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1.  Analysis of the factors motivating HCV-infected patients to accept interferon therapy 
BMC Research Notes  2012;5:470.
Background
The aims of this study were to analyze factors motivating the acceptance of interferon (IFN) therapy and to clarify the prevalence of oral mucosal diseases in hepatitis C virus (HCV)-infected Japanese patients treated with IFN.
Findings
A total of 94 HCV-infected patients who were admitted to our hospital for IFN therapy were asked questions regarding their motivation to accept IFN therapy and were investigated for the presence of oral lichen planus (OLP) before and during IFN treatment. Recommendation and encouragement from other people were the most common factors motivating the acceptance of IFN therapy (49/94, 52.13%). The other motivators were independent decision (30.85%), economic reasons (5.32%), and others. According to multivariate analysis, three factors – sex (male), retreatment after previous IFN therapy, and independent decision to accept IFN therapy - were associated with patients after curative treatment of hepatocellular carcinoma (HCC). The adjusted odds ratios for these three factors were 26.06, 14.17, and 8.72, respectively. The most common oral mucosal lesions included OLP in 11 cases (11.70%). One patient with OLP had postoperative squamous cell carcinoma of the tongue. The rate of sustained virological response (SVR) was 45.45% in cases with OLP and 54.55% in cases without OLP. There were no patients who discontinued IFN therapy because of side effects such as oral mucosal diseases.
Conclusions
We should give full explanation and recommend a course of treatment for a patient to accept IFN therapy. The system to support liver disease as well as oral diseases is also necessary for patient treated for IFN therapy.
doi:10.1186/1756-0500-5-470
PMCID: PMC3500275  PMID: 22932002
Hepatitis C virus; Interferon therapy; Chronic hepatitis C; Hepatocellular carcinoma; Oral lichen planus
2.  Anti-Interferon Autoantibodies in Autoimmune Polyendocrinopathy Syndrome Type 1 
PLoS Medicine  2006;3(7):e289.
Background
The autoimmune regulator (AIRE) gene influences thymic self-tolerance induction. In autoimmune polyendocrinopathy syndrome type 1 (APS1; OMIM 240300), recessive AIRE mutations lead to autoimmunity targetting endocrine and other epithelial tissues, although chronic candidiasis usually appears first. Autoimmunity and chronic candidiasis can associate with thymomas as well. Patients with these tumours frequently also have high titre immunoglobulin G autoantibodies neutralising type I interferon (IFN)–α and IFN-ω, which are secreted signalling proteins of the cytokine superfamily involved in both innate and adaptive immunity.
Methods and Findings
We tested for serum autoantibodies to type I IFNs and other immunoregulatory cytokines using specific binding and neutralisation assays. Unexpectedly, in 60/60 Finnish and 16/16 Norwegian APS1 patients with both AIRE alleles mutated, we found high titre neutralising immunoglobulin G autoantibodies to most IFN-α subtypes and especially IFN-ω (60% homologous to IFN-α)—mostly in the earliest samples. We found lower titres against IFN-β (30% homologous to IFN-α) in 23% of patients; two-thirds of these (from Finland only) also had low titres against the distantly related “type III IFN” (IFN-λ1; alias interleukin-29). However, autoantibodies to the unrelated type II IFN, IFN-γ, and other immunoregulatory cytokines, such as interleukin-10 and interleukin-12, were much rarer and did not neutralise.
Neutralising titres against type I IFNs averaged even higher in patients with APS1 than in patients with thymomas. Anti–type I IFN autoantibodies preceded overt candidiasis (and several of the autoimmune disorders) in the informative patients, and persisted for decades thereafter. They were undetectable in unaffected heterozygous relatives of APS1 probands (except for low titres against IFN-λ1), in APS2 patients, and in isolated cases of the endocrine diseases most typical of APS1, so they appear to be APS1-specific.
Looking for potentially autoimmunising cell types, we found numerous IFN-α+ antigen-presenting cells—plus strong evidence of local IFN secretion—in the normal thymic medulla (where AIRE expression is strongest), and also in normal germinal centres, where it could perpetuate these autoantibody responses once initiated. IFN-α2 and IFN-α8 transcripts were also more abundant in antigen-presenting cells cultured from an APS1 patient's blood than from age-matched healthy controls.
Conclusions
These apparently spontaneous autoantibody responses to IFNs, particularly IFN-α and IFN-ω, segregate like a recessive trait; their high “penetrance” is especially remarkable for such a variable condition. Their apparent restriction to APS1 patients implies practical value in the clinic, e.g., in diagnosing unusual or prodromal AIRE-mutant patients with only single components of APS1, and possibly in prognosis if they prove to predict its onset. These autoantibody responses also raise numerous questions, e.g., about the rarity of other infections in APS1. Moreover, there must also be clues to autoimmunising mechanisms/cell types in the hierarchy of preferences for IFN-ω, IFN-α8, IFN-α2, and IFN-β and IFN-λ1.
Almost all of nearly 100 APS1 patients studied made large amounts of auto-antibodies that blocked the function of IFN-α and IFN-ω. The antibodies appeared early during development of the disease and may play a role in its etiology.
Editors' Summary
Background.
The human body is under constant attack by viruses, bacteria, fungi, and parasites, but the immune system usually prevents these pathogens from causing disease. To be effective, the immune system has to respond rapidly to foreign antigens (bits of protein specific to pathogens) while ignoring self-antigens. If tolerance to self-antigens breaks down, autoimmunity develops, often causing disease. There are many common autoimmune diseases—type I diabetes and multiple sclerosis, for example—but because these involve defects in many genes as well as environmental factors, the details of how autoimmunity develops remain unclear. Autoimmune polyendocrinopathy syndrome type 1 (APS1), however, is caused by defects in a single gene. Patients with this rare disease characteristically have defects (or mutations) in both copies of a gene called AIRE (for autoimmune regulator). In normal people, the protein product of this gene helps to establish tolerance to a subset of self-antigens. People carrying AIRE mutations make an autoimmune response against some of their own tissues, typically the endocrine (hormone-producing) tissues that control body metabolism. A major component of this autoimmune response are “autoantibodies” (antibodies are immune molecules that normally recognize and attack foreign substances, whereas autoantibodies are directed against the body's own molecules).
Why Was This Study Done?
For a diagnosis of APS1, a patient must have at least two of the following symptoms: recurrent, localized yeast infections (usually the first symptom of the disease to appear in early childhood), hypoparathyroidism (failure of the gland that controls calcium levels in the body), and Addison disease (failure of the steroid-producing adrenal glands, which help the body respond to stress). The researchers who did this study had previously noticed that these yeast infections and autoimmunity (usually against muscle) can also occur in patients with tumors of the thymus (thymomas). The thymus is the organ that generates immune cells called T cells. Generation of the T cell repertoire in the thymus involves selection of those T cells that recognize only foreign substances. T cells that can react against self-antigens are eliminated, and the AIRE gene is thought to be involved in this “education process.” Like those with APS1, patients with thymomas make autoantibodies not only against target organs (especially muscle in their case), but also against interferon alpha (IFN-α) and interferon omega (IFN-ω), two secreted immune regulators. The researchers wanted to know if patients with APS1 also make autoantibodies against interferons, because this could provide insights into how autoimmunity develops in APS1 and other autoimmune diseases.
What Did the Researchers Do and Find?
The researchers tested blood from nearly 100 APS1 patients for antibodies to IFN-α, IFN-ω, and other immunoregulatory cytokines. They found that almost all patients made large amounts of antibodies that blocked the function of IFN-α and IFN-ω; some also made lower amounts of antibodies against two related interferons, but none made blocking antibodies against unrelated interferons or other immune regulators. For many patients, serum samples were available at different times during their disease, which allowed the researchers to show that the antibodies appeared early in disease development, before the onset of yeast infections or damage to endocrine tissues, and their production continued for decades as the patient aged. Furthermore, only patients with APS1 made these antibodies—they were absent in patients with Addison disease alone, for example.
