Monday, February 20, 2017

Healthcare, patient groups oppose hep-C drug patents

Healthcare, patient groups oppose hep-C drug patents
MUMBAI: Healthcare aid and patient groups have come together in patent courts to fight against ``abusive strategies'' of Big Pharma, to ensure access to affordable treatment in hepatitis C. The Initiative for Medicines, Access & Knowledge (I-MAK) together with Delhi Network of Positive People and international medical humanitarian organisation, Medecins Sans Frontieres filed three cases on crucial new hepatitis C medicines: two patent challenges on daclatasvir, one on velpatasvir and a further challenge on sofosbuvir.

The patent challenges could remove barriers to production and distribution of affordable generic versions of direct-acting antiviral (DAA) medicines, including Gilead's sofosbuvir and velpatasvir, and Bristol-Myers Squibb's daclatasvir.

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HCV Screening Shouldn't Just Focus on At-Risk Populations

HCV Screening Shouldn't Just Focus on At-Risk Populations
FEB 20, 2017 | CAITLYN FITZPATRICK
At the Conference on Retroviruses and Opportunistic Infections (CROI 2017) in Seattle, Washington, researchers from MedStar Health Research Institute in Maryland presented new data on hepatitis C virus (HCV)-positive non-baby boomers.

It’s widely acknowledged that those individuals belonging to the baby boomer age group (those born between 1946 and 1964) are at higher risk of acquiring HCV infection. According to the Centers for Disease Control and Prevention (CDC), these individuals are five times more likely to be infected with HCV. However, other at-risk populations may not be getting adequately tested for the virus.

Listen - Liver transplant and organ donation

Mayo Clinic Radio: Liver transplant and organ donation / clinical trials / constipation

According to the U.S. Department of Health and Human Services, more than 14,000 people are waiting for a liver transplant today in the U.S. Liver transplant usually is reserved as a treatment option for people who have significant complications due to end-stage chronic liver disease. In rare cases, sudden failure of a previously normal liver may occur. The liver is just one of several organs, including kidney, heart and lung, that have long transplant waiting lists. On the next Mayo Clinic Radio program, transplant surgeon Dr. Charles Rosen will discuss liver transplant and the importance of organ donation. Also on the program, Toni Mangskau, clinical trials referral coordinator at Mayo Clinic’s Cancer Education Center in Rochester, Minnesota, will explain how clinical trials are conducted. And gastroenterologist Dr. Michael Camilleri will offer prevention tips for the common problem of constipation.


Links
Access archived shows.

Why should we worry about conflict of interest?
Janice Boughton, MD | Physician | February 19, 2017
A recent issue of the Journal of the American Medical Association (JAMA) reads like an expose. Well, at least three of the research articles do. So exciting! I don’t want medicine — my field — to be ethically unsavory, but it is sometimes. It makes me proud to see that it polices itself and that such information is published in a high profile journal.
The third article was even more concerning from a financial standpoint. In the last few years, we have seen major changes in the way we treat hepatitis C and elevated cholesterol levels. Guidelines released in 2013 by the American Heart Association recommended that we extend the number of people who will be treated with cholesterol-lowering “statin” drugs to anyone with a 10-year risk of atherosclerotic cardiovascular disease (heart attacks and the like) of over 7.5%. Guidelines released in 2015 for the treatment of hepatitis C, a chronic liver disease caused by a blood-borne virus, suggested that we treat everyone with hepatitis C with extremely expensive drugs which, kudos to pharmaceutical researchers, can cure the disease.
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SF working on ambitious plan to eliminate hepatitis C

February 19, 2017
San Francisco is trying to become the first city in the nation to eliminate hepatitis C, rolling out an ambitious plan that would involve curing everyone who already has it and stopping further spread of the infectious disease, which can cause severe liver damage.

Just two or three years ago, the plan, called End Hep C SF, would have been impossible. But a new cure that is effective and relatively easy to take, combined with growing enthusiasm for programs to increase access to health care, has doctors and public health officials convinced that they can wipe out the virus over the next decade.

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February 2017 - WHO guidelines on testing for chronic HBV and HCV infection

Publication details
Number of pages: 204
Publication date: February 2017
Languages: English
ISBN: 978-92-4-154998-1

Downloads
Guidelines on hepatitis B and C testing

Overview
Testing and diagnosis of hepatitis B (HBV) and C (HCV) infection is the gateway for access to both prevention and treatment services, and is a crucial component of an effective response to the hepatitis epidemic. Early identification of persons with chronic HBV or HCV infection enables them to receive the necessary care and treatment to prevent or delay progression of liver disease. Testing also provides an opportunity to link people to interventions to reduce transmission, through counselling on risk behaviours and provision of prevention commodities (such as sterile needles and syringes) and hepatitis B vaccination.

These are the first WHO guidelines on testing for chronic HBV and HCV infection and complement published guidance by WHO on the prevention, care and treatment of chronic hepatitis C and hepatitis B infection. These guidelines outline the public health approach to strengthening and expanding current testing practices for HBV and HCV, and are intended for use across age groups and populations.

Viral Hepatitis - World Day of Social Justice: fighting for our right to health

http://blogs.biomedcentral.com/on-health/2017/02/20/world-day-of-social-justice-fighting-for-our-right-to-health/

World Day of Social Justice: fighting for our right to health

Sorafenib benefit dependent on hepatitis status in patients with HCC

February 19, 2017
Sorafenib improved OS among patients with hepatocellular carcinoma who were hepatitis C positive but hepatitis B negative, suggesting that the beneficial effects of sorafenib may be based on hepatitis status, according to results of a meta-analysis.

