Hepatitis C-infected Patients Research Articles

Increased Th1, Th17 and pro-fibrotic responses in hepatitis C-infected patients are down-regulated after 12 weeks of treatment with pegylated interferon plus ribavirin.

Hepatitis C virus causes significant morbidity and mortality worldwide. The infection induces up-regulation of cytokine and chemokines commonly linked to the development of cellular and pro-inflammatory antiviral responses. The current standard in hepatitis C treatment consists of combination regimens of pegylated interferon-alpha plus ribavirin. The impact of combined treatment in the host immune response is still poorly understood. In the present study, we profiled 27 cytokines, chemokines and growth factors involved in the innate and adaptive responses to the virus in the serum of 27 hepatitis C virus-infected patients, before and after 12 weeks of combined treatment, and compared them to 10 healthy controls. Hepatitis C virus infection induced not only the secretion of chemokines and cytokines participating in Th1 responses (MIP-1 alpha, IP-10, TNF-alpha, IL-12p70, IL-2), but also cytokines involved in the development of Th17 responses (IL-6, IL-8, IL-9 and IL-17) and two pro-fibrotic factors (FGF-b, VEGF). The most important increases included MIP-1 alpha (4.7-fold increase compared to the control group), TNF-alpha (3.0-fold), FGF-b (3.4-fold), VEGF (3.5-fold), IP-10 (3.6-fold), IL-17 (107.0-fold), IL-9 (7.5-fold), IL-12p70 (7.0-fold), IL-2 (5.6-fold) and IL-7 (5.6-fold). Combined treatment with pegylated interferon-alpha plus ribavirin down-modulated the secretion of key Th1 and Th17 pro-inflammatory mediators, and pro-fibrotic growth factors as early as 12 weeks after treatment initiation. MIP-1 alpha, FGF-b, IL-17 decreased in a more dramatic manner in the group of responder patients than in the group of non-responders (fold-change in cEVR; fold-change in NcEVR): MIP-1 alpha (4.72;1.71), FGF-b (4.54;1.21), IL-17 (107.1;1.8). Correlation studies demonstrated that the decreases in the levels of these mediators were significantly associated with each other, pointing to a coordinated effect of the treatment on their secretion (r coefficient; p value): [ FGF-b versus IL-17 (0.90; 0.00), IL-17 versus VEGF (0.88; 0.00), MIP-1 alpha versus IL-17 (0.84;0.00), FGF-b versus MIP-1 alpha (0.96;0.00), FGF-b versus IL-12p70 (0.90; 0.00), VEGF versus IL-12p70 (0.89; 0.00)]. Th17 immunity has been previously associated with autoimmune diseases and asthma, but this is the first work reporting a role for this profile in viral hepatitis. These results provide an opportunity to evaluate the impact of the treatment with Peg-INF-alpha and RBV on the prevention of immune-driven tissue damage in infected patients.

Pegylated interferon alpha-2a for treatment of chronic HCV infection in hemodialysis patients: a single Saudi center experience

