Showing posts with label Other Conditions Related To HCV. Show all posts
Showing posts with label Other Conditions Related To HCV. Show all posts

Tuesday, May 8, 2018

Higher risk of hepatocellular carcinoma in Hispanic patients with hepatitis C cirrhosis and metabolic risk factors

Published:08 May 2018 - scientific reports

Higher risk of hepatocellular carcinoma in Hispanic patients with hepatitis C cirrhosis and metabolic risk factors
Alina Wong, An Le, Mei-Hsuan Lee, Yu-Ju Lin, Pauline Nguyen, Sam Trinh, Hansen Dang & Mindie H. Nguyen


In summary, this study shows that patients with CHC cirrhosis and super-imposed metabolic syndrome have increased risk of liver-related complications including both hepatic decompensation and HCC. Hispanic patients with two or more metabolic risks are at especially increased risk of developing liver-related complications. As the prevalence of obesity and metabolic syndrome increase across the world, targeted health interventions will be needed to help curb the effects of metabolic syndrome in chronic hepatitis C patients.

The effect of metabolic syndrome on chronic liver diseases other than non-alcoholic fatty liver disease has not been fully elucidated. Our goal was to evaluate if metabolic syndrome increased the risk of liver-related complications, specifically hepatocellular carcinoma (HCC) and decompensation, in cirrhotic chronic hepatitis C (CHC) patients. We conducted a retrospective cohort study of 3503 consecutive cirrhotic CHC patients seen at Stanford University from 1997–2015. HCC developed in 238 patients (8-year incidence 21%) and hepatic decompensation in 448 patients (8-year incidence 61%). The incidence of HCC and decompensation increased with Hispanic ethnicity, diabetes, and number of metabolic risk factors. Multivariate Cox regression analysis demonstrated that, independent of HCV therapy and cure and other background risks, Hispanic ethnicity with ≥2 metabolic risk factors significantly increased the risk of HCC and hepatic decompensation. There was no interaction between Hispanic ethnicity and metabolic risk factors. All in all, metabolic risk factors significantly increase the risk of liver-related complications in cirrhotic CHC patients, especially HCC among Hispanics. As the prevalence of metabolic syndrome increases globally, targeted health interventions are needed to help curb the effects of metabolic syndrome in CHC patients.

Saturday, April 14, 2018

Hepatitis C Symptoms Can Persist After Cure Cryoglobulins observed 2 years after sustained virologic response

Meeting Coverage > EASL
Hepatitis C Symptoms Can Persist After Cure Cryoglobulins observed 2 years after sustained virologic response
by Ed Susman, Contributing Writer, MedPage Today April 13, 2018

PARIS – Long after hepatitis C virus has been eradicated by direct acting antiviral therapy, manifestations of the disease persist and can relapse with potentially deadly consequences, researchers suggested here.

Despite having achieved a sustained virologic response to therapy, 10% of symptomatic cryoglobulinemic vasculitis still had relapses of symptoms of their disease, said Martin Bonacci, MD, a hepatologist at the Liver and Digestive Diseases Networking Biomedical Research Centre in Barcelona.

"Clinical and particularly immunological response improves significantly over time after hepatitis C virus cure in symptomatic and asymptomatic patients," Bonacci said in his presentation at the International Liver Congress, sponsored by the European Association for the Study of the Liver. "However, 2 years after hepatitis C virus elimination cryoglobulinemia may persist and clinical relapse may occur in a small proportion of patients, suggesting that a longer monitoring of these patients is still warranted."
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All Updates @ MedPage Today
Coverage: International Liver Congress

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Thursday, April 12, 2018

The Benefits of Hepatitis C Virus Cure via DAAs: Every Rose Has Thorns

In case you missed it

The Benefits of Hepatitis C Virus Cure: Every Rose Has Thorns
D. Salmon; M. U. Mondelli; M. Maticic; J. E. Arends

J Viral Hepat. 2018;25(4):320-328.

The advent of DAAs has revolutionized the treatment of HCV infection, enabling a cure for most patients. This will result in declining mortality rates due to HCC and to fewer extrahepatic manifestations. However, it will require early treatment of HCV at an individual and population level, with broad access to DAAs. To achieve the collective targets, a radical change is needed, with highly motivated national policies to improve screening and access to care, particularly in high–risk populations.

To examine mid–term benefits on hepatic complications, extrahepatic clinical syndromes and quality of life associated with HCV cure; to review the few safety issues linked to oral direct–acting antivirals (DAAs); and to discuss the potential population benefits of reducing the burden of HCV infection. DAAs cure HCV infection in more than 95% of patients. The halting of liver inflammation and fibrosis progression translates into both hepatic and extrahepatic benefits and reduces the need for liver transplantation. A reduction in the frequency of extrahepatic manifestations such as mixed cryoglobulinaemia and vasculitis and improvements in quality of life and fatigue have also been described. A few safety issues linked to DAAs such as the potential recurrence of aggressive HCC, the flares of hepatitis B virus in patients with overt or occult HBV infection are been discussed. Curing HCV infection also has a high potential to reduce the burden of HCV infection at the population level. With widespread scaling up of HCV treatment, several modeling studies suggest that major reductions in HCV prevalence and incidence are possible, and that elimination of viral hepatitis is an achievable target by 2030.

