Hepatitis C Coinfected Patients Undergoing Interferon Therapy

JANAC Vol. 14, No. 5, Supplement to September/October 2003 ARTICLE/ Neuropsychiatric Changes in Patients 10.1177/1055329003255589 Corcoran

Neuropsychiatric Changes in HIV/ Hepatitis C Coinfected Patients Undergoing Interferon Therapy Colleen P. Corcoran, MSN, NP A large percentage of HIV-infected patients are coinfected with hepatitis C virus (HCV). Current treatment available for HCV combines interferon and ribavirin therapy for 6 months or longer. Interferon is associated with numerous neuropsychiatric side effects including depression, cognitive impairment, anxiety, and irritability. The potential for developing depression is particularly concerning with coinfection because the incidence of depression is higher in the HIV-seropositive population than in the general population. This article discusses the mechanism and prevalence of interferon-induced depression and the debate regarding appropriateness of treatment in certain segments of the HIV population. The role of antidepressants as both treatment and a prophylaxis against interferon-related depression is reviewed. Nurses have a critical role in the care of HIV/HCV coinfected patients who are undergoing treatment with interferon and ribavirin. They both assess for treatment readiness prior to initiation and provide close monitoring for the development of neuropsychiatric disturbances while on therapy. Key words: hepatitis C, coinfection, depression, interferon, neuropsychiatric

An estimated 3.9 million Americans are infected with hepatitis C virus (HCV) and HIV, and HCV coinfection is prevalent within populations with a history of intravenous drug use (IDU) and among hemophiliacs. Samples from a recent seroprevalence study utilizing patients enrolled in the AIDS Clinical Trials Group were stratified based on the patients’risk, either

high risk (i.e., those who reported having hemophilia or a history of injection drug use) or low risk (all other patients). Among patients in the high risk category, 72.7% were HCV positive, whereas only 3.5% of the patients in the low risk group were infected (Sherman, Rouster, Chung, & Rajicic, 2002). Current treatment for HCV infection consists of interferon and ribavirin combination therapy, and it is recommended that all coinfected patients be evaluated for HCV treatment (National Institutes of Health, 2002). Interferon is a cytokine that is part of the body’s natural defense mechanism against tumors and microbes, and it is used clinically to treat different types of cancer in addition to hepatitis B and C. Interferon is associated with many inherent side effects such as chills, fever, headache, myalgias, arthralgias, nausea, diarrhea, anorexia, weight loss, and fatigue (McHutchinson et al., 1998; Schering, 2001). Of greater concern, however, are the neuropsychiatric side effects associated with interferon therapy, which include depression, irritability, anxiety, apathy, memory loss, cognitive retardation, confusion (Fried, 2002; McHutchinson et al., 1998; Okanoue et al., 1996; Trask, Esper, Riba, & Redmen, 2000; Valentine, Meyers, Kling, Richelson, & Hauser, 1998), changes in the Mini Mental status exam score (Kamei et al, 2002), and occasionally mania (Greenberg, et al., 2000; Strite, Valentine, & Meyers, 1997). There have also been reported cases of attempted suicide by Colleen P. Corcoran, MSN, NP, is a research nurse practitioner in the Infectious Disease Division, Massachusetts General Hospital.

JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 14, No. 5, Supplement to September/October 2003, 80S-86S DOI: 10.1177/1055329003255589 Copyright © 2003 Association of Nurses in AIDS Care

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patients on interferon (Schering, 2001). The incidence of neuropsychiatric effects of interferon therapy differ in literature, as researchers often used different instruments to assess depression and other mood changes, but it may be as high as 37% (McHutchinson et al., 1998). The vast majority of research has been devoted to the identification, description, and treatment of depression rather then the other neuropsychiatric changes.

