Friday, September 28, 2018

Cardiovascular Risk Management and Hepatitis C: Combining Drugs

Cardiovascular Risk Management and Hepatitis C: Combining Drugs
Elise J. SmoldersPeter J. G. ter HorstSharon WoltersDavid M. Burger Elise J. Smolders

Article First Online: 27 September 2018

Direct-acting antivirals (DAAs) are known victims (substrate) and perpetrators (cause) of drug–drug interactions (DDIs). These DAAs are used for the treatment of hepatitis C virus (HCV) infections and are highly effective drugs. Drugs used for cardiovascular risk management are frequently used by HCV-infected patients, whom also are treated with DAAs. Therefore, the aim of this review was to describe DDIs between cardiovascular drugs (CVDs) and DAAs. An extensive literature search was performed containing search terms for the marketed DAAs and CVDs (β-blocking agents, ACE inhibitors, angiotensin II antagonists, renin inhibitors, diuretics, calcium channel blockers, statins/ezetimibe, fibrates, platelet aggregation inhibitors, vitamin K antagonists, heparins, direct Xa inhibitors, nitrates, amiodarone, and digoxin). In particular, the drug labels from the European Medicines Agency and the US Food and Drug Administration were used. A main finding of this review is that CVDs are mostly victims of DDIs with DAAs. Therefore, when possible, monitoring of pharmacodynamics is recommended when coadministering these drugs with DAAs. Nevertheless, it is sometimes better to discontinue a drug on a temporary basis (statins, ezetimide). The DAAs are victims of DDIs in combination with bisoprolol, carvedilol, labetalol, verapamil, and gemfibrozil. Despite there are many DDIs predicted in this review, most of these DDIs can be managed by monitoring the efficacy and toxicity of the victim drug or by switching to another CVD/DAA.

Key Points
Drug-drug interactions (DDIs) can be of major concern in hepatitis C patients with cardiovascular issues as there are many potential DDIs.

Especially clopidogrel and ticagrelor are drugs of which the potential drug-interactions are complex and hard to manage.

With increasing number of new direct-acting antivirals (DAAs) available the number clinical relevant DDIs are decreasing.

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Are direct-acting antiviral agents for treatment of HCV safe and effective for use in patients over 65?

Journal of the American Geriatrics Society 
J Am Geriatr Soc. 2018 Jul;66(7):1339-1345. doi: 10.1111/jgs.15392.
Epub 2018 May 25.
PMID: 29799112 DOI: 10.1111/jgs.15392

Efficacy and Tolerability of Direct–Acting Antivirals for Hepatitis C in Older Adults 
Chiara Mazzarelli, MD; Aisling Considine, MPharm; Kate Childs, MBBS, MPH; Ivana Carey, MD, PhD; Matteo Angelo Manini, MD; Abid Suddle, MBBS, MD; Geoffrey Dusheiko, MB, BCh; Kosh Agarwal, BMed Sci (Hons), MD; Mary D. Cannon, MB, BCh, PhD Disclosures J Am Geriatr Soc. 2018;66(7):1339-1345.

Full-text article
Now available online @ Medscape 

To evaluate the efficacy and tolerability of direct-acting antiviral (DAA) therapy in individuals aged 65 and older.

Retrospective review between June 2014 and January 2017.

Viral hepatitis outpatient clinic.

Individuals aged 65 and older treated with DAA therapy for hepatitis C virus (HCV) during the study period (N=113) divided into 2 cohorts: aged 65 to 74 (n=88) and aged 75 and older (n=25).

Drug-drug interactions (DDIs), adverse events (AEs), and rates of sustained virologic response with DAA therapy were assessed.

Sustained virologic response rate was 97.7% in individuals aged 65 to 74 and 95.8% in those aged 75 and older. Individuals aged 75 and older were more likely to be taking more than 2 medications per day for chronic conditions (84% vs 62%, p=.02) and more likely to have clinically significant DDIs necessitating cessation or adjustment of medications before commencement of DAA therapy (80% vs 36%, p=.001). Moreover, individuals aged 75 and older were more likely to experience an AE during therapy (50% vs 26%, p=.03) and were more susceptible to developing anemia secondary to ribavirin (60% vs 20%, p=.02).

DAA therapy is highly efficacious for the treatment of HCV in older adults, but those aged 75 and older are more likely to have clinically significant pretreatment DDIs and experience AEs, including ribavirin-induced anemia, during therapy.

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Hepatitis C Infection May Be a Blessing for Patients in Need of a Transplant

Hepatitis C Infection May Be a Blessing for Patients in Need of a Transplant
Lara C. Pullen PHD
First published: 27 September 2018

This month's installment of “The AJT Report” looks at how transplanting HCV‐positive organs can reduce risks for patients awaiting organs. We also report on Bristol Myers Squibb's recent easement of restrictions in prescribing belatacept (Nulojix).

