Friday, January 19, 2018

Exposure to previous cART is associated with significant liver fibrosis and cirrhosis in human immunodeficiency virus-infected patients

Exposure to previous cART is associated with significant liver fibrosis and cirrhosis in human immunodeficiency virus-infected patients
Evrim Anadol , Kristina Lust , Christoph Boesecke, Carolynne Schwarze-Zander, Raphael Mohr, Jan-Christian Wasmuth, Jürgen Kurt Rockstroh , Jonel Trebicka

Published: January 18, 2018
https://doi.org/10.1371/journal.pone.0191118

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Abstract
Introduction
Combined antiretroviral therapy (cART) has improved survival in HIV-patients. While the first antiretrovirals, which became available in particular D-drugs (especially didanosine and stavudine) and unboosted protease inhibitors, may impair liver function, the modern cART seems to decrease liver fibrosis. This study assessed the influence of exposure to previous antiretrovirals on liver fibrosis in HIV-infected patients.

Methods
This observational cross-sectional single-center study recruited 333 HIV patients and assessed liver fibrosis using transient elastography (TE).

Results
83% were male with a median age of 45, while 131 were co-infected with viral hepatitis. Overall, 18% had significant fibrosis and 7.5% had cirrhosis. 11% of HIV mono-infected patients had significant fibrosis and 2% had cirrhosis. HCV infection (OR:5.3), history of exposure to didanosine (OR:2.7) and HIV load below 40copies/mL (OR:0.5) were independently associated with significant fibrosis, while HCV (OR:5.8), exposure to didanosine (OR:2.9) and azidothymidine (OR:2.8) were independently associated with cirrhosis. Interestingly, in HIV mono-infected patients, a HIV-load below 40copies/mL (OR:0.4) was independently associated with significant fibrosis, and didanosine (OR:20.8) with cirrhosis.

Conclusion
In conclusion, history of exposure to didanosine and azidothymidine continues to have an impact on the presence of liver cirrhosis in HIV patients. However, HCV co-infection and ongoing HIV-replication have the strongest effect on development of significant fibrosis in these patients.

Full Text: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191118

Flu may be spread just by breathing

It is easier to spread the influenza virus (flu) than previously thought, according to a new University of Maryland-led study released today. People commonly believe that they can catch the flu by exposure to droplets from an infected person's coughs or sneezes or by touching contaminated surfaces. But, new information about flu transmission reveals that we may pass the flu to others just by breathing.

The study "Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community," published in the Proceedings of the National Academy of Sciences, provides new evidence for the potential importance of airborne transmission because of the large quantities of infectious virus researchers found in the exhaled breath from people suffering from flu.

"We found that flu cases contaminated the air around them with infectious virus just by breathing, without coughing or sneezing," explained Dr. Milton, M.D., MPH, professor of environmental health in the University of Maryland School of Public Health and lead researcher of this study. "People with flu generate infectious aerosols (tiny droplets that stay suspended in the air for a long time) even when they are not coughing, and especially during the first days of illness. So when someone is coming down with influenza, they should go home and not remain in the workplace and infect others."

Researchers from the University of Maryland, San Jose State University, Missouri Western State University and University of California, Berkeley contributed to this study funded by the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health.

Dr. Milton and his research team captured and characterized influenza virus in exhaled breath from 142 confirmed cases of people with influenza during natural breathing, prompted speech, spontaneous coughing, and sneezing, and assessed the infectivity of naturally occurring influenza aerosols. The participants provided 218 nasopharyngeal swabs and 218 30-minute samples of exhaled breath, spontaneous coughing, and sneezing on the first, second, and third days after the onset of symptoms.

The analysis of the infectious virus recovered from these samples showed that a significant number of flu patients routinely shed infectious virus, not merely detectable RNA, into aerosol particles small enough to present a risk for airborne transmission.

Surprisingly, 11 (48%) of the 23 fine aerosol samples acquired in the absence of coughing had detectable viral RNA and 8 of these 11 contained infectious virus, suggesting that coughing was not necessary for infectious aerosol generation in the fine aerosol droplets. In addition, the few sneezes observed were not associated with greater viral RNA copy numbers in either coarse or fine aerosols, suggesting that sneezing does not make an important contribution to influenza virus shedding in aerosols.

