Spontaneous Clearance of HCV Infection in Patients with Chronic Infection

NEJM Journal Watch

July 28, 2016
Spontaneous Clearance of HCV Infection in Patients with Chronic Infection

Atif Zaman, MD, MPH reviewing Bulteel N et al. J Hepatol 2016 Aug.

Atif Zaman, MD, MPH
Factors associated with this rare event were younger age, female gender, HBV coinfection, and lower HCV RNA level.

Atif Zaman, MD, MPH
The incidence of spontaneous clearance of hepatic C virus (HCV) infection in the acute phase (infected <6 months) is high (estimated at 20%–40%) but is unknown in the chronic phase.

In a population-based case-control study performed in Scotland, investigators assessed spontaneous clearance incidence and its associated risk factors, using HCV testing data from 1994 to 2013. Case patients were defined as those who spontaneously resolved HCV infection and control patients as those who remained chronically infected. All patients had no prior HCV treatment and had ≥2 sequentially positive HCV RNA tests at least 6 months apart, followed by ≥2 negative tests in cases and no negative tests in controls. Four controls were randomly selected for each case.

Among 10,318 patients identified with positive hepatitis B virus (HBV) RNA samples, 50 had documented late spontaneous clearance, for an incidence of 0.36 per 100 person-years of follow-up. Median duration of infection was 50 months in both cases and controls. Spontaneous clearance was significantly associated with younger age at infection (median age, 29 vs. 33 years), female gender, co-infection with HBV infection, and lower HCV RNA level.

Comment
These data demonstrate that spontaneous clearance of HCV infection can occur in patients who are chronically infected, albeit at an extremely low rate. Although the exact mechanism of this late spontaneous clearance is unknown, as seen here, certain host and viral factors appear to play a role. On rare occasion, clinicians may see this occur in practice.

Editor Disclosures at Time of Publication
Disclosures for Atif Zaman, MD, MPH at time of publication Nothing to disclose

Citation(s):
Bulteel N et al. Factors associated with spontaneous clearance of chronic hepatitis C virus infection. J Hepatol 2016 Aug; 65:266. (http://dx.doi.org/10.1016/j.jhep.2016.04.030)

http://www.jwatch.org/gastroenterology

New at NEJM Journal Watch

Gastroenterology Common Reasons for Hospital Readmissions in Patients with Cirrhosis
Atif Zaman, MD, MPH reviewing Tapper EB et al. Clin Gastroenterol Hepatol 2016 Aug.
Top readmission causes were acute complications of cirrhosis, substance abuse, and cancer complications.

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 Genotype 1, 2,3,4 or 6 / Phase 2 Trial

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Source: Gastroenterology

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Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with HCV Genotype 2, 3, 4, or 6 Infections in an Open-label, Phase 2 Trial
Edward Gane, Kris V. Kowdley, David Pound, Catherine A.M. Stedman, Mitchell Davis, Kyle Etzkorn, Stuart C. Gordon, David Bernstein, Gregory Everson, Maribel Rodriguez-Torres, Naoky Tsai, Omer Khalid, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Myron Tong, Raymond T. Chung, Kimberly Beavers, John E. Poulos, Paul Y. Kwo, Mindie H. Nguyen
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.038
Publication stage: In Press Accepted Manuscript

Published online: July 30, 2016

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Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections who have failed by a prior course of antiviral therapy, and the feasibility of further shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients.

DISCUSSION ONLY
With the recent approval of DAAs, safe and effective combination regimens are now available for the majority of patients chronically infected with HCV. SVR rates exceeding 90% can be achieved in most patient populations regardless of genotype, treatment experience, or presence of cirrhosis. Although the proportion of patients who do not achieve SVR with currently approved DAA regimens is small, the absolute number of DAA failures will steadily increase in parallel with the rate of treatment uptake. DAA failures represent an unmet medical need without, at this time, any approved retreatment options. In this open-label, phase 2 study, the combination of sofosbuvir velpatasvir plus GS-9857 for 12 weeks was safe and highly effective for the treatment of patients with genotypes 2, 3, 4, or 6 HCV infection with or without compensated cirrhosis who were treatment-experienced, including those who had failed previous DAA regimens. The high SVR12 rate among treatment-experienced patients with genotype 3 HCV infection and cirrhosis is noteworthy, given the lower SVR12 rates generally experienced by patients this patient population.

Currently approved regimens for non-genotype 1 HCV have durations of 12 to 24 weeks, depending on choice of regimen and patient’s baseline characteristics, such as HCV genotype, treatment history and presence or absence of cirrhosis. The feasibility of further shortening the duration of treatment has been a goal of research, especially for non-ribavirin containing regimens. Several trials have evaluated various combinations of DAAs for four weeks, but with uniformly disappointing 0utcomes—SVR12 rates of 20% to 40%

In this trial, 6 weeks of sofosbuvir-velpatasvir plus GS-9857 achieved suboptimal results (<90% SVR12 rate) in a historically easy-to-treat population of treatment-naïve patients without cirrhosis. Eight weeks of sofosbuvir-velpatasvir plus GS-9857 was safe and effective for treatment-naïve patients with cirrhosis, including those with HCV genotype 3. Thus, the 8-week regimen may serve as a shorter-duration option for treatment-naïve patients with or without cirrhosis and is currently being evaluated in Phase 3 clinical trials.

Additionally, the high SVR12 rates across genotypes suggests the pangenotypic treatment potential of sofosbuvir-velpatasvir plus GS-9857. While genotype 1 patients were not treated in this study, a parallel open-label, phase 2 study of patients infected with HCV genotype 1 was also conducted,where patients received treatment for 6 to 12 weeks.

This study was limited by its small sample size and open-label design. Although the first Phase 2 clinical trial to evaluate retreatment of non-genotype 1 HCV infected patients previously treated with DAA-regimens that included NS5A inhibitors, only six patients in this subgroup were enrolled. Also, no patients with genotype 5 HCV and only 3 patients with genotype 6 HCV were enrolled, reflecting the low prevalence of these infections in North America and New Zealand.

In conclusion, sofosbuvir-velpatasvir plus GS-9857 is a safe and effective treatment in patients with HCV genotypes 2, 3, 4, and 6, with and without compensated cirrhosis. High SVR rates were achieved in treatment-experienced patients, including those with DAA-experience, after12 weeks of sofosbuvir-velpatasvir plus GS-9857 and in treatment-naïve patients with compensated cirrhosis after 8 weeks of this regimen. These three potent pangenotypic DAAs have been coformulated into afixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination in patients for eight weeks treatment-naïve patients of all genotypes and for twelve weeks in patients of all genotypes who had received previous treatment with a DAA.

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Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with Genotype 1 Hepatitis C Virus Infection in an Open-label, Phase 2 Trial
Eric Lawitz, Nancy Reau, Federico Hinestrosa, Mordechai Rabinovitz, Eugene Schiff, Aasim Sheikh, Ziad Younes, Robert Herring Jr., K. Rajender Reddy, Tram Tran, Michael Bennett, Ronald Nahass, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Brian Pearlman, Mitchell Shiffman, Trevor Hawkins, Michael Curry, Ira Jacobson
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.039
Publication stage: In Press Accepted Manuscript

The best regimen to retreat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus (HCV) genotype 1 infection.

Published online: July 30, 2016

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DISCUSSION ONLY
The development of oral DAAs represents a major advance in the treatment of HCV in patients of all genotypes. Currently available DAA combination regimens offer SVR rates well over 90% overall and in most patient subpopulations. Nevertheless, some patients do not achieve SVR with existing regimens. Patients who have failed prior treatment with first generation NS3/4A protease inhibitors (e.g., telaprevir, boceprevir, or simeprevir) may be retreated with ledipasvir sofosbuvir, but patients who have been unsuccessfully treated with a regimen that includes an NS5A inhibitor have no approved retreatment options. In a previous trial, patients with genotype 1 HCV who did not achieve SVR after 8 or 12 weeks of ledipasvir-sofosbuvir-based regimens and were subsequently retreated with 24 weeks of ledipasvir-sofosbuvir had an SVR12 rate of only 71%. In this population, the presence of baseline NS5A RASs was associated with a higher rate of virologic failure (Lawitz et al: J Hepatol 62:S192 Abstract, 2015).

