Hepatitis C - Impact of treatment with direct-acting antivirals on anxiety and depression

Impact of treatment with direct-acting antivirals on anxiety and depression in chronic hepatitis C 
Marta Gallach , Mercedes Vergara, Joao Pedro da Costa, Mireia Miquel, Meritxell Casas, Jordi Sanchez-Delgado, Blai Dalmau, Núria Rudi, Isabel Parra, Teresa Monllor, Meritxell Sanchez-Lloansí, Angelina Dosal, Oliver Valero, Xavier Calvet
Published: December 19, 2018 https://doi.org/10.1371/journal.pone.0208112

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Abstract
Background and aim
Treatment of hepatitis C with direct-acting antiviral agents (DAA) has few side effects. Although pivotal studies suggested that DAA were safe in patients with psychiatric diseases who could not be treated with previous antiviral therapies, their effects on anxiety and depression have not yet been analysed in clinical practice. The aim of our study was to analyse anxiety and depression in the setting of DAA treatment in a clinical practice series.

Methods
All patients starting DAA treatment between November 1, 2014 and October 31, 2015 were eligible. Patients completed the Hospital Anxiety and Depression scale at different times during treatment. The results were plotted on line graphs and evaluated using a linear regression model with repeated measures.

Results
One hundred and forty-five patients were included (11% with major psychiatric disorders; 32% on psychiatric treatment). Sustained virologic response (SVR) was achieved in 97.3% of cases. Anxiety and depression measures did not differ between time points. No differences between patients on psychiatric treatment or with advanced fibrosis or cirrhosis were found at any time point analysed.

Conclusion
DAA treatment had no impact on anxiety or depression during or after chronic hepatitis C infection treatment, even in high-risk patients with major psychiatric disorders.
Read More: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208112

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
https://doi.org/10.1186/s12876-017-0679-5
Received: 26 June 2017 Accepted: 15 November 2017 Published: 25 November 2017

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Abstract

Background
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.

Method
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.

Results
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).

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

Continue to full text article: https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-017-0679-5

Keywords
Cognition Memory Attention Neuropsychology Hepatitis C Depression

Editorial: Health-Related Quality of Life in Chronic Hepatitis C

View Original Journal Article - Health-Related Quality of Life in Portuguese Patients with Chronic Hepatitis C, editorial provided below.

GE Port J Gastroenterol 2017;24:55-57

https://doi.org/10.1159/000453319

Editorial
Health-Related Quality of Life in Chronic Hepatitis C
Cardoso H. · Silva M.                       

Hepatitis C virus (HCV) infection is one of the main causes of liver disease and has a great impact on patient outcomes. The estimate of chronically infected persons is about 160 million worldwide, but most of them are unaware of the disease. The clinical impact of HCV infection is highly variable, from minimal changes to cirrhosis and hepatocellular carcinoma, with or without extrahepatic manifestations. Nevertheless, the outcome of HCV infection is not restricted to the clinical endpoints, as it can affect multiple health and psychosocial dimensions.

In recent years, HCV infection has become increasingly noticeable for different reasons. On the one hand, the development of highly effective antiviral therapy has enabled the actual treatment and cure of most diagnosed patients, but on the other hand, the burden from the most severe complications, such as hepatocellular carcinoma, keeps increasing [1,2].

A comprehensive assessment of overall outcomes would include, besides clinical hepatic and extrahepatic manifestations, patient-reported outcomes (PRO) and economic consequences. A PRO is any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else. It reflects patient experience using surrogate markers such as health-related quality of life (HRQoL), functional status, perceived stigma, and work productivity [3,4]. In this context, the study by Rei et al. [5] addresses an important topic and contributes to improve the scarce available Portuguese data. The main self-administered instruments used were the SF-12 (generic) and CLDQ (disease-specific) HRQoL questionnaires.

The first studies on the effects of HCV infection on patients' quality of life, using the short form SF-36 Health Survey, revealed that patients were polysymptomatic and had diminished quality of life with significant reductions in all domains. The reduction in quality of life could not be attributed to the degree of liver inflammation or to the mode of acquisition of the infection. Hence, the authors conclude that chronic HCV infection gives rise to physical symptoms that reduce the quality of life of infected patients [6]. Also, studies with matched controls demonstrated that work productivity is significantly impaired [7]. Regarding cognitive performance, a meta-analysis of studies in HIV-infected patients demonstrated a higher level of cognitive impairment associated with HCV infection [8].

One of the most frequent extrahepatic manifestations is depression. A review of neuropsychiatric symptoms commonly associated with HCV infection showed that major depression was related to illness perception, functional disability, impaired quality of life, fatigue severity, and the presence of psychiatric comorbidity [9]. Likewise, in the study of Rei et al. [5], there was a high prevalence of mood disorders (namely depression) with a negative impact on HRQoL, and the authors therefore recommend screening and suitable psychosocial interventions in a multidisciplinary setting.

Regarding the impact of antiviral therapy on PRO, there were several concerns regarding interferon-based regimens, which negatively affected quality of life during treatment [4,10,11]. Recent studies with antiviral regimens without interferon or ribavirin demonstrated an improvement of quality of life during treatment coinciding with viral suppression within the first month of therapy [12]. Also, Rei et al. [5] reported that oral antiviral treatment could be correlated with HRQoL increases in some domains, which provides growing evidence for the multiple benefits of appropriate HCV treatment.

The achievement of a sustained virological response is associated with an improvement of clinical outcomes, namely a reduction of all-cause mortality [13]. The impact on PRO following successful HCV therapy is also significant; several studies with paired HRQoL assessments demonstrated an overall improvement of all domains of SF-36. Viral eradication leads to HRQoL improvement, regardless of fibrosis stage. HCV patients with early fibrosis experience similar improvement of PRO as those with advanced fibrosis [12,14,15]. Curiously, the HRQoL improvement was progressive over time after the end of treatment, with scores after 24 weeks greater than at 12 weeks [15]. It might be interesting to study what will be the time frame for an extensive recovery of HRQoL after sustained virological response, in relation to healthy controls. Another issue that would benefit from research is the extent of recovery of other PRO, such as perceived stigma and work productivity.

In this era of widespread HCV antiviral therapy, it is important to recognize the comprehensive burden of this disease as well as the value of achieving HCV cure, which translates into benefits at different levels for the patient and society.
https://www.karger.com/Article/FullText/453319

Extrahepatic manifestations of HCV & Treatment

Found On This Blog
A collection of research articles on ailments related to HCV

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July 14, 2017

Extrahepatic manifestations of HCV: The role of direct acting antivirals

María Laura Polo and *Natalia Laufer
Expert Review of Anti-infective Therapy DOI: 10.1080/14787210.2017.1354697

Introduction:

Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations.

This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions.  Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.
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Clinics in Liver Disease, Volume 21, Issue 3

Chronic Hepatitis C Virus Infection and Depression
Luigi Elio Adinolfi, Riccardo Nevola, Luca Rinaldi, Ciro Romano, Mauro Giordano

KEYWORDS
HCV Depression Quality of life

KEY POINTS
Depression is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection reported in one-third of patients.