What Do These Findings Mean?
The discovery that autoantibodies to IFN-α and IFN-ω are made persistently in patients with APS1 suggests ways in which autoimmunity develops in these patients. These can now be investigated further both in patients and in animal models of the disease. The discovery also has practical implications. Measurement of these autoantibodies might help some APS1 patients by allowing earlier diagnosis—and prompter treatment—than in current practice. The levels of these autoantibodies might also help to predict the time course of APS1 in individual patients, although more studies will be needed to check this out. Finally, if future studies show that interferon autoantibodies are responsible for the patients' susceptibility to yeast infections (which seems plausible), treatment with IFN-γ, an interferon to which APS1 patients do not make autoantibodies, might provide an alternative way to deal with this problem.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030289.
• MedlinePlus pages on autoimmune diseases
• Online Mendelian Inheritance in Man page on APS1
• Links to patient information on APS1 from the Stanford Health Library
• Wikipedia page on autoendocrine polyendocrinopathy (note: Wikipedia is a free online encyclopedia that anyone can edit)
• Information on autoimmunity from the American Autoimmune Related Diseases Association
doi:10.1371/journal.pmed.0030289
PMCID: PMC1475653  PMID: 16784312
3.  Clinical experience with nonstandard doses ofinterferon alfa-2b and ribavirin in the treatment of chronic hepatitis C infection: A retrospective analysis 
Background:
Hepatitis C virus (HCV) infection is the most common blood-borne virus in the United States. Several mono- and combination therapies have been approved by the US Food and Drug Administration for the treatment of HCV, but their routes of administration, dosing approaches, eras of introduction, and actual use in clinical practice and resulting effectiveness have not yet been reported.
Objectives:
The aim of this article was to characterize clinical use and virologic response (VR) of the HCV treatments interferon alfa-2b plus ribavirin (IFN + RBV) and peginterferon alfa-2b plus ribavirin (peg-IFN + RBV).
Methods:
This retrospective chart review of office-based practices in theUnited States was conducted at 200 physicians' offices across the United States. We collected data concerning dosing patterns, VR (HCV RNA load, ≤1000 IU/mL or “negative” on polymerase chain reaction qualitative analysis), and adverse events (AEs) from the medical records of a geographically diverse sample of patients receiving treatment for chronic HCV infection in the United States from July 2001 to June 2002. For efficacy assessment, factors that were statistically different at baseline were adjusted using logistic regression. Providers also reviewed the medical records for symptoms or signs consistent with HCV treatment-related AEs.
Results:
Data from the records of 675 patients (423 men, 252 women; mean [SD] age of 45.5 [8.2] years; mean [SD] body weight, 80.8 [19.4] kg) were analyzed. At baseline, the IFN + RBV treatment group (330 patients) had significantly higher percentages of black patients (22.1% vs 15.7%; P = 0.032) and patients with hepatic disease based on clinician-reported cirrhosis and liver dysfunction (18.8% vs 9.9%; P < 0.001), and a significantly lower percentage of white patients (60.3% vs 69.6%; P = 0.012) compared with the peg-IFN + RBV treatment group (345 patients). The difference in log-transformed baseline HCV RNA loads between the 2 treatment groups in this study was <1 log unit. A significantly higher percentage of IFN + RBV-treated patients compared with peg-IFN + RBV-treated patients were prescribed HCV therapy on diagnosis (37.3% vs 29.9%; P = 0.041), and the mean (SD) duration of treatment was significantly different between the 2 treatment groups (52.5 [37.0] vs 27.5 [15.0] weeks; P < 0.001). Peg-IFN + RBV was associated with a higher rate of VR compared with IFN + RBV on univariate analysis (28.5% vs 17.5%; P = 0.018). Recommended doses of peg-IFN and higher-than-recommended doses of RBV were associated with an increased likelihood of VR. Higher-than-recommended doses of peg-IFN without a concomitant increase in RBV was not associated with an increased likelihood of VR. The incidences of the 3 most commonly reported AEs in the IFN + RSV group were significantly higher compared with those in the peg-IFN + RSV group: fatigue, 217 (65.8%) versus 185 (53.6%) patients (P = 0.001); depression, 147 (44.5%) versus 120 (34.8%) (P = 0.009); and anxiety, 87 (26.4%) versus 64 (18.6%) (P = 0.014). Nausea, however, was reported in a significantly higher number of patients in the peg-IFN group compared with the IFN + RBV group (74 [21.4%] vs 51 [15.5%]; P = 0.045). The frequencies of dose modification and treatment discontinuation due to AEs were similar between the 2 treatments and were similar to or less than those reported in other studies.
Conclusions:
In this retrospective data analysis of US office-based practicesconcerning HCV treatment, clinicians were observed to prescribe IFN + RBV at doses that differ from recommendations in the product information (PI), as well as prescribe the RBV component of peg-IFN + RBV at doses that differed from PI recommendations. Although patients treated with peg-IFN + RBV appeared to achieve higher VR compared with those treated with IFN + RBV in our analysis of data from clinical practice, peg-IFN + RBV was associated with lower VR rates compared with those reported in clinical studies.
doi:10.1016/j.curtheres.2005.10.005
PMCID: PMC4003805  PMID: 24790244
hepatitis C; pegylated interferon; interferon alfa-2b and ribavirin; ribavirin; dosing; outcomes
4.  IL28B, HLA-C, and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort: A Cross-Sectional Study 
PLoS Medicine  2011;8(9):e1001092.
Vijayaprakash Suppiah and colleagues show that genotyping hepatitis C patients for the IL28B, HLA-C, and KIR genes improves the ability to predict whether or not patients will respond to antiviral treatment.
Background
To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%–50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control.
Methods and Findings
We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 “G” was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10−8, 1.67–2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10−14, 2.67–5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05–2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10−6, 2.03–7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B.
Conclusions
Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 170 million people harbor long-term (chronic) infections with the hepatitis C virus (HCV) and 3–4 million people are newly infected with the virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread though contact with infected blood. Transmission can occur during medical procedures (for example, transfusions with unscreened blood or reuse of inadequately sterilized medical instruments) but in developed countries, where donated blood is routinely screened for HCV, the most common transmission route is needle-sharing among intravenous drug users. HCV infection can cause a short-lived illness characterized by tiredness and jaundice (yellow skin and eyes) but 70%–80% of newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs—pegylated interferon-alpha and ribavirin (PegIFN/R). However, PegIFN/R is expensive, causes unpleasant side-effects, and is ineffective in about half of people infected with HCV genotype 1, the commonest HCV strain.
Why Was This Study Done?
It would be extremely helpful to be able to identify which patients will respond to PegIFN/R before starting treatment. An individual's genetic make-up plays a key role in the safety and effectiveness of drugs. Thus, pharmacogenomics—the study of how genetic variants affects the body's response to drugs—has the potential to alter the clinical management of many diseases by allowing clinicians to provide individually tailored drug treatments. In 2009, scientists reported that certain single nucleotide polymorphisms (SNPs, a type of genetic variant) lying near the IL28B gene (which encodes an immune system protein made in response to viral infections) strongly influence treatment outcomes and spontaneous clearance in HCV-infected people. This discovery is now being used to predict treatment responses to PegIFN/R in clinical practice but genotyping (analysis of variants of) IL28B only correctly predicts treatment failure two-thirds of the time. Here, the researchers investigate whether genotyping two additional regions of the genome—the HLA-C and KIR gene loci—can improve the predictive value of IL28B genotyping. Human leukocyte antigen C (HLA-C) and the killer immunoglobulin-like receptors (KIRs) are interacting proteins that have been implicated in HCV viral control.
