Psychiatric disorders and substance use (termed Mental Health/Substance Use, or MH/SU) concerns are highly prevalent among those diagnosed with HCV, especially in Veteran populations [14, 15]. In a large-scale study of over 22,000 Veterans with HCV receiving services at the Houston VA between 1992 and 1999, the most common mental health conditions were depression (49.5%), post-traumatic stress disorder (PTSD; 33%), psychosis (23.7%), and bipolar disorder (16%) [14]. Similarly, another study of 300 Veterans with chronic HCV receiving care at the Portland VA found that 81% were diagnosed with depression, 61.8% with PTSD, and 19.8% with bipolar disorder [16].

Substance use is a major risk factor for HCV infection; the primary route of infection is considered to be IVDU [17]. Hagan et al. [18] found that 50-90% of persons engaging in IVDU test positive for HCV and seroconversion typically began in the first 1-3 years of use. Even among those using non-injected drugs (i.e., cocaine), the occurrence of HCV is 5-29%, higher than in the general population [19]. Of Veterans with HCV receiving care through the VHA in 2013, 55% carried a prior/current diagnosis of alcohol use disorder, 39% had a prior/current “other and unspecified drug use” diagnosis, and 35% had a prior/current diagnosis of a stimulant use disorder [20]. Results from Dominitz et al. [2] indicated that within a large sample of Veterans with HCV, 78% reported either IVDU or a blood transfusion.

While alcohol use does not cause HCV, the research suggests that alcohol consumption does alter the course of HCV and may result in progression of advanced liver disease [21]. Alcohol has also been associated with poor treatment outcomes, treatment discontinuation [22], and development of liver and/or alcoholic cirrhosis [23]. Corrao et al. [24] found that alcohol consumption in addition to HCV increased the risk of cirrhosis nine times more than those with HCV who abstained from alcohol. Other studies have suggested a dose-response relationship between alcohol consumption and risk for cirrhosis, fibrosis, and mortality [25, 26]. Recent findings suggest that heavy alcohol consumption does not impact liver disease progression in and of itself, but has an additive impact on already poor liver functioning among those with chronic HCV and fibrosis [27]. While some studies show strong links, others have failed to show a relationship between excessive alcohol consumption and severity of HCV [21, 28]. Two methodological issues have been hypothesized to account for this discrepancy, such as varied definitions of excessive alcohol use and the possibility of a Type II error (i.e., the failure to reject a false null hypothesis due to statistical error) [27].

Previous HCV treatment involved a complex, funneling-down process [29] that resulted in more than two thirds of individuals not adequately treated due to the multifactorial barriers that existed in the treatment process, such as barriers with diagnosis, evaluation, and referral [30-33]. Evaluation and diagnosis of HCV have been impacted by low rates of uniform and standardized screening. In 2013, the Centers for Disease Control and Prevention (CDC) and VHA recommended focused HCV testing of the birth cohort ranging from 1945 to 1965, as this birth cohort is at higher risk for HCV [34]. By 2011, VHA providers had tested 63.5% of these individuals within this cohort who were enrolled in care, compared to 40% of those enrollees born before 1945, and 57% born after 1965 [29]. Although testing has been a focus at VHA, especially for the 1945-1965 birth cohort, a large percentage of Veterans have not been tested for HCV [29]. Factors that contribute to issues with screening and diagnosis of HCV may include decreased access to resources and care for patients who are homeless or live in rural communities [35].

Once a patient is tested and diagnosed with HCV, follow up care is crucial, though variable due to a number of challenges and barriers. Research examining the referral process has demonstrated that 24-57% of individuals will miss their first appointment in specialty care clinics for HCV treatment [36]. Once individuals present for treatment, they may discontinue treatment early or not fully adhere to the treatment protocol. In the VHA, these missed opportunities have resulted in Veterans being lost to follow-up and ultimately not receiving the benefits of treatment. Missed opportunities are often attributed to limited access to care. Recent national estimates suggest that HCV-related visits in rural settings occur at very low rates, possibly due to inadequate resources for testing and treatment [37]. Access to care remains a significant barrier and public health burden for those who are not insured and, thus, more likely to use the emergency department than any other type of health care service [37]. In the past era, evaluations for HCV treatment also presented significant treatment barriers as many patients were deemed ineligible candidates for treatment due to MH/SU concerns [38]. A disproportionately high percentage (68-84%) of Veterans had psychiatric disorders or active substance use, and were often delayed for treatment [39, 40] or excluded from interferon-based treatment [41, 42]. Treatments were commonly contingent on abstinence, and individuals with unmanaged psychiatric disorders or active substance use issues were commonly excluded due to the perceived risk of non-adherence or treatment resistance [38, 43, 44]. A review of the literature found that the level of adherence, particularly during the first 12 weeks of treatment, was a strong predictor of SVR for the older regimens; this placed a heavy emphasis on assessing problematic adherence [45]. Among Veterans with HCV, and particularly among those coinfected with HIV, ribavirin-based regimens were found to be more sensitive to non-adherence behaviors than were interferon-based regimens [46].