“We are very proactive about our hepatitis C patients,” says Uttam Reddy, MD, medical director of the kidney transplant program at the University of California, Irvine (UCI) Medical Center. This is because in Southern California, the average wait time for a hepatitis C virus (HCV)‐negative organ is 8 to 10 years. If, however, a patient with HCV is willing to receive an HCV‐positive organ, the typical wait time is less than two years, a difference that Dr. Reddy describes as a “notably significant benefit.” In fact, he adds, “Before treating HCV in patients with advanced kidney disease, we recommend that they be evaluated at UCI first to assess the degree of their liver disease. If their liver disease is not advanced, we recommend proceeding with transplant and then treating their HCV after transplantation.”

Key Points
• Hepatitis C virus (HCV)-positive patients who elect to receive HCV-positive organs may cut years off their wait time.
• While the risk from an HCV-positive organ is difficult to quantify, it needs to be weighed against known risk from years on dialysis.
• Direct-acting antivirals (DAAs) lower risks associated with receiving HCV-positive organs.
• More frequent HCV diagnoses, greater use of DAAs and a potential ebbing of the opioid epidemic mean that fewer HCV-positive organs will be available in the future.

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Hepatocellular carcinoma among US and non-US-born patients with chronic hepatitis B: Risk factors and age at diagnosis

Research Article

Hepatocellular carcinoma among US and non-US-born patients with chronic hepatitis B: Risk factors and age at diagnosis 
Kaitlyn Kennedy, Susan M. Graham, Nayan Arora, Margaret C. Shuhart, H. Nina Kim
Published: September 25, 2018

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Risk factors for hepatocellular carcinoma (HCC) have not been well characterized among African immigrants with chronic hepatitis B virus (HBV) infection. We conducted a case-control study to identify demographic and clinical factors associated with HCC among a diverse cohort of patients with chronic HBV infection seen in a large academic health setting.

We identified a total of 278 patients with HCC and chronic HBV seen at two medical centers in a 14-year span from January 2002 to December 2015. These cases were age- and sex-matched in a 1:3 ratio with 823 non-cancer control subjects with chronic HBV. Conditional logistic regression was used to estimate the odds of HCC by race, with black race stratified by African-born status, after adjusting for diabetes, HIV or HCV coinfection, alcohol misuse and cirrhosis.

Of the 278 HCC cases, 67% were 60 years of age or older, 78% were male, 87% had cirrhosis and 72% were Asian. HIV infection was present in 6% of cases. Only 7% (19 of 278) of HCC cases were black, of whom 14 were African immigrants. The median age at HCC diagnosis was 44 years in Africans. Notably, nearly all (93%) of the African-born patients with HCC were diagnosed at an age younger than 60 years compared with 52% of Asian cases (P<0.001). The main factors independently associated with greater odds of HCC overall were Asian race (adjusted odds ratio [aOR] 3.3, 95% confidence interval [CI] 1.9–5.5) and cirrhosis (aOR 19.7, 95% CI 12.2–31.8).

African immigrants accounted for a small proportion of HBV-associated HCC cases overall compared with Asians but appeared to have greater likelihood of early-onset HCC. Optimal strategies for HCC prevention in these key subroups with chronic HBV warrant further study.

Differences in hepatocellular carcinoma risk, predictors and trends over time according to etiology of cirrhosis

Of Interest
Sci Rep. 2018; 8: 13651.
Published online 2018 Sep 12. doi: 10.1038/s41598-018-31839-y

Differences in hepatocellular carcinoma risk, predictors and trends over time according to etiology of cirrhosis 
George N. Ioannou , Pamela Green, Elliott Lowy, Elijah J. Mun, Kristin Berry
Published: September 27, 2018

Full-text Article 
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Background and aims
Hepatocellular carcinoma (HCC) risk is high in cirrhosis. We sought to describe differences in HCC risk, predictors and trends over time according to etiology of cirrhosis.

We identified 116,404 patients with cirrhosis diagnosed between 2001–2014 in the VA healthcare system and determined incident HCC cases occurring from the date of cirrhosis diagnosis until 01/31/2017. Patients were divided by cirrhosis etiology into hepatitis C virus (HCV, n = 52,671), alcoholic liver disease (ALD, n = 35,730), nonalcoholic fatty liver disease (NAFLD, n = 17,354), or OTHER (n = 10,649).

During a mean follow-up of 4.3 years, 10,042 new HCC cases were diagnosed. Patients with HCV had >3 times higher incidence of HCC (3.3 per 100 patient-years) than patients with ALD (0.86/100 patient-years), NAFLD (0.90/100 patient-years) or OTHER (1.0/100 patient-years), an association that persisted after adjusting for baseline characteristics. HCC incidence was 1.6 times higher in patients with cirrhosis diagnosed in 2008–2014 (2.47/100 patient-years) than in 2001–2007 (1.55/100 patient-years). 