The prevalence of depression in patients with HCV has been estimated to be 1.5 to 4.0 times higher than that observed in the general population.

Direct HCV neuro-invasion, induction of local and systemic inflammation, neurotransmission, and metabolic derangements are the hypothesized pathogenic mechanisms of depression.

Depression considerably impacts health-related quality of life of HCV-positive patients.

Clearance of HCV by antiviral treatments is associated with an improvement of both depression and quality of life.
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Metabolic Manifestations of Hepatitis C Virus
Lawrence Serfaty

KEYWORDS
Hepatitis C Steatosis Hypobetalipoproteinemia Microsomal triglyceride transfer protein Insulin resistance. Tumor necrosis factor

KEY POINTS
Out of excessive alcohol consumption, steatosis should be classified into 2 types according to hepatitis C virus (HCV) genotypes: metabolic steatosis, which is associated with features of metabolic syndrome and insulin resistance in patients infected with nongenotype 3, and viral steatosis, which is correlated with viral load and hyperlipemia in patients infected with genotype 3.

HCV interacts with host lipid metabolism by several mechanisms, such as promotion of lipogenesis, reduction of fatty acid oxidation, and decreases of lipids export, leading to hepatic steatosis and hypolipidemia.

A strong link between HCV infection and diabetes mellitus has been found in subjectbased studies and, to a lesser degree, in population-based studies.

HCV-mediated insulin resistance may be promoted through multiple pathogenic mechanisms, such as direct inhibition of insulin signaling pathway by HCV core protein in the liver, overproduction of tumor necrosis factor-alpha, oxidative stress, modulation of incretins, or pancreatic ß-cells dysfunction.
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Neurologic manifestations of hepatitis C virus infection
Sentia Iriana, MD, Michael P. Curry, MD, Nezam H. Afdhal, MD, DSc

KEYWORDS
Hepatitis C Fatigue Neurocognition MR spectroscopy Interferon Ledipasvir/sofosbuvir Cerebrovascular disease

KEY POINTS
The extrahepatic manifestations of hepatitis C virus (HCV) in the brain include neurocognitive dysfunction, which is manifested by subtle changes in memory, attention, and processing speed.

Neurocognitive defects are independent of the histologic stage of disease and may be induced by a direct effect of HCV on microglial cells or mediated by systemic cytokines crossing the blood-brain barrier.

Magnetic resonance spectroscopy demonstrates abnormal metabolism in basal ganglia and prefrontal and frontal cortex, which has been associated with fatigue and abnormal neurocognitive testing. Interferon and direct-acting antiviral therapy can improve cerebral metabolism and neurocognition if a sustained virologic response is obtained.

Cerebrovascular events and mortality are increased in patients with HCV and may be through an increased risk of carotid artery disease and plaque formation.
Link - Full Text PDF Article
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Rheumatologic manifestations of hepatitis C virus

Patrice Cacoub, Cloé Comarmond, Anne Claire Desbois, David Saadoun

KEYWORDS
Hepatitis C (HCV) Rheumatic disorders Arthritis Vasculitis Arthralgia Sicca syndrome

KEY POINTS
Main rheumatologic manifestations reported with hepatitis C virus (HCV) chronic infection include arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome.

Immunologic factors predisposing to developsuch manifestations include stimulation of B cells, expansion of B-cell–producing immunoglobulin M with rheumatoid factor activity and of clonal marginal zone, like B cells, and a decrease of regulatory T cells.

The treatment of HCV infection with interferon alpha has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders.

New oral interferon-free combinations now offer an opportunity for patients with HCV extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a high efficacy rate and a low risk of side effects.

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Other EHM of HCV infection (pulmonary, idiopathic thrombocytopenic purpura, nondiabetes endocrine disorders

Daniel Segna, Jean-François DuFour

KEYWORDS
Hepatitis C Extrahepatic manifestations Pulmonary Endocrine Idiopathic thrombocytopenic purpura

KEY POINTS
Hepatitis C Virus (HCV) infection may increase the risk for obstructive, interstitial, and vascular lung disease, lung cancer, and mortality in HCV-infected lung transplant recipients.

HCV infection may increase the risk of idiopathic thrombocytopenic purpura, nonresponse to corticosteroids during the treatment, and higher rates of splenectomy.

HCV infection may increase the risk of autoimmune thyroiditis, infertility, growth hormone and adrenal deficiency, osteoporosis, and low-trauma fractures.

Targeted prospective cohorts may confirm these results mostly obtained from small casecontrol studies with different study populations and low level of evidence.

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Hepatitis C Virus–Associated Non-Hodgkin Lymphomas
Gabriele Pozzato, Cesare Mazzaro, Valter Gattei

KEYWORDS
Hepatitis C virus Marginal zone lymphoma Non-Hodgkin lymphoma Direct antiviral agents

KEY POINTS
Eradication of hepatitis C virus (HCV) in indolent non-Hodgkin lymphomas (NHLs), especially in marginal zone lymphomas(MZLs), determines the regression of the hematological disorder in a significant fraction of cases.

Because direct antiviral agents (DAAs) show an excellent profile in terms of efficacy, safety, and rapid onset of action, these drugs can be used in any clinical situation and the presence of any comorbidities.

To avoid the progression of the NHL, despite HCV eradication, antiviral therapy should be provided as soon as the viral infection is discovered; before that, the chronic antigenic stimulation determines the irreversible proliferation of neoplastic B cells.
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Dermatologic manifestations of chronic hepatitis C
Mehmet Sayiner, Pegah Golabi, Freba Farhat, Zobair M. Younossi

KEYWORDS
Hepatitis C Extrahepatic manifestation Dermatologic manifestation Cryoglobulinemia Porphyria Lichen planus

KEY POINTS
HCV infection is associated with several dermatologic diseases, such as symptomatic mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda, and necrolytic acral erythema.

Most of the dermatologic manifestations may be caused by immune complexes. In the interferon and ribavirin era, treatment was associated with dermatologic side effects.

The new generation of interferon-free and ribavirin-free anti-HCV regimens is devoid of dermatologic side effects.
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Hepatitis C Infection - A systematic disease
Zobair M. Younossi
KEYWORDS
Hepatitis C virus Hepatic complications Extrahepatic complications

KEY POINTS
It is critical to recognize that hepatitis C virus (HCV) infection is a multifaceted systemic disease with both hepatic and extrahepatic complications.

The comprehensive burden of HCV should not only include its clinical burden, but also its burden on the economic and patient-reported outcomes.

It is only through this comprehensive approach to HCV infection that we can fully appreciate its true burden, and understand the full benefit of curing HCV for the patient and the society.
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Thank you Henry E. Chang

Inflammation markers could guide depression treatments

Inflammation markers could guide depression treatments
Inflammation connected to elevated glutamate in brain

Psychiatrists investigating depression have been energized in recent years by reports of rapid, successful treatment with drugs that interfere with the brain chemical glutamate, such as the anesthetic ketamine.