"The study findings suggest that keeping surfaces clean, washing our hands all the time, and avoiding people who are coughing does not provide complete protection from getting the flu," said Sheryl Ehrman, Don Beall Dean of the Charles W. Davidson College of Engineering at San José State University. "Staying home and out of public spaces could make a difference in the spread of the influenza virus."

According to the authors, the findings could be used to improve mathematical models of the risk of airborne influenza transmission from people with symptomatic illness and to develop more effective public health interventions and to control and reduce the impact of influenza epidemics and pandemics. Improvements could be made to ventilation systems to reduce transmission risk in offices, school classrooms and subway cars, for example. Meanwhile, we can all heed the advice to stay home, if possible, when we are beginning to get sick to prevent even greater numbers of flu cases. And, get vaccinated -- it is not perfect but does prevent a significant amount of severe illness.

https://www.sciencedaily.com/releases/2018/01/180118142611.htm

First-Time Data for Merck’s KEYTRUDA® (pembrolizumab) in Patients with Previously Treated Advanced Hepatocellular Carcinoma (HCC) to be Presented at 2018 ASCO GI Symposium

First-Time Data for Merck’s KEYTRUDA® (pembrolizumab) in Patients with Previously Treated Advanced Hepatocellular Carcinoma (HCC) to be Presented at 2018 ASCO GI Symposium

KENILWORTH, N.J.--(BUSINESS WIRE)--Jan. 19, 2018-- Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced findings from the registrational phase 2 KEYNOTE-224 trial investigating the use of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, in patients with advanced hepatocellular carcinoma (HCC), the most common type of liver cancer, who were previously treated with systemic therapy (sorafenib). Results showed an overall response rate (ORR) of 16.3 percent (95% CI, 9.8-24.9) (n=17/104) with KEYTRUDA as monotherapy. Data also include six-month overall survival (OS) and progression-free survival (PFS) rates. The findings will be presented at the 2018 American Society of Clinical Oncology Gastrointestinal (ASCO GI) Cancers Symposium in San Francisco in an oral presentation on Friday, Jan. 19, from 1:10-1:15 p.m. PT (Location: Level 3 – Room 3014) (Abstract #209).

“There continues to be a significant need for new options in the treatment of advanced hepatocellular carcinoma,” said Andrew Zhu, M.D., Ph.D., lead investigator and director of liver cancer research at Massachusetts General Hospital Cancer Center. “The durable responses observed with KEYTRUDA monotherapy in this difficult-to-treat cancer are encouraging.”

“Merck is committed to understanding the clinical benefit of KEYTRUDA monotherapy across a range of gastrointestinal cancers, including advanced liver cancer,” said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. “The findings from this study demonstrate the potential of KEYTRUDA in patients with advanced HCC following prior systemic therapy and support the advancement of our clinical development program in this cancer type.”

Merck has the industry’s largest immuno-oncology clinical research program, which currently involves more than 650 trials studying KEYTRUDA (pembrolizumab) across a wide variety of cancers and treatment settings, including multiple gastrointestinal disorders such as HCC and gastroesophageal cancer.

The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Data in Previously Treated Advanced HCC, KEYNOTE-224 (Abstract #209)

KEYNOTE-224 is a registrational, open-label phase 2 trial investigating KEYTRUDA monotherapy in patients with advanced HCC who had previously received systemic therapy with sorafenib. The primary endpoint is ORR; secondary endpoints include duration of response, disease control rate, time to progression, PFS and OS.