Independent predictors of HCC among all cirrhosis etiologies included: age, male sex, Hispanic ethnicity, high serum alpha fetoprotein, alkaline phosphatase and AST/√ALT ratio and low serum albumin and platelet count. Diabetes was associated with HCC in ALD-cirrhosis and NAFLD-cirrhosis, and BMI in ALD-cirrhosis.

HCC risk is 3 times greater in cirrhotic patients with HCV than ALD or NAFLD. HCC risk continues to increase over time in analyses extending to 2017 in cirrhosis of all etiologies. Multiple readily available risk factors for HCC were identified that were influenced by cirrhosis etiology and could be used to develop HCC risk estimation models.

Thursday, September 27, 2018

Gilead Subsidiary to Launch Authorized Generics of Epclusa® (Sofosbuvir/Velpatasvir) and Harvoni® (Ledipasvir/Sofosbuvir) for the Treatment of Chronic Hepatitis C

Of Interest
October 29, 2018
Gilead $1,100 a day drug. Now it will launch a generic at quarter the price
Sep 27, 2018
An ‘unusual decision’: Gilead to launch hep C generics ten years early

Sept 26 2018
The U.S. drug pricing system is a mess. It's an absolute disaster. Just about every entity involved, from drug companies to consumers to insurers to the government, agrees that offering discounts off the list price is a convoluted way to sell a life-saving product.

Maria Carolina Marcello, Gram Slattery
A Brazilian court has stripped the patent protection of a Gilead Sciences Inc big-selling hepatitis C treatment in Brazil, paving the way for cheaper generics, a presidential candidate who pushed for the move said on Monday....

Gilead Sciences to Sell Authorized Generics of Hepatitis C Drugs
Gilead Sciences will sell authorized generics of its blockbuster hepatitis C drugs Epclusa and Harvoni, Bloomberg reported. The brand-name versions sparked widespread debate about US pharmaceutical costs when they were introduced at a price of more than $1000 per pill. The less expensive versions will cost $24,000 for a course of treatment, which compares with a list price for Harvoni of $94,500. The company’s hepatitis C drugs remain among the best-selling pharmaceutical products in history, but they've also made Gilead the subject of congressional hearings and accusations of greed.

Gilead Press Release
United States
Gilead Subsidiary to Launch Authorized Generics of Epclusa® (Sofosbuvir/Velpatasvir) and Harvoni® (Ledipasvir/Sofosbuvir) for the Treatment of Chronic Hepatitis C
-- List Price of Authorized Generics to Reflect Discounts in the System Today --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Sep. 24, 2018-- Gilead Sciences, Inc. (NASDAQ: GILD) announced today plans to launch authorized generic versions of Epclusa® (sofosbuvir 400mg/velpatasvir 100mg) and Harvoni® (ledipasvir 90mg/sofosbuvir 400mg), Gilead's leading treatments for chronic hepatitis C virus (HCV), in the United States, through a newly created subsidiary, Asegua Therapeutics LLC. The authorized generics will launch at a list price of $24,000 for the most common course of therapy and will be available in January 2019.

Since the launch of Gilead's first HCV medication in 2013, the average price paid for each bottle of medicine in the United States has decreased by more than 60 percent off of the public list prices, across health insurers and government payers. Due to the complexity and structure of the U.S. healthcare system, however, these discounts provided by Gilead may not always translate into lower costs for patients. Further, existing contracts, together with laws associated with government pricing policies, make it challenging to quickly lower a product's list price once it is on the market.

The authorized generics are priced to more closely reflect the discounts that health insurers and government payers receive today. Insurers will have the choice of offering either the authorized generics or the branded medications for both Epclusa and Harvoni. In the Medicare Part D setting, the authorized generics could save patients up to $2,500 in out-of-pocket costs per course of therapy. The authorized generics will also offer substantial savings to state managed Medicaid plans that do not currently benefit from negotiated rebates and that represent a significant number of people in need, potentially opening up access to our medications to beneficiaries who were previously denied coverage.

"Launching these authorized generics is the best solution available to us today to quickly introduce a lower-priced alternative to our HCV medications without significant disruption to the healthcare system and our business," said John F. Milligan, PhD, President and Chief Executive Officer, Gilead Sciences. "This launch also will hopefully help increase transparency by more closely aligning our medications' list prices with their cost. Our ultimate goal is to lower the list price of Epclusa - a medication we believe is of great importance given its clinical profile across genotypes - and Harvoni. We are committed to working with all of our partners in the healthcare system to help enable list price reductions of our HCV medications and find better solutions to reduce patients' out-of-pocket costs."

Beyond the company's efforts to reduce patient costs, Gilead is continuing to pursue innovative collaborations and long-term financing models, such as a potential subscription model, that could not only expand access, but aim to eliminate HCV in the United States and around the world.

