Role of IL-28B genetic variants in HCV-related liver disease severity in patients with different viral genotypes

Medicine: March 2018 - Volume 97 - Issue 10 - p e9782
Role of IL-28B genetic variants in HCV-related liver disease severity in patients with different viral genotypes
Huang, Ching-I MDa,b; Huang, Chung-Feng MDa,b,c; Yeh, Ming-Lun MDb,c; Lin, Yi-Hung MDb,d; Liang, Po-Cheng MDb,d; Liu, Shang-Yin Vanson PhDe; Hsieh, Meng-Hsuan MDb,c,f; Lin, Zu-Yau MD, PhDb,c; Chen, Shinn-Cherng MD, PhDb,c; Huang, Jee-Fu MD, PhDa,b,c; Chuang, Wan-Long MD, PhDa,b,c; Dai, Chia-Yen MD, PhDa,b,c,f,*; Yu, Ming-Lung MD, PhDa,b,c,*

Full Text
https://journals.lww.com/md-journal/fulltext/2018/03090/Role_of_IL_28B_genetic_variants_in_HCV_related.41.aspx

Abstract
Reports of the role of host interleukin 28B (IL-28B) genetic variants in liver disease severity in patients with chronic hepatitis C (CHC) have obtained conflicting results. The impact of IL-28B in Asian patients with different viral genotypes remains elusive. We try to elucidate the effect of IL-28B genetic variants in a large Asian cohort with different viral genotypes.

The association between the IL-28B rs8099917 genotype and liver fibrosis was investigated in 1288 patients with biopsy-proven CHC. Patients with hepatitis C virus genotype 1 (HCV-1) infection comprised 59.4% of the population. The remaining 40.6% (518 patients) did not have HCV-1 infection. Of the 1084 patients with the IL-28 genotype, 85.6% (928 patients) had the TT genotype. Univariate analysis revealed that, compared to patients without advanced liver fibrosis, patients with advanced liver fibrosis (Metavir fibrosis score 3-4) had an older age, a lower platelet count, a higher α-fetoprotein level, a higher alanine aminotransferase level, a higher incidence of diabetes, and a higher frequency of rs8099917 non-TT genotype carriage.

Logistic regression analysis revealed that factors significantly associated with advanced liver fibrosis included age (odds ratio [OR]/95% confidence interval [CI]: 1.023/1.009-1.037, P = .001), diabetes (OR/CI: 1.736/1.187-2.539, P = .004), α-fetoprotein (OR/CI: 1.007/1.002-1.012, P = .009), platelet count (OR/CI: 0.991/0.988-0.993, P < .001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.585/0.400-0.856, P = .006).

When patients were classified by viral genotype, factors that had significant independent associations with advanced liver fibrosis in patients with HCV-1 infection included diabetes (OR/CI: 2.379/1.452-3.896, P = .001), α-fetoprotein (OR/CI: 1.023/1.012-1.035, P < .001), platelet count (OR/CI: 0.99/0.987-0.994, P < .001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.529/0.328-0.854, P = .009).

In patients who had advanced liver fibrosis but not HCV-1 infection, factors that had significant independent associations with advanced liver fibrosis included age (OR/CI: 1.039/1.016-1.063, P = .001) and platelet count (OR/CI: 0.99/0.986-0.995, P < .001); additionally, IL-28B genetic variants were not associated with liver disease severity.

Unfavorable IL-28B genetic variants were associated with advanced liver disease. The genetic effect is limited to patients with HCV-1 infection.

Hepatitis C patients with certain gene type more prone to diabetes: Study

Hepatitis C patients with certain gene type more prone to diabetes: Study

The study has been accepted for publication in the coming issue of the Journal of Clinical and Translational Hepatology. 

By: Express News Service | New Delhi | Published:January 21, 2016 2:32 am

Patients with Hepatitis C who also carry a particular type of gene may be more prone to developing diabetes, a two-year study by Sir Ganga Ram Hospital has found.

The study on more than 100 Hepatitis C patients has found that in those carrying “non-CC genotype” of interleukin-28b gene, the possibility of developing diabetes is 31 per cent, compared to 13 per cent in those carrying “CC genotype” of the same gene.

The study has been accepted for publication in the coming issue of the Journal of Clinical and Translational Hepatology. Dr Anil Arora, the principal investigator of the study, said the non-CC genotypes were associated with insulin resistance. 

“There is an association between interleukin-28b gene and insulin resistance, which in turn leads to diabetes,” added Dr Arora, head of gastroenterology at Sir Ganga Ram Hospital.

Doctors studied 115 patients with Hepatitis C-related chronic liver diseases between 2012 and 2014. “When we put both the categories of the interleukin-28b gene together, diabetes prevalence was 22 per cent, which is anyway higher than the general population. 

So patients with hepatitis, irrespective of the genotype of the gene do have a higher chance of contracting diabetes. But those with the particular genotype we analysed, or patients from a particular subgroup of hepatitis C, have an even higher chance of getting the disease,” said Dr Arora. Doctors have said in the study that testing for this gene “may be useful in patients of Hepatitis C, in order to determine their likelihood of developing diabetes mellitus.” 

Recently, many epidemiological studies had shown a significant two-way association between diabetes mellitus and Hepatitis C virus infection. While many of these have shown that people with diabetes are more prone to acquire Hepatitis C, studies are now showing the correlation is true the other way round too. According to doctors, when Hepatitis C and diabetes affect patients at the same time, there is rapid progression of liver cirrhosis and a high chance of liver cancer. 

“Because of this two-way association of diabetes mellitus and HCV infection, it is advisable that all diabetics should get tested for HCV. This is especially true for those diabetics who have liver function tests abnormalities which can be an early indicator of developing insulin resistance,” said Dr Arora. 