In another small trial, 14 of 16 patients (88%) who had previously failed a daclatasvir-containing regimen achieved SVR12 after retreatment with simeprevir-sofosbuvir for 12 weeks. Thirteen of the 16 patients had NS5A RASs at baseline, and of these 13, 11 (85%) achieved SVR12. The 2 patients who did not achieve SVR12 had Q30K and L31M substitutions as the dominant viral populations at retreatment baseline.16

In this open-label, phase 2 study, 12 weeks of treatment with sofosbuvir-velpatasvir plus GS9857 was safe and highly effective in patients with HCV genotype 1, with and without cirrhosis, who did not achieve SVR after prior treatment with DAA, including those who had previously received an NS5A inhibitor. In treatment-naive patients, the 8-week regimen was safe and effective, regardless of cirrhosis status. Among the treatment-naïve patients who relapsed, the presence of baseline RASs appeared to have no impact on treatment outcome. Treatment emergent RASs by deep sequencing with a 1% cutoff were rare (3/17, 18%) and no treatment emergent RASs among relapsers were detected with the 15% cutoff. This is consistent with the anticipated high barrier of resistance of the combination therapy based on in vitro data (Lawitz et al: Hepatology XXX Abstract 2015).

Treatment-naïve patients without cirrhosis treated for 8 weeks achieved a SVR12 rate of 100%,which is higher than results reported in other recent studies of combining 3 or 4 DAAs for treatment for the same population and treatment duration.20,21 Treatment-naïve patients with cirrhosis treated for 8 weeks had lower SVR12 rates of 81-94% than patients without cirrhosis. Larger studies will determine whether this short duration is adequate for this patient population. One unexpected result in our trial was the apparent lack of benefit of the addition of ribavirin to sofosbuvir-velpatasvir plus GS-9857 for treatment-naïve patients with cirrhosis. Although patients in this group receiving ribavirin had a numerically lower rate of SVR12 than treatment naïve patients with cirrhosis who received sofosbuvir-velpatasvir plus GS-9857 without ribavirin (81% vs 94%), the confidence intervals overlap and it is likely that this reflects the small sample sizes. 

Factors limiting the interpretation of these results of this trial include its small size and uncontrolled, open-label design. Although the trial enrolled only patients with genotype 1 HCV, another trial of similar design has been conducted to assess this combination regimen in patients with non-genotype 1 HCV.

In conclusion, sofosbuvir-velpatasvir plus GS-9857 for 12 weeks provided a high rate of SVR12 (100%) and was well-tolerated in a group of patients currently without treatment options—those with and without compensated cirrhosis who have not achieved SVR after previous treatment with a NS5A inhibitor-containing regimen. The addition of GS-9857 to sofosbuvir-velpatasvir was also safe in the treatment-naïve population where it was effective in reducing the treatment duration to 8 weeks while preserving a high rate of SVR12. These three potent pangenotypic DAAs have been coformulated into a fixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination for eight weeks in treatment-naïve patients and for twelve weeks in DAA-experienced patients, including those who have previously received an NS5A inhibitor.

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Shire’s SHP626 (Volixibat) Receives FDA Fast Track for Adults who have NASH with Liver Fibrosis

Shire’s SHP626 (Volixibat) Receives FDA Fast Track Designation for an Investigational Treatment for Adults who have Nonalcoholic Steatohepatitis (NASH) with Liver Fibrosis

July 29, 2016

Lexington, Mass. – July 29, 2016 – Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that the United States Food and Drug Administration (FDA) has granted Fast Track designation for SHP626 (volixibat) for an investigational treatment of adults who have nonalcoholic steatohepatitis (NASH) with liver fibrosis. Shire is developing SHP626 as a once daily, orally-administered inhibitor of the apical sodium dependent bile acid transporter (ASBT), a protein which is primarily responsible for recycling bile acids from the intestine to the liver. NASH is a serious, chronic liver disease for which there are currently no approved drugs.

"Shire’s development plan for SHP626 is designed to address the unmet need in the treatment of adult patients who have NASH with liver fibrosis,” said Philip J. Vickers, Ph.D., Head of R&D, Shire. "This Fast Track designation is further recognition of the critical need to develop new, effective therapeutic options for patients with this serious condition." The FDA Fast Track Designation for SHP626 in NASH was supported by preclinical and Phase 1 studies. The FDA’s Fast Track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need. However, it does not guarantee that the FDA will ultimately approve SHP626 for NASH or the timing of any such approval.

Shire will initiate its Phase 2 trial with SHP626 as a randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability and efficacy of three doses of volixibat over 48-weeks in adult patients with NASH. The Phase 2 study will be conducted in the U.S., Canada and the United Kingdom.

Additional information on the SHP626 Phase 2 study can be found on clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT02787304?term=volixibat&rank=1

SHP626 has been evaluated in preclinical and Phase 1 studies, in which the safety, tolerability and preliminary activity of SHP626 compared to placebo in healthy volunteers, as well as in overweight and obese volunteers, was assessed. The most common adverse events occurring in Phase 1 trials of SHP626 were gastrointestinal in nature, predominantly diarrhea. While this occurred in most patients, it was not considered serious. There was one serious adverse event reported that was considered related to SHP626, alanine aminotransferase elevation, that led to discontinuation of drug.

About Nonalcoholic Steatohepatitis (NASH)

NASH is a type of nonalcoholic fatty liver disease (NAFLD), characterized by inflammation and the accumulation of fat in the liver, for which there are currently no approved drugs. It can be severe and lead to fibrosis, cirrhosis, liver failure and liver cancer. There is a steady rise in the prevalence of NASH in the U.S. and globally, and the disease is typically associated with obesity, type 2 diabetes, hypertension, high cholesterol and triglycerides. NASH is currently the second leading cause of liver transplantation in adults in the U.S., and is estimated to become the leading cause for liver transplantation if the current trajectory continues.

https://www.shire.com/newsroom/2016/july/7zve23

Wider access to hepatitis C drugs is humane and pragmatic

Wider access to hepatitis C drugs is humane and pragmatic
 Boston Globe

The long-term health prospects for thousands of Massachusetts residents are about to improve. As of Monday, MassHealth will require private insurers that manage coverage for two-thirds of the state Medicaid plan’s members to loosen rules that cruelly prevent people infected with hepatitis C from receiving drugs that cure the disease. Until now, these low-income patients have been forced to wait until they are suffering from potentially deadly symptoms before getting a prescription for one of a new generation of medicines that kills the liver-ravaging virus in as little as eight weeks.

The insurance company restrictions were a misguided reaction to the cost of the breakthrough treatments for hepatitis C, a disease which previously could only be kept in check — but not cured — by drugs that came with terrible side effects. When Gilead Sciences Inc.’s Sovaldi became the first of the more effective medicines to hit the market, in 2013, its $84,000 list price — $1,000 a pill — caused sticker shock for payers nationwide. Fearing their budgets would be drained by a rush of people who wanted to get well instead of living with uncertainty, many insurers limited access to Sovaldi. Even from a cold-blooded accountant’s perspective, it was a foolish policy — providing months or years of medical care for someone suffering from cirrhosis costs much more.

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New medication shows promise against liver fibrosis in animal studies

New medication shows promise against liver fibrosis in animal studies

A new drug developed by scientists at the National Institutes of Health limits the progression of liver fibrosis in mice, a hopeful advance against a condition for which there is no current treatment and that often leads to serious liver disease in people with chronic alcoholism and other common diseases.

“This study represents an important step towards an effective treatment for liver fibrosis.”

—George F. Koob, Ph.D., Director, NIAAA

“This study represents an important step towards an effective treatment for liver fibrosis,” said George F. Koob, Ph.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of NIH. A report of the study, led by NIAAA scientists, is now online in JCI Insight.