Interferon Therapy, Depression, and the Decision to Treat The mechanism of interferon-induced depression is unclear, but it is speculated that increased norepinephrine and epinephrine levels, and/or decreased serotonin levels, may contribute to depression (Valentine et al., 1998). In addition, it appears that interferon increases cortisol levels, and a chronically stimulated hypothalamic-pituitary-adrenal axis can lead to depression (Dieperink, Willenbring, & Ho, 2000). It is suggested that pegylated interferon, the newer form of interferon alpha that needs to be given only once per week due to extended serum half-life (compared to standard interferon alpha, which is administered three times per week), may cause fewer mood changes. In a recent study by Fried et al. (2002), depression was reported in 22% of patients receiving pegylated interferon alpha 2a compared to 30% of those receiving standard interferon alpha 2b, which was a statistically significant difference (p = 0.01); however, there was no significant difference in reported irritability between the two groups. Interferon therapy is associated with an additional set of concerns in the decision to initiate treatment in HIV-infected patients because there is an associated high rate of comorbidity of depression with HIV infection. Bing et al. (2001) surveyed almost 3,000 HIVinfected patients utilizing the University of Michigan Composite International Diagnostic Interview, and they identified that 47.9% of those interviewed were depressed. In the general population, the lifetime risk of having a depressive illness is only 7% to 12% for men and 20% to 25% for women (American Psychiatric Association, 1994). In Italy, a large study compared cognitive and psychiatric dysfunction in HIV-infected

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patients on highly active antiretroviral therapy (HAART) versus individuals not on HAART medication. Depression was reported to be lower in the group taking HAART than in the group that was not (14.1% vs. 23.8%, respectively); however, cognitive impairment, as assessed by neuropsychological testing that evaluated motor control, memory, attention, and verbal production, was more prevalent in the HAART group (Starace et al., 2002). Because the presence of HIV infection in those who are HCV-positive accelerates the course of HCV, HIVinfected individuals should be evaluated to determine their candidacy for treatment. The comorbidity of HIV infection and psychiatric illness can be a challenge when compounded with the additional burden of HCV infection. A recent study in an urban medical setting evaluated the percentage of coinfected patients who were appropriate for interferon and ribavirin therapy. Exclusion criteria for therapy were ongoing alcohol or drug use in the preceding 6 months and active psychiatric illness, which was defined as symptomatic depression or psychosis within the previous year. Utilizing these definitions, 21% of the HIV/HCV coinfected patients in the clinical setting were considered ineligible due to active psychiatric illness, and 23% were ineligible for current or recent substance abuse (Fleming, Craven, Thornton, Tumilty, & Nunes, 2003). In a small pilot study of 23 HIV/HCV coinfected patients undergoing interferon and ribavirin therapy, 22% developed depression over the course of 48 weeks and 11% had depression severe enough to require discontinuation of interferon (Rockstroh et al., 2002). Other researchers have validated the concern of treating patients with mental health issues. In a monoinfected population, Kraus et al. (2001) reported that patients who demonstrated high scores for paranoid ideation, hostility, and anxiety on the Symptom Checklist 90 items revised at baseline had poor adherence to therapy, whereas those in the adherent group had a lower incidence of depression. Capuron and Ravaud (1999) reported a correlation in melanoma patients being treated with interferon between baseline scores on the Montgomery-Asberg Depression Rating Scale and the intensity of depression at week 4 of therapy. A study of HCV monoinfected patients in a veteran’s hospital receiving interferon therapy

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reported that those who had a diagnosis of a psychiatric disorder (posttraumatic stress disorder, obsessivecompulsive disorder, depression, bipolar illness, and/ or substance abuse) had a twofold greater incidence of a neuropsychiatric adverse event that required either intervention or discontinuation of therapy compared to those patients who at baseline did not have psychiatric comorbidity (Ho et al., 2001). Utilizing the Beck Depression Inventory, other researchers following a cohort of 448 HCV monoinfected patients in a hepatology practice undergoing treatment reported that 18.3% developed mild depression, 9.3% developed moderate depression, 6.7% developed severe depression, 9% thought of suicide but would not carry it out, 11% desired to kill themselves, and 6% would kill themselves if they had the chance (Bernstein, Belkin, & Steinberg, 2002). Conversely, research has revealed no significant difference in the incidence of adverse psychiatric effects between patients with and without a preexisting psychiatric illness (Pariante, Orru, Baita, Farci, & Carpiniello, 1999; Pariante, Landau, & Carpiniello, 2002) and that patients who have preexisting depression did not worsen on interferon (Mulder et al., 2000). The majority of research findings support the prevalence of neuropsychiatric changes due to interferon. It is important to remember that side effects of interferon therapy, including neuropsychiatric changes, should resolve within weeks or months of therapy discontinuation. Sylvestre and Clements (2002) evaluated the impact of preexisting mental illness, substance abuse, and limited length of sobriety on sustained virologic response (SVR) in HCV-monoinfected, recovering IDUs on methadone maintenance compared with a population without negative prognostic factors. Overall, the SVR in those with mental illness and IDU were lower than the control group (40% vs. 24%, respectively.) Those who had less than 6 months sobriety had a trend toward a lower rate of SVR than those with a longer length of sobriety, but it was not statistically significant (p = 0.38). Interestingly, however, patients who reported occasional drug use during treatment did not have a different rate of SVR than those who abstained. One may extrapolate from these data that even when ideal conditions are not met it may be