Of Interest
MicroRNA-125a-5p is a downstream effector of sorafenib in its antiproliferative activity toward human hepatocellular carcinoma cells.
Article ID: 669739
Released: 17-Feb-2017 3:05 PM EST
Source Newsroom: Sbarro Health Research Organization (SHRO)

Sorafenib is a multikinase inhibitor with specific activity against Raf kinase and several receptor tyrosine kinases. The addition of sorafenib to hepatocellular carcinoma cells increased cellular expression of miR-125a. Upregulation of this miRNA inhibited cell proliferation and induced cell cycle arrest by targeting c-Raf, part of the ERK pathway that is involved in cell proliferation and sirtuin-7, (SIRT-7) a NAD(+)-dependent deacetylase that inhibits transcriptional activation of the cell cycle inhibitor p21. Therefore, sorafenib inhibits Raf activity and upregulates miR125 that, in turn, targets c-Raf and SIRT7; this dual inhibition of Raf activity and expression together with p21-dependent cycle arrest coherently combine to explain the antiproliferative activity of the drug.

Newswise — Treatment options for liver cancer are often limited and almost exclusively involve transplantation if possible, or local chemoembolization and radiofrequency ablation. Medical treatments for more advanced stages have been explored during recent decades, but only the drug sorafenib, a small molecule multi-kinase inhibitor, has shown promising results and been approved for use by international medical agencies. Unfortunately, only 25% of patients respond to sorafenib treatment, so researchers have endeavored to understand its mechanism of action and discover a way to boost its effectiveness.

A recent study, published in the journal Journal of Cellular Physiology, describes further scientific insight into the involvement of a small non coding RNA, miR-125a, in the anti-cancer effects of sorafenib in the treatment of liver cancer, or hepatocellular carcinoma. These results are interesting as miRNAs have multiple available intracellular targets and could contribute to the amplification of the effects of sorafenib.

The link between small kinase inhibitors such as sorafenib, and the existing molecular pathways that govern cell proliferation such as miR-125a, may be useful to potentiate the anticancer activity of sorafenib. Clinical applications of this knowledge might seek to identify and increase the number of liver cancer patients that respond positively to the drug.

The study includes work done by Prof. Michele Caraglia and Aniello Russo, of the University of Campania “L. Vanvitelli” in Naples, and Caserta, Italy, in collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia.

“Sorafenib is still the only drug indicated in the treatment of hepatocellular carcinoma, which highlights the difficulty in the medical treatment of liver cancer,” says Prof. Antonio Giordano. “Sorafenib is effective because it acts upon multiple intracellular targets and interferes with both cancer proliferation and tumor blood supply. However, its activity is limited to only 25% of patients that are sensitive to its effects. This strongly pushes the researchers to define the mechanism of action of the drug,” Giordano concludes.

“MicroRNAs can act as either cancer-fighting tumor suppressors, or as cancer-causing oncogenes,” says Professor Michele Caraglia. "We have found that the expression of miR-125a is strongly involved in the mechanism of action of sorafenib and its ability to regulate cancer cell proliferation. These findings suggest the possible use in the future of miR125a in combination with sorafenib in order to potentiate the anti-cancer activity of the drug,” Caraglia concludes.

The study results open a new scenario of intervention in the treatment of hepatocellular carcinoma in which small molecules such as sorafenib can be used in association to nucleic acids such as miR-125a. The latter could be administered to patients systemically encapsulated in novel drug delivery options such as nanocarriers. Researchers plan to further study the in vivo efficacy of these strategies to increase treatment options for this difficult form of cancer.

Citations
Potenza N, Mosca N, Zappavigna S, Castiello F, Panella M, Ferri C, Vanacore D, Giordano A, Stiuso P, Caraglia M, Russo A. MicroRNA-125a-5p Is a Downstream Effector of Sorafenib in its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells. J Cell Physiol. 2016 Dec 16. doi: 10.1002/jcp.25744.

HCV Infection Linked to Nonhepatic Cancers in the Elderly

HCV Infection Linked to Nonhepatic Cancers in the Elderly

Chronic HCV infection is a known cause of HCC and B-cell non-Hodgkin lymphomas (NHLs), but epidemiologic data suggest that HCV may be associated with cancers involving the kidney, oropharynx, and bile duct. HCV antigens and RNA have been identified in some of these cancers, but the exact role of the virus in oncogenesis is unclear. Since the majority of patients with HCV infection were born in the “baby boomer” era, HCV-associated cancers may present a potential public health issue as the baby boomer population ages.

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Sunday, February 19, 2017

Gallstones in Patients with Chronic Liver Diseases

Gallstones in Patients with Chronic Liver Diseases
Greetings from sunny Michigan, not sure what happened but it sure is warm outside, we might hit 60 today. Glad you stopped by folks, in this edition of weekend reading we take a quick look at gallstone disease, cirrhosis and HCV.

Research has shown that people with chronic liver disease, especially those with cirrhosis have a greater tendency to develop gallstones. Although cirrhosis is a known risk factor for gallstones, little is known about gallbladder disease in individuals with chronic hepatitis C - research is sparse. Today's focus is on gallstone disease in chronic liver diseases including risk associated with gallstones occurrence in people with chronic hepatitis C.

The articles or abstracts provided below were found in online journals or accessed through PubMed.

2017
Review Article
Gallstones in Patients with Chronic Liver Diseases
Xu LiXiaolin GuoHuifan JiGe Yu, and Pujun Gao
With prevalence of 10–20% in adults in developed countries, gallstone disease (GSD) is one of the most prevalent and costly gastrointestinal tract disorders in the world. In addition to gallstone disease, chronic liver disease (CLD) is also an important global public health problem. The reported frequency of gallstone in chronic liver disease tends to be higher. The prevalence of gallstone disease might be related to age, gender, etiology, and severity of liver disease in patients with chronic liver disease. In this review, the aim was to identify the epidemiology, mechanisms, and treatment strategies of gallstone disease in chronic liver disease patients.
Read the article published January 2017 online in BioMed Research International.