New research from Emory University School of Medicine is providing hints as to which forms of depression may respond best to drugs that target glutamate.

The findings are scheduled for publication online on January 12 in Molecular Psychiatry.

Depressed patients with signs of systemic inflammation have elevated levels of glutamate in regions of the brain that are important for motivation, the researchers have found.

"Our results suggest that inflammation markers can guide us to which depressed patients respond best to glutamate blockers," says lead author Ebrahim Haroon, MD, assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine and Winship Cancer Institute. "This could be an important step toward personalizing treatment for depression."

Glutamate is a chemical messenger used by neurons to communicate. However, at high levels, it can become toxic to both neurons and glia, cells that support brain health. It is unlikely that the elevated levels seen in some depressed patients are acutely toxic, Haroon says.

"Still, we think that one of the ways that inflammation may harm the brain and cause depression is by increasing levels of glutamate in sensitive regions of the brain, possibly through effects on glia," he says.

Researchers examined 50 patients with depression who were not receiving antidepressant medication at that time. Inflammation was determined by a blood test for C-reactive protein (CRP), which was measured on repeat visits to make sure its levels were stable.

The team used an imaging technique called magnetic resonance spectroscopy (MRS) to measure glutamate levels in the basal ganglia, a brain region important for motor control, motivation and decision making. The researchers also measured levels of myo-inositol, a marker of glial health.

High glutamate and myo-inositol levels in the basal ganglia were associated with patients' reports of anhedonia, an inability to experience pleasure, and slow motor function, as measured by finger tapping speed.

"We focused on the basal ganglia because we had previously seen that a treatment for hepatitis C virus that arouses inflammation and can trigger depressive symptoms could also increase glutamate levels there," Haroon says.

He adds that the paper's findings do not directly address how ketamine and other glutamate-targeting drugs may work against depression, but may indicate which patients would be likely candidates.

A previous study of people with difficult-to-treat depression found that only those with high inflammation markers tended to improve in response to the anti-inflammatory antibody infliximab.

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Emory co-authors include Andrew H. Miller, MD, professor of psychiatry and behavioral sciences, Jennifer Felger, PhD, assistant professor of psychiatry and behavioral sciences, and Xiaoping Hu, PhD, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.


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Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments

World J Hepatol 2015 September 8; 7(19): 2209-2213
World J Hepatol. 2015 September 8; 7(19): 2209-2213.
Published online 2015 September 8. doi: 10.4254/wjh.v7.i19.2209.
Copyright©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments
Paul J Rowan and Nizar Bhulani

Abstract
Chronic hepatitis C virus (HCV) is a global concern. With the 2014 Food and Drug Administration approvals of two direct-acting antiviral (DAA) regimens, ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, we may now be in the era of all-pill regimens for HCV. Until this development, interferon-alpha along with Ribavirin has remained part of the standard of care for HCV patients. That regimen necessitates psychosocial assessment of factors affecting treatment eligibility, including interferon-alpha-related depressive symptoms, confounding psychiatric conditions, and social aspects such as homelessness affecting treatment eligibility. These factors have delayed as much as 70% of otherwise eligible candidates from interferon-based treatment, and have required treating physicians to monitor psychiatric as well as medical side effects throughout treatment. All-pill DAA regimens with the efficaciousness that would preclude reliance upon interferon-alpha or ribavirin have been anticipated for years. Efficacy studies for these recently approved DAA regimens provide evidence to assess the degree that psychosocial assessment and monitoring will be required. With shorter treatment timelines, greatly reduced side effect profiles, and easier regimens, psychosocial contraindications are greatly reduced. However, current or recent psychiatric comorbidity, and drug-drug interactions with psychiatric drugs, will require some level of clinical attention. Evidence from these efficacy studies tentatively demonstrate that the era of needing significant psychosocial assessment and monitoring may be at an end, as long as a manageable handful of clinical issues are managed.

Keywords: Depression, Therapy, Psychiatry, Clinical, Direct-acting antivirals

Core tip: The recently Food and Drug Administration approved direct-acting antiviral regimens for hepatitis C virus (HCV), ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, have demonstrated great efficacy, and thus far seem to have short treatment timelines and relatively benign side effect profiles. Depression has not emerged as a side effect of these treatments. With efficacious regimens that include no interferon-alpha and no ribavirin, there may no longer be a need for strong psychosocial assessment and monitoring built into the routine of HCV treatment. Good history-taking, strong pharmaceutical review, and reliable consultative relationships should be adequate for meeting psychosocial needs in HCV treatment.

INTRODUCTION
Chronic hepatitis C Virus (HCV) is a global concern, with approximately 170 million people affected worldwide. It is the leading cause of liver cirrhosis in developed countries[1,2]. Of the 6 genotypes, genotype 1 is the most prevalent[3]. Interferon alpha was recognized as a successful treatment in the 1980s, but success rates were low. Since 1998, Interferon-alpha along with ribavirin has remained the standard of care for HCV infected patients, with success rates in genotype 1 only at approximately 40%, while success rates for genotypes 2 and 3 hover around 80%. Until recently, the only significant change to this regimen was the approval of pegylated interferon-alpha treatment, in 2001, making the regimen less challenging by reducing injections per week and boosting efficacy to some degree.

Due to side effects of this regimen, candidates must be assessed for eligibility. As much as 70% of otherwise eligible patients are not eligible to begin treatment due to contraindications[4,5]. A leading contraindication has been depression, since a leading side effect is the depression that may emerge or be exacerbated by interferon-alpha. Clinicians have also had to monitor other psychosocial issues, such as substance abuse. Some evidence suggests that treatment does not seem to work in active alcohol users[6], although some assessment have shown similarly successful outcomes regardless of current alcohol abuse[7]. Injection drug users have been perceived as at risk for insufficient adherence[8], and also at risk for re-infection[9], so this poses another area of psychosocial assessment. Clinically, a common practice has been to refer an otherwise eligible candidate for psychiatric care when any of these psychiatric conditions are present or have been recently active.

Another psychosocial concern is social stability: since treatment may take as long as 48 wk, a candidate must have stable housing and have means for refrigerating the interferon-alpha. Those with unstable housing or unstable income might need to have those issues addressed by social work before treatment can be initiated. For women of child-bearing age, the teratogenic risk of ribavirin requires attention to pregnancy risk. A recommended practice has been to assure mandatory birth control adherence for any woman of child-bearing age to be prescribed any extended regimen that includes ribavirin[10]. Thus, while the prevailing regimen promises good outcomes for many, psychosocial assessment and monitoring has been a necessary part of HCV treatment.

Major changes to this clinical picture began in 2011, with approval of the first direct-acting antivirals (DAA), boceprevir and teleprevir. While these drugs greatly boosted genotype-1 success rates and shortened treatment time by months, these successes were gained by augmenting an interferon-alpha and ribavirin regimen with these newer drugs. So, patients still faced the side effects and contraindications associated with interferon-alpha and with ribavirin.