Liver fibrosis is a gradual scarring of the liver that puts people at risk for progressive liver disease and liver failure. It may develop as a late consequence of chronic alcoholism, viral hepatitis, obesity or diabetes and can progress to cirrhosis and liver cancer, yet currently there is no therapy approved by the U.S. Food and Drug Administration.

The new compound is a chemically modified version of ibipinapant, a brain-penetrating cannabinoid type 1 (CB-1) receptor antagonist used in scientific research. Senior author and NIAAA Scientific Director, Dr. George Kunos’ team modified its structure to reduce its ability to penetrate the brain, and to include a molecular group that directly inhibits iNOS, the enzyme responsible for generating nitrogen compounds that promote inflammation.

“Fibrosis is a multifactorial, complex disorder that can benefit from simultaneous targeting of more than one cellular process,” explained Dr. Kunos.

Dr. Kunos and his NIAAA team developed a new medication that concurrently inhibits both CB-1 receptors and iNOS. The new compound was designed to have only very limited ability to enter the brain in order to avoid the psychiatric side effects that limit the usefulness of currently available, brain-penetrant CB-1 receptor-blocking compounds.

“Inducible nitric oxide synthase, or iNOS, is an enzyme that has been shown to play a fundamental role in liver fibrosis pathology and is a potential target for fibrosis therapy,” said Dr. Kunos. “It is also an important factor in alcoholic liver disease, viral hepatitis, fatty liver disease, and other pathologies that promote liver fibrosis.”

Previous studies have also shown that endocannabinoids, natural messengers in the body that help regulate many biological functions, play a role in liver fibrosis and, current compounds that block CB-1 receptors in the liver are moderately effective against liver fibrosis in animal models of the disease. However, because such compounds penetrate the brain and also block CB-1 receptors in the brain, they have undesirable psychiatric effects.

In the current study, Dr. Kunos and his colleagues tested the compounds in two widely used mouse models of liver fibrosis unrelated to obesity. They found that the new compound was more effective in limiting fibrosis than compounds targeting either CB-1 receptors or iNOS alone.

Dr. Kunos notes that, in addition to the new compound’s decreased ability to cause psychiatric side effects, it has also passed preliminary screening tests for other possible side effects such as genotoxicity or interactions with other receptors or ion channels that could generate “off-target” effects. He adds, however, that the compound will require more extensive safety screening in animals before seeking FDA approval for studies of its therapeutic potential in humans. Dr. Kunos and his colleagues will collaborate with other researchers on such studies in the coming months.

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at: https://www.niaaa.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES

A. A. Butt^1,2,3,*, P. Yan¹, K. Marks³, O. S. Shaikh^1,4, K. E. Sherman⁵

Version of Record online: 26 JUL 2016

DOI: 10.1111/apt.13748

Background

Ribavirin is a key component of several hepatitis C virus (HCV) treatment regimens. However, its utility in combination with newer directly acting anti-viral agents regimens is unclear.

Aim
To determine the SVR rates with paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimen ± ribavirin and compare this with sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens.

Methods
We used Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans to identify HCV genotype 1 infected persons initiated on the above regimens. We excluded those with HIV coinfection, positive HBsAg and missing HCV RNA.

Results
We identified 1235 persons on PrOD (75.5% ribavirin), 1254 on sofosbuvir/simeprevir (16.9% ribavirin) and 4247 on sofosbuvir/ledipasvir (23.3% ribavirin). Among HCV genotype 1a infected persons, ribavirin was prescribed to 99.2% on PrOD, 18.2% on sofosbuvir/simeprevir and 23.3% on sofosbuvir/ledipasvir. The SVR rates ranged from 92.6% to 100% regardless of the treatment regimen, presence of cirrhosis or HCV subtype, except in PrOD group without ribavirin, HCV genotype 1a without cirrhosis (SVR 80%, N = 5). There were minor, clinically insignificant differences in SVR rates in those treated with or without ribavirin in each of the treatment groups, regardless of presence of cirrhosis at baseline. In multivariable logistic regression analysis, ribavirin use was not associated with achieving SVR in any group.

Conclusions
In HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens, are associated with high rates of SVR in actual clinical settings, which are comparable to clinical trials results (except PrOD genotype 1a with cirrhosis where the number was too small). The benefit of adding ribavirin to these regimens in the ERCHIVES treated cohort is not established.

Discussion Only

Full Text Article Available @ Alimentary Pharmacology & Therapeutics

In this large national observational study of HCV infected persons in actual clinical settings, ribavirin use was not associated with any clinically meaningful differences in SVR rates among patients treated with newer DAA regimens. Presence of cirrhosis at baseline, HCV subtype and prior treatment status did not affect these results. Number of HCV genotype 1a infected persons treated with PrOD (without ribavirin) was too small to make any conclusions in this group (n = 6).

Our study demonstrates that treatment for HCV infection with newer oral regimens is associated with high SVR rates in actual clinical settings, and that these rates are comparable to those seen in clinical trials.[23] We have previously shown that treatment with sofosbuvir-based regimens in actual clinical settings is associated with SVR rates similar to clinical trials,[8] and this study provides similar assurance with PrOD regimen in similar settings. To our knowledge, this is among the first and largest study with data from actual clinical settings, that compares the three commonly used newer DAA agents.

Ribavirin was considered an important part of the treatment regimen with pegylated interferon and first generation DAAs. However, its role in all-oral regimens of newer DAAs is less clear. In one recent trial, virological failure was more common without ribavirin than with ribavirin among HCV genotype 1a infected patients but not among those with genotype 1b infection.[10] In another trial, ledipasvir + sofosbuvir + ribavirin for 12 weeks and ledipasvir + sofosbuvir without ribavirin for 24 weeks provided similar SVR12 rates in previous nonresponders with HCV genotype 1 and compensated cirrhosis.[24] Use of ribavirin is associated with significant haematological toxicity and drug–drug interactions, and it is a highly teratogenic agent.[25, 26] In a recent analysis of 1952 patients enrolled in phase III ION clinical trials, treatment-related adverse events were observed in 71% of patients treated with RBV, but in only 45% of patients treated without RBV.[26] While most adverse events were mild in severity and not associated with treatment discontinuation, there is some cost and risk to adding ribavirin to the regimen. Regimens without ribavirin are attractive in such settings.

The strongest and most consistent predictor of achieving SVR was duration of treatment. This is not surprising, and is consistent with numerous previous studies which have assessed patients treated in actual clinical settings.[8, 9] Future studies should assess the role of treatment adherence upon virological outcomes in these patients. Presence of cirrhosis at baseline was associated with a numerically large reduction in SVR rates (37% lower SVR rates for PrOD, 44% for sofosbuvir/simeprevir, 53% for sofosbuvir/ledipasvir), though this did not reach statistical significance in the PrOD group.

The newer treatment regimens remain associated with a low rate of adverse haematological adverse events.[27] Although anaemia was more common in those who received ribavirin, severe (grade 3/4) anaemia remains uncommon overall. In previous studies, we have shown that haematological parameters revert towards baseline after completion of treatment, providing some reassurance regarding the safety of these regimens.[9]

While our study provides new and important clinical information about newer DAA regimens derived from a well-established national database, there are certain limitations that need to be addressed when analysing administrative databases. The information in such databases is collected as part of routine clinical care, and is thus not always collected at rigorously defined time-points during the course of treatment. Given this is an observational study and not a randomized study of ribavirin use, confounding by indication is of concern. Persons who received ribavirin may have been harder to treat; however, in multivariate analysis controlling for these baseline predictors did not reveal a benefit of ribavirin use. Laboratory testing was performed at different laboratories, and subtle differences in results may affect overall results. Definition of cirrhosis was based on a non-invasive clinical marker (FIB-4 score), which was based on routine laboratory testing which may have been performed at different time-points prior to baseline. Number of persons in HCV genotype 1a PrOD group was too small (n = 6) to make any conclusions, and clinical trials data suggest that adding ribavirin in genotype 1a patients may be of some benefit.[10] We also did not analyse the role of resistance associated mutations upon virological response rates.

