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1.
Eur J Clin Pharmacol ; 74(7): 971-978, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29632961

ABSTRACT

PURPOSE: Introduction of the direct-acting antivirals (DAAs) for treatment of chronic hepatitis C (CHC) infection has been challenging in all health systems. In Sweden, a national protocol for managed introduction was developed. It was optional, but all county councils agreed to implement and follow it. The purpose of this study was to study (a) cure rates among all patients initiated on treatment in 2014-2015, (b) prescribers' adherence to the drug recommendations and treatment eligibility criteria in the protocol, and (c) introduction rate in the six Swedish healthcare regions. METHOD: A cross-sectional study where national data from the Prescribed Drug Register and the quality register InfCare Hepatitis defined the study population, and clinical data from the Patient Register and InfCare Hepatitis were used to monitor outcomes. Descriptive statistics were used. RESULTS: A total of 3447 patients were initiated on treatment during 2014-2015. The overall cure rate, based on data from 85% of the cohort, was 96%, with variation between genotypes. Adherence to drug recommendations increased over time and varied between 43.2 and 94.2%. Adherence to the treatment eligibility criteria was initially 80% and increased to 87% when treatment restrictions were widened. The introduction rate differed initially between the regions and reached stable levels 15-18 months after the launch of the first DAA. CONCLUSION: The estimated overall cure rate was 96%, with some variations between genotypes. A high level of adherence to the introduction protocol as well as similar introduction rates in the health care regions indicate that the introduction protocol, alongside with other measures taken, contributed considerably to a rapid uptake and equal distribution of DAAs in Sweden.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Genotype , Hepacivirus/genetics , Humans , Infant , Infant, Newborn , Male , Middle Aged , Registries , Sweden , Treatment Outcome , Young Adult
2.
J Viral Hepat ; 25(7): 802-810, 2018 07.
Article in English | MEDLINE | ID: mdl-29406590

ABSTRACT

We aimed to assess fibrosis with liver stiffness measurement long-term after sustained virological response of chronic hepatitis C and to identify risk factors associated with persisting fibrosis. In this cross-sectional study, patients with chronic hepatitis C and pretreatment advanced fibrosis or cirrhosis treated successfully at Karolinska University Hospital with an interferon-containing regimen underwent liver stiffness measurement with FibroScan. The impact of potential risk factors for persisting fibrosis was estimated. We included 269 patients with a median follow-up time of 7.7 years (range 0-20), 84 with a follow-up time of ≥10 years. Patients with pretreatment cirrhosis had a significantly higher median liver stiffness level (8.5 kPa 95% CI 7-9.1) at follow-up, than patients with advanced fibrosis (6 kPa 95% CI 5.5-6.4). A majority improved their fibrosis stage after sustained virological response, but 24% had persisting advanced fibrosis with a liver stiffness level of ≥ 9.5 kPa. Among patients with pretreatment cirrhosis, the proportion with persisting advanced fibrosis diminished with longer follow-up time, from 48% after <5 years to 21% after >10 years. The main risk factors for persisting advanced fibrosis were pretreatment cirrhosis, high age and body mass index. In conclusion, fibrosis improves substantially during long-term follow-up after sustained virological response in hepatitis C patients with pretreatment advanced liver fibrosis. Lifestyle intervention to decrease weight in obese persons and treatment before establishment of cirrhosis should therefore be recommended to avoid persistence of advanced fibrosis after virological cure.


Subject(s)
Age Factors , Antiviral Agents/therapeutic use , Body Mass Index , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/epidemiology , Sustained Virologic Response , Adolescent , Adult , Aged , Cross-Sectional Studies , Elasticity Imaging Techniques , Female , Humans , Male , Middle Aged , Risk Factors , Treatment Outcome , Young Adult
3.
Clin Microbiol Infect ; 21(8): 772-8, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25934159

ABSTRACT

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.