With the 2014 Food and Drug Administration (FDA) approvals of the ledipasvir/sofosbuvir “Harvoni” regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir “Veikira Pak” regimen, and with more regimens under development, we may now be in the era of all-pill regimens for HCV. Compared to the prevailing standard of interferon-alpha-plus-ribavirin regimen that has prevailed since the 1990s, this advancement in HCV treatment is revolutionary for a few reasons: these new regimens have superior efficacy across genotypes; the treatment timeline is relatively brief; and patients no longer need to self-administer a medication by injection. Also, a further advancement seems to be the favorable side effect profile.

Clinics treating HCV patients have had to develop the capacity to provide the noted psychosocial assessment and monitoring. With the advent of these new regimens, it is worth reviewing their side effect profiles to consider the degree that psychosocial assessment and monitoring will continue to be part of HCV treatment. This requires examining how lengthy and complex any regimen is, the rates of discontinuation, the degree of psychiatric adverse events experienced by study enrollees, and whether any regimen medications have any psychosocial contraindications (e.g., homelessness, risk of pregnancy). This review draws upon previously published data, and no original data, so no institutional review board approval was needed, and no consenting of any participants was required; it is also noted that the authors have no conflicts of interest.

Ledipasvir-sofosbuvir regimen: Psychosocial aspects
The ledipasvir-sofosbuvir regimen, commercially available as Harvoni®, received FDA approval on October 10, 2014. The ION series of studies[11] established safety and efficacy for this regimen. ION-1 allowed individuals with mental illness to enroll, as long as the condition had been well-controlled for at least a year. Also, exclusion criteria included those with any psychiatric hospitalization, suicide attempt, or psychiatric disability period in the recent five years (ION-1 Study Protocol, 4.3 g). A positive drug screen, elevated AUDIT (excessive-alcohol screener) score, or drug abuse in the recent 12 mo were also exclusionary criteria. Therefore, enrollees could have a mental illness such as depression, but had to be free from recent complications of that condition. In the ION-1 study, there was no drop-out due to side effects (one enrolled participant dropped out after only one dose), and only 4 of the 431 participants receiving the ledipasvir-sofosbuvir regimen regimen were lost to follow-up: loss to follow-up can reflect any of many factors, including a passive refusal to continue a regimen due to side effects or a regimen that is too complex. This rate of loss to follow-up is much lower than interferon-based trials. In the initial study providing the superiority of pegylated interferon, by Fried et al[12], 677 participants were randomized and began treatment in the two pegylated interferon arms (one with ribavirin, one with placebo); of these, 145 (21.4%) experienced depression, and 28 (4.1%) discontinued treatment (20 refused to continue treatment at some point after beginning, and 8 had failure to return). About the same time, a similar efficacy study of pegylated interferon-alpha was conducted by Manns et al[13]. In this study, 30% of the 1025 patients in the two study arms receiving pegylated interferon-alpha experienced depression symptoms. In another analyses of these data[14], the researchers noted that 218 of 1010 (21.6%) patients receiving interferon-alpha sustained treatment for less than 80% of the planned treatment time span. Thus, depressive side effects and other aspects of interferon-based regimens have been challenging for patients to tolerate. For the ledipasvir-sofosbuvir regimen, low rates of discontinuation may also be due to the ease of compliance with the regimen: both medications are combined in one pill, taken orally once daily.

In the ION-1 trial, no psychiatric serious adverse events were reported among participants taking the ledipasvir-sofosbuvir regimen, although other serious adverse events, such as chest pain and pneumonia, occurred in a few of these patients. Thus, overall, there does not yet seem to be any notable risk of psychiatric symptomatology for the ledipasvir-sofosbuvir regimen, per study adverse event reporting or as might be suggested by drop-out/loss to follow-up or by adherence data. These study data indicate that, so far, psychiatric problems such as depressive symptoms do not seem to be a side effect of treatment, although it must be acknowledged that study criteria excluded those with current or recent psychiatric difficulty.

A related study, ION-3, was conducted to determine whether a more brief regimen, 8 wk vs 12 wk of ledipasvir-sofosbuvir, could be as efficacious[15]. This study, with a protocol largely parallel to ION-1, included 215 participants in the 8 wk ledipasvir-sofosbuvir arm and 216 in the 12 wk arm. Among these participants, the study’s Supplementary Materials indicate no psychiatric adverse events, and report very low rates of drop-out/loss-to-follow-up (4 of 431; 0.9%). So, again, the ledipasvir-sofosbuvir regimen seems very unlikely to produce psychiatric adverse events, or to have treatment discontinuation.

Is pregnancy risk a concern for the ledipasvir-sofosbuvir regimen, as for the interferon-alpha/ribavirin regimen? Thorough data, such as a randomized clinical trial with pregnant women, have not been conducted, and post-marketing surveillance is still young, so human data are limited. The FDA-approved medication insert data report that animal-model studies have failed to find any teratogenic effect when given to rats or rabbits at exposures that are 3 or more times greater than human doses. The status for pregnant women is currently Category B: animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Does the ledipasvir-sofosbuvir regimen have contraindications with any psychiatric medications, requiring close scrutiny in patients prescribed psychiatric medications? Prescribing information report no such noted conflicts, and neither of the two component medications have metabolism by cytochrome P450 genes, a common biological indicator of possible drug-drug difficulties for psychiatric medications. Post-marketing surveillance has been brief, but thus far contraindications for psychiatric medications have not been detected for this regimen.

Ombitasvir-paritaprevir-ritonavir and dasabuvir: Psychosocial aspects
Ombitasvir-paritaprevir-ritonavir plus dasabuvir is commercially available as Viekira Pak®, which is a once daily pill of ombitasvir-paritaprevir-ritonavir and a twice daily pill of dasabuvir[16]. Two related studies with similar protocols, PEARL-III and PEARL-IV[16], assessed the efficacy and adverse events of this regimen. Each studied the ombitasvir-paritaprevir-ritonavir plus dasabuvir regimen with or without ribavirin in randomized, placebo-controlled trials. PEARL-IV studied patients with genotype 1a, and PEARL-III studied those with genotype 1b. The placebo arms (no ribavirin) of each of these studies provide relevant data regarding possible psychosocial issues to be assessed and monitored in this no-interferon-alpha, no-ribavirin regimen.

Potential participants with current or recent alcohol or substance abuse (recent 6 mo) were excluded, but otherwise psychiatric comorbidity was not an exclusion. Together, in the placebo arms (no ribavirin), there were 414 participants who participated in 12 wk treatment. Aside from those discontinuing treatment due to virologic failure or to adverse events that had no psychosocial aspect, there were only 6 (1.4%) who did not complete treatment (consent withdrawn, lost to follow-up, or “other” reason). As noted earlier, reason for loss to follow-up cannot be ascertained, but it must be considered that psychiatric side effects or adverse events could be involved. These rates of non-completion are far lower than the rates, noted earlier, for interferon-alpha regimens.

The Supplementary Materials for PEARL-III and IV note adverse events, reported per Medical Dictionary for Regulatory Activities vocabulary. No distinctly psychiatric adverse events are noted except for “memory impairment”, reported by 14 (3.3%) of participants in the no-ribavirin arms of these studies.