Source

Mother To Child HCV Transmission Among Three Brothers: A Long-Term Follow-Up

Case Report
Volume 5, Number 4, April 2014, pages 227-231 

Transmission of Hepatitis C Virus From a Mother to a Child Carrying IL28B Heterozygote rs8099917 Among Three Brothers: A Long-Term Follow-Up

Takafumi Saitoa, c, Kei Mizunoa, Tomohiro Katsumia, Kyoko Tomitaa, Chikako Satoa, Kazuo Okumotoa, Yuko Nishisea, Hisayoshi Watanabea, Li Shaob, Yoshiyuki Uenoa aDepartment of Gastroenterology, Yamagata University School of Medicine, Yamagata 990-9585, Japan bPublic Health, Yamagata University School of Medicine, Yamagata 990-9585, Japan cCorresponding author: Takafumi Saito, Department of Gastroenterology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan

Manuscript accepted for publication March 4, 2014
Short title: Mother-to-Child HCV Transmission
doi: http://dx.doi.org/10.14740/jmc1736w
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Abstract
Three male children were born every 2 years by spontaneous delivery from a mother infected with hepatitis C virus (HCV) genotype 2b, and all have been followed up after birth. The viral load in the serum of the mother was high before their deliveries, and anti-HCV antibody immunoglobulin G, which is allowed to pass through placenta, was positive in the umbilical blood of all the children. Mother-to-child transmission of HCV was confirmed in the second son, who was positive for both anti-HCV antibody and serum HCV RNA when first examined 108 days after birth, but not in the other siblings. Persistent HCV genotype 2b infection with mild elevation of the serum alanine aminotransferase level has been established in the second son for more than 14 years. The interleukin 28B (IL28B) genotype (rs8099917) of the second son showed the TG heterozygote, which is unfavorable for viral clearance, and this may predict persistent HCV infection. Among the three brothers sharing the same delivery conditions with exposure to the same virus, as well as sharing the same environment after birth, HCV infection has not been consistent, and one of them possessing the TG genotype of the IL28B gene (rs8099917) has had chronic HCV infection. These cases suggest that maternal HCV transmission does not occur so often, even among multiple children who are exposed to the same HCV with a high viral load, and that this variation might be attributable to very minor events that can impact on viral exposure in the perinatal period.

Keywords: Hepatitis; HCV; Perinatal infection; Vertical infection; Interleukin 28B

Introduction
Mother-to-child transmission of hepatitis C virus (HCV) is a serious health problem, and no effective preventive vaccine has yet been developed. The mechanism and timing of mother-to-child HCV transmission are not understood, nor is the natural history of the infection in mothers and their children. The rate of HCV transmission from HCV-infected mother to child is reported to be approximately 4-10% [1-7], but the associated factors are not fully defined [8].

HCV infection leads to development of chronic hepatitis with a risk of progression to cirrhosis and liver cancer, but some individuals clear the virus spontaneously and the hepatitis resolves in a self-limiting manner in the acute phase of infection [9-11]. Recently, it has been reported that the host genetic single nucleotide polymorphism (SNP) in the region of the interleukin 28B (IL28B) gene encoding interferon-λ-3, rs12979860, is associated with spontaneous HCV clearance in adults [12, 13], and even in infants vertically infected with HCV from their mothers [14]. This SNP is in high linkage disequilibrium with rs8099917, as reported for Japanese subjects [15, 16]. Furthermore, upstream of the IL28B gene, a dinucleotide variant ss469415590 in the IFNL4 gene encoding interferon-λ-4 protein has been reported to be more strongly associated with HCV clearance, and this variant is in high linkage disequilibrium with the SNPs of IL28B [17]. Thus, these genetic markers are worth investigating further for their possible usefulness in predicting the outcome of maternal HCV infection in children.

The pattern of maternal HCV transmission in multiple children from the same mother is still unclear. There is little evidence to indicate whether mother-to-child transmission of HCV occurs evenly or unevenly in this situation. Such cases would be informative for understanding the risk of perinatal HCV infection. We have experienced three deliveries from the same HCV-monoinfected mother, and prospectively followed up the three children after birth. In all of them, the factors possibly related to maternal HCV transmission, namely, the gender of the children, birth weight, delivery conditions, a high viral titer in the mother before their births, positivity for anti-HCV antibody in their umbilical blood and their environment after birth were uniform.

Here, we report the results of HCV transmission in these three children born from the same mother infected with HCV, with special reference to both the natural course of HCV infection in the children and their genotypes of IL28B (rs8099917) and IFNL4 (ss469415590) associated with the outcome of infection.

Case Report
The mother has been followed up for hepatitis C at our hospital for 18 years. The long-term course of her HCV infection is shown in Fig. 1. The serum alanine aminotransferase (ALT) level was low, at under 30 U/L, during the follow-up period except for two occasions when it exceeded 30 U/L just after delivery of the first and second sons. She had been infected with HCV genotype 2b, and the viral load was always high before she received antiviral therapy. Both hepatitis B surface antigen and anti-immunodeficiency virus antibody were negative in her serum. Six years after the third delivery, she received antiviral therapy with pegylated interferon plus ribavirin for chronic hepatitis C according to the Japanese standard protocol [18], and the therapy was successful in achieving a sustained virologic response.

Figure 1. Clinical course and serum alanine aminotransferase (ALT) levels in the mother with chronic HCV genotype 2b infection. Positivity and negativity for serum HCV RNA are represented as plus (+) and minus (-), respectively. PegIFN/RBV: pegylated interferon plus ribavirin treatment.

The characteristics of the three children are summarized in Table 1 below.

All were boys who were born by normal spontaneous delivery 40 weeks after the start of pregnancy. All were healthy and their birth weight was almost the same, at approximately 3,400 g. Nothing in their history suggested any concern about contamination with HCV during their perinatal periods, namely, wounds, surgery or transfusion of blood products. Anti-HCV antibody in the umbilical blood was tested for at birth, and it was positive in all of them. The first and third sons had no evidence of HCV infection because neither anti-HCV antibody nor HCV RNA in serum was positive after birth. However, the second son was confirmed to be infected with HCV 108 days after the delivery showing positivity for both anti-HCV antibody and HCV RNA in serum by the first postnatal assay. HCV transmission to this child resulted in persistent infection. The long-term follow-up and clinical course of this HCV-infected child are shown in Fig. 2. The serum ALT level had been low, at under 30 U/L, for approximately the first 2 years after birth, but thereafter fluctuated above and below 30 U/L until approximately 14 years of age. The HCV genotype of this child was 2b, which was the same as the mother’s, and the high-level viremia has continued during the follow-up period. Although the factors possibly influencing maternal HCV transmission, namely, gender, birth weight, delivery conditions, the mother’s high viral titer and positivity for anti-HCV antibody in the umbilical blood, were the same among the three siblings, HCV transmission from the mother occurred only in the second child. The genetic polymorphisms of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) associated with spontaneous viral clearance were examined after obtaining written informed consent from their mother. The genotypes of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) in the second son, in whom persistent HCV infection had become established, were TG and ΔG/TT, respectively. Those in the other children who were not infected with HCV varied, being TG and ΔG/TT in the first child, and TT and TT/TT in the third child. 

