Showing posts with label HCV-elderly. Show all posts
Showing posts with label HCV-elderly. Show all posts

Saturday, June 30, 2018

HepCure Webinar Series - Hep C & Fatty Liver, Treatment, Alcohol Use, Elderly Patients and More

Watch experts discuss important HCV related topics in this easy to access webinar series presented by HepCure.

June 26, 2018
Transplant & HCV
On Tuesday, June 26th, Dr. Thomas Schiano of Mount Sinai Medical Center presented on: “Transplant & HCV”
Watch, here….
Download Slides, here.....

June 19, 2018
Nonalcoholic Fatty Liver Disease and Hepatitis C
On June 19th Dr. Amon Asgharpour of the Icahn School of Medicine at Mount Sinai. Dr. Asgharpour presented “Nonalcoholic Fatty Liver Disease and Hepatitis C.”


Watch, here.….
Download Slides, here...…

Of Interest
Michael Carter
Published: 18 June 2018
Fatty liver improves rapidly after hepatitis C cure
Liver stiffness and liver fat (steatosis) in people with chronic hepatitis C virus (HCV) infection both improve significantly after treatment with direct-acting antivirals (DAAs) resulting in sustained virological response (SVR), investigators from Japan report in Alimentary Pharmacology and Therapeutics. Both measures of liver health were assessed six months after SVR. Improvement was associated with a reduction in ALT levels and an increase in platelet count.

On This Blog
June 18, 2018
Hepatitis C Weekend Video: NASH What Is It

Elsewhere
July 1, 2018
In the July Issue of the patient-friendly HCV Advocate newsletter, Lucinda Porter, RN., writes a must read article about: Avoiding Fatty Liver.

June 2018
Hepatitis C and Alcohol
On Tuesday, June 5th, Peter Hauser, MD, Director of the National VA Telemental Health Hub Long Beach presented on: “Hepatitis C and Alcohol”.


Watch, here...
Download Slides, here....

May 2018 - HCV Treatment
“Ace the Case” 

Program presented last month led by Dr. Douglas Dieterich of the Icahn School of Medicine at Mount Sinai. This webinar is patient based, with question and answer participation.

Topics
Late relapse in people with HCC
Reinfection
Chemo On HCV
Treating Patients with HCV & Depression & More....
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HCV in the Elderly Patient
On May 29th, Dr. Roxana Bodin of Westchester Medical Center Health presented on: “HCV in the Elderly Patient”


Watch, here...
Download Slides here.....

Of Special Interest
"Innovation as Usual: Sustainable Financing for Viral Hepatitis Elimination" with Dr. Henry Chang. This webinar will discuss the global target to eliminate viral hepatitis as a major public health problem by the year 2030.
Watch, here.....
Download Slides, here...

Additional Topics
The HCV-Opioid Syndemic in Appalachia: Evidence from a Cohort of Rural Drug Users
Hepatitis C in Children and Adolescents
Cirrhosis & HCV

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Webinar Archive

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@hepcure 

HepCure Patient App
The patient app is a free resource for patients with hepatitis C, which allows them to track medication adherence, symptoms, and gain access to resources. It is available to download for free on iOS (App Store) and Android (Google Play) operating systems. While the app can be used by patients independently from the dashboard, it can also be linked with the provider dashboard. Providers can push lab data to patients and track treatment adherence and symptom data input by patients in real time.
Learn more here...…

Wednesday, June 27, 2018

Direct-Acting Antivirals Effective for Hepatitis C in Seniors

MONDAY, June 25, 2018 -- For older patients with hepatitis C virus (HCV), direct-acting antiviral (DAA) therapy is effective, according to a study published online May 25 in the Journal of the American Geriatrics Society.

Chiara Mazzarelli, M.D., from King's College Hospital in London, and colleagues conducted a retrospective review involving individuals aged 65 years and older treated with DAA therapy for HCV. Participants were divided into two cohorts: 88 aged 65 to 74 years and 25 aged 75 years and older.

Abstract
Clinical Investigation Efficacy and Tolerability of Direct‐Acting Antivirals for Hepatitis C in Older Adults 

Articles available on this blog

Sunday, June 10, 2018

USA HCV Dataset - Patients’ age, location, disease severity, treatment and cure status 2013-2016

Advances in Therapy
Development of a Comprehensive Dataset of Hepatitis C Patients and Examination of Disease Epidemiology in the United States, 2013–2016
Viktor V. Chirikov Steven E. Marx Shivaji R. Manthena John P. Strezewski Sammy Saab

First Online: 09 June 2018
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Hepatitis C virus (HCV) infection may cause serious health problems and death. Unfortunately, the health care community does not have complete identification of patients with HCV. This study describes the creation of a dataset that combines information for HCV patients and shows relevant information about HCV patients’ age, geographic location, disease severity, and treatment and cure status from 2013 through 2016. This dataset helps the health care community understand the HCV patient landscape and make informed decisions about how to best treat this population.

Abstract
Introduction
Chronic infection with hepatitis C virus (HCV) is a leading cause of liver disease and infectious disease deaths. While recent and emerging treatment options for HCV patients have enabled higher rates of sustained virologic response (SVR), the demographic, clinical, geographic, and payer characteristics of the estimated 3.4 million chronic HCV patients in the USA are poorly understood. The goal of this study was to create a dataset describing the current HCV patient landscape in the USA.

Methods
Data from two large national laboratory companies representing the majority of US patients screened for HCV antibody and/or tested for HCV RNA from 2013 through 2016 were organized into the present study dataset. Age, gender, payer channel, 3-digit ZIP code and ordering physician specialty, and 3-digit ZIP code information were available for all patients. Among RNA-positive patients, additional clinical characteristics included HCV genotype, fibrosis stage, renal function, and HIV status. Initiating treatment and attaining cure were imputed using data-driven algorithms based on successive RNA viral load measurements.

Results
The number of RNA-positive HCV patients increased from 200,066 patients in 2013 to 469,550 in 2016. The availability of clinical data measurements and rates of treatment initiation increased over the study period, indicating improved care engagement for HCV patients. Treatment and cure rates varied by age, disease severity, geographic location, and payer channel. Sensitivity and specificity of the cure prediction algorithms were consistently above 0.90, validating the robustness of the data imputation approach.

Conclusion
This is the largest, most comprehensive dataset available to describe the current US HCV patient landscape. Our results highlight that the epidemiology of HCV is evolving with an increasing number of patients who are younger and have milder disease than described in previous years. Results of this study should help guide efforts toward the elimination of HCV in this country. Future work will focus on factors associated with varying treatment and cure patterns and describing recent changes in the HCV patient landscape.

Analysis of Treated Patients by State
To investigate treatment trends further, the prevalence of nearly 90,000 treated HCV patients in 2016 was determined on a state-by-state basis. States with the highest prevalence of treated HCV patients were mainly found on the West Coast, Appalachia, the Northeast, and the Southeast, while much of the Upper Midwest and Great Plains had the lowest prevalence of treated patients 


Continue reading: https://link.springer.com/article/10.1007/s12325-018-0721-1

Wednesday, February 21, 2018

Hepatitis C Virus Clearance in Older Adults

Hepatitis C Virus Clearance in Older Adults
Does HCV clearance with direct-acting antiviral therapy improve outcomes in individuals aged 80 and older--even in the face of severe liver disease and multiple comorbidities?
February 21, 2018

Journal of the American Geriatrics Society
Hepatitis C Virus Clearance in Older Adults
Antonio Massimo Ippolito, MD; Angelo Iacobellis, MD; Michele Milella, MD; Fabio Conti, MD; Vincenzo Messina, MD; Maria Rosa Valvano, PhD; Grazia Anna Niro, MD; Filomena Morisco, MD; Michele Barone, MD; Antonio Patrizio Termite, MD; Giuseppina Brancaccio, MD; Angelo Andriulli, MD

Full Text

Abstract and Introduction
Abstract
Objectives To determine whether older adults with the hepatitis C virus (HCV) achieve a sustained viral response (SVR) after treatment with direct-acting antiviral therapy.

Participants Individuals aged 80 and older with chronic HCV infection (N = 253; n = 213 with cirrhosis, n = 40 with advanced fibrosis).

Measurements
We investigated the efficacy, safety, and global clinical effect of treatment with different combinations of direct antiviral agents (DAAs). Participants with cirrhosis were staged according to Child-Pugh-Turcotte class, Model for End-Stage Liver Disease score, and the D'Amico staging system. The type and number of comorbidities at baseline and hepatic and nonhepatic events during follow-up were registered.

Results
Ninety-five percent of participants with cirrhosis and 95% of those with advanced fibrosis attained SVR. The rate was independent of sex, HCV genotype, and treatment schedule. During a mean follow-up of 14 ± 4 months (range 5–23 months), 34 events occurred in 27 participants: 10 hepatocellular carcinomas, 12 hepatic decompensations, 9 nonhepatic events, 3 deaths. Multivariate analysis of risk factors for experiencing adverse events during follow up showed that participants in D'Amico Stages 4 and 5, with a baseline serum albumin level of 3.5 mg/dL or less, and 3 or more comorbidities were the most at risk.

Conclusion
In a real-world setting, DAAs are safe and effective in older adults with HCV-related advanced fibrosis or cirrhosis. Individuals with preserved albumin synthesis and fewer than 3 comorbidities at baseline have the most to gain from long-term DAA therapy.

Wednesday, February 7, 2018

Hepatitis C: daclatasvir/asunaprevir may improve HRQOL and hepatic functional reserve, particularly in elderly patients

Exp Ther Med. 2018 Jan;15(1):970-976. doi: 10.3892/etm.2017.5488. Epub 2017 Nov 10.

Health-related quality of life on the clinical course of patients with chronic hepatitis C receiving daclatasvir/asunaprevir therapy: A prospective observational study comparing younger (<70) and elderly (≥70) patients.
Ohashi K1,2, Ishikawa T2,3, Suzuki M2,4, Abe H1,2, Koyama F1,2, Nakano T1,2, Ueki A1,2, Noguchi H1,2, Hasegawa E1,2, Hirosawa S1,2, Kobayashi M1,2, Hirosawa H2,5, Sato K2,6, Fukazawa T2,6, Maruyama Y2,7, Yoshida T3.

