New Doubts About Ginkgo Biloba

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

Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy

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.

Durability of the response to peginterferon-α2b and ribavirin in patients with chronic hepatitis C: a cohort study in the routine clinical setting.

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

Boceprevir benefits null, partial responders to prior HCV therapy with peginterferon/ribavirin

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

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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

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).

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).

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

1. Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.

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.

5. Chen Y, Xu HX, Wang LJ, Liu XX, Mahato RI, Zhao YR. Meta-analysis: IL28B polymorphisms predict sustained viral response in HCV patients treated with pegylated interferonalpha and ribavirin. Aliment PharmacolTher 2012; 36: 91–103.

6. Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346–355.

7. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 1433–1444.

8. Whiting PF, Rutjes AW, Westwood ME et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann InternMed 2011; 155: 529–536.

9. Owens DK, Lohr KN, Atkins D et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions– agency for healthcare research and quality and the effective health-care program. J Clin Epidemiol 2010; 63: 513–523.

10. Stattermayer AF, Stauber R, Hofer H et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C. Clin GastroenterolHepatol 2011; 9: 344–350.

11. Sarrazin C, Susser S, Doehring A et al. Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 2011; 54: 415–421.

12. Bochud PY, Bibert S, Negro F et al. IL28B polymorphisms predict reduction of HCV RNA from the first day of therapy in chronic hepatitis C. JHepatol 2011; 55: 980–988.

13. Moghaddam A, Melum E, Reinton N et al. IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection. Hepatology 2011; 53: 746–754.

14. Fattovich G, Covolo L, Bibert S et al. IL28B polymorphisms, IP-10 and viral load predict virological response to therapy in chronic hepatitis C. Aliment Pharmacol Ther 2011; 33: 1162–1172.

15. Bitetto D, Fattovich G, Fabris C et al. Complementary role of vitamin D deficiency and the interleukin- 28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C. Hepatology 2011; 53: 1118–1126.

16. de Rueda PM, Lopez-Nevot MA, Saenz-Lopez P et al. Importance of host genetic factors HLA and IL28B as predictors of response to pegylated interferon and ribavirin. Am JGastroenterol 2011; 106: 1246–1254.

17. Amanzada A, Goralczyk A, Moriconi F et al. Ultra-rapid virological response, young age, low gamma- GT/ALT-ratio, and absence of steatosis identify a subgroup of HCV Genotype 3 patients who achieve SVR with IFN-alpha(2a) monotherapy. Dig Dis Sci 2011; 56: 3296–3304.

18. Halfon P, Bourliere M, Ouzan D et al. A single IL28B genotype SNP rs12979860 determination predicts treatment response in patients with chronic hepatitis C Genotype 1 virus. Eur J Gastroenterol Hepatol 2011; 23: 931–935.

19. Lindh M, Lagging M, Farkkila M et al. Interleukin 28B gene variation at rs12979860 determines early viral kinetics during treatment in patients carrying genotypes 2 or 3 of hepatitis C virus. J Infect Dis 2011; 203: 1748–1752.

20. Kawaoka T, Hayes CN, Ohishi W et al. Predictive value of the IL28B polymorphism on the effect of interferon therapy in chronic hepatitis C patients with genotypes 2a and 2b. J Hepatol 2011; 54: 408–414.

21. Yu ML, Huang CF, Huang JF et al. Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 infection in Asian patients. Hepatology 2011; 53: 7–13.

22. Sakamoto N, Nakagawa M, Tanaka Y et al. Association of IL28B variants with response to pegylatedinterferon alpha plus ribavirin combination therapy reveals intersubgenotypic differences between genotypes 2a and 2b. J Med Virol 2011; 83: 871–878.

23. Sinn DH, Kim YJ, Lee ST et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in Asian patients. J GastroenterolHepatol 2011; 26: 1374–1379.

24. Ochi H, Maekawa T, Abe H et al. IL-28B predicts response to chronic hepatitis C therapy–fine-mapping and replication study in Asian populations. J Gen Virol 2011; 92: 1071–1081.

25. Mangia A, Santoro R, Minerva N et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005; 352: 2609–2617.

26. von Wagner M, Huber M, Berg T et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522–527.

27. Alter MJ, Kruszon-Moran D, Nainan OV et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N EnglJ Med 1999; 341: 556–562.