Table 1. Characteristics of Children Born From the HCV-Infected Mother
 

First child Second child Third child Sex Male Male Male Delivery NSD (39 weeks) NSD (40 weeks) NSD (40 weeks) Body weight at birth 3,364 g 3,492 g 3,400 g HCV RNA in mother’s serum before birth 8.2 Meq/mL* 6.0 log IU/mL** 40.0 Meq/mL* Anti-HCV antibody in umbilical blood Positive (CI > 5.0) Positive (CI > 5.0) Positive (CI > 5.0) HCV RNA in umbilical blood n.t. < 0.5 Meq/mL* n.t. Anti-HCV antibody in serum after birth Negative Positive (CI > 5.0) Negative HCV RNA in serum after birth Negative*** Positive*** Negative*** Persistent HCV viremia (period) Not applicable 15 years Not applicable IL28B polymorphism (rs8099917) TG TG TT IFNL4 polymorphism (ss469415590) ΔG/TT ΔG/TT TT/TT

NSD: normal spontaneous delivery; n.t.: not tested; CI: cutoff index. **This assay was done using the preserved sample. HCV RNA was measured by *branched DNA assay, **real time PCR, ***qualitative PCR.

 

Figure 2. Long-term follow-up of serum alanine aminotransferase (ALT) levels in the second child with maternal HCV genotype 2b infection. Positivity for serum HCV RNA is represented as plus (+).

Discussion
In this study, we observed different outcomes of HCV transmission among three brothers who had been exposed to the same HCV strain from the mother during the perinatal period. Interestingly, maternal HCV genotype 2b transmission did not occur evenly in these three siblings, despite the fact that all had the same HCV exposure as well as upbringing environment, and only the second child was infected with HCV genotype 2b. This HCV transmission led to persistent infection in this child, in whom the genotypes of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) were TG and ΔG/TT, respectively, which are unfavorable for spontaneous viral clearance after the establishment of infection [13, 19].

It is still unclear how mother-to-child HCV transmission occurs in the perinatal period, and our present findings may help to shed some light on the route of infection. During the perinatal period, there are two possible major routes of HCV transmission from mother to child: placental infection and birth canal infection. Placental infection results from active transport of virus from mother to child, or from micro-transfusion of virus due to placental membrane damage. In all of the three brothers, blood exchange between the fetus and the mother through the placenta had been good, because anti-HCV antibody (immunoglobulin G) had been transferred to all fetuses and was detected in the umbilical blood at birth in all cases. However, only the second child had been infected with HCV. Negativity for HCV RNA in the umbilical blood of this child was different from the viral titer in the serum of his mother, which indicated a very high level of HCV RNA, as shown in Table 1. Thus placental infection by active transport of HCV from mother to fetus appeared to have been negligible. Placental membrane damage possibly induced by a small wound that goes unnoticed at delivery may result in maternal HCV infection. In cases of twin delivery, HCV transmission is more likely to affect the second child because possible partial placental separation upon delivery of the first baby increases the chance of exposing the second child to maternal blood [20]. Otherwise, any small wound in child, such as on the skin or in the mucosa of the oral cavity, or the bulbar conjunctiva, may allow micro-transfusion of HCV from mother to a child, and this may result in maternal HCV transmission in the birth canal. After birth, the present three brothers were brought up in the same environment, and were breast-fed. This kind of background carries little risk of HCV infection [21]. These findings suggest that maternal HCV transmission does not usually occur in the perinatal period, with only rare exceptions due to accidental exposure such as minor placental damage or micro-wounds in the child. The prevalence of maternal HCV infection seems to be relatively low even among children exposed to the same virus, although serologic tests for HCV in children should be carefully conducted during follow-up.

Most adults with HCV infection fail to clear the virus and develop chronic hepatitis, but some are known to show resolution of the infection in a self-limiting manner. The rate of spontaneous viral clearance in the acute phase of infection is reported to be approximately 15-40% of all HCV-infected adults [9-11], and a systematic review of 31 studies has estimated this rate to be 26% [11]. In a recent genome-wide association study, the SNPs in the region of the IL28B gene encoding interferon-λ-3 were shown to be associated with the virologic response of HCV to antiviral therapy [15, 22]. Patients carrying an IL28B homozygote for the major alleles of rs12979860 (CC genotype) [22] or rs8099917 (TT genotype) [15] show a greater propensity for achieving a sustained virologic response to pegylated interferon-α and ribavirin therapy than those carrying an IL28B heterozygote or homozygote for its minor allele. This SNP (rs12979860) also influences the outcome of HCV infection in the context of natural history; the CC genotype of rs12979860, which is in high linkage disequilibrium with the TT genotype of rs8099917, enhances the resolution of HCV infection with spontaneous clearance [12, 13]. Furthermore, upstream of the IL28B gene, a dinucleotide variant ss469415590 (TT or ΔG) has been reported to be more strongly associated with HCV clearance in individuals of African ancestry than the SNP of IL28B (rs12979860) [17].

The genotype of IL28B is also associated with the outcome of infection in maternal HCV transmission; self-limiting hepatitis or persistent hepatitis has been reported in a child infected with HCV genotype 1 during the perinatal period [14]. The three children in the present report were checked for the SNPs of both the IL28B (rs8099917) and IFNL4 (ss469415590) genes, and the second son in whom HCV genotype 2b infection had been established and led to persistent infection with mild fluctuation of the ALT levels was found to carry the TG (rs8099917) type and ΔG/TT (ss469415590) type in the IL28B and IFNL4 genes, respectively. Thus the SNPs in these two genes predicted the outcome of infection in the second son with chronic HCV genotype 2b infection.

