June 4, 2013

New Doubts About Ginkgo Biloba

30CONS-articleInline

The Consumer April 29, 2013, 3:28 pm

By RONI CARYN RABIN

Millions of Americans take ginkgo biloba supplements to boost memory and prevent dementia. Studies have never found any solid evidence that ginkgo does any such thing, but it did not seem to be doing much harm.

But last month, scientists released the first government toxicology study of ginkgo biloba, which found that the extract — one of the top-selling herbal supplements in the country — caused cancer in lab animals, including an excessive number of liver and thyroid cancers, as well as nasal tumors.

The findings were somewhat surprising because ginkgo biloba has had a long and apparently benign history of human use. Although it has been associated with bleeding and cerebral hemorrhages in the elderly, there have generally been few reports of serious side effects.

The results of the study do not confirm that ginkgo biloba is dangerous to humans, but it is disturbing that the laboratory animals all tended to suffer the same sorts of injuries, said Cynthia Rider of the National Toxicology Program and the lead scientist of the ginkgo biloba study.

“We often see different targets depending on the sex of the animal or the species, finding one thing here and one thing there,” Dr. Rider said. “But with the ginkgo studies it was consistent across the sexes and the species. The liver was a target, the thyroid was a target, and the nose.”

“That consistency strengthens our conclusions,” she added.

The study concluded that there is clear evidence that ginkgo causes carcinogenic activity in the livers of mice and some evidence linking it to carcinogenic activity in rats’ thyroids.

The mice developed large numbers of multiple liver cancers, including a particularly aggressive type that is rarely seen in the rodents. The number of cancers exceeded the total in the comparison group. In some instances, the number of cancers exceeded the numbers ever seen in mice in the lab, the investigators said.

Officials with the American Herbal Products Association, a trade organization for companies that sell herbs and botanical products, and the American Botanical Council, a nonprofit group that publishes and educates people about medicinal plants, have sharply criticized the study, saying that the ginkgo extract used had a different chemical composition than the extract typically sold in the United States. The government scientists say they purchased it from a major supplier to American supplement companies.

More important, the critics questioned how applicable animal toxicity studies — long considered a mainstay in evaluating cancer risk — are to human health, and how the high doses often used in these studies relate to human consumption.

It is a valid criticism, as doses used in toxicology studies tend to be very high. In the new ginkgo study, mice were given up to 2,000 milligrams of extract per kilogram of body weight, or just over 900 milligrams per pound of body weight, five times a week. Doses sold for human consumption range from 30 to 120 milligrams, regardless of body size.

“This says nothing about toxicity in people, or what would be a safe dose in people,” said Steven Dentali, the trade association’s chief scientific officer. “It’s just a crude tool toxicologists have to determine if something is harmful. If it hurts the animals, maybe it hurts people.”

The Food and Drug Administration already bans ginkgo biloba from food and beverages, and the agency has repeatedly told drink manufacturers to remove ginkgo from its products.

Most recently, F.D.A. officials warned Stewart Brothers, a company in Hood River, Ore., that its juice drinks were “adulterated” with ginkgo, which it called an unsafe and unapproved additive, citing the new report. Several beverage companies, including Rockstar and Just Chill, have removed ginkgo biloba from beverages after receiving letters from the F.D.A.

But when it comes to supplements, the government has a different standard. A substance that is considered unsafe in food items or drinks can be legally sold as a supplement.

“We don’t review supplements before they go to market,” said Tamara Ward, an F.D.A. spokeswoman. “We get involved when there is a risk to the consumer, but manufacturers are responsible for making sure the products do not pose a risk to the consumer and for making sure claims are not misleading.”

The distinction has long rankled consumer advocates. The Center for Science in the Public Interest no longer regards ginkgo biloba as safe and is urging consumers to avoid it.

“The burden now shifts to industry to prove that it is safe,” said Michael F. Jacobson, executive director of the center. “There is no way to do a study in humans. You would need millions of people who take ginkgo biloba and millions who don’t, who all eat the same diet and have the same lifestyle. Government, industry and academia have all generally accepted animal studies as indicators of human risk.”

Moreover, he pointed out, several large clinical trials that followed thousands of elderly people to see if ginkgo biloba delayed cognitive decline failed to find any evidence that the extract was beneficial.

The studies included a large randomized controlled clinical trial of more than 3,000 people aged 75 years and older in the United States and a French study that included 2,820 people over age 70 who were followed for five years.

The F.D.A. is reviewing the new evidence from the toxicology study and could change its guidance in the future, Ms. Ward said.