Findings presented at ASCO GI were based on data from 104 evaluable patients, previously treated with sorafenib, who received one or more doses of KEYTRUDA (200 mg intravenous infusion on day 1 of each 3-week cycle for up to 35 administrations). Data showed an ORR of 16.3 percent (95% CI, 9.8-24.9) (n=17/104) with a complete response rate of one percent (95% CI, 0.0-5.2) and a partial response rate of 15.4 percent (95% CI, 9.1-23.8). ORR was similar across subgroups with different etiology, including Hepatitis B and Hepatitis C positive patients. At the time of analysis, the median duration of response was 8.2 months (range: 2.3+ to 8.3+) with 94 percent of responses ongoing for six months or longer (calculated per Kaplan-Meier method). The disease control rate was 61.5 percent (95% CI, 51.5-70.9) (n=64/104). The median PFS was 4.8 months (95% CI, 3.4-6.6) with a six-month PFS rate of 43.1 percent. The median OS had not been reached at the time of analysis (95% CI, 9.4-not reached) with a six-month OS rate of 77.9 percent.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. The treatment-related adverse events (any grade occurring in 10% or more of patients) were fatigue (12.5%), increased aspartate aminotransferase (9.6%), diarrhea (9.6%) and pruritus (21.2%). Grade 3-5 treatment-related adverse events occurred in 26 (25%) patients and there was one treatment-related death. Immune-mediated adverse events occurred in 2.9 percent of patients. Seven patients discontinued treatment due to treatment-related adverse events.

About Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults. Worldwide, more than 782,000 new cases of liver cancer were diagnosed in 2012. In the U.S., the incidence of liver cancer has more than tripled since 1980 and it is estimated that 42,220 new cases will be diagnosed in this year. In Europe, around 63,500 new cases were diagnosed in 2012. Risk factors for liver cancer include gender, ethnicity, chronic viral hepatitis (Hep-B or Hep-C) infection, cirrhosis, heavy alcohol abuse and obesity. HCC – which is frequently diagnosed at an advanced stage – has one of the highest mortality rates of solid cancers, with a 5-year survival rate of less than 15 percent.

About KEYTRUDA ® (pembrolizumab) Injection 100mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
KEYTRUDA (pembrolizumab) Indications and Dosing

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Thursday, January 18, 2018

Healthcare costs of liver cancer in Veterans with cirrhosis in the USA

Healthcare costs of liver cancer in Veterans with cirrhosis in the USA

January's issue of the Clinical Gastroenterology & Hepatology investigates healthcare costs related to treatment of hepatocellular carcinoma among Veterans with cirrhosis in the United States.

It is important to quantify medical costs associated with hepatocellular carcinoma (HCC), the incidence of which is rapidly increasing in the United States, for development of rational healthcare policies related to liver cancer surveillance and treatment of chronic liver disease.

Dr David Kaplan and colleagues aimed to comprehensively quantify healthcare costs for HCC among patients with cirrhosis in an integrated health system and develop a model for predicting costs that is based on clinically relevant variables.

The research team noted that 3 years subsequent to liver cancer diagnosis, costs accrued by patients included in the Veteran’s Outcome and Cost Associated with Liver disease cohort were compiled by using the Department of Veterans Affairs Corporate Data Warehouse.

3-year total cost of care in HCC patients was $154,688
Clinical Gastroenterology & Hepatology

The cohort includes all patients with HCC diagnosed in 2008–2010 within the VA with 100% chart confirmation as well as chart abstraction of tumor and clinical characteristics.

Cancer cases were matched 1:4 with non-cancer cirrhosis controls on the basis of severity of liver disease, age, and comorbidities to estimate background cirrhosis-related costs.

The team's analysis included 3188 cases of HCC and 12,722 controls.

The researchers found that the mean 3-year total cost of care in HCC patients was $154,688 compared with $69,010 in matched cirrhotic controls, yielding an incremental cost of $85,679, and 65% of this value reflected increased inpatient costs.

The research team observed that receipt of transplantation, Barcelona Clinic Liver Cancer (BCLC) stage, liver disease etiology, hospital academic affiliation, use of multidisciplinary tumor board, and identification through surveillance were associated with cancer-related costs.

Multivariable generalized linear models incorporating transplantation status, BCLC stage, and multidisciplinary tumor board presentation accurately predicted liver cancer–related costs.