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Wednesday, April 11, 2018

The link between hepatitis C virus and diabetes mellitus: Improvement in insulin resistance after HCV eradication
Updates published in Clinical Liver Disease (CLD)
Clinical Liver Disease (CLD) is a digital educational resource published on behalf of the American Association for the Study of Liver Diseases (AASLD).

Radiology in Liver Disease
The link between hepatitis C virus and diabetes mellitus: Improvement in insulin resistance after eradication of hepatitis C virus
Justine Hum M.D. Janice H. Jou M.D., M.H.S.
Pages: 73-76
First Published:6 April 2018
Watch a video presentation of this article
Watch the interview with the author
Full text

Controversies in HCV Management
Hepatitis C: Who should treat hepatitis C virus? The role of the primary care provider
Tram T. Tran M.D.
Pages: 66-68
First Published:6 April 2018
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Saturday, April 7, 2018

HCV Screening: Important for Rheumatology Patients

HCV Screening: Important for Rheumatology Patients
Cassandra Calabrese, DO, shares her experiences
by Cassandra Calabrese, DO
April 07, 2018
I spent this past week seeing hepatitis C virus (HCV) patients with our hepatologists. Being a rheumatologist, I was looking forward to seeing extrahepatic manifestations of HCV that we read about in textbooks -- cryoglobulinemic vasculitis, sicca syndrome, porphyria cutanea tarda, and many others. I suppose I should not be surprised that the week passed without seeing a single one of these.

While a wide array of extrahepatic manifestations, including may rheumatologic ones, will occur in 40%-70% of chronic HCV patients, the advent of direct-acting antivirals (DAA) has changed HCV outcomes, such that I do not think we will be seeing these cases much longer...

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Other Conditions That May Be Related To HCV

Thursday, March 8, 2018

Neurological manifestation in chronic hepatitis C: Peripheral neuropathy

Research Article
Neurological manifestations in chronic hepatitis C patients receiving care in a reference hospital in sub-Saharan Africa: A cross-sectional study
N. Y. Mapoure , M. N. Budzi, S. A. F. B. Eloumou, A. Malongue, C. Okalla, H. N. Luma

Published: March 7, 2018

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Abstract Background
Chronic hepatitis C infection is a major public health concern, with a high burden in Sub-Saharan Africa. There is growing evidence that chronic hepatitis C virus (HCV) infection causes neurological complications. This study aimed at assessing the prevalence and factors associated with neurological manifestations in chronic hepatitis C patients.

Through a cross-sectional design, a semi-structured questionnaire was used to collect data from consecutive chronic HCV infected patients attending the outpatient gastroenterology unit of the Douala General Hospital (DGH). Data collection was by interview, patient record review (including HCV RNA quantification, HCV genotyping and the assessment of liver fibrosis and necroinflammatory activity), clinical examination complemented by 3 tools; Neuropathic pain diagnostic questionnaire, Brief peripheral neuropathy screen and mini mental state examination score. Data were analysed using Statistical package for social sciences version 20 for windows.

Of the 121 chronic hepatitis C patients (51.2% males) recruited, 54.5% (95% Confidence interval: 46.3%, 62.8%) had at least one neurological manifestation, with peripheral nervous system manifestations being more common (50.4%). Age ≥ 55 years (Adjusted Odds Ratio: 4.82, 95%CI: 1.02–18.81, p = 0.02), longer duration of illness (AOR: 1.012, 95%CI: 1.00–1.02, p = 0.01) and high viral load (AOR: 3.40, 95% CI: 1.20–9.64, p = 0.02) were significantly associated with neurological manifestations. Peripheral neuropathy was the most common neurological manifestation (49.6%), presenting mainly as sensory neuropathy (47.9%). Age ≥ 55 years (AOR: 6.25, 95%CI: 1.33–29.08, p = 0.02) and longer duration of illness (AOR: 1.01, 1.00–1.02, p = 0.01) were significantly associated with peripheral neuropathy.

Over half of the patients with chronic hepatitis C attending the DGH have a neurological manifestation, mainly presenting as sensory peripheral neuropathy. Routine screening of chronic hepatitis C patients for peripheral neuropathy is therefore necessary, with prime focus on those with older age and longer duration of illness.

Continue reading:

Recommended Reading
October 24, 2017
In the past, peripheral neuropathy was believed to be confined to people only infected with hepatitis C-related cryoglobulinemia, but now it is known that peripheral neuropathy may occur even in the absence of cryoglobulinemia.

Of Interest In The Media
Mar 12, 2018

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Tuesday, March 6, 2018

Hepatitis C Virus Eradication by Direct Antiviral Agents Improves Carotid Atherosclerosis in patients with Severe Liver Fibrosis

In case you missed it

J Hepatol. 2018 Mar 2. pii: S0168-8278(18)30132-6. doi: 10.1016/j.jhep.2018.02.015. [Epub ahead of print]

Article in Press
Hepatitis C Virus Eradication by Direct Antiviral Agents Improves Carotid Atherosclerosis in patients with Severe Liver Fibrosis
Salvatore Petta, Luigi Elio Adinolfi, Anna Ludovica Fracanzani, Francesca Rini, Rosalia Caldarella, Vincenza Calvaruso, Calogero Cammà, Marcello Ciaccio, Vito Di Marco, Stefania Grimaudo, Anna Licata, Aldo Marrone, Riccardo Nevola, Rosaria Maria Pipitone, Antonio Pinto, Luca Rinaldi, Daniele Torres, Antonino Tuttolomondo, Luca Valenti, Silvia Fargion, Antonio Craxì


Atherosclerosis is a condition in which the arteries become narrow as a result of gradual plaque accumulation. Cholesterol plaque may slowly build up in the carotid artery wall, over decades. The growing plaque may eventually narrow the carotid artery, known as stenosis, and can lead to a stroke.