possible to successfully treat HCV-infected patients. Treating HCV-infected IDUs may reduce transmission by lowering the HCV RNA levels in the blood (National Institutes of Health, 2002), and it is recommended that IDUs be treated on a case-by-case basis and not blanketly excluded from HCV treatment. Of note, however, is that alcohol consumption of greater than 80g/day can seriously compromise HCV treatment (National Institutes of Health, 2002). In the New England Journal of Medicine in 2001, two Sounding Board articles were published, one which argued against treating IDUs for HCV, and the other which took the position that drug abusers should be offered treatment. Davis and Rodrigue (2001) argued that in patients who are currently injecting drugs, addressing the addiction is a more pressing issue than HCV therapy. Also, these authors emphasized that, in the event of SVR, an active IDU is at high risk for reinfection with HCV, as past infection does not confer immunity. However, Edlin et al. (2001) questioned the ethics of excluding a population from a potentially life-saving treatment and pointed out that there is a dearth of research either confirming or refuting that IDUs can adhere to HCV treatment. Edlin concurs, however, that treatment is more likely to be successful if preempted or accompanied by drug addiction treatment. Although Edlin et al. are correct in their assertion that very little research has been done regarding adherence issues among substance abusers, one group of researchers discovered that adherence levels for former substance abusers was comparable to that found in other medication event monitoring system adherence studies conducted in the general HIVpositive population; however, active cocaine use was associated with a very poor compliance and subsequent low percentage of viral suppression (Arnsten et al., 2002). Schaefer et al. (2003) noted that HCVinfected patients on methadone completed the prescribed course of interferon therapy at the same rates as a control group without a substance abuse history. Goldsmith et al. (2002) implemented a multidisciplinary approach to treating HCV monoinfected veterans in which 67% had major mood disorders and 89% had addiction issues. With the collaboration of hepatologists, psychiatrists, nurses, and pharmacists trained in HCV treatment who participated in intense

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management of the patients, approximately 90% of the patients in the study completed the prescribed 6-month course of therapy.

Treatment of InterferonInduced Depression Dose reductions to mitigate depression or discontinuation of therapy are two common ways of managing interferon-induced neuropsychiatric changes, as there are no definitive guidelines for pharmacologic treatment. However, the National Institutes of Health’s Consensus Development Conference Statement released in 2002 suggests that selective serotonin reuptake inhibitors (SSRIs) are useful antidepressants in treating interferon-induced depression. Because it is possible that interferon-induced depression is related to decreased serotonin levels in the brain, it is biochemically feasible that SSRIs may be beneficial. Kraus, Schafer, Faller, Csef, and Scheurlen (2002) treated a group of HCV-monoinfected patients who experienced major depression while on therapy administering paroxetine 20 mg every day. Of the patients, 78% were able to complete the full course of interferon therapy, and within 4 weeks, depression scores as assessed by the Hospital Anxiety and Depression Scale and Symptom Checklist had improved in all patients. Case studies published in the literature cite successes with other SSRIs including sertraline (Gleason & Yates, 1999; Schramm, Lawford, Macdonald, & Cooksley, 2000), fluoxetine (Levenson & Fallon, 1993), and with the tricyclic antidepressants imipramine (Gleason & Yates, 1999) and nortriptyline (Goldman, 1994). Gleason, Yates, Isbell, and Philipsen (2002) conducted an open label study using citalopram to treat depression in HCVmononinfected patients and reported a 50% decrease in their Hamilton Rating Scale for Depression (HAMD) scores, which indicates a lowered level of depression and reduced perceived level of fatigue. Only 4 of the 15 patients in this study were on interferon; however, this small subgroup had a greater than 50% decrease in their HAM-D scores. The role of prophylaxis against interferon-induced depression has been investigated. In one randomized, double blind, placebo-controlled clinical trial of patients undergoing high dose interferon alfa for

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malignant melanoma, paroxetine 20 mg to 40 mg was used to pretreat patients prior to initiation of therapy. In the group who initiated paroxetine 2 weeks prior to starting interferon, only 11% developed symptoms consistent with major depression compared to 45% in the placebo group (Musselman et al., 2001). Because the clinician’s goal is to assist a patient to complete the course of interferon and ribavirin combination therapy at full dose to maximize effectiveness and encourage a sustained virologic response or histologic improvement, further research into the usefulness of depression prophylaxis would prove valuable.