Dr Kaplan's team concludes, "In a model developed to comprehensively quantify healthcare costs for HCC among patients with cirrhosis in an integrated health system, we associated receipt of liver transplantation, BCLC stage, and multidisciplinary tumor board with higher costs."

"Models that predict total costs on the basis of receipt of liver transplantation were constructed and can be used to model cost-effectiveness of therapies focused on HCC prevention."

Summary: http://www.gastrohep.com/news/news.asp?id=112988
Clin Gastroenterol Hepatol 2018: 16(1): 106–114.e5
18 January 2018

Editorial: direct-acting antivirals significantly improve quality of life in patients with HCV

INVITED EDITORIALS

Editorial: direct-acting antivirals significantly improve quality of life in patients with hepatitis C virus infection 
Authors S. Sanagapalli, M. Danta

First published: 17 January 2018
DOI: 10.1111/apt.14467

Abstract
Linked Content
This article is linked to Younossi et al and Younossi papers. To view these articles visit https://doi.org/10.1111/apt.14423 and https://doi.org/10.1111/apt.14481.

The effect of direct-acting antiviral chronic Hepatitis C (HCV) therapies on patients’ quality of life has been a topic of minor attention compared with their impressive effects on virological endpoints. Yet, therapeutic benefits on quality of life are important to patients, and knowledge regarding such benefits may be an important tool in improving compliance in real-world scenarios.[1] For this reason, Younossi and colleagues are to be commended for their study, which describes clinically significant improvements in almost all measured physical and mental health-related quality of life outcomes following therapy with sofosbuvir and velpatasvir with or without voxilaprevir.[2] This replicates findings from other direct-acting antiviral regimens, but also confirms our own observations from clinical experience using these drugs.

Comparison with quality of life data from the interferon era may help us to tease out the mechanisms behind these findings. First, impairments in both mental and physical aspects of quality of life have long been described in chronic HCV, with or without cirrhosis, using the SF-36, one of the four instruments used in this study.[3] Second, very similar improvements in quality of life parameters were described 24 weeks after completion of interferon-based therapy, with the benefit confined only to those with sustained virological response.[4] More recent data comparing interferon-containing to interferon-free regimens clearly demonstrates that while both regimens result in equivalent improvements in quality of life (in responders) post therapy, the interferon-containing treatments are associated with significant worsening of quality of life during therapy. In contrast, quality of life seems to be improved early during interferon-free therapy and improves further following completion of successful treatment.[5, 6] Taken cumulatively we can infer that virological clearance plays a key role in improvement of quality of life, but cannot be the only factor, since improvement continues long after the virus has completely cleared from the serum.

What might such other factors be? The authors propose that improvement of liver function may play a role, though this still fails to explain the persistent improvement in benefit in non-cirrhotics post therapy. On the other hand, cerebral inflammation due to chronic HCV may explain some of the findings. Magnetic resonance spectroscopy and positron emission tomography scanning have demonstrated significant metabolic abnormalities in the brains of noncirrhotics with HCV, implying a low-grade inflammatory state, with the microglial cells being a focus of activation.[7, 8] In a small study, Byrnes and colleagues demonstrated that successful treatment with pegylated interferon and ribavirin led to normalisation of these central nervous system metabolic changes. Crucially, however, normalisation occurred gradually and improvement in metabolic abnormalities continued until 12 weeks post therapy, implying that the neuroinflammatory process may take time to settle after HCV therapy.[9] While the underlying mechanisms for improved quality of life are of interest, this study adds to the weight of evidence for the overall benefits of direct-acting antiviral therapies for HCV.
http://onlinelibrary.wiley.com/doi/10.1111/apt.14467/full

Editorial: direct-acting antivirals significantly improve quality of life in patients with hepatitis C virus infection—Author's reply
Z. M. Younossi

First published: 17 January 2018
DOI: 10.1111/apt.14481

Abstract
Linked Content
This article is linked to Younossi et al and Sanagapalli and Danta papers. To view these articles visit https://doi.org/10.1111/apt.14423 and https://doi.org/10.1111/apt.14467.