Source

Journal of Hepatology

Article in Press

Received 5 March 2013; received in revised form 19 April 2013; accepted 13 May 2013. published online 28 May 2013.
Accepted Manuscript

Eiichi Ogawa, Norihiro Furusyo, Makoto Nakamuta, Eiji Kajiwara, Hideyuki Nomura, Kazufumi Dohmen, Kazuhiro Takahashi, Takeaki Satoh, Koichi Azuma, Akira Kawano, Yuichi Tanabe, Kazuhiro Kotoh, Shinji Shimoda, Jun Hayashi The Kyushu University Liver Disease Study (KULDS) Group

Abstract

Background & aims

Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PEG-IFN) α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PEG-IFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy.

Methods

This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PEG-IFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb) <85 g/L.

Results

101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb<135 g/L (Hazard ratio [HR], 2.53; P=0.0013), estimated glomerular filtration rate <80 mL/min/1.73m2 (HR, 1.83; P=0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; P=0.0024). For patients with ITPA CC (n=227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; P=0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; P=0.0281).

Conclusions

Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Keywords: Hepatitis C virus, Anemia, Telaprevir, Inosine triphosohatase, Pegylated interferon, Ribavirin

Abbreviations: HCV, hepatitis C virus, PEG-IFN, pegylated interferon, RBV, ribavirin, SVR, sustained virological response, TVR, telaprevir, ITPA, inosine triphosphatase, SNP, single nucleotide polymorphism, Hb, hemoglobin, eGFR, estimated glomerular filtration rate, RVR, rapid virological response, HR, hazard ratio, CI, confidence interval, AUROC, area under the receiver operating characteristic curve

No full text is available. To read the body of this article, please view the PDF online

Source.

Giordanino C, et al. Show all

Giordanino C, Sacco M, Ceretto S, Smedile A, Ciancio A, Cariti G, De Blasi T, Picciotto A, Marenco S, Grasso A, Pirisi M, Smirne C, Colletta C, Traverso A, Mazzucco D, Ciccone G, Simondi D, Rizzetto M, Saracco G.

Journal

Eur J Gastroenterol Hepatol. 2013 May 29. [Epub ahead of print]

Affiliation

aDepartment of Oncology, Division of Gastroenterology bDepartment of Internal Medicine, Division of Hepatogastroenterology cDepartment of Infectious Diseases, Amedeo di Savoia Hospital dUnit of Cancer Epidemiology, Molinette Hospital and CPO Piemonte, University of Turin, Turin eDepartment of Internal Medicine, Division of Gastroenterology, University of Genoa, Genoa fDivision of Gastroenterology, San Paolo Hospital, Savona gDepartment of Translational Medicine, Università del Piemonte Orientale 'A. Avogadro', Novara hDivision of Internal Medicine, Ospedale Madonna del Popolo, Omegna iDivision of Infectious Diseases, Ospedale Umberto Parini, Aosta jDivision of Gastroenterology, Ospedale degli Infermi, Rivoli, Italy.

Abstract

OBJECTIVES: To evaluate whether, in chronic hepatitis C-positive naive patients recruited in the routine clinical setting and treated with pegylated-interferon-α2b (Peg-IFN) and ribavirin (RBV), the sustained virologic response (SVR) is durable over the long term and whether it is associated with a decrease in liver complications and incidence of glucose abnormalities.

PATIENTS AND METHODS: This was a prospective long-term follow-up study of 182 naive patients enrolled in 2001-2002 and treated with Peg-IFN and RBV and followed up to December 2010, with clinical, biochemical, and virological evaluations every 6-12 months.

RESULTS: None of the 115 (63.2%) sustained responders showed late viremic relapse during the follow-up. SVR was better defined at 24 weeks (16/16 relapsers, 100%) than at 12 weeks after the end of therapy (14/16 relapsers, 87.5%). On multivariable analysis, viral genotype (odds ratio 0.16, 95% confidence interval 0.07-0.36, P=0.0001) and a greater than 20% RBV reduction (odds ratio 5.21, 95% confidence interval 1.54-17.67, P=0.008) predicted long-term response (LTR) independently. The incidence of cirrhosis was significantly higher among nonresponders (21.3%) compared with long-term responders (0.9%, P≤0.0001), but the risk of developing glucose abnormalities was not significantly reduced in long-term responders (hazard ratio 1.36, P=0.363). Hepatocellular carcinoma occurred only in three cases.

