rs8099917 TT genotype inpatients infected withHCV genotype 1 or 4, irrespective of race, treatment history or the status of HIV co- infection. However, no relationship was found inpatients infected withHCV genotype 2 or 3. A possible interpretation is that the effect of SNPs is attenuated by a better treatment response inpatientswith genotype 2 or 3 HCV as several studies have reported that rs12979860 CC or rs8099917 TT genotype was associated with faster early viral elimination inpatientswith genotype 2 or 3 HCV [17,20,21,24] and the rate of SVR in treatment-naı¨ve subjects infected with genotype 2 or 3 is 80.6%, much higher than 48.5% inpatientswithHCV genotype 1 or 4. Rs12979860, located about 3 kb upstream to the IL28B coding region, resides in the putative promoter or the regulatory region ofIL28B gene and may affect the gene expression as predicted by a bioinformatics tool, FastSNP (http://fastsnp.ibms.sinica.edu.tw/ pages/input_SNPListAnalysis.jsp). The C allele has been reported to be linked to higher serum levels ofIL28B, IL28A and IL29 levels, which are all involved in the induction of expression of IFN- responsive genes . The CC genotype has also been reported to be associated with lower levels of intrahepatic interferon- stimulated gene (ISG) expression, which is linked to better IFN- based treatment response . However, the exact mechanism underlying effects of the SNP on treatment response still remains to be clarified. Nonetheless, several facts are noteworthy. Frequencies of favorable CC genotype of rs12979860 vary in different races, but in the same direction as SVR rates to PegIFN/ RBV treatment [49,50]. And the frequencies of CC genotype increase from the lowest inpatients failed to treatment, to intermediate inpatientswith treatment-induced clearance, and then to the highest inpatientswith spontaneous clearance [50,51]. In our analysis, the SVR rate declines with the reduction ofC allele (72.7% for CC, 41.6% for CT, 34.4% for TT, Table 2) when data from the Caucasian HCV G1/4 treatment-naı¨ve patients were combined. Rs8099917 has been reported to be in strong linkage disequilibrium with rs12979860 [4,14–18]. Similar associations withHCV treatment are observed and the predictive value could not be increased when determined simultaneously . Therefore, rs8099917 may share similar mechanism as rs12979860 on the association with treatment response although the mechanism is still unclear and determination of the genotype of one SNP may be enough in clinical practice.
The combined therapy with interferon alfa plus ribavirin (INF+RBV) is considered the most appropriate treatment for patientswithchronichepatitisC virus genotypes 2 and 3 in Brazil. However, wide variations in the rates of sustained viral response (SVR) have been reported among such patients. We evaluated, retrospectively, factors associated with SVR in subjects withchronichepatitisC virus genotypes 2 and 3 and that received medication from the Health Secretariat of the state of São Paulo. One-hundred-seventy-seven consecutive patientswithchronichepatitisC were treated for 24 or 48 weeks according to the viral genotype. Patients co-infected with associated hepatic diseases or who had problems with alcohol abuse were excluded. The genotype of the HCV-RNA was identified through restriction analysis, the viral load through quantitative PCR (Amplicor, Roche) and the degree of hepatic fibrosis according to the Metavir score. Demographic, virological and histological parameters were submitted to binary logistic regression analysis to identify the variables associated with SVR. The overall rate of SVR was 36.4% for the 177 patients, and genotype 2 or 3 was the main parameter independently associated with SVR. Among the 77 patientswith these viral genotypes, only the stage of fibrosis had a significant effect on the SVR (odds ratio (OR) = 3.035; 95% CI (confidence interval) = 1.196-7.699; p=0.019). The rate of SVR among the subjects with fibrosis at an advanced stage (F3-F4) was 38%, compared to 75% for patientswith fibrosis at an initial stage (F0- F2). Consequently, other therapeutic options should be considered for patientswithgenotypes 2 and 3 who have advanced fibrosis.