In conclusion, our present findings suggest that the chance of maternal HCV transmission is not so high even in multiple children exposed to the same HCV strain with a high viral load, and that maternal HCV transmission might be attributable to very minor events that can potentially result in viral exposure during the perinatal period. Here, the multiple deliveries did not largely affect the serum levels of ALT and HCV RNA in the mother. The genotype defined by SNPs in the IL28B gene (rs8099917) and the IFNL4 gene (ss469415590) was able to predict the development of persistent infection in the child with established maternal HCV genotype 2b transmission.

Conflict of Interest
The authors have no conflict of interest.

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Digital Object Identifier (DOI): http://dx.doi.org/10.14740/jmc1736w
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Healio: Maternal transmission cause of HCV in children

Maternal transmission cause of HCV in children

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Andriulli A. J Hepatol. 2013;doi:10.1016/j.jhep.2013.07.040.

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IL-28B Polymorphisms and the Response to Antiviral Therapy in HCV Genotype 2 and 3 Varies by Ethnicity

 

Journal of Viral Hepatitis

IL-28B Polymorphisms and the Response to Antiviral Therapy in HCV Genotype 2 and 3 Varies by Ethnicity

A Meta-Analysis

A. S. Rangnekar, R. J. Fontana

Disclosures

J Viral Hepat. 2013;20(6):377-384.

Abstract
Studies of IL-28B genotype in patients with hepatitis C virus (HCV) genotype 2/3 infection have yielded conflicting results. The aim of this meta-analysis was to obtain a pooled odds ratio (OR) of the impact of IL-28B genotype on achieving sustained virologic response (SVR) in patients with HCV genotype 2/3 infection treated with pegIFN and ribavirin. A meta-analysis with a random effects model was performed, and study heterogeneity and publication bias were assessed. Forty-three percent of the Caucasians (11 studies) and 86% of Asians (five studies) had the favourable IL-28B genotype. In Caucasians, the pooled OR of SVR with the favourable IL-28B genotype was 1.36 (95%CI: 0.98–1.88, P = 0.07) in all patients and 1.55 (95%CI: 1.10–2.18, P = 0.01) in patients treated with pegIFN and ribavirin for ≥24 weeks. In Asians, the pooled OR of SVR in patients with the favourable IL-28B genotype was 1.99 (95%CI: 0.94–4.25, P = 0.07). The favourable IL-28B genotype was also significantly associated with rapid virologic response (RVR) in both groups (Caucasians: OR: 1.82, 95%CI: 1.12–2.96, P = 0.02; Asians: 2.39, 95%CI: 1.39–4.11, P = 0.002), as well as the likelihood of an SVR in a subgroup of 350 Caucasian patients without an RVR (OR: 3.29, 95%CI: 1.67–6.51, P = 0.001). The favourable IL-28B genotype is a statistically significant predictor of SVR and RVR in Caucasian patients treated with pegIFN and ribavirin for 24 weeks. In contrast, the favourable IL-28B genotype is associated with RVR, but not SVR in Asian HCV genotype 2 patients.

Introduction
A single nucleotide polymorphism (SNP) upstream of the interleukin 28B (IL-28B) gene is associated with hepatic responsiveness to interferon therapy in hepatitis C virus (HCV) genotype 1 patients.^[1] The highly variable prevalence of the favourable IL-28B genotype in patients of varying ethnicity, in part, explains differences in the observed sustained virologic response (SVR) rates. Although other host, viral and treatment factors may influence a patient's chance of SVR, the favourable IL-28B genotype is the single most important pretreatment predictor of achieving SVR with peginterferon (pegIFN) and ribavirin therapy in genotype 1 patients.^[2] In contrast, the association of IL-28B and SVR in patients with HCV genotype 2/3 infection remains unclear.^[3–5]
                       
Although patients with HCV genotype 2/3 are more responsive to pegIFN and ribavirin, up to 30% of treated patients will not achieve SVR.^[6] Furthermore, the new direct acting antiviral agents (DAAs), boceprevir and telaprevir, are not approved for the use in patients with HCV genotype 2/3 infection.^[7] As such, pegIFN and ribavirin remain the only currently approved treatment for these patients. This meta-analysis was undertaken to better quantify the effect of the favourable IL-28B genotype on achieving SVR after treatment with pegIFN and ribavirin in patients with chronic HCV genotype 2/3 infection. In addition, the effect of IL-28B on achieving a week 4 rapid virologic response (RVR) as well as the impact of patient ethnicity on SVR was evaluated.

Materials and Methods
Literature Search

A search of the MEDLINE, PUBMED and EMBASE computer databases was performed of manuscripts published between January 2000 and January 2012, using the text words IL-28B, IL28B, IL28 and interleukin 28. Additional electronic and manual searches of abstracts presented at the American Association for the Study of Liver Diseases and American Gastroenterological Association meetings were undertaken from 2007 to 2012. Finally, consultation with expert hepatologists and recursive manual searches of references from published studies were performed.

Study Selection Criteria
Criteria for study inclusion were as follows: (i) published studies of IL-28B genotyping in adults with HCV genotype 2 or 3 infection; (ii) treatment with pegIFN and ribavirin and (iii) a reported outcome of SVR. All published studies were included regardless of sample size, but studies published solely as abstracts were excluded due to a lack of extractable data for SVR stratified by IL-28B genotype. The following exclusion criteria were applied: (i) human immunodeficiency virus (HIV) co-infection, (ii) prior liver transplantation, (iii) use of DAAs and (iv) use of IL-28B SNPs other than rs12979860 or rs8099917. After reviewing all citations identified in the literature search, two investigators (AS, RF) independently applied these selection criteria and extracted data. Any disagreements were resolved by consensus.