Chronic hepatitis C infection is common among patients on dialysis. While the associated liver disease is usually relatively mild during dialysis, disease progression can accelerate due to immunosuppression following kidney transplantation, and interferon therapy after transplantation stimulates graft rejection. Pegylated interferon and ribavirin are now the recommended treatment for chronic hepatitis C virus in patients without renal failure. However, until now, there has been relatively little information on the efficacy and tolerability of pegylated interferon in dialysis patients. To evaluate the response to pegylated interferon alpha-2a in chronic hepatitis C-infected patients on chronic hemodialysis. This controlled study included 28 patients with end-stage renal disease who had been on dialysis in the Prince Salman Center for Kidney Disease for more than 6 months and tested positive for HCV RNA on repeated occasions. Thirteen patients were treated with pegylated interferon alpha-2a therapy (of which three were also receiving ribavirin), and the remaining fifteen served as controls. Viral genotyping and both qualitative and quantitative PCR were carried out before starting therapy. Treatment was continued for 48 weeks. After 24 weeks of treatment, the biochemical and virological responses were evaluated. Biochemical response was evaluated at the end of the treatment, with sustained virological response (SVR) being evaluated 24 weeks later. The side effects were monitored throughout the treatment period. All patients in the treatment group completed 48 weeks of therapy without any drop out. Their mean age was 43.38 ± 11.62 years. After 24 weeks of therapy, 10 patients (76%) were initial responders, while 3 patients (24%) were resistant. Six months after termination of therapy, 9 patients (69%) were sustained responders, while one patient relapsed. Their ALT and AST dropped from 55.78 ± 33.79 IU/dl and 34.04 ± 19.58 IU/dl before starting therapy to 27.22 ± 16.54 IU/dl and 18.88 ± 12.28 IU/dl after termination (P = .06 and .08, respectively). Their mean hemoglobin (Hb) level dropped from 11.05 ± 1.43 to 9.48 ± 1.24 g/dl (P = 0.3), and white blood cell count (WBC) dropped from 6.82 ± 2.6 × 10(3)/mm(3) to 4.1 ± 2.34 × 10(3)/mm(3); (P = 0.57). Platelet count fell from 194.56 ± 129.78 × 10(3)/mm(3) to (152.33 ± 107.66 × 10(3)/mm(3); P = 0.39). When initial responders (n = 10) were compared to resistant patients (n = 3), the only observable difference was higher ALT and AST levels in resistant patients. Pegylated interferon alpha-2a was well tolerated, and none of the patients stopped interferon because of hematological side effects while dose modification was carried out in most of the patients. All three patients who received combination therapy from the start were sustained responders. None of the patients in the control group seroconverted to HCV negative status during the study period. Pegylated interferon alpha-2a was well tolerated among our hemodialysis patients. Hematological disturbances appeared to be the most important adverse effects. At the end of therapy a response rate of up to 76%, with 69% sustained response, can be obtained with pegylated interferon alpha-2a therapy.

Fibrotest or Fibroscan for evaluation of liver fibrosis in haemophilia patients infected with hepatitis C

Non-invasive modalities to estimate fibrosis stage are desirable in hepatitis C-infected haemophilia patients. Previous studies found a high rate of significant fibrosis both by Fibrotest (FT) and Fibroscan (FS) in these patients. To estimate liver fibrosis and to assess the concordance between FT and FS in hepatitis C-infected haemophilia patients. FT and FS were performed at different laboratories and were unaware of the results of the alternative test. Three successive liver stiffness measurements (LSM) were performed at different sites on the liver. Two-validated algorithms were used to improve evaluation of fibrosis by non-invasive methods. Fifty-seven hepatitis C-infected haemophilia patients were evaluated by FT and FS. Acquisition of LSMs was not feasible in two patients: obesity--one, surgical scars--one. Fibrosis stage > or=F2, > or =F3 or =F4 were estimated in about a half, about a third and in 15-20% of the evaluated patients by FS and FT respectively. The corresponding concordance rates and kappa score for fibrosis stage > or =F2, > or =F3 or =F4 between FT and FS were 62%, 69%, 85% and 0.24, 0.32, 0.44 respectively. Using the two aforementioned algorithms, additional 14 patients could be reliably estimated for fibrosis stage > or =F2. High proportion hepatitis C-infected haemophilia patients were estimated with significant or advanced stages of liver fibrosis using both tests. Nevertheless, the agreement between modalities was only fair and improved with more advanced stages of fibrosis. Practical algorithms for the accuracy of FT and FS may improve reliable evaluation of fibrosis in this population.

Schistosoma mansoni coinfection could have a protective effect against mixed cryoglobulinaemia in hepatitis C patients

The association between mixed cryogloblinaemia and chronic hepatitis C virus (HCV) infection has been established. However, the factors underlying its great geographical heterogeneity of prevalence have not yet been identified. Concomitant HCV and Schistosoma mansoni infections are common in Egypt. Chronic helminthic infections have been found to decrease the incidence and manifestations of immune-related diseases. To date, no study has focused on the influence of S. mansoni coinfection on the risk of cryoglobulinaemia in hepatitis C patients. A cohort of 119 consecutively recruited chronic hepatitis C-infected patients was studied. Patients' sera were assessed for S. mansoni antibodies and cryoglobulins (CGs) were determined and characterized. Cryoglobulins were detected in 18 of 119 patients (15.1%) included in this study. They were detected in 12 of 45 hepatitis C (26.7%) and six of 74 coinfected patients (8.1%), which was statistically significant, P=0.01. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were also found to be significantly lower in the CG-positive group compared with the CG-negative group, P=<0.01. CGs were detected in seven of 21 (33.3%) and in 11 of 98 (11.2%) hepatitis C female and male patients, respectively, indicating a significantly positive association with the female gender, P=0.02. A logistic regression adjusted for gender, AST and ALT showed that hepatitis C patients without schistosomal coinfection are more likely to have cryoglobulinaemia, odds ratio=4.12, 95% confidence interval=1.42-11.95. There is an apparent protective effect of S. mansoni coinfection against mixed cryoglobulinaemia in chronic hepatitis C patients.