In conclusion, in HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens are associated with high rates of SVR in actual clinical settings, which are comparable to those achieved in clinical trials (except PrOD genotype 1a with cirrhosis where number was too small). Addition of ribavirin to the regimen does not appear to enhance SVR rates in a clinically meaningful way, with the caveat that the number of persons in HCV genotype 1a PrOD group was too small to make any conclusions.

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1. Summary
2. Introduction
3. Methods
4. Results
5. Discussion
6. Authorship
7. Acknowledgements
8. References
9. Supporting Information
   
   

Discovery of new Hepatitis C Virus mechanism

Discovery of new Hepatitis C Virus mechanism

Osaka University

IMAGE: SPP inhibition reduces production of infectious HCV particles and pathogenesis, view more

Credit: Aizawa and Okamato et al. Nat Commun (2016)

Researchers at Osaka University, Japan uncovered the mechanisms that suppress the propagation of the hepatitis C virus (HCV) with the potential of improving pathological liver conditions. Using model mice, they confirmed that when a certain enzyme is inhibited, HCV particle production is reduced leading to an improvement of pathological liver conditions. They thereby identified a new drug target for the development of new HCV drugs.

About 200 million people around the world are infected with the HCV virus. HCV infection may cause fatty liver, hepatic fibrosis and liver cancer. In Japan, the HCV virus is the main cause for viral liver cancer, constituting 70% of liver cancers. Although the recent development of effective drugs targeting HCV replicative enzymes has enabled the elimination of HCV, challenges remain including the emergence of resistant viruses and the development of liver cancer after virus elimination. So far it was known that the cleavage of the HCV core protein by the enzyme signal-peptide peptidase (SPP) in infected host cells played an important role in the formation of viral particles and the development of pathological liver conditions. However, the details of this mechanism were not understood.

A research group led by Toru Okamoto, assistant professor and Yoshiharu Matsuura, professor at Research Institute for Microbial Diseases, Osaka University has now discovered that when the enzyme SPP is inhibited, HCV particle production is reduced resulting in an improvement of pathological liver conditions.

The researchers found a chemical compound that inhibits the SPP enzyme in the y-secretase inhibitor which is currently in the development process for Alzheimer's disease treatment. They also discovered that the immature core proteins which are not cleaved by SPP are recognized by the enzyme TRC8 and quickly degraded. If this degradation process is suppressed, cellular damage is strongly induced by endoplasmic reticulum stress (ER stress). The endoplasmic reticulum is central to protein biosynthesis and in a state of ER stress, the proteins synthesizing there are unable to fold up correctly thereby causing cell damage. This degradation process can therefore be considered as a quality control mechanism for new proteins. When the researchers administered the SPP inhibitor to model mice, HCV particle production was significantly reduced, improving HVC pathologic conditions such as insulin resistance and fatty liver.

The results of this study suggest the development of SPP inhibitors as a new hepatitis C drug. In addition, the observed protein quality control mechanism via SPP/TRC8 is thought to be related to other diseases as well thereby being potentially useful for the drug development for a variety of diseases.

###

This research was featured in the electronic version of Nature Communications on Wednesday, May 4, 2016 (British Time).

http://www.eurekalert.org/pub_releases/2016-07/ou-don072716.php

FDA Hepatitis Update/ VIEKIRA XR - DOSAGE AND ADMINISTRATION

FDA Hepatitis Update

On July 22, 2016 FDA approved VIEKIRA XR extended release tablets. VIEKIRA XR is a fixed dose combination tablet of previously approved antiviral drugs containing dasabuvir, a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor, ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, and ritonavir, a CYP3A inhibitor, indicated for the treatment of adult patients with chronic hepatitis C virus (HCV):

• genotype 1b infection without cirrhosis or with compensated cirrhosis
• genotype 1a infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin.

VIEKIRA XR differs from VIEKIRA Pak in that all of the HCV antiviral drugs are now combined in one fixed dose combination tablet for once daily dosing. The daily mg dose of dasabuvir is higher, and dasabuvir is administered once daily as part of the fixed dose combination.

The recommended dosage of VIEKIRA XR is three tablets taken orally once daily. VIEKIRA XR must be taken with a meal.

The approval of VIEKIRA XR is based on comparability of bioavailability for each of the components in VIEKIRA XR compared to that of the previously approved formulations in VIEKIRA Pak. A clinical trial to evaluate the efficacy and safety of Viekira XR FDC was not required because the efficacy and safety of the components of VIEKIRA XR were established previously in six clinical trials enrolling 2,308 Chronic Hepatitis C patients with and without cirrhosis.

DOSAGE AND ADMINISTRATION
Testing Prior to Initiation of VIEKIRA XR
Prior to initiation of VIEKIRA XR, assess for laboratory and clinical evidence of hepatic decompensation.

Recommended Dosage in Adults
VIEKIRA XR is a 4-drug fixed-dose combination, extended-release tablet containing 200 mg of dasabuvir, 8.33 mg of ombitasvir, 50 mg of paritaprevir, and 33.33 mg of ritonavir. The recommended dosage of VIEKIRA XR is three tablets taken orally once daily.

• VIEKIRA XR must be taken with a meal because administration under fasting conditions may result in reduced virologic response and possible development of resistance.
• Swallow tablets whole. Splitting, crushing, or chewing tablets may compromise the extended-release performance, efficacy, and/or safety of VIEKIRA XR.
• For optimal release of dasabuvir, alcohol should not be consumed within 4 hours of taking VIEKIRA XR.   

VIEKIRA XR is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA XR, the recommended dosage of RBV is based on weight: 1000 mg/day for subjects

For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1.
Table 1 shows the recommended VIEKIRA XR treatment regimen and duration based on patient population.

Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced)

Patient Population	Treatment*	Duration
Genotype 1a, without cirrhosis	VIEKIRA XR + ribavirin	12 weeks
Genotype 1a, with compensated cirrhosis (Child-Pugh A)	VIEKIRA XR + ribavirin	24 weeks**
Genotype 1b, with or without compensated cirrhosis (Child-Pugh A)	VIEKIRA XR	12 weeks

*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.
**VIEKIRA XR administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history

Use in Liver Transplant Recipients
In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or lower), the recommended duration of VIEKIRA XR with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype. When VIEKIRA XR is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed.

Hepatic Impairment
VIEKIRA XR is contraindicated in patients with moderate to severe hepatic impairment (Child Pugh B and C)
The complete label for VIEKIRA XR is available at Drugs@FDA.

VIEKIRA XR full Prescribing Information, including the Medication Guide.
VIEKIRA PAK full Prescribing Information, including the Medication Guide.

AbbVie Press Release
AbbVie Receives U.S. FDA Approval of Once-Daily VIEKIRA XR™ (dasabuvir, ombitasvir, paritaprevir and ritonavir) for the Treatment of Genotype 1 Chronic Hepatitis C

Know your hepatitis status – increasing access to testing for a hidden infection.

25 July 2016 – A staggering 95% of people infected with hepatitis B or C do not know they are infected, often living without symptoms for many years. Ahead of World Hepatitis Day, 28 July 2016, WHO and its partner, Social Entrepreneurship for Sexual Health (SeSH), recently launched a global contest to find innovative ways to reach different populations and encourage testing for hepatitis

Know your hepatitis status – increasing access to testing for a hidden infection.
July 2016 

Do you know if you could be infected with hepatitis B or C? What that could mean for your health?

A staggering 95% of people infected with hepatitis B or C around the world do not know they are infected. One reason for this is that people can live without symptoms for many years. When they find out they have hepatitis, it is often too late for treatment to be fully effective. As a result, liver damage becomes cirrhosis or liver cancer.

To help countries build up national hepatitis testing and treatment programmes and to encourage more people globally to get tested, WHO will shortly release new testing guidelines for hepatitis B and C.

To show how the testing guidelines could translate into real action on the ground, WHO and its partner, Social Entrepreneurship for Sexual Health (SeSH) recently launched a contest to find real-world examples of innovative ways to reach different populations across various countries and settings and test for hepatitis.