2016
Hepatitis C Virus Infection Is Positively Associated with Gallstones in Liver Cirrhosis
Zhang F.-M. · Chen L.-H. · Chen H.-T. · Shan G.-D. · Hu F.-L. · Yang M. · Chen W.-G. · Xu G.-Q.
Aim - To elucidate the prevalence and risk factors of gallstone disease (GD) among patients with liver disease and explore their association with the aetiology and severity of hepatic injury.
CONCLUSION: HCV infection is positively associated with gallstone formation especially in those with cirrhosis patients.
Abstract available, here.

2014
Hepatitis C - A Risk Factor For Gallstone Disease
Syed Inamullah Shah, Sajida Shah*, Abdul Hannan
This cross-sectional study aimed to establish an association between HCV infection and gallstones by excluding subjects with all other risk factors for gallstones.
There is a strong association between HCV infection and gallstones. HCV infection is definitely a risk factor for gallstone disease particularly in young males. By invalidating young subjects and rendering them as potential candidates for surgery, this association has a profound effect on health economy. There is a predilection for HCV positive patients to acquire multiple gallstones. Further studies are needed to evaluate the precise cause for this association.
Download the original 2014 article, here.

2009
Hepatitis C Virus Infection is a Risk Factor for Gallstone Disease: A Prospective Hospital-based Study of Patients with Chronic Viral C Hepatitis
M. Acalovschi; C. Buzas; C. Radu; M. Grigorescu
A Prospective Hospital-based Study of Patients with Chronic hepatitis C.

We decided to investigate whether the gallstone risk in patients with chronic HCV infection was linked only to cirrhosis or also to the HCV infection per se.
Our study shows that even HCV patients with chronic hepatitis but not cirrhosis have an increased prevalence of gallstones. Compared with controls, gallstones are present in HCV patients at a younger age and are associated with central obesity and liver steatosis, but not with gallstone heredity, dyslipidaemia, diabetes mellitus or metabolic syndrome. Although we could not establish a temporal relationship, the association between HCV infection and gall stone disease is real and appears to be causally linked, at least in predisposed individuals (obese and with liver steatosis).
Published in Journal of Viral Hepatitis, full text article available @ Medscape.

2011
Gallstones and Liver Disease: an Overview
Dario Conte, Mirella Fraquelli, Mariangela Giunta, Clara Benedetta Conti
Nowadays, there is much interest in discovering the relationship between GS and liver disease and in the last issue Coelho and colleagues [3] decided to assess the prevalence of cholelithiasis in patients undergoing liver transplantation for end stage liver disease. Their study deals with a really interesting and new issue. In fact, whereas many studies observed a higher prevalence of GS in chronic liver disease, up to now none have assessed GS prevalence in the subset of patients subjected to liver transplantation. In addition, this article evaluates this particular issue in Latin America, a geographical area from which few data are available in current literature. The reference standard to detect GS was represented not only by the ultrasonographic scan of the gallbladder but also on the direct examination of the explanted liver. The results of the study by Coelho and colleagues deserve some considerations that could be summarized by answering three main questions:
a) How did we get here?
b) What  is the reason for the increased frequency of gallstones in cirrhosis?
c) Do gallstones worsen the course of liver cirrhosis?
Download the editorial  here..

Gallstones (cholelithiasis) - causes, symptoms, diagnosis & pathology
What are gallstones? Gallstones are solid stones that are produced in the gallbladder when there’s an imbalance in the composition of bile. The main types of gallstones are cholesterol stones, bilirubin stones, and brown stones.



Enjoy the rest of your weekend!
Tina

Safety of new DAAs for chronic HCV infection in a real life experience: role of a surveillance network based on clinician and hospital pharmacist

Safety of new DAAs for chronic HCV infection in a real life experience: role of a surveillance network based on clinician and hospital pharmacist
A. Nappi Email author , A. Perrella, P. Bellopede, A. Lanza, A. Izzi, M. Spatarella and C. Sbreglia Infectious Agents and Cancer
DOI: 10.1186/s13027-017-0119-8©
Published: 7 February 2017

View Article Online

Abstract
Background
Direct Antiviral Agents (DAAs) for HCV therapy represents a step ahead in the cure of chronic hepatitis C. Notwithstanding the promising results in several clinical trials, few data are available on adverse effects in real life settings.

Methods
We have evaluated 170 patients with persistent infection and on those eligible to treatment we have followed up them through a network managed by clinician and hospital pharmacist.

Results
According to our data we have found that 41% (32 out of 78) of enrolled patients experienced adverse reactions, of these 40% were in those under 65 years while 60% was in patients older than 65 years, SVR was achieved in 88% of the patients (including drop-out). We had 4 drop-out treatment due to major adverse reaction (heart and lung related).

Conclusion
Even if new antiviral drugs seem to be promising, according to SVR, they require careful follow-up, possibly managed by clinician and hospital pharmacist, to avoid unrecognized side effects which may affect adherence and the real impact of these drugs on chronically infected subjects.

Keywords: HCV, DAAs, Antiviral, Adverse drug reactions, Pharmacology, Hepatitis C, SVR

Abbreviation
ADR: Adverse drug reaction DAAs: Direct antiviral agents FDA: Food and drug administration HCV: Hepatitis C virus SVR: Sustained virological response