•HCV eradication by direct antiviral agents improves carotid atherosclerosis.
•Atherosclerosis improvement is confirmed after stratification for cardiovascular risk factors.
•Atherosclerosis improvement is observed in patients with and without cirrhosis.

Background and Aim
Recent studies suggest an association between HCV infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis.

Materials and Methods
One hundred eighty-two consecutive HCV patients with advanced fibrosis or compensated cirrhosis were evaluated by virological, anthropometric and metabolic measurements. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT≥1 mm) and carotid plaques, defined as focal thickening of ≥ 1.5 mm at the level of common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy.

Fifty-six percent of patients were males, mean age was 63.1±10.4 years and 65.9% had compensated cirrhosis. One patient out of five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. Mean IMT was 0.94±0.29 mm, 42.9% had IMT≥1 mm, and 42.9% had carotid plaques. All patients achieved a 12-weeks sustained virological response. IMT significantly decreased from baseline to follow-up (0.94±0.29 mm vs. 0.81±0.27, p<0.001). Consistently, a significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs. 17%, p<0.001), while no changes were reported for carotid plaques (42.8% vs. 47.8%, p=0.34). These results were confirmed in sub-groups of patients stratified for cardiovascular risk factors and liver disease severity.

HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis without or with additional metabolic risk factors. The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term.

Lay of Summary
Hepatitis C Virus (HCV) eradication by direct antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis

The improvement in intima-media thickness and carotid thickening was confirmed after stratification for severity of liver disease and cardiovascular risk factors

HCV eradication by DAA also lead to improvement in glucose homeostasis and increase in cholesterol levels

Of Interest:
HCV eradication with DAAs improves carotid thickening
March 6, 2018
Hepatitis C eradication by direct-acting antivirals improved carotid atherosclerosis in patients with severe fibrosis regardless of the presence of additional metabolic…

Evolving Recognition of Chronic Hepatitis C Infection as a Modifiable Risk Factor for cardiovascular disease (CVD)
Increasingly, data have amassed exploring whether HCV infection acts as an independent risk factor for cardiovascular diseases. However, the results are conflicting and have led to some ambiguity.

Risk of Cardiovascular Disease (CVD) Due to Chronic Hepatitis C Infection: A Review
The current data support the assertion that CHC infection increases the risk of subclinical and likely clinical CVD, through a multifactorial cascade which may include direct and indirect immune and inflammatory effects, metabolic derangements and possibly direct cardiotropism exhibited by the HCV virus. There is an urgent need for translational research to delineate these proposed mechanisms for the apparent association between HCV and CVD. Additionally, more prospective cohort studies conducted in different patient populations are needed to confirm the findings of HCV infection and increased subclinical and clinical CVD. Furthermore, larger, well-designed therapeutic studies are critical to establish whether CHC truly increases CVD risk and to evaluate if HCV treatment can attenuate or even eliminate that increased CVD risk. The promise of large-scale HCV therapy ushered in by the highly efficacious and well tolerated DAAs has arrived, and therefore understanding the relationship between HCV and CVD and how this relationship is affected by HCV eradication with treatment has substantial public health implications.

Hepatitis C Virus Infection and Cardiovascular Disease Risk
A strong association between HCV infection and immune-related disorders, such as cryoglobulinemia, and metabolic alterations, such as insulin resistance, has been demonstrated. More recent evidence suggests HCV infection is linked to an increased risk for cardiovascular disorders. Whether a relationship between HCV infection and cardiovascular disease exists may have important implications for HCV treatment.

Infectious Disease Advisor spoke with David E. Bernstein, MD, from the Hofstra-Northwell School of Medicine, and Vincent Lo Re, MD, MSc, from the Perelman School of Medicine at the University of Pennsylvania, regarding the link between HCV infection and cardiovascular disease.
Continue reading....

Monday, March 5, 2018

Outcomes - HCV psoriatic patients using Pegylated Interferon plus Ribavirin compared to new Direct-Acting Antiviral agents

World J Hepatol. Feb 27, 2018; 10(2): 329-336
Published online Feb 27, 2018. doi: 10.4254/wjh.v10.i2.329

Outcomes assessment of hepatitis C virus-positive psoriatic patients treated using pegylated interferon in combination with ribavirin compared to new Direct-Acting Antiviral agents
Giovanni Damiani, Chiara Franchi, Paolo Pigatto, Andrea Altomare, Alessia Pacifico, Stephen Petrou, Sebastiano Leone, Maria Caterina Pace, Marco Fiore

Core tip: Psoriasis is a chronic inflammatory disease affecting approximately the 2% of population in Europe and North America. The hepatitis C virus (HCV) infection affects approximately the 3% of the world population with an estimated prevalence of 5 million people in the United States. Up to 0.06% of people in the United States suffer from both psoriasis and HCV. Psoriatic patients with HCV are excluded by randomized controlled clinical trials. Therefore, no data is currently available concerning the concomitant administration of biological disease modifying drugs and the new Direct-Acting Antiviral agents (DAAs) medications approved for the treatment of HCV infection. The aim of this study is to evaluate the outcomes in biological treatment and quality of life of psoriatic patients with HCV infection treated with DAAs compared to the previous standard therapy of Pegylated Interferon plus Ribavirin.