Cirrhosis Regression in Chronic Hepatitis C: An Old Tale With a New Ending

Cirrhosis Regression in Chronic Hepatitis C: An Old Tale With a New Ending

Uncovering Glucose Abnormalities in People With Hepatitis C Infection: Should Oral Glucose Tolerance Test Become a Standard of Care?

Hepatitis C and type 2 diabetes mellitus (DM) are two rising epidemics with significant impact on each other. Hepatitis C-infected patients have a higher incidence of type 2 diabetes, and diabetic patients have a high prevalence of hepatitis C. There is mounting evidence that glucose abnormalities have a negative impact on the disease progression as well as antiviral therapy outcomes. Utilization of oral glucose tolerance testing has the potential to uncover previously undetected DM as well as impaired glucose tolerance or prediabetes in patients with chronic hepatitis C (CHC). Early detection of diabetes and prediabetes with oral glucose tolerance testing in CHC patients can lead to interventions, with significant positive impact on disease progression and antiviral therapy outcomes.

Treating nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a chronic illness with multiple consequences. The spectrum of disease ranges from simple steatosis, with benign prognosis, to a potentially progressive form, nonalcoholic steatohepatitis, which may lead to liver fibrosis and cirrhosis, leading to an increase in morbidity and mortality. Furthermore, hepatocellular carcinoma incidence in NAFLD is comparable with that observed in hepatitis C-infected patients once cirrhosis is established. Current therapy is limited to lifestyle changes and control of associated metabolic disorders; however, new treatments are on the way from basic research to bedside. A review of the current literature on treatment of nonalcoholic fatty liver disease is presented in this article.

Improving estimation of liver fibrosis using combination and newer noninvasive biomarker scoring systems in hepatitis C‐infected haemophilia patients

Non-invasive biomarkers have gained popularity for estimating fibrosis stage. In our hepatitis C-infected haemophilia patients, Fibrotest (FT) correctly identified clinically advanced or minimal liver disease. More accurate tests, like the FibroMeters, have recently been validated. The aim of the study was to improve the estimation of liver fibrosis in hepatitis C-infected haemophiliacs using a combination of biomarkers and FibroMeters. One hundred and thirty-two hepatitis C-infected haemophilia patients (124 male, mean age: 39+/-14 years) were evaluated. The following biomarkers were used: FT, AST-to-platelet ratio index (APRI), Forns index, hyaluronic acid and FibroMeter. We applied a published algorithm suggesting that if FT is in concordance with APRI and/or Forns score, then the FT concurs with liver biopsy for estimation of fibrosis. Concordance of three or more biomarkers was present in 43.2% (57/132) of the patients. This high discordance rate was mainly because of indeterminate scores. Significant fibrosis (F2-F4) was estimated at 34.8% (46/132) and 37.9% (50/132) by the FT and FibroMeter respectively. The discordance rate between the FT and FibroMeter was 16.7% (22/132), (P<0.01 vs. other biomarkers). Using the algorithm, liver histology could be confidently estimated in 69.7% (92/132) of the patients. Concordance between the FT and FibroMeter in those patients who met the terms of the algorithm was 90.2% (83/92). Discordance between biomarkers is significant, and is mainly because of biomarkers with indeterminate results. The concordance rate between FT and FibroMeter is higher compared with the other biomarkers. Practical combination of tests may potentially limit the need of liver biopsy in the majority of haemophilia patients.