Numerous studies have examined the negative impact of stigma on persons diagnosed with HCV, which is defined as the reception of discrimination and prejudice motivated by disease status. Approximately 22 - 100% of participants of these studies indicated perceived stigma related to HCV due to the association of the disease with drug use, sexual promiscuity, sexually transmitted diseases such as HIV, and alcohol abuse [47-51]. Stigma can lead to fears related to others discovering one’s HCV status; thus, stigma can be viewed as a chronic stressor [51]. In a 2006 study by Zacks et al., 55% of participants reported non-disclosure of HCV status to a physician [51]. Internalized stigma (i.e., adopting self-denigrating beliefs about HCV) accounts for shame, insecurity, and fears of spreading the disease to others by unrealistic means, such as sharing drinking glasses [51]. Stigma has also been correlated with depression, anxiety, and anger [51, 52]. In sum, treatment eligibility requirements, access to care, and stigma have historically presented barriers to receiving HCV care.

Despite findings that indicate that psychiatric side effects are a major predictor of early treatment discontinuation [53], research has demonstrated that individuals with a history of MH/SU concerns were able to successfully complete HCV interferon-based treatment, especially when provided interdisciplinary medical and mental health care [54-58]. One study found that HCV treatment rates were maximized in a methadone-based clinic when a psychologist, specifically, was part of the patient’s interdisciplinary care [59]. In two studies conducted by Schaefer et al. [60, 61], clearance rates of HCV among those with prior mental health conditions (50%) and substance use disorders (53.8%) were comparable with the SVR rate of a control group (58.8%). Other studies have demonstrated that strong SVR rates were achieved among individuals with substance use disorder histories, including alcohol use disorders, but only when treatments were provided in the context of interdisciplinary medical and mental health care [59, 62]. Individuals with known histories of clinical depression who were not receiving antidepressant medication at the time of treatment initiation were at higher risk of discontinuation than those with depressive disorders actively taking medications [63]. In a retrospective study that examined the safety and efficacy of HCV treatment with persons with schizophrenia engaged in active mental health care, findings demonstrated SVR and treatment discontinuation rates similar to persons without schizophrenia [33].

Historically, the clinical health psychologist in hepatology clinics often performed evaluations to determine treatment candidacy for HCV care, thus serving as a type of treatment gatekeeper [38]. The purpose of the comprehensive psychological evaluation was to assist in clinical-decision making based on the identification of individual risks and benefits associated with treatment, assess a patient’s readiness and preparedness for treatment, and inform the overall treatment timeline [37, 64, 65]. The Structured Interview for the Treatment of Hepatitis C Virus (SIT-HCV) by Silberbogen et al. [66] was one of the most common psychosocial interviews utilized by clinical health psychologists in determining psychological appropriateness for treatment. Six major areas covered in the psychological assessment included HCV history, understanding of illness and treatment, social support, motivation and adherence history, MH/SU history, and current psychiatric status [66]. In addition to the structured interview, the recommended self-report psychometric battery typically included the Minnesota Multiphasic Personality Inventory- Second Edition (MMPI-2) [67], the Beck Depression Inventory (BDI) [68], the COPE Inventory [69], the Multidimensional Health Locus of Control (MHLC) [70], and a demographics questionnaire [66]. The Millon Behavioral Medicine Diagnostic (MBMD) [71] has also been used in place of the MMPI-2 or as an adjunctive measure. Overall, the clinical health psychologist played a vital role in the past-era HCV clinical care by aiding in the assessment of patient eligibility for interferon-based treatment.