HepatitisC virus (HCV) infection is a serious public health problem, since 80% to 85% ofHCV carriers develop a persistent infection that can progress into liver cirrhosis and hepatocarcinoma. Considering that the response ofhepatitisCpatients to combination therapy with interferon andribavirindependsonHCV characteristics as well as on host features, we made a retrospective analysisof demographic and anthropometrical data andHCV genotype distribution ofchronichepatitisCpatientstreatedin public and private reference centers in Brazil. The medical records of 4,996 patients were reviewed, 81% from public and 19% from private institutions. Patients’ median age was 46 years, and there was a higher prevalence of male (62%) and white patients (80%). The analysisofHCV-infecting strains showed a predominance of genotype 1 (64%) over genotypes 2 and 3. The patients’ mean weight was 70.6 kg, and 65% of the patients weighed less than 77kg. Overweight and obesity were observed in 37.8% and 13.6% of the patients, respectively. Since a body weight of 75 kg or less has been considered an independent factor that significantly increases the odds of achieving a sustained virological response, the Brazilian population seems to have a more favorable body weight profile to achieve a sustained response than the American and European populations. The finding that 65% ofchronichepatitisCpatients have a body weight of 77 kg or less may have a positive pharmacoeconomic impact on the treatment of genotype 1 HCVpatientswith weight-based doses of peginterferon.
Our review included eligible clinical trials that assessed the efficacy of combination therapy with Peg-IFN and RBV inchronicHCV-6 patients. For inclusion, published articles or abstracts had to: (a) have a protocol with an adequate course of treatment (24 or 48 weeks); (b) provide information on a primary outcome of interest clearly defined as sustained virological response (SVR), which was defined as undetectable HCV RNA at least 24 weeks after the end of treatment; (c) focus on treatment-naı¨ve adult patients; (d) be reported in English. We excluded the studies referring to patientswith other HCVgenotypes, hepatitis B virus or human immune deficiency virus co-infections, other liver diseases, hemophilia, chronic renal failure, liver decompensation, liver transplantation, liver cancer, and psychosis. The studies that had less than 10 HCV-6 patients were also excluded. When there were multiple publications from the same population, only data from the most recent and complete ones were selected. Moreover, we contacted the authors if further detailed data was required.
The clinical picture of CHC without HCC was low symptomatic, and clinical signs were absent in 36% ofpatients. With the development of HCC in CHC patients, clinical manifestations were absent only in 2.2% ofpatients. In some patients, the disease was diagnosed in connection with the “accidental” discovery of elevated levels of serum transaminases and/or detection of anti-HCV. Often, especially in women, the irst clinical signs of the disease were extrahepatic signs. Determining factors in HCC development are male sex, mature age, the maintained HCV replication, moderate and severe ibrosis, disease duration of more than 10 years, and the lack of effect of AVT.
defined date of contamination and an average annual liver fibrosis progression rate calculated by means of a single liver biopsy specimen. Poynard’s study originated a model suggesting a broad spectrum of progression and defining three groups ofpatientswith fibrosis: those with slow progression fibrosis (cirrhosis over 50 years of age), moderate fibrosis (cirrhosis at 20 to 50 years of age), or rapid progression fibrosis (period of infection under 20 years).The literature shows that patientswith normal ALT can represent the relatively slow fibrosis progression rate population 12,13,16,19 .
In Brazil, the treatment ofhepatitisC virus (HCV) infection is funded by the national public health system (SUS). To evaluate treatment resultsin the state of Mato Grosso, central Brazil, we have consulted the files of the office of the State Department of Health responsible for supplying such medications. We obtained information on 232 treat- ments of 201 patients who underwent treatment in or prior to 2008. The study was conducted by reviewing medical records, making telephone calls and interviewing the assistant physicians. Thirty-nine patients (19.4%) had cirrho- sis andHCV genotype 1 predominated (64.3%). Excluding patientswith comorbidities or treatment without ribavirin we analysed 175 treatments (sustained virologic response occurred in 32.6% of cases). Twenty-six of these 175 were retreatments and the sustained virological response (SVR) rate among them was 30.8%; the SVR rate was 32.9% among those receiving treatment for the first time. The SVR rate of genotype 1 patients was 27.8%, whereas it was 37.5% in non-1 genotype patients. The adjusted multivariate analysis showed association of SVR with the absence of cirrhosis [odds ratio (OR): 7.7; confidence interval (CI) 95%: 2.5, 33.3], the use of pegylated interferon (OR: 5.8; CI 95%: 1.5, 21.4), non-1 genotype (OR: 5.3; CI 95%: 1.7, 16.7) and uninterrupted treatment (OR: 9.0; CI 95%: 3.3, 45.4). The SVR rates were similar to those found in other Brazilian studies about HCV, but lower than those found in national and international clinical trials. These data suggest that the treatments ofchronichepatitisC that are made available by SUS does not, under normal conditions, work as well as the original controlled studies indicated.