Nursing Implications Due to the intensity and duration of both constitutional and neuropsychiatric side effects of therapy for hepatitis C infection, the role of nursing in the setting of an HIV/HCV coinfection clinic is imperative. Some of the functions nurses can perform as they care for the coinfected patient considering treatment are to assess sobriety, and preexisting mood disorders, evaluate adherence issues, assess treatment readiness, encourage social support during therapy, and monitor and evaluate frequently while the patient is receiving HCV treatment. Assessment of Sobriety Davis and Rodrigue (2001) as well as Edlin et al. (2001) reported in the New England Journal of Medicine that drug treatment should be an integral part of the HCV-infected patient’s treatment plan of care. Although these two authors differ on whether the actively drug-abusing patient should be offered treatment, both concur that interferon therapy without substance abuse treatment, either preemptive or concurrent, is substandard care. Because HIV adds an additional burden to the substance abuser with HCV, an assessment of sobriety and a commitment to recovery will evaluate the patient’s ability to cope with the inevitable, unpleasant side effects of interferon. Assessment of Preexisting Mood Disorders Given the rate of depression in HIV-infected patients, interferon-induced depression resulting from

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the treatment of this patient population for HCV is a grave concern. Addressing and treating preexisting depression prior to initiating interferon is the preferable method to introduce treatment. The patient should be assessed by psychiatrists when being considered for therapy and episodically thereafter, although this is not always feasible. Therefore, nurses can play a critical role in assessing a patient’s past history of depression and substance abuse and in initiating a dialogue regarding a patient’s current mood state. Despite the growing acceptance in our society that depression is a physical disorder that has nothing to do with the strength of one’s character, many patients still believe depression is a manifestation of their strength; therefore, education regarding the biochemical nature of interferon-induced depression is critical. Focusing the patient on the fact that the goal of therapy is to complete the prescribed course to achieve a sustained virologic response and/or histologic improvement may help them become more accepting of either treating preexisting depression with medication, prophylaxing against interferon-induced depression, or willingly taking medication if depression develops. Utilizing depression inventories initially to assess baseline depression and periodically during the course of therapy to detect changes may be useful. A few of the depression scales commonly cited and used in research are the HAM-D, the Beck Depression Inventory, and the Short Form Health Survey. Evaluation of Adherence Issues If a patient is nonadherent with their antiretroviral regimen, it is unlikely that they will be adherent to weekly injections plus the four to six extra pills per day required with ribavirin. Addressing adherence issues with HAART medications and identifying areas that need intervention may lead a patient to a point where they feel capable of managing both HAART and HCV combination therapy successfully.

ribavirin therapy in patients who feel pressured by their provider or family to start treatment or in patients who poorly understand the potential side effects or importance of being treated is most likely going to lead to early self-discontinuation. Teaching materials are available for HIV/HCV coinfected patients that explain the two viruses, their interaction, and the side effects of therapy. Ensuring that the patient is educated when the possibility of therapy is introduced and sharing these materials will create opportunities for the patient to ask questions of both nursing and medical staff, speak to friends or acquaintances who have gone through therapy, and talk to family members about the implications of therapy. Encouragement of Social Support During Therapy Teaching about interferon therapy should include the patient’s partner, roommate, friends, or family members in the session for two reasons. First, it is helpful for these individuals to hear from a health care professional that the patient may not feel well enough to perform household chores while on therapy. Having a nurse tell a patient’s partner that he or she may not feel well enough to cook, clean, or perform all the child care as usual emphasizes the point and relieves the patient from the burden of having to make this point themselves. It also provides the patient with a sense of permission to expect assistance during the course in therapy that they might otherwise not have felt entitled to or wanted to accept. Second, those who are close to the patient may notice the development of irritability, lability, and depression before the patient recognizes these feelings. The opportunity to speak directly with the patient’s support system gives the nurse the opportunity to stress the importance of alerting the health care provider of any neuropsychiatric symptoms. Peer support groups are extremely valuable to patients who are either on therapy or are considering therapy.