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Abstract
Interferon-free direct acting antiviral agent regimens for chronic hepatitis C (CHC) have been developed. These regimens have shown a high rate of sustained virologic response (SVR), and a reduction in side effects during treatment is also anticipated. However, the impact of the regimens on health-related quality of life (HRQOL) and side effects during treatment is not fully understood. The purpose of the present study was to evaluate HRQOL in the clinical course of patients with CHC receiving daclatasvir/asunaprevir (DCV/ASV) therapy using the Short Form-36 (SF-36) method. Twenty-eight patients with CHC receiving DCV/ASV therapy were analyzed in the present study, and HRQOL was measured by SF-36. Patients were asked to fill out the SF-36 prior to therapy (baseline), following 12 weeks of therapy, at the end of treatment and at SVR week 24 (SVR24) to evaluate HRQOL. Laboratory data were also investigated during the same period, and associations between these results and SF-36 were investigated. Aspartate aminotransferase, alanine aminotransferase, serum albumin, α-fetoprotein, platelet counts and Fibrosis (Fib)-4 index were all significantly improved at each time point when compared with baseline. With regard to alterations in HRQOL during therapy, the ≥70-year-old group displayed a significantly greater improvement in physical functioning during the period between baseline and 12 weeks when compared with the <70-year-old group. In the analysis of the SF-36 differences within each group, general health improved significantly in the ≥70-year-old group, as well as albumin levels. In addition, Fib-4-index significantly improved at all time points (12 and 24 weeks, and SVR24) when compared with baseline in the ≥70-year-old group. Therefore, DCV/ASV therapy may improve HRQOL and hepatic functional reserve, particularly in elderly patients.

Tuesday, January 23, 2018

Combating Frailty's Fatal Impact in Liver Disease

COMMENTARY
Advice for Combating Frailty's Fatal Impact in Liver Disease
Rowen K. Zetterman, MD
January 22, 2018

Dr Rowen Zetterman on the various ways in which frailty imperils outcomes in liver disease, and the most useful strategies for addressing them.

Diagnosing Frailty in Patients With Cirrhosis 
Frailty also increases the risk for morbidity and mortality in patients with chronic liver disease.[6,7] Sarcopenia (loss of muscle mass) and frailty may not directly correlate with the clinical severity of liver disease, and must be carefully sought to establish the diagnosis.[6]

Using observation alone to diagnose frailty in patients with end-stage liver disease is inadequate, because frailty may not be recognized by clinicians until late in the course of disease or simply be overlooked in well-groomed patients, some women, and those with obesity. Using body mass index as an indicator of malnutrition and frailty can be deceptive, because it fails to consider the functional issues of frailty. Multiple clinical measures of frailty have been published using a combination of findings, such as unintentional weight loss, reduced walking or gait speed, muscle weakness, and evidence of reduced physical activity.[1,2,7,8]

Free registration may be required

Friday, December 29, 2017

Efficacy and safety of Harvoni in Japanese patients aged 75 years or over with hepatitis C genotype 1

World J Hepatol. Dec 28, 2017; 9(36): 1340-1345
Published online Dec 28, 2017. doi: 10.4254/wjh.v9.i36.1340
Retrospective Cohort Study

Efficacy and safety of sofosbuvir and ledipasvir in Japanese patients aged 75 years or over with hepatitis C genotype 1
Yoshinori Ozono, Kenji Nagata, Satoru Hasuike, Hisayoshi Iwakiri, Kenichi Nakamura, Mai Tsuchimochi, Yuri Yamada, Yuka Takaishi, Mitsue Sueta, Tadashi Miike, Yoshihiro Tahara, Shojiro Yamamoto, Kotaro Shide, Tomonori Hidaka, Yoko Kubuki, Kazunori Kusumoto, Toshimasa Ochiai, Junya Kato, Naoto Komada, Shuichi Hirono, Kazuo Kuroki, Masafumi Shigehira, Kazuya Shimoda

AIM
To evaluate the efficacy and safety of a regimen containing sofosbuvir (SOF) and ledipasvir (LDV) in Japanese patients aged ≥ 75 years with hepatitis C genotype 1.

METHODS
This multicenter, retrospective study consisted of 246 Japanese patients with HCV genotype 1 at nine centers in Miyazaki prefecture in Japan. Demographic, clinical, virological, and adverse effects (AE)-related data obtained during and after SOF/LDV therapy were collected from medical records. These patients were divided into two groups, younger (aged < 75 years) and elderly (aged ≥ 75 years). Virological data and AEs were analyzed by age group.

RESULTS
The sustained virological response (SVR) rates at 12 wk after treatment were 99.2%, 99.4%, and 98.7% in the overall population and in patients aged < 75 and ≥ 75 years, respectively. Common AEs during therapy were headache, pruritus, constipation, and insomnia. These occurred in fewer than 10% of patients, and their incidence was not significantly different between the younger and elderly groups. Two patients discontinued treatment, one due to a skin eruption and the other due to cerebral bleeding.

CONCLUSION
Compared with younger patients, elderly patients had a similar virological response and tolerance to SOF/LDV therapy.

Core tip: Most Japanese patients with hepatitis C are elderly, and those aged ≥ 75 years account for more than 50%. However there are few reports regarding sofosbuvir (SOF) and ledipasvir (LDV) therapy in patients aged ≥ 75 years in the real-world. The present study demonstrated that patients aged ≥ 75 years had a similar virological response and tolerance to SOF/LDV therapy compared with patients aged < 75 years in the real-world cohorts. Therefore, SOF/LDV therapy might be effective and safe in elderly patients.

Monday, November 13, 2017

NIH blood pressure study supports important part of new AHA/ACC hypertension guidelines

Data from landmark NIH blood pressure study supports important part of new AHA/ACC hypertension guidelines

This is a field of blood cells. The bi-concave disks are red blood cells or erythrocytes. The white cell with the dark purplish, multi-lobed nucleus is a neutrophil, a type of white blood cell or leukocyte. The smaller spikey objects are platelets.

What
Findings from a landmark study funded by the National Institutes of Health (NIH) support a key component of the new 2017 Hypertension Clinical Practice Guidelines announced by the American Heart Association (AHA) and the American College of Cardiology (ACC) at the annual AHA meeting in Anaheim, California.

In 2013, the National Heart, Lung, and Blood Institute (NHLBI), part of the NIH, adapted to changing times and refined its focus to generating high quality scientific evidence in support of the development of clinical practice guidelines worthy of the public trust. The new high blood pressure guidelines illustrate the utility and impact of NHLBI scientific studies.

Today the AHA and the ACC issued the first comprehensive new high blood pressure guidelines in more than a decade that indicate high blood pressure should be treated earlier with lifestyle changes and in some patients with medication – at 130/80 mm Hg rather than 140/90. An important component of these guidelines was informed by the results of the Systolic Blood Pressure Intervention Trial (SPRINT), a clinical study sponsored in part by the NHLBI and designed to determine the best way to treat blood pressure in adults with hypertension, 50 years or older, who are at high risk for heart disease.

SPRINT, which began in the fall of 2009, included more than 9,300 participants, recruited from about 100 medical centers and clinical practices throughout the United States. It remains the largest study of its kind to date to examine how maintaining systolic blood pressure at a lower than previously recommended level would impact cardiovascular and kidney diseases.

The pace of scientific advances today requires systematic synthesis for developing guidelines that will assist busy practitioners. The successful implementation of these guidelines will lead to improvements in the health of the nation and reduce the risks posed by heart disease and stroke. Heart disease is the United States’ leading cause of death.

In addition to primary sponsorship by the NHLBI, SPRINT is also co-sponsored by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke and The National Institute on Aging.

Who
Dr. David Goff, Director, Division of Cardiovascular Sciences, NHLBI, is available to comment on the SPRINT study and its relationship to the new high blood pressure guidelines.
Contact

For more information or to schedule an interview, please contact the NHLBI Office of Science Policy, Engagement, Education, and Communications at 301-496-5449 or nhlbi_news@nhlbi.nih.gov (link sends e-mail).

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI, a part of the National Institutes of Health (NIH), plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at www.nhlbi.nih.gov.

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

Wednesday, October 25, 2017

HCV in the Older Patient - Natural history, extrahepatic disorders, safety and efficacy of treatment regimens

Infectious Diseases Clinics
December 2017
Volume 31, Issue 4, Pages 827–838
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Hepatitis C Virus Infection in the Older Patient

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States and is of concern in older adults. HCV infection is associated with not only hepatic but also extrahepatic comorbidities common to the aging patient including diabetes, kidney and cardiovascular diseases, and neurocognitive impairment. The effect of direct-acting antiviral agents to treat HCV on these outcomes is limited. This article summarizes the literature regarding the epidemiology and natural history of HCV infection; the impact of age on clinical outcomes in HCV-infected persons; and current knowledge regarding safety and efficacy of HCV treatment regimens in the older patient.


Introduction
Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States and is of concern in older adults. Although the rate of new HCV infections has declined over the last two decades because of implementation of HCV screening of donated blood and harm-reduction programs, the proportion of HCV-infected patients that are of older age and that have had infection for a prolonged duration of time has increased. The growing burden of older HCV-infected patients poses challenges for clinicians who care for these patients and for the health care system because of the increased use of health care resources to treat the long-term sequelae of HCV-associated liver disease including cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation.

Before the advent of all oral direct-acting antiviral (DAA) agents, HCV treatment was associated with poor response and increased adverse side effects with some studies showing worse outcomes in the older patient. Since the introduction of DAA agents in 2011 to treat HCV infection, clinicians are now able to successfully treat the growing number of HCV-infected patients of older age. However, information regarding the effect of HCV treatment on short- and long-term clinical outcomes in the older HCV-infected patient is limited.

This article summarizes the literature regarding the epidemiology, natural history, and clinical course of HCV infection; the impact of age on clinical outcomes in persons with HCV infection; and current knowledge regarding the safety and efficacy of newer HCV treatment regimens in the older HCV-infected patient.