Study population - In total, 49 patientswithchronic viral hepatitis, consisting of 28 HBV-infected patientsand 21 HCV-infected patients, and 33 healthy, non-infected controls were included in the study. The patients were recruited from the Clinic of Infectious Diseases of Julio Muller Hospital (Federal University of Mato Grosso, Cui- abá, state of Mato Grosso, Central-West Brazil). Chronic HBV infection was confirmed by persistent HBV surface antigenemia lasting more than six months. ChronicHCV infection was confirmed by the presence ofHCV RNA in blood tests. Cirrhosis was diagnosed by liver biopsy or based on clinical observations, laboratory tests or ul- trasonographic evidence. Non-infected subjects were re- cruited from a group of healthy blood donors at the Public Blood Bank of Mato Grosso State. The absence of infec- tion in the control group was confirmed by laboratory tests. Information about alcohol consumption, tobacco use, ethnicity and age was obtained from medical records andfrom an interviewer-administered questionnaire, which also included questions about exposure to muta- gens and any history of cancer in the individual.
IFN-alpha treatment for various conditions has been associated with thyroid autoimmunity. The incidence of interferon-induced thyroid autoimmunity has been reported to range from 2.5% to 42%, possibly depending upon dose and duration of medical therapy and patient characteristics. It is not known whether IFN-alpha initiates autoimmune thyroid disease or simply exacerbates in individuals with subclinical disease . However, it is interesting to observe the thyroid in the first 24 hours of IFN-alpha therapy. The TSH levels tend to decrease while free T4 and free T3 remain unchanged. Interleukin 6 (IL-6) levels increase, and tumor necrosis factor and IL-1 levels fall . The main effect of IFN-alpha on the immune system is the enhancement of cell cytotoxicity, very likely sustained by suppression of T helper (Th) 2 and an increase in Th1 immune response .
The HCV genome is a positive-stranded RNA molecule of ~10 kb and is highly variable 6,8,9 . Some regions of the viral genome, such as 5’ non-coding (NC) and core regions are rather conserved, while the envelope (E1 and E2) and the non-structural (NS) 5A regions exhibit marked variability. At present, 11 major types and at least 80 (sub)types can be differentiated according to the classification based upon various genetic analysis procedures 24 . The distribution of different HCV geno- types varies according to the geographic region and seems to be related to their time of divergence (500-2000 years ago) 35 . In South America, Europe, the United States and Japan, HCVgenotypes 1, 2 and 3 account
Specimens: We studied 183 samples sent to the Clinical Laboratory of the University Hospital, Londrina, PR, between December 2001 and September 2002. The samples were selected frompatients attending infectious diseases ambulatories and detected anti-HCV reactive at routine laboratorial screening. These subjects (48 blood donors and 127 HIV-patientswith serological evidence of co-infection withHCV) were undergoing their first clinical evaluation for hepatitisC after the anti-HCV reactive result, and their status about HCV infection was unknown. Other eight patients selected had a confirmed diagnosis ofchronichepatitisC, and they were previously known to be HCV-RNA positive, but HCV genotype was not still determined. No patient was under interferon therapy. The study was approved by the Research Ethics Committee of the institution and all patients signed a written informed consent.
stratified by the stage of disease. RESULTS: Annual outpatient costs per patient were 694; 877; and US$1409 for Qingdao, Nanjing, and Beijing, respectively. Among out- patient expenses, western medications formed the bulk of these costs in Qingdao (58.9%) and Beijing (62.9%), but a lesser amount in Nanjing (46.9%). The use of antivirals is 20% in Nanjing and 37% in Qingdao of total western medications. TCM prescriptions for CHB varied across these different cities with the greatest usage in Nanjing (20.8%). For hospitalized patients, annual costs per patient were 1893; 2101, and US$2622 in Nanjing, Qingdao, and Beijing, respectively. The costs increased progressively inpatientswith compensated liver disease, (US$1983) decompensated liver disease (US$2802) and hepatocellular cancer (US$3019), respectively. Patients contributed around 50% towards outpatient costs and 30% towards inpatient care. CONCLUSIONS: CHB exerts a significant health and financial burden which progres- sively increases as patients progress from early to late stages of the disease. While antivirals are associated with a reduction in disease progression, their use remains relatively low in urban areas in China. Further work is required to determine whether an early treatment with effective CHB medications can reduce the overall financial burden within China.
Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Paque gradient centrifugation (PAA Laboratories GmbH, Linz, Austria) from heparinized blood ofpatientswithchronichepatitisC. Freshly isolated PBMC (5x10 5 cells/ml) were stimu- lated with recombinant HCV core protein (10 m g/ml) in the presence of rIL-2 (100 U/ml). After 10 days, cells were re- stimulated with core protein and supplemented with irradiated autologous feeder cells (5x10 5 PBMC/ml). After 20 days, cells were seeded in Terasaki plates (Greiner bio-one, Frickenhausen, Germany) under conditions of limiting dilution (0.1, 0.3, and 0.5 cells/well). After 10 days, clones were picked from plates with less than 10% positive wells and re-stimulated at 10–14 day intervals in the presence of IL-2 and Treg Expander beads. Clones were classified into TH1, TH2 cells and Tregs by analyzing cytokine secretion and proliferation after stimulation with anti-CD3/anti- CD28 (1 and 2.5 m g/ml) (table 1). Overall we obtained 8, 9, and 7 TH1, TH2 and Treg clones from the 12 HCV-infected patientsof this study, respectively. TH1 cells were IFN-gamma high , IL-4 low and IL-10 negative . TH2 cells were IFN-gamma negative , IL-4 high and produced variable amounts of IL-10. The antigen-specificity of TH1 and TH2 clones was undetermined. Tregs were IFN- gamma negative , IL-4 negative , IL-10 positive and did not proliferate after stimulation with anti-CD3/anti-CD28. All Treg clones expressed a typical Treg phenotype (CD25 + , Foxp3 + , CD127 2 , CTLA-4 + )
2. Graham C.S., Baden L.R., Yu E., et al. Influence of human immunodeficiency virus infection on the course ofhepatitisC virus infection: a meta-analysis. Clin Infect Dis 2001;33:562-9. 3. Brau N., Salvatore M., Ríos-Bedoya C.F., et al. Slower fibrosis progression in HIV/HCV-coinfected patientswith successful HIV supression using antiretroviral therapy. J Hepatol 2006;44:47-55. 4. Manns M.P., Mchutchison J.G., Gordon S.C., et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment ofchronichepatitisC: a randomised trial. Lancet 2001;358:958-65.
ABSTRACT – Background – Vitamin D is known for its immunomodulatory, anti-inlammatory and antiibrotic properties, which are quite relevant in the pathogenesis and treatment of many causes ofchronic liver disease. Objective – This study aimed to evaluate the association between serum vitamin D levels and the histopathological indings inpatientswithchronichepatitisC virus infection. Methods – Cross-sectional study composed ofpatientswithchronichepatitisC. All patients underwent vitamin D 25 dosage and anthropometric data analysis. Liver biopsy was performed in a maximum 36-month period before inclusion in the study. Results – Of the 74 patients included in the study, 45 (60.8%) were women, mean age was 57.03±9.24 years, and 63 (85.1%) were white. No association was observed between the serum levels of vitamin D and inlammatory activity (P=0.699) nor with the degree of liver ibrosis (P=0.269). Conclusion – In this study, no association was observed between vitamin D and inlammatory activity, as well as the degree of liver ibrosis, inpatientswithchronichepatitisC.
W e appreciate the interest of Dr. Wiwanitkit in our article recently published in Journal of the Brazilian Society of Endocrinology and Metabology. According to the study results, chronichepatitisCpatientswith insulin resistance (HOMA IR> 2.5) had more advanced HCV – related liver ibrosis (1). One of the issues considered by Dr. Wiwanitkit is that our results may have been inluenced by the other liver diseases. However, as described in the methods section, previous antiviral treatment, co-infection with HBV or HIV, chronic renal disease, DM2, decompensated liver cirrhosis, hepatocellular carcinoma, and alcohol intake above 20 g ethanol/d were exclusion criteria. The second question issue raised by him, is that although theon the fact that it was an observational study, data were submitted to statistical analysis (univariate analysis) andresults were considered statistically signiicant when p < 0.05. Therefore, we found possible to conclude that there was an association between IR andHCV-induced liver ibrosis. We did not analyze in our study whether insulin resistance was independently associated withHCV-induced liver ibrosis.