So, the ombitasvir-paritaprevir-ritonavir plus dasabuvir regimen seems to be well-tolerated, with strong compliance and a very small burden of psychiatric side effects. Substance abuse may reasonably be a contraindication; more data are likely needed on the degree that those with current or recent psychiatric difficulties may need to be delayed from treatment, but this regimen seems to hold promise for those with psychiatric comorbidities.

There are two well-recognized psychosocial issues with this regimen: the inclusion of ritonavir is problematic for women of reproductive age, and there is a long list of drug-drug interactions between ritonavir and other medications, including several medications used for psychiatric indications. These challenges arise mainly because ritonavir inhibits the liver enzyme cytochrome P450-3A4[17], and so affects to some degree the pharmacokinetics of any drug affected by this enzyme. Extensive data exist regarding pharmacology of ritonavir because it has been recognized for years as part of efficacious human immunodeficiency virus (HIV) treatment[18]. Also, the University of California San Francisco “HIVInsite” website[19] has extensive data on HIV/AIDS drugs, including ritonavir, and is the source of some of the following observations regarding drug-drug interactions.

Ritonavir reduces the efficacy of hormone-based birth control[20,21]. The PEARL study protocols have required that women participating in the trials avoid pregnancy by using at least two forms of birth control, neither of which can be hormone-based. So, along with recognized evaluation for HCV treatment, providers will need to assess and monitor pregnancy risk, and pregnancy prophylaxis, for women of reproductive age.

Many of the ritonavir drug-drug interactions are with medications that have psychiatric indications, including carbamazepine (bipolar disorder), nefazodone (depression), and triazolam (insomnia). So, assessment and monitoring will require surveillance of psychiatric conditions and any medications for these. It is possible that patients taking triazolam for insomnia may not perceive themselves as having a “psychiatric” condition, so merely asking about “psychiatric” diagnoses or prescriptions may not reveal that a patient is using this drug; as is generally advisable, patients should be encouraged to report any and all prescription drugs, as well as over-the-counter drugs and any herbal or “alternative” remedies. Regarding herbal/alternative drugs, patients should avoid taking both ritonavir and John’s Wort[22], a fairly commonly utilized herbal remedy for depression. Ritonavir also has a drug-drug interaction with sildenafil, used for erectile dysfunction; use of both drugs can lead to pulmonary arterial hypotension, and there are drug-drug interactions with other drugs used for erectile dysfunction as well, including avanafil, tadalafil, and vardenafil. There is a fair amount of clinical folklore and evidence that sildenafil is misused for recreational purposes[23,24], so the clinical management of HCV treatment that includes ritonavir must assess and monitor the use of erectile dysfunction drugs, whether this use is legitimate use or recreational use.

In conclusion, clinical trial data indicate that these recently approved, all-pill, no-interferon-alpha/no ribavirin regimens are far more readily tolerated by patients generally, and do not seem to have notable psychiatric contraindications. Challenges of these regimens may be limited to examining drug-drug interactions, including the prescription of drugs for psychiatric indications or for birth control. None of these issues requires significant involvement of specialty mental health or social work professionals, although it is necessary to have these services readily available by consultation.

The type of psychosocial assessment and monitoring required for these regimens is typical in medical care delivery, and the adoption of the electronic medical record and e-prescribing can support the detection of potential drug-drug interactions. In many cases, precautions or alternative clinical management strategies can be determined for the duration of the 12 wk treatment, in consultation with a pharmacist, the prescriber overseeing the psychiatric condition, or both. So, with these recently FDA-approved DAA regimens for HCV, with no interferon-alpha and no ribavirin, treatment settings may no longer need to have strong psychosocial assessment and monitoring built into the routine of HCV treatment.

There are some further research issues to be assessed for these recently-approved DAA regimens. As clinical experience builds with all-pill DAA regimens, the experience of patients with well-controlled or poorly-controlled psychiatric comorbidity should be noted and reported. One or both of these regimens may be well-tolerated in patients with a range of psychiatric comorbidities. If the DAA regimens are well-tolerated by those with current or recent psychiatric comorbidities, this would greatly broaden the range of patients eligible to initiate therapy. Also, it would be valuable to investigate patient preferences for avoiding pregnancy for the duration of treatment. As evidence builds, we will be able to more firmly determine whether we have entered an era in which there is no longer any great need for psychosocial assessment and monitoring of patients undergoing HCV treatment.

Footnotes
P- Reviewer: Garcia-Elorriaga G, Isamu S S- Editor: Qiu S L- Editor: A E- Editor: Liu SQ
Conflict-of-interest statement: The authors have no conflicts of interest.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: July 5, 2015
First decision: July 31, 2015
Article in press: August 31, 2015

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Depression rather than liver impairment reduces quality of life in patients with hepatitis C

Revista Brasileira de Psiquiatria
Print version ISSN 1516-4446
Rev. Bras. Psiquiatr. vol.37 no.1 São Paulo Jan./Mar. 2015
http://dx.doi.org/10.1590/1516-4446-2014-1446

ORIGINAL ARTICLES

Depression rather than liver impairment reduces quality of life in patients with hepatitis C

Luciana D. Silva12, Cláudia C. da Cunha1, Luciana R. da Cunha1, Renato F. Araújo1, Vanessa M. Barcelos1, Penélope L. Menta1, Fernando S. Neves3, Rosangela Teixeira12, Gifone A. Rocha4, Eliane D. Gontijo5
1Viral Hepatitis Outpatient Clinic, Instituto Alfa de Gastroenterologia, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte - MG - Brazil
2Department of Internal Medicine, School of Medicine, UFMG, Belo Horizonte - MG - Brazil
3Department of Mental Health, School of Medicine, UFMG, Belo Horizonte - MG - Brazil
4Laboratory of Research in Bacteriology, School of Medicine, UFMG, Belo Horizonte - MG - Brazil
5Department of Preventive and Social Medicine, School of Medicine, UFMG, Belo Horizonte - MG - Brazil

Abstract, introduction, and discussion only provided below, for full text article please click here. 

ABSTRACT
Objective:
Patients with chronic hepatitis C (CHC) have a poorer quality of life than those with other chronic liver diseases. However, some of the factors that determine health-related quality of life (HRQOL) in these patients, such as the degree of liver fibrosis, are still controversial. Therefore, the aim of the present study was to investigate the impact of CHC on HRQOL by conducting clinical, psychiatric, and sociodemographic evaluations.

Methods:
One hundred and twenty-four consecutive patients attending a referral center for hepatitis were evaluated using the Mini-International Neuropsychiatry Interview, the Hamilton Depression Rating Scale, the Hospital Anxiety and Depression Scale, and the Medical Outcomes Study 36-Item Short-Form Health Survey. Multiple linear regression analyses were used to quantify independent associations between HRQOL and the clinical, psychiatric, and sociodemographic variables of interest.