CONCLUSION: SVR achieved in patients treated in the routine clinical setting with Peg-IFN and RBV is durable over the long term and LTR significantly reduces the risk of progression to cirrhosis; however, in a population with mild liver fibrosis, the clinical impact of LTR on the risk of glucose abnormalities seems negligible.

PMID
23719564 [PubMed - as supplied by publisher]

Full text: Lippincott Williams & Wilkins

Source

Many with Hepatitis C Have Abnormal Thyroid

May 23, 2013

“Although the physiological mechanics between thyroid disorders and Hepatitis C remain elusive, an association between the two is irrefutable.”

By Nicole Cutler L.Ac.

Discovering individuals with a thyroid disorder to be chronically infected with the Hepatitis C virus (HCV) is becoming an increasingly common occurrence. Although new diagnoses of HCV are confirmed each day, an estimated four million Americans are currently known to be living with this virus. Because approximately 20 million Americans are currently living with a thyroid disorder and those with HCV are at a significantly higher risk of thyroid disorders, awareness of symptoms for both ailments can be helpful in recognizing this kind of dual affliction. While a majority of people with HCV are asymptomatic, signs of a thyroid condition may be substantial enough to investigate the possibility of Hepatitis C infection. Likewise, living with a thyroid disorder may mask any symptoms prompting someone to be evaluated for Hepatitis C.

Thyroid abnormalities in HCV-infected patients have been previously reported in respected medical journals, but little is known about the prevalence and nature of thyroid disorders in such patients. Dr. Alessandro Antonelli and colleagues from the University of Pisa School of Medicine, Italy examined the prevalence and nature of thyroid disorders in those with Hepatitis C in a 630-patient study. The authors reported that of those testing positive for anti-thyroid antibodies, significantly more people had Hepatitis C than those with Hepatitis B or with no infection at all.

Continue reading this entire article …..

Naim Alkhouri, MD, discusses interferon-free regimens for HCV

Provided by Healio

June 3, 2013

ORLANDO, Fla. — Naim Alkhouri, MD, of the Digestive Disease Institute at the Cleveland Clinic, provides his perspective on interferon-free therapies for hepatitis C at Digestive Disease Week 2013.

Alkhouri cites encouraging data from trials of sofosbuvir and ribavirin in patients with HCV genotypes 2 and 3, in which high SVR rates were observed after 12 to 16 weeks of treatment. He suggests that interferon-free treatments may become available in the near future, including compounds for use in patients with HCV genotype 1.

Source

Provided by Healio

June 4, 2013

ORLANDO, Fla. — Therapy with boceprevir in addition to pegylated interferon and ribavirin led to high sustained virologic response rates in patients with hepatitis C who failed previous interferon-based treatment in a study presented at Digestive Disease Week.

In the single-arm, open-label, multicenter roll-over PROVIDE study, researchers randomly assigned 168 patients with chronic HCV genotype 1 to 800 mg boceprevir three times daily, in addition to a standard dose of peginterferon alfa-2a and weight-based ribavirin (PR), for up to 44 weeks. All participants had been in control arms of prior phase 2 and 3 boceprevir studies and had experienced relapse or null or partial response to PR (51% partial responders, 31% null responders and 17% relapse responders, with 1% not classifiable).

Patients enrolled more than 2 weeks after their previous therapy also received a 4-week lead-in with PR alone (n=156). Four patients discontinued treatment during this period, leaving 164 boceprevir recipients for analysis.

Sustained virologic response (SVR) at 24 weeks occurred in 41% of null responders, 67% of partial responders and 96% of relapsers in final analysis, for an overall SVR rate of 65%. Relapse occurred in 13% of null responders, 15% of partial responders and no relapsers (11% average rate). Most patients who experienced SVR were men, not of black race, and had viral loads of 800,000 IU/mL or lower upon initiation. SVR rates were similar among those with HCV genotype 1a and 1b, and poorer among patients with platelet counts less than 200,000.

Commonly reported adverse events included anemia (49% of cases), dysgeusia (35%) and neutropenia (23%), and the safety profile was similar to previous studies. Eight percent of the cohort discontinued treatment because of adverse events.

“Overall, the data of this final analysis led to the conclusion that boceprevir combined with peginterferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders; and, most importantly, null responders,” researcher John M. Vierling, MD, professor of medicine and surgery, director of Baylor Liver Health and chief of hepatology at Baylor College of Medicine in Houston, said.

Disclosure: The researchers report numerous financial disclosures.