Background
Hepatitis C virus (HCV) chronically infects approximately 185 million people worldwide and it still represents and important issue in public health. The rate of persistent infection after acute hepatitis ranges from 20 to 40% [1, 2, 3]. Once chronically infected patients may undergo antiviral treatment, however in the last decades, according to old antiviral regimen, chronic infection was characterized by low sustained virological response (SVR) [4]. Persistent infection can lead to cirrhosis, liver cancer, and death, and is one of the leading cause of liver transplantation in the European Country [5]. Italy has one of the highest HCV prevalence and according to data managed until 2002 with substantial geographic differences in the prevalence, with a range from 2.6% in the north [5, 6] to 16.2% in the south of Italy, However other reports suggest a decreasing trend in our country [6, 7].
Despite the lack of recent data, HCV chronic infection still remains an issue in our country. Currently thanks to the direct-acting antivirals (DAA) HCV is treatable and the goal of treatment is to achieve a sustained virological response (SVR), considered to be a functional cure (absence of plasma HCV RNA 12 weeks after completing therapy). [4]. In addition, these new antivirals have been demonstrated to be effective regardless of race, gender, or HIV status, leaving few barriers to treatment having so the potential to reduce long-term costs of complications and interrupt the current global HCV epidemic even if more expansive than previous regimen. [8, 9]. However several drug to drug interactions have been reported for some of these, requiring careful in the management. According to previous studies on first line antiviral as protease inhibitors SVR rates increased with the use of these drugs but so did the adverse events, resulting in discontinuation rates of 9–19% in patients on these triple therapy regimens [10]. Therefore the new DAAs seem to have all quality to be considered as a miracle drug [11]. However despite these new drugs has been presented as the new miracle in the infectious disease and been characterized by a very low adverse events rate in the published clinical trials, few data are available on adverse events based real life studies [12]. At the beginning of 2015 when DAAs were available in Campania Region in south Italy, where HCV is epidemic, we decided to assess impact of these new drugs on healthiness of the patients according to their adverse reactions. This kind of approach has been managed trough the creation of a network involving clinician and pharmacist to improve the follow-up of the patients under treatment not only from the efficacy point of view but mainly according to safety of these antivirals. Here we present our analysis and results on a surveillance network based on clinician and pharmacist to evaluate the safety of DAAs for HCV chronic infection in a real life in out-patients clinic of a tertiary care infectious disease division of a regional Hospital Center for Infectious disease in Campania Region.

Methods
All patients were enrolled in this study according to national guidelines for the evaluation of HCV treatment eligibility assessed following the priority criteria established by the national registry of the Italian Medicines Agency committee (AIFA) (www.agenziafarmaco.gov.it). Data related to the efficacy of the DAAs is not the primary objective of the study therefore they are treated marginally. Data related to adverse drug reactions were collected through standard-of-care operating procedures utilized in a specialty pharmacy setting. These procedures utilized prescription claims software and a clinical assessment management program according to national network for pharmacovigilance (RNF - Rete Nazionale Farmacovigilanza). All patients were counseled prior to receiving their initial prescription according to clinician evaluation in out-patients clinic. Further, during all follow-up a survey based on two simple questions was also proposed and collected by clinician to assess the psychological health status in the course of therapy and to assess possible unrecognized side effects every month during therapy (Fig. 1). All patients were invited to communicate any changes in their health status or wellbeing during the entire treatment period. All concomitant therapies were evaluated and possible drug to drug interactions were assessed according to producer package insert and University of Liverpool web site (http://www.hep-druginteractions.org/). Patients were encouraged to contact their clinicians to report any adverse reaction during treatment. Before the enrollment in any treatment regimen, every patients signed an informed consent under the prescribing physician surveillance. Any enrolled patients performed the following laboratory tests at the following time points: T0 (before starting treatment genotype, initial viral load, HBsAg, Anti-HIV, Haematological, Liver, Renal, Pancreatic Function Test, Cardiological assessment (including Pro-BNP serum levels), at T1 and T3 according to antiviral schedule (on month and three months after starting therapy) Viral load, ETR (the end of treatment) and one month and three months after the end of therapy to evaluate sustained virological response (SVR). Red blood cells count and haemoglobin levels were assessed every week for the first month thereafter every two weeks or according to haematological alterations. Every patient underwent a clinical examination in out-patients clinic and any significant clinical condition was registered and used in case of treatment suspension or antiviral dose adjustment. Adverse events were defined according to FDA regulation (http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm).

All required information for possible adverse drug reaction (ADR) were entered into the RNF home page according to italian surveillance submission form (http://www.agenziafarmaco.gov.it/sites/default/files/tipo_filecb84.pdf). DAAs Regimen according to genotype and Italian National Health system guidelines were as follows: Sofosbuvir + Ribavirin, Sofosbuvir + Simeprevir +/− Ribavirin, Sofosbuvir + Daclatasvir +/− Ribavirin, Ledipasvir + Sofosbuvir +/− Ribavirin and Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir plus ribavirin. Data were extracted and analyzed using Microsoft Excel and GraphPad for Mac Os X.



Fig. 1
Figure shows the survey proposed by Clinician every month during treatment period. According to possible changes in health status perceived by the patient as well as any relevant clinical and laboratory condition, adverse events notification were reported and discussed with Hospital Pharmacist and entered in the online based Italian system for adverse drug reaction notifications

Results
A total of 170 subjects were evaluated from March 2015 to March 2016. 104 out 170 were found to be eligible to HCV therapy. 78 out of 104 patients (pts) were enrolled and reached the end of treatment at the moment of our analysis based on the above mentioned antiviral regimens. Sustained virological response (SVR) was reached in 88% of the enrolled patients (percentage is actually including drop-out due to severe adverse reactions with relapse). According to our enrolment protocol to follow-up ADRs, as part of the surveillance network including clinician and hospital pharmacist, we found the following results about demographic, efficacy and safety (also reported in Table 1 and Table 2): 35% of enrolled were < 65 years old while the remaining patients (65%) were ≥ 65 years old. The cohort of subjects ≥ 65 years old had a mean age of 72 years (range, 65–80 years). In the < 65 years old cohort, the mean age was 48 (range, 18–58 years), 59% (n = 17) of the subjects were male. Almost all patients (93%) with age ≥ 65, had Genotype 1b while other genotypes were as follows Genotype 2 (4%), Genotype 3 (3%). In the subjects with age < 65, 86% of the subjects had genotype 1b while the other genotypes were Genotype 2 (6%) and Genotype 3 (15%). Elderly had a higher rate of compensated diagnosed cirrhosis according to Fibroscan as F4 (82% vs. 57%). Adverse events, categorized according to the above reported schedules from FDA and AIFA (Italian Agency for Drugs Administration) were classified as severe, when requiring hospitalization or life-threatening approach or as common when averse events could be managed in out-patients clinic without hospitalization. The most important adverse events are reported in Table 1 and Fig. 2. Basically we had a total of 37 out of 78 enrolled patients (46%) reporting common adverse drug reactions related to all used drugs. Severe adverse events were 11 out 78 pts of these reported ADRs we have that severe were mostly related to Sofosbuvir/Ledipasvir treatment and were related to cardio-pulmunary system. According to our survey we found that majority of the patients experienced asthenia or fatigue were 53% of the enrolled patients, however that adverse events did not require any dose adjustment or have any impact in social life and was considered as minor adverse drug reaction. 12 out 37 adverse events were in patients <65 years old and 25 in those > 65 years old. Major adverse events, according to FDA classification, were about 80% of all reported adverse reactions and were more frequent in those older than 65 years. The majority of ADR for treated patients were found in Sofosbuvir plus Simeprevir (Fig. 3) and in all remaining having Ribavrin as concomitant antiviral, requiring in about 60% of the patients dose reduction.