Results:
Reduced HRQOL was independently associated with major depressive disorder (MDD) and with elevated levels of alanine aminotransferase, but was not associated with hepatic cirrhosis.

Conclusions:
MDD rather than the grade of liver fibrosis was strongly associated with HRQOL impairment in patients with CHC. These findings highlight that, in patients with CHC, the psychological effects of the disease deserve more attention and the implementation of integrated medical, psychiatric, and psychological care may be helpful.

Key words: Chronic hepatitis C; cirrhosis; health-related quality of life; major depressive disorder

Introduction

Approximately 170 million individuals are infected with the hepatitis C virus (HCV) worldwide.¹ HCV is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC), and is responsible for more than 475,000 deaths around the world each year.¹ The natural course of chronic hepatitis C infection (CHC) is slow and insidious; 50-80% of acutely infected individuals will progress to HCV chronic carrier status. Of these, 20% develop cirrhosis and its complications after 20 to 30 years of infection.² In addition, HCV infection is associated with a series of extrahepatic manifestations, including depressive and anxiety symptoms, fatigue, and musculoskeletal/joint pain, which have been linked to reduced health-related quality of life (HRQOL).³

Issues linked to HRQOL have become remarkably important in the healthcare field.⁴ HRQOL is one dimension of broader quality of life that is more directly related to health, and it focuses on the patient's subjective evaluation of well-being, individual experiences, and values regarding the process of being sick.⁵ Evaluation of this parameter is essential, because it is known that the distress caused by a disease transcends target organ damage. Consequently, patients with a similar pattern of liver injury might have different degrees of suffering.

Although HRQOL is variably impaired in cirrhotic patients, the results of studies evaluating the impact of the degree of liver fibrosis on HRQOL are still controversial.⁶,⁷ Particularly in patients with CHC, scores indicative of poorer HRQOL have been identified even in the absence of clinically significant hepatic disease when compared with the scores of healthy individuals.⁸

Furthermore, the influence of viral load on HRQOL is unclear. Although it has been suggested that host factors are the major determinants of HRQOL in patients with CHC, some studies have shown that a sustained viral response improves HRQOL in patients receiving specific treatment for HCV.⁹
Despite the fact that CHC has a negative influence on all dimensions of HRQOL, including its physical, psychological, and social aspects,¹⁰ relevant issues should be raised, such as the translation of the results measured with generic or specific HRQOL instruments into clinical practice and, consequently, how these findings may influence clinical decision-making. Furthermore, regardless of the stage of liver disease, other potential predictors contribute to impaired HRQOL in patients with CHC, particularly psychiatric illness, which is common among these subjects.¹¹ The interrelationship between liver function and psychiatric profile may be more multifaceted than suspected.¹¹,¹² Few prospective studies have assessed HRQOL in CHC patients using detailed clinical and psychiatric approaches in combination with semi-structured interviews for psychiatric diagnosis.¹³,¹⁴
Depressive symptoms have been extensively identified in adults with chronic health conditions,¹⁵ and correlate negatively with HRQOL. Patients with CHC have a high prevalence of depressive disorders,¹¹,¹⁶ up to 70%, which is seven-fold higher than that found in the general population, independently of the degree of hepatic injury.⁸ As described above, CHC interferes not only with physical symptoms but also with psychological and social functioning.⁸

This study focuses on the integration of the patients' medical history, especially the evaluation of aspects beyond liver disease, while simultaneously measuring quality of life in the context of CHC. To this end, a multiprofessional and interdisciplinary approach was used to integrate the diverse health-related, psychological, and social aspects that are strongly linked to HRQOL. Expanding the assessment of these patients enables us to not only enhance knowledge about hepatitis C and other liver diseases, but also to recognize other medical issues, such as comorbid psychiatric difficulties, which, as a whole, may significantly influence the HRQOL of patients with chronic diseases,¹⁷ such as CHC.

Therefore, the aim of this study was to investigate whether variables related to sociodemographic characteristics, degree of liver impairment, clinical comorbidities, and psychiatric illnesses - especially depressive disorders - are independently associated with HRQOL in patients with CHC. We hypothesized that depressive symptoms might be significantly associated with reduced HRQOL in HCV-infected patients, regardless of the presence of clinically significant hepatic disease.

Discussion Only - Full text article, click here. 
In the present study, depressive disorder had a deeper impact on the HRQOL of patients with CHC than did the severity of liver disease. These results confirm that depressive symptoms have a negative influence on quality of life in individuals with chronic infection, as observed elsewhere.8,28,29 Additionally, our results demonstrated that not only the presence of MDD but also the severity of depressive disorder was associated with lower scores in all SF-36 domains, as well as in the physical component summary. It should be emphasized that the SF-36 domain scores and summary component scores were analyzed in combination. Several studies have demonstrated that the SF-36 summary component scores are not independent, i.e., the PCS and MCS may be partially measuring the same constructs.26 Therefore, the PCS/MCS scoring method imprecisely summarizes the scores of the SF-36 domains, and must be carefully analyzed and interpreted in combination with the domain scores.26

In health care, an alternative manner of assessing the HRQOL of patients would be to use instruments that are targeted at specific aspects of a particular disease. These disease-specific questionnaires are designed to identify disease-specific domains with high specificity and sensitivity.30 In addition to hepatic disease severity, other factors that influence CHC patients' HRQOL should be recognized. The administration of an instrument able to detect small changes in quality of life may increase identification of HRQOL-related issues. Among them, the diagnosis of psychological factors, such as depressive symptoms and anxiety, should be emphasized. Moreover, this process also permits physicians to make changes in patient management. In the present study, when a specific instrument was used to evaluate HRQOL in patients with CHC, MDD was strongly associated with poorer HRQOL, independently of the stage of liver disease.31 Altogether, these findings highlight the significance of psychiatric issues in HRQOL impairment in CHC patients.

The high prevalence of MDD (30.6%) observed in the present study is consistent with the results of previous investigations using structured psychiatric interviews in CHC patients.14 However, the pathogenesis of HCV-related psychiatric symptoms has not been completely clarified. Several lines of evidence have demonstrated that the virus is able to cross the blood-brain barrier. Recently, studies focusing on the analysis of quasispecies have allowed the identification of HCV-RNA in brain tissue.32 Otherwise, the role played by the host's immune response (especially cytokine-related effects) on psychiatric disorders in CHC should not be disregarded.33

In addition to depression, CHC has been shown to be associated with other psychiatric comorbidities that may themselves contribute to a poorer HRQOL.4,16,34 Despite the results of multivariate analyses in this study, the influence of anxiety disorder influence on the HRQOL of patients with CHC should not be ignored. The prevalence of anxiety disorders in patients with CHC has been shown to be as high as that of clinical depression.13,16 Some authors have explained that these elevated levels of psychiatric morbidity are related to coping with stigma and prejudice during the disease process.35 Overall, these life experiences and feelings may be responsible for increased rates of anxiety and contribute to the negative impact of chronic diseases, such as CHC, on HRQOL.36 Additionally, in this study, alcohol abuse was another psychiatric comorbidity associated with a reduction in the scores of two domains of the SF-36. This negative impact of alcohol use on HRQOL is consistent with previous studies.37

To the best of our knowledge, this is the first study to demonstrate an association between lower scores on the Functional Capacity domain of the SF-36 and HTN in patients with CHC. The high (35.5%) prevalence of HTN may be explained by the older age of the study population. Ethnicity and dietary and cultural habits should also be considered.