For more information:

Vierling JM. 869c: Sustained Virologic Response (SVR) in Prior PegInterferon/Ribavirin (PR) Treatment Failures After Retreatment With Boceprevir (BOC) and PR: Final Results of the PROVIDE Study. Presented at: Digestive Disease Week 2013; May 18-21, Orlando, Fla

Source

Journal of Viral Hepatitis

A Meta-Analysis

A. S. Rangnekar, R. J. Fontana

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

Abstract and Introduction
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 ().

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).

804135-fig1

Figure 1.

Study selection overview. From a total of 308 studies, 16 studies met the inclusion criteria

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 (). 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 ().

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).

804135-fig2

Figure 2.

Forest plots of IL-28B genotype and SVR in patients with hepatitis C virus (HCV) genotype 2/3 infection stratified by race. (A) There were 11 studies of 1599 Caucasian HCV genotype 2/3 patientsm and (B) there were five studies of 833 Asian HCV genotype 2 patients. SVR, sustained virologic response.

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.

References
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  2. Rangnekar AS, Fontana RJ. Metaanalysis: IL-28B genotype and sustained viral clearance in HCV genotype 1 patients. Aliment PharmacolTher 2012; 36: 104–114.

  3. Mangia A, Thompson AJ, Santoro R et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response. Gastroenterology 2010; 139: 821–827, 7 e1.

  4. Montes-Cano MA, Garcia-Lozano JR, Abad-Molina C et al. Interleukin- 28B genetic variants and hepatitis virus infection by different viral genotypes. Hepatology 2010; 52: 33–37.

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Abbreviations
ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; BMI, Body mass index; CI, Confidence interval; DAA, Direct acting antiviral agent; HCV, Hepatitis C virus; HIV, Human immunodeficiency virus; IL-28B, Interleukin 28B; OR, Odds ratio; PCR, Polymerase chain reaction; pegIFN, Peginterferon; RVR, Rapid virologic response; SNP, Single nucleotide polymorphism; SVR, Sustained virologic response.

Author contributions
Amol Rangnekar carried out study concept, design, data acquisition, analysis and interpretation, manuscript drafting and finalization, statistical analyses. Robert J. Fontana performed study concept, design, data acquisition, analysis and interpretation, manuscript drafting and finalization, overall supervision.

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

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Expansion of Therapies Offering Benefits Over Current Standard of Care Will Drive Growth Despite Price Controls in Market, According to a New Report from Decision Resources

BURLINGTON, Mass., June 4, 2013 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, forecasts that, from 2012 to 2017, the hepatitis C virus (HCV) market in Turkey will more than triple, reaching $275 million in 2017. The Emerging Markets report, Hepatitis C Virus in Turkey, finds that an increased drug-treated population and the launch of premium-priced novel therapies will drive high growth in this market, despite the Turkish government's statutory and reference price discounts.

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Novel HCV-specific antiviral protease inhibitors, polymerase inhibitors and NS5A inhibitors -- such as Johnson & Johnson/Medivir's simeprevir, Gilead's sofosbuvir and Bristol-Myers Squibb's daclatasvir -- will become available in Turkey during the 2012-2017 period. These novel agents will be more efficacious in both treatment-naive and treatment-experienced patients than peg-interferon (IFN)-alphas, and will cause fewer adverse events and discontinuations. These direct-acting antivirals (DAAs) can be added to peg-IFN-alpha/ribavirin (triple therapy) or combined into IFN-free regimens.

The report also finds that, through 2017, peg-interferon-alpha will continue to be a major component of HCV therapies. However, expected price cuts for Roche's Pegasys and Merck's PegIntron and their shortened treatment duration in triple therapy regimens will result in a decrease in sales of these two brands. The prescribing of HCV-specific protease inhibitors, Johnson & Johnson's Incivo and Merck's Victrelis will continue to grow until simeprevir launches and becomes reimbursed in Turkey. By 2017, simeprevir may largely supplant both Incivo and Victrelis as the preferred protease inhibitor in triple-therapy regimens.

"In 2012, Roche and Merck dominated the HCV therapeutic market in Turkey," said Decision Resources Analyst Jing Wu , M.S., M.B.A. "However, we expect the HCV market to become more fragmented after new DAAs from other companies like Johnson & Johnson, Gilead, Bristol-Myers Squib and AbbVie successfully launch and integrate into the future care for HCV-infected patients."

The new report features extensive primary research with Turkish gastroenterologists and infectious disease specialists as well as a market outlook through 2017.

About Decision Resources

Decision Resources (www.decisionresources.com) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources Group company.

About Decision Resources Group

Decision Resources Group is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources Group at www.DecisionResourcesGroup.com.

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