Data Extraction
All eligible studies were reviewed in an independent and duplicate manner by both investigators (AS, RF). For each study, the following data were collected: (i) Study: year, location, design, publication status; (ii) Patient factors: number, mean age, baseline serum aspartate aminotransferase (AST), baseline alanine aminotransferase (ALT), body mass index (BMI) and percentage with diabetes mellitus, male gender, treatment naïve and HIV co-infection; (iii) HCV factors: HCV genotype, baseline HCV RNA level, number of patients achieving RVR and SVR; (iv) Treatment factors: duration of pegIFN and ribavirin, type of pegIFN, dose reduction of antiviral medications, use of growth factors; and (v) IL-28B: IL-28B SNP tested and number with each IL-28B genotype who achieved RVR and SVR. Discrepancies in data extraction were resolved by discussion between the investigators.

IL-28B Testing
The two IL-28B SNPs reported in the individual studies were rs12979860 and rs8099917. The favourable genotype for rs12979860 is CC, while the unfavourable genotypes are CT and TT. The favourable genotype for rs8099917 is TT, while the unfavourable genotypes are TG and GG.

Primary Outcome
The primary outcome measure was achievement of SVR after pegIFN and ribavirin treatment, defined as undetectable serum HCV RNA by polymerase chain reaction (PCR) testing 24 weeks after treatment.

Secondary Outcome
A secondary outcome measure was achievement of RVR with pegIFN and ribavirin treatment, defined as an undetectable serum HCV RNA at week 4.

Quality Assessment
Study quality was assessed using an 8-item scoring system based on previously validated tools that focused on study design, population homogeneity and potential study biases.^[8,9] High quality was defined by a score of ≥6 (Table 2).

Statistical Analysis
The estimate of effect was a pooled odds ratio (OR) determined using the DerSimonian and Laird method for a random effects model. Study heterogeneity was assessed by the I ² test, with I ² > 50% suggesting substantial heterogeneity. Publication bias was assessed through the Harbord and Peters tests. Influence analysis was performed to determine whether a single study exerted undue influence. Data from the included studies were analysed separately by patient race. Sensitivity and subgroup analyses were performed based on treatment algorithm, prior treatment and study quality score. All statistics were computed using STATA 11.0 (StataCorp LP, College Station, TX, USA).

Results
An initial search revealed 308 studies of IL-28B among which 88 specifically evaluated virologic outcomes in treated patients An additional 63 studies were excluded due to the inclusion of previously treated patients, acute HCV infection, use of alternative IL-28B SNPs, use of DAAs, inclusion of liver transplant recipients, combined ethnicities or nongenotype 2/3 patients. Of the remaining 25 studies, nine were excluded due to redundant study populations, HIV co-infection or use of alternative treatment regimens, leaving 16 studies in the current analysis (Fig. 1).'

Caucasians With HCV Genotype 2/3

SVR Outcome.There were 11 studies of Caucasians with HCV genotype 2/3.^[3,10–19] Among 1599 patients, 43% had the favourable IL-28B genotype CC at rs12979860 (Table 1). Overall, 83% of patients with the favourable IL-28B genotype achieved SVR as compared to 78% of patients with the unfavourable genotype, with a pooled OR of 1.36 (95%CI: 0.98–1.88, P = 0.07) with low heterogeneity between studies (I ² = 29%). In a subgroup analysis of eight studies that included only treatment naïve patients, the pooled OR of SVR was 1.21 (95%CI: 0.85–1.74, P = 0.29). Among the eight studies with pegIFN and ribavirin treatment for at least 24 weeks, the pooled OR of SVR was 1.55 (95%CI: 1.10–2.18, P = 0.01) as compared to 1.17 (95%CI: 0.53–2.58, P = 0.70) in the studies with variable duration treatment regimens. Among the four studies that used a ribavirin dose ≥800 mg/day for at least 24 weeks, the pooled OR of SVR was 1.02 (95%CI: 0.55–1.92, P = 0.95). The pooled OR was 1.49 (95%CI: 1.02–2.19, P = 0.04) in the six high-quality studies vs 1.33 (95%CI: 0.72–2.43, P = 0.36) in the five low-quality studies (Table 2).

RVR Outcome.
Six studies reported RVR data in 1265 Caucasian patients of which 42% had the favourable IL-28B genotype. Seventy-seven percent of patients with the favourable IL-28B achieved RVR as compared to 65% of patients with the unfavourable genotype, with a pooled OR of 1.82 (95%CI: 1.12–2.96, P = 0.02) and moderate heterogeneity between studies (I ² = 69%).
Among 350 patients who achieved RVR in three studies, 89% of 142 patients with the favourable IL-28B genotype and 85% of 208 patients with the unfavourable IL-28B genotype also achieved SVR (pooled OR: 1.37, 95%CI: 0.71–2.67, P = 0.35). In contrast, among 184 patients who did not achieve RVR, 78% of 68 patients with the favourable IL-28B and 50% of the 116 with the unfavourable IL-28B genotype achieved SVR (pooled OR: 3.29, 95%CI: 1.67–6.51, P = 0.001).

Asians With HCV Genotype 2

SVR Outcome.
There were five studies^[20–24] of 833 Asian patients with HCV genotype 2 infection, in which 86% had the favourable IL-28B genotype. Overall, 86% of patients with the favourable IL-28B genotype achieved SVR, while 75% of patients with the unfavourable IL-28B genotype achieved SVR with a pooled OR of 1.99 (95%CI: 0.94–4.25, P = 0.07). There was low to moderate heterogeneity between studies (I ² = 44%). In a subgroup analysis of the two studies that explicitly included only treatment naïve patients, the pooled OR of SVR was 1.54 (95%CI: 0.81–2.93, P = 0.18). Among the four low-quality studies, the pooled OR was 2.22 (95%CI: 01.14–4.35, P = 0.02).

RVR Outcome. In the two studies reporting RVR data, 88% of the 594 patients had the favourable IL-28B genotype. Eighty-two percent of patients with the favourable IL-28B genotype and 62% of patients with the unfavourable genotype achieved RVR, with a pooled OR of RVR of 2.39 (95%CI: 1.39–4.11, P = 0.002).

