV viremia.

Hepatocellular carcinoma in Sweden: its association with viral hepatitis, especially with hepatitis C viral genotypes.

Viral markers of chronic hepatitis were tested for in 95 frozen serum samples from 299 patients from Malmö, Sweden, with hepatocellular carcinoma (HCC), diagnosed between 1977 and 1994. Hepatitis B analysis included anti-HBc, HBsAg and, if anti-HBc positive, HBV DNA. Hepatitis C infection analysis included anti-HCV screening, RIBA, HCV RNA and HCV genotyping. HCV genotyping was also carried out in 9 HCV-viraemic HCC-patients from Gothenburg. HCV genotype distribution in HCC cases was compared with Swedish HCV-infected blood donors. Among the 95 patients from Malmö, 28 (29%) had anti-HBc, but only 5 (5%) were chronic HBV carriers, compared with 16 (17%) with chronic hepatitis C (p = 0.021). HCV-related HCC was more common among immigrants (8/16 vs. 8/79; p < 0.001). Genotyping of 25 HCV-infected cases showed genotype 1a in 6 (24%), genotype 1b in 13 (52%), genotype 2b in 4 (16%), and genotype 3a in 2 (8.0%) patients. Genotype 1b was more common among HCC patients than among blood donors (p < 0.001), but 8 of 13 genotype 1b-infected patients were from countries where genotype 1b is predominant. Among native Swedes there was no difference between the HCV genotypes infecting blood donors and those found in HCC patients.

Long-term outcome of acute hepatitis B and C in an outbreak of hepatitis in 1969-72.

The objective of this study was to investigate the epidemiology, etiology, and long-term outcome of an extended outbreak of acute hepatitis that occurred in an area of Sweden between 1969 and 1972. The outbreak was analyzed retrospectively by retesting stored frozen serum samples for the presence of hepatitis A, B and C markers. The results were compared with the diagnoses that had been determined during the outbreak. Of 180 patients, 29 (16%) had acute hepatitis A, 126 (70%) had acute hepatitis B, and eight (4.4%) had acute hepatitis C. The Australia antigen test used during the outbreak had failed to identify 21 patients with acute hepatitis B virus infection. Genotyping of the hepatitis B virus strains showed that genotype D was the most prevalent, irrespective of the transmission route. An attempt was made to follow up patients with unresolved hepatitis B virus infection, 25-27 years after the acute infection. None of the 100 patients with acute hepatitis B infection who were traced had become chronic carriers. In ten patients with hepatitis C virus infection, the follow-up showed considerable variation in the outcome, ranging from spontaneous resolution to death through liver cirrhosis. Intravenous drug users had a high prevalence of hepatitis C virus infection, with 52% testing positive for hepatitis C antibodies.

Mixed infection with two types of hepatitis C virus is probably a rare event.

A search for the simultaneous presence of two hepatitis C virus (HCV) types in sera of a group of chronically infected intravenous drug users, hemodialysis patients and hemophiliacs from Sweden and Russia was performed with two genotyping methods based on the use of type-specific primers from core and NS4 regions of the viral genome. An important feature of NS4 based assay is that type-specific primers are used in both rounds of nested PCR, thus providing the possibility of the identification not only of the abundant type, but also of the minor HCV type present in a particular serum. The experiments, however, did not reveal the simultaneous presence of two or more HCV types in any of the 40 samples. These results suggest that the frequency of mixed infections in serum with different HCV types is very low even in high-risk groups, at least in the geographic region studied.

TT virus infections among blood donors in Iceland: prevalence, genotypes, and lack of relationship to serum ALT levels.

BACKGROUND: The TT virus (TTV) is a newly identified blood-borne virus. Its association with disease is still unknown, and screening of blood donors has not been implemented. Several genotypes of the TTV have been identified. STUDY DESIGN AND METHODS: Three hundred seventy healthy blood donors were randomly selected and tested for TTV by the PCR method. Sequencing of a part of the genome was performed to identify various genotypes of the virus. ALT levels were determined in both infected and uninfected individuals. RESULTS: The TT virus (TTV), was detected in the sera of 23 (6.2%) of 370 healthy Icelandic blood donors; this prevalence is lower than that reported in Japan but higher than that in Scotland. The virus was found in all groups over the age of 19. Sequencing and phylogenetic analysis of 202 bp from open reading frame 1 demonstrated genotypes 1b and 2b 2c and genotype 4 isolates, with the latter bearing 89-percent nucleotide homology with other genotype 4 sequences deposited at GenBank. One sample showed a mixed genotype 1b/2c infection. Serum ALT levels were within normal limits in all infected individuals. CONCLUSION: The TTV carrier state does not cause significant liver injury.