Full Text

To evaluate the outcomes in biological treatment and quality of life of psoriatic patients with chronic hepatitis C (CHC) treated with new Direct-Acting Antiviral agents (DAAs) compared to pegylated interferon-2α plus ribavirin (P/R) therapy.

This is a retrospective study involving psoriatic patients in biological therapy who underwent anti-hepatitis C virus (HCV) treatment at the Department of Dermatology Galeazzi Orthopaedic Institute Milan, Italy from January 2010 to November 2017. The patients were divided into two groups: patients that underwent therapy with DAAs and patients that underwent HCV treatment with P/R. Patients were assessed by a dermatologist for psoriasis symptoms, collecting Psoriasis Area Severity Index (PASI) scores and the Dermatology Quality of Life Index (DLQI). PASI and DLQI scores were evaluated 24 wk after the end of HCV treatment and were assumed as an outcome of the progression of psoriasis. Switching to a different bDMARD was considered as an inadequate response to biological therapy. The dropout of HCV therapy and sustained virological response (SVR) were considered as outcomes of HCV therapy.

Fifty-nine psoriatic patients in biological therapy underwent antiviral therapy for CHC. Of this, 27 patients were treated with DAAs and 32 with P/R. After 24 wk post treatment, the DLQI and the PASI scores were significantly lower (P < 0.001 and P < 0.005, respectively) in the DAAs group compared with P/R group. None of the patients in the DAAs group (0/27) compared to 8 patients of the P/R group (8/32) needed a shift in biological treatment.

DAAs seem to be more effective and safe than P/R in HCV-positive psoriatic patients on biological treatment. Fewer dermatological adverse events may be due to interferon-free therapy.

Full Text :

Friday, March 2, 2018

Monday, February 12, 2018

Is global elimination of HCV realistic?

Liver International 
Is global elimination of HCV realistic?
Vincenza Calvaruso, Salvatore Petta, Craxì A
DOI: 10.1111/liv.13668

First published: 10 February 2018


The elimination of hepatitis C virus (HCV) has been made possible through the availability of new antiviral drugs which may now be administered to all patients with HCV infection, even those with decompensated cirrhosis. The goal of the World Health Organization (WHO) is to reduce the incidence of chronic hepatitis infection from the current 6-10 million to 0.9 million cases of chronic infections by 2030, and annual deaths from 1.4 million to fewer than 0.5 million. Achieving these targets will require full implementation of epidemiological knowledge of HCV infection, screening and testing practices and strategies to link HCV patients to care. This review will focus on the current state of knowledge in the epidemiology of HCV and what can be done to increase patient awareness and reduce the barriers to treatment. Furthermore, we will discuss the role of HCV clearance on the control of HCV-related outcomes

Monday, February 5, 2018

Managing the Fruits of HCV Cure: How Much Care do the Cured Need?

In case you missed it

The following article appeared in the January/February print edition of HCV NEXT, provided online at Healio

Managing the Fruits of HCV Cure: How Much Care do the Cured Need?

The feature by Eric Lawitz, MD, very nicely encapsulates the revolutionary changes occurring within hepatitis C therapy over the past few years. As he explains, this extraordinary newfound ability to cure almost all patients with chronic HCV raises many questions about clinical outcomes.

We’ve felt strongly for years that it was unjust to deny therapy to patients who didn’t have “sufficiently advanced scarring of the liver to warrant treatment” — a cost-based position that was anathema to most clinicians and patients. Today, there’s a wealth of literature showing fibrosis progression stabilizes or reverses after achieving SVR. Even patients with cirrhosis may have regression of cirrhosis after SVR. But an additional dimension of HCV infection about which our knowledge has dramatically expanded is the potential for extrahepatic morbidity and mortality associated with HCV infection, and the opportunity to ameliorate or prevent such outcomes by effecting virologic cure — problems such as diabetes, atherosclerosis, renal disease, cryoglobulinemia, lymphoma and others.

Monday, January 29, 2018

Impact of hepatitis C virus infection on long-term mortality after acute myocardial infarction

BMJ Open. 2018 Jan 26;8(1):e017412. doi: 10.1136/bmjopen-2017-017412.

Impact of hepatitis C virus infection on long-term mortality after acute myocardial infarction: a nationwide population-based, propensity-matched cohort study in Taiwan.
Kuo SH1, Hung WT1, Tang PL1, Huang WC1,2,3, Yang JS2, Lin HC1, Mar GY1, Chang HT1, Liu CP1,3.

Myocardial infarction , commonly known as a heart attack, occurs when blood flow decreases or stops to a part of the heart, causing damage to the heart muscle. 

The influence of hepatitis C virus (HCV) infection on long-term outcomes of patients with acute myocardial infarction (AMI) is unclear. Therefore, this study aimed to analyse the impact of HCV infection on 12-year mortality rates after AMI using data from the Taiwan National Health Insurance Research Database (NHIRD).