Pooled Analysis
After combining the 16 studies with 2432 patients, the pooled OR of SVR in patients with the favourable IL-28B genotype was 1.48 (95%CI: 1.09–2.02, P = 0.01). There was low heterogeneity between studies (I ² = 34%). The pooled OR was 1.27 (95%CI: 0.95–1.69, P = 0.11) in the 10 studies with only treatment naïve patients and 1.44 (95%CI: 0.98–2.11, P = 0.06) among the seven high-quality studies. There was no evidence of publication bias by the Harbord or Peters tests (P = 0.69 and P = 0.33, respectively).

Discussion

While IL-28B genotyping has an important role in HCV genotype 1 patients treated with pegIFN and ribavirin, its value in HCV patients with genotype 2/3 remains less clear.^[2] This meta-analysis demonstrates that the favourable IL-28B genotype is a significant predictor of SVR in Caucasian patients with HCV genotype 2/3 treated with pegIFN and ribavirin for 24 weeks. Additionally, IL-28B genotype may be predictive of SVR in Asian patients with HCV genotype 2, although the pooled OR of SVR did not reach statistical significance perhaps due to inadequate sample size (Fig. 2).

Our results also suggest that the favourable IL-28B genotype increases the odds of achieving RVR in Caucasian and Asian patients with HCV genotype 2/3 infection, a finding similar to that reported in HCV genotype 1 patients.^[2] Furthermore, the results of this study demonstrate that IL-28B genotype may be helpful in stratifying the odds of SVR in patients with HCV genotype 2/3 who do not achieve RVR. Prior data suggest that HCV genotype 2/3 patients with low viral load who achieve RVR may be candidates for a shortened duration of therapy to 12–16 weeks.^[25,26] However, it is unclear whether the favourable IL-28B genotype can be used to further identify patients from this group who are more likely to achieve SVR and/or are at lower risk of relapse. Individual studies have not found an association between IL-28B genotype and SVR rates in patients treated for <24 weeks after achieving RVR, but they may be under-powered.^[13,19] Therefore, IL-28B testing may play an important role in counselling individual patients that are receiving antiviral therapy and particularly in those experiencing side effects who do not achieve RVR.

In the era of DAAs, IL-28B testing in HCV genotype 1 patients may be limited to specific populations in which DAAs are not yet approved, such as in those with HIV co-infection.^[2] In contrast, pegIFN and ribavirin are the only currently approved agents for HCV genotype 2/3 infection. An improved ability to predict SVR may be particularly important for patients intolerant to this regimen, but the absolute difference in response rates in those with and without the favourable IL28-B genotype is small.

In contrast to our results, another recent meta-analysis of IL-28B testing and SVR in patients of combined HCV genotypes reports a statistically significant pooled OR of SVR in Asians with HCV genotype 2 infection,^[5] a finding likely due to the inclusion of only two Asian studies. Our own subgroup analysis of five Asian studies identified a strong trend which does not reach statistical significance. The meta-analysis by Chen et al. also demonstrates a lack of association between the favourable IL-28B genotype and SVR in Caucasian patients with HCV genotype 2/3, although only five studies were included. Assessing the role of IL-28B testing in nonCaucasian patients with HCV genotype 2/3 was limited in our study. Among the five pooled Asian studies, two explicitly included some treatment-experienced patients who may have reduced the impact of IL-28B genotyping in predicting SVR. In addition, there were no studies of HCV genotype 2/3 African American patients, a group with traditionally lower response to interferon. However, a substantially lower proportion of African Americans are infected with HCV genotype 2/3 in the general US population compared to Caucasians (i.e. 5% vs 20–30%).^[27,28] Because of the lack of stratification by HCV genotype in many studies, we were unable to determine whether IL-28B genotype has greater utility in patients with HCV genotype 2 vs 3. However, this issue is worthy of further study because HCV genotype 3 patients with a high baseline HCV RNA level are more prone to relapse after a 24-week course of treatment compared to those with HCV genotype 3 and low viral load or HCV genotype 2 infection.^[29] Finally, how IL-28B testing fits in with other known pretreatment predictors of SVR remains unknown.

In conclusion, this meta-analysis demonstrates that the favourable IL-28B genotype is significantly associated with SVR in Caucasian patients with HCV genotype 2/3 infection treated with pegIFN and ribavirin for 24 weeks. However, the magnitude of the absolute difference in SVR rates (83% vs 78%) is small and may not influence the decision to initiate treatment. In addition, the favourable IL-28B genotype is associated with RVR as well as SVR in patients who do not achieve RVR, and this information may prove useful to clinicians when counselling individual patients during therapy.

Abstract and Introduction

Materials and Methods

Results

Discussion

EASL- MK-5172 : New Drug Holds Promise in Hepatitis C

New Drug Holds Promise in Hepatitis C

By Michael Smith, North American Correspondent, MedPage Today
Published: April 28, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM -- An investigational protease inhibitor for hepatitis C (HCV) achieved high response rates in treatment-naive patients when given in what one expert called an "old-fashioned" regimen.

Action Points

This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

An investigational protease inhibitor (MK-5172) for hepatitis C achieved higher response rates than treatment with an approved protease inhibitor, boceprevir, in treatment-naive patients who also received pegylated interferon and ribavirin.

Point out that only 7% of patients stopped therapy owing to adverse events in the combined MK-5172 arms compared with 14% in the boceprevir arm.

The drug (MK-5172) rendered the virus undetectable 24 weeks after the end of therapy in almost 90% of patients with the difficult-to-treat HCV genotype 1, according to Michael Manns, MD, of Hannover Medical School in Hannover, Germany.

In contrast, treatment with an approved protease inhibitor, boceprevir (Victrelis), led to an SVR24 in just 54%, Manns reported at the meeting of the European Association for the Study of the Liver (EASL).

But both drugs were combined with pegylated interferon and ribavirin, medications that are widely regarded as likely to fade from practice as a range of investigational direct-acting agents reaches the clinic.

The direct-acting agents, such as boceprevir and MK-5172, attack elements of the virus, in contrast to interferon and ribavirin, which respectively boost the immune system and target general viral replication.

Both have a range of unpleasant side effects and interferon in particular is seen as both difficult to tolerate and dangerous to use.

MK-5172 "is a very good drug," commented Alessio Aghemo, MD, of the University of Milan in Italy, who was not involved with the study but who moderated the EASL session at which it was presented.