28. Howell C, Jeffers L, Hoofnagle JH. Hepatitis C in African Americans: summary of a workshop. Gastroenterology 2000; 119: 1385–1396.

29. Zeuzem S, Hultcrantz R, Bourliere M et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40: 993–999.

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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Turkey's Hepatitis C Virus Drug Market Will More Than Triple by 2017

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.

(Logo:  http://photos.prnewswire.com/prnh/20130103/MM36784LOGO)

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.

All company, brand, or product names contained in this document may be trademarks or registered trademarks of their respective holders.

SOURCE Decision Resources

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Infection, CVD more prevalent among liver transplant recipients with metabolic syndrome

Provided by Healio

June 3, 2013

ORLANDO, Fla. — The presence of metabolic syndrome post-liver transplantation increased the risk for infection and cardiovascular disease, according to data presented at Digestive Disease Week.

In a retrospective cohort study, researchers evaluated 158 patients who underwent liver transplantation between 2002 and 2007 at a single medical facility, with follow-up through September 2012. The presence of metabolic syndrome (MetS) before transplant and at 6 and 12 months post-transplant was determined in each case.

Before transplantation, 25% of the cohort had MetS, which increased at 6 months (51% of cases) and 12 months post-transplant (61%). Thirty-one percent of participants who did not have prior MetS developed it de novo at 6 months, while 54% developed it by 12 months.

Investigators observed a significant association between MetS at 6 months and infection-related hospitalizations within the first post-transplant year (53% of those with compared with 31% of those without MetS; P=.005). Hospitalizations due to cardiovascular disease (CVD) also were more common among those with post-transplant MetS (26% of cases at 5 years post-transplant vs. 13%; P=.05).

Patients with MetS and nonalcoholic fatty liver disease (NAFLD) were not at increased risk for either infection- or cardiovascular-related hospitalization compared with those with MetS alone. NAFLD, however, significantly increased the risk for CVD among patients without MetS (14% vs. 0% of those without NAFLD; P=.03). Neither MetS nor NAFLD significantly impacted post-transplant survival, according to Kaplan-Meier analysis.

“We were able to show there was a statistically significant association with early infectious morbidity, as well as later cardiovascular morbidity, if you have symptoms of [MetS],” researcher Nicholas Kim, MD, an internal medicine resident at the University of Wisconsin, told Healio.com. “Our data suggest that it’s important to prevent metabolic syndrome from developing post-liver transplant. It’s a very common complication due to a variety of reasons, but if we are able to prevent it, we might be able to reduce the amount of early infectious complications and later cardiovascular complications after liver transplant.”

For more information:

Kim N. Tu1019: Development of the Metabolic Syndrome and Its Outcomes After Liver Transplantation. Presented at: Digestive Disease Week 2013; May 18-21, Orlando, Fla.

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Blood Tests OK for Fibrosis Dx in Hep C

By Salynn Boyles, Contributing Writer, MedPage Today

Published: June 03, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Action Points

• While liver biopsy remains the gold standard for predicting disease progression in people with HCV infection, it is no longer recommended as necessary in all patients before the initiation of antiviral therapy with newer medications.
• This study suggests that blood tests can help to identify HCV-infected patients with clinically significant fibrosis, with somewhat greater accuracy for identifying cirrhosis than for less advanced fibrosis.

Blood testing can accurately identify clinically significant fibrosis and cirrhosis in people with hepatitis C virus (HCV) infection and may be an alternative to liver biopsy in some patients, a new study found.

The analysis of 172 studies comparing various blood tests to biopsy in HCV patients revealed that some of the simplest, cheapest blood tests performed as well as more expensive, complex tests, reported Roger Chou, MD, and Ngoc Wasson, MPH, from the Evidence-Based Practice Center at Oregon Health and Science University in Portland.

Six tests identified clinically meaningful fibrosis with a median positive likelihood ratio of 5 to 10 at commonly used cutoffs and areas under the receiver-operating characteristic curve (AUROCs) of 0.70 or greater (range 0.71 to 0.86), they wrote in the June 4 issue of the Annals of Internal Medicine.

The tests were the platelet count, age-platelet index, aspartate aminotransferase-platelet ratio index (APRI), FibroIndex, FibroTest, and Forns index.