What Did the Researchers Do and Find?
The researchers genotyped 417 patients chronically infected with HCV genotype 1 whose infection had been cleared by PegIFN/R treatment, 493 patients whose infection had not responded to treatment, and 234 patients whose infection had cleared spontaneously for two HLA-C variants (C1 and C2), the presence of several KIR genes (individuals carry different combinations of KIR genes), and two IL28B SNPs (rs8099917 and rs12979860). Carriage of “variants” of either IL28B SNP was associated with absence of treatment-induced clearance and absence of spontaneous clearance. That is, these variant SNPs were found more often in patients who did not respond to treatment than in those who did respond, and more often in patients who did not have spontaneous clearance of their infection than those who did. The HLA-C C2C2 genotype (there are two copies of most genes in the genome) was also more common in patients who failed treatment than in those who responded but was not associated with spontaneous clearance. The rate of correct prediction of treatment failure increased from 66% with IL28B genotyping alone to 80% with combined IL28B and HLA-C genotyping. Finally, carriage of specific KIR genes in combination with specific HLA-C and IL28B variants was also associated with an altered HCV treatment response.
What Do These Findings Mean?
These findings show that the addition of HCL-C and KIR genotyping to IL28B genotyping improved the prediction of HCV treatment response in the patients investigated in this study. Because all these patients were European or of European descent, these findings need confirming in people of other ethnic backgrounds. They also need confirming in other groups of Europeans before being used in a clinical setting. However, the discovery that the addition of HLA-C genotyping to IL28B genotyping raises the rate of correct prediction of PegIFN/R treatment failure to 80% is extremely promising and should improve the clinical management of patients infected with HCV genotype 1. In addition, these results provide new insights into how PegIFN/R clears HCV infections that may lead to improved therapies in the future.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001092.
The World Health Organization provides detailed information about hepatitis C (in several languages)
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
The Hepatitis C Trust is a patient-led, patient-run UK charity that provides detailed information about hepatitis C and support for patients and their families; a selection of personal stories about patients' experiences with hepatitis C is available, including Phil's treatment story, which details the ups and downs of treatment with PegIFN/R
MedlinePlus provides links to further resources on hepatitis C
The Human Genome Project provides information about medicine and the new genetics, including a primer on pharmacogenomics
doi:10.1371/journal.pmed.1001092
PMCID: PMC3172251  PMID: 21931540
5.  Hematological Adverse events and Sustained Viral Response in Children Undergoing Therapy for Chronic Hepatitis C Infection 
Hepatitis Monthly  2011;11(12):968-974.
Background
Treatment of hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin (RBV) is associated with adverse events, which may affect the patient's adherence to the treatment regimen and the treatment efficacy.
Objectives
The aim of this study was to assess the sustained viral response (SVR) and interdependence between the haematological characteristics (leukocyte count, platelet count, and haemoglobin levels) in patients with chronic hepatitis C (CHC) infection during treatment with IFN and RBV.
Patients and Methods
We conducted a retrospective cohort study of 170 children with CHC infection who completed treatment with IFN-α and RBV. The children were divided into 2 groups: the first group (group I, n = 119) underwent a 48-week course of treatment with recombinant IFN α-2b (Intron A) at a dosage of 3 MU 3 times a week subcutaneously and RBV at a dosage of 15 mg/kg per day orally, and the second group (group II, n = 51) was administered pegylated IFN (peg-IFN)-α-2b (PegIntron) at a dosage of 1.5 μg/kg per week subcutaneously and RBV at a dosage of 15 mg/kg per day orally for 48 weeks. The dose of IFN was not adjusted but that of ribavirin was in 2 children from group II. Hematological growth factors and erythropoietin were not used. SVR was defined as undetectable serum HCV RNA 24 weeks after the end of treatment (study week 72). Serum HCV RNA was determined by performing polymerase chain reaction, and the HCV genotypes and hematological parameters were evaluated. Serum HCV RNA levels were analysed by descriptive statistics. Means and standard deviations were calculated for values collected at the baseline, on the 12th and 48th weeks during treatment, and after 24 weeks of untreated follow-up (study week 72).
Results
Eighty-six (50%) of the 170 patients who underwent treatment achieved SVR: 62 (51%) out of 119 children from group I and 24 (47%) out of 51 from group II. The mean serum hemoglobin levels and leukocyte and platelet counts at week 12 were significantly lower than the baseline values in both responders and non-responders from both the groups (P < 0.05). In the responders in group I, the mean levels of serum hemoglobin after 24 weeks of treatment and at the end of therapy were significantly lower than the mean levels at baseline. In the group treated with peg-IFN-α-2b and RBV (group II), the mean serum hemoglobin levels at week 12 was lower in the responders than in the non-responders (P < 0.05). The decrease in the hemoglobin levels was associated with viral response. In both the responders and non-responders from both the groups, leukocyte counts decreased during treatment, and after 12 weeks, they were more significantly lower than the baseline value. The decrease was more marked in children treated with peg-IFN-α-2b + RBV (P < 0.05). After 12 weeks of treatment, the platelet count was low in children from group II who had achieved SVR.
Conclusions
A mild decrease in hemoglobin levels and leukocyte and platelet counts during treatment with IFN and RBV in children with CHC infection may be factors responsible for SVR induction.
doi:10.5812/kowsar.1735143X.789
PMCID: PMC3282029  PMID: 22368680
Hepatitis C; Child; Therapeutics
6.  Effect of Retreatment with Interferon Alone or Interferon plus Ribavirin on Hepatitis C Virus Quasispecies Diversification in Nonresponder Patients with Chronic Hepatitis C 
Journal of Virology  1999;73(9):7241-7247.
Alpha interferon (IFN-α) treatment is effective on a long-term basis in only 15 to 25% of patients with chronic hepatitis C. The results of recent trials indicate that response rates can be significantly increased when IFN-α is given in combination with ribavirin. However, a large number of patients do not respond even to combination therapy. Nonresponsiveness to IFN is characterized by evolution of the hepatitis C virus (HCV) quasispecies. Little is known about the changes occurring within the HCV genomes when nonresponder patients are retreated with IFN or with IFN plus ribavirin. In the present study we have examined the genetic divergence of HCV quasispecies during unsuccessful retreatment with IFN or IFN plus ribavirin. Fifteen nonresponder patients with HCV-1 (4 patients with HCV-1a and 11 patients with HCV-1b) infection were studied while being retreated for 2 months (phase 1) with IFN-α (6 MU given three times a week), followed by IFN plus ribavirin or IFN alone for an additional 6 months (phase 2). HCV quasispecies diversification in the E2 hypervariable region-1 (HVR1) and in the putative NS5A IFN sensitivity determining region (ISDR) were analyzed for phase 1 and phase 2 by using the heteroduplex tracking assay and clonal frequency analysis techniques. A major finding of this study was the relatively rapid evolution of the HCV quasispecies observed in both treatment groups during the early phase 1 compared to the late phase 2 of treatment. The rate of quasispecies diversification in HVR1 was significantly higher during phase 1 versus phase 2 both in patients who received IFN plus ribavirin (P = 0.017) and in patients who received IFN alone (P = 0.05). A trend toward higher rates of quasispecies evolution in the ISDR was also observed during phase 1 in both groups, although the results did not reach statistical significance. However, the NS5A quasispecies appeared to be rather homogeneous and stable in most nonresponder patients, suggesting the presence of a single well-fit major variant, resistant to antiviral treatment, in agreement with published data which have identified an IFN sensitivity determinant region within the NS5A. During the entire 8 months of retreatment, there was no difference in the rate of fixation of mutation between patients who received combination therapy and patients who were treated with IFN alone, suggesting that ribavirin had no major effects on the evolution of the HCV quasispecies after the initial 2 months of IFN therapy.