Role of signal transducer and activator of transcription 3 in liver fibrosis progression in chronic hepatitis C-infected patients

In vitro and animal data suggest that hepatitis C virus (HCV) proteins might interfere with signal transducer and activator of transcription 3 (Stat3) signaling. It remains unknown whether Stat3 influences the apoptotic–proliferation balance and how this may relate to liver fibrosis progression in HCV-infected patients. We assessed Stat3 expression and DNA-binding as well as expression of its regulators protein inhibitor of activated Stat 3 (Pias3) and suppressor of cytokine signaling 3 (Socs3) in 65 HCV-infected livers at various stages of fibrosis progression. We then determined the level of expression of the proliferation markers cyclin D1 and proliferating cell nuclear antigen (PCNA) in conjunction with pro- and antiapoptotic markers Bax and Bcl-2 in the same liver samples. With the onset of fibrosis, Stat3 DNA-binding decreased and became almost undetectable in livers with bridging fibrosis or cirrhosis. Stat3 DNA-binding inversely correlated with Pias3 expression and Stat3-Pias3 interaction increased with the progression of fibrosis. Cyclin D1 and PCNA in hepatocytes decreased dramatically during fibrosis progression and levels highly correlated with Stat3 expression. In addition, an antiapoptotic profile due to upregulation of Bcl-2 principally in infiltrating inflammatory cells was observed with progressing fibrosis. In conclusion, fibrosis progression is characterized by a continuous decline in Stat3 DNA-binding activity related to overexpression and progressive interaction of Pias3–Stat3. The decrease in Stat3 activity correlated with reduced hepatocytes proliferation and a positive antiapoptotic balance in infiltrating inflammatory cells that are known mediators of cell damage in HCV.

Chronic Hepatitis C in Patients With Persistently Normal Alanine Transaminase Levels

Many patients with chronic hepatitis C virus (HCV) have persistently normal serum alanine transaminase (ALT) levels. We compared characteristics of chronic hepatitis C patients with patients with normal and elevated ALT levels using data from 3 randomized phase III trials of peginterferon alfa-2a (40 kDa). The characteristics of 480 patients with normal ALT values (on >or=3 occasions without any increases in ALT level over a 6- to 18-month period) and 1993 patients with elevated ALT levels were compared. Sixty-eight of the 480 patients with normal ALT levels were randomized to no treatment and monitored for 72 weeks. More patients with normal ALT levels than patients with elevated ALT levels were women (59% vs 32%; P<.01). The serum HCV RNA titer was significantly lower in patients with normal ALT levels (P<.01 vs in patients with elevated ALT levels). Patients with normal ALT levels had significantly lower inflammation and fibrosis scores on liver biopsy examination than patients with elevated ALT levels, but almost two-thirds had portal fibrosis and 10% had bridging fibrosis. No correlation between baseline ALT activity, HCV RNA level, and liver histology was observed in patients with normal ALT levels. During the 72-week follow-up period, ALT activity elevated above the upper limit of normal in 53% of the untreated patients with normal levels of ALT. None became HCV RNA undetectable. Chronic hepatitis C patients with normal ALT levels should be evaluated in a similar manner as patients with elevated ALT levels because they are at risk for developing significant liver disease. The decision to treat with peginterferon alfa and ribavirin should be based on multiple factors, rather than on ALT levels alone.

Applicability, Tolerability and Efficacy of Preemptive Antiviral Therapy in Hepatitis C-Infected Patients Undergoing Liver Transplantation

Applicability, Tolerability and Efficacy of Preemptive Antiviral Therapy in Hepatitis C-Infected Patients Undergoing Liver Transplantation

Differential display analysis of gene expression in brains from hepatitis C-infected patients

Hepatitis C virus (HCV) infection is often associated with cognitive dysfunction, fatigue and depression. The current study was undertaken to determine whether HCV infection affects gene expression in brain tissue. We analysed the gene expression pattern in brain tissue in a group of HCV-infected patients compared with HCV-negative controls. Brain tissue samples were obtained at autopsy from three HCV-positive patients and three HCV-negative control patients. The analysis of gene expression was conducted using differential display and reverse Northern hybridization. Only those genes that were up or downregulated more than 1.8 times were considered to be differentially expressed. Altogether, 29 differentially expressed genes were identified by differential display and subsequently confirmed by reverse Northern hybridization. A prominent finding was the downregulation of mitochondrial oxidative phosphorylation genes in HCV-infected patients. The impairment of brain oxidative/energy metabolism has previously been suggested to be the proximate cause of many disorders that impair mentation. Another finding was the downregulation of some ribosomal protein genes and several genes involved in transcription regulation, perhaps reflecting reduced metabolic activities. Our findings suggest for the first time that there may be a biological basis for the neuropsychiatric symptoms and cognitive impairment associated with HCV infection.