Epidemiology and screening of hepatitis C virus infection in the United States
An estimated 4.1 million persons in the United States (or 1.6% of the US population) have been exposed to HCV.1 About 70% of these persons were born between 1945 and 1964, and most were infected between 1970 and 1990 when the incidence of new HCV infections peaked.2 Since the identification of HCV as the main cause of non-A/non-B chronic hepatitis in 1989, HCV incidence has declined because of the implementation of donor blood screening and increased availability of harm-reduction programs for persons who inject drugs. However, recent data suggest that there may be an emerging epidemic of HCV infection among young nonurban persons mainly of white race; prescription opioid use has been implicated as a factor.3

In 2012, the US Centers for Disease Control and Prevention revised their recommendations to include one-time HCV serologic testing of all adults born from 1945 through 1965 regardless of HCV risk status.4 The prevalence of HCV antibodies in persons born between 1945 and 1964 (also known as the Baby Boomer cohort in the United States) has been estimated to be about 3.5%, which is more than double the reported HCV prevalence in the US population. The revised recommendations were based on findings from the Chronic Hepatitis Cohort Study of 4689 HCV-infected persons who completed a survey regarding the reason for their HCV testing.5 That study found that less than 25% of the HCV-infected persons had an identifiable risk factor for HCV infection; rather, 78% were born during the period between 1945 and 1965. With implementation of this new recommendation, an increase in incident HCV infections is expected.

Recent studies6, 7 have also suggested that older patients in long-term care facilities should be targeted for HCV screening and confirmatory HCV RNA screening, and that there should be a shared commitment by all health care facilities to adhere to basic infection control procedures. These studies have largely been borne out of reports of viral hepatitis outbreaks resulting from lapses in infection control practices, particularly in ambulatory care settings. A systematic review and meta-analysis of HCV infection prevalence in long-term care facilities found a pooled prevalence of 3.3% (95% confidence interval, 1.5%–7.2%) compared with the 0.9% to 1.0% prevalence reported in noninstitutionalized elders (generally defined as older than 65 years of age).6 In that study, it was unclear if adults were previously infected or were exposed to HCV in the long-term care setting.

Another case-control study7 examined the association of health care exposures with acute hepatitis B and C from 2006 to 2008 in 71 (mostly acute hepatitis B infection) cases who were 55 years and older and found that 37% of new infections were likely attributable to injections of parenteral medications and 8% to hemodialysis. There is concern that as the Baby Boomer cohort of HCV-infected persons seeks more health care in ambulatory settings and residency in long-term care facilities, there could be a growing reservoir of infected persons who could serve as a source of transmission. Therefore, studies advocate for greater adherence to HCV screening recommendations (particularly in institutionalized settings), basic infection control precautions, and safe injection practices.

Natural history and clinical course of hepatitis C virus infection and the impact of age
Studies estimate that between 55% and 75% of newly infected persons develop chronic HCV infection as determined by detectable HCV RNA in the blood.8 Patients of older age at time of infection and impaired immune system are at increased risk of developing chronic HCV infection.8
A large proportion of chronically HCV-infected persons in the United States are now about 50 to 70 years old and have lived with HCV infection for about 25 to 45 years.9

The increased duration of HCV infection has been accompanied by an increased incidence of liver disease and related sequelae. Over the natural course of HCV infection, it is expected that at least one-third of HCV-infected persons progress to advanced fibrosis and cirrhosis, and among those with cirrhosis, about 3% to 5% per year develop decompensated cirrhosis (ie, ascites, hepatic encephalopathy, esophageal varices) and/or HCC (Fig. 1).10



Because several decades can elapse from incident HCV infection until the peak prevalence of cirrhosis, it has been estimated that the proportion of liver-related deaths and patients diagnosed with HCV-related cirrhosis and HCC is fast approaching its peak.11 This increase is largely driven by the burden of HCV in the Baby Boomer cohort and will be associated with increased health care use and hospitalizations for end-stage liver disease and the subsequent need for liver transplantation.12

Because the clinical sequelae of HCV disease is expected to increase in the older patient, some studies have specifically examined the association of older age (defined as 65 years or older) with clinical outcomes in HCV-infected persons. One retrospective cohort study13 of 161,744 HCV-infected patients in the US Veterans Health Administration Hepatitis C Clinical Case Registry compared HCV-infected veterans aged greater than 65 with those aged 20 to 49 years. They found that even after adjusting for several metabolic factors, including diabetes and obesity, age greater than or equal to 65 years remained associated with a 1.14, 2.44, and 2.09 greater risk of cirrhosis, HCC, and death from all causes, respectively. Longer duration of HCV infection is likely a primary reason for the increased risk in older HCV-infected persons. Prolonged duration of HCV infection has been shown to predict faster progression to cirrhosis14 and has been associated with increased risk of HCC.15

However, studies suggest that age-related mechanisms may also play a role. In one study of patients who acquired HCV infection during transfusion, the median time to development of cirrhosis was reported to decrease from 33 years in patients who acquired the infection between the ages of 21 and 30 years to 16 years in patients who acquired the infection when they were 40 years or older.16 Another study of patients who acquired HCV infection during transfusion found that the mean time to development of HCC was 15 years in persons 50 years or older compared with 32 years in those infected when they were under 50 years of age.15 Although Poynard and colleagues14 established that duration of HCV infection predicted faster progression to cirrhosis, they also demonstrated that in those older than 50 years at the time of infection, the progression of fibrosis was substantially greater when compared with those less than 50 years at the time of infection. Finally, recurrent HCV infection after liver transplantation is nearly universal among patients with HCV viremia at the time of transplant, and in this context, older donor age has consistently been associated with accelerated graft loss.17 These studies indicate that older age independent of duration of HCV infection may also play a role in the progression of HCV-associated liver disease.

Aging-related mechanisms that have been postulated to increase the risk of liver disease outcomes in the setting of HCV infection include a greater vulnerability to environmental factors, such as oxidative stress, with increasing age; reduction in the rate of hepatic flow; reduced mitochondrial capacity; impaired immunity; and increased carcinogenic potential caused by a reduced ability to repair DNA.18, 19 There are also limited data that HCV infection may be associated with increased markers of immune-senescence, which has been shown to occur in the setting of human immunodeficiency virus (HIV) infection and is thought to play a role in the earlier onset of aging-related comorbidities in HIV infection. HCV infection itself might be associated with loss of early differentiated T cells and progressive accumulation of chronically activated, late-differentiated senescent T cells. One small study20 comparing HCV-infected individuals with healthy control subjects, all of whom were less than 54 years of age, found that the CD4 and CD8 T cells from HCV-infected individuals showed a significant increase in the T-cell immunosenescent phenotype that is more commonly associated with advancing age. Whether or not this increase is associated with the premature onset of not only liver but also nonliver clinical outcomes related to aging in HCV-infected persons is unclear.21

Hepatitis C virus infection and extrahepatic clinical outcomes
HCV infection is also associated with extrahepatic disorders (Box 1), likely because in addition to being a hepatotropic virus, it is also lymphotropic leading to immune-system dysregulation. Thus, a variety of autoimmune disorders have been associated with HCV infection including systemic disorders, such as mixed cryoglobulinemia and less commonly arthritis, sicca syndrome, and porphyria cutanea tarda, or organ-specific disorders, such as glomerulonephritis, diabetes, or thyroiditis. Apart from diabetes, these disorders are thought to be uncommon, so few studies have been able to adequately examine the effect of age on these disorders in the HCV-infected patient.


By contrast, HCV infection is a chronic inflammatory process leading to not only hepatic inflammation but also persistent systemic inflammation, which has been associated with extrahepatic outcomes that are also common with aging including extrahepatic malignancies, cardiometabolic complications, and neurocognitive disturbances. The complex interplay between aging outcomes and HCV-induced immune dysregulation and systemic inflammation could partly explain why some but not all studies show an association of HCV infection with these outcomes.

Hepatitis C Virus Infection and Malignancy
Few studies have examined the association of HCV infection with non-HCC malignancy in the older patient. A recent registry-based case-control study22 using the Surveillance, Epidemiology, and End Results Medicare database in US adults aged greater than or equal to 65 years from 1993 to 2011 found that as expected, HCV infection was strongly associated with cancers of the liver compared with those without HCV infection. However, HCV infection was also associated with higher odds of intrahepatic (adjusted odds ratio [aOR], 3.40) and extrahepatic (aOR, 1.90) bile duct cancer, pancreatic cancer (aOR, 1.23), anal cancer (aOR, 1.97), nonmelanoma nonepithelial skin cancer (aOR, 1.53), myelodysplastic syndrome (aOR, 1.56), and diffuse large B-cell lymphoma (aOR, 1.57).

The increased risk for non-HCC cancers could indicate that HCV infection directly promotes oncogenesis. As a lymphotropic virus, HCV infection is thought to trigger B-cell proliferation and thus, has been associated with a greater risk of lymphoproliferative disorders, such as B-cell lymphoma.23, 24 Alternatively, the increased risk for non-HCC cancers could also be explained as confounding by shared risk factors. Such risk factors as high-risk sexual behaviors and injection drug use could explain the association with anal cancer and skin cancer, but were not accounted for in the analysis. These findings suggest that in addition to HCC, providers should be vigilant to the fact that HCV-infected patients who are 65 years or older could have an increased risk of non-HCC malignancies compared with HCV-uninfected patients who are 65 years or older.

Hepatitis C Virus Infection and Diabetes
An association between HCV infection and diabetes mellitus (DM) has been demonstrated in several studies.32, 33, 34, 35 In one longitudinal study, the development of DM was found to be 11 times more common in HCV-infected than HCV-uninfected persons.36 In persons older than 39 years of age, HCV infection increased the risk of DM by almost four times.37 Although a direct effect of HCV on the hepatocyte insulin-signaling cascade38, 39, 40 and pancreatic β-cell function41 has been postulated as a cause of insulin resistance, the cause of DM is invariably multifactorial. In older HCV-infected persons, DM onset may be a result of the direct effects of HCV and increasing visceral adiposity that occurs with older age.

Hepatitis C Virus Infection and Cardiovascular Disease

Similarly, there is growing evidence that HCV infection is associated with an increased risk of cardiovascular disease (CVD) and heart failure.42 The mechanisms by which HCV infection might be associated with CVD include an HCV-induced proinflammatory state43 and possible direct effects of the virus on the myocardium and endothelium.44 HCV infection is also associated with a higher prevalence of DM, a well-known risk factor for CVD. However, low-density lipoprotein (LDL) cholesterol and total cholesterol are reported to be lower in HCV-infected persons compared with those without HCV infection.45 Lower circulating levels of LDL cholesterol are commonly observed in primates and humans in response to infection and inflammation, but other changes in LDL cholesterol metabolism (ie, increased small LDL particle size) may occur that could promote atherogenesis.46 There may also be direct effects of HCV infection that lower LDL levels by lowering very low density lipoprotein (VLDL) secretion independent of liver fibrosis severity,47 which could potentially decrease the risk of CVD. The contribution of aging to lipid levels and thus CVD in the setting of direct effects of HCV infection and HCV-associated systemic inflammation add some uncertainty as to whether HCV infection is associated with an increased risk of CVD compared with those without HCV infection.