About Gilead Sciences, Inc.
Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. The company strives to transform and simplify care for people with life-threatening illnesses around the world. Gilead has operations in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2018, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

Wednesday, September 26, 2018

Heavy drinkers and teetotalers alike may have heightened dementia risk

Of Interest
Alcohol use disorder therapy could improve chronic liver disease outcomes
Fuster D, Samet JH. N Engl J Med. 2018;doi:10.1056/NEJMra1715733.
September 26, 2018
Details from a recently published review discussed expanded use of alcohol use disorder medications and treatments in everyday clinical practice for patients with advanced liver disease.

In HCV, alcohol use increases infection exposure and persistence, causes more extensive liver damage than the infection alone, leads to faster progression of liver fibrosis and results in higher rates of mortality. These effects are common in HBV as well, although alcohol use in patients with HBV also demonstrated an increased risk for hepatocellular carcinoma.

Along with increased fibrosis progression and an increased risk for hepatocellular carcinoma, alcohol use in patients with NAFLD leads to a greater prevalence of steatosis and abnormal liver tests. In hereditary hemochromatosis, alcohol use increases fibrosis progression as well as iron overload.

“Assessment of alcohol use is appropriate for any person with liver disease, given the elevated risks of alcohol-related hepatotoxicity,” Fuster and Samet wrote. “In fact, there is no known safe threshold of alcohol consumption for patients with chronic liver disease, especially those with HCV infection, obesity, or the metabolic syndrome.”

Heavy drinkers and teetotalers alike may have heightened dementia risk 
Lisa Rapaport
(Reuters Health) - Middle-aged adults who avoid alcohol altogether, and those who consume the equivalent of seven glasses of wine or more a week are both more likely than light drinkers to develop dementia in their later years, a long-term study suggests.

Abstinence is also associated with a higher likelihood of having heart disease or diabetes, which explains part of the increased dementia risk for teetotalers, the study found. Abstinence may also be tied to dementia in people who stopped drinking due to misuse or addiction, Sabia said by email...

“Findings on abstainers should not motivate people who do not drink to start drinking alcohol due to the adverse effects of alcohol on mortality, cirrhosis of the liver and cancer,” Sabia noted. “In addition, given the detrimental effect of alcohol for several health outcomes, people who drink in an excessive manner should be encouraged to reduce their alcohol consumption.” 

Recommended Reading
Alcohol abuse kills 3 million a year, most of them men: WHO
Of all deaths attributable to alcohol, 28% were due to injuries, such as those from traffic crashes, self-harm and interpersonal violence; 21% due to digestive disorders; 19% due to cardiovascular diseases, and the remainder due to infectious diseases, cancers, mental disorders and other health conditions...

Study: Damaged liver cells undergo reprogramming to regenerate

Study: Damaged liver cells undergo reprogramming to regenerate
Sep 26, 2018 8
by Steph Adams | Science Writer

The Greek hero Prometheus was punished by being lashed to a rock and having his liver eaten each day by an eagle, a myth that hints at the extraordinary regenerative powers of the human liver. A new study offers insight into how RNA splicing generates alternate forms of the “Hippo signaling pathway” to promote liver regeneration.

Graphic by Jose Luis Vasquez, Beckman Institute

CHAMPAIGN, Ill. — In Greek mythology, Zeus punishes the trickster Prometheus by chaining him to a rock and sending an eagle to eat a portion of his liver every day, in perpetuity. It was the right organ to target – the liver has the ability to regenerate itself, though not overnight nor for eternity.

New research conducted by biochemists at the University of Illinois has determined how damaged liver cells repair and restore themselves through a signal to return to an early stage of postnatal organ development. The findings are reported in the journal Nature Structural & Molecular Biology.

“The liver is a resilient organ,” said U. of I. biochemistry professor Auinash Kalsotra, who led the new research. “It can restore up to 70 percent of lost mass and function after just a few weeks.

“We know that in a healthy adult liver, the cells are dormant and rarely undergo cell division,” he said. “However, if the liver is damaged, the liver cells re-enter the cell cycle to divide and produce more of themselves.”

The human liver can become chronically damaged by toxins such as alcohol and even certain medicines, but still continue to function and self-repair, Kalsotra said.

“This research looked at what is happening at the molecular level in a damaged liver that enables it to regenerate while still performing normal functions,” he said.

Using a mouse model of a liver severely damaged by toxins, the researchers compared injured adult liver cells with healthy cells present during a stage of development just after birth. They found that injured cells undergo a partial reprograming that returns them to a neonatal state of gene expression.

The team discovered that fragments of messenger RNA, the molecular blueprints for proteins, are rearranged and processed in regenerating liver cells in a manner reminiscent of the neonatal period of development. This phenomenon is regulated through alternative splicing, a process wherein exons (expressed regions of genes) are cut from introns (intervening regions) and stitched together in various combinations to direct the synthesis of many different proteins from a single gene. These proteins can have different cellular functions or properties.