In addition, three of those tests, platelet count, age-platelet index, APRI, plus Hepascore, all identified cirrhosis with median positive likelihood ratios of 5 to 10 and AUROCs of 0.80 or greater (range 0.80 to 0.91).

"Our results suggest that blood tests can help to identify HCV-infected patients with clinically significant fibrosis, with somewhat greater accuracy for identifying cirrhosis than for less advanced fibrosis," the researchers wrote.

Liver biopsy remains the gold standard for predicting disease progression in people with HCV infection, but it is no longer recommended in all patients before the initiation of antiviral therapy. Drawbacks of liver biopsy include the potential for sampling error and risk for complications such as bleeding, severe pain, and infection,

Blood tests have been proposed as a less invasive alternative to liver biopsy, and more than two dozen tests have been studied for this purpose.

"We expect to see all-oral, interferon-free HCV treatment regimens in a few years, and that means many more people are likely to begin antiviral therapies," they wrote. "Having blood tests to help identify patients who can benefit from these treatments will be increasingly important."

Using MEDLINE, the Cochrane Library database, and other reference lists, the authors identified studies that compared blood tests to liver biopsy for diagnosing fibrosis or cirrhosis in HCV-infected people.

Most of the studies included in the analysis were conducted in the U.S., Europe, Asia and northern Africa, and 15 were rated as good quality studies, while five were rated poor quality. The remainder were considered fair quality.

Chou said one of the most surprising findings was that the simple APRI blood test performed as well or better than more complex and expensive tests.

"This test provided useful information about the severity of underlying liver disease," he told MedPage Today. "For patients trying to decide if they should begin antiviral therapy, this and other blood tests may be an alternative to biopsy."

In a subanalysis in which APRI was compared to FibroTest (known as FibroSure in the U.S.), the predictive value of the two tests was very similar, Chou said.

FibroTest is a patented, six blood serum test for liver damage marketed by French company BioPredictive.

APRI was associated with a slightly lower AUROC than the FibroTest for fibrosis (18 studies: median difference, -0.03; range, minus 0.10-0.07), but there was no difference for cirrhosis (seven studies; median difference, 0.0; range, minus 0.04 to 0.06).

Chou and Wasson noted several limitations to their analysis, including the fact that only English-language studies were included and that most trials failed to describe blinded interpretation of liver biopsy specimens. Many also included inadequate descriptions of enrollment methods.

The added that the results may not apply to populations excluded from the review, including patients coinfected with hepatitis B virus, HIV, and those receiving hemodialysis.

The study was funded by a grant from the Agency for Healthcare Research and Quality.

Primary source: Annals of Internal Medicine
Source reference:
Chou R, et al "Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis c virus infection" Ann Intern Med 2013; 158.

Source

WHO: Improving the health of patients with viral hepatitis

World Health Organization

EXECUTIVE BOARD EB133/17
133rd session 29 May 2013
Agenda item 6.5

Report by the Secretariat

1. Viral hepatitis is caused by five distinct viruses (hepatitis A, B, C, D, and E), each of which has a distinct transmission route, and consequent disease course. Hepatitis A and E viruses are spread through fecal–oral contamination and hepatitis E virus is also transmitted by consumption of meat from infected animals. The disease caused by hepatitis A and E viruses is usually self-limiting, but can cause death due to acute liver failure. In addition, infection with hepatitis E virus results in high mortality among pregnant women. Hepatitis B and C viruses are spread through bloodborne transmission (e.g. blood transfusion, contaminated injections); through sexual intercourse; and from mother to child. Although these viruses cause some cases of acute disease, their greatest damage is caused decades after infection, as most deaths result from liver cancer and cirrhosis. For this reason, viral hepatitis is called the “silent epidemic”.

2. Viral hepatitis causes a significant burden of disease. Estimates vary, but approximately 240 million persons are chronically infected with hepatitis B virus and 150 million with hepatitis C virus. These viruses are also responsible for significant mortality. Annually, some 500 000 persons die from diseases related to hepatitis B and some 350 000 from hepatitis-C-related diseases. The most notable new piece of evidence that catalogues the burden of hepatitis-related disease comes from the Global Burden of Disease 2010 study: the estimate is that, annually, a total of 1.4 million deaths are due to acute and chronic hepatitis infections (hepatitis A–E). This is similar to the number of deaths attributable to HIV infection, and makes viral hepatitis the eighth leading cause of death globally.