Assessment of Treatment Readiness Continued Monitoring and Evaluation Prior to initiating therapy, the nurse needs to evaluate several factors. First of all, the nurse must explore whether the patient is truly ready to make the 6-month or longer commitment to a therapy regimen that has significant side effects. Initiating interferon and

Nurses can play a critical role in closely monitoring the patient for symptom management purposes and emotional support. Frequent phone calls at the initiation of therapy, when a flulike illness is most common,

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can address symptom management issues and give the nurse the opportunity to reinforce that such symptoms usually abate in approximately the first month of therapy. Weekly phone calls and nursing visits can allow the nurse to assess the patient for the development of a mood disorder or the effectiveness of antidepressants and to encourage the patient to continue their treatment. Because pegylated interferon is only administered weekly, the establishment of an injection clinic in which patients come to the clinic versus self-injection allows nursing staff to connect with the patient, answer questions, and continually assess their physical and mental status. It also alleviates the discomfort many recovering injection drug users have when forced to self-inject.

Conclusion Given the accelerated course of hepatitis C in the presence of HIV infection, all coinfected patients should be evaluated for the necessity and appropriateness of combination interferon and ribavirin therapy. An understanding of the neuropsychiatric side effects that treatment involves is mandatory to fully understand the burden that treatment places on a HIV/HCV coinfected person. There is a profound dearth of research on HCV in the presence of HIV in general and regarding mood disorders in particular. Being forced to extrapolate from the monoinfected literature may not provide an accurate picture of the neuropsychiatric side effects. Therefore, in addition to calling for better and more easily tolerated treatments for HCV infection to be developed, encouraging more research in the coinfected population to enhance the delivery of care is imperative.

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Rockstroh, J. K., Mudar, M., Lichterfeld, M., Nischalke, H. D., Klausen, G., Göltz, J., et al. (2002). Pilot study of interferon alpha high-dose induction therapy in combination with ribavirin for chronic hepatitis C in HIV coinfected patients. AIDS, 16, 2083-2085. Schaefer, M., Schmidt, F., Folwaczny, C., Lorenz, R., Martin, G., Schindlbeck, N., et al. (2003). Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology, 37, 443-451. Schering Corporation. (2001). PEG-Intron™ (Peginterferon alfa2b) powder for injection [Product information]. Kenilworth, NJ: Author. Schramm, T. M., Lawford, B. R., Macdonald, G. A., & Cooksley, W. G. (2000). Sertraline treatment of interferon-alfa–induced depressive disorder. Medical Journal of Australia, 173, 359361. Sherman, K. E., Rouster, S. D., Chung, R. T., & Rajicic, N. (2002). Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: A cross-sectional analysis of the U.S. Adult AIDS Clinical Trials Group. Clinical Infectious Disease, 34, 831-837. Starace, F., Bartoli, L., Aloisi, M. S., Antinori, A., Narciso, P., Ippolito, G., et al. (2002). Cognitive and affective disorders associated to HIV infection in the HAART era: Findings from the NeuroICONA study. Acta Psychiatry Scandinavia, 106, 2026. Strite, D., Valentine, A. D., & Meyers, C. A. (1997). Manic episodes in two patients treated with interferon alpha. Journal of Neuropsychiatry & Clinical Neurosciences, 9, 273-276. Sylvestre, D. L., & Clements, B. J. (2002, November). The impact of negative prognostic factors on hepatitis C treatment outcomes in recovering injection drug users. Presented at the 53rd Annual Meeting of the American Association for the Study of Liver Diseases, Abstract #225. Trask, P. C., Esper, P., Riba, M., & Redmen, B. (2000). Psychiatric side effects of interferon therapy: Prevalence, proposed mechanisms, and future directions. Journal of Clinical Oncology, 18, 2316-2326. Valentine, A. D., Meyers, C. A., Kling, M. A., Richelson, E., & Hauser, P. (1998). Mood and cognitive side effects of interferon-alpha therapy. Seminars in Oncology, 25, 39-47.