NHIRD data for approximately 23 000 000 patients between January 2000 and December 2012 were analysed. A total of 186 112 cases of first AMI admission were identified. A total of 4659 patients with HCV infection not receiving interferon therapy were enrolled and divided into those with (n=107) or without (n=4552) cirrhosis. Using one-to-one matching, 4552 matched controls were included in the final analysis.

The 12-year mortality rate was significantly higher in patients with AMI with HCV infection and cirrhosis than in those with HCV infection but without cirrhosis (P<0.0001) or controls (P<0.0001). Patients with HCV infection but without cirrhosis had significantly higher long-term mortality rates than the matched controls (P<0.0001). The HR for mortality was higher in patients with HCV infection (HR 1.12; 95% CI 1.06 to 1.18). HCV influenced outcomes among the subgroups of patients who were male (HR 1.15) and those who had hypertension (HR 1.14).

HCV infection influenced the 12-year mortality rates of patients with AMI, especially those who were male and those who had hypertension. Cirrhosis further increased the long-term mortality rates of patients with AMI with HCV infection.

View full text article online:

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Wednesday, January 24, 2018

Treating Insulin Resistance in Hepatitis C-Infected Patients With Diabetes

Treating Insulin Resistance in Hepatitis C-Infected Patients With Diabetes
Elizabeth Kukielka, PharmD
Publish Date: Wednesday, January 24, 2018
Both insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are more prevalent in patients with chronic hepatitis C virus (HCV) infection compared with the general population. 
As this is one of the first studies to demonstrate the benefit of treating HCV-positive patients who also have IR with both standard HCV therapy and metformin to achieve SVR, more studies are needed to confirm the results and help determine a standard regimen for patients with HCV and IR, researchers noted.

Full Text

Thursday, January 18, 2018

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


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

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

Linked Content
This article is linked to Younossi et al and Younossi papers. To view these articles visit and

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

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

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

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

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

Linked Content
This article is linked to Younossi et al and Sanagapalli and Danta papers. To view these articles visit and

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

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

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

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

Friday, December 29, 2017

Direct medical costs associated with the extrahepatic manifestations of Hep C

In Case You Missed It

Direct medical costs associated with the extrahepatic manifestations of Hep C
January's issue of the Alimentary Pharmacology & Therapeutics examines the direct medical costs associated with the extrahepatic manifestations of hepatitis C virus infection.

Volume 47, Issue 1
January 2018
Pages 123–128

The economic impact of extrahepatic manifestations of hepatitis C virus (HCV) infection remains unknown for France. Dr Cacoub and colleagues from France estimated the prevalence of extrahepatic manifestations of HCV and the direct medical costs associated with them.

Estimates of 13 extrahepatic manifestations prevalence were obtained from a retrospective data analysis of HCV-infected patients in a specialized center, and the baseline prevalence in the general French population, and an international systematic review.

The impact of achieving HCV cure after anti-viral therapy was applied to the French healthcare costs. Using the first approach, the team found increased prevalence rates in HCV patients compared to the general population were observed for most extrahepatic manifestations.

The researchers observed that the mean per-patient-per-year cost of these manifestations in the tertiary centre was 3296 €. In France, HCV-extrahepatic manifestations amounted to a total cost of 215 million € per year.

Using a systematic review, the team found that the mean per-patient-per-year cost was estimated to be 1117 €. The estimated total cost reduction in France associated with HCV cure was 13.9 million € for diabetes, 8.6 million € for cryoglobulinemia vasculitis, 6.7 million € for myocardial infarction, 2.4 million € for end-stage renal disease and 1.4 million € for stroke.

Dr Cacoub's team concludes, "Extrahepatic manifestations of HCV infection substantially add to the overall economic burden of the disease in France." "HCV cure after anti-viral therapy is expected to significantly reduce the total costs of managing these manifestations in France."
Aliment Pharmacol Ther 2017: 47(1): 123–128
22 December 2017

Direct medical costs associated with the extrahepatic manifestations of hepatitis C virus infection in France
P. Cacoub, M. Vautier, A. C. Desbois, D. Saadoun, Z. Younossi
First published: 18 October 2017

Patients chronically infected by the hepatitis C virus (HCV) are at risk of developing major liver complications.[1] Up to two-thirds of HCV-infected patients also experienced extrahepatic manifestations that include HCV-related autoimmune and/or lymphoproliferative disorders, and cardiovascular, renal, metabolic and central nervous system diseases.[2-7] The link between extrahepatic manifestations and HCV infection has been demonstrated for many years for lymphoproliferative disorders (mixed cryoglobulinemia, lymphoma), whereas it became more recently evident for cardiovascular, renal and metabolic diseases.[4, 5] Nevertheless, HCV infection showed higher morbidity and mortality rates for extra-hepatic complications, while viral eradication reduced the rate of extra-hepatic complications and deaths.[3, 5]

New oral, interferon-free direct-acting anti-virals (DAA) offer opportunities to cure most patients.[1] Sofosbuvir plus ledipasvir has been shown to improve patient-reported outcomes after achieving sustained virological response (SVR).[8-10] As new all-oral interferon-free DAA regimens for HCV are approved, their effectiveness in a real-world setting and their economic impact on health systems and society require further assessment. Previous analyses have typically focused on the hepatic complications of HCV infection and have not considered the burden of extra-hepatic manifestations.[8, 11] There is a need to accurately characterise the burden of extrahepatic manifestations in HCV-infected patients, and the impact of achieving a SVR on the costs of managing these manifestations outside the United States.[12] The objective of this study was to estimate the annual direct medical costs associated with the extrahepatic manifestations of HCV infection in France.