Table 1
Adverse events experienced by patients treated with antiviral schedule regimens

SOF/LDV
SOF/DAK
SOF/SIM+/− RBV
SOF/RBV
OMB/PTR/r/DAS +/− RBV
ENROLLED PTS per regimen
20
15
28
4
11
PTS WITH SERIOUS ADRs
4 (20%)
3 (20%)
1 (4%)
1 (25%)
1 (9%)
DISCONTINUATION
3
0
0
0
1
DEATHS
0
0
0
0
0
COMMON ADRs
10 (50%)
6 (40%)
12 (43%)
4 (100%)
5 (45%)
FATIGUE
6
5
11
4
4
HEADACHE
0
0
0
0
0
NAUSEA
0
0
0
0
0
PRURITUS
0
0
4
0
0
INSOMNIA
1
3
0
0
0
DIARRHOEA
0
0
0
0
0
ASTHENIA
7
2
11
4
3
RASH
0
0
4
0
0
IRRITABILITY
0
4
0
0
0
ANAEMIA
6
3
12
3
3
DYSPNOEA
2
0
0
0
1
*Common adverse drug reactions are not to single patients, one patient may experience more than one common adverse drug reaction. Data are expressed as absolute number plus percentage
Table 2
Table shows daemographic data, SVR (in months) and ADRs according to overall enrolled population, genotype (Gt) and disease stage (chirrosis and chronic hepatitis C F3 stage according to metavir)

CHIRROSIS
CHC
TOT
ADRs
20/51
15/27
35/78
Sex
M 44 – F 22
M 14 – F 4
M 58 - F 26
Age
<65: 10
<65: 17
<65: 27
>65:41
>65:11
>65:51
Genotype in overall population
 Gt 1
38
20
58
 Gt 2
9
5
14
 Gt 3
4
2
6
SVR in over all population
 SVR 3 mts
44/51
25/27
69/78
 SVR 6 mts
44/51
24/27
68/78
 RELAPSE
6/51
4/27
10/78



Fig. 2 Figure represents the frequency (expressed as absolute number) of all adverse drug reactions reported in all patients during treatment follow-up. They are classified according to organ for each single antiviral schedule. According to our findings we had that patients undergoing schedule Simeprevir/Sofosbuvir had a higher frequency of skin disorders, while anaemia and asthenia were most frequently observed in those undergoing Sofosbuvir/Ledipasvir/Ribavirin treatment. Of note the Central Nervous System adverse events related to mood alteration and sleep disorders in those patients under Daklinza/Sofosbuvir antiviral schedule



Fig. 3 Figure represents percentage of Total Adverse Drug Reactions on the whole treated patients according to antiviral regimens. Detailed data on absolute number can be found in Table. Sofosbuvir plus Simeprevir was the regimen with more frequently reported common ADR

We had 4 discontinuations during treatment representing 5% of all enrolled cases, two of those were related to heart failure during Sofosbuvir/Ledipasvir plus Ribavirin therapy, one due to allergic reaction to Harvoni and the last one related to pulmonary hypertension with heart failure during Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir plus ribavirin therapy. Of note we had 4 patients during Daklatasvir/Sofosbuvir therapy experiencing change in mood of mild grade, two of them requiring Psychiatric assessment, however none of those patients required therapy suspension. All psychiatric symptoms diminished and disappeared after two weeks from the end of therapy with Daklatasvir/Sofosbuvir.