LKM1 Autoantibodies in Chronic Hepatitis C Infection: A Case of Molecular Mimicry? *

Anti-liver-kidney microsome type 1 (LKM1) autoantibodies directed against the cytochrome P450 2D6 (CYP2D6) are considered specific markers of type 2 autoimmune hepatitis, but are also found in 5% of sera from patients chronically infected by hepatitis C virus (HCV). Molecular mimicry between HCV proteins and CYP2D6 has been proposed to explain the emergence of these autoantibodies. Anti-LKM1 autoantibodies from hepatitis C-infected patients were affinity-purified against immobilized CYP2D6 protein and used to screen a phage display library. CYP2D6 conformational epitopes were identified using phage display analysis and the identification of statistically significant pairs (SSPs). Cross-reactivity between CYP2D6 and HCV protein candidates was tested by immunoprecipitation. Nineteen different clones were isolated, and their sequencing resulted in the mapping of a conformational epitope to the region of amino acids 254-288 of CYP2D6. Candidate HCV proteins for molecular mimicry included: core, E2, NS3 and NS5a. Affinity-purified autoantibodies from HCV+/LKM1+ patients immunoprecipitated either NS3, NS5a, or both, and these reactivities were specifically inhibited by immobilized CYP2D6. In conclusion, HCV+/LKM1+ sera recognize a specific conformational epitope on CYP2D6 between amino acids 254 to 288, the region that contains the major linear epitope in type 2 autoimmune hepatitis patients. Cross-reactivity due to molecular mimicry at the B-cell level was shown between the CYP2D6 and the HCV NS3 and NS5a proteins and could explain the presence of anti-LKM1 in patients chronically infected with HCV. Further investigation of the role played by this molecular mimicry in HCV-infected patients may lead to more specific strategies for diagnosis and treatment.

Applicability, Tolerability and Efficacy of Preemptive Antiviral Therapy in Hepatitis C-Infected Patients Undergoing Liver Transplantation

Preliminary studies suggest preemptive anti-HCV therapy in liver transplant recipients may enhance the rates of viral clearance, but the applicability and tolerability of preemptive therapy has not been evaluated in a contemporary cohort. In this randomized study, the safety and tolerability of preemptive standard (IFN) or pegylated (peg-IFN) interferon alfa-2b (3 MU thrice weekly or 1.5 microg/kg weekly), or IFN/peg-IFN plus ribavirin (600 mg increased to 1.0-1.2 g daily) was initiated 2-6 weeks post-transplantation and continued for a total of 48 weeks. Only 51 (41%) of 124 transplant recipients were eligible for preemptive treatment; eligible patients had lower model for end-stage liver disease (MELD) and Childs-Pugh scores pre-transplantation and were more frequently live donor transplant recipients than ineligible patients. Dose reductions and discontinuations were required in 85% and 37% of patients, respectively, and 27% experienced serious adverse events. Growth factor (GF) use (erythropoietin and GCSF) in the latter half of the study did not significantly affect the frequency of dose reductions. Only 15% of patients were able to achieve full-dose treatment during treatment. End-of-treatment and sustained virological responses were 13.6% and 9.1%, respectively, with most responders in the combination therapy group. We conclude that preemptive antiviral therapy is applicable to only a portion of transplant recipients, with 'sicker' patients less likely to be managed by this approach. Living donor liver transplant recipients were more frequently eligible for treatment than deceased donor recipients. Virological response rates are low, likely related to the poor tolerability of therapy and the lack of achievement of target drug doses. Future studies should focus on alternative dosing schedules with more aggressive use of adjuvant therapies, including GFs.

Genetic variants in the CCR gene cluster and spontaneous viral elimination in hepatitis C-infected patients.