3. In view of the different routes of transmission, effective prevention requires a comprehensive approach that includes a number of interventions. To reduce infection with hepatitis A and E viruses, improved sanitation and access to clean water are a priority. The improvement in living standards in many countries has resulted in a documented reduction in incidence of hepatitis A disease. Vaccination is also an effective preventive strategy. Several countries have adopted universal vaccination of infants against hepatitis A infection, further reducing the incidence of hepatitis A disease.

4. An effective vaccine also exists against hepatitis B infection. Over the past two decades, countries have adopted universal vaccination for children, and by 2011, 180 countries had included universal vaccination against hepatitis B for infants as well. Globally, coverage with hepatitis B vaccine is estimated at 75% and is as high as 91% in the Western Pacific Region, and 90% in the Region of the Americas. Vaccination against hepatitis B in the South-East Asia Region reached 56% in 2011. The current emphasis is on raising the universal coverage of vaccination of infants at birth against hepatitis B (i.e. within 24 hours of birth). Thanks to these interventions, the Western Pacific Region was the first WHO region to achieve the goal of controlling hepatitis B (the prevalence of hepatitis B surface antigen is less than 2% among five-year-olds). According to a WHO analysis, through continued investments in hepatitis B vaccination, an estimated 3.4 million hepatitis B-related deaths due to liver cancer and cirrhosis will be prevented. In fact, vaccination coverage against hepatitis B virus is one of the 25 indicators of the draft action plan for the prevention and control of noncommunicable diseases 2013–2020.1

5. Progress is also noted in the prevention of bloodborne transmission of hepatitis B and C. Among countries that provide reports, 90% indicate that all blood donations are screened for hepatitis B and C viruses. Regarding injection safety, continued efforts both to improve access to disposable syringes and needles, and to train health care workers in universal precautions have decreased the rate of unsafe injections.

6. The most significant advances regarding hepatitis control are in the area of treatment. Treatment experts predict that in the next two to five years, 90% of hepatitis C infections will be curable with an all-oral, once-daily,12-week regimen of safe medicines (as compared to the current regimen that requires 24 to 48 weeks of weekly injections and that has a cure rate of between 45% and 80%). The new medicines have the potential to cure millions of persons who have chronic infection and thereby prevent deaths from cancer and cirrhosis. Therapy to treat chronic hepatitis B infection is also improving; new medicine regimens are being developed that are more potent and are easier to administer. The complexity and toxicity of existing regimens have deterred advocacy for making these medicines available in low-income countries. Few national governments have plans for scaling up hepatitis therapy. However, with the arrival of the new medicines in the next few years, Member States, WHO and other international organizations can expect patients’ advocacy groups to exert significant pressure in pursuit of lower prices and greater access to the medicines. Currently, some groups are advocating for WHO to include pegylated interferon in the WHO Model List of Essential Medicines, to prequalify diagnostic tests and medicines for hepatitis, and to negotiate with industry for lower medicine prices.

PREVIOUS HEALTH ASSEMBLY ACTION AND SECRETARIAT ONGOING RESPONSE

7. The Health Assembly has previously considered specific aspects of hepatitis. In 2010, the Health Assembly adopted resolution WHA63.18, in which, inter alia, it urged Member States to support or enable an integrated and cost-effective approach to the prevention, control and management of viral hepatitis, recognizing the scale of the disease burden attributable to viral hepatitis. To facilitate implementation of the resolution, the Secretariat established the global hepatitis programme in December 2011. In 2012 the Sixty-fifth World Health Assembly noted a progress report on implementation of the resolution.2

8. Resolution WHA63.18 requests the Director-General, inter alia, to establish in collaboration with Member States the necessary guidelines, strategies, time-bound goals and tools for the surveillance, prevention and control of viral hepatitis. The framework for global action responds to this request, with work aligned along four strategic axes:

1 See document A66/9, Appendix 2.

2 Document A65/26, section G, and document WHA65/2012/REC/3, summary record of the sixth meeting of Committee B.

• Strategic axis 1: raising awareness and mobilizing resources. Activities focus on increasing awareness about viral hepatitis among policy-makers, health professionals and the public; strengthening prevention and control measures; and removing discrimination against those who are infected. Priority activities include working with Member States to commemorate World Hepatitis Day (July 28) more visibly.
• Strategic axis 2: data for policy and action. The Secretariat is updating estimates of the global prevalence and burden of viral hepatitis. Guidelines and standards for disease surveillance are being finalized so that countries can better prioritize resources and select appropriate interventions. The Secretariat is developing approaches that will allow countries to better assess the cost-effectiveness of various hepatitis interventions, including expanding therapy. The next step is to create a comprehensive approach to the development of national hepatitis control plans and programmes.
• Strategic axis 3: prevention of transmission. Successful prevention efforts are being adapted in response to growing populations, changing epidemiology and new economic constraints. WHO is re-examining policies on immunization such as those relating to immunization schedules, the protection of neonates and health care workers (especially against infection with hepatitis B virus), expanded roles for existing hepatitis A vaccines and new hepatitis E vaccines, and innovative approaches for the future. WHO continues to work with partners to enhance the screening of blood for bloodborne pathogens including hepatitis B and C viruses and to reduce unnecessary and unsafe injections.
• Strategic axis 4: screening, care and treatment. The Secretariat is developing guidelines for treatment of infection with hepatitis B and C viruses. WHO is also assessing whether pegylated interferon should be included in the WHO List of Essential Medicines and is initiating discussions with global partners to advocate for increased access to medicines to treat hepatitis.

ACTION BY THE EXECUTIVE BOARD

9. The Executive Board is invited to take note of the report and provide further strategic guidance.

Source

Drugs Go From Hit to Dud in $15 Billion Hepatitis Race: Health

A research scientist for Gilead Sciences Inc., works on the synthesis of a potential hepatitis C virus drug candidate at the company's lab in Foster City, California. Photographer: David Paul Morris/Bloomberg

By Simeon Bennett June 02, 2013

Jean-Michel Pawlotsky has déjà vu.

The doctor in the town of Creteil, just outside Paris, is telling hepatitis C patients to delay treatment until later this year, when two new drugs that may boost their chances of defeating the lethal liver infection hit the market.

It’s the same advice he offered two years ago, when earlier medicines developed by Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. (MRK) were poised for approval. Now he says those drugs, hailed as breakthroughs in 2011, will soon be superseded by products fromGilead Sciences Inc. (GILD) and Johnson & Johnson. (JNJ)

The pace of innovation, spurred by drugmakers jostling for a slice of a market that may reach $15 billion by 2018, has turned hepatitis C research into one of the fastest-developing areas of medicine. That boosted Gilead’s shares to a record last month, and left others like Vertex facing dwindling sales as their products quickly go from revolutionary to outdated.

“Things are moving very fast,” Pawlotsky, who teaches medicine at the University of Paris-Est, said by phone. “People are frustrated, they want more, better.”

Hepatitis C, an infectious disease that can scar the liver and afflicts about 170 million people worldwide, is still treated largely with injections that can take six months to clear the virus, sometimes don’t work, and cause side effects ranging from flu-like symptoms to depression. If untreated for longer periods, hepatitis C can cause cancer.

Gilead, a newcomer to the field, in April applied for regulatory clearance of a drug known as sofosbuvir. The pill may become the Foster City, California-based company’s top-selling product by 2015, and reach sales of $6.3 billion by 2016, according to the average of nine analyst estimates (GILD) compiled by Bloomberg. The stock has more than doubled in the past year on optimism about the pill.

Drug Deluge

Until 2011, there was only one standard treatment: the generic antiviral ribavirin, together with a weekly injection called pegylated interferon, sold by Roche Holding AG and Merck.

Two years ago, doctors and patients embraced the new drugs from Vertex and Merck because they boosted cure rates to about 80 percent from 50 percent. But they came with more side effects, including skin rashes and the risk of birth defects.

In clinical studies, newer formulations from Gilead and J&J show similar or better results in ridding patients of the disease, and fewer risks. Both may win regulatory approval this year. Johnson & Johnson’s Janssen unit applied in March for clearance of its product, simeprevir, which was developed by Medivir AB. (MVIRB) Other drugs from AbbVie Inc. (ABBV) and Bristol-Myers Squibb Co. (BMY) are in late-stage trials.

Much Promise

“It’s not often you’re in a field that moves so fast and offers so much promise,” said Graham Cooke, a clinician at Imperial College London. “We’ve had very difficult treatments for so long, and we’re now in this era of incredible throughput from the pipeline.”