In our sample, IR patients had higher levels of blood glucose, fasting insulin and HOMA-IR. Disor- dered glucose metabolism is certainly the main conse- quence of IR, supporting the higher prevalence rates of DM2 inpatientswithchronichepatitisC. The levels of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were similar in both groups. The levels of ALT, AST and GGT were signiicantly higher in IR patients, which may relect more severe inlammatory injury and the presence of steatosis. IR patients have a greater production of inlammatory cytokines, such as IL-6, resistin, TNF-alfa and CRP, which may promote inlammatory injury to the hepatocytes. Furthermore, adiponectin is a potent anti-inlammatory cytokine, and IR patients typically have lower levels of this cytokine. In this study, we found a higher rate of liver steatosis in IR patients, which may also explain the higher levels of ALT and AST. Higher levels of GGT have been obser- ved in subjects with hyperinsulinemia, central obesity and hypertension (38). The lower levels of albumin and the increased INR in our study likely represent the hi- gher stage of liver ibrosis observed in this group, and the consequent impairment of liver synthetic activity.
In this meta-analysis, we summarized the occurrence rate of SVR in total as well as the rate in IL-28B favorable genotype inHCV-4 patients. When given PegIFN plus Rbv, the total rate of achieving SVR inHCV-4 patients was 53.0%, while in rs12979860 CC genotype patients, SVR rate reached up to 76.7% and decreased to 42.4% in CT/TT patients. For rs12979860, the CC genotype obviously correlated with a higher probability to achieve SVR inHCV-4 patients (OR = 3.95). The meta-analysisresultsof those studies which had adjusted odds ratio again consolidated the significant association (OR = 2.66, 95%CI = 1.30–4.03). And these results jointly indicated that IL- 28B rs12979860 CC genotype favored SVR inHCV-4 patients, compared with CT/TT genotype. The patients who had rs12979860 CC genotype would have a better outcome when initiating the standard care. Similar results were observed in rs8099917, which could still herald the sustained response when receiving PegIFN plus Rbv. These conclusions were similar to those reported inHCV-1 patients that rs12979860 and rs8099917 could be as the strongest pretreatment predictors of SVR to PegIFN plus Rbv [4–6,32]. Moreover, we found rs12980275 had similar associations, but only 1 article investigated this SNP, thus more studies are warranted. However, the mechanisms underlying the association of IL-28B with SVR are still only partly understood. Urban et al  thought that IL28Bgenotypes associated with IFN-stimulated gene expression and different IL- 28B genotypes would have different viral kinetics. InHCV-1 patients, the rs12979860 CC genotype presented a quicker decline of the viral load once PegIFN plus Rbv is started, which contributes to rapid viral response and eventually achieving SVR. While for rs12979860 CT/TT genotype, the patients
The population study included all patientswith CHC who were scheduled to receive combined double therapy with pegylated interferon andribavirinin accordance with current guidelines , and who attended since June 2003 to the outpatient clinic of the Gastroenterology Department (Liver Unit), San Carlos University Hospital, Madrid, Spain, Only patients who had completed a full course of therapy or who had stopped therapy due to therapeutic failure, defined with widely accepted criteria , were included in the study. Patients who had had to stop therapy due to drug intolerance, and those co-infected with HIV or HBV or with superimposed hepatocellular carcinoma were not included. The study was designed in accordance with the guidelines of the Declaration of Helsinki and approved by the ethics committee of the San Carlos University Hospital, Madrid, Spain. Written informed consent was obtained for all participants. The final study group was composed of 238 patientsof Caucasian descent (221 Spaniards). Baseline and clinical characteristics are summarized in Table 1. Blood samples for biochemical, virologic and genetic studies were obtained during the month previous to the onset of therapy. Histological data were collected when a liver biopsy performed within the previous six months was available. In the remaining cases the resultsof transient elastography were included, when available.