The #HepTestContest Innovation Contest received 64 contributions from 27 countries. The project selected around 20 of the best approaches to testing for hepatitis, and then whittled down the list to 5 finalists.

A multi-faceted approach

As well as national testing campaigns, approaches include testing in prisons, testing in the workplace and hospital emergency rooms, integrated HIV-hepatitis testing, as well as the use of internet, social media, and electronic medical records to flag higher risk patients for testing in primary care.

“We needed examples of innovations and best practices to help guide and inspire others,” said Philippa Easterbrook from the WHO Global Hepatitis Programme, who co-led the project. “From prisons in Australia, use of an internet-based risk self-assessment tool in the Netherlands, community testing camps for drug users in India, to testing in primary care in Mongolia we learned some great lessons about how to build awareness of this hidden disease, improve testing rates and link those infected to treatment and care.“

In Manipur, a small state in North East India, an estimated 92% to 98% of drug users are estimated to have hepatitis C. Although HIV testing is free here, testing for hepatitis is not. Awareness about the virus is low and treatment expensive.

A community network organization, the Community Network for Empowerment (CoNE) led the campaign: “We organized awareness-raising sessions, and encouraged free voluntary testing for over a month. Of the 1011 people tested, just under half were positive for hepatitis C. We provided post-test counselling and were also able to offer treatment,” described Rajkumar Nalinikanta, the organization’s president.

Community involvement and strategic partnerships

A critical feature of this approach was the strong community involvement and support as well as strategic partnerships to leverage reductions in the price of treatments. “Bringing together pharmaceutical companies, government, research organizations and communities helped negotiate price reductions make hepatitis treatments more affordable,” concluded Dr Easterbrook.”

Thousands of miles away in the Netherlands, another campaign used an internet-based risk assessment to target populations of people infected with hepatitis C who were difficult to identify and hard to reach.

“We used social media and the web to draw in people who might be at risk to undertake a self-assessment in a choice of 7 languages. The anonymity of the internet helped enormously,” said Janke Schinkel of the Public Health Service of Amsterdam. “This was balanced with highly visible and creative public communication campaigns – that reached a cross-section of Dutch society.”

“The contest demonstrated a range of possibilities. It showed that if we can develop acceptable testing approaches to suit different contexts and cultures, then we can increase effective hepatitis testing in more countries and communities,” concluded Dr Easterbrook.

These 2 approaches were among the 5 finalists selected by a panel of experts including representatives from WHO, World Hepatitis Alliance, and Médecins sans Frontières, who reviewed the testing models for innovation, effectiveness, and plans for sustainability.

http://www.who.int/en/

World Hepatitis Day 2016

News release for World Hepatitis Day 2016

Why baby boomers need a hepatitis C screening

Why baby boomers need a hepatitis C screening
26-Jul-2016

Electronic medical record alerts contribute to dramatic rise in HepC screening

University of Michigan Health System

Baby boomers, adults born between 1945 and 1965, are five times more likely to have been exposed to the hepatitis C virus (HCV).

As a result, the Centers for Disease Control and Prevention and the U.S. Preventive Service Task Force recommend that all patients in that age group get tested.

But the simple blood test, designed to detect and prevent illness before the virus wreaks havoc, is infrequently performed on baby boomers whose routine medical appointments are often crammed with other preventive measures and tests -- as well as time spent addressing active problems that require a doctor's immediate attention.

Investigators at the University of Michigan Health System recently found an easy way to help primary care physicians ensure that an HCV screening is part of the routine: Electronic medical record alerts.

The automated alert, programmed to appear if a patient was within the at-risk age group, reminds doctors not only to issue the test but also provide educational materials about the virus.

Implemented in fall 2015 in primary care clinics throughout the U-M health system, the strategy contributed to a significant rise in screenings -- an eightfold boost -- in the first six months alone.

"A large part of the success was figuring out how to take the logistical work away, which involves more than looking at a patient's date of birth," says Monica Konerman, M.D., M.Sc., a hepatologist at the University of Michigan who treats patients facing the prospect of hepatitis damaging their liver.

A population in need

It isn't entire clear why hepatitis C rates are higher in baby boomers -- although many, according to the CDC, are believed to have become infected during the 1970s and 80s when rates were highest (and before screenings of donated blood and organs became available in 1992).

Hepatitis C, likewise, can be asymptomatic for decades. Many patients could have been exposed to risk factors years ago but never sought testing or treatment.

A universal one-time HCV screening based on age, then, can bypass the discomfort of having to talk about potentially embarrassing topics such as prior drug use or sharing needles.

It also helps democratize preventive care. Prior to launching the alert, HCV screening was higher in men, Asian and African Americans, and in patients with Medicaid insurance. Screening rates also varied greatly by clinic site (ranging from 20 to 32 percent).

After the alert was adopted, however, screenings increased equally among genders, races, insurance plans and UMHS clinic sites.

Why screening matters

The screening test for hepatitis C is the virus antibody. If the hepatitis C antibody is detected, a confirmation test for the virus' RNA (genetic material) is recommended to confirm chronic infection.

Of the 16,773 baby boomers targeted for screening via electronic alert at UMHS, fewer than 1 percent tested positive for the hepatitis C antibody.

Despite that low rate, the alert system nonetheless helped identify people who would benefit from curative hepatitis C treatment, says Konerman, who presented the findings in May at the Digestive Disease Week conference in San Diego.

After all, a new era in hepatitis treatment began in 2013 with the approval of interferon-free oral combination therapy that was demonstrated in clinical trials studies led by the U-M to cure hepatitis C in 95 percent of patients. If treated and the body responds, patients can get rid of the virus before liver damage and liver failure occur.

Which is why the new alert technology is crucial for a population that could benefit most from HCV screening.

"The availability of direct-acting antiviral agents has been a game-changer," says Konerman. "Previously, many providers thought screening had low utility: (that) the treatment was terrible and didn't work well. Today, short courses of all oral treatments are highly effective and can prevent progressive liver disease."

http://www.med.umich.edu

Children Exposed To Hepatitis C May Be Missing Out On Treatment

Public Health

Children Exposed To Hepatitis C May Be Missing Out On Treatment
July 26, 20165:00 AM ET
Elana Gordon

Several times a month, Jessica Wen, a pediatrician specializing in liver diseases, has a teenager show up at her clinic at the Children's Hospital of Philadelphia with an unexpected diagnosis: hepatitis C.

Hepatitis C virus, or HCV, is the most common bloodborne infection in the U.S. and a leading cause of liver failure and cancer. Injection drug use is a common risk factor, as is receiving a blood transfusion before 1992. But some of the teens Wen sees picked up the illness another way: at birth, from their mothers.

"I have diagnosed moms after diagnosing the kids," Wen says, referring to mothers who have hepatitis C, didn't know it and then passed it to their babies during childbirth. Wen estimates that about 1 or 2 of every 1,000 young children have chronic hepatitis C.

A study by the Philadelphia Department of Health points to what Wen and others in the medical profession see as a worrisome trend: Children with hepatitis C may be unaware of their diagnosis and the potential need for treatments down the road in order to prevent long-term liver damage.

Using city surveillance data, the study found that as many as 8 in 10 children at high risk for hepatitis C exposure in Philadelphia were never screened for the condition. More specifically, of the approximately 500 moms-to-be who were registered as having hepatitis C between 2011 and 2013, only 84 of their newborns, or about 16 percent, were tested for the virus by 20 months of age.

"Sixteen percent is really low," says Danica Kuncio, lead author of the study. "When you think about children, you hope that the number would be 100 percent, that it should be in the interest of every provider to be doing the best they can to get information to the next provider."

Kuncio, an epidemiologist with the city, worries that people who don't know they contracted hepatitis C as babies won't get the health care they need or realize they could spread the virus to others through blood-to-blood contact. It's a concern intensified by a rise in both injection drug use and hepatitis C among women of childbearing age, she said.