“We found that the liver cells after birth use a specific RNA-binding protein called ESRP2 to generate the right assortment of alternatively spliced RNAs that can produce the protein products necessary for meeting the functional demands of the adult liver,” said graduate student Sushant Bangru, the lead author of the study. “When damaged, the liver cells lower the quantity of ESRP2 protein. This reactivates fetal RNA splicing in what is called the ‘Hippo signaling pathway,’ giving it instructions about how to restore and repopulate the liver with new and healthy cells.”

Kalsotra described the science in mythological terms: “When Zeus’ eagle comes in for its daily snack, damaging the liver, the alternatively spliced form of Hippos come into play – repairing Prometheus’s liver so the poor guy can go through this whole punishment again the next day.”

The National Institutes of Health, March of Dimes and American Heart Association supported this

The paper “Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration” is available online and from the U. of I. News Bureau.
DOI: 10.1038/s41594-018-0129-2

Blood flow forces liver growth

26 September 2018

Blood flow forces liver growth
Sina Y. Rabbany & Shahin Rafii
Increases in biomechanical forces in the liver’s blood vessels have now been shown to activate two mechanosensitive proteins. The proteins trigger blood-vessel cells to deploy regenerative factors that drive liver growth. 

The molecular pathways that initiate and sustain liver growth during development and after injury are orchestrated in part by a balanced supply of stimulatory and inhibitory factors secreted from specialized liver sinusoidal endothelial cells (LSECs), which line the organ’s blood vessels14. But it is unclear how the liver vasculature senses the need to produce these endothelial-cell-derived (angiocrine) growth factors, such as hepatocyte growth factor (HGF) and Wnt proteins, to guide proper organ growth4. In a paper in Nature, Lorenz et al.5 show how mechanical forces created by the passage of blood through the liver activate signalling pathways that promote the production of angiocrine factors and the proliferation of the organ’s main cell type, hepatocytes, in mice.

Continue reading online @ Nature

Behind The Headlines: Older adults mixing prescription drugs and herbal remedies

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.

Concerns raised about older adults mixing prescription drugs and herbal remedies
Tuesday September 25 2018
"One million over-65s could be suffering dangerous side effects from mixing 'hazardous' combinations of drugs and herbal remedies, study warns," reports the Mail Online.

This follows a postal survey of 149 adults aged 65 and above from southeast England. The survey wanted to see whether people were choosing to take herbal or dietary supplements while also taking prescription medication. All respondents were taking at least 1 prescription drug, and a third of them were also taking some kind of supplement.

Most of the combinations were not harmful, but the researchers did find some people taking combinations that were potentially harmful.

These included:
a class of blood pressure drug (calcium channel blockers) with the herbal remedy St John's wort, which may reduce the effectiveness of the blood pressure drug
the type 2 diabetes drug metformin with glucosamine, which may affect blood glucose control
another blood pressure medication bisoprolol with omega-3 fish oil, which may further reduce blood pressure

The study gives an indication of how common supplement use is, and in some cases raises concerning patterns. However, it was a very small study and it is difficult to know whether the results would generalise to the wider population. There may be other drug-supplement interactions that were not found in this small group, but which might exist in other populations.

Some people mistakenly think a treatment or supplement marketed as "herbal" means it does not cause any side effects or drug interactions.

If you are unsure whether it is safe to take a supplement with your prescribed medication, read the leaflets provided with both medicines, or talk to your pharmacist or GP.

It's worth noting that these sorts of drug interactions can affect people of any age, not just people aged over 65.

Where did the story come from?
This study was carried out by researchers from the University of Hertfordshire and NHS Improvement. The study did not receive any funding. It was published in the peer-reviewed British Journal of General Practice.

The UK media generally covered the story fairly well, although the headlines tended to focus on the estimate that more than a million people could be affected. This figure is uncertain as it was based on a very simple calculation scaling up from a small study.

Also, many of the papers used the phrase "alternative medicines", when some of the substances studied in this research were actually commonly used food and vitamin supplements.

By talking about alternative medicines, people might not realise that this study is relevant to them, as they may have a different understanding of that phrase. 

What kind of research was this?
This was a cross-sectional survey, which means that a group of people were studied at a single point in time. This kind of study has the benefit of being relatively simple and quick to carry out. It's also a good way to look at how common something is (like use of herbal supplements) at a particular time.

However, cross-sectional studies can't tell us much more than this or explore the reasons behind observed patterns. We don't know the details of why people were taking drugs and supplements at the same time, for how long they had done this, and whether this had caused problems for them. Also, studies need to include a large and random cross-section of the relevant population to be able to give a reliable estimate of how common something is. So this small localised study may not be truly representative.

What did the research involve?
Between January and April 2016, this study mailed questionnaires to 400 older adults who were not living in care homes. Some were from a GP practice based in a rural area of Essex with a mainly white population. The others were from a GP practice in an area of London with a higher proportion of people from black, Asian and other minority ethnic groups.

Eligible participants were randomly selected people aged 65 or over who were taking at least 1 prescription medication. People with dementia, those who were terminally ill, and those who would not be able to consent to participate were excluded.