Hepatitis C virus (HCV) infection results in chronic hepatitis in more than 80% of infected patients while 10-20% of patients recover spontaneously. Host genetic factors may influence the ability to clear the virus after infection. Six single nucleotide polymorphisms and a 32 bp deletion in the genes coding for CCR3, CCR2 and CCR5 (which are all located in a cluster on chromosome 3) were investigated in 465 consecutively recruited patients infected with HCV and 370 matched controls. Genetic variants were tested for association with spontaneous viral elimination and, in the chronically infected patients, stage of fibrosis and response to antiviral therapy. The G190A polymorphism (variant allele Ile64) in the first transmembrane domain of CCR2 was under-represented in the 29 patients who had cleared the hepatitis C virus spontaneously (P = 0.018). None of the other variants in the CCR gene cluster showed association with the natural course of the infection, stage of fibrosis or response to therapy.

Cost-effectiveness of ribavirin plus interferon alpha-2b for either interferon relapsers or non-responders in chronic hepatitis C: a Japanese trial.

The aim of this study was to examine the cost-effectiveness of combination therapy with ribavirin plus interferon alpha-2b compared with interferon monotherapy for hepatitis C-infected Japanese patients who had either temporarily responded or not responded to initial interferon treatment. Data from a recent randomized clinical trial among relapsed or non-responding patients comparing combination therapy to interferon alone were applied to a computer cohort simulation Markov process model to project lifelong clinical and economic outcomes. Combination therapy for 24 weeks should increase life expectancy by 1.6 quality-adjusted life years and should reduce discounted (3% per year) lifetime costs by yen 121,000 when compared to retreatment with interferon alone. For the subgroup of patients with genotype 1b and high viral load, combination therapy should be cost-effective ( yen 187,000 per QALY gained with a 3% annual discount rate) by well-accepted international standards. These results were robust with combination therapy remaining cost-effective or cost saving in sensitivity analysis involving reasonable variation in all parameters. For patients similar to those enrolled in the interferon alpha-2b and ribavirin trials in Japan, combination therapy should be considered cost-effective with the higher drug treatment costs nearly completely offset by future savings through reductions in future liver complications from hepatitis C.

Genetic polymorphisms of steroid hormone metabolizing enzymes and risk of liver cancer in hepatitis C-infected patients

Background/Aims: Genetic polymorphisms of enzymes involved in hormone metabolism can influence hormonal activities and risk of hormone-dependent cancers. As progression of chronic hepatitis C and risk of liver cancer is higher in males than in females, we evaluated whether the polymorphisms of three enzymes participating in the pathway of estrogen and androgen biosynthesis and inactivation, 5α-reductase type II (SRD5A2), cytochrome P450c17α (CYP17) and catechol- O-methyltransferase (COMT), might affect the expression of hepatitis C virus (HCV)-related liver disease. Methods: The study included 78 healthy subjects and 387 HCV patients: 100 asymptomatic carriers, 105 hepatitis, 90 cirrhosis and 92 hepatocellular carcinomas (HCC). Variant positions SRD5A2 V89L and A49T, CYP17 (−34)T/C and COMT V108M were analysed by polymerase chain reaction and restriction fragment length polymorphism. A cross-sectional study of association was performed, considering carriers as reference category. Results: The CYP17 (−34)C/C genotype was over-represented in HCC patients as compared to carriers (22.5 vs. 11.2%, odds ratio (OR): 2.29, P: 0.05). Females mostly contributed to this association (OR: 4.95, P: 0.01) and OR values increased in post-menopausal women (OR: 6.00, P: 0.03). No differences were observed for SRD5A2 and COMT gene polymorphisms. Conclusions: CYP17 high-activity alleles associated with increased circulating levels of estrogens and androgens may affect liver cancer risk in HCV-infected women.

HLA class I B44 is associated with sustained response to interferon + ribavirin therapy in patients with chronic hepatitis C.