In the new era of HCV care, the pre-treatment psychological evaluation remains a critical component of the evaluation process; the evaluation can assist in the identification of a Veteran’s barriers (e.g. poor adherence to medications) and strengths (e.g. good social support) that might influence or interfere with successful completion of treatment. Assessment of MH/SU concerns will remain pertinent for the purposes of providing comprehensive care, but in the context of HCV treatment specifically, to maximize adherence, as prior studies have indicated that MH/SU complicates medication adherence [22]. Briefer screens may be more useful in the context of the newer regimens, and may include the Alcohol Use Disorders Identification Test (AUDIT) [86], Generalized Anxiety Disorder 7-item scale (GAD-7) [87], the Montreal Cognitive Assessment (MoCA) [88], and the Patient Health Questionnaire Depression Scale (PHQ-9) [89]. Brief measures may also act as an initial screening tool, aiding the interdisciplinary liver team in deciding whether a psychological evaluation is warranted, perhaps expediting the process for otherwise healthy treatment candidates. In addition, briefer screens can aid the clinician in monitoring a patient pre-, post-, and throughout treatment.

Treatment adherence remains a critical, multifactorial issue that may impact treatment success even in the wake of new antiviral therapies that are achieving SVR in shorter periods of time and with fewer side effects when compared to previous treatment protocols [10, 90]. According to Bonner and colleagues [30], factors related to non-adherence can be person-specific, treatment-related, or related to the patient-provider relationship. Individual factors related to adherence include: mental health and emotional problems, substance use and abuse, self-efficacy and confidence, health beliefs about illness severity and benefits of treatment, cognitive impairment, socio-economic status, and employment status [30]. Beliefs about illness severity (i.e., willingness to be sick; beliefs about past treatment regimens) and benefits of treatment (e.g., “I’ll take it if it works”) are commonly referenced in the existing literature as major barriers to adherence but rarely assessed [65]. In a study examining illness uncertainty and depressive symptoms during periods of watchful waiting, 54% of participants reported moderate levels of illness uncertainty, and 40% were at risk for clinical depression. Illness uncertainty was significantly correlated with depressive symptoms (r = 0.49, p < 0.01), while liver progression and stage of fibrosis were not related to either overall [65]. In the context of the new regimens, assessment of illness beliefs and benefits of treatment remain important, particularly for experienced patients who failed to tolerate past treatments. Findings suggest that psychoeducation, a commonly utilized intervention, may not be sufficient in reducing uncertainty or depressive symptoms [65], thus alternate interventions are indicated to assist those with illness apprehension and/or ambivalence.

Treatment factors related to non-adherence include the medication side effect profile, number of pills and dosing regimen, and complexity and duration of treatment [30]. In the new era, these specific adherence factors may be significantly reduced with objectively less complex treatment durations and dosing regimens, and reduced adverse side effects. However, clinical experience tells us new pillbox packaging presents new challenges for Veterans, with dispensing directions that may be interpreted as complex or confusing to the older adult. In addition, as previously mentioned, adherence to ribavirin will continue to constitute monitoring as adverse side effects remain an issue with this often added medication [46]. Lastly, patient-provider relationship factors affecting adherence may include: individual dissatisfaction, a poor working relationship, poor communication, and lack of sufficient and detailed information provided to the patient [30]. A provider may be more reluctant to monitor a non-adherent patient, or may have limited adherence tools available to them to correct the non-adherence, contributing to overall patient dissatisfaction and less than adequate communication. Provider adherence tools may include routine self-report adherence screeners, adherence counseling groups, pill boxes, sample pill packaging, and tools to measure or calculate pharmacy refills. The provider’s interest in addressing and/or processing adherence challenges while on treatment is also a factor, and may be attenuated by the aforementioned adherence tools that are available in their respective clinic.

Medication adherence is a predictor of successful SVR; thus, it is emphasized in the psychological literature and multiple interventional approaches have been offered to address non-adherence among patients undergoing HCV treatment [45, 91]. Clinical health psychologists are well suited to intervene by helping patients to identify strategies to improve adherence and address the underlying psychological variables that can impact adherence, such as depression and active alcohol use. In the wake of new antiviral therapies that are achieving SVR in shorter periods of time and with less toxicity and fewer side effects than traditional agents, maximizing medication adherence becomes imperative as a failed trial of these new agents increases resistance [10, 76, 90]. Community-based research shows that psycho-educational efforts, such as a 15-minute discussion of HCV with a health care provider, significantly increases HCV screening and improves patient follow-through with specialty care referrals [92]. However, systemic constraints on appointment lengths and panel sizes limit physicians’ freedom to provide education on medications and the importance of adherence when prescribing HCV treatment. The task of patient education can be shifted to or augmented by clinical health psychologists, which affords medical providers the opportunity to improve efficiency and to endorse interdisciplinary care.