Subject(s)
Endocarditis, Bacterial/epidemiology , Endocarditis, Bacterial/therapy , Staphylococcal Infections/epidemiology , Staphylococcal Infections/therapy , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Endocarditis, Bacterial/mortality , Female , Humans , Incidence , Male , Middle Aged , Retrospective Studies , Sex Factors , Staphylococcal Infections/mortality , Survival Analysis , Sweden/epidemiology , Thoracic Surgery , Treatment Outcome , Young Adult
4.
Aliment Pharmacol Ther ; 41(6): 532-43, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25627143

ABSTRACT

BACKGROUND: A sustained viral response (SVR) after interferon-based therapy of chronic hepatitis C virus (HCV) infection is regarded to represent a cure. Previous studies have used different markers to clarify whether an SVR truly represents a cure, but no study has combined a clinical work-up with highly sensitive HCV RNA detection, and the determination of immune responses. AIM: To determine clinical, histological, virological and immunological markers 5-20 years after SVR. METHODS: In 54 patients, liver biochemistry, histology and elastography were evaluated. Liver biopsies, plasma and peripheral blood mononuclear cells (PBMCs) were tested for minute amounts of HCV RNA. HCV-specific T-cell responses were monitored by ELISpot and pentamer staining, and humoral responses by measuring HCV nonstructural (NS)3-specific antibodies and virus neutralisation. RESULTS: Liver disease regressed significantly in all patients, and 51 were HCV RNA-negative in all tissues tested. There was an inverse association between liver disease, HCV-specific T-cell responses and HCV antibody levels with time from SVR, supporting that the virus had been cleared. The three patients, who all lacked signs of liver disease, had HCV RNA in PBMCs 5-9 years after SVR. All three had HCV-specific T cells and NS3 antibodies, but no cross-neutralising antibodies. CONCLUSIONS: Our combined data confirm that a SVR corresponds to a long-term clinical cure. The waning immune responses support the disappearance of the antigenic stimulus. Transient HCV RNA traces may be detected in some patients up to 9 years after SVR, but no marker associates this with an increased risk for liver disease.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/immunology , Hepatitis C Antibodies/immunology , Hepatitis C, Chronic/drug therapy , Adult , Biomarkers/metabolism , Biopsy , Female , Follow-Up Studies , Hepacivirus/genetics , Hepatitis C, Chronic/immunology , Humans , Leukocytes, Mononuclear/virology , Male , Middle Aged , RNA, Viral/blood , T-Lymphocytes/immunology
5.
J Viral Hepat ; 20(11): 770-8, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24168256

ABSTRACT

The IL-28 gene is associated with sustained viral response (SVR) after treatment with peg-IFN and ribavirin in liver transplant recipients with chronic hepatitis C genotype 1 infection. We analysed the importance of recipient and donor IL-28B genotype for response to treatment and fibrosis progression in 54 liver transplant recipients. Fibrosis stage (F) was defined as mild when F≤2 and severe when F≥3 in a liver biopsy or according to liver elasticity analysis. We found a significantly lower prevalence of IL-28B SNP CC in the recipients (22%) than in the donors (67%), P<0.0001. SVR was seen in 61% of the recipients with mild and 27% with severe fibrosis pretreatment, P=0.01. Recipients with IL-28 CC and non-CC had mild fibrosis in 64% and 38% prior to treatment, P=0.13. At follow-up, after treatment, significantly more recipients with CC had mild fibrosis than non-CC recipients (75% versus 32%, P=0.0072), and all with CC and SVR had mild fibrosis. The strongest baseline factor predicting SVR was genotype. Hence, 13/19 (68%) genotype non-1 patients reached SVR versus only 9/35 (26%) genotype 1 patients, P=0.0022. In summary, we found that liver transplant recipients with IL-28B CC tended to have less advanced fibrosis prior to and significantly less after SOC treatment and that all recipients with IL-28B CC who achieved SVR had mild fibrosis at follow-up. A significantly higher SVR rate was achieved in recipients with mild than severe fibrosis pretreatment and with genotype non-1 than 1 infection. Our findings indicate that treatment for post-transplant HCV recurrence should be offered before advanced fibrosis is seen in the recipient.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/therapy , Interferons/therapeutic use , Interleukins/genetics , Liver Cirrhosis/pathology , Polymorphism, Single Nucleotide , Ribavirin/therapeutic use , Adolescent , Adult , Aged , Child , Female , Genetic Predisposition to Disease , Genotype , Hepatitis C, Chronic/pathology , Humans , Liver Transplantation , Male , Middle Aged , Recurrence , Severity of Illness Index , Young Adult
6.
J Viral Hepat ; 20(4): e82-9, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23490394

ABSTRACT

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.


Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C, Chronic/drug therapy , Interferon-alpha/administration & dosage , Polyethylene Glycols/administration & dosage , Ribavirin/administration & dosage , Adult , Aged , Drug Therapy, Combination/methods , Female , Hepacivirus/isolation & purification , Humans , Male , Middle Aged , RNA, Viral/blood , Recombinant Proteins/administration & dosage , Time Factors , Treatment Outcome , Viral Load , Young Adult
7.
J Viral Hepat ; 20(3): 193-9, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23383658

ABSTRACT

The IL28 gene is highly associated with sustained viral response (SVR) in patients infected with genotype 1 after standard of care (SOC) treatment with peg-IFN and ribavirin. It is also associated with a steeper first phase HCV RNA decline during treatment. In genotype 2 and 3 infections, these correlations are less obvious. We studied the IL28B association to rapid viral response (RVR), SVR, first and second phase HCV RNA decline during treatment in 100 HCV mono-infected and 13 HCV/HIV co-infected patients. We found a significantly higher mean baseline HCV RNA level in IL28B SNP CC than non-CC mono-infected patients, 6.99 vs 6.30 log(10) IU/mL (P = 0.02), and a significantly larger median 1st phase decline in patients with CC than non-CC genotype, 2.03 vs 1.37 log(10) IU/mL, respectively. The overall SVR rate in HCV mono-infected patients was 87% vs 77% in HCV/HIV co-infected patients, with no correlation to IL28B SNP. In mono-infected patients with RVR, the SVR rate was high and independent of IL28B genotype. In mono-infected patients who failed to achieve RVR who had IL28B CC and non-CC genotype, 64% and 67% achieved SVR, respectively. In genotype 2 and 3 infected patients, the 1st phase HCV RNA decline was steeper in patients with IL28B CC vs non-CC genotype during SOC treatment. This did not translate into a higher frequency of RVR or SVR. Hence, the clinical relevance of pretreatment analysis of IL28B polymorphisms in genotype 2 and 3 infected patients can be questioned in patients with expected high SVR rate.


Subject(s)
Hepacivirus/isolation & purification , Hepatitis C, Chronic/virology , Interleukins/genetics , Polymorphism, Genetic , RNA, Viral/blood , Standard of Care , Viral Load , Adult , Aged , Antiviral Agents/therapeutic use , Coinfection/virology , Female , Genotype , HIV Infections/complications , Hepacivirus/classification , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Humans , Interferons/therapeutic use , Male , Middle Aged , RNA, Viral/genetics , Ribavirin/therapeutic use , Treatment Outcome , Young Adult
8.
J Viral Hepat ; 19(9): 635-9, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22863267