PMCID: PMC104248  PMID: 10438811
7.  Dental problems delaying the initiation of interferon therapy for HCV-infected patients 
Virology Journal  2010;7:192.
Background
There has been little discussion about the importance of oral management and interferon (IFN) therapy, although management of the side effects of therapy for chronic hepatitis C has been documented. This study determined whether dental problems delayed the initiation of IFN therapy for hepatitis C virus (HCV)-infected patients.
Results
We analyzed 570 HCV-infected patients who were admitted to our hospital from December 2003 to June 2010 for treatment consisting of pegylated IFN (Peg-IFN) monotherapy or Peg-IFN/ribavirin combination therapy. The group comprised 274 men and 296 women with a mean age 57.2 years. Of the 570 patients, six could not commence Peg-IFN therapy, despite their admission, because of dental problems such as periodontitis, pupitis, and pericoronitis. The ages of six whose dental problems delayed the initiation of Peg-IFN ranged from 25 to 67 years, with a mean age of 47.3 ± 15.2 years. IFN therapy was deferred for 61.3 ± 47.7 days. Among the six subjects for whom IFN treatment was delayed, only one had a salivary flow that was lower than the normal value.
Conclusions
Treatment of dental infections is required before IFN therapy for HCV infection can be started. To increase the depth of understanding of oral health care, it is hoped that dentists and medical specialists in all areas will hold discussions to generate cooperation.
doi:10.1186/1743-422X-7-192
PMCID: PMC2933590  PMID: 20712912
8.  Retreatment of hepatitis C patients with pegylated interferon combined with ribavirin in non-responders to interferon plus ribavirin. Is it different in real life? 
BMC Infectious Diseases  2010;10:212.
Background
More than 50% of hepatitis C viruses (HCV)-infected patients do not respond to the classical Interferon (IFN)/Ribavirin (RBV) combination therapy. The aim of this study was to evaluate the efficacy of retreatment with Peg-Interferon alpha-2b (PEG-IFN alpha-2b) plus RBV, in patients with HCV, genotypes 1 or 3, who were non-responders to the previous standard treatment with IFN/RBV.
Methods
In the period 2005-2007, a total of 238 HCV chronic patients were non-responders to previous treatment with IFN plus RBV. Of these 130 agreed to be retreated with PEG-IFN alpha-2b and participated in this evaluation (90 with genotype 1 HCV and 40 with genotype 3 HCV). Patients were retreated at assisted IFN application hubs in compliance with the country's public health system rules. They received subcutaneous PEG-IFN alpha-2b, 1.5 μg, once weekly, associated with RBV, through the oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 kg and 1,250 mg if > 75 kg). Patients with genotype 1 HCV were retreated for over 48 weeks and patients with genotype 3 HCV for over 24 weeks. HCV-RNA was tested by polymerase chain reaction (PCR) at baseline, at week 12, at the end of the treatment, and 6 months thereafter. The predictiveness of week 12 in the development of a sustained virologic response (SVR) was also evaluated. Patients with negative HCV-RNA at week 12 were considered as early virologic responders (EVR).
Results
EVR was observed in 25% of the patients with genotype 1 HCV and in 64% of the patients genotype 3 HCV (risk = 2.075 and p-value = 0.0414). SVR was observed in 22.2% of the patients with genotype 1 HCV and in 40% with genotype 3 HCV (intention-to-treat analysis). The positive predictive value (PPV) of the HCV-RNA testing at week 12, in order to obtain the SVR, was 65% for genotype 1 and 56% for genotype 3, and the negative predictive value (NPV) was 88% for genotype 1 and 89% for genotype 3.
Conclusions
PEG-IFN alpha-2b plus weight-based ribavirin is effective in re-treating previous interferon-α plus RBV failure; 22.2% of the patients with genotype 1 HCV and 40% of patients with genotype 3 HCV achieved SVR.
doi:10.1186/1471-2334-10-212
PMCID: PMC2912909  PMID: 20646277
9.  Recombinant Interferon-Beta-1α Plus Ribavirin for the Treatment of Chronic HCV Infection: A Prospective, Randomized, Comparative Pilot Study 
Gut and Liver  2009;3(1):20-25.
Background/Aims
Interferon beta (IFN-β) has been shown to have antiviral activity, and thus could be useful in treating viral infections. Therefore, we compared the efficacy and safety of recombinant IFN-β (IFN-β-1a) plus oral ribavirin versus interferon alpha (IFN-α) plus ribavirin therapy for the treatment of chronic hepatitis C (HCV).
Methods
Twenty treatment-naïve patients were randomized into two equal-sized treatment groups. Both IFN-β-1a (44 µg) and IFN-α (3 MIU) were given subcutaneously three times a week, while ribavirin was given orally at 1,000-1,200 mg/day. Patients were treated for 24 weeks and followed for an additional 24 weeks.
Results
After 24 weeks of treatment, six (60%) and four patients (40%) in the IFN-β-1a group and IFN-α groups, respectively, achieved viral clearance. The sustained virological response (SVR) at the end of the observation period was similar in both groups (40%). However, the baseline viral load was significantly higher (p=0.034) in the IFN-β-1a group than in the IFN-α group, and there were more HCV genotype 1 patients in the IFN-β-1a group (eight versus seven). The IFN-β-1a group was associated with similar adverse events in terms of frequency and severity.
Conclusions
The SVR rate and safety profile were similar for the combination of IFN-β-1a and ribavirin and that of IFN-α and ribavirin.
doi:10.5009/gnl.2009.3.1.20
PMCID: PMC2871561  PMID: 20479896
Hepatitis C; Treatment outcome; Interferons; Prospective studies
10.  A retrospective case-control study of hepatitis C virus infection and oral lichen planus in Japan: association study with mutations in the core and NS5A region of hepatitis C virus 
BMC Gastroenterology  2012;12:31.
Background
The aims of this study were to assess the prevalence of hepatitis C virus (HCV) infection in Japanese patients with oral lichen planus and identify the impact of amino acid (aa) substitutions in the HCV core region and IFN-sensitivity-determining region (ISDR) of nonstructural protein 5A (NS5A) associated with lichen planus.
Methods
In this retrospective study, 59 patients (group 1-A) with oral lichen planus among 226 consecutive patients who visited our hospital and 85 individuals (group 1-B, controls) with normal oral mucosa were investigated for the presence of liver disease and HCV infection. Risk factors for the presence of oral lichen planus were assessed by logistic regression analysis. We compared aa substitutions in the HCV core region (70 and/or 91) and ISDR of NS5A of 12 patients with oral lichen planus (group 2-A) and 7 patients who did not have oral lichen planus (group 2-B) among patients (high viral loads, genotype 1b) who received interferon (IFN) therapy in group1-A.
Results
The prevalence of anti-HCV and HCV RNA was 67.80% (40/59) and 59.32% (35/59), respectively, in group 1-A and 31.76% (27/85) and 16.47% (14/85), respectively, in group 1-B. The prevalence of anti-HCV (P < 0.0001) and HCV RNA (P < 0.0001) in group 1-A was significantly higher than those in group 1-B. According to multivariate analysis, three factors - positivity for HCV RNA, low albumin level (< 4.0 g/dL), and history of smoking - were associated with the development of oral lichen planus. The adjusted odds ratios for these three factors were 6.58, 3.53 and 2.58, respectively, and each was statistically significant. No significant differences in viral factors, such as aa substitutions in the core region and ISDR of NS5A, were detected between the two groups (groups 2-A and -B).