The questionnaire asked people what prescription drugs they were taking, as well as what "herbal medicinal products" or dietary supplements they might also be using. The questionnaire included examples of common herbal products (such as St John's wort or gingko) so that people understood what might be included in that category.

The researchers used a database to check whether people were taking any combination of prescription medicine and herbal remedy known to be potentially harmful. They labelled each interaction according to the following criteria:

action: whether it needed action or not
severity: how likely it was to cause a problem for the patient if the situation was not managed
evidence: how good is the evidence around the interaction

Reminder letters were sent after 2 weeks, and further questionnaires were then sent to people who hadn't previously responded. In total, 149 people responded and could be included in the analysis.

What were the basic results?
People were taking an average of 3 prescription drugs on a regular basis, with the most common including statins, beta-blockers and calcium channel blockers (used in the treatment of heart conditions and high blood pressure) and non-steroidal anti-inflammatory drugs (NSAIDs).

Around a third (33.6%) of the people in the study were using herbal remedies or supplements alongside their regular medications. This rate was higher in women (43.3%) than men (22.5%). People who were using herbal remedies or supplements were taking just 1 on average, though some people took as many as 8.

Most of the people (78%) who took supplements alongside their prescribed medication were taking vitamin and mineral supplements including cod liver oil, multivitamins, vitamin D and glucosamine.

They found 20% of people were using herbal products only. The most common were evening primrose oil, valerian, Nytol Herbal®, and garlic. Just over half of the reported potential interactions were considered to not be of clinical significance. However, 21 combinations were identified as having uncertain consequences, and 6 were considered potentially hazardous or significantly hazardous.

The combinations considered particularly risky were:
-the supplement Bonecal with levothyroxine (medicine for an underactive thyroid); the calcium in Bonecal reduces the effectiveness of levothyroxine
-peppermint taken with the medicine lansoprazole (which lowers stomach acid) – the medicine may affect the protective coating of peppermint capsules, which could lead to side effects caused by the peppermint
-St John's wort with the blood pressure drug amlodipine, which may make the drug less effective
-the supplement glucosamine with metformin (a diabetes drug), a combination that may affect blood glucose control 
-omega-3 fish oil with the blood pressure drug bisoprolol, which can lower blood pressure too much
the herbal remedy gingko with the stomach acid drug rabeprazole – this makes the drug less effective

How did the researchers interpret the results?
The researchers noted that if their study was representative of the population as a whole, then potentially 1.3 million older adults in the UK might be at risk of at least 1 herb-drug or supplement-drug interaction. They suggest GPs should routinely question the use of herbals and supplements among older adults.

This study gives us an interesting snapshot into the habits of a group of older adults who are using supplements alongside their prescription medications.

But we don't know how representative this study is of the wider population of older adults in the UK. The study includes patients from only 2 GP surgeries in southeast England. Although the researchers chose practices with different population characteristics, the people in the study might not be representative of the country as a whole.

The study was also very small, at just 149 people. We don't know anything about the people who did not participate. For example, it may be that these people were more likely to be users of herbal remedies and didn't want to share this information with their doctor. Or they might not have used herbal remedies at all and didn't think the study was relevant to them. Either way, this could affect the results and mean the study is not representative.

Finally, the study did not explore the reasons why people were taking supplements or herbal products alongside prescribed drugs, for how long they had done this, and whether they were aware of potential interactions. We also don't know whether there were any actual side effects or harms reported by the people in the study.

If you are unsure whether it is safe to take a herbal remedy or supplement along with your regular medication, talk to a pharmacist or your GP. It is also a good idea to do this if you are taking a lot of different medications that have been added to your prescription over the years, or if you are unsure what any of your medications are for.

Analysis by Bazian
Edited by NHS Website

Links to the headlines 
Mail Online, September 25 2018

Alternative medicine use may put 1.3 million older people at risk, study suggests
The Independent, September 25 2018

Millions of pensioners ‘at risk’ from alternative remedies as they ‘could react with their prescription drugs’
The Sun, September 25 2018 

The Times (subscription required), September 25 2018

Links to the science
Agbabiaka TB, Spencer NH, Khanom S, Goodman C. Prevalence of drug–herb and drug–supplement interactions in older adults: a cross-sectional surveyBritish Journal of General Practice. Published online September 24 2018

Tuesday, September 25, 2018

How I Manage Low-Level Viremia in Patients Receiving HBV Therapy

How I Manage Low-Level Viremia in Patients Receiving HBV Therapy 
Robert S. Brown, Jr., MD, MP

An ongoing challenge is how to manage patients with HBV infection who have intermittent or persistent low-level viremia on treatment, but who do not meet the criteria for viral breakthrough. In my practice, I divide these patients into 2 groups: those with HBV that is detectable but not quantifiable (< 20 IU/mL) and those with HBV that is quantifiable (≥ 20 IU/mL).