ABSTRACT

Relapse of hepatitis C virus infection after liver transplantation is universal. Standard-of-care (SOC) treatment for relapse offers less satisfactory treatment response than in nontransplanted patients. Tolerance for treatment is suboptimal and withdrawals owing to adverse events induced by treatment frequent. To improve tolerance for SOC, and ribavirin (RBV) in particular, concentration-guided RBV dosing calculated by a formula taking renal function and weight into consideration was utilized. A serum RBV concentration of 10 µm was set as the goal. All patients were given maintenance darbepoetin therapy from 2 weeks prior to initiation of treatment. In total, 21 patients with a mean age of 52 (range 25-64) years were included. The mean RBV concentration at week 4 was 10.2 and 7.36 µm in genotype 1/4 and non-1/4 patients, respectively, and 11.7 and 9.42 at week 12. The mean haemoglobin drop was 25 g/L vs 21 g/L in the genotype 1/4 and non-1/4 group, respectively, a nonsignificant difference. With this treatment approach, 80-90% of patients could be kept adherent to treatment. Sustained viral response was achieved 8/16 (50%) with low-grade fibrosis (fibrosis stage ≤ 2) vs in none of five patients with advanced fibrosis (Fibrosis stage 3 and 4), P < 0.05. We conclude that a treatment algorithm utilizing concentration-guided RBV dosing during darbepoetin maintenance therapy substantially improves tolerance and allows high adherence to a SOC treatment schedule, and that therapy needs to be initiated before advanced fibrosis is developed.


Subject(s)
Drug Monitoring/methods , Erythropoietin/analogs & derivatives , Hepatitis C/drug therapy , Interferon-alpha/administration & dosage , Liver Transplantation , Polyethylene Glycols/administration & dosage , Ribavirin/administration & dosage , Adult , Aged , Darbepoetin alfa , Drug Therapy, Combination/methods , Erythropoietin/administration & dosage , Female , Humans , Male , Medication Adherence/statistics & numerical data , Middle Aged , RNA, Viral/blood , Recombinant Proteins/administration & dosage , Recurrence , Ribavirin/pharmacokinetics , Treatment Outcome , Viral Load
9.
J Viral Hepat ; 15(9): 641-5, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18507753

ABSTRACT

Mono-therapy with pegylated interferon (peg-IFN) has shown that a lower-than-standard dose yields the same sustained viral response (SVR) rates as standard doses for chronic hepatitis C virus (HCV) infection caused by genotypes 2 or 3. Our aim was to see if a fixed, lower-than-standard dose of peg-IFN alfa-2a (135 microg weekly) in combination with ribavirin 11 mg/kg daily for 24 weeks yields sufficient SVR rates for genotypes 2 or 3. Hundred consecutive patients with a mean age of 44 years (range 20-69 years), 59 with genotype 3 and 41 with genotype 2, were studied. Rapid viral response (RVR) with HCV-RNA <15 IU/mL at treatment week 4 and SVR were calculated. RVR was achieved by 28/40 (70%) patients with genotype 2 and 41/58 (71%) with genotype 3. Significantly more genotype 2 patients with RVR achieved SVR 27/28 (96%) than genotype 2 patients who failed to achieve RVR, 8/12 (66%), P = 0.009. The corresponding figures for genotype 3 patients were 39/41 (95%) vs 11/17 (65%), respectively, P = 0.002. In total, SVR was achieved by 35/41 (85%) patients with genotype 2 and 51/59 (86%) patients with genotype 3, respectively. We found that 135 microg peg-IFN alfa-2a weekly was sufficient for treatment of genotype 2 and 3 chronic hepatitis C when combined with RBV dosed daily according to body weight. This combination yielded high SVR rates (85-86%) and may be cost-saving.


Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Hepatitis C/classification , Interferon-alpha/administration & dosage , Polyethylene Glycols/administration & dosage , Ribavirin/administration & dosage , Adult , Aged , Drug Therapy, Combination , Female , Genotype , Hepatitis C/genetics , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Male , Middle Aged , Polyethylene Glycols/adverse effects , RNA, Viral/blood , Recombinant Proteins , Ribavirin/adverse effects , Treatment Outcome , Viral Load
10.
Transplant Proc ; 38(8): 2675-6, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17098036

ABSTRACT

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.