Recommended Reading
Extrahepatic manifestations of HCV & Treatment

On This Blog
A collection of current research articles on ailments related to HCV
Categorized article directory on the extrahepatic manifestations of hepatitis C.

Tuesday, December 12, 2017

Impact of HCV eradication on insulin resistance (IR), and the control of type 2 diabetes.

What We Know
Achieving Sustained Virologic Response (SVR) in patients treated with direct-acting antivirals (DAAs) is associated with the reversal of fibrosis, reduces the risk of liver transplant, liver cancer, and risk of other complications of chronic liver disease, including extrahepatic manifestations of HCV. The hepatitis C virus is associated with various extrahepatic manifesations, some of these include systemic manifestations such as thyroid disease, cardiovascular disease, renal disease, eye disease (sicca syndrome), skin disease (PCT, vasculitis, and lichen planus), lymphomas, and type II diabetes mellitus. As for the latter, previous research has demonstrated a significant association between hepatitis C - type 2 diabetes - and insulin resistance.

The Stats
According to The World Health Organization (WHO) people infected with HCV are at risk for liver related complications, worldwide around 399 000 people die each year from hepatitis C, mostly from cirrhosis and hepatocellular carcinoma.

Extrahepatic Consequences of HCV
However, because these estimates do not included extrahepatic consequences of HCV infection the risks of morbidity and mortality are underestimated, according to a systematic review investigating the relationship between HCV infection and glucose abnormalities; Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review, published in World J Gastroenterol.

New In The Journals
Learn more about the impact of HCV eradication on insulin resistance (IR), and the control of type 2 diabetes by viewing this collection of recent articles.

Journal of Medical Virology
Volume 90, Issue 2 February 2018 Pages 320–327
Authors Alessia Ciancio, Roberta Bosio, Simona Bo, Marianna Pellegrini, Marco Sacco, Edoardo Vogliotti, Giulia Fassio, Andrea G. F. Bianco Mauthe Degerfeld, Monica Gallo, Chiara Giordanino, Lodovico Terzi di Bergamo, Davide Ribaldone, Elisabetta Bugianesi, Antonina Smedile, Mario Rizzetto, Giorgio Maria Saracco
First published: 14 November 2017
Full publication history DOI: 10.1002/jmv.24954
Many studies showed insulin resistance amelioration in HCV-patients achieving Sustained Virologic Response (SVR) but results on glycemic control in diabetic patients are unclear. This study aimed to assess fasting glucose (FG) and glycated hemoglobin (HbA1c) values before and after therapy with direct-acting antivirals (DAAs) in HCV-patients with type 2 diabetes mellitus (T2DM). Of the 122 consecutively recruited patients with chronic hepatitis C and T2DM, 110 patients were treated with DAAs and 12 remained untreated. Clinical, biochemical, virological, and metabolic features were collected both at baseline and at 12 weeks after the end of therapy (EOT) or after a comparable period of time in untreated patients. A total of 101 patients obtained a SVR (Group 1), while nine were relapsers. Group 2 (21 patients) was composed by the nine relapsers and the 12 untreated patients. A significant reduction of mean FG (134.3 ± 41.32 mg/dL vs 152.4 ± 56.40 mg/dL, P = 0.002) and HbA1c values (46.51 ± 16.15 mmoL/moL vs 52.15 ± 15.43 mmoL/moL, P <  0.001) was found in Group 1 but not in Group 2 (140.6 ± 47.87 mg/dL vs. 145.31 ± 30.18 mg/dL, P = 0.707, and 55.31 ± 20.58 mmoL/moL vs. 53.38 ± 9.49 mmoL/moL, P = 0.780). In Group 1, 20.7% of patients could reduce or suspend their antidiabetic therapy compared to none in Group 2 (P = 0.03), despite the significant weight increase observed in Group 1. SVR induced a significant amelioration of glycemic control in diabetic HCV-patients, despite a significant weight increase; larger prospective studies are needed to verify whether these results are maintained over the long-term.
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Journal of Gastroenterology and Hepatology
Luigi E Adinolfi,Riccardo Nevola,Barbara Guerrera,Giovanni D’Alterio,Aldo Marrone,Mauro Giordano, Luca Rinaldi
Accepted manuscript online: 11 December 2017
DOI: 10.1111/jgh.14067
Abstract Background and Aim
Chronic hepatitis C (HCV), particularly genotype 1, is associated with insulin resistance (IR) and diabetes. We evaluated the impact of HCV clearance by all-oral direct-acting antiviral (DAAs) treatments on IR and glycemic control.

Included in this prospective case-control study were 133 consecutive HCV-genotype 1 patients with advance liver fibrosis (F3-F4) without type 2 diabetes. Sixty-eight treated with DAAs and 65 untreated. Liver fibrosis was assessed by transient elastography. Pre-, end- and 3 months post-treatment withdrawal IR homeostasis was assessed by HOMA-IR, QUICKI and HOMA-B.