"It's a call to arms to figure out how we can do this better," said Dr. Michael Narkewicz, who specializes in pediatric liver diseases and hepatitis C at the University of Colorado School of Medicine.

Not so long ago, the lack of drugs to cure hepatitis C made screening less of a priority. But in 2013, the Food and Drug Administration approved the first of several drugs that effectively eliminate the virus. Now, with access to these expensive medicines, the condition has gone from chronic and debilitating to curable.

Narkewicz and others say the next frontier is to prove these treatments are safe and effective in children. Clinical trials are underway, and he thinks the drugs could become available for children in the next year or two.

But unlike HIV, which has safe and effective treatments that can dramatically reduce transmission of the virus from mother to child, "for hepatitis C, there are no treatments to prevent transmission in a mom or in a newborn," said Narkewicz.

Hepatitis C in children may be lacking attention for another reason: perinatal transmission rates are a lot lower for Hepatitis C compared to hepatitis B and HIV. For every 100 babies born to women with HCV, five to seven will contract the virus. Of those who do get it, 30 to 40 percent will clear it on their own before the age of two, said Narkewicz. That's why the current protocols for children exposed to HCV call for monitoring and then screening them at 18 months with an antibody test.

But up to 15 percent of those born with HCV will develop a more aggressive form of the disease during adolescence, said Narkewicz, which can result in advanced fibrosis or liver scarring that can progress over time. "It's a small percentage, but it's still a real number," he said.

The medical community really hasn't done a good job of projecting the costs and benefits of early identification and treatment in children, according to Dr. Rhavi Javeri, a pediatrician at UNC Children's Hospital in Chapel Hill, N.C.

"A lot of these other issues related to mom-to-infant transmission, it really all fallen by the wayside," Javeri says. "[The conversation] still falls on, we don't have resources to treat patients that are the priority right now."

Having new drugs to treat hepatitis C in children will be a game-changer, according to Dr. Regino Gonzalez-Peralta, a pediatrician at the University of Florida Health System in Gainesville.

"The old dogma was, why screen mothers if there's nothing to be done?" says Gonzalez-Peralta, who has also been studying gaps in identifying children infected with HCV.

He says that while drugs to prevent transmission are not yet available, there are promising developments. "Now we've got drugs that potentially might be useful in preventing maternal-fetal transmission. This is going to become a hotter area," he says.

Another issue under debate is universal screening for the virus. Dr. Damien Croft, an obstetrician at Hahnemann University Hospital in Philadelphia, doesn't advocate it for everyone in the country. But he thinks it might be a good idea for his pool of patients. "There [are] enough women who are high risk for hepatitis C in Philadelphia that maybe we should consider doing that."

Croft also thinks it's important to improve communication between obstetricians and pediatricians so the pediatrician will know which children are at higher risk for having hepatitis C and can recommend screening.

In the meantime, Philadelphia's health department has begun working with health care providers and at-risk mothers in the city to improve the testing of infants born to women with hepatitis C, and when necessary, linking mother or child to specialists.

This story is part of a reporting partnership with NPR, WHYY's health show The Pulse and Kaiser Health News.

http://www.npr.org

Also See;
Earlier Identification of HCV in Young Women, Babies Needed​

(MMWR) Increased Hepatitis C Detection in Women of Childbearing Age and Potential Risk for Vertical Transmission

Shared Drug Snorting Straws May Transmit Hepatitis C Virus
FRIDAY, July 22, 2016 (HealthDay News) -- Sharing snorting straws for noninjection drug use may be a source for hepatitis C virus (HCV) transmission, according to research published in the August issue of Obstetrics & Gynecology.
Here is the report; Sharing of snorting straws and hepatitis C virus infection in pregnant women

Pricey drugs overwhelm Medicare safeguard

Pricey drugs overwhelm Medicare safeguard
July 25, 2016 by Ricardo Alonso-Zaldivar

A safeguard for Medicare beneficiaries has become a way for drugmakers to get paid billions of dollars for pricey medications at taxpayer expense, government numbers show.

The cost of Medicare's "catastrophic" prescription coverage jumped by 85 percent in three years, from $27.7 billion in 2013 to $51.3 billion in 2015, according to the program's number-crunching Office of the Actuary.

Out of some 2,750 drugs covered by Medicare's Part D benefit, two pills for hepatitis C infection—Harvoni and Sovaldi—accounted for nearly $7.5 billion in catastrophic drug costs in 2015.

Continue reading....

Weekend Reading: Coffee can play a role in reducing risks of cancer and diabetes

Coffee can play a role in reducing risks of cancer and diabetes

Good day folks, in this issue of "Weekend Reading" we point you to a podcast over at ABC Radio on the many health benefits of drinking coffee, hosted by Dr. Kruszelnicki.

Topics covered in the two part program include the effect of caffeine on; liver cancer, type II diabetes, prostate cancer, oral cancer, and heart disease.

But what about the side effects of drinking coffee, good or bad?

There is a body of evidence that some of the side effects of coffee may actually be good for you, and they appear to have nothing to do with caffeine. But Dr Karl Kruszelnicki's grind is the observational studies that make up the 'statistics' behind the health benefits.

Listen to the podcast or read the transcript;

Coffee is now good for us—or is it?
Part One - Listen here
July 12 2016
Yes, it is a drug, and so we should remember the words of Paracelsus, 'all drugs are poisons, what matters is the dose.' Based on the fact that coffee has been used widely for over a millennium, we would expect its bad side-effects would be fairly minimal—so long as we don't take too much.
Read the transcript

Part Two - Listen here
July 19,2016
Coffee can play a role in reducing risks of cancer and diabetes
It seems that beside caffeine, there are other natural chemicals in coffee that can help with medical conditions. With regard to liver cancer, two chemicals, kahweol and cafestrol, have direct cancer protection and anti-inflammatory properties. They seem to 'upregulate biochemical pathways in the liver that protect the body from toxins, including aflatoxin and other carcinogenic compounds'.
Read the transcript

Cheers!

Behind the Headlines - Alcohol 'a direct cause of seven types of cancer'

Behind The Headlines: Analysis by Bazian edited by NHS Choices

What is Behind the Headlines?
Each day the NHS Choices team selects health stories that are making headlines. These, along with the scientific articles behind the stories, are sent to Bazian, a leading provider of evidence-based healthcare information. Bazian's clinicians and scientists analyse the research and produce impartial evidence-based assessments, which are edited and published by NHS Choices.

Alcohol 'a direct cause of seven types of cancer'
Friday July 22 2016
Several studies looking at whether alcohol causes cancer were looked at during the research

Alcohol can increase your cancer risk
"Even one glass of wine a day raises the risk of cancer: Alarming study reveals booze is linked to at least seven forms of the disease," reports the Mail Online.

The news comes from a review that aimed to summarise data from a range of previous studies to evaluate the strength of evidence that alcohol causes cancer.

The main finding was that existing evidence supports the link between alcohol consumption and cancer at seven sites, including the throat, gullet, liver, colon, rectum and female breast.

The links were said to be strongest for heavy drinking, but this study suggested that even low or moderate drinking may contribute to a significant proportion of cancer cases because of how common this level of drinking is. The study also suggests there's no evidence of a "safe" level of drinking with respect to cancer.

However, it's important to be aware that this review doesn't state how the author identified and assessed the research they've drawn upon. We don't know whether all relevant research has been considered and the conclusions must be considered largely the opinion of this single author.

Nevertheless, the main finding of the link between alcohol and these seven cancers is already well recognised.  Recently updated government recommendations state there's no safe level of alcohol consumption, and men and women are advised not to regularly drink more than 14 units a week. This review further supports this advice.

Where did the story come from?
The study was published in the peer-reviewed scientific journal Addiction. It is available on an open-access basis and is free to read online.

The study was published in the peer-reviewed scientific journal Addiction. It is available on an open-access basis and is free to read online.

Generally the media coverage of this topic was accurate, although the tone of the reporting tended to suggest this was a new discovery, when the link between alcohol and certain types of cancer is well established.