Subject(s)
Hepatitis C/surgery , Liver Cirrhosis/surgery , Liver Cirrhosis/virology , Liver Transplantation/physiology , Adolescent , Adult , Aged , Child , Female , Humans , Liver Transplantation/mortality , Male , Middle Aged , Reoperation , Retrospective Studies , Survival Analysis , Sweden
11.
Gut ; 55(2): 266-74, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16105887

ABSTRACT

BACKGROUND: The hepatitis C virus (HCV) mutates within human leucocyte antigen (HLA) class I restricted immunodominant epitopes of the non-structural (NS) 3/4A protease to escape cytotoxic T lymphocyte (CTL) recognition and promote viral persistence. However, variability is not unlimited, and sometimes almost absent, and factors that restrict viral variability have not been defined experimentally. AIMS: We wished to explore whether the variability of the immunodominant CTL epitope at residues 1073-1081 of the NS3 protease was limited by viral fitness. PATIENTS: Venous blood was obtained from six patients (four HLA-A2+) with chronic HCV infection and from one HLA-A2+ patient with acute HCV infection. METHODS: NS3/4A genes were amplified from serum, cloned in a eukaryotic expression plasmid, sequenced, and expressed. CTL recognition of naturally occurring and artificially introduced escape mutations in HLA-A2-restricted NS3 epitopes were determined using CTLs from human blood and genetically immunised HLA-A2-transgenic mice. HCV replicons were used to test the effect of escape mutations on HCV protease activity and RNA replication. RESULTS: Sequence analysis of NS3/4A confirmed low genetic variability. The major viral species had functional proteases with 1073-1081 epitopes that were generally recognised by cross reactive human and murine HLA-A2 restricted CTLs. Introduction of mutations at five positions of the 1073-1081 epitope prevented CTL recognition but three of these reduced protease activity and RNA replication. CONCLUSIONS: Viral fitness can indeed limit the variability of HCV within immunological epitopes. This helps to explain why certain immunological escape variants never appear as a major viral species in infected humans.


Subject(s)
Hepacivirus/genetics , Hepatitis C/immunology , Immune Tolerance , Viral Nonstructural Proteins/genetics , Acute Disease , Adult , Animals , Cytotoxicity, Immunologic , Epitopes, T-Lymphocyte/immunology , Female , Genes, Viral , Genetic Variation/immunology , HLA-A2 Antigen/metabolism , Hepacivirus/immunology , Hepatitis C/virology , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/virology , Humans , Immunodominant Epitopes/genetics , Immunodominant Epitopes/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Mutation , Peptide Fragments/immunology , RNA, Viral/genetics , T-Lymphocytes, Cytotoxic/immunology , Viral Nonstructural Proteins/immunology , Virus Replication/genetics , Virus Replication/immunology
12.
J Viral Hepat ; 12(5): 473-80, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16108761

ABSTRACT

SUMMARY: To optimize treatment of chronic hepatitis C early identification of patients who will not achieve a sustained virological response (SVR) is desirable. We investigated hepatitis C virus (HCV) RNA kinetics at day 1 (in 15 patients; genotypes 1 and non-1, 9 and 6 respectively) at weeks 1, 4 and 12 (in 53 patients; genotypes 1 and non-1, 19 and 34, respectively) during treatment with pegylated interferon alpha-2a and ribavirin. Patients with SVR had a significantly more pronounced mean log10 decline from baseline in HCV RNA levels at weeks 1 and 4 compared with patients who failed to achieve SVR (1.99 vs 0.85 at week 1, P = 0.0003 and 2.89 vs 1.72 at week 4, P = 0.0159), whereas no difference was noted after day 1. For patients with a 2-log10 decrease in HCV RNA levels at day 7, the positive predictive value (PPV) for a SVR was 92%, whereas week 12 was the best time point for predicting a later nonresponse [negative predictive value (NPV) 92%] in patients failing to achieve a 2-log10 drop. For patients with genotype non-1 and a 2-log10 decrease in HCV RNA levels the PPV for a SVR was 89% week 1, and 79% weeks 4 and 12. The corresponding NPV for patients with genotype non-1 were 43, 40 and 100% respectively. During treatment with pegylated interferon alpha-2a plus ribavirin the HCV RNA decline at week 1 was an accurate predictor of SVR in patients who had achieved a 2-log10 drop in HCV RNA levels, whereas the lack of such decline week 12 was an accurate marker of a nonresponse.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Ribavirin/therapeutic use , Adult , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepatitis C, Chronic/virology , Humans , Interferon alpha-2 , Interferon-alpha/metabolism , Male , Middle Aged , Polyethylene Glycols/metabolism , RNA, Viral/blood , RNA, Viral/drug effects , Recombinant Proteins , Treatment Outcome , Viremia/drug therapy
13.
Gut ; 53(10): 1504-8, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15361504