Conclusion
We observed a high prevalence of HCV infection in patients with oral lichen planus. Longstanding HCV infection, hypoalbuminemia, and smoking were significant risk factors for the presence of oral lichen planus in patients. It is advisable for Japanese patients with lichen planus to be tested for HCV infection during medical examination.
doi:10.1186/1471-230X-12-31
PMCID: PMC3364160  PMID: 22490000
11.  Incidence and Severity of Acute Allograft Rejection in Liver Transplant Recipients Treated With Alfa lnterferon 
Interferon alfa-2b (IFN-α) therapy has been shown to be effective in the treatment of viral hepatitis B (HBV) or viral hepatitis C (HCV) in patients who did not undergo transplantation. However, in allograft recipients, treatment with IFN-α often leads to allograft rejection. The aim of the present study was to determine if IFN-α therapy increases the incidence or severity of acute rejection in human liver allograft recipients. One hundred five orthotopic liver transplant (OLT) recipients with HBV (n = 32), HCV (n = 58), or Non A Non B Non C (n = 15) viral infections were treated with a 6-month course of IFN-α, 5 million U subcutaneously three times a week, which began 2 to 97 months after transplantation. The mean hepatitis activity index (HAI) at the beginning of the therapy was 10.1 ± 3.0. The baseline immunosuppression was achieved by tacrolimus in 77 patients and by cyclosporine A (CyA) in 28 patients. Contemporaneous controls consisted of 132 OLT patients (100 who received tacrolimus and 32 who received CyA) who did not receive IFN-α. A retrospective analysis was performed on this group of patients. The incidence of rejection and the baseline immunosuppression were compared. All biopsies were reviewed without knowledge of clinical data and scored for HAI and for rejection activity index (RAI). The biochemical response to IFN-α was also examined. The mean baseline maintenance dose of prednisone was greater by 2 mg daily in patients who received IFN-α with tacrolimus compared with control patients who did not receive IFN-α with tacrolimus (IFN-α 5.3 ± 5.2 mg daily v controls 3.3 ± 4.9 mg daily; P ≤ .05). Similarly, the mean maintenance dose of prednisone was greater by 2.5 mg daily in patients who received IFN-α compared with controls who received CyA-based immunosuppression (IFN-α 9.8 ± 3.1 mg daily v controls 7.3 ± 3.3 mg daily; P = .01). Acute rejection episodes were detected in 10.5% (n = 11) of IFN-α–treated patients compared with 8.8% of controls for the similar time period from OLT and period of exposure to risk of rejection. Mean RAI was 2.0 ± 2.4 for the IFN-α–treated group and 2.1 ± 1.7 for controls. Rejection episodes with IFN-α treatment were mild and responded to steroid therapy. In OLT recipients, the risk of acute rejection was not increased by the introduction of IFN-α. However, in this study, patients were exposed to greater levels of immunosuppression.
PMCID: PMC3005707  PMID: 9563957
12.  Adjuvant interferon gamma in patients with pulmonary atypical Mycobacteriosis: A randomized, double-blind, placebo-controlled study 
Background
High antibiotic resistance is described in atypical Mycobacteriosis, mainly by Mycobacterium avium complex (MAC).
Methods
A randomized, double-blind, placebo-controlled clinical trial was carried out in two hospitals to evaluate the effect of interferon (IFN) gamma as immunoadjuvant to chemotherapy on patients with atypical mycobacteria lung disease. Patients received placebo or 1 × 106 IU recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to daily oral azithromycin, ciprofloxacin, ethambutol and rifampin. Sputum samples collection for direct smear observation and culture as well as clinical and thorax radiography assessments were done during treatment and one year after. Cytokines and oxidative stress determinations were carried out in peripheral blood before and after treatment.
Results
Eighteen patients were included in the IFN group and 14 received placebo. Groups were homogeneous at entry; average age was 60 years, 75% men, 84% white; MAC infection prevailed (94%). At the end of treatment, 72% of patients treated with IFN gamma were evaluated as complete responders, but only 36% in the placebo group. The difference was maintained during follow-up. A more rapid complete response was obtained in the IFN group (5 months before), with a significantly earlier improvement in respiratory symptoms and pulmonary lesions reduction. Disease-related deaths were 35.7% of the patients in the placebo group and only 11.1% in the IFN group. Three patients in the IFN group normalized their globular sedimentation rate values. Although differences in bacteriology were not significant during the treatment period, some patients in the placebo group converted again to positive during follow-up. Significant increments in serum TGF-beta and advanced oxidation protein products were observed in the placebo group but not among IFN receiving patients. Treatments were well tolerated. Flu-like symptoms predominated in the IFN gamma group. No severe events were recorded.
Conclusion
These data suggest that IFN gamma is useful and well tolerated as adjuvant therapy in patients with pulmonary atypical Mycobacteriosis, predominantly MAC. Further wider clinical trials are encouraged.
Trial registration
Current Controlled Trials ISRCTN70900209.
doi:10.1186/1471-2334-8-17
PMCID: PMC2275277  PMID: 18267006
13.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection 
PLoS Medicine  2006;3(12):e492.
Background
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.
Methods and Findings
We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).
Conclusions
These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
HIV infection impairs the immune response to HCV. Even individuals who have cleared HCV infection remain at significant risk for a second episode of HCV viremia.
Editors' Summary
Background.
Because of shared transmission routes (contaminated needles, contaminated blood products, and, to a lesser extent, unprotected sex), a large proportion of HIV-infected individuals (estimates range between 25% and 33%) are also infected with the hepatitis C virus (HCV). In most but not all individuals infected with HCV, the virus infection is chronic and causes liver disease that can eventually lead to liver failure. Disease progress is slow; it often takes decades until infected individuals develop serious liver disease. In people infected with both HCV and HIV, however, liver disease caused by HCV often appears sooner and progresses faster. As highly active antiretroviral therapy (HAART) and prophylaxis of opportunistic infections increase the life span of persons living with HIV, HCV-related liver disease has become a major cause of hospital admissions and deaths among HIV-infected persons.
Why Was This Study Done?
A sizable minority of people who are infected with HCV manage to control the virus and never get liver disease, and scientists have found that these people somehow mounted a strong immune response against the hepatitis C virus. CD4+ T cells, the very immune cells that are infected and destroyed by HIV, play an important role in this immune response. The goal of the present study was to better understand how infection with HIV compromises the specific immune response to HCV and thereby the control of HCV disease progression.
What Did the Researchers Do and Find?
The researchers recruited four groups of patients, 94 in total, all of whom were infected with HCV. Two groups comprised patients who were infected with HIV as well as HCV, with either high or undetectable levels of HCV (30 patients in each group). The two other groups included patients not infected with HIV, either with high or undetectable levels of HCV (17 patients in each group). The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4+ T cells that specifically recognize HCV. However, a quarter of these patients (six out of 25) failed to keep HCV levels down for the entire observation period of up to 2.5 years; their blood levels of HCV rose substantially, most likely due to recurrence of the previously suppressed virus (the researchers could not be certain that none of the patients had become infected again after a new exposure to HCV-contaminated blood, but there was no evidence that they had engaged in risky behavior). The rise of HCV levels in the blood of the relapsed patients coincided with a drop in overall CD4+ T cell numbers. Following relapse in these individuals, HCV did not return to undetectable levels during the study. During the same period none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.
What Do These Findings Mean?
Despite the relatively small numbers of patients, these results suggest that recurrence of HCV after initial control of the virus is more likely in people who are coinfected with HIV, and that HCV control is lost when CD4+ T cell counts fall. This is one more reason to test all HIV-positive patients for HCV coinfection. Coinfected patients, even those who seem to be controlling HCV and would not automatically receive HCV treatment, should be regularly tested for a rise of HCV levels. In addition, maintaining CD4+ T cells at a high level might be particularly important for those patients, which means that doctors might consider starting HAART therapy earlier than is generally recommended for HIV-infected individuals. Additional studies are needed to support these recommendations, however, especially as this study did not follow the patients long enough to determine the consequences of the observed loss of control of HCV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030492.