Vertex, of Cambridge, Massachusetts, gets 76 percent of its revenue from Incivek, the hepatitis drug it developed with Janssen, which markets the treatment as Incivo in Europe. The drug won U.S. regulatory approval in May 2011 and prescriptions and sales reached a peak in the fourth quarter of that year, but have declined since. The drug may only garner sales of $669 million this year, the average of 12 analyst estimates (VRTX) compiled by Bloomberg.

“We recognize that fewer patients are starting treatment for hepatitis C, however there are still patients who want or need to be treated now,” Erin Emlock, a spokeswoman for Vertex, said by e-mail. “Three of four people who start treatment today get Incivek, a number that’s unchanged since launch.”

‘Almost Unethical’

To stoke demand, Incivo’s booth at a meeting of the European Association For the Study of the Liver in Amsterdam in April featured a video with the message, “Treat now to take your patient’s life off hold.”

Some doctors agree. The practice of delaying treatment to wait for better drugs, known as warehousing, is “irrational, and almost unethical,” said Mitchell Shiffman, a clinician who sees about 1,000 new hepatitis C patients a year at the Liver Institute of Virginia. “If a patient can be cured now, why do you want to tell them to wait?”

French doctor Pawlotsky says people with mild disease aren’t harmed by a short delay. Most of his patients want to try the new drugs by participating in clinical trials, he says.

“Obviously if we thought that the new treatments would come in something like five or six years, we would not warehouse,” he said. “But it’s a matter of months.”

Mark Thursz, the secretary-general of the European Association for the Study of the Liver, says many people he has put on experimental drugs are faring better than those using treatments now on the market.

$100,000 Treatment

“Our patients are struggling with the current regimes,”Thursz said. “The sooner we can get the new drugs licensed and in the clinic for our patients, the better.”

Gilead may charge up to $100,000 per patient for a course of sofosbuvir, according to ISI Group in New York. The drugmaker says it doesn’t comment on drug prices before they’re approved, but says the medicine can shorten treatment times to as little as 12 weeks, from as long as a year now.

Even as doctors disagree on whether to delay treatment, they’ve got one eye on the next wave of drugs. At least three are in the final stage of clinical trials and may become available within two years.

‘Therapeutic Jacuzzi’

Gilead is testing a combination of sofosbuvir with an experimental drug called ledipasvir in a cocktail that cured 100 percent of patients in a mid-stage trial presented in Amsterdam in April. AbbVie’s three-in-one combo won designation as a“breakthrough therapy” from the U.S. Food and Drug Administration on May 6, meaning it may be reviewed more quickly, after a study showed it cured 96 percent of patients after 24 weeks. Bristol-Myers Squibb’s three-in-one experimental combo won the same accelerated status just weeks earlier.

That means yet more difficult decisions about whether to treat or wait, said Dominique Larrey, a doctor at Saint-Eloi Hospital in Montpellier, France.

“I tell my students it’s like we’re in a therapeutic jacuzzi,” he said. “Each bubble is a new drug.”

To contact the reporter on this story: Simeon Bennett in Geneva at sbennett9@bloomberg.net 

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net 

Source

New Hepatitis C Clinical Trial Now Enrolling at Avail Clinical Research near Orlando, Florida; Accepting M/F Patients with Hep C Age 18-65

Avail is conducting a 12-week, Phase 2, Randomized Study to Evaluate the Safety and Efficacy of a new drug in Subjects with Chronic Hepatitis C Infection.

DeLand, Florida (PRWEB) June 03, 2013

*To see if you qualify for this Hepatitis C Clinical Trial, visit Avail Clinical Research on the web or contact us directly at (386) 785-2404.

BACKGROUND

The Hepatitis C virus (HCV) infection is a global public health problem. The global prevalence of hepatitis C infection is estimated to average 3% resulting in approximately 170 million HCV-infected persons worldwide. Most of those infected develop persistent, chronic infection. An estimated 20-50% of patients with chronic HCV infection are at risk for developing such long-term complications as cirrhosis and hepatocellular carcinoma (HCC).

PRIMARY OBJECTIVES

The primary objectives of this Hep C Clinical Study are to evaluate the:

Safety and tolerability of a new Hep C drug and simeprevir when given in combination with RBV for up to 12 weeks.

Efficacy of a new Hep C drug and simeprevir when given in combination with RBV for up to 12 weeks.

