HCV coinfected patients under antiviral treatment for hepatitis C

Psychiatry Research 246 (2016) 173–181

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Mental disorders in HIV/HCV coinfected patients under antiviral treatment for hepatitis C ⁎

Marta Martin-Suberoa,b, , Crisanto Diez-Quevedob,c,⁎⁎ a b c

FIDMAG Research Foundation, Barcelona, Spain Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Badalona, Spain Department of Psychiatry, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

A R T I C L E I N F O

A BS T RAC T

Keywords: HIV Hepatitis C Coinfection Mental disorders Interferon-alpha Direct-acting Antivirals

This paper aims to review the epidemiology and management of mental disorders in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients, the need for antiviral therapy in this specific population, and current treatment strategies for HIV/HCV patients with psychiatric and/or substance use disorders. This is a narrative review. Data was sourced from electronic databases and was not limited by language or date of publication. HIV infection has become a survivable chronic illness. Prevalence of HCV infection among HIV-infected patients is high ranging from 50% to 90%. Patients with psychiatric diseases have also an increased risk for HIV/HCV coinfection. The most effective strategy to decrease HCV-related morbidity and mortality in coinfection is to achieve viral eradication. Although psychiatric symptoms often appear during antiviral treatment and may be associated with the use of interferon-alpha (IFN-α), recent evidence suggests that many patients with comorbid mental and substance use disorders can be treated safely. Recent data indicate that IFNα-induced psychiatric side effects have a similar prevalence in HIV/HCV coinfected patients than in monoinfected patients and they can be managed and even prevented successfully with psychopharmacological strategies in the frame of a multidisciplinary team. New antivirals offer INF-free therapies for this specific population.

1. Introduction In Western countries, the prevalence of HCV infection ranges between 1.3% and 2.7% (Ghany et al., 2009) and it is recognized as one of the fastest-growing health problems. Prevalence of HCV among HIV-infected patients is high, especially in people who inject drugs (PWID), ranging from 50% to > 90% (Strader, 2005; Walsh and Maher, 2012). Furthermore, HCV incidence is increasing internationally among HIV-infected men who have sex with men (MSM) (Bottieau et al., 2010; Urbanus et al., 2014; Vogel et al., 2010). In the Swiss HIV Cohort from 1998 to 2011, HCV incidence rose among HIV-infected MSM to a worrying rate of 4.1 cases per 100 person-years, while decreasing to 85% among PWID (Wandeler et al., 2012). Actually, the majority of new HCV cases among HIV-infected patients are occurring amid non–PWID (Wandeler et al., 2012). HCV infection is the most frequent cause of chronic hepatitis and a significant risk factor for liver cirrhosis and hepatocellular carcinoma. About 18.5% of HCV infected patients develop cirrhosis and 1.3% of

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them, a hepatocellular carcinoma (HCC) (Kanwal et al., 2011). Natural history of both HCV and HIV is altered by dual infection. HCV coinfection increases the risk of all-cause mortality even with the use of HAART (Hernando et al., 2012). HIV can worsen HCV illness course, leading to an accelerated progression to cirrhosis, liver failure, HCC, and increased HCV-related death (Graham et al., 2001; Joshi et al., 2011). Hence, HCV is a leading non-AIDS cause of mortality in HIV-infected persons in regions where HAART is accessible (Weber et al., 2006; Wise et al., 2008). Thus, HCV has become a priority in the care of HIV individuals who are coinfected with HCV in USA and Europe since 2005 (Alberti et al., 2005; Butt et al., 2006). Successful HCV treatment has been to date the most effective means of preventing liver related complications in the setting of HIVHCV coinfection (Berenguer et al., 2009). In spite of this, only a minority of individuals have initiated antiviral treatment (Grebely et al., 2009; Vellozzi et al., 2011). Antiviral combination therapy with pegylated IFNα (PegIFNα) and ribavirin is often associated with significant psychiatric side effects, such as depression, fatigue, insomnia, anxiety, cognitive disturbances

Corresponding author at: FIDMAG Research Foundation, Avda. Jordà, 8, 08035 Barcelona, Spain. Correspondence to: Universitat Autònoma de Barcelona, Facultat de Medicina, Badalona, Spain. E-mail address: [email protected] (M. Martin-Subero).