AIDS Treatment Data Network factsheet on HIV/HCV coinfection
US CDC factsheet on HIV/HCV coinfection
American Liver Foundation, information on HIV and HCV
MedlinePlus pages on HCV
doi:10.1371/journal.pmed.0030492
PMCID: PMC1705826  PMID: 17194190
14.  Innate Immune Tolerance and the Role of Kupffer Cells in Differential Responses to Interferon Therapy Among Patients With HCV Genotype 1 Infection 
Gastroenterology  2012;144(2):10.1053/j.gastro.2012.10.044.
BACKGROUND & AIMS
In patients with hepatitis C virus (HCV) infection, interferon alfa (IFN-α) alters expression of IFN-stimulated genes (ISGs), but little is understood about factors that determine outcomes of therapy. We used a systems biology approach to evaluate the acute response of patients with chronic hepatitis C to IFN-α therapy.
METHODS
We collected liver biopsy samples from 8 treatment-naïve patients with chronic HCV genotype 1 infection at baseline and 24 hours after treatment with IFN-α-2a (10 MU subcutaneously). Blood samples were collected before and up to 48 hours after administration of IFN-α-2a to measure HCV RNA levels and for gene expression analysis. Patients then received pegylated IFN-α-2a and ribavirin on day 5 of the study; therapy continued for up to 48 weeks.
RESULTS
Based on the kinetics of HCV RNA during the first 12 weeks of therapy, 2 patients were rapid virologic responders, 4 were early virologic responders, and 2 did not respond to therapy (nonresponders). Nonresponders had high pretreatment levels of ISG expression in the liver but not in peripheral blood mononuclear cells. In responders, after administration of IFN-α, intrahepatic ISG expression increased significantly from baseline and was associated with a rapid phase 1 decrease in HCV. We identified distinct hepatic expression and tissue distribution patterns of ISGs that segregated with treatment outcome. Importantly, Kupffer cells were a local source of IFN that promoted basal expression of ISG in hepatocytes of non-responders. This finding was validated in cultured THP1 human macrophages that expressed IFN-β after exposure to viable HCV 2a. When Huh7 K2040 and Huh7 L2198S hepatoma cells were incubated with IFN-α-2a, expression of ISGs peaked by 4 hours and decreased by 72 hours, associated with an increase in level of HCV RNA. This indicates that constitutive exposure to IFN causes hepatoma cells to become tolerant of ISG function.
CONCLUSIONS
In patients with chronic HCV infection, IFN production by Kupffer cells might promote innate immune tolerance, characterized by a lack of response to IFN therapy. Strategies to disrupt the virus-host interactions that induce innate immune tolerance should improve therapy.
doi:10.1053/j.gastro.2012.10.044
PMCID: PMC3822610  PMID: 23123437
PBMC; Microarray Analysis; Therapeutic Efficacy; Drug
15.  Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy 
AIM: To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNA-dependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear.
METHODS: HCV quasispecies were studied by cloning and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-α2b for 3 mo followed by IFN-α2b alone or combined IFN-R therapy for 9 additional months. Patients were categorized intro two groups based on their response to the treatments: 7 with sustained virological response (SVR) (quasispecies = 150) and 3 non-responders (NR) to IFN-R (quasispecies = 106).
RESULTS: Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispecies during therapy. Analysis of amino acids substitutions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate the two groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients.
CONCLUSION: These results suggest that detailed molecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection.
doi:10.3748/wjg.v13.i8.1195
PMCID: PMC4146993  PMID: 17451199
Hepatitis C virus; Quasispecies; NS5A region; Interferon sensitivity-determining region; V3 domain
16.  Therapy for treatment-refractory chronic hepatitis C virus genotype 1b infection: A retrospective analysis 
Background:
The most effective current therapy for hepatitis C virus (HCV) infection is the combination of pegylated interferon (peg-IFN) plus ribavirin (RBV).
Objective:
The aim of this retrospective analysis was to determine the rateof response to this therapy, and the factors affecting outcome, in patients with treatment-refractory chronic HCV genotype l b.
Methods:
The records of patients with chronic HCV infection and HCV geno-type1b who failed (nonresponse or relapse) previous treatment with standard interferon (IFN) + RSV were retrospectively analyzed for demographic data, virologic load, liver histology, biochemistry, treatment-related adverse effects (AEs), and the effects of dose reduction during treatment with peg-IFN + RBV for 48 weeks. Early virologic response (EVR) was defined as ≥2-log (copies/mL) decrease from baseline in serum HCV RNA concentration or the absence of detectable serum HCV RNA at treatment week 12. End-of-treatment response (ETR) was defined as the absence of detectable serum HCV RNA at treatment week 48. Sustained virologic response (SVR) was defined as the absence of detectable serum HCV RNA 24 weeks after treatment was discontinued. Factors affecting treatment outcome were determined using correlation analyses.
Results:
Data from the files of 17 patients (12 men, 5 women; mean [SD] age, 48 [2] years) were analyzed. EVR was achieved in 7 patients; however, viral breakthrough occurred in 2 of these patients during the treatment period, and 5 of these patients discontinued treatment because of severe treatment-related AEs (depression [1 patient] and neutropenia [4]). Seven patients achieved ETR, but HCV infection relapsed during the follow-up period. Three (18%) patients achieved SVR. Data concerning previous patterns of response to IFN + RBV therapy were available in 10 patients. Of these, 3 of 6 patients who had experienced relapse with the previous treatment achieved SVR with peg-IFN + RBV; neither of the 2 patients with nonresponse to the previous treatment achieved SVR. Major determinants of failure to reach SVR in these patients included previous nonresponder pattern, noncompliance with the therapy, and advanced-stage liver fibrosis. Tolerability was similar to that with the previous treatment.
Conclusions:
In this study in patients with chronic HCV genotype lb infectionand a history of relapse or nonresponse to standard IFN + RSV treatment, treatment with peg-IFN + RBV achieved an SVR rate of 18%. Further research is needed to determine the role of peg-IFN + RBV in the re-treatment of HCV infection.
doi:10.1016/j.curtheres.2005.10.002
PMCID: PMC4003808  PMID: 24790245
hepatitis C; treatment; nonresponders; ribavirin combination; pegylated interferon; treatment failure; retrospective
17.  Prospective Characterization of Full-Length Hepatitis C Virus NS5A Quasispecies during Induction and Combination Antiviral Therapy 
Journal of Virology  2000;74(19):9028-9038.
The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein has been controversially implicated in the inherent resistance of HCV to interferon (IFN) antiviral therapy in clinical studies. In this study, the relationship between NS5A mutations and selection pressures before and during antiviral therapy and virologic response to therapy were investigated. Full-length NS5A clones were sequenced from 20 HCV genotype 1-infected patients in a prospective, randomized clinical trial of IFN induction (daily) therapy and IFN plus ribavirin combination therapy. Pretreatment NS5A nucleotide and amino acid phylogenies did not correlate with clinical IFN responses and domains involved in NS5A functions in vitro were all well conserved before and during treatment. A consensus IFN sensitivity-determining region (ISDR237–276) sequence associated with IFN resistance was not found, although the presence of Ala245 within the ISDR was associated with nonresponse to treatment in genotype 1a-infected patients (P < 0.01). There were more mutations in the 26 amino acids downstream of the ISDR required for PKR binding in pretreatment isolates from responders versus nonresponders in both HCV-1a- and HCV-1b-infected patients (P < 0.05). In HCV-1a patients, more amino acid changes were observed in isolates from IFN-sensitive patients (P < 0.001), and the mutations appeared to be concentrated in two variable regions in the C terminus of NS5A, that corresponded to the previously described V3 region and a new variable region, 310 to 330. Selection of pretreatment minor V3 quasispecies was observed within the first 2 to 6 weeks of therapy in responders but not nonresponders, whereas the ISDR and PKR binding domains did not change in either patient response group. These data suggest that host-mediated selective pressures act primarily on the C terminus of NS5A and that NS5A can perturb or evade the IFN-induced antiviral response using sequences outside of the putative ISDR. Mechanistic studies are needed to address the role of the C terminus of NS5A in HCV replication and antiviral resistance.