What kind of research was this?
This was a review which aimed to summarise data from published biological and epidemiological research, and meta-analyses that have pooled data, to evaluate the strength of evidence that alcohol causes cancer.

Alcoholic drinks have been considered potentially carcinogenic (cancer causing) for a while, but there are still concerns about the validity of some observational studies finding links with cancer, and uncertainty about precisely how alcohol causes cancer.

A systematic review is the best way of gathering and summarising the available research around a particular topic area. But in this case the exact methods are not described in the paper and it's not possible to say whether they were systematic.

There's a possibility that some relevant research may have been missed and that this review is giving an incomplete picture of the issue

What did the research involve?
The author of this review reports drawing upon biological and epidemiological research as well as meta-analyses conducted in the last 10 years by a number of institutions, including the World Cancer Research Fund and American Institute for Cancer Research, the International Agency for Research on Cancer and the Global Burden of Disease Alcohol Group.

The majority of epidemiological research seemed to come from cohort and observational studies.
The research was reviewed and summarised in a narrative format which explored the evidence that alcohol causes cancer, while contrasting this with the notion that alcohol consumption may offer some form of protection from cardiovascular disease.

No methods are provided and the author does not describe how they identified the research, as you would expect from a systematic review.  For example, they do not give the literature databases searched, the search dates, search terms, study inclusion or exclusion criteria, or descriptions of how studies were quality assessed.  

What were the basic results?
There were several findings from this study, the main one being that existing evidence supports the link between alcohol consumption and cancer at seven sites: oropharynx (mouth and throat), larynx (voice box), oesophagus (gullet), liver, colon (bowel), rectum and female breast.

The strength of the association differed by the site of the cancer. It was strongest for the mouth, throat and oesophagus, with the review suggesting that someone who drinks more than 50g of alcohol a day is four to seven times more likely to develop these types of cancer compared to someone who doesn't drink. As the author says, the interaction of smoking with alcohol is also believed to contribute to the risk of these cancers.

The link was comparatively weaker for colorectal, liver and breast cancer. The review suggests someone who drinks more than 50g of alcohol a day is 1.5 times more likely to develop these types of cancer compared to someone who doesn't drink.

For all of these associations there was a dose-response relationship, where increased consumption was linked with an increase in cancer risk. This applied to all types of alcoholic drinks. The highest risks were associated with heavier drinking. There was also some suggestion that the level of risk goes down over time when alcohol consumption stops.

Recent large studies have found uncertain evidence whether low to moderate consumption has a significant effect on total cancer risk. But given that this level of consumption is common in the general population, the author considers that it could still contribute to a significant number of cases.

Furthermore, they say there is no clear threshold of what constitutes a harmful level of alcohol consumption, and therefore no safe level of drinking with respect to cancer.

The author also suggests that confounding factors may be responsible for the protective effect between alcohol consumption and cardiovascular disease that has been found in previous studies. For example, this may be due to the potential bias caused by misclassification of former drinkers as abstainers.

The research went on to report that alcohol is estimated to be responsible for approximately half a million deaths from cancer in 2012 and 5.8% of cancer deaths worldwide, deeming it to be a significant public health burden.

How did the researchers interpret the results?
The author concluded: "There is strong evidence that alcohol causes cancer at seven sites, and probably others. The measured associations exhibit gradients of effect that are biologically plausible, and there is some evidence of reversibility of risk in laryngeal, pharyngeal and liver cancers when consumption ceases."

"The highest risks are associated with the heaviest drinking, but a considerable burden is experienced by drinkers with low to moderate consumption, due to the distribution of drinking in the population."

Conclusion
This narrative review aimed to summarise data from published biological and epidemiological research to discuss the strength of evidence that alcohol causes cancer.

The author gives their main finding as a link between alcohol consumption and cancer at seven sites, and also that the highest risks seem to be associated with heavier drinking. However, they state there's no "safe" drinking threshold and that low to moderate consumption still contributes to a significant number of cancer cases.

The biggest limitation of this review is that it doesn't appear to be systematic. The author provided no methods for how they identified and appraised the research they drew on. Despite referencing a number of large studies and reviews, this study and its conclusions have to be considered largely the opinion of the author following their appraisal of the evidence.

We don't know whether the review has considered all research relevant to the topic and is able to reliably quantify the risks of cancer – overall or at specific sites – associated with alcohol consumption.

An additional limitation to keep in mind is that this data mainly appeared to be from observational studies. These cannot prove cause and effect. The individual studies will likely have varied considerably in the additional health and lifestyle factors they took account of when looking at the links with alcohol. For example, smoking, diet and physical activity are all factors likely to be associated both with level of alcohol consumption and cancer risk.

As the author notes in particular, confounding factors may be responsible for the observed protective effect between alcohol consumption and cardiovascular disease.

Another limitation is that alcohol consumption is likely to be self-reported in the studies analysed, which may be inaccurate and lead to misclassification. For example, a potential bias that the author notes is classifying former drinkers as abstainers.

The author does consider the limitations of these observational findings, saying: "The limitations of cohort studies mean that the true effects may be somewhat weaker or stronger than estimated currently, but are unlikely to be qualitatively different."

But despite the methodological limitations of this review, it does support current understanding around this topic. Cancer Research UK also reports that alcohol can increase risk of these seven cancers and that there is no "safe" alcohol limit.

While we can't give a safe limit to drink when it comes to cancer, people are advised to follow current alcohol recommendations, which are to drink no more than 14 units per week and to spread your drinking over three days or more if you drink as much as 14 units a week.

Analysis by Bazian
Edited by NHS Choices

Links to the headlines
Even one glass of wine a day raises the risk of cancer: Alarming study reveals booze is linked to at least seven forms of the disease. Mail Online, July 22 2016
Alcohol is a direct cause of seven ​​forms of cancer, finds study. The Guardian, July 22 2016
Alcohol linked to at least seven types of cancer, study says, while 'health benefits are irrelevant'. The Telegraph, July 22 2016
Alcohol raises risk of seven different cancers, experts warn – even just one glass. Daily Mirror, July 22 2016
Alcohol causes seven types of cancer – and probably others, study finds. The Independent, July 22 2016

Links to the science
Connor J. Alcohol consumption as a cause of cancer. Addiction. Published online July 21 2016

Twin epidemics of new and prevalent hepatitis C infections in Canada: BC Hepatitis Testers Cohort

Twin epidemics of new and prevalent hepatitis C infections in Canada: BC Hepatitis Testers Cohort

Naveed Zafar JanjuaEmail author, Amanda Yu, Margot Kuo, Maria Alvarez, Darrel Cook, Jason Wong, Mark W. Tyndall and Mel Krajden BMC Infectious DiseasesBMC series – open, inclusive and trusted201616:334 DOI: 10.1186/s12879-016-1683-z © The Author(s). 2016

Received: 12 January 2016 Accepted: 13 June 2016 Published: 19 July 2016
Open Access Full Text - BMC Infectious Diseases

Abstract
Background

We characterized the twin epidemics of new and prevalent hepatitis C virus (HCV) infections in British Columbia, Canada to inform prevention, care and treatment programs.

Methods
The BC Hepatitis Testers Cohort (BC-HTC) includes individuals tested for HCV, HIV or reported as a case of HBV, HCV, HIV or active TB between 1990–2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Prevalent infection was defined as being anti-HCV positive at first test. Those with a negative test followed by a positive test were considered seroconverters or new infections.

Results
Of 1,132,855 individuals tested for HCV, 64,634 (5.8 %) were positive and an additional 3092 cases tested positive elsewhere for a total of 67,726. Of 55,781 HCV positive individuals alive at the end of 2013, 7064 were seroconverters while 48,717 had prevalent infection at diagnosis. The HCV positivity rate (11.2 %) was highest in birth cohort 1945–1964 which declined over time. New infections were more likely to be male, 15–34 years of age (born 1965-1984), HIV- or HBV-coinfected, socioeconomically disadvantaged, have problematic drug and alcohol use and a mental health illness. The profile was similar for individuals with prevalent infection, except for lower odds of HBV-coinfection, major mental health diagnoses and birth cohort >1975.