Hepatitis C Virus and Neuropsychological and Neurocognitive Effects
Up to 30% of HCV-infected persons report neuropsychological disorders, not limited to depression, and up to two-thirds complain of fatigue; the older HCV-infected patient may be at particular risk.48 Although the presence of depressive symptoms might be related to the psychological burden of chronic HCV infection, some studies suggest that HCV infection directly affects the central nervous system (CNS) through alterations in serotoninergic and dopaminergic neurotransmission, with resultant depressive symptoms.49 This mechanism might also explain other CNS symptoms seen in HCV infection, such as fatigue, although a causal link has not been established.50, 51

HCV infection is also associated with increased cognitive impairment when compared with those without HCV infection.52 Between 33% and 50% of all HCV-infected persons report some degree of impaired neurocognition.53, 54 Whether this impairment is directly attributable to HCV infection, advancing age, progressive liver disease, and/or other comorbid conditions is often difficult to elucidate. Studies have demonstrated HCV RNA in brain tissue and cerebrospinal fluid suggesting active HCV replication in the CNS.55 There is also a growing body of evidence that HCV directly affects the brain and nerves independently of hepatic-mediated processes.56, 57

Hepatitis C virus treatment in the older patient with hepatitis C virus infection
Because patients between the ages of 50 and 70 will constitute a large proportion of the patients being treated in the next decade, understanding the impact of age on HCV treatment outcomes in the era of all-oral DAA regimens is important. Before the advent of DAA agents, some58, 59 but not all studies13, 60 found that HCV-infected patients that were of older age had worse sustained virologic response (SVR) rates than those that were of younger age. Some attributed the worse response to the more frequent treatment discontinuation and/or dose reductions in the older patient resulting from treatment with an interferon-based regimen plus ribavirin, which are often accompanied by adverse effects including cytopenia, flu-like symptoms, and CNS effects.

Few studies have examined the association of older age with SVR rates using all oral DAA regimens partly because elderly patients are often excluded from clinical trials. A recent study of four open-label phase 3 clinical trials was able to examine the safety and efficacy of ledipasvir/sofosbuvir for the treatment of genotype 1 HCV in subjects 65 years or older.61 Of the 2293 subjects in the four trials, 264 (12%) were greater than or equal to 65 years of age (and 24 of those were ≥75). That study found little difference in SVR rates (97% in those <65 years vs 98% in those ≥65 years) despite subjects greater than 65 years being more likely to have cirrhosis. Furthermore, there was little difference by age in the proportion reporting at least one adverse effect (78% in those <65 years vs 80% in those ≥65 years).

The most common adverse effects were fatigue and headache in both groups, but in subjects who were also on ribavirin, the rate of study drug modification or interruption was double in the older group (6% in those <65 years vs 13% in those ≥65 years). That study suggests that age is not a barrier to achieving SVR in patients taking ledipasvir/sofosbuvir, but ribavirin-free regimens should be considered for the treatment of elderly patients. If ribavirin must be used, then close monitoring is needed for the development of anemia.

Furthermore, because sofosbuvir and ribavirin are renally eliminated, safe and effective doses of sofosbuvir in those with an estimated glomerular filtration rate less than 30 mL/min have not been established. In the HCV-infected patient with severely compromised renal function, other HCV regimens, such as grazoprevir plus elbasvir, have been shown to be safe and effective.

Another cohort-based retrospective study62 of 17,487 HCV-infected patients grouped into six age categories (<55 years, 55–59, 60–64, 65–69, 70–74, and ≥75 years) in the Veterans Affairs Healthcare System who started an all-oral HCV regimen between 2014 and 2015 also found that DAAs were associated with high SVR rates (from 90% to 94%) even in the oldest age cohort (≥75 years) and that advanced age was not a negative predictor for SVR. Although the SVR rates were lower in those with cirrhosis compared with those without cirrhosis, the SVR rates were similar between age groups among those with cirrhosis. Similarly, SVR rates were lower in treatment-experienced patients compared with treatment-naive patients but similar between age groups among those who were treatment-experienced.

Another question of tremendous interest to clinicians is whether HCV treatment will be associated with improvement in long-term outcomes, especially in the older patient. A study of US veterans13 before the advent of DAA therapy found that successful HCV treatment is associated with significant reductions in HCC and overall mortality. That study found mortality benefit in all age categories including those 65 to 85 years. The same group also reported in another publication63 that although achievement of SVR was associated with decreased HCC risk, the annual risk of HCC among those who cleared the virus was not negligible ranging from 0.1% to 1.55% (overall 0.33%) with the highest residual risk in those diagnosed with cirrhosis followed by those who achieved SVR after age 65 irrespective of cirrhosis. They concluded that there remains a risk of HCC post-SVR, and the risk may be greater in those with cirrhosis or in the elderly, supporting HCV treatment before the development of cirrhosis and continued surveillance even after SVR in those who already developed cirrhosis.

Finally, whether HCV treatment improves long-term nonliver disease outcomes is unclear. A recent small study of HIV/HCV-coinfected persons demonstrated that even after SVR, older patients treated with DAA agents did not experience any change in neuropsychological assessments.64 By contrast, a small study from the interferon era of 34 HCV-infected adults with a median age less than 40 years found that successful HCV eradication can lead to improvements in cognitive function, at least for individuals with mild deficits.65 These apparently contradictory findings from the pre- and post-DAA area may reflect how older patients with more advanced neurocognitive deficits who may not have been candidates for treatment are now being treated more readily. Additional studies examining the impact of HCV cure in the era of DAA agents on long-term outcomes are needed.

Summary
Understanding the impact of older age and HCV infection on liver and nonliver outcomes is critical. The advent of potent all-oral DAA agents for HCV infection has ushered in a new era where declines in HCV-associated liver disease are tangible; yet whether there will be an effect on longer-term outcomes in other organ tissues besides the liver is unclear and needs study. Examination of limited published studies of the safety and efficacy of DAAs in the older HCV-infected patient suggests that age should not be a barrier to treatment. Given that the proportion of older patients with HCV is increasing, clinical trials of DAA agents should include older HCV-infected patients.
References

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Monday, October 2, 2017

Hepatitis C - Interferon-free therapy in elderly patients with advanced liver disease

Interferon-free therapy in elderly patients with advanced liver disease
The most recent issue of the American Journal of Gastroenterology assessed the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice.

Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce.

Dr Sabela Lens and colleagues assessed the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice.

The team performed a retrospective analysis of hepatitis C virus (HCV) patients aged ≥65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C).

The researchers recorded data of 1,252 patients.

Of these, 76% were aged 65–74 years, 17% were aged 75–79 years, and 7% were aged ≥80 years at the start of antiviral therapy.

The team found that 86% had HCV genotype-1b, and 48% were previous non-responders. The rate of severe adverse events increased with age category
American Journal of Gastroenterology

A significant proportion of patients had cirrhosis, of whom 11% presented decompensated liver disease.

The researchers found that most used regimens were SOF/LDV, 3D, and SOF/SMV.

The team noted that ribavirin was added in 49% of patients.

Overall, the sustained virological response rate was 94% without differences among the 3 age categories.

Albumin 3.5 g/dl or less was the only independent negative predictor of response.

Regarding tolerability, the rate of severe adverse events increased with age category.

In addition, the team noted that the main predictors of mortality were age 75 years or more, and albumin 3.5 or less.

Dr Lens' team conclude, "Sustained virological resposne rates with interferon-free regimens in elderly patients are high and comparable to the general population."

"Baseline low albumin levels was the only predictor of treatment failure."

"Importantly, the rate of severe adverse events and death increased with age."

"Elderly patients or those with advanced liver disease presented higher mortality."

"Thus a careful selection of patients for antiviral treatment is recommended."

Source - https://www.gastrohep.com/news/news.asp?id=112812
Am J Gastroenterol 2017; 112:1400–1409
02 October 2017

Wednesday, July 12, 2017

Safety and Efficacy of Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C in a Real-world Population Aged 65 Years and Older

News & Perspective > Journal of Viral Hepatitis

Are direct-acting antivirals safe and effective in elderly patients with HCV-related advanced fibrosis or cirrhosis?

Safety and Efficacy of Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C in a Real-world Population Aged 65 Years and Older
F. Conti; S. Brillanti; F. Buonfiglioli; R. Vukotic; M. C. Morelli; C. Lalanne; M. Massari; F. G. Foschi; V. Bernabucci; I. Serio; G. M. Prati; E. Negri; L. Badia; P. Caraceni; P. Muratori; G. Vitale; A. Porro; M. Morotti; G. Mazzella; P. Andreone Disclosures J Viral Hepat. 2017;24(6):454-463. 

Abstract
The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P = .074). Similar data were also reported in subgroup of patients aged ≥75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child-Pugh-Turcotte (CTP)-B cirrhosis and 95.4% in CTP-A (P = .013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis.

In conclusions, in a real-world setting, DAAs are safe and effective in elderly patients with HCV-related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class.

Discussion Only
Full Text Article
Older patients with CHC will become an increasingly larger group over the next decade, and they are expected to develop more cirrhosis and liver cancer with a significant increase in health-related disease costs. Therefore, achieving a SVR could halt the progression of liver disease. In Southern Europe and especially in Italy, the treatment of aged patients with CHC is an important issue, because of the higher prevalence of HCV infection, and the older age of HCV carriers, compared to other European countries, thus contributing to the disease burden and complications.[27–30] Progress in pharmacotherapy will continue to extend healthy life expectancy and a chance for HCV eradication in the elderly, historically considered poor candidates to IFN-based treatments, is now offered by new all-oral DAA regimens. Despite this, the experience with IFN-free regimens in these patients has been very limited in phase three studies, in which only few patients older than 65 years were included, often without advanced fibrosis or cirrhosis. Hence, evidence for the benefit of virologic response in elderly patients has yet to be clearly demonstrated.