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http://dx.doi.org/10.1016/j.psychres.2016.09.041 Received 15 January 2016; Received in revised form 27 July 2016; Accepted 24 September 2016 Available online 26 September 2016 0165-1781/ © 2016 Elsevier Ireland Ltd. All rights reserved.

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M. Martin-Subero, C. Diez-Quevedo

(13% vs 6%) (Goulet et al., 2005). Yoon J and Crane P wanted to understand the connection between HCV and depression in HIVinfected patients. They analyzed the data from 764 HIV-infected patients from which 21% were coinfected with HCV and they found a higher prevalence and severity of depression among the coinfected group, interestingly the association between HCV and depression severity persisted after taking into account associations between past or current substance use and presence of somatic symptoms (Yoon et al., 2011). As we now know, depression is linked to a lower quality of life perception, lower treatment compliance, and may influence the decision to initiate HCV treatment (Braitstein et al., 2005; Buti et al., 2006). One of the most disabling HIV-complications is the neurocognitive disorder associated to the chronic stage of the infection. HAART has largely transformed HIV from a fatal to a chronic illness, thus allowing the virus and its comorbidities to impact on the central nervous system (CNS). There is increasing evidence that cognitive dysfunctions might also be directly related to infection on the CNS by HCV. In fact, HCV viral sequences have been found in brain tissue and it has been observed that HCV can replicate in macrophages, lymphocytes and peripheral nerves (Letendre et al., 2007). Until now, just a few studies have analyzed the cognitive functions among HIV/HCV coinfected patients. Ryan et al. compared a sample of 67 coinfected participants with 49 HIV-infected participants in terms of neuropsychological functioning and they observed that the coinfected group exhibited decrements in sustained attention, psychomotor speed and set-shifting, and this was not associated to cirrhosis or liver fibrosis (Ryan et al., 2004). Ciccarelli et al. studied the expression of cognitive disorders among three groups of participants: (1) HIV mono-infected; (2) HCV mono-infected; (3) HIV/HCV coinfected, with 50 participants each. They observed that 39.3% of all participants showed minor cognitive impairment and the prevalence was significantly higher in HCV/HIV coinfected patients (54%) than in mono-infected groups. Furthermore, the coinfected group had worse performance in long-term memory tasks and speed of mental information processing. In addition to these results, they observed that depression confirmed as an independent risk factor for cognitive impairment (Ciccarelli et al., 2013). It is important to recognize the patient's perspective and subjective experience of their illness to provide valuable information about outcome. We know that changes in functioning and general well-being that are linked to chronic illnesses may have an impact in the patient's perception of their position in life. A good measure to assess this, is the health-related quality of life (HRQoL) which is a more specific concept that refers to features of an individual's life that impact directly upon their health (IsHak et al., 2014). We already know that persistent depressive symptoms are strong predictors of psychological and physical QoL impairment (Martín-Subero et al., 2014) and as we have seen, depression is highly prevalent among HIV/HCV coinfected patients. Indeed, a few studies have shown that HRQoL is reduced in HCV/HIV coinfected patients compared with HIV-monoinfected (Fleming et al., 2004; Kanwal et al., 2005; Thein et al., 2007). Moreover, Kemmer et al. demonstrated that the higher the depressive level and distress symptoms, the lower the HORQoL profile score (Kemmer et al., 2012).

or suicide attempts (Schaefer et al., 2012). These psychiatric symptoms have an intense repercussion strong on quality of life, treatment adherence, and are risk factors for treatment failure (Schaefer et al., 2012). Furthermore, they are often used to exclude PWID and psychiatric patients from accessing antiviral therapy. Thus, the majority of these patients still remain untreated despite fulfilling the medical criteria for antiviral treatment