ABSTRACT

BACKGROUND: The key end point for treatment efficacy in chronic hepatitis C is absence of detectable virus at six months after treatment. However, the incidence of clinical events during long term follow up of patients with sustained virological response is still poorly documented and may differ between the Eastern and Western world. AIMS: To assess clinical end points during long term follow up of European patients with a sustained virological response to interferon monotherapy. METHODS: Meta-analysis of individual patient data from eight European protocolled follow up studies of interferon treatment for chronic hepatitis C. RESULTS: A total of 286 sustained virological responders and 50 biochemical responders (detectable virus but normal alanine aminotransferase levels) were followed up for 59 months. Fifteen sustained virological responders (5.2%) had cirrhosis before treatment and 112 (39%) had genotype 1. The late virological relapse rate after five years of follow up was 4.7% (95% confidence interval (CI) 2.0-7.4) among sustained virological responders; all late relapses occurred within four years after treatment. Among sustained virological responders, the rate of decompensation after five years of follow up was 1.0% (95% CI 0.0-2.3) and none developed hepatocellular carcinoma (HCC). Survival was comparable with the general population, matched for age and sex, the standard mortality ratio being 1.4 (95% CI 0.3-2.5). Clinical outcome of patients with cirrhosis was similar to other sustained virological responders. For biochemical responders, the rates of development of decompensation and HCC during long term follow up were 9.1% (95% CI 0.5-17.7) and 7.1% (95% CI 0-15.0), respectively. CONCLUSIONS: Five year survival of European sustained virological responders was similar to the overall population, matched for age and sex. No HCCs were detected during long term follow up.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Interferons/therapeutic use , Adolescent , Adult , Aged , Female , Hepatitis C, Chronic/pathology , Humans , Male , Middle Aged , Regression Analysis , Survival Analysis , Treatment Outcome
14.
Scand J Gastroenterol ; 39(2): 164-7, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15000279

ABSTRACT

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.


Subject(s)
Hepacivirus/genetics , Hepatitis C, Chronic/virology , Liver/pathology , Adolescent , Adult , Aged , Female , Genotype , Hepatitis Antibodies/blood , Hepatitis C, Chronic/pathology , Hepatitis C, Chronic/therapy , Humans , Male , Middle Aged , RNA, Viral/blood , Retrospective Studies , Sweden
15.
Gene Ther ; 11(6): 522-33, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14999224

ABSTRACT

We have recently shown that the NS3-based genetic immunogens should contain also hepatitis C virus (HCV) nonstructural (NS) 4A to utilize fully the immunogenicity of NS3. The next step was to try to enhance immunogenicity by modifying translation or mRNA synthesis. To enhance translation efficiency, a synthetic NS3/4A-based DNA (coNS3/4A-DNA) vaccine was generated in which the codon usage was optimized (co) for human cells. In a second approach, expression of the wild-type (wt) NS3/4A gene was enhanced by mRNA amplification using the Semliki forest virus (SFV) replicon (wtNS3/4A-SFV). Transient tranfections of human HepG2 cells showed that the coNS3/4A gene gave 11-fold higher levels of NS3 as compared to the wtNS3/4A gene when using the CMV promoter. We have previously shown that the presence of NS4A enhances the expression by SFV. Both codon optimization and mRNA amplification resulted in an improved immunogenicity as evidenced by higher levels of NS3-specific antibodies. This improved immunogenicity also resulted in a more rapid priming of cytotoxic T lymphocytes (CTLs). Since HCV is a noncytolytic virus, the functionality of the primed CTL responses was evaluated by an in vivo challenge with NS3/4A-expressing syngeneic tumor cells. The priming of a tumor protective immunity required an endogenous production of the immunogen and CD8+ CTLs, but was independent of B and CD4+ T cells. This model confirmed the more rapid in vivo activation of an NS3/4A-specific tumor-inhibiting immunity by codon optimization and mRNA amplification. Finally, therapeutic vaccination with the coNS3/4A gene using gene gun 6-12 days after injection of tumors significantly reduced the tumor growth in vivo. Codon optimization and mRNA amplification effectively enhances the overall immunogenicity of NS3/4A. Thus, either, or both, of these approaches should be utilized in an NS3/4A-based HCV genetic vaccine.