In agreement with previous studies, none of the SF-36 scores correlated with presence of cirrhosis, presence of necroinflammatory activity, or viral load.8,10,38 However, in contrast to previous investigations,10,38 higher ALT concentrations in this study were associated with decreased SF-36 scores in five domains and in two summary components. As CHC has been associated with several extrahepatic manifestations,3 one may speculate that elevated ALT concentrations might be associated with the activation of a systemic host immune response. This event might interfere with target organs beyond the liver, including the central nervous system.

Among the sociodemographic variables evaluated in the current study, family income and educational attainment were positively associated with three SF-36 domain scores. Helbling et al. showed that low income was the major factor associated with a reduced HRQOL among patients with CHC.10 In addition, previous investigations have demonstrated the positive influence of education on the HRQOL of patients with this disease.3,4

Of note, regarding host-related variables, it should be emphasized that the majority of studies assessing the HRQOL of patients affected by CHC have taken place in the context of routine medical care and did not use structured psychiatric interviews to confirm anxiety or mood disorders. Our subjects were patients of a university hospital; consequently, a close working relationship between clinicians, hepatologists, psychiatrists, and psychologists evaluating and treating these subjects was enhanced. An interdisciplinary and multiprofessional approach was developed for a better comprehension of CHC patients' clinical/psychiatric manifestations, with a particular focus on evaluating the deleterious effects of HCV that extend beyond liver disease.

The present study has some limitations. First, the subjects included were recruited from a referral center and, consequently, may not be representative of all patients with CHC. Second, although the SF-36 is considered to be the most appropriate generic instrument for HRQOL assessment in patients with chronic liver disease,22 some issues need to be evaluated. Independent of clinical/psychiatric illnesses, HCV infection alone has been shown to negatively impact HRQOL.8 Upon receiving a diagnosis of HCV, which is a contagious liver disease, these patients are faced with various challenges, such as adjusting to chronic comorbidity and coping with the stigma and the stress of social and familial relationships.35 In addition, individuals with CHC live with illness uncertainty, which may become a great psychological stressor for these subjects.39 Based on these aspects, use of the SF-36 instrument only may be insufficient for an appropriate evaluation of the HRQOL of patients with CHC, which is influenced by multiple complex factors. Furthermore, some studies point to the possibility of an overlap between HRQOL domains and psychiatric abnormalities, especially depressive symptoms. In the present study, the “depressive view” of depressed patients may have introduced bias in the interpretation of the SF-36 domain scores and summary component scores.40

In conclusion, we have clearly demonstrated that psychiatric disorders (particularly MDD) and active medical comorbidities, rather than the severity of liver disease, are the determinants of HRQOL impairment in patients with CHC. These findings highlight that the psychological effects of the disease on patients living with CHC deserve more attention, and that implementation of integrated medical, psychiatric, and psychological care may be helpful for patients with CHC.

Full text article, click here. 

Predictors of poor mental and physical health in HCV

Predictors of poor mental and physical health in HCV

This month's issue of Hepatology identifies predictors of poor mental and physical health status among patients with chronic hepatitis C infection.

Dr Joseph Boscarino and colleagues from Pennsylvania, USA assessed the extent and risk factors for depression and poor physical health among patients with chronic hepatitis C virus (HCV) infection.

The researchers surveyed HCV-infected patients seen at four large healthcare systems participating in the Chronic Hepatitis Cohort Study (CHeCS).

Survey data included demographics, depression and physical health measures, substance use history, current social support, recent stressor exposures, and, from the electronic medical record, treatment history, and Charlson Comorbidity Index scores.

There were 4,781 respondents, who had a mean age of 57 years.

The researchers found that 51% reported past injection drug use, 34% were current smokers, and 18% had abused alcohol in the previous year.

Additionally, the team noted that 47% had been previously treated for HCV, and 15% had a 12-week sustained viral response (SVR) following HCV therapy.

Overall, 30% of patients met criteria for current depression, and 25% were in poor physical health.

The researchers observed that significant predictors of depression and poor health included male gender, Black race, having education less than high school, being employed, having high life stressors, having low social support, and having high Charlson scores.

Achieving a 12-week SVR was found to be protective for depression.

Dr Boscarino's team concludes, "This large survey of U.S. HCV patients indicates the extent of adverse health behaviors and mental and physical comorbidities among these patients."
Hepatol 2015:  61(3): 802–811

19 March 2015

December Issue HCV Next - Diabetes and HCV: Unraveling a Complicated Relationship

Diabetes and HCV: Unraveling a Complicated Relationship

Hello folks, hope you all had a lovely holiday. The following articles appeared in the December 2014 print edition of "HCV Next" published online at "Healio."

"HCV Next" offers information on a range of topics, which include HCV diagnosis, new combination therapies, side effects, drug/drug interaction, guidelines, and more.

A few topics from the December issue is provided below, please click here to view the complete table of contents....

5 Questions

A Conversation with Donald M. Jensen, MD

What area of research in hepatology most interests you?

There is little mystery that HCV therapy has been central to my career. Beginning with recombinant interferon trials for HBV and NANB in the mid-80s, to the discovery of HCV by Chiron in 1989, through multiple clinical trials in the 1990s and early 2000s, and finally to the miracle of direct-acting antiviral agents over the past decade, it has been a phenomenal ride. I have been awed by the courage of my patients who suffered through the interferon days, and now join them in their joy at being cured without interferon. The past 25 years have witnessed a remarkable success story — one with industry and academic centers cooperating to bring this miracle to millions of patients...

Case Challenges

An Overlooked Overlap Syndrome
Neha Nigam, MD; James H. Lewis, MD, FACP, FACG, AGAF

A 24-year-old white female with hepatitis C virus from IV drug abuse, depression and herpes simplex virus infection was referred to the liver clinic by her primary care doctor due to significant interim elevations in her liver-associated enzymes from a normal baseline 6 months earlier.

Cover Story

Diabetes and HCV: Unraveling a Complicated Relationship
Some research suggests that curing HCV would reduce the likelihood of developing diabetes, that controlling diabetes would improve HCV outcomes, and that adequately treating one condition would allow the other to be more manageable. In conflict with those studies, recent study data published in Hepatology suggested no association between HCV and diabetes.

Editorial
A Still-Unraveling Connection Creates Heated Debate
In a time when the obesity epidemic is blossoming into a diabetes epidemic, it becomes harder to distinguish the impact of a disease like HCV on patients with diabetes or even those at risk.

In the Journals
Depression, Illness, Uncertainty Evident in Chronic HCV Patients on Watchful Waiting
Patients with chronic hepatitis C virus on watchful waiting showed evidence of illness uncertainty and depressive symptoms; however, these were not correlated with any reassuring histological data, according to study results.