Frequently, we see patients with test results reporting detectable but not quantifiable HBV levels, and I do not worry about these patients. In fact, many of these nonquantifiable readings are likely false positives.

However, I become concerned if the low-level viremia is quantifiable, even though this finding is much rarer in my practice. Although during the last 5 years the clinical community shifted from frequent use of combination therapy to monotherapy with entecavir or tenofovir even with intermittent low-level viremia, recent data indicate that quantifiable low-level viremia may be associated with worse outcomes, particularly in patients with cirrhosis....

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Prevalence of occult hepatitis C virus infection in patients who achieved sustained virologic response to direct-acting antiviral agents

Infez Med. 2018 Sep 1;26(3):237-243.

Prevalence of occult hepatitis C virus infection in patients who achieved sustained virologic response to direct-acting antiviral agents.



The reappearance of HCV infection months or years after sustained virologic response (SVR) may be due to the persistence of HCV in tissue cells in spite of being undetected in serum. This situation is known as occult hepatitis C infection (OCI). We aimed to assess the prevalence of OCI in Egyptian patients with chronic hepatitis C (CHC) who achieved SVR after treatment with direct-acting antiviral agents (DAA). We carried out a cross-sectional study at the Advanced Center for Liver Diseases of Zagazig University Hospitals and Al-Ahrar Viral Hepatitis Treatment Center, Sharkia Governorate, Egypt. One hundred and fifty adult patients with CHC, who achieved SVR 12-24 weeks after end of treatment with sofosbuvir/daclatasvir ± ribavirin (139 patients, 92.67%), sofosbuvir/ledipasvir ± ribavirin (eight patients, 5.33%), sofosbuvir/simeprevir (two patients, 1.33%), and ombitasvir/ paritaprevir/ritonavir + ribavirin (one patient, 0.67%), according to the Egyptian National Committee for Control of Viral Hepatitis, were included in the study. We tested these patients for HCV RNA in peripheral blood mononuclear cells (PBMCs) immediately after confirmation of SVR12-24 weeks. Statistical analysis was performed by means of the Shapiro-Wilk test, Mann-Whitney U test, Chi-square test, and Fisher's exact test. Seventeen patients (11.33%) were positive for PBMNCs HCV RNA. The prevalence of OCI was highest in patients treated with simeprevir/sofosbuvir (2/2 patients). There is a substantially high prevalence of OCI after treatment with DAAs. We recommend dual testing for HCV RNA in both serum and PBMCs at the end of treatment of HCV infection with DAAs and during validation of the SVR following the initial response.

Editorial: interferon‐free DAAs are a great boon for patients with hepatitis C and cryoglobulinaemia

Aliment Pharmacol Ther. 2018 Oct;48(7):770-771. doi: 10.1111/apt.14899.

Editorial: interferon‐free DAAs are a great boon for patients with hepatitis C and cryoglobulinaemia
M. Atsukawa, A. Tsubota
Pages: 770-771
First Published: 23 September 2018 

Chronic hepatitis C is often accompanied by various extrahepatic manifestations that affect the health‐related quality of life (HRQoL) and mortality of patients.1, 2 In particular, mixed cryoglobulinaemia (MC) and MC syndrome (MCS) are closely associated with hepatitis C virus (HCV) infection. Thus, the most rational treatment strategy for HCV‐related MC/MCS is HCV eradication. As expected, interferon (IFN)‐based treatment can alleviate MC/MCS in patients with a sustained virological response (SVR).3 However, the SVR rate is low and drug adherence is frequently reduced due to adverse events.4 MCS patients exhibit systemic complications that may attenuate the efficacy of IFN‐based treatment. Moreover, MC is a negative, independent predictor of virological response.5 Currently, IFN‐free direct‐acting antiviral (DAA) combination therapy that yields a high SVR rate with high tolerability is the standard of care for chronic hepatitis C. DAA treatment for MC patients reportedly achieved a SVR rate of 74%‐100% and reduced or resolved the symptoms in 61%‐100% of the patients with SVR.6

To our knowledge, Gragnani and colleagues were the first to conduct a prospective, case‐control study to evaluate the virological/clinical/immunological response and the HRQoL score following IFN‐free, DAA‐based treatment for cryoglobulinaemic vasculitis (CV) patients, MC patients without vasculitis, and control patients without CV/MC.7 This comparative study reconfirmed the excellent efficacy/safety profile of DAA‐based treatment even in CV/MC patients. The SVR rate (89.9%) was almost twice that (48.6%) with pegylated IFN/ribavirin treatment.5, 7 It was noteworthy that SVR persistently improved the clinical indices at a high rate in CV patients. Immunological response progressively improved in CV patients with SVR. Moreover, the HRQoL score, including physical and mental components, was lower at baseline in CV patients than in MC/control patients, while it significantly improved in CV patients with SVR. Therefore, the highly effective and safe DAA treatment is a great boon for CV patients, because it consequently reduces their physical and/or mental burden future healthcare costs.