In our knowledge, this study represents the largest experience on all-oral antiviral therapy in HCV patients aged ≥65 years with advanced liver disease, in a real-life setting. It reports the efficacy and safety of the available DAA regimens, but its retrospective cohort design and the real-life setting do not allow comparing the efficacy and safety of the different DAA regimens.
Several important findings emerged from our study. First, the results of our analysis demonstrate that all-oral DAA treatments were quite effective in elderly patients with advanced CHC and that older age was not a barrier to achieve a SVR12. Second, older age was not associated with increased SAEs during antiviral treatment.

In contrast with clinical trials,[31] where patients over 65 years old with advanced fibrosis or cirrhosis were underrepresented, this study was carried out in a clinical practice setting where about 50% of this population consisted of elderly patients. As expected, in comparison with younger patients treated during the same period, elderly had more severe liver disease, a higher prevalence of HCC history and comorbidities as arterial hypertension and renal disease. During IFN era, elderly patients were generally less treated than younger probably because they were excluded from the randomized controlled trials and physicians are reluctant to treat elderly patients with antiviral therapy because of possible side effects.[32] In our country, the majority of elderly patients have a HCV genotype-1b or 2 infection, and this epidemiology has influenced the choice of antiviral regimens in our cohort and led to highly effective results. In fact, response rates were 100% in patients with advanced fibrosis and 94.7% in patients with cirrhosis (95% in GT-1b and 91.7% in GT-2). The high SVR12 rate observed in the latter group was also probably due to a high prevalence of subjects in CTP-A class (about 90%).

High efficacy in a real-world setting was recently reported also by Vermehren et al.[33] even if the sample size of elderly patients was lower than in our study and less than 50% had cirrhosis.
The majority of patients were treated with SOF/SMV regimen, and viral eradication was obtained in 82/89 (92.1%) of those with cirrhosis. These results confirm data recently reported in a large prospective observational cohort study by Sulkowski et al.[34] Efficacy of other DAA regimens (as SOF/DCV±RBV and LDV/SOF±RBV) was even more encouraging even if the limited sample size does not allow definitive conclusions. Furthermore, the SVR12 rates observed in patients with genotype 2 treated with SOF plus RBV have yielded very favourable results, comparable to those of our younger population and higher than those reported in previous real-life studies.[35,36] In these clinical practice studies, authors reported SVR12 rates lower in patients with liver cirrhosis (83–87%) than in our cohort. Probably this difference is due to the use of a 24-week regimen of SOF and RBV in about 50% of our patients with cirrhosis, considering that extended treatment duration in cirrhotics has been shown to increase SVR.[37]

Interestingly, and probably unexpectedly, our data showed that sex, diabetes, genotype 1, renal function, previous treatment failure and RBV use were not negatively associated with SVR12 in elderly patients with cirrhosis. Only severity of liver disease at baseline had a significant impact on SVR12. In fact, patients with CTP-A at the time of treatment initiation were more likely to achieve SVR12 compared to those in CTP-B class (95.4% vs 80.8%, respectively, P = .010). Similar trend has been previously reported in other studies.[38,39]

RBV was not used in 34.6% (66/191) of elderly patients with HCV genotype 1 or 4 cirrhosis due to the presence of anaemia at baseline (68.2%) or concomitant cardiovascular disease (18.2%), for intolerance to a previous RBV-containing treatment (7.6%) and for treating physicians' choice (6%). Despite this, no difference was found in terms of SVR12 compared to patients treated with RBV. In HCV genotype 2 or 3 patients treated with SOF+RBV (which was the only schedule available for these genotypes during the study period), hematopoietic growth factor supplementation and dose reduction were successful used to manage the anaemia.

Our study confirms previous observations reported by others[40] that undetectable viremia after 4 weeks of treatment is not a predictor of SVR12. Conversely, also in our experience, SVR4 continues to be a strong predictor of SVR12 and only two patients relapsed in our cohort after achieving SVR4.[41]

All the DAA regimens were generally well tolerated, with only less than 2% of patients discontinuing treatment due to adverse events. SAEs were observed in about 5% of patients; nevertheless, two patients died during treatment due to worsening of liver and/or renal function. Anaemia was frequent in this cohort of patients aged ≥65 years and mostly managed with RBV dose reductions or discontinuation. Hyperbilirubinemia was well tolerated in most patients, did not require premature discontinuation of treatment and resolved within a few weeks after treatment discontinuation. Most common AEs corresponded to those previously reported in pivotal phase III studies.[12–18]

In addition, our findings demonstrated that the rate of AEs in patients aged 65–74 years was not different from that observed in patients aged 75 years or older. In this setting, fatigue and skin complaints were confirmed to be the most common AEs. Finally, some complications of liver disease occurred during the short period of the study, including HCC. Recently some studies, also from our group,[42–44] reported increased rates of HCC recurrence in patients treated with DAAs suspecting a deregulation of the antitumour response after the sharp decrease of HCV viral load induced by DAA. To date, data on the effect of HCV eradication after DAA in patients who have already developed HCC are still few and not conclusive and it is as yet unclear whether interferon-free treatment could result in patients being free from the HCC occurrence.[45–47] Until now, there are no findings supporting the role of the age per se as a risk factor for the development of HCC after interferon-free treatment. Therefore, all patients with cirrhosis remain at increased risk for HCC even after they have been cleared HCV. This observation highlights the need for these patients to continue a regular screening for liver complications, even after SVR.

Some limitations should be considered in the interpretation of our results, including the retrospective design and the lack of data on the emergence of resistance-associated viral strains. Furthermore, the short follow-up period (12 weeks) limits our ability to assess the long-term impact of SVR on those patients. Another objection could be that we arbitrarily defined as "elderly" those patients aged 65 years or above. Nonetheless, in the cohort of patients over 75 years of age data about efficacy and safety of IFN-free regimens were superimposable, suggesting that prescription of these new treatments should not be limited by any age.

In conclusion, the results of this study demonstrate that age per se does not influence the success of IFN-free treatments in elderly patients with CHC and that all the DAA regimens seem well tolerated and safe, also in subjects with advanced liver disease and in those aged 75 years or older. Based on these evidences, there are no reasons to deny treatment with new DAA using the age as a criterion for prescription. Nonetheless, some conditions may limit the use of these drugs in elderly subjects such as the presence of severe comorbidities, affecting the short-term life expectancy, and/or the risk of serious drug interactions. Therefore, a careful assessment of the patient's geriatric status is mandatory. Finally, a longer follow-up of this cohort may provide additional useful information about the lifetime utility of HCV eradication in terms of reduction in outcomes and survival.

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Friday, June 2, 2017

Direct-acting antivirals in elderly patients with chronic hepatitis C

European Journal of Gastroenterology & Hepatology:
doi: 10.1097/MEG.0000000000000871

Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C
Sherigar, Jagannath M.a; Gayam, Vijayb; Khan, Arifab; Mukhtar, Osamab; Arefiev, Yavgeniya; Khalid, Mazinb; Siddiqui, Imranb; Rangaraju, Ayyappa M.b; Budhathoki, Nibashb; Mansour, Mohammedb; Guss, Debraa; Mohanty, Smruti R

Conclusion
The age of the patient does not seem to have a major impact on the virologic response rate when treating chronic HCV infection. Older patients (age 65 years and older) do not appear to have a higher frequency of adverse events compared with younger patients. Increased fibrosis, cirrhosis, some of the baseline laboratory studies including AST, ALT, Hemoglobin, and platelet levels seem to affect the SVR in the elderly and require further studies. More studies should be carried out in an older population of patients to assess the safety, efficacy, and adverse reactions of newer DAAs regimens. Treatment should not be withheld purely on the grounds of advanced age.

Abstract
Background: There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN).

Patients and methods: Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups.

Results: No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups.

Conclusion: DAAs with or without IFN and RBV in the standard recommended 12 or 24-week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C.

Discussion Only
Full Text Article Available Online
Eradication of HCV reduces the risk of progression to cirrhosis, HCC, and liver-related mortality, and thus leads to an improvement in overall survival and quality of life 9. Historically, the standard longer duration of IFN and RBV treatment produced significant adverse events in elderly patients, necessitating dose reduction or discontinuation of medications 10,11. The overall SVR rate was less than 50% with standard dual therapy with Peg IFN and RBV regimens. With the introduction of first DAAs in 2011, the triple therapy (boceprevir or telaprevir with Peg IFN and RBV) increased the SVR12 to 65–70% in GT 1 patients. Subsequent, substantial progress with further trials including combination NS5A and NS5B inhibitors, SVR12 approached more than 90%.

Current guidelines do not specify the age limit for treating elderly patients. The American Association of Study of Liver Disease recommends one of the six- DAA combination regimens for GT 1, the most common type of chronic HCV infection in the United States 12. RBV is still an integral part of the treatment regimen and utilized in combination with DAAs in GT 4 and as an alternative treatment regimen in GTs 1 and 3 patients with compensated cirrhosis.

A recent meta-analysis by Yang et al. 8 concluded that the overall SVR in patients aged older than or equal to 65 years treated with a prolonged course of IFN/RBV regimens was significantly lower and had a significantly higher risk of relapse than in patients younger than 65 years of age. IFN and RBV discontinuation rate were also significantly higher in older patients than in younger patients. We did not find any significant difference in RBV dose reduction or discontinuation rate (P=0.913) in patients aged 65 years and older compared with younger patients. These findings indicate that elderly patients are tolerating equally the shorter course of treatment involving IFN-based and RBV-based regimens as younger patients. ETR and SVR12 for elderly patients were similar to those of younger patients (93.06 vs. 94.12%), supporting previous observations, but with the improved virologic response rate in combination with DAAs 13. Fatigue is the most common adverse event observed in both IFN-based and IFN-free treatment regimens (Tables 6 and 7). Most of the incidences of anemia and leukopenia noted in IFN-free regimens were because of RBV in combination with newer agents. None of the patients discontinued the treatment because of adverse events, supporting the fact that a shorter duration of IFN/RBV-based treatment is better tolerated and can be administered to any age group safely with close monitoring during the treatment.