At baseline, treated and untreated patients showed similar liver fibrosis levels, HOMA-IR was 4.90±4.62 and 4.64±5.62, respectively. HOMA-IR correlated with HCV RNA levels. At the end of treatment, all patients cleared HCV RNA, regardless of liver fibrosis and BMI, a reduction in HOMA-IR at 2.42±1.85 was showed (p<0.001), in addition, increased insulin sensitivity, decreased insulin secretion, reduction of serum glucose and insulin levels were observed. Data were confirmed 3 months after treatment withdrawal in the 65 patients who cleared HCV. No variation occurred in untreated patients. Overall, 76.5% of SVR patients showed IR improvements, of which 41.2% normalized IR. Improvement of IR was strict associated with HCV clearance, however, patients with the highest levels of fibrosis remain associated with some degree of IR.

The data underline a role of HCV in development of IR and that viral eradication reverses IR and improves glycemic control and this could prevent IR-related clinical manifestations and complications.
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Diabetes Care
Diabetes Care 2017 Sep - Justine Hum,1 Janice H. Jou,1 Pamela K. Green,2 Kristin Berry,2 James Lundblad,3 Barbara D. Hettinger,3 Michael Chang,1 and George N. Ioannou2,4 1Division of Gastroenterology, Portland Veterans Affairs Medical Center, Portland, OR 2Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, WA 3Division of Endocrinology, Portland Veterans Affairs Medical Center, Portland, OR 4Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, WA

Hepatitis C virus (HCV) infection is associated with diabetes and may worsen glycemic control in patients with diabetes. We aimed to investigate whether eradication of HCV infection with direct-acting antiviral (DAA) agents is associated with improved glycemic control in patients with diabetes.

In summary, glycemic control improves in patients with diabetes after DAA-induced SVR. Patients not only have an improvement in HbA1c level after achieving SVR, they are also less likely to require insulin. These endocrine benefits of SVR provide additional justification for considering antiviral treatment in all patients with diabetes. ....hepatitis C virus (HCV) infection is associated with a higher prevalence of type 2 diabetes mellitus (T2DM) . In addition, HCV proteins increase the release of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, which then upregulate gluconeogenesis and enhance lipid accumulation in the liver

Future studies are needed to confirm our findings, to determine how durable the SVR-induced improvement in glycemic control is over time, and to assess the long-term effect on complications of diabetes such as nephropathy, neuropathy, and cardiovascular disease.
View Full Text Article: Available at NATAP

Medpage Today
Commentary: Improvement in Glycemic Control of Type 2 Diabetes After Successful Treatment of Hepatitis C Virus
Researchers at the VA health system—the largest provider of integrated hepatitis C care in the country—recently tested the role of viral eradication on the control of type 2 diabetes
By Kristin Bundy
Researchers at the VA health system—the largest provider of integrated hepatitis C care in the country—recently tested the role of viral eradication on the control of type 2 diabetes (T2D). Previous data demonstrated that the risk of developing T2D is about 4 times higher in people infected with the hepatitis C virus (HCV) than those without. Investigators wanted to know: Could HCV suppression lead to better control of T2D?
Continue reading: Available at Medpage Today

Nature - Scientific Reports
Yun Soo Hong, Yoosoo Chang, Seungho Ryu, Miguel Cainzos-Achirica, Min-Jung Kwon, Yiyi Zhang, Yuni Choi, Jiin Ahn, Sanjay Rampal, Di Zhao, Roberto Pastor-Barriuso, Mariana Lazo, Hocheol Shin, Juhee Cho & Eliseo Guallar
Published online:04 2017
In conclusion, in this large study of men and women at low risk of diabetes, we found that serologic evidence of HBV and HCV infection was associated with the prevalence of diabetes. In addition, HBV infection was associated with the risk of incident diabetes in prospective analyses, but we could not reliably evaluate the prospective association between HCV infection and diabetes due to the small number of infected participants. Our studies add to the growing body of evidence suggesting that diabetes is an additional metabolic complication of HBV and HCV infection.

On This Blog

Sunday, November 26, 2017

Hepatitis C - Impact of SVR on cognitive performance

BMC Gastroenterology
Hepatitis C virus eradication improves immediate and delayed episodic memory in patients treated with interferon and ribavirin
Mary Ellen Dias Barbosa, Ana Luiza Zaninotto, Daniel Ferraz de Campos Mazo, Mario Guimarães Pessoa, Cláudia Pinto Marques Souza de Oliveira, Flair José Carrilho and Alberto Queiroz Farias
Received: 26 June 2017 Accepted: 15 November 2017 Published: 25 November 2017

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Chronic hepatitis C virus (HCV) infection is associated with impairment of cognitive function and mood disorders. Our aim was to evaluate the impact of sustained virological response (SVR) on cognitive function and mood disorders.

A prospective exploratory one arm study was conducted. Adult clinically compensated HVC patients were consecutively recruited before treatment with interferon and ribavirin for 24 to 48 weeks, according to HCV genotype. Clinical, neurocognitive and mood assessments using the PRIME-MD and BDI instruments were performed at baseline, right after half of the expected treatment has been reached and 6 months after the end of antiviral treatment. Exclusion criteria were the use of illicit psychotropic substances, mental confusion, hepatic encephalopathy, hepatocellular carcinoma, severe anemia, untreated hypothyroidism, Addison syndrome and major depression before treatment.