The aim of this study was to assess the influence of host genetic factors on response to combination therapy for chronic hepatitis C infection. Patients with biopsy-proved chronic hepatitis C infection were treated with interferon alone (n = 143) or combined therapy of interferon + ribavarin (n = 105; 46 treatment naïve, 59 relapsers). Human leukocyte antigen (HLA) class I was determined by microlymphocytotoxicity and class II by polymerase chain reaction-single specific oligonucleotide. The two biallelic tumor necrosis factor-alpha promoter polymorphisms were studied by a polymerase chain reaction-amplification refractory mutation system. Other variables measured were viral genotype, hepatitis C virus RNA load, liver function tests, and ferritin concentration. Univariate analysis indicated that patients bearing HLA B44+, DRB1*03, infected by genotype non-1, with higher concentrations of transaminases and shorter duration of infection showed a higher sustained response (SR) rate than those on combination therapy. HLA class II and TNF-alpha promoter polymorphisms were not related to SR. In multivariate analysis, non-1 genotype (OR 2.42, 95% CI 1.12-5.55, p = 0.026) and HLA B44+ (OR 4.84, 95% CI 1.3-17.8, p = 0.017) were the independent variables associated with SR. However, HLA B44+ was not associated with SR in patients treated with interferon alone. HLA class I B44 is related to a higher rate of SR in combination therapy but not in interferon monotherapy, whereas HLA class II, tumor necrosis factor-alpha -238A or -308A seem not to influence response to the antiviral therapy. These findings may be of value in therapy selection for hepatitis C-infected patients.

HLA class I B44 is associated with sustained response to interferon + ribavirin therapy in patients with chronic hepatitis C

Objective The aim of this study was to assess the influence of host genetic factors on response to combination therapy for chronic hepatitis C infection. Methods Patients with biopsy-proved chronic hepatitis C infection were treated with interferon alone (n = 143) or combined therapy of interferon + ribavarin (n = 105; 46 treatment naïve, 59 relapsers). Human leukocyte antigen (HLA) class I was determined by microlymphocytotoxicity and class II by polymerase chain reaction-single specific oligonucleotide. The two biallelic tumor necrosis factor-α promoter polymorphisms were studied by a polymerase chain reaction-amplification refractory mutation system. Other variables measured were viral genotype, hepatitis C virus RNA load, liver function tests, and ferritin concentration. Results Univariate analysis indicated that patients bearing HLA B44+, DRB1*03, infected by genotype non-1, with higher concentrations of transaminases and shorter duration of infection showed a higher sustained response (SR) rate than those on combination therapy. HLA class II and TNF-α promoter polymorphisms were not related to SR. In multivariate analysis, non-1 genotype (OR 2.42, 95% CI 1.12–5.55, p = 0.026) and HLA B44+ (OR 4.84, 95% CI 1.3–17.8, p = 0.017) were the independent variables associated with SR. However, HLA B44+ was not associated with SR in patients treated with interferon alone. Conclusions HLA class I B44 is related to a higher rate of SR in combination therapy but not in interferon monotherapy, whereas HLA class II, tumor necrosis factor-α −238A or −308A seem not to influence response to the antiviral therapy. These findings may be of value in therapy selection for hepatitis C-infected patients.

Sarcoidosis and interferon therapy: report of five cases and review of the literature

Background: Sarcoidosis is a multi-system disease of unknown etiology. Interferons (IFN) have been implicated in its pathogenesis. The objective of this study was to examine the causal relationship between sarcoidosis and IFN therapy. Methods: Patients admitted for sarcoidosis ( n=60) were reviewed for a history of IFN therapy. In addition, all cases of sarcoidosis in a cohort of hepatitis C-infected patients treated with IFN-α ( n=1159) were analyzed. Results: Five patients with prior IFN-α therapy and sarcoidosis were identified; an additional 23 have been reported in the literature. The median age of the 28 reported patients was 50 years, 16 (57%) were female, and 16 (57%) had isolated cutaneous disease. The median time to diagnosis was 4 months (range 1–16 months) following the introduction of IFN. A remission was observed in all patients with adequate follow-up ( n=27): 15 (53%) upon dosage reduction or IFN discontinuation, seven (25%) with systemic corticosteroids, three (11%) with topical treatment, and three (11%) despite ongoing IFN therapy. Relapse was observed in both of the patients rechallenged with IFN. Conclusions: There is a potential causal relationship between IFN therapy and sarcoidosis. In patients with sarcoidosis in the setting of IFN therapy, the majority respond to IFN withdrawal or dosage reduction; however, some require corticosteroid therapy.