PMCID: PMC102099  PMID: 10982347
18.  Interferon-γ and interleukin-4 detected in serum and saliva from patients with oral lichen planus 
Our previous salivary study had demonstrated an apparent T helper 2 (Th2)-predominance in saliva of oral lichen planus (OLP) patients and suggested a potential of salivary interleukin-4 (IL-4) as a biomarker for monitoring disease severity. To further determine the consistency of Th1/Th2 bias of OLP, this study investigated the expression profile of interferon-γ (IFN-γ) and IL-4 in serum and the relationship of the serum levels of these cytokines with their saliva partners. Sixty ethnic Chinese patients with OLP (40 of the erythematous/ulcerative form and 20 of the reticular form) were recruited for this study, with 40 age–sex-matched healthy volunteers as control group. IFN-γ and IL-4 levels in serum and paired saliva samples were screened by enzyme-linked immunosorbent assay. OLP patient showed a low-level IFN-γ but high-level IL-4 expression profile in both serum and saliva, with a lower IFN-γ/IL-4 ratio. Serum IL-4 level in the erythematous/ulcerative group was significantly higher than that in the reticular group. Serum levels of IFN-γ and IL-4 were significantly and positively correlated with their saliva partners. These results provided more evidence for Th2 cytokine-predominant immune imbalance in OLP, as well as the potential of IL-4 as the biomarker for monitoring severity of OLP.
doi:10.1038/ijos.2013.74
PMCID: PMC3967304  PMID: 24158143
oral lichen planus; saliva; serum; T helper cytokines
19.  Oral lichen planus: A retrospective study of 633 patients from Bucharest, Romania 
Objective: In this retrospective study, patients’ medical records were reviewed to investigate the profiles of 633 OLP cases in a group of Romania. Material and Methods: In this retrospective study, the following clinical data were obtained from the medical charts of patients: gender, age, clinical presentation of OLP, site affected, presence of symptoms, extraoral manifestations of lichen planus, presence of systemic diseases, and history of medications. Results: Most (78.67%) OLP patients were female and the mean age at presentation was 52 years. The white type of the disease (reticular/papular/plaque lesions) was the main form encountered in this sample (48.97%). Among patients with available hepatitis C virus test results, 9.6% were serum-positive. OLP was associated with gallbladder disease (i.e. cholecystitis, cholelithiasis) in 19% of patients. Six patients (0.95%) developed squamous cell carcinoma at a site with confirmed OLP lesions. Conclusions: To the best of our knowledge, no similar study has been conducted in a Romanian population. The present investigation revealed the predominance of OLP among middle-aged white women and the prevalence of bilateral involvement of the buccal mucosa with reticular white lesions. Anti-HCV circulating antibodies were more common in patients with OLP than in the general population and, notably, OLP was associated with gallbladder disease (cholecystitis, cholelithiasis) in 19% of patients.
Key words:Oral lichen planus, oral mucosal diseases, retrospective study.
doi:10.4317/medoral.18035
PMCID: PMC3613870  PMID: 23229244
20.  New agents for the treatment of hepatitis C in patients co-infected with HIV 
Pilot trials evaluating the efficacy and safety of the first licensed hepatitis C virus (HCV) protease inhibitors (PIs), boceprevir (BOC) and telaprevir (TVR), for the treatment of genotype 1 infection in HCV/HIV co-infected patients revealed similar results as in HCV mono-infected patients. HCV liver disease progresses more rapidly in co-infected patients, particularly with advanced immunodeficiency. Therefore, HCV treatment in HIV is of great importance. However, dual therapy with pegylated interferon (PegIFN) and ribavirin (RBV) has been associated with lower cure rates and increased toxicities in co-infected subjects, thereby limiting overall HCV therapy uptake. The availability of HCV PIs opens new perspectives for HCV cure in co-infected patients, with a 70% sustained virologic response (SVR) rate in HCV treatment-naïve patients. Despite these impressive advances, the use of the new treatment options has been low, reflecting the complex issues with modern triple HCV therapy. Indeed pill burden, adverse events (AEs), drug–drug interactions (DDIs) and high costs complicate HCV therapy in HIV. So far, studies have shown no tolerability differences in mono- and co-infected patients with the early stages of liver fibrosis. Regarding DDIs between HVC PIs and antiretroviral drugs, TVR can be safely administered with efavirenz (with dose adjustment of TVR), etravirine (ETR), rilpivirine, boosted atazanavir (ATV/r) and raltegravir (RAL), while BOC can be safely administered with ETR, RAL and potentially ATV/r for treatment-naïve patients under careful monitoring. Currently, the great number of HCV molecules under development is promising substantially improved treatment paradigms with shorter treatment durations, fewer AEs, less DDIs, once-daily administration and even interferon-free regimens. The decision to treat now with the available HCV PIs or defer therapy until the second generation of HCV direct acting antivirals become available should be based on liver fibrosis staging and fibrosis progression during follow up. More data are urgently needed regarding the efficacy of triple therapy in HIV/HCV co-infected patients who previously failed PegIFN/RBV therapy as well as in patients with more advanced fibrosis stages.
doi:10.1177/2049936113479591
PMCID: PMC4040720  PMID: 25165545
HIV; hepatitis C; DAA; pegylated interferon; ribavirin
21.  Effect of branched-chain amino acid-enriched nutritional supplementation on interferon therapy in Japanese patients with chronic hepatitis C virus infection: a retrospective study 
Virology Journal  2012;9:282.
Background
The aims of this study were to evaluate the effects of nutritional supplementation with branched-chain amino acids (BCAA) with zinc component (Aminofeel®) on adherence to and outcome of therapy in patients treated with interferon (IFN) for chronic hepatitis C and cirrhosis and to determine whether to recommend the supplement.
Methods
In this retrospective study, 51 patients who received IFN therapy were investigated among 203 consecutive patients who visited our hospital and were advised regarding the potential benefit of taking Aminofeel®. Each patient was free to choose whether to purchase and take Aminofeel®.
Results
Twenty four patients (group 1-A) took Aminofeel® during standard IFN therapy and 13 (group 1-B) did not. Low-dose, long-term IFN (maintenance) therapy, mainly peglated (Peg)-IFN alpha 2a, was administered to 14 patients who were difficult to treat, because of no effect or harmful side effects with standard IFN therapy, and who had advanced liver fibrosis. Among the 14, 11 patients (group 2-A) took Aminofeel® and 3 (group 2-B) did not. The prevalence of obesity was significantly higher (P=0.04) in group 1-A than in group 1-B. The rate of adherence to IFN therapy was higher in group 1-A (83.3%) than in group 1-B (53.8%, P=0.05). There were no significant differences between the two groups in the rates of sustained virological response (SVR) to IFN therapy. According to multivariate analysis, two factors, SVR and intake of Aminofeel®, were associated with successful adherence to IFN therapy. The adjusted odds ratios for these two factors were 13.25 and 12.59, respectively, and each was statistically significant. The SVR rate of maintenance IFN therapy was in 18.2% group 2-A and 0% in group 2-B.
Conclusion
Our data show that BCAA intake is useful for adherence to and effect of IFN therapy for patients with chronic hepatitis C. Nutritional supplementation with BCAA seems to be useful for HCV-infected patients receiving IFN therapy because it is impossible to introduce standard treatment for all patients among Japan's aging population.
doi:10.1186/1743-422X-9-282
PMCID: PMC3545893  PMID: 23173649
Branched-chain amino acids (BCAA); Interferon (IFN); Hepatitis C virus (HCV); Standard IFN therapy; Low-dose long-term IFN therapy
22.  Interleukin-18 and Gamma Interferon Production by Oral Epithelial Cells in Response to Exposure to Candida albicans or Lipopolysaccharide Stimulation  
Infection and Immunity  2002;70(12):7073-7080.