In most initial trials on protease inhibitors, a small number of patients older than 65 years of age were included. Although there was no upper age limit in NS5B nucleotide polymerase inhibitor SOF and NS3/4A second-generation protease inhibitor simeprevir trials, the number of elderly patients included was too small to draw any conclusion 14,15. In most of the trials involving SOF, most of the patients treated were in their 50s 16–21. In our study, 54 (27 in each group) patients treated with SPV and the SOF regimen showed similar SVR12 rates (P=0.607) and adverse events profile. Overall, SVR12 treated with an SOF-based regimen was 91–98%, in agreement with the results observed from the major trials involving SOF 18–22. In trials involving Viekira Pak, the study group involved were younger than 71 years, with a mean age in the 50s, and the SVR rate was well above 88% 22–26. Overall, the response rate with Viekira Pak in our study was 100% (12<65 and 6> 65 years), with good tolerance to medication in elderly patients.

Clinical trials involving IFN and RBV-free regimens also did not include enough patients aged 65 years and older to determine whether they respond differently from a younger population. Trials involving the NS5A inhibitor LDV and SOF in ION1, 2, and 3 trials included only 117 patients aged 65 years and older, and the patient population included in LONESTAR Study involving the LDV and the SOF combination was younger than 70 years 27–30. No overall difference in tolerability and effectiveness was observed with elderly patients, but the data available for the treatment of the aged population with newly approved therapies are still limited not only in registration trials but also in real-world treatments and community-based HCV regimens. Results of evaluation of 80 (52<65 and 28> 65 years) patients treated with Harvoni in our study yielded an ETR of 97% and an SVR12 of 94%, consistent with the results observed in clinical trials. No statistically significant difference was noted in our study with ETR (P=0.209) or SVR12 (P=0.120) between the two age groups, consistent with the recently published study by Saab et al. 31. They analyzed the data from four open-label phase 3 clinical trials that evaluated the safety and efficacy of LDV+SOF and concluded that the combination of LDV and SOF is safe, effective, and well tolerated in patients older than 65 years of age who have GT 1 hepatitis C infection 31. Of the 2293 patients enrolled in four phase 3 trials, 264 (12%) were older than or equal to 65 years of age, of whom 24 were aged older than or equal to 75 years. 97% of patients aged younger than 65 years achieved SVR12 (1965/2029) and 98% (258/264) of patients aged older than or equal to 65 years achieved SVR12. The most common adverse events in both age groups that occurred in 10% or more patients were headache and fatigue. Most adverse events noted in our study were minor and did not require any intervention, comparable with the study reports from major trials involving similar treatment regimens (Table 5). Adverse events did not differ significantly between the groups, except abdominal pain (P=0.018). Ten (6.4%) patients, all younger than 65 years of age, complained of nonspecific abdominal pain on treatment. Considering that the population involved had significant pain issues at baseline, it appears that this symptom may not be entirely related to the medication agent used. There were two serious adverse reactions during treatment with the regimen involving RBV with severe anemia requiring a blood transfusion and two patients received darbepoietin infusion for correction of anemia. None of the patients discontinued the complete treatment regimen in our study because of adverse reactions, although four patients discontinued the RBV during the treatment; they all achieved SVR12. In 12% of the patients, the RBV dose was reduced during treatment. A recent study by Pernas 32 raised a concern about possible drug interactions and RBV dose reduction because of adverse reactions in a significant number of patients after following 125 patients 65 years and older who were treated for hepatitis C with newer DAA agents. Of the 61.2% of patients who received RBV, in almost half, the dose was reduced during treatment 32. Clinical trials involving a recently approved IFN-free regimen for GTs 1 and 4, elbasvir, and grazoprevir (Zepatier; Merck & Co Inc, Kenilworth, New Jersey, USA) with or without RBV included 187 patients aged 65 years or older 33. The higher rate of late ALT elevation was observed in elderly patients; however, no dosage adjustment was required and the ALT level of most patients normalized after the completion of treatment.

SVR differs with GTs. We found a statistically significant low SVR rate with GT 1 in an elderly age group. There are no data identifying which patients will achieve an SVR among older patients with a DDA-based treatment. Our analysis indicates that cirrhosis and increased MELD score are important factors for low SVR in general and in elderly patients. Univariate analysis showed that baseline BMI, ALT, AST, and hemoglobin are factors that are associated significantly with an SVR (P=0.020, 0.020, 0.000, and 0.013, respectively).

In our study, 12 (6.28%) patients failed to respond to treatment (7<65 and 5≥65 years). Age was not a factor for the poor virologic response and the failure rate between the groups was not significant (P=0.767). All patients reported adherence to the medication regimen, and there was no clinical evidence of any reinfection in relapsed patients. None of these patients had any pretreatment-resistant or post-treatment-resistant associated variants and are awaiting further treatment. Seventy-five (nine out of 12) percent of the patients who failed to respond to treatment were cirrhotic and 41% (five out of 12) were coinfected with HIV. Further studies are required to evaluate these significant numbers of relapses in HIV-coinfected patients. Nine patients who failed to treatment received one or the other SOF-based regimen.

Some of the limitations of this study are the retrospective nature of our study, the fact that documentation of the common adverse events may not be complete, and that elderly patients involved are still a small number compared with registration trials. However, to our knowledge, our study is the first study involving a real-world community-based treatment comparing HCV patients younger than 65 years of age and 65 years of age and older. Going forward, the IFN-free regimens seem to be the standard of care in both age groups. RBV in combination with other DAAs may still be useful in treating some of the difficult to treat patient groups and in less developed countries, where the cost of newer antiviral medicines is a major hurdle. Shortened treatment course may reduce the drug-related adverse events in general including elderly patients. There is a pressing need to include older patients in future trials involving IFN-free agents. They require more complex decision-making because of their age and comorbid conditions with multiple medications.

Conclusion
The age of the patient does not seem to have a major impact on the virologic response rate when treating chronic HCV infection. Older patients (age 65 years and older) do not appear to have a higher frequency of adverse events compared with younger patients. Increased fibrosis, cirrhosis, some of the baseline laboratory studies including AST, ALT, Hemoglobin, and platelet levels seem to affect the SVR in the elderly and require further studies. More studies should be carried out in an older population of patients to assess the safety, efficacy, and adverse reactions of newer DAAs regimens. Treatment should not be withheld purely on the grounds of advanced age.

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Thursday, April 13, 2017

Efficacy and safety of dual therapy with daclatasvir and asunaprevir in elderly patients

World J Hepatol. Apr 18, 2017; 9(11): 544-550
Published online Apr 18, 2017. doi: 10.4254/wjh.v9.i11.544
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Efficacy and safety of dual therapy with daclatasvir and asunaprevir in elderly patients
Kazuo Tarao, Katsuaki Tanaka, Akito Nozaki, Akira Sato, Toshiya Ishii, Hirokazu Komatsu, Takaaki Ikeda, Tatsuji Komatsu, Shozo Matsushima, Kenji Oshige

Core tip: Recently, it was demonstrated that dual oral therapy with daclatasvir and asunaprevir without pegylated-interferon/ribavirin was well tolerated and achieved high sustained virological response rates in Japanese patients with chronic hepatitis C virus genotype Ιb infection, including patients with liver cirrhosis (Child A stage). However, the efficacy and side effects of these drugs was previously studied in non-elderly patients (less than 70 years of age). Those in elderly patients, who are supposed to have higher incidence of hepatocellular carcinoma, have not been studied. We demonstrated that efficacy and side effects in elderly patients were nearly the same as in non-elderly patients.

Abstract
AIM
To survey the efficacy and safety of dual therapy with daclatasvir and asunaprevir in the elderly hepatitis C virus (HCV) patients multicentricity.
METHODS
Interferon-ineligible/intolerant patients and non-responders to previous pegylated-interferon/ribavirin therapy with chronic HCV genotype 1b infection were enrolled. Child B, C cirrhotic patients were excluded. Patients received oral direct acting antiviral treatment consisting of 60 mg daclatasvir once daily plus 200 mg asunaprevir twice daily for 24 wk. We divided the patients into two groups of 56 elderly patients (≥ 75 years-old) and 141 non-elderly patients (< 75 years old) and compared the efficacy and safety.
RESULTS
Ninety-one point one percent of elderly patients and 90.1% of non-elderly patients achieved sustained virological response at 24 wk (SVR24). In the former, 1.8% experienced viral breakthrough, as compared with 3.5% in the latter (not significant). Adverse events occurred in 55.4% of the former and 56.0% of the latter. In the former, 7 cases (12.5%) were discontinued due to adverse events, and in the latter 9 cases were discontinued (6.4%, not significant).
CONCLUSION
Dual therapy with daclatasvir and asunaprevir achieved the same high rates of SVR24 in HCV elderly patients without more adverse events than in the non-elderly patients.
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Healio - Hepatitis C associated with increased risk for various cancers in older patients

Hepatitis C associated with increased risk for various cancers in older patients
Hepatitis C virus infection was associated with an increased risk for cancers other than hepatocellular carcinoma among elderly patients, a registry-based case–control study found.

“Hepatitis C virus infection is the most common chronic blood-borne infection in the United States, and approximately 3 million individuals are infected with this virus,” Parag Mahale, MBBS, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and colleagues wrote, adding that HCV can lead to development of hepatocellular carcinoma. “Approximately 70% of HCV–infected individuals in the United States were born between 1945 and 1965, prompting the CDC to recommend a one-time screening for HCV in this birth cohort. As baby boomers age, HCV–associated cancers in the elderly population may become an important public health issue in the United States in the near future.”
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Tuesday, April 11, 2017

Toxicity and risks from drug-to-drug interactions of new antivirals for chronic hepatitis C

European Review for Medical and Pharmacological Sciences

Toxicity and risks from drug-to-drug interactions of new antivirals for chronic hepatitis C
BINDA, A. TORTORA, M. GARCOVICH, B.E. ANNICCHIARICO, M. SICILIANO
2017; 21 (1 Suppl): 102-111 C.

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Abstract. – The new direct acting antivirals (DAAs), defined as those drugs that are effective in combinations without interferon, have totally changed HCV treatment and probably in few years will also totally change global landscape of advanced liver diseases. The advantage of DAAs is a low-risk/high-benefit ratio. Although overall adverse events during DAAs treatment are limited in frequency and severity, some toxicity issues emerged during the first years of real-life experience with these drugs. Another peculiar characteristic of present DAAs is a high probability of interaction with other “common-use” drugs, such as anti-hypertensive, anti-platelet, antiarrhythmic and cholesterol lowering agents. Above all, special attention should be paid in older patients and in those belonging to special populations, who more frequently require the concomitant use of polytherapy.

Table II. Side effects reported in real-life.