We appreciate the Editorial comments by Drs. Sanagapalli and Danta about our recent study reporting patient-reported outcomes in patients with hepatitis C virus infection who were treated with sofosbuvir (SOF), velpatasvir (VEL) with or without voxilaprevir (VOX).[1, 2] We agree with their comments and would like to emphasise the importance of these findings in the context of the “comprehensive benefit” of HCV cure.

To fully understand the comprehensive benefit of HCV treatment, we believe it is important to assess the comprehensive impact of HCV infection including all the pertinent clinical consequences (hepatic and extrahepatic manifestations of HCV infection), the impact on patient-reported outcomes (health-related quality of life or HRQL) and the economic burden of HCV (resource utilisation and cost of illness).[3] Similarly, the benefit of anti-HCV treatment must be assessed in this comprehensive manner.[3] The most clinically relevant endpoint of HCV treatment is achieving sustained virologic response (SVR), a surrogate of improving survival by reducing the hepatic and extrahepatic complications.[3] Another important endpoint of HCV treatment should be its positive impact on patient-reported outcomes, a surrogate of HCV patients' experience.[4] Finally, we must assess the impact of anti-HCV treatment on important economic outcomes (resource utilisation, cost of illness, cost-effectiveness of treatment) must also be assessed.[5] Although the total impact of HCV infection has been well established,[3, 6] the comprehensive benefit of “HCV cure” has only recently been recognised.[1-6] In this context, our study provides additional evidence that the new regimen of SOF/VEL+/-VOX not only has superior clinical outcomes (high SVR) but also improves patient-reported outcomes during treatment and after SVR.[2]

In their Editorial, the authors have reflected about the mechanism of patient-reported outcome improvement post-SVR-12; we agree that this improvement is partly related to viral eradication. It is plausible that the additional patient-reported benefits of SVR may be related to the amelioration of the inflammatory environment of chronic hepatitis, which takes longer to resolve. This “inflammatory milieu” of HCV infection may exert its influence on the brain or the periphery of the infected patients. In fact, HCV has been associated with a number of extrahepatic manifestations such as neuropsychiatric diseases, chronic fatigue and others.[7, 8] In this context, neurocognition, fatigue and their changes after SVR may be differentially affected which in turn can influence changes in patient-reported outcome scores.[7, 8] In fact, the impact of SVR on fatigue has been recently substantiated and the data have shown that while most patients with HCV improve fatigue scores post-SVR, some do not improve.[9] Furthermore, these subjects who continue to report disabling fatigue post-SVR seem to have significant comorbidities such as depression, anxiety, type 2 diabetes.[9] Nevertheless, in the majority of HCV subjects with SVR, fatigue continues to improve and seems to maximise by post-treatment week 48.[10]

In summary, we believe that the initial patient-reported outcome improvements are due to viral eradication. The subsequent improvement may be due to a number of post-SVR changes including improvement of the inflammatory milieu and its impact of HCV on the brain and other extrahepatic targets. In contrast, patients with HCV who continue to show residual patient-reported outcome impairments post-SVR seem to have other comorbidities, which will require other treatment modalities to optimise their well-being. In this context, we believe that patient-reported outcomes must be a routine part of assessment of any chronic liver disease. These assessments will complement the clinical outcomes and provide evidence for the comprehensive impact of treatment on the patients and the society.

Wednesday, January 17, 2018

Treating Chronic Hepatitis C Infection: A Call to Action for Primary Care Providers

Experts And Viewpoints, January 2018
Treating Chronic Hepatitis C Infection in Primary Care
New treatment guidelines aim to support primary care clinicians in the treatment of hepatitis C infection. 

COMMENTARY
Treating Chronic Hepatitis C Infection: A Call to Action for Primary Care Providers

Christine A. Kerr, MD; Josh S. Aron, MD
January 17, 2018

Despite a revolutionary opportunity to end the global HCV epidemic, there clearly is a need for a concerted effort to help many more people benefit from curative therapy. It is evident that we, as healthcare providers, must step up our efforts to reach and treat patients who can benefit from DAA therapy. Only 9% of the 4 million Americans living with HCV have been successfully treated.