SECONDARY OBJECTIVES

The secondary objectives are to evaluate the:

1. Pharmacokinetics (PK) of a new Hepatitic C drug and simeprevir when given in combination with RBV.

2. PK/Pharmacodynamics (PK/PD) of a new Hepatitic C drug and simeprevir when given in combination with RBV.

3. Emergence of resistance mutations over 12-weeks of combination treatment of a new Hepatitic C drug, simeprevir and RBV and in the post-treatment follow-up period.

INCLUSION CRITERIA

1. 18 (or the legal age of consent per local regulations, if greater than 18 years) to 65 years of age, inclusive.

2. Female subjects of both childbearing potential and non-childbearing potential may be included, unless the local regulatory authority requires that only females of non-childbearing potential be included. Non-childbearing potential is defined as one of the following:

Postmenopausal, defined as amenorrheic for at least 2 years and serum follicle stimulating hormone (FSH) level consistent with postmenopausal status at Screening, OR

A documented hysterectomy, bilateral oophorectomy or bilateral tubal ligation at least 6 months prior to study initiation.
3. All female subjects must have a negative serum beta-human chorionic gonadotropin (β-HCG) at Screening and a negative urine pregnancy test prior to the first dose of study medication on Day 1.

4. Women of childbearing potential and men must have agreed to use an acceptable double method of birth control (one of which must be a barrier method) from Screening through at least 6 months after the last dose of study drugs.

5. Male subjects must have agreed not to donate sperm from the first dose through at least 6 months after the last dose of study drugs.

6. QTcF interval ≤ _450 ms at Screening and prior to dosing on Day 1.

7. Documented clinical history compatible with chronic hepatitis C, including any one of the following:

a) anti- HCV antibody positive at least 6 months prior to Screening or dosing, OR

b) HCV RNA present in plasma by a sensitive and specific assay at least 6 months prior to Screening or dosing, OR

c) HCV genotype at least 6 months prior to Screening or dosing, OR

d) histologic evidence of chronic hepatitis C infection.

8. Must not have received prior antiviral treatment for HCV infection.

9. Plasma HCV RNA positive at Screening with minimal viral load according to genotype:

a) Genotype 1b HCV RNA ≥5 log10 IU/mL

b) Genotype 4 HCV RNA ≥ _4 log10 IU/mL

10. HCV genotype 1b or 4 by HCV genotyping performed at Screening (Note: mixed subtypes are not acceptable).

11. Documented absence of cirrhosis within 36 months of Screening or dosing (histology or non-invasive equivalent, according to local standard of care).

12. Subject is, in the opinion of the investigator, willing and able to comply with the protocol and all other study requirements.

13. Subject has provided written informed consent to participate in the study.

BENEFITS OF PARTICIPATION

• Receive medical care at No Cost
• Health Insurance is not required
• Receive Compensation for time & travel
• Help Advance medical research

*Achieve Clinical Research conducts Clinical Research Trials in Florida. For more information about participating in a Hep C Clinical Study, please visit our website or contact us directly at (386) 785-2404.

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CROI 2013: complications of HIV disease, viral hepatitis, and antiretroviral therapy

Top Antivir Med. 2013 Apr-May;21(2):62-74.

Luetkemeyer AF, Havlir DV, Currier JS.

University of California San Francisco and San Francisco General Hospital, San Francisco, CA, USA.

Abstract

Studies with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) monoinfection and HIV coinfection were highlighted at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI). In HCV monoinfected patients, several interferon alfa-sparing, all-oral regimens demonstrated cure rates of greater than 90% with 12 weeks of treatment, including for hard-to-treat patients. Cure rates of 75% were attained in HIV/HCV coinfected patients with the addition of the investigational HCV protease inhibitor (PI) simeprevir to peginterferon alfa and ribavirin. Drug-drug interaction data to inform safe coadminstration of antiretroviral therapy with DAA-based HCV treatment were presented. There was continued emphasis on pathogenesis, management, and prevention of the long-term complications of HIV disease and its therapies, including cardiovascular disease, renal disease, alterations in bone metabolism, and vitamin D deficiency, along with a growing focus on biomarkers to predict development of end-organ disease. Understanding the elevated risk for non-AIDS-defining malignancies in the HIV-infected population and optimal management was a focal point of this year's data. Finally, the conference provided important information on tuberculosis coinfection and cryptococcal meningitis.