Subject(s)
Codon , Hepacivirus/genetics , Hepatitis C/prevention & control , RNA, Messenger/genetics , Vaccines, DNA/genetics , Viral Hepatitis Vaccines/genetics , Animals , Antibodies, Viral/blood , Cricetinae , Female , Flow Cytometry , Gene Amplification , Genetic Engineering/methods , Hepacivirus/immunology , Hepatitis C/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Animal , T-Lymphocytes, Cytotoxic/immunology , Vaccines, DNA/immunology , Viral Hepatitis Vaccines/immunology
16.
Scand J Gastroenterol ; 37(10): 1228-34, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12408530

ABSTRACT

BACKGROUND: The early decline of hepatitis C virus (HCV) RNA levels during therapy may predict the outcome and can be utilized to improve treatment regimens. We studied the HCV RNA levels during induction and standard interferon (IFN) and ribavirin treatment. METHODS: Patients received IFN 3 MU daily for 14 days followed by 3 MU three times a week (induction group; n = 10), or IFN 3 MU three times a week from start (standard group; n = 21), in combination with ribavirin 1000-1200 mg/day. HCV RNA was quantified day 0, 1, 2, 3, 7, 14, 28, 56 and 84 during treatment, and tested qualitatively at the end of treatment and at follow-up. RESULTS: The initial viral load decline was more pronounced in the induction group, and in patients infected with genotype non-1. The sustained response rate was not significantly different between the study groups. At day 1, the mean viral load decline from baseline was significantly greater in patients who became sustained responders than in those who became non-responders; 1.4 log (96%) versus 0.3 log (55%) (P < 0.05). All sustained responders had a viral load decline of at least 0.7 log (79%) after the first IFN dose. CONCLUSIONS: Our short-term induction treatment did not improve the long-term treatment outcome significantly, although a trend was seen. An absent or low initial viral load decline can be used to predict non-response in the individual patient.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepacivirus/isolation & purification , Hepatitis C/drug therapy , Hepatitis C/virology , Interferon-alpha/therapeutic use , Interferons/therapeutic use , Ribavirin/therapeutic use , Adult , Aged , Antiviral Agents/administration & dosage , Drug Therapy, Combination , Female , Follow-Up Studies , Hepacivirus/genetics , Hepatitis C/genetics , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferons/administration & dosage , Male , Middle Aged , Recombinant Proteins , Remission Induction , Ribavirin/administration & dosage , Time Factors , Treatment Outcome
17.
Lakartidningen ; 98(36): 3780-4, 2001 Sep 05.
Article in Swedish | MEDLINE | ID: mdl-11586807

ABSTRACT

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.


Subject(s)
Hepatitis B Vaccines/administration & dosage , Hepatitis B, Chronic/prevention & control , Adult , Child , Emigration and Immigration , Global Health , Hepatitis B Vaccines/history , Hepatitis B Vaccines/standards , Hepatitis B, Chronic/epidemiology , Hepatitis B, Chronic/history , History, 20th Century , Humans , Immunization Programs , Infant , Risk Factors , Sweden/epidemiology
18.
Scand J Infect Dis ; 33(8): 572-80, 2001.
Article in English | MEDLINE | ID: mdl-11525349