Discussion
Despite major progresses have been made in the treatment of chronic hepatitis C, patients should always be managed with caution to avoid the side effects of therapy. Currently the choice of DAAs should be made according to viral genotypes and treatment history to avoid cross-resistance issues [8, 13]. As more safety and efficacy data are becoming available in compensated cirrhosis, antiviral therapy should be considered a priority in these patients and treatment should also be started based on possible adverse reactions and therefore related clinical implications according to age and possible pre-existing factors. In this context, all relevant clinical conditions prior of antiviral treatment should also be careful evaluated being possibly correlated to the onset of adverse events during treatment. For instance, the management of decompensated cirrhotic, could result to be more difficult to manage and to be predictable in its complications as only a few studies of DAA combinations are available [9, 12]. Despite these patients should be treated in an urgent manner, on the other hand they should be managed with caution as at now only few safety data are available for DAAs in real life on the above mentioned clinical condition. Same consideration should also be done for possible cardiovascular system adverse events in those patients having cardiac diseases, since the new antivirals seem to be related to the onset of cardiotoxicity, particularly in elder population [13, 14]. In fact, according to our results on adverse events and some literature evidences [13, 14], all patients, particularly those over 65 years, should be referred to a reference centre in case of rapid clinical deterioration. The same caution applies in the pre- and post-transplant setting where drug-to-drug interactions, kidney function and many other factors should be taken into consideration [13]. In our study, we have found a high rate of a total ADR in enrolled patients compared to previous report, particularly we had higher serious adverse events in patients undergoing Sofosbuvir/Ledipasvir, Daclatasvir/Sofosbuvir compared to those reported in published clinical trials [15] particularly in those aged over 65 years. It is of note that in those latter subjects we had the most critical ADR requiring in four cases treatment suspension due to major severe adverse events, life threatening, related to heart function (submitted papers as clinical report). Regarding common adverse events, they have been previously reported to range from 10 to 50% in several clinical trials [15]. In our study of real life we have found a percentage of about 50% with some relevant clinical condition related to mood alterations during Daclatasvir/Sofosbuvir schedule not previously reported in common adverse events at our knowledge. It also should be said that our findings on all reported adverse drug reactions could also be strictly correlated to the presence of a surveillance network based on clinician and pharmacist cooperation. Indeed, one of the most interesting results of our study is mainly the usefulness of that kind of approach to the follow-up based on a network between clinician and pharmacist. Indeed this approach may also justify the evidence of a wider and more detailed assessment of adverse reaction that patients may experience compared to other previous reported paper [12]. Further, it seems also to be really interesting and effectiveness the use of a simple survey as alerting system for clinician and therefore pharmacist for a wide understanding of possible unrecognized adverse events. Certainly, it is our opinion that without this network and that kind of approach, in a real life setting, it would be really hard to identify minor adverse events related to these antivirals that could have important impact on patients. According to previous evidences and our results on possible cardiovascular system adverse events [14, 15, 16], a well defined approach and management to this new treatment focusing on ADR according to our network may really be useful for future strategies in treatment schedule in particular setting of patients as our findings on over 65 years old seem to suggest.

Conclusion
Therefore, in conclusion, even if DAAs seem to be promising for their ability to achieve SVR, a careful and clinician and pharmacist based network should be managed to have a better understanding and follow-up of any significant adverse reaction that may occur particularly on cardiovascular system and in elderly patients. This approach should be used in all real life study to have a wider and better approach to the use of new drugs.

Declarations
Acknowledgments
We would like to thanks to all nurses both in out-patient’s ward and pharmacy department for their precious help in data collection. In Memory of Oreste Perrella MD PhD who gave a very important contribution to Hospital D Cotugno in terms of Research and Clinical Activity.

Funding
No to declare.

Authors’ contributions
The name of the author who is acting as the submission’s guarantor is AP and he takes (responsibility for the integrity of the work as a whole, from inception to published article). All authors contributed equally to the papers, particularly AN was involved in adverse drug reactions data collection, writing and results analysis, AP was involved in clinical follow-up, ADR recognizing, writing and results analysis, PB, CS, AI, AGL were involved in clinical follow-up and discussion writing, MS, was involved in adverse drug reaction data analysis and discussion writing. All authors approved the final version of the manuscript.

Competing interest
The authors declare that they have no competing intersts.

Consent for publication
All data and materials (where applied) are available.

Ethics approval and consent to participate
Was not required, since the study has been managed on approved and commercialized drugs and all patients signed informed consent.

Influence of vitamin D on liver fibrosis in chronic hepatitis C: A systematic review and meta-analysis of the pooled clinical trials data 

Systematic Review
World J Hepatol. Feb 18, 2017; 9(5): 278-287
Published online Feb 18, 2017. doi: 10.4254/WJH.v9.i5.278

Influence of vitamin D on liver fibrosis in chronic hepatitis C: A systematic review and meta-analysis of the pooled clinical trials data
Alia S Dadabhai, Behnam Saberi, Katie Lobner, Russell T Shinohara, Gerard E Mullin

Core tip: Vitamin D levels are associated with more advanced fibrosis in chronic hepatitis C

Abstract
AIM
To investigate the relationship between vitamin D and liver fibrosis in hepatitis C-monoinfected or hepatitis C virus (HCV)-human immunodeficiency virus (HIV) co-infected patients.

METHODS
Pertinent studies were located by a library literature search in PubMed/Embase/Cochrane/Scopus/LILACS by two individual reviewers. Inclusion criteria: (1) studies with patients with HCV or co-infected HCV/HIV; (2) studies with patients ≥ 18 years old; (3) studies that evaluated liver fibrosis stage, only based on liver biopsy; and (4) studies that reported serum or plasma 25(OH)D levels. Studies that included pediatric patients, other etiologies of liver disease, or did not use liver biopsy for fibrosis evaluation, or studies with inadequate data were excluded. Estimated measures of association reported in the literature, as well as corresponding measures of uncertainty, were recorded and corresponding odds ratios with 95%CI were included in a meta-analysis.

RESULTS
The pooled data of this systematic review showed that 9 of the 12 studies correlated advanced liver disease defined as a Metavir value of F3/4 with 25(OH) D level insufficiency. The meta-analysis indicated a significant association across studies.

CONCLUSION
Low vitamin D status is common in chronic Hepatitis C patients and is associated with advanced liver fibrosis.

INTRODUCTION
Hepatitis C virus (HCV) infection remains one of the most common etiologies of liver disease worldwide. A number of epidemiological papers have addressed the global prevalence of Hepatitis C. Lanini et al[1] reported that 100 million people globally have serological evidence of current or past HCV infection causing 700000 deaths annually while others suggest that the actual occurrence is double[2]. HCV remains the most common indication for liver transplantation in the United States[3]. Chronic infection with HCV can lead to liver inflammation, liver fibrosis, cirrhosis, and hepatocellular carcinoma.

Liver fibrosis is a result of excessive accumulation of extracellular matrix proteins, as part of the wound healing response to chronic injury and chronic inflammation[4]. Various factors have been associated with progression of fibrosis including duration of infection, age, male sex, diabetes, alcohol consumption and human immunodeficiency virus (HIV) co-infection[5].