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Tuesday, March 28, 2017

Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C

Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C
Sherigar, Jagannath M.; Gayam, Vijay; Khan, Arifa; Mukhtar, Osama; Arefiev, Yavgeniy; Khalid, Mazin; Siddiqui, Imran; Rangaraju, Ayyappa M.; Budhathoki, Nibash; Mansour, Mohammed; Guss, Debra; Mohanty, Smruti R.

European Journal of Gastroenterology & Hepatology: Post Author Corrections:
March 24, 2017 doi: 10.1097/MEG.0000000000000871

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Abstract
Background: There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN).

Patients and methods: Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups.

Results: No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups.

Conclusion: DAAs with or without IFN and RBV in the standard recommended 12 or 24-week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C.

Introduction
Globally, chronic hepatitis C virus (HCV) infection has been estimated to affect 2–3% (about 170 million) of the world’s population [1]. A National Health and Nutrition Examination Survey 2003–2010 analysis estimated that ∼2.7 (1.0%) million USA residents have infection with chronic HCV [2]. Chronic HCV is the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and its related complications, and thus elimination of HCV significantly reduces the risk of HCC, liver failure, and death [3].

An increased prevalence of chronic HCV infection is observed with advancing age. These patients are likely to have an advanced liver disease including cirrhosis of the liver and related complications [4,5]. In countries such as Japan, Taiwan, and some European countries, the prevalence of chronic hepatitis C infection is the highest in the aged population [6]. According to the USA Census Bureau, by 2030, more than 20% of USA residents are projected to be aged 65 years and older. The baby boomers (born between 1945 and 1965) began turning 65 in 2011 and currently account for three-fourth of all chronic HCV infections among adults in the USA [7].

Older individuals infected with chronic HCV are historically considered a difficult to treat category with less success and more treatment failures than the younger population. The pegylated interferon (peg IFN) and ribavirin (RBV) combination therapy was associated with a high discontinuation rate in the elderly because of the longer duration of treatment and associated adverse events [8]. With the recent introduction of IFN-free direct-acting antivirals (DAAs), the treatment success for chronic HCV infection has improved markedly, with the overall cure rate reaching above 90%. Even though some of the newer drug trials included aged populations, the numbers of elderly patients enrolled were limited. Although we have achieved considerable advancements in treatment with newer agents, the coadministration of RBV in combination with newer agents still exists in certain patient groups to achieve an acceptable response rate. A shorter duration of treatment with these regimens and better tolerability are expected in both younger and older populations. We, therefore, examined the effectiveness and tolerability of newer DAAs in older patients aged older than 65 years compared with younger patients. We also evaluated the factors associated with sustained virologic response (SVR) and the tolerability of DAAs in combination with Peg IFN, RBV, or both with a shorter duration of treatment in an aged population compared with younger patients aged younger than 65 years.

Patients and methods
This retrospective cohort study protocol was approved by the institutional review board of each hospital (New York Presbyterian Brooklyn Methodist Hospital New York and Interfaith Medical Center, New York).

Patients
A total of 279 consecutive patients with chronic HCV treated with either a combination of DAAs or at least one of the newer agents in combination with IFN and RBV between January 2013 and July 2015 at two institutions were retrospectively analyzed. Thirty-nine patients were excluded from the study for various reasons including insufficient documentation of viral load during the treatment and failure to attend follow-up after the end of treatment (Fig. 1). All the 240 patients included in this retrospective cohort study received at least eight weeks of treatment with one of the recommended combination regimens in standard doses for chronic HCV infection. Patients were divided into two groups: patients aged younger than 65 years (N=156) and those aged 65 years and older (N=84). The choice of treatment regimens used was made on the basis of the American Association of Study of Liver Disease guidelines during that period. During early 2013, treatment recommendation was triple therapy with a protease inhibitor, Peg IFN, and RBV. In the years 2014 and 2015, the rest of the regimens were used as they were approved one after the other by the Food and Drug Administration.

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The combination treatment regimens used were Peg IFN α-2a+RBV+sofosbuvir `(SOF), SOF+RBV, ledipasvir (LDV)+SOF (Harvoni; Gilead Sciences, Foster City, California, USA), LDV+SOF+ RBV (Harvoni+RBV), ombitasvir+paritaprevir+ritonavir+dasabuvir(ViekiraPak;AbbVie Inc, Illinois, NorthChicago, USA), ombitasvir+paritaprevir+ritonavir+dasabuvir+RBV (Viekira Pak+RBV), and simeprevir (SPV)+sofosbuvir. Only three patients were treated with Peg IFN+RBV+telaprevir andone patienteachreceivedthe PegIFN+RBV+boceprevir, Peg IFN+RBV+Harvoni, and SPV+SOF+RBV combination(Fig.2).

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Fig.2


The duration of the treatment periodranged from a minimum of 8weeks(N=3, all with Harvoni) to a standard 12 weeks (N=201) or 24 weeks (N=36) depending on their status of previous treatment and cirrhosis. All patients who received the IFN-based regimen received PegIFN at a standard dose of 180mg subcutaneously once a week. A weight-based RBV dose was used at 1200mg daily in two divided doses for those weighing 75kg and 1000mg for those weighing less than 75kg.

Study assessments
Pretreatment baseline characteristics (Table 1), laboratory studies, baseline HCV viral load, treatment efficacy with the end of treatment response (ETR), and sustained virologic response at 12 weeks after the completion of treatment (SVR12) were compared between the groups. We determined the factors associated with SVR on baseline characteristics by univariate analysis. A separate analysis was carried out in patients aged older than or equal to 65 years to determine the factors associated with SVR in the elderly group. The safety and tolerability of antiviral drug regimens were assessed by reviewing the documented common or serious adverse events, treatment completion rate, and reduction in the medication dosage or discontinuation of medications.

Assessment of liver fibrosis was performed with invasive liver biopsy in some cases and noninvasive testing with a fibrosure test or a fibroscore test and the aspartate aminotransferase (AST)-to-aspartate platelet ratio index (APRI) score. Patients who had clinical, laboratory, and radiologic evidence of cirrhosis were treated without any further assessment of fibrosis. Treatment response was assessed with HCV RNA viral load (IU/ml) at four weeks after initiation of treatment, at the end of treatment, and 12 weeks after the completion of treatment.

The test was performed using Cobas AmpliPrep/Cobas TaqMan HCV Quantitative Test, v2.0 (Roche Molecular Diagnostics, Pleasanton, California, USA) with a lower limit of quantification of HCV RNA 15IU/ml. ETR was defined as undetectable viral load at the end of completion of treatment. SVR12 was defined as undetectable viral load at 12 weeks after the end of treatment.

Statistical analysis
The SPSS statistics software package (IBM SPSS Statistics, version 21; IBM Corp, Armonk, New York, USA) was used for statistical analysis. Values were expressed as mean±SD and the mean quantitative values were analyzed using Student’s t-test. The χ2-test was used to analyze differences in qualitative values. All P values were two tailed and a P value of less than 0.05 was considered significant. One-way analysis of variance was used to determine whether there were differences among the group means. Univariate analysis was used to identify the factors related to SVR.

Results
Patients Sixty-five percent (N=156) of the total of 240 patients were younger than 65 years and patients aged 65 years or older comprised 35% (N=84) of treated patients, with the range being 22–94 years (59.96±10.89). Ninety-nine patients were men and 57 patients were women in the group younger than 65 years of age and 46 were men and 38 were women in the group 65 years of age and older, respectively. Most of the patients were Black (51%, 123/240), followed by White (23%, 56/240), Hispanic (11%, 27/240), and Asians (1%, 2/240). The 32 (13%) patients categorized as others were genotype (GT) 4 and were of Middle-Eastern or Egyptian origin. Also, 32 patients were coinfected with HIV and were receiving their antiretroviral therapy for HIV infection during HCV treatment; no dose adjustment was required. The basic clinical characteristics of all treated patients are summarized in Table 1.

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Table 1


GTs 1a and 1b was present in 78.3% of the treated patients. The next most common genotype was GT 4, found in 11.7% of patients. GTs 2 and 3 were present in 6.7 and 3.3% of all treated patients, respectively.

Seventy five patients were treatment experienced, 50 of whom were <65 years old and 25 patients who were ≥65 years. These treatment experienced patients had either previously failed treatment with the IFN and RBV combination or IFN and RBV in combination with newer DAAs. Model for end-stage liver disease (MELD) score was high in patients aged 65 years and older and was statistically significant (P=0.048). A significant difference was observed between the groups with baseline medical comorbidities HTN (P=0.004), coronary artery disease (P=0.041), and chronic kidney disease (P=0.008) in patients aged 65 years and older, and tended to have more comorbidities than younger age groups. Except for baseline hemoglobin (P=0.004) and alanine aminotransferase (ALT) (P=0.018), no difference was noted between the initial laboratory studies within the groups. The mean viral load remained similar in both groups (P=0.624). No statistical significance was observed with sex (P=0.189), BMI (P=0.713), APRI score (P=0.619), or status of previous treatment (P=0.715).

Response to therapy
In seven out of the total 240 patients, no end of treatment response was recorded; however, viral load was recorded as undetectable at 4 or 8 weeks on treatment, except one patient, who had a quantifiable viral load at 2 weeks. SVR12 was not reported in 49 patients, either because of pending follow-up or because it was not determined and recorded. With all the treatment regimens combined, the overall ETR rate was 98.2% (N=233) and SVR12 was 94% (N=191) (Figs 3 and 4).

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Figs 3 and 4


No statistically significant difference was observed with ETR (98.8 vs. 98%, P=0.667) and SVR12 (93.1 vs. 94.1%, P=0.767) between patients aged 65 years and older and those younger than 65 years of age. SVR12 for DAA with IFN and RBV treatment was 98% (49/50), higher than 91.4% (118/129) achieved with IFN-free DAA regimens, but was not statistically significant. A similar response rate was observed in patients older than or equal to 65 years, with 100% of the patients on the IFN-based regimen achieving an SVR compared with only 91.07% SVR with the IFNfree treatment regimen. ETR and SVR12 for GTs 1a, 1b, 2, 3, and GT 4 were 97.7, 100, 93.8, 100, and 100% and 92, 100, 92.9, 83.3, and 91.7%, respectively (Fig. 6).