But he told MedPage Today that clinicians and researchers are withholding judgment until it is tested without interferon and perhaps without ribavirin.

"The SVR rates are high with (interferon and ribavirin) but it's an old-fashioned regimen," he said. "It needs to go into an interferon-free regimen."

The study, Manns reported, included 332 treatment-naïve patients with genotype 1 virus and without cirrhosis. They were randomly assigned to one of four doses (100, 200, 400, or 800 mg) of MK-5172 or to boceprevir as a control. All patients also received pegylated interferon, and ribavirin for durations that varied according to early treatment response.

Manns presented data on the proportion of patients in each arm who reached SVR24 or who had undetectable virus at their last visit if that occurred before they completed 24 weeks after the end of therapy.

When the data were compiled in March, 311 patients had either reached the 24-week mark or had dropped out of the study before then, but all patients had completed treatment.

Analysis showed that the SVR24 rates in the MK-5172 arms ranged from 86% to 92%, compared with 54% in the boceprevir arm.

When the researcher added those who had not reached the 24-week mark, but who had undetectable virus at their last study visit, the rates ranged from 92% to 99% for MK-5172 and rose to 67% in the boceprevir arm.

Interestingly, there was little variation when the researchers stratified patients by polymorphisms of the IL28B gene, which predicts response to interferon, although the favorable CC allele tended to yield slightly better response rates numerically.

Manns noted that some patients getting higher doses of MK-5172 (400 and 800 mg ) were "down-dosed" to 100 mg daily, which will be the dose used in future studies.

There were no deaths on the study and the rates of serious adverse events were similar – 9% in the combined MK-5172 arms and 8% in the boceprevir arm, Manns said. Adverse events included gastrointestinal problems, rash, and anemia.

Only 7% of patients stopped therapy owing to adverse events in the combined MK-5172 arms compared with 14% in the boceprevir arm.

A total of 26 patients had bilirubin elevations, possibly because MK-5172 inhibitors some transporter molecules and enzymes, he said. The elevations mostly occurred early and were not associated with decreases in hemoglobin.

In general, the drug was well tolerated but the investigators noted dose-related elevations in liver enzymes, he said.

The study was supported by Merck. Manns reported financial links with the company, as well as with Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche, Idenix, and Valeant.

Aghemo reported financial links with Roche, Gilead, Jannsen, and Merck.

Primary source: EASL 2013
Source reference:
Manns M, et al. "High Sustained Viral Response at 12- and 24-Week Follow-Up of MK-5172 with Pegylated Interferon Alfa-2B and Ribavirin (PR) in HCV Genotype Treatment-Naive Non-Cirrhotic Patients" EASL 2013;abstract 66.

EASL Coverage @ MedPage Today

Updates

Triple Therapy Can Help in Advanced Hep C
4/28/2013   
AMSTERDAM -- About 40% of people with advanced hepatitis C (HCV) can benefit from triple therapy even if they have cirrhosis and previous treatment failures, a researcher said here.
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Shunt Correction Eases Hepatic Encephalopathy

4/28/2013

AMSTERDAM -- Elimination of spontaneous liver shunts, or reducing the size of surgically placed shunts, is an effective treatment for hepatic encephalopathy in cirrhotic patients, researchers said here. 

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Read more @ MedPage Today

Slides @ NATAP EASL Coverage @ NATAP

High Sustained Viral Response of MK-5172 with Pegylated Interferon Alfa-2b and Ribavirin in HCV Genotype 1 Treatment-Naive Non-Cirrhotic Patients -

EASL: New Data Showed High Viral Cure Rates with 12 and 24 Wks of Telaprevir Combination Among People with Geno 1 Hepatitis C Who Have the IL28B CC Genotype

Vertex Announces New Data that Showed High Viral Cure Rates with a Total of 12 and 24 Weeks of Telaprevir Combination Treatment Among People with Genotype 1 Hepatitis C Who Have the IL28B CC Genotype

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- Interim analysis of the Phase 3b CONCISE study showed SVR12 rates of 87 percent with 12 total weeks of treatment and 97 percent with 24 total weeks of treatment among people who achieved RVR and completed 12 weeks of treatment -
   
AMSTERDAM--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced new data from an interim analysis of the exploratory global Phase 3b CONCISE study evaluating the potential to shorten total treatment with telaprevir combination therapy to 12 weeks in certain people with genotype 1 chronic hepatitis C virus (HCV) infection who have the IL28B CC genotype. In the CONCISE trial, telaprevir was administered twice daily in combination with pegylated-interferon and ribavirin. Of the 239 people in the study, 159 people completed 12 weeks of telaprevir combination treatment and had undetectable hepatitis C virus at week four of treatment (rapid viral response, or RVR) and were eligible to be randomized. One hundred seven¹ people were randomized to receive no further treatment and 52 people were randomized to receive an additional 12 weeks of treatment with pegylated-interferon and ribavirin alone, for a total of 24 weeks of treatment. In the 12-week total treatment group, of the 85 people with data available at the time of the interim analysis, 87 percent (74/85) had undetectable hepatitis C virus 12 weeks after the end of treatment (SVR12). In the 24-week treatment group, of the 30 people with data available at the time of the interim analysis, 97 percent (29/30) achieved SVR12.
   
This study includes people with genotype 1 chronic HCV who were new to treatment or who had relapsed after at least one prior course of treatment with pegylated-interferon and ribavirin alone. Approximately one-third of people with hepatitis C have the ‘CC' genotype, which has been associated with higher sustained viral response (SVR, or viral cure) rates and faster response to interferon-based treatment. The safety profile of telaprevir combination therapy observed in the CONCISE study through the time of the interim analysis was similar to that seen in previously reported clinical trials. The interim results of this study will be presented at the 48th Annual Meeting of the European Association for the Study of the Liver (EASL) in Amsterdam, Netherlands, April 24 to 28, 2013 (poster #881).
   
Telaprevir is approved for use in combination with pegylated-interferon and ribavirin by the U.S. Food and Drug Administration (FDA) and Health Canada under the brand name INCIVEK^® (telaprevir) tablets for people with genotype 1 chronic HCV infection with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK's approved dosing schedule is two 375mg tablets three times daily, and it is given for 12 weeks in combination with pegylated-interferon and ribavirin. After the first 12 weeks, all patients stop receiving INCIVEK and continue treatment with pegylated-interferon and ribavirin alone for an additional 12 weeks or 36 weeks.
   