Vitamin D is a hormone that has numerous biological properties that influence host physiology by regulating epigenetic regulation of more than 2000 genes throughout the body. Vitamin D is best known for its role in maintaining bone mineralization but has diverse and profound influences which can determine disease development and outcome. Although referred to as a vitamin, this steroid hormone is synthesized in the body by a series of hydroxylation reactions that occur in skin (7-hydroxylation), the liver (25-hydroxylation) and the kidney (1-hydroxylation)[6] (Figure 1). Reduction of the enzymatic conversion of 7-dehydrocholesterol to 1.25 hydroxy vitamin D at any of the three conversion steps can result in suboptimal vitamin D status[7].

Vitamin D has a number of influences on innate and adaptive immunity which are pertinent to study in conditions that are driven by chronic inflammation and maladaptive tissue injury[8,9]. Given the ubiquitous distribution of vitamin D receptors in virtually every cell in the body-suboptimal vitamin D status has been studied for its relationship to numerous diseases[10].

For example, there is substantial evidence that vitamin D benefits rheumatoid arthritis, due to its immunomodulatory effect[11]. The role of vitamin D in various cancers has been established linked to its antiproliferative action mediated through vitamin D nuclear receptor[12]. There have been numerous reports on lower serum vitamin D levels in patients with chronic liver disease from various etiologies[13]. In chronic HCV, Low vitamin D levels have been reported in 46% to 92% of patients[10] raising suspicion of its potential contribution to disease pathogenesis.

There is growing evidence from various groups, that vitamin D levels are inversely correlated with liver inflammation and stage of liver fibrosis in patients with HCV; however, the studies are heterogeneous with occasionally the results are conflicting. Additionally, the methods of reporting liver fibrosis were variable.


Figure 1 Vitamin D metabolism.
Vitamin D has diverse influences throughout the body as vitamin D receptors present on virtually every cell. The actions of vitamin D can be subdivided into two larger categories: Calcemic and non-calcemic actions. The non-calcemic actions of vitamin D are legion and have been reviewed elsewhere[6,54-58]. Reproduced with permission[6].

The aim of this study was to evaluate the relationship between vitamin D status and hepatic fibrosis based on histopathological staging in patients with chronic HCV mono-infection or co-infected HIV-HCV infection, by performing a systematic review of the scientific literature followed by a meta-analysis.

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Of Interest
January 9, 2017
Is there an association between vitamin D and liver fibrosis in patients with chronic hepatitis C?
This study aimed to evaluate the association between serum vitamin D levels and the histopathological findings in patients with chronic hepatitis C virus infection.

Results
Of the 74 patients included in the study, 45 (60.8%) were women, mean age was 57.03±9.24 years, and 63 (85.1%) were white. No association was observed between the serum levels of vitamin D and inflammatory activity (P=0.699) nor with the degree of liver fibrosis (P=0.269).

Conclusion
In this study, no association was observed between vitamin D and inflammatory activity, as well as the degree of liver fibrosis, in patients with chronic hepatitis C.
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APASL 2017 - Triple DAA combo containing ritonavir effective, safe for HCV GT1b in Asians


Triple DAA combo containing ritonavir effective, safe for HCV GT1b in Asians
13 hours ago, Pearl Toh
A combination of the direct-acting antiviral agents (DAAs) ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) and dasabuvir (DSV) resulted in sustained virologic response at post-treatment week 12 (SVR12) in almost all Asian adult patients with genotype 1b (GT1b) chronic hepatitis C virus (HCV) infection without cirrhosis, according to the ONYX-I* study presented at the recent Asian Pacific Association for the Study of the Liver Annual Meeting (APASL 2017) held in Shanghai, China.

July 25, 2016

NEJM Listen To Interview - Addressing the Fentanyl Threat to Public Health

Addressing the Fentanyl Threat to Public Health
Richard G. Frank, Ph.D., and Harold A. Pollack, Ph.D.
N Engl J Med 2017; 376:605-607
DOI: 10.1056/NEJMp1615145

Interview with Dr. Richard Frank on the increasing number of deaths involving fentanyl in the United States.
Supplement to the N Engl J Med 2017; 376:605-607

Article
Addressing the Fentanyl Threat to Public Health
Fentanyl, a powerful synthetic opioid, poses an increasing public health threat. Low production costs encourage suppliers to “cut” heroin with the drug, particularly white powder heroin sold in the eastern United States.1 Fentanyl also appears as a prevalent active ingredient in counterfeit OxyContin (oxycodone) tablets. The result is that fentanyl plays a major role in rising mortality due to heroin or opioid overdose. It poses a serious overdose risk because it can rapidly suppress respiration and cause death more quickly than do other opioids.

Saturday, February 18, 2017

Liver steatosis in children with chronic hepatitis B and C: Prevalence, predictors, and impact on disease progression

Liver steatosis in children with chronic hepatitis B and C: Prevalence, predictors, and impact on disease progression

Pokorska-Śpiewak, Maria MD, PhD; Kowalik-Mikołajewska, Barbara MD, PhD; Aniszewska, Małgorzata MD, PhD; Pluta, Magdalena MD; Walewska-Zielecka, Bożena MD, PhD; Marczyńska, Magdalena MD, PhD

Medicine:   
doi: 10.1097/MD.0000000000005832
Research Article: Observational Study


Fatty liver is the most common form of chronic liver disease in children and adults worldwide and has a large spectrum of causes including many general or systemic diseases, genetic-metabolic causes, hereditary genetic disorders, and drug hepatotoxicities.[1] Chronic infections with hepatitis B and C viruses (HBV and HCV, respectively) are among the many possible causes of liver steatosis.
The relationship between chronic hepatitis C (CHC) and liver steatosis is well documented.[2–6]