ABSTRACT

GB virus C (GBV-C), or hepatitis G virus (HGV), is a recently discovered enveloped RNA virus belonging to the Flaviviridae family. GBV-C/HGV is transmitted by contaminated blood and/or blood products, intravenous drug use, from mother to child, sexually, and possibly through close social contacts. Several reports indicate a high prevalence of GBV-C/HGV viremia (1-4%) within healthy populations in Europe and North America, and an even higher prevalence (10-33%) among residents in South America and Africa. GBV-C/HGV has been suggested to be a causative agent for non-A-non-E hepatitis. However, several contradictory observations suggest that its ability to cause hepatitis is questionable. Taken together most data suggest that GBV-C/HGV is not a major cause of liver disease despite recent data indicating that it may infect and replicate in hepatocytes.


Subject(s)
Flaviviridae Infections/complications , Flaviviridae Infections/virology , GB virus C/isolation & purification , Hepatitis, Viral, Human/virology , Acute Disease , Africa/epidemiology , Chronic Disease , Europe/epidemiology , Flaviviridae Infections/epidemiology , Flaviviridae Infections/transmission , Hepatitis, Viral, Human/epidemiology , Hepatitis, Viral, Human/transmission , Humans , Immunocompromised Host , North America/epidemiology , Prevalence , South America/epidemiology
19.
Scand J Infect Dis ; 33(11): 838-42, 2001.
Article in English | MEDLINE | ID: mdl-11760165

ABSTRACT

We studied HCV kinetics during the first 84 d of interferon-alpha (IFN) treatment. IFN was administered either at a dose of 3 million units daily for the first 14 d and thereafter 3 times per week (t.i.w.) (induction treatment), or at a dose of 3 million units t.i.w. throughout (standard treatment). No patient had received HCV treatment previously, and all had a pretreatment viral load of < 1.2 x 10(6) IU/ml at screening. Ten patients were given induction treatment and 21 received the standard t.i.w. regimen. Twenty patients were infected with genotype 1. At Day 2, the median HCV RNA level in the induction group was significantly lower compared to that of the standard treatment group. This significant difference persisted during the study period for patients infected with genotype 1, but was not maintained from Day 14 onwards for patients with genotype non-1. At Day 84, 80% (8/10) of patients in the induction group, compared to 16% (3/19) in the standard treatment group, had undetectable (< 600 IU/ml) HCV RNA levels (p < 0.05). We conclude that induction treatment resulted in a significantly greater decline in HCV RNA levels than standard treatment.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C/drug therapy , Interferon-alpha/therapeutic use , RNA, Viral/drug effects , Adult , Antiviral Agents/administration & dosage , Female , Humans , Interferon-alpha/administration & dosage , Kinetics , Male , Middle Aged , RNA, Viral/metabolism , Treatment Outcome
20.
J Infect Dis ; 182(6): 1756-60, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11069249

ABSTRACT

Thirty-seven persons were identified with GB virus C (GBV-C) single infection by polymerase chain reaction screening of 1254 healthy blood donors. Of 33 donors who returned for clinical examination, 17 underwent liver biopsy. Clinical, biochemical, and histologic evaluation did not reveal any signs of liver disease. Liver biopsies of 15 donors were analyzed by in situ hybridization with GBV-C RNA probes and immunologic staining for the GBV-C envelope 2 protein. GBV-C replication was identified in the cytoplasm of hepatocytes of 10 (67%) donor livers but in none of 7 liver biopsies of chronic hepatitis B virus carriers negative for serum GBV-C RNA. Thus, there was no evidence of liver disease in GBV-C-infected healthy blood donors despite viral replication in hepatocytes.


Subject(s)
Blood Donors , Flaviviridae/isolation & purification , Liver/virology , Virus Replication , Adult , Biopsy , Cohort Studies , Female , Flaviviridae/genetics , Hepatitis, Viral, Human/blood , Hepatitis, Viral, Human/pathology , Hepatitis, Viral, Human/virology , Hepatocytes/virology , Humans , In Situ Hybridization , Liver/pathology , Male , Middle Aged , RNA, Viral/analysis , RNA, Viral/blood , Viral Load
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