About CONCISE
CONCISE is a randomized, placebo-controlled, global, multi-center Phase 3b study designed to evaluate the safety and efficacy of a 12-week regimen of telaprevir tablets in combination with pegylated-interferon and ribavirin in people with genotype 1 chronic HCV infection who have the IL28B CC genotype. In this study, telaprevir was dosed as three 375mg tablets twice daily. The study includes 239 people with hepatitis C who are new to treatment as well as those who relapsed after at least one prior course of treatment with pegylated-interferon and ribavirin alone. The primary endpoint of the study is the proportion of randomized people who achieve a sustained viral response (HCV RNA < lower limit of quantification) 12 weeks after the last planned dose of study drug (SVR12). All study participants were assigned to receive telaprevir in combination with pegylated-interferon and ribavirin for 12 weeks. People who continued all study drugs for 12 weeks and achieved a rapid viral response to treatment (measured as undetectable HCV RNA at week 4) were randomized 2:1 to receive no further treatment or an additional 12 weeks of pegylated-interferon and ribavirin alone. People who did not achieve a rapid viral response or who did not continue all study drugs for 12 weeks were assigned a total pegylated-interferon and ribavirin treatment duration of 24 or 48 weeks based on virologic response.

- Interim analysis of the Phase 3b CONCISE study showed SVR12 rates of 87 percent with 12 total weeks of treatment and 97 percent with 24 total weeks of treatment among people who achieved RVR and completed 12 weeks of treatment -

About INCIVEK
INCIVEK^® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication. INCIVEK has been prescribed to more than 60,000 patients in the United States. Approximately three out of four U.S. patients who are prescribed a direct-acting antiviral for the treatment of genotype 1 chronic hepatitis C (HCV) are prescribed INCIVEK combination therapy.
   
In Phase 3 clinical studies, 79 percent of people who had not previously been treated for HCV achieved a viral cure following treatment with INCIVEK combination therapy, compared with 46 percent of those who received pegylated-interferon and ribavirin (P/R) alone. Among people who were treated previously but did not achieve a viral cure, in the Phase 3 studies: 86 percent of relapsers achieved a viral cure with INCIVEK combination therapy compared to 22 percent with P/R alone; 59 percent of partial responders achieved a viral cure compared with 15 percent with P/R alone; and 32 percent of null responders achieved a viral cure compared with 5 percent with P/R alone. In addition, many people are eligible to complete treatment with INCIVEK combination therapy in 24 weeks — half the time required for treatment with P/R alone.
   
INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for adults with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).
   
Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO^® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic^®.
   
IMPORTANT SAFETY INFORMATION
   
Indication
INCIVEK^® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.
   
Important Safety Information
INCIVEK^® (telaprevir) should always be used in combination with peginterferon alfa and ribavirin. INCIVEK combination treatment may cause serious side effects including skin rash and serious skin reactions, anemia (low red blood cell count) that can be severe, and birth defects or death of an unborn baby.
   
Skin rashes are common with INCIVEK combination treatment. Sometimes these skin rashes and other skin reactions can become serious, require treatment in a hospital, and may lead to death. Patients should call their healthcare provider right away if they develop any skin changes during treatment with INCIVEK. Their healthcare provider will decide if they need treatment or if they need to stop INCIVEK or any of their other medicines. Patients should not stop taking INCIVEK combination treatment without talking with their healthcare provider first.
Patients' healthcare providers will do blood tests regularly to check for anemia. If anemia is severe, the healthcare providers may tell them to stop taking INCIVEK.
   
INCIVEK combined with peginterferon alfa and ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Females who can become pregnant and females whose male partner takes these medicines must have a negative pregnancy test before starting treatment, every month during treatment, and for 6 months after treatment ends. Patients must use two forms of effective birth control during treatment and for 6 months after all treatment has ended. These two forms of birth control should not contain hormones, as these may not work during treatment with INCIVEK.
   
INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life-threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.
The most common side effects of INCIVEK combination treatment include itching, nausea, diarrhea, vomiting, anal or rectal problems (including hemorrhoids, discomfort , burning or itching around or near the anus), taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare provider about any side effect that bothers them or doesn't go away.
Please see full Prescribing Information including Boxed Warning, and the Medication Guide for INCIVEK available at www.INCIVEK.com.
   
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.² Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.² Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.² Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.³ If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.^4,5
More than 170 million people worldwide are chronically infected with hepatitis C.⁶ In the United States, up to 5 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.^7,8 Hepatitis C is four times more prevalent in the United States compared to HIV.⁸ The majority of people with hepatitis C in the United States were born between 1945 and 1965, accounting for 82 percent of people with the disease.⁹ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 15,000 deaths annually.^10,11 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.¹²
   
About Vertex
Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and for three years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences.
Vertex's press releases are available at www.vrtx.com.
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Footnote:
¹ One person had genotype 6 HCV infection and was excluded from the efficacy analysis but included in the safety analysis.
   
References:
² Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf Updated June 2010. Accessed March 29, 2013.
³ Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.
⁴ Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
⁵ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
⁶ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
⁷ Chak, E, et. al. Hepatitis C Virus Infection In USA: An Estimate of True Prevalence. Liver Intl. 2011;1096 -1098.
⁸ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx Updated January 11, 2010. Accessed March 29, 2013.
⁹ Smith, BD, et al. Hepatitis C Virus Antibody Prevalence, Correlates and Predictors among Persons Born from 1945 through 1965, United States, 1999-2008. AASLD 2011 Annual Meeting.
¹⁰ Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
¹¹ Ly KN, et al. The Increasing Burden of Mortality From Viral Hepatitis in the United States Between 1999 and 2007. Ann Intern Med. 2012;156:271-278.
¹² Pyenson B, Fitch K, and Iwasaki K. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. Milliman, Inc. May 2009. Available at: http://www.vrtx.com/assets/pdfs/MillimanReport.pdf Accessed March 29, 2013.
   
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