Steatosis is a common finding in the course of CHC and occurs in approximately 50% of adults with CHC and up to 74% of patients infected with HCV genotype 3.[7–9] Both host and viral factors may contribute in the formation of steatosis. In adults with CHC, there are 2 different possible pathomechanisms for developing hepatic steatosis, including viral and metabolic, depending on the virus genotype. HCV genotype 3 directly affects the infected hepatocytes, and this cytopathic effect leads to viral-induced steatosis, which is correlated with HCV viral load.[7–10] In this type, the degree of steatosis may improve after antiviral therapy after achieving a sustained viral response.[9] Steatosis associated with non-3 genotype HCV is a marker of metabolic abnormalities, and insulin resistance playing a key role in its pathophysiology.[7,8] Several studies have confirmed that the presence of steatosis in patients with CHC has prognostic and therapeutic implications due to its independent prediction of fibrosis progression and its association with a lower rate of response to the antiviral therapy.[4,7,11–14]

In contrast to CHC, liver steatosis has not been adequately analyzed in chronic hepatitis B (CHB), and available data on its prevalence and significance in patients with HBV infection are much less abundant and consistent.[11,15] The frequency of hepatic steatosis in adults with CHB was estimated to be 22% to 76%.[15–18] Available data suggest that steatosis in HBV infection is more strongly associated with metabolic factors than viral determinants.[11,19] However, the ability of HBV to indirectly facilitate the development of steatosis has also been considered.[20] The implications of liver steatosis on disease progression and response to antiviral treatments in patients with CHB remain unknown.[11]

Only scarce and inconsistent data are available about liver steatosis in children with CHB and CHC with respect to its prevalence, pathogenesis, relation to metabolic and viral determinants, and impact on disease progression or response to the treatment.[3,6,21] However, pediatric patients are considered to be an ideal model to study hepatic steatosis because they are not often affected by other potential confounding risk factors responsible for its development, such as alcohol intake, metabolic syndrome, dyslipidemia, insulin-resistance, or diabetes.[3,21] Thus, the aim of this study was to evaluate the prevalence of liver steatosis in children with CHB and CHC and analyze its relationship with clinical and laboratory factors to assess its predictors and impact on the disease progression

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Identification of Predictors for Treatment Failure in Hepatitis C Virus Patients Treated With Ledipasvir and Sofosbuvir.

Identification of Predictors for Treatment Failure in Hepatitis C Virus Patients Treated With Ledipasvir and Sofosbuvir.
Jansen JW, et al. Ann Pharmacother. 2017.

Authors
Jansen JW1, Powderly GM1, Linneman TW1.

Author information
11 VA Saint Louis Health Care System, St Louis, MO, USA.
Citation

Ann Pharmacother. 2017 Feb 1:1060028017693348. doi: 10.1177/1060028017693348. [Epub ahead of print]

First Published February 13, 2017

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Abstract
BACKGROUND: New hepatitis C virus (HCV) therapies report cure rates of ~90% but are expensive. Identification of predictors for treatment failure could help decrease health care costs, limit unnecessary drug exposure and adverse events, and prevent drug-drug interactions. Failure to achieve rapid viral response (RVR), defined as detectable viral load at 4 weeks, has previously been identified as a predictor of treatment failure with some previous HCV therapies.

OBJECTIVE: To evaluate RVR, and other potential variables, as predictors of treatment failure in patients treated with ledipasvir and sofosbuvir (LDV/SOF).

METHODS: A retrospective, case-control analysis of adult veterans treated with LDV/SOF was conducted. Included patients had a viral load obtained between weeks 3 and 6 of therapy (RVR) and between weeks 12 and 16 after the end of therapy for sustained viral response (SVR12) evaluation. Identified SVR12 failures (viral load detectable) constituted the case population. The control population was randomly selected in a 1:4 case: control ratio from all identified SVR12 successes.

RESULTS: In all, 12 SVR12 failures were identified; 48 of 144 SVR12 successes were randomly selected for inclusion. Overall failure rate was 7.7% (12/156). Univariate analysis identified histamine-2 receptor antagonist, previous treatment failure, and pretreatment creatinine clearance (CrCl; Cockcroft-Gault) >90 mL/min as potential predictors of SVR12 failure; these variables were included in the regression model with RVR per protocol. In multivariate analysis, pretreatment CrCl >90 mL/min was independently associated with SVR12 failure (odds ratio = 7.27; 95% CI = 1.33 to 39.72; P = 0.022).

CONCLUSIONS: Patients with pretreatment CrCl >90 mL/min were more likely to fail SVR12 than patients with CrCl <90 mL/min.
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Wide Use of New HCV Drugs Prevents New Cases

Wide Use of New HCV Drugs Prevents New Cases
by Michael Smith
North American Correspondent, MedPage Today

SEATTLE -- Unrestricted use of new direct-acting agents against hepatitis C (HCV) can markedly reduce the rate of new infections, a researcher said here.

That's based on analysis of what happened in the Netherlands among gay men with both HIV and HCV when unlimited access to the new, highly effective agents was rolled out in 2015, according to Bart Rijnders, MD, PhD, of Erasmus University Medical Center in Rotterdam, the Netherlands

Uptake of the drugs was substantial and the rate of new HCV infections was cut in half, Rijnders told reporters at the annual Conference on Retroviruses and Opportunistic Infections (CROI).
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Related
New hepatitis C infections among HIV-positive gay men drop by half after direct-acting antiviral roll-out in Netherlands
A little more than a year after the Netherlands instituted a policy allowing unrestricted access to direct-acting antivirals for the treatment of hepatitis C, researchers have already seen a dramatic decline in acute hepatitis C virus (HCV) infections among one at-risk population, HIV-positive men who have sex with men.

These findings were reported on Thursday at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) in Seattle, in a session that also included presentations on rising incidence of HCV infection among HIV-positive gay men in San Diego and predictions about eradication of HIV/HCV co-infection in France.
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Conference Coverage
Conference on Retroviruses and Opportunistic Infections (CROI)
February 13-16, 2017, Seattle WA
NATAP