Oral candidiasis is a collective name for a group of disorders caused by the dimorphic fungus Candida albicans. Host defenses against C. albicans essentially fall into two categories: specific immune mechanisms and local oral mucosal epithelial cell defenses. Since oral epithelial cells secrete a variety of cytokines and chemokines in response to oral microorganisms and since C. albicans is closely associated with oral epithelial cells as a commensal organism, we wanted to determine whether interleukin-18 (IL-18) and gamma interferon (IFN-γ) were produced by oral epithelial cells in response to C. albicans infection and lipopolysaccharide (LPS) stimulation. Our results showed that IL-18 mRNA and protein were constitutively expressed by oral epithelial cells and were down-regulated by Candida infections but increased following LPS stimulation. Both C. albicans and LPS significantly decreased pro-IL-18 (24 kDa) levels and increased active IL-18 (18 kDa) levels. This effect was IL-1β-converting-enzyme dependent. The increase in active IL-18 protein levels promoted the production of IFN-γ by infected cells. No effect was obtained with LPS. Although produced only at an early stage, secreted IFN-γ seemed to be a preferential response by oral epithelial cells to C. albicans growth. These results provide additional evidence for the contribution of oral epithelial cells to local (direct contact) and systemic (IL-18 and IFN-γ production) defense against exogenous stimulation such as C. albicans infection or LPS stimulation.
doi:10.1128/IAI.70.12.7073-7080.2002
PMCID: PMC133048  PMID: 12438388
23.  Relationships between cellular immune responses and treatment outcomes with interferon and ribavirin in HIV/hepatitis C virus co-infection 
AIDS (London, England)  2006;20(3):345-351.
Objective
To test the hypothesis that hepatitis C virus (HCV)-specific interferon (IFN)γ immune responses are correlated with HCV virological response following treatment in subjects with HIV-1 and HCV co-infection.
Design
Immune responses were studied in a treatment trial comparing standard interferon alfa (IFN) to pegylated interferon alfa (PEG-IFN), each with ribavirin (R).
Methods
Using HCV antigens core, NS3 and NS5, and Candida, enzyme-linked immunosorbent spots on peripheral blood mononuclear cells measured IFNγ and interleukin (IL)-10 production. Immunologic, virologic and clinical variables were modeled using recursive partitioning (CART) to identify factors associated with HCV virological response at week 24 (VR) and week 72 (SVR) in 108 patients.
Results
There were no significant differences in baseline IFNγ immune responses and higher IL-10 to NS3 in subjects with VR versus non-responders. Subjects who had significant decreases in IL-10 responses at week 24 compared to baseline for NS3, NS5, or summed HCV responses were more likely to be VR. Using baseline immunological responses and clinical data in CART models, patients who were randomized to PEG-IFN/Rand had high IL-10 responses to summed HCV proteins were more likely to be VR (73%), whereas those on IFN/R who had low IFNγ responses to Candida were less likely to be VR (5%). The main correlate of SVR for genotype-1 subjects was maintenance of HCV-specific IFNγ responses from baseline to week 72.
Conclusions
In this cohort of subjects with HIV and HCV, a decrease in HCV-specific IL-10 responses and maintenance of IFNγ responses during treatment with IFN were associated with week 24 or 72 virological response.
doi:10.1097/01.aids.0000206500.16783.2e
PMCID: PMC4060610  PMID: 16439867
hepatitis C virus; interferon α; cellular immunity; interferon gamma; interleukin 10
24.  Safety and efficacy of Hansenula-derived PEGylated-interferon alpha-2a and ribavirin combination in chronic hepatitis C Egyptian children 
AIM: To investigate the safety and efficacy of a Hansenula-derived PEGylated (polyethylene glycol) interferon (IFN)-alpha-2a (Reiferon Retard) plus ribavirin customized regimen in treatment-naïve and previously treated (non-responders and relapsers) Egyptian children with chronic hepatitis C infection.
METHODS: Forty-six children with chronic hepatitis C virus (HCV) infection were selected from three tertiary pediatric hepatology centers. Clinical and laboratory evaluations were undertaken. Quantitative polymerase chain reaction (PCR) for HCV-RNA was performed before starting treatment, and again at 4, 12, 24, 48, 72 wk during treatment and 6 mo after treatment cessation. All patients were assigned to receive a weekly subcutaneous injection of PEG-IFN-alpha-2a plus daily oral ribavirin for 12 wk. Thirty-four patients were treatment-naïve and 12 had a previous treatment trial. Patients were then divided according to PCR results into two groups. Group I included patients who continued treatment on a weekly basis (7-d schedule), while group II included patients who continued treatment on a 5-d schedule. Patients from either group who were PCR-negative at week 48, but had at least one PCR-positive test during therapy, were assigned to have an extended treatment course up to 72 wk. The occurrence of adverse effects was assessed during treatment and follow up. The study was registered at www.ClinicalTrials.gov (NCT02027493).
RESULTS: Only 11 out of 46 (23.9%) patients showed a sustained virological response (SVR), two patients were responders at the end of treatment; however, they were lost to follow up at 6 mo post treatment. Breakthrough was seen in 18 (39.1%) patients, one patient (2.17%) showed relapse and 14 (30.4%) were non-responders. Male gender, short duration of infection, low viral load, mild activity, and mild fibrosis were the factors related to a better response. On the other hand, patients with high viral load and absence of fibrosis failed to respond to treatment. Before treatment, liver transaminases were elevated. After commencing treatment, they were normalized in all patients at week 4 and were maintained normal in responders till the end of treatment, while they increased again significantly in non-responders (P = 0.007 and 0.003 at week 24 and 72 respectively). The 5-d schedule did not affect the response rate (1/17 had SVR). Treatment duration (whether 48 wk or extended course to 72 wk) gave similar response rates (9/36 vs 2/8 respectively; P = 0.49). Type of previous treatment (short acting IFN vs PEG-IFN) did not affect the response to retreatment. On the other hand, SVR was significantly higher in previous relapsers than in previous non-responders (P = 0.039). Only mild reversible adverse effects were observed and children tolerated the treatment well.
CONCLUSION: Reiferon Retard plus ribavirin combined therapy was safe. Our customized regimen did not influence SVR rates. Further trials on larger numbers of patients are warranted.
doi:10.3748/wjg.v20.i16.4681
PMCID: PMC4000504  PMID: 24782620
Children; Chronic hepatitis C; Hansenula polymorpha; PEGylated interferon; Response rate; Ribavirin; Treatment
25.  Association of Oral Lichen Planus with Chronic C Hepatitis. Review of the Data in Literature 
Mædica  2014;9(1):98-103.
The relationship between chronic hepatitis C virus infection (HCV) and oral lichen planus (OLP) is a current topic in the field of oral medicine. Many studies of this association have been made over time. The geographic variation of the hepatitis C prevalence proved to be an important factor influencing the statistical results of the studies analyzing the association of the oral plan lichen with the hepatitis C virus. Approaching this issue is not to be neglected. Treatment outcomes in patients with oral lichen planus associated with chronic hepatitis C virus are often unsatisfactory compared to patients suffering from idiopathic oral lichen planus. Also, the evolution of oral lesions is often fluctuating, with repeated periods of relapse according to the degree of liver function decompensation. Background therapy for liver disease itself may influence lichen planus lesions. Thus, during therapy with interferon and ribavirin oral lesions may appear or become acute.
PMCID: PMC4268302  PMID: 25553136
hepatitis C virus; oral lichen planus

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