However, the SVR rates in CV/MC patients (90.6% and 88.9%, respectively) were lower (although not significantly) than those in control patients (95.3%).7 In fact, most patients with treatment failure had cryoglobulinaemia and some exhibited severe manifestations before treatment. Such patients failed to experience clinical improvement during the post‐treatment period. These outcomes suggest the importance of early treatment for CV/MC patients before disease progression to severe stages.

DAAs are rapidly developing, and treatment options are increasing; therefore, personalised medication by regimen optimisation is possible for cryoglobulinaemic patients with various complications. For instance, sofosbuvir/ribavirin is administered to CV patients.6 However, 8%‐58% of cryoglobulinaemic patients have renal impairment.8 Sofosbuvir and ribavirin are mainly excreted in the urine; thus, both are contraindicated for, or should be carefully administered to, patients with moderate/severe renal dysfunction. Currently, the AASLD guidelines specify elbasvir/grazoprevir or glecaprevir/pibrentasvir as the first‐line treatment.9 Moreover, the EASL guidelines recommend ribavirin‐free treatment for cryoglobulinaemic patients with renal dysfunction.10 Precision medicine is required, particularly for cryoglobulinaemic patients with severe complications and refractory features.

Declaration of personal interests: M Atsukawa has served as a speaker for AbbVie, MSD and Gilead Sciences, and has received research funding from AbbVie and MSD. 

Zignego AL, et al. Aliment Pharmacol Ther. 2018

We would like to express our gratitude to Drs Atsukawa and Tsubota for their comments and the correct interpretation of the main messages that may be deduced from our study,1, 2 especially concerning the future challenges in the treatment of cryoglobulinaemic vasculitis (mixed cryoglobulinaemia syndrome, MCS), a HCV‐related disease that is often under‐estimated and not sufficiently known.3

The occurrence of MCS represents a condition that justifies careful prioritization of Interferon‐free anti‐HCV treatment. This appears to be the most effective as soon as it is carried out, whereas, when the therapy is too late and the patients have already developed severe damage (especially renal), MCS requires careful evaluation and accurate tailoring of non‐aetiological therapies (e.g, anti‐inflammatory and immunosuppressant) to be performed before, but also after, and sometimes concomitantly with anti‐viral therapy.

The complex pathogenetic cascade that underlies this lymphoproliferative disorder, and that originates from the clonal expansion of specific B‐cells (RF‐B cells), may lead to the subsequent overcoming of points of no return whose identification would be important for the assessment of a rational approach to the patients. Above all, in case of the persistence of MCS symptoms and/or signs, it would be important to distinguish the causes indicating the risk of evolution of the lymphomagenetic process (the overcoming of points of no return), from those without this risk, such as the simple occurrence of irreversible tissue damage.4

In this light, it seems conceivable that a key factor for the correct interpretation of the persistence of MCS stigmata even after viral eradication, is the evaluation of the persistence of B cell clonal expansion. Various factors have been suggested as playing a key role in inducing clonal expansion, first the important and sustained activation of the B‐cell compartment by both viral and host factors. Among the latter, special emphasis was placed on the binding of the viral E2 protein and the CD81 molecule on the surface of the B cells5 and the effect of the B‐cell‐activating factor (BAFF)/B‐lymphocyte stimulator (BLyS), especially in subjects harbouring particular genetic variants.6 Such an important and persistent B‐cell activation would cooperate to the lymphomagenetic process with B‐cell anti‐apoptotic factors including, first, the t (14; 18) translocation7 and could possibly be correlated with an exhaustion of the B cells observed during MCS.8 Consequently, it seems conceivable that the detection of persistent B cell expanded clones through sensitive methods, after HCV eradication, could help in understanding the condition that we are facing; this would be helpful in deciding the best approach to the patient (more frequent follow‐ups and/or specific therapies).

In conclusion, following the demonstration of the positive effect of viral eradication in MCS patients, the most important future challenge is the identification of markers useful in assessing the best approach to patients that maintain clinical and/or immunological MCS stigmata after SVR.

The authors’ declarations of personal and financial interests are unchanged from those in the original article.2

Monday, September 24, 2018

What Is a Healthy Stool ?

Of Interest - posted Feb 2018:
Clinical Gastroenterology and Hepatology (CGH)
February 2018 Volume 16, Issue 2, Page A22
What Causes Constipation?
Constipation is usually a symptom, not a disease. Some of the most common causes of constipation are as follows....

What Does My Stool Color Or Change In Bowel Movement Mean?
On this page an overview of stool color changes due to either medications, diet, or indicate an underlying medical condition such as gallstones and liver disease is explored. For instance according to a recent article published 21 September 2018 online at Medical News Today, a yellow stool may indicate problems with the pancreas, liver, or gallbladder.

Further down this page is the famous Bristol Stool Scale, developed by UK gastroenterologists at the University of Bristol. The chart explains various stool types by identifying physical attributes and the length of time the stool remained in the colon.