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Fig. 6

Patients with GT 3 were the lowest responders, highlighting the fact that GT 3 is the most difficult to treat with DAA agents. The ETR rate and SVR12 rates for subgroups Peg IFN+RBV+SOF, SOF+RBV, Harvoni, Viekira Pak/ Viekira Pak+RBV, and SPV+SOF were 100, 96.7, 97.4, 100, 98.1%, and 97.8, 88, 94.1, 100, and 90.6%, respectively.

For patients who had previous treatment failure or were naïve to treatment, no significant difference in ETR (P=0.783) or SVR12 (P=0.947) was observed between the younger and the older age groups. The univariate analysis determined the factors associated with an SVR (Table 2). The SVR12 was significantly lower in patients with high APRI and a high MELD score, indicating that advanced fibrosis is a major factor in determining the response to treatment (P=0.001 and 0.008, respectively). Baseline ALT and AST were significantly higher in patients who failed to achieve an SVR than in patients who did achieve SVR12 (P=0.016 and 0.000, respectively). BMI was significantly higher in patients who achieved SVR12 (P=0.000) Table 2. Factors associated with SVR12 were analyzed separately for patients aged older than or equal to 65 years (Table 4).

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Table 4


The ratio of GT 1 patients who achieved an SVR12 was significantly lower compare to other genotypes (P=0.001). Cirrhosis and MELD score of more than ten were associated with a low SVR (P=0.001 and 0.042, respectively). Baseline ALT and AST tended to be higher in those who did not achieve an SVR (P=0.020 and 0.000, respectively) and BMI tended to be lower in patients who failed to respond to treatment. Only seven patients had the IL28B GT tested and hence were not included in the evaluation of factors predicting the SVR. There were 12(6.28%) patients(5≥65and7<65years) who failed to respond to treatment. Eight patients developed relapse after treatment, three responded partially, and one achieved a virologic breakthrough during the treatment period (Table 3). Nine out of 12 patients who did not respond to treatment were cirrhotic. The difference in the failure rate between the two groups was not significant statistically (P=0.767).

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Table 3


Safety and tolerability
None of the adverse reactions reported were severe, except severe anemia in two patients. Fatigue was the most common adverse event recorded (32.5%), followed by 65 years) patients discontinued the RBV treatment because of severe anemia (decrease in hematocrit >25% from baseline); however, they all achieved SVR12. RBV dose reduction or discontinuation did not reach statistical significance between the two groups (P=0.913) (Fig. 5).

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Fig. 5


Discussion
Eradication of HCV reduces the risk of progression to cirrhosis, HCC, and liver-related mortality, and thus leads to an improvement in overall survival and quality of life [9]. Historically, the standard longer duration of IFN and RBV treatment produced significant adverse events in elderly patients, necessitating dose reduction or discontinuation of medications [10,11]. The overall SVR rate was less than 50% with standard dual therapy with Peg IFN and RBV regimens. With the introduction of first DAAs in 2011, the triple therapy (boceprevir or telaprevir with Peg IFN and RBV) increased the SVR12 to 65–70% in GT 1 patients. Subsequent, substantial progress with further trials including combination NS5A and NS5B inhibitors, SVR12 approached more than 90%. Current guidelines do not specify the age limit for treating elderly patients.

The American Association of Study of Liver Disease recommends one of the six- DAA combination regimens for GT 1, the most common type of chronic HCV infection in the United States [12]. RBV is still an integral part of the treatment regimen and utilized in combination with DAAs in GT 4 and as an alternative treatment regimen in GTs 1 and 3 patients with compensated cirrhosis.

A recent meta-analysis by Yang et al. [8] concluded that the overall SVR in patients aged older than or equal to 65 years treated with a prolonged course of IFN/RBV regimens was significantly lower and had a significantly higher risk of relapse than in patients younger than 65 years of age. IFN and RBV discontinuation rate were also significantly higher in older patients than in younger patients.

We did not find any significant difference in RBV dose reduction or discontinuation rate (P=0.913) in patients aged 65 years and older compared with younger patients. These findings indicate that elderly patients are tolerating equally the shorter course of treatment involving better tolerated and can be administered to any age group safely with close monitoring during the treatment.

In most initial trials on protease inhibitors, a small number of patients older than 65 years of age were included. Although there was no upper age limit in NS5B nucleotide polymerase inhibitor SOF and NS3/4A second generation protease inhibitor simeprevir trials, the number of elderly patients included was too small to draw any conclusion [14,15]. In most of the trials involving SOF, most of the patients treated were in their 50s [16–21]. In our study, 54 (27 in each group) patients treated with SPV and the SOF regimen showed similar SVR12 rates (P=0.607) and adverse events profile. Overall, SVR12 treated with an SOF-based regimen was 91–98%, in agreement with the results observed from the major trials involving SOF [18–22]. In trials involving Viekira Pak, the study group involved were younger than 71 years, with a mean age in the 50s, and the SVR rate was well above 88% [22–26]. Overall, the response rate with Viekira Pak in our study was 100% (12<65 and 6> 65 years), with good tolerance to medication in elderly patients. Clinical trials involving IFN and RBV-free regimens also did not include enough patients aged 65 years and older to determine whether they respond differently from a younger population.

Trials involving the NS5A inhibitor LDV and SOF in ION1, 2, and 3 trials included only 117 patients aged65yearsandolder,andthepatientpopulationincluded in Lone Star Study involving the LDV and the SOF combination was younger than 70 years [27–30]. No overall difference in tolerability and effectiveness was observed with elderly patients, but the data available for the treatment of the aged population with newly approved therapies are still limited not only in registration trials but also in real-world treatments and community-based HCV regimens. Results of evaluation of 80 (52<65 and 28> 65 years) patients treated with Harvoni in our study yielded an ETR of 97% and an SVR12 of 94%, consistent with the results observed in clinical trials. No statistically significant difference was noted in our study with ETR (P=0.209) or SVR12 (P=0.120) between the two age groups, consistent with the recently published study by Saab et al. [31]. They analyzed the data from four open-label phase 3 clinical trials that evaluated the safety and efficacy of LDV+SOF and concluded that the combination of LDV and SOF is safe, effective,andwelltoleratedinpatientsolderthan65yearsof age who have GT 1 hepatitis C infection [31]. Of the 2293 patients enrolled in four phase 3 trials, 264 (12%) were older than or equal to 65 years of age, of whom 24 were aged older than or equal to 75 years. 97% of patients aged younger than 65 years achieved SVR12 (1965/2029) and 98% (258/264) of patients aged older than or equal to 65 years achieved SVR12. The most common adverse events in both age groups that occurred in 10% or more patients were headache and fatigue.

Most adverse events noted in our study were minor and did not require any intervention, comparable with the study reports from major trials involving similar treatment regimens (Table 5). Adverse events did not differ significantly between the groups, except abdominal pain (P=0.018). Ten (6.4%) patients, all younger than 65 years of age, complained of nonspecific abdominal pain on treatment. Considering that the population involved had significant pain issues at baseline, it appears that this symptom may not be entirely related to the medication agent used. There were two serious adverse reactions during treatment with the regimen involving RBV with severe anemia requiring a blood transfusion and two patients received darbepoietin infusion for correction of anemia. None of the patients discontinued the complete treatment regimen in our study because of adverse reactions, although four patients discontinued the RBV during the treatment; they all achieved SVR12. In 12% of the patients, the RBV dose was reduced during treatment.

A recent study by Pernas [32] raised a concern about possible drug interactions and RBV dose reduction because of adverse reactions in a significant number of patients after following 125 patients 65 years and older who were treated for hepatitis C with newer DAA agents. Of the 61.2% of patients who received RBV, in almost half, the dose was reduced during treatment [32].

Clinical trials involving a recently approved IFN-free regimen for GTs 1 and 4, elbasvir, and grazoprevir (Zepatier; Merck & Co Inc, Kenilworth, New Jersey, USA) with or without RBV included 187 patients aged 65 years or older [33]. The higher rate of late ALT elevation was observed in elderly patients; however, no dosage adjustment was required and the ALT level of most patients normalized after the completion of treatment. SVR differs with GTs. We found a statistically significant low SVR rate with GT 1 in an elderly age group. There are no data identifying which patients will achieve an SVR among older patients with a DDA-based treatment. Our analysis indicates that cirrhosis and increased MELD score are important factors for low SVR in general and in elderly patients. Univariate analysis showed that baseline BMI, ALT, AST, and hemoglobin are factors that are associated significantly with an SVR (P=0.020, 0.020, 0.000, and 0.013, respectively). In our study, 12 (6.28%) patients failed to respond to treatment (7<65 and 5≥65 years). Age was not a factor for the poor virologic response and the failure rate between the groups was not significant (P=0.767). All patients reported adherence to the medication regimen, and there was no clinical evidence of any reinfection in relapsed patients.

None of these patients had any pretreatment-resistant or post-treatment-resistant associated variants and are awaiting further treatment. Seventy-five (nine out of 12) percent of the patients who failed to respond to treatment were cirrhotic and 41% (five out of 12) were coinfected with HIV. Further studies are required to evaluate these significant numbers of relapses in HIV-coinfected patients. Nine patients who failed to treatment received one or the other SOF-based regimen.

Some of the limitations of this study are the retrospective nature of our study, the fact that documentation of the common adverse events may not be complete, and that elderly patients involved are still a small number compared with registration trials.

However, to our knowledge, our study is the first study involving a real-world community-based treatment comparing HCV patients younger than 65 years of age and 65 years of age and older. Going forward, the IFN-free regimens seem to be the standard of care in both age groups. RBV in combination with other DAAs may still be useful in treating some of the difficult to treat patient groups and in less developed countries, where the cost of newer antiviral medicines is a major hurdle. Shortened treatment course may reduce the drug-related adverse events in general including elderly patients. There is a pressing need to include older patients in future trials involving IFN-free agents. They require more complex decision-making because of their age and comorbid conditions with multiple medications.

Conclusion
The age of the patient does not seem to have a major impact on the virologic response rate when treating chronic HCV infection. Older patients (age 65 years and older) do not appear to have a higher frequency of adverse events compared with younger patients. Increased fibrosis, cirrhosis, some of the baseline laboratory studies including AST, ALT, Hemoglobin, and platelet levels seem to affect the SVR in the elderly and require further studies. More studies should be carried out in an older population of patients to assess the safety, efficacy, and adverse reactions of newer DAAs regimens. Treatment should not be withheld purely on the grounds of advanced age.

References