Survival Among HCV Patients with SVR Reaches that of General Population
The life expectancy of patients with hepatitis C virus infection and advanced hepatic fibrosis or cirrhosis who achieved sustained virologic response was comparable with that of the general population, according to a research letter published in JAMA.

Specialists Anticipate Preference for Newly Approved Combination to Treat HCV
Surveyed specialists said they would prescribe ledipasvir-sofosbuvir to a high proportion of patients with hepatitis C virus genotype 1, according to results of a survey conducted by Decision Resources Group.

The Take Home

The Liver Meeting 2014
HCV Next had the opportunity to sit down with leading experts in the field while onsite at The Liver Meeting. They each provided insight into the data presented and how it will impact care of patients with HCV

Vantage Point: Transplantation

Treatment of HCV Following Liver Transplantation in the Era of Direct-Acting Antivirals
Stevan A Gonzalez, MD, MS

Chronic infection with hepatitis C virus remains the leading indication for liver transplantation in the United States. As the prevalence of cirrhosis and hepatocellular carcinoma attributed to HCV infection are expected to rise during the next 2 decades, HCV will continue to be a major source of morbidity and will contribute to a growing health care burden associated with advanced chronic liver disease.

Click here to read the December issue of HCV Next...........

Watchful Waiting: Role of Disease Progression on Uncertainty and Depressive Symptoms in Patients With Chronic Hepatitis C

Journal of Viral Hepatitis
Watchful Waiting: Role of Disease Progression on Uncertainty and Depressive Symptoms in Patients With Chronic Hepatitis C

J. P. Colagreco, D. E. Bailey, J. J. Fitzpatrick, C. M. Musil, N. H. Afdhal, M. Lai

J Viral Hepat. 2014;21:727-733.

Watchful Waiting in Chronic Hepatitis C

Discussion Only

View Abstract, Introduction, Materials and Methods, Subjects, and Results @ Medscape

We found a substantial rate of illness uncertainty (54%) and depressive symptoms (40%) in our cohort of patients with CHC on watchful waiting, consistent with the prior studies.[15,16] Surprisingly, the histological data did not correlate with overall illness uncertainty and depressive symptoms. The stage of fibrosis was significantly related to the Complexity subscale of illness uncertainty, but not to the overall illness uncertainty score or other illness uncertainty subscales. Clinicians often make recommendations for the patient to defer treatment and offer reassurances about their minimal and/or stable disease based on liver biopsy. However, reassuring histological data do not seem to lower the patients' feelings of illness uncertainty or depressive symptoms. Recognizing this paradox is important for clinicians and points to the need for additional research about how patients process relevant medical information.

We confirmed the previous finding of the association between overall illness uncertainty and depressive symptoms in patients with CHC following watchful waiting with a similar mean uncertainty score (86.5 vs 87.1).[17] Bailey et al.[17] found that patients with CHC following watchful waiting experience depressive symptoms associated with illness uncertainty. In his study on uncertainty, symptoms, and quality of life in patients with CHC, three constructs of illness uncertainty, Ambiguity, Inconsistency and Complexity, were significantly related to depressive symptoms. Unpredictability, another construct of illness uncertainty, was not significantly related to depressive symptoms.[17] In our study, we also found the Ambiguity and Inconsistency subscale scores to be positively significantly correlated with the CES-D scores, indicating a strong positive relationship between inconsistency and ambiguity in illness and depressive symptoms (See Table 3). The high rates of depressive symptoms and the correlation of the depressive symptoms to illness uncertainty point to the importance of illness uncertainty (especially the Ambiguity and Inconsistency components) as a possible target for intervention.

This correlational study was not designed to show clear cause and effect. While illness uncertainty is correlated with depressive symptoms, it is unclear whether illness uncertainty contributes directly to depressive symptoms or whether those who have depressive symptoms have higher levels of illness uncertainty because of their depressed disposition. It may be the case that those patients with depressive symptoms have higher levels of illness uncertainty and that the correlations are related to personality traits or neuropsychiatric attributes than knowledge of the disease or the extent of disease present. An intervention study to reduce illness uncertainty might help elucidate the causal relationship between illness uncertainty and depressive symptoms if the reduction of illness uncertainty resulted in decreased depressive symptoms. Measuring illness uncertainty before and after liver biopsy, and after treatment might also provide insight into the causal relationship of the two variables.

There is also data showing that patients with CHC experience cognitive impairment (in the areas of concentration, working memory, sustained attention and processing speed) and have cerebral metabolite abnormalities suggestive of frontal–subcortical dysfunction.[22–24] Patients with CHC were found to be impaired on more cognitive tasks than those who cleared hepatitis C, suggesting a direct viral effect. While these studies looked at cognitive function rather than depressive symptoms and illness uncertainty, they raise the questions of whether the depressive symptoms and illness uncertainty seen in patients with CHC might be from a direct viral effect and whether clearance of hepatitis C leads to decreased depressive symptoms and illness uncertainty because of its direct affect on the brain. Answering these questions would require brain imaging to be part of future studies.

Recent new information regarding medication advancements in hepatitis C treatment likely contributed to higher scores on the Inconsistency subscale of the MUIS-A for this population as new therapies were emerging at the time data were collected for this study. Advancement in treatment for HCV-infected patients probably raised concerns about the possible success or failure of viral eradication for this cohort, questions about the possibility of additional treatment advances, and concerns in general regarding the timing of treatment, the possibility of side effects of treatment and the duration of treatment. Some patients may have experienced more uncertainty, while others may have experienced less because hope for cure might have influenced uncertainty levels in both directions.

While the study was not powered to detect statistically significant differences in the scores between the different subgroups (reasons for deferral), the treatment naïve patients had lower mean scores on both the illness uncertainty and depressive symptoms scales. Additional studies with larger samples are required to explore the influence of the reasons for deferral on illness uncertainty and depressive symptoms.

There are no other studies available to provide insight into why the factors other than illness uncertainty might not have been significant in this population. More work is needed to determine the factors that cause and ameliorate patients' feelings of illness uncertainty and depressive symptoms while in watchful waiting. Qualitative studies designed to understand illness uncertainty in patients with hepatitis C on watchful waiting could provide insight into the illness experience of patients in this population. This insight can, in turn, help researchers design intervention studies using the Theory of Uncertainty in Illness, as has been carried out in populations who have other diseases.[25–29] We also hope to reassess illness uncertainty and depressive symptoms in this cohort of patients on follow-up after they have been treated to determine whether those who are cured have a decrease in their illness uncertainty and depressive symptoms.

With more efficacious and tolerable therapies on the horizon, many patients are advised to defer treatment. Given this population's high risk for illness uncertainty and depressive symptoms, part of the informed deferral process should be assessment for illness uncertainty and depressive symptoms.

In conclusion, we found that reassuring histological data were not correlated with less depressive symptoms and illness uncertainty in patients with CHC on watchful waiting. Clinicians who advise patients to defer treatment should be aware of the possibility of the symptoms and address them.

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