Empirically supported behavioral health treatment protocols are often used by clinical health psychologists to increase adherence and manage comorbid psychiatric symptoms [45]. Specifically, Motivational Interviewing (MI) techniques developed by Rollnick and Miller [93] is a treatment modality often used with medically ill populations in order to facilitate an individual’s progress towards health goals by augmenting patient knowledge and maximizing investment in change. MI carries strong empirical support for medication non-adherence and has become the primary treatment approach for this issue [94]. Also, Cognitive-Behavioral Therapy for Adherence and Depression (CBT-AD) [95] is a behavioral health treatment designed to promote adherence to chronic illness treatment protocols while simultaneously providing evidence-based treatment for symptoms of depression. Though not well studied in individuals living with HCV with comorbid depression, CBT-AD has been shown to be effective at improving treatment adherence in individuals living with other chronic conditions, such as HIV [96] and diabetes [97].

High-risk behaviors that may predispose an individual to HCV, such as IVDU and unprotected high-impact anal sex, are the same risk factors for HIV infection and transmission. Co-infection of HCV and HIV occurs in approximately 5 –10 million in the Western world. Approximately 15 –37% of Veterans living with HCV have a diagnosis of HIV, whereas the prevalence of HIV is 1.49% in the non-HCV infected Veteran population [106, 107]. Similar to mono-infection, co-infection is correlated with MH/SU concerns [108].

Undiagnosed or untreated HIV/HCV co-infection has detrimental effects on overall health status and liver disease progression [109, 110]. Research demonstrates that co-infection accelerates the HCV disease process [111], increases risk for cirrhosis of liver [109] and non-response to HCV antiviral medications, increases progression of hepatocellular carcinoma (HCC) [110], accelerates AIDS-defining illnesses, and increases rates of mortality [112, 113]. Among co-infected individuals with access to HIV antiviral treatments, HCV is the leading non-AIDS related cause of death [114]. Use of alcohol among co-infected individuals adds an additional risk, with a 2001 meta-analysis indicating that the relative risk of decompensated liver disease or cirrhosis is 2.9 (95% confidence interval, 1.7-5.0) in co-infected individuals compared to individuals with HCV mono-infection [108]. The data demonstrates the need to simultaneously screen for HCV and HIV in order to identify, diagnose, and treat those with co-infections in order to maximize treatment outcomes [115]. The clinical health psychologist situated within infectious disease and liver clinics is in a unique position to inform, refer, and monitor co-infected patients, thus increasing collaboration across clinics and strengthening continuity of care.

Approximately one third of persons living with HCV demonstrate cognitive impairment [116]. As the HCV population ages and we see an increasing incidence of HCV in those with IVDU [117], a vital role of the clinical health psychologist is to screen for cognitive impairment and provide intervention, when appropriate. Traditionally, neurocognitive changes were only considered in the context of antiviral treatment effects, liver disease, or both. However, current literature has now demonstrated that HCV infection alone, whether through direct neurotoxicity or indirect processes such as inflammation-triggered induction of cytokine cascades, plays a role in the etiology of neurocognitive changes. In other words, cognitive complaints related to HCV infection are independent from neurocognitive changes resulting from advanced liver disease [116, 118], HIV-co-infection [119], and/or substance use [120]. Moreover, HCV serostatus is a risk factor for within-person fluctuations in neurocognitive performance with HCV-positive individuals demonstrating significantly higher levels of variability compared to their seronegative counterparts [116]. According to the existing literature, cognitive domains affected that are correlated with HCV include attention, executive function, information processing speed, working memory, fine motor function, and verbal and visual learning [119].

Collectively, the aforementioned evidence suggests neurocognitive performance is inversely associated with HCV viral load [119], successful SVR can potentially reverse poor neurocognitive performance [118], and HCV-associated cognitive impairments are not necessarily attributable to a history of substance use [120]. Though cognitive status is also influenced by mental health (e.g. depression, PTSD) and physical comorbidities (e.g. fatigue, pain), overall findings indicate cognitive deficits persist after controlling for these comorbidities [118, 119]. Importantly, medical comorbidities pose the greatest risk for poor prognostic outcomes, including elevated risk of death [121].