PMID: 23681961 [PubMed - in process]

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What's Holding Back Cures? Our Collective Ignorance (And No, Not A Pharma Conspiracy)

Pharma & Healthcare 5/10/2013 @ 2:58AM

David Shaywitz, Contributor

The birthers, it turns out, aren’t the only ones with wacky conspiracy theories; evidently a lot of people out there really think there are cures “They” don’t want you to know about.

In particular, there seems to be a surprisingly pervasive belief that drug companies aren’t working on cures for disease because it’s far more profitable to chronically maintain patients on medication. This also explains (so the reasoning goes) why drug companies offer so many incremental therapeutics, and so few revolutionary treatments.

If only this explanation were true.

Drug companies, in fact, are desperate to identify radically improved treatments for dreadful disease. Even if you don’t accept (as I’ve recently argued) that most industry researchers I know aspire to create such profoundly effective medicines, imagine the economic value of a drug that cured Parkinson’s Disease or pancreatic cancer – consider what such a therapy would be worth.

Exhibit A is the explosion of pharmaceutical interest in hepatitis C. How do you explain the billions of dollars in investment– including an eye-popping $10.8B acquisition — if companies weren’t looking to cure patients? The entire premise of this field has been coming up with approaches to cure more patients faster.

Of course, progress in HCV has been exceptional; by and large, medicine has seen mostly incremental gains, and has witnessed few transformative therapies. Why?

The unfortunate truth is that drug companies really want to cure disease, but rarely know how. Medical science simply isn’t up to the challenge. Most diseases aren’t well enough understood to enable the rational development of truly transformative treatments.

When high-profile pharma studies fail – such as the slew of recent Phase 3 Alzheimer’s Disease trials – it’s fashionable to characterize them as yet another industry failure. There’s some truth to this: the proximal cause may well be a poor decision to continue the development of a questionable drug. But the root cause is likely insufficient understanding of disease pathophysiology.

We should also be careful about dismissing the value of incremental advances– a reflex I know I still have, although I’ve recognized the value of seemingly small tweaks from the time I was a resident. Even today, when I critique (as derivative) formulation plays like liquid Ritalin, I’m glad to be reminded of the kids who stand to benefit from just such a medication.

What’s Next?

As the healthcare system looks more critically at value – demanding more evidence of effectiveness from providers and products alike – drug companies will be faced with two options.

The best choice, of course, would be to figure out how to come up with truly revolutionary treatments. Perhaps unexpected insights will emerge from big data and the integration of phenotypic and genotypic information, in the framework of system biology; maybe a new therapeutic modality will arrive on the scene. It’s possible intensified collaboration between academic and industry researchers will eventually yield something useful, or that open-data approaches (as championed by organizations like Sage Bionetworks [disclosure: I served as a founding advisor]) will achieve critical mass, and deliver impactful insights. But unless something substantial changes, progress is likely to remain slow and stochastic, and truly game-changing novel therapeutics will continue to be the exceptions rather than the rule.

Given the ongoing challenges of creating transformative medications, there’s likely to be intensified focus on capturing, in a more granular fashion, the benefits of incrementally improved drugs; such assessments will not be a “nice to have” but a “must have,” table stakes for consideration by payors, and (to the extent these measures are used to demonstrate efficacy) regulators as well. I also suspect pharmas will increasingly look to offer “solutions” (e.g. associated app or access to an online community) not just pills, to deliver value, though it’s unclear whether such approaches will either prove effective or represent an attractive value proportion for the relevant stakeholders.

In a sense, things would be much simpler if pharma really was as malevolent as some seem to fear; if only there was a secret refrigerator somewhere with cures to our deadliest diseases. That would be a far more solvable problem than the one we actually must confront: science is extremely hard.

Even so, this doesn’t let pharma off the hook. As savvy industry watchers such as Bernard Munos, David Grainger and others have pointed out (see here as well), pharmas could run far more efficiently, and make better, smarter, and faster decisions.

But at the end of the day, the fundamental challenge in the creation of new medicines remains the complexity of the underlying science. Improved operational efficiencies may help reduce the cost and time of failure, but new understanding – ideally coupled with improved empirical approaches permitting progress in the absence of such understanding — will be required for enduring success.

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