Conclusions
The HCV positivity rate is highest in birth cohort 1945–1964 which represents most prevalent infections. New infections occur in younger birth cohorts who are commonly coinfected with HIV and/or HBV, socioeconomically marginalized, and living with mental illness and addictions.

KeywordsHCV Hepatitis B HIV Epidemiology Screening Cohort study

Discussion Only

View full text article, here..

We used a large cohort of more than one million people tested for HCV in BC, and while accounting for mortality, we found that a large number of people are currently living with HCV. The highest positivity rate was among people born in 1945-64, which declined over time and was lowest in 2013. New infections were detected mainly among younger age groups. The new HCV infection (seroconversion) rate was highest among males, those with HIV or HBV co-infection, mental health conditions, problematic alcohol or illicit drug use, and socioeconomically disadvantaged persons. Prevalent HCV infection was associated with being male, born 1945-64, HIV co-infected, problem alcohol and illicit drug use, and socioeconomic deprivation. These findings of twin epidemics highlight important opportunities for prevention, testing and treatment of HCV.

In this analysis, we identified two groups of HCV infected individuals: new infections (seroconverters) and those with prevalent HCV infection. Most of those with prevalent HCV were born 1945-1964, while most newly infected individuals were younger. However, the seroconverters are not a homogeneous group: 24-month seroconverters differed from >24 months seroconverters in terms of age, sex, testing patterns, and HBV co-infection rate. Surveillance data on acute HCV infections indicate that 70 % of seroconverters reported injection drug use in the past 12 months [18]. In a BC-HTC subset for whom self-reported risk factor data was available, 85 % of those who self-reported injection drug use had a medical visit for illicit drug use. Thus, 24-month seroconverters most likely acquired HCV through their injection drug use networks.

Most of the HCV cases, especially prevalent infections, were identified among those born 1945-64 and the positivity rate was much higher in this group, especially for those born 1950-1960. Similarly high 1945-64 birth cohort positivity rates have been reported in various studies from the United States [19, 20, 21, 22]. Using reported HCV cases in Canada, Trubnikov et al. found the highest HCV prevalence among the 1950-54 and 1955-59 birth cohorts, followed by 1960-64 and 1966-69, while prevalence among those born 1945-49 was lower than for those born 1965-69 [2]. In contrast, in our study, the positivity rate for birth cohort 1945-49 was higher than for birth cohort 1965-69 (Fig. 2). Our findings are also consistent with a study which assessed HCV related hospital admissions where the 1950-54 and 1955-59 birth cohorts had the highest rates [23]. Although the positivity rate is still highest among the 1945-64 birth cohort, the rate in this cohort has been declining over successive years suggesting a decreasing pool of undiagnosed prevalent HCV infections. Canada has had risk based testing guidelines since 1994 [24]. The declining positivity rate in this birth cohort suggests that testing driven by risk based guidelines have been able to identify most people with current or past risk activities and diagnose most of the HCV infections in this cohort. However, risk based testing may not identify individuals who are unable to recall or are unwilling to disclose remote risk behaviors. The US Preventive Services Task Force has recommended one time testing of individuals born 1945-65 [22]. Further studies on feasibility and cost effectiveness of various strategies are needed to identify undiagnosed infections in BC.

Risk factors for both new and prevalent HCV infections were similar with some notable exceptions, including age, birth cohort, drug use, HBV co-infection and mental health diagnoses. HBV co-infection and mental health problems were significantly associated with increased odds of new infection but decreased odds of prevalent HCV infection, while ORs for illicit drug use compared to no drug use among new infections (AOR = 21) were four times than those for prevalent HCV infection (AOR = 5.0). ORs for prevalent HCV infection were highest for birth cohort 1945-64 and declined thereafter, while among new infections, ORs were highest for those born later, consistent with an earlier analysis demonstrating a higher HCV incidence rate in younger birth cohorts [25]. Demographic characteristics and risk factors for prevalent HCV were also consistent with recent data from the United States and Canada [8, 20]. Likewise, in a recent electronic medical record based study from the US, being a baby boomer, male, people who injects drugs (PWID), HIV co-infected and having low income were associated with HCV positivity [26]. Risk factors among new infections were also similar to those identified with HCV infection in high risk populations, mainly PWID. Among seroconverters especially 24-months seroconverters, those born 1965-84, HIV/HBV co-infection, socioeconomic deprivation, mental illness, illicit drug use and problematic alcohol use were more common than among prevalent HCV infections (Table 1/Fig. 1). These findings highlight the presence of syndemics of blood-borne infections (BBI), mental illness, addiction, and socioeconomic marginalization in this population as has been reported by others [27, 28, 29]. Addressing these syndemics requires comprehensive services including integrated testing, prevention and treatment for STI/BBIs, as well as mental health and addiction services to address the needs of this population group.

Findings from this paper should be interpreted in the context of some methodological issues. The validity of our estimates depends on the successful linkage rate. Linkage rates were very high for HCV (>85 %), especially in recent years [14]. Linkage rates for those HIV co-infected were much higher than the overall HIV linkage rate, especially before 2005. Thus, the HIV co-infection rate may have been underestimated. However, as reported earlier, we used multiple sources of HIV status identification to reduce underestimation. In this study, we did not have access to immigration and Aboriginal status data and hence we were not able to characterize the disease burden among immigrants and Aboriginal populations. Other data suggest that Aboriginal people are five times more likely to be infected with HCV [30]. Immigrants from endemic countries are also more likely to have higher HCV infection rates.

To date, laboratory testing for HCV has followed risk based guidelines and hence a higher positivity rate among HCV testers in this cohort is expected compared to the general population. However, general population surveys such as the Canadian Health Measures Survey may not capture high risk populations with higher HCV prevalence thus and may underestimate total population of infected individuals [8, 20]. Categorizing prevalent infections based on being positive at the first test may be an over-estimate as some of these individuals are likely to be recent seroconverters as shown in our recent molecular analysis [31]. The prevalent HCV case detection could be affected by presence of late stage symptomatic disease or survival. Survival may also affect the difference in risk factor profile between prevalent and new cases. In the BC-HTC, data is available on all cohort members many years before cohort initiation to assess risk factors as presented in Table 1. Thus, for all cohort members regardless of first test or diagnosis date, data on risk factors started at the same time, providing ample time to assess risk factors from the available data. Furthermore, after accounting for mortality in the cohort, there was no difference in identified risk factor patterns in models including both currently alive and dead and only those currently who are currently alive. Thus, survival bias is unlikely to explain difference in risk factor profile between prevalent and new infections. However, survival bias is not expected to be completely eliminated especially in early nineties, when people could have died before HCV diagnosis or getting diagnosed because of symptoms related to late stage disease. In another analysis, we found that late HCV diagnosis in relation to advance stage liver disease (hepatocellular carcinoma and decompensated cirrhosis) was common in early nineties and have declined substantially over time [32].

In the current paper, data on RNA testing and active infection was not presented, which is important to assess people living with active infection and need treatment to prevent progressive liver disease. The BC-HTC provides a platform to assess program progress through cascade of care monitoring, long term outcomes related to HCV and impact of treatment on long term outcomes. These data are in the process of being analyzed and will be presented in future reports.

Conclusions

The HCV positivity rate was highest in the 1950-54 and 1955-59 birth cohorts and overall among those born between 1945- 1964, which declined over time. Furthermore, the year over year decline in the positivity rate suggests that most of the HCV infections in these cohorts have already been identified. However, current risk based testing may not identify individuals who are unable to recall or are unwilling to disclose remote risk behaviors. Further studies are needed to estimate the number of undiagnosed HCV infection and assess optimal strategies to identify the remaining undiagnosed infections. Newly acquired infections are occurring mainly in younger birth cohorts and these groups are more likely to be co-infected with HIV and/or HBV, socioeconomically marginalized, and living with serious mental illnesses and addictions. Comprehensive syndemic approaches that take into account co-infections, mental health, additions and socioeconomic vulnerabilities are urgently required to identify, treat, and support people with HCV infection.

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