As liver disease progresses, individuals with HCV are at risk of medical instability due to hepatic encephalopathy (HE) and/or vascular comorbidities. HE is classified into low-grade or minimal hepatic encephalopathy (MHE) versus overt HE. MHE is characterized by subtle neurocognitive impairment whereas overt HE involves changes in mental status ranging from disorientation to coma [121]. Even after remission of persistent HE, several neurocognitive impairments persist, including concerns with working memory, processing speed, learning/memory, and executive function [122]. The presence of HE is associated with poor prognosis and more rapid medical instability; therefore, early identification and treatment of MHE is vital. Neuropsychological testing is but one important approach to aid in the detection of HE. In a recent review article [121], the International Society on Hepatic Encephalopathy and Nitrogen Metabolism endorsed both the PSE-Syndrome-Test, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [123]. While clinical psychologists are not regularly trained in the administration and interpretation of the RBANS, clinical health psychologists are often trained in this screening instrument for dementia and other types of neurocognitive impairment. The RBANS is a valid, standardized measure supported by robust literature for its utility and has demonstrated to be predictive of disability in liver patients [121]. Clinical health psychologists are well-equipped to consult and refer to neuropsychology based on identified concerns in order to further test neuropsychological functioning.

Chronic HCV infection remains the principal indication for liver transplantation [22, 35]. It is well documented that psychological factors influence morbidity, mortality, and quality of life following liver transplantation [124-130]. Many organ transplant programs require potential transplant candidates to have a mental health evaluation conducted in order to identify potential barriers to candidacy and provide appropriate care throughout the transplant process – a function that amounts to life sustaining decisions in some cases [131]. Similar to the HCV evaluation process, the involvement of the clinical health psychologist varies widely as do the psychological contraindications for transplant across transplant programs. For instance, behavioral contraindications most often considered include nonadherence and recent alcohol and drug use. However, many psychologists focus their efforts on improving the candidacy of an individual, advocating for deferment rather than rejection with suggestions outlined so the candidate has the opportunity to make recommended changes. Ongoing psychiatric follow-up is warranted post-transplant according to the existent literature [132], with numerous studies being conducted on alcohol consumption following liver transplant [128-131]. Approximately 8 - 22% of transplanted individuals return to drinking within the first year, 30 - 40% by five years [128]. A minimum of six months of abstinence from alcohol, pre-transplant, is the widely accepted objective cutoff; however, there is inconsistent support for duration of abstinence as a predictor of relapse prior to transplant [128, 130]. In a 2008 meta-analysis aimed to clarify the inconsistencies that exist in risk for relapse to alcohol after transplantation, poor social support, family history of alcohol abuse/dependence, and pre-treatment alcohol abstinence of less than six months significantly, though modestly, correlated with alcohol relapse [126].

Tobacco use across all time periods, particularly resumption post-transplant, is an underestimated problem according to existing literature with 39 - 58% of liver transplant recipients using tobacco post-transplant [127]. In a 2008 meta-analysis by Dew et al. [126] examining the average rates of use post-transplant, tobacco use was the most prevalent with 10 cases for every 100 persons, per year (PPY) compared to alcohol relapse and illicit drug use (6 and 4, respectively). Taken together, current findings suggest that longer abstinence predicts less risk of alcohol use [129] in combination with other adverse (e.g., depression, tobacco use) and protective factors (e.g., cohabiting partner, insight into alcohol use) [130].

Liver transplantation is the only viable treatment option for individuals with end-stage liver disease. In 2014, about 4,410 liver transplants were performed and 16,216 candidates were on the wait list for a liver in the U.S. at the time of this report (based on OPTN data as of November 23, 2014) [133]. In addition, many individuals get deferred or never make it on the list; thus, most individuals will not receive the life-saving organ they need to survive [134]. Ample opportunity exists for clinical health psychologists to monitor and treat a patient awaiting transplant listing or on listing, as well as those candidates ultimately rejected from listing. Current literature suggests palliative care should be discussed as an option in the initial assessment of the transplant process in order to reduce barriers that might exist when transplant is no longer an option [124]. In sum, the treatment needs for patients with HCV and progressive complications necessitate the involvement of clinical health psychologists, and include the treatment of psychiatric and substance use concerns, neurocognitive and psychological assessment, behavioral health modification, and end-of-life care for patients along the continuum of disease progression.