Thirty six patients were enrolled and 21 completed HCV treatment (n = 16 with SVR and n = 5 without). Regardless of the viral clearance at the end of treatment, there was a significant improvement in the immediate verbal episodic memory (p = 0.010), delayed verbal episodic memory (p = 0.007), selective attention (p < 0.001) and phonemic fluency (p = 0.043). Patients with SVR displayed significant improvement in immediate (p = 0.045) and delayed verbal episodic memory (p = 0.040) compared to baseline. The baseline frequency of depression was 9.5%, which rose to 52.4% during treatment, and returned to 9.5% 6 months after the end of treatment, without significant difference between patients with and without SVR. Depressive symptoms were observed in 19.1% before treatment, 62% during (p = 0.016) and 28.6% 6 months after the end of treatment (p = 0.719).

Eradication of HCV infection improved cognitive performance but did not affect the frequency of depressive symptoms at least in the short range.

Cognition Memory Attention Neuropsychology Hepatitis C Depression

Friday, November 17, 2017

Efficacy/prognosis of antiviral therapy on hepatitis C following treatment of lymphoma in HCV-positive diffuse large-cell lymphoma

Annals of HematologyDecember 2017, Volume 96, Issue 12, pp 2057–2061 |

Efficacy and prognosis of antiviral therapy on hepatitis C following treatment of lymphoma in HCV-positive diffuse large-cell lymphoma
Yutaka Tsutsumi, Chie Nakayama, Koki Kamada, Ryo Kikuchi, Daiki Kudo, Shinichi Ito, Satomi Matsuoka, Souichi Shiratori, Yoshiya Yamamoto, Hirohito Naruse, Takanori Teshima

Full Text

It was recently reported that performing antiviral therapy against HCV in the treatment of HCV-positive lymphoma has had positive effects including improvement of the lymphoma, and that antiviral therapy including interferon against low-grade lymphoma may be able to improve the prognosis when performed following chemotherapy for low-grade lymphoma [9, 10]. In our report, since HCV is often stained in tissue samples, and since cases where there is a drop in HCV viral RNA are less likely to recur [7], it is suggested that HCV is directly or indirectly associated with the occurrence and progression of lymphoma. However, the main causes of the transition to lymphoma are still unclear. Furthermore, it has been reported that improvements can be obtained with antiviral therapy alone (e.g., in cases of splenic marginal zone lymphoma), and it is expected that the use of antiviral therapy against HCV-positive lymphoma yields an improved prognosis [11, 12, 13].

On the other hand, studies of whether treatment of HCV with antiviral drugs after treatment for diffuse large-cell lymphoma contributes to the prognosis are being conducted either retrospectively or through a combination of retrospective and prospective methods [14, 15]. It has been reported that the 5-year OS and PFS can both be improved [14, 15]. Also, a report by Michot et al. pointed out the possibility of including cases where diffuse large B cell lymphoma is thought to have transformed from splenic marginal zone lymphoma [14], but in this case, cases that have transformed from splenic marginal zone lymphoma are not included. In Europe and the USA, there are many cases where splenic marginal zone lymphoma is associated with HCV. These cases are highly responsive to HCV antiviral therapy, suggesting the possibility of an improved prognosis. On the other hand, in a report by Michot et al., there were cases in which SVR could not be obtained in the antiviral therapy group, while in a report by Hosry et al., there were many cirrhosis cases among the analysis subjects, and it is thought that these factors may have acted on OS and PFS in a negative direction [14, 15]. In our analysis, genotype 2 was more common in the DAA group, while genotype 1 was more common in the control 1 group, and the difference in genotype may also have affected the outcome of treatment. It is thought that this affected the OS and PFS analysis of this report and earlier reports [14, 15].

Since DAA was used after obtaining confirmation of chronic HCV-positive hepatitis by liver biopsy in the cases analyzed here, DAA therapy was performed about 6 weeks after treatment with anticancer drugs. However, there are no clear guidelines on the appropriate timing for DAA treatment, such as whether antiviral therapy should be performed after or during lymphoma treatment, or before anticancer treatment of the lymphoma. A recent report investigated the interactions of DAA administered simultaneously with various anticancer drugs in cancer cases complicated by HCV infection. In this report, although blood toxicity and gastrointestinal toxicity were found, the change brought about by DAA therapy was only 10%, and the SVR was also 95%, and it was reported that it may be possible to use DAA therapy simultaneously with anticancer treatment [16, 17]. On the other hand, in this analysis, there were no problems arising from the continued use of DAA therapy, or complications requiring a change of medication regime, but this could be because there were no cases where DAA therapy was performed at the same time as the anticancer treatment.

In this study, we are conducting a prospective examination of five cases, and so far, 2 years has elapsed since the start of treatment, but in all five cases, the patients have survived without any recurrence, and it seems that following chemotherapy with antiviral therapy may contribute to the prognosis in cases of HCV-positive diffuse large-cell lymphoma. Furthermore, although analysis has only been performed in a few cases, it seems that HCV-RNA-positive cases may have a poorer prognosis than non-HCV-infected diffuse large-cell lymphoma cases, and although there are signs that the prognosis is improved for DAA treatment cases, it may be recommended that DAA treatment is performed after remission in HCV-RNA-positive diffuse large-cell lymphoma. However, since we have only examined a few cases for a short period of time, we are hopeful that the usefulness of antiHCV therapy will be demonstrated more clearly by a prospective study involving a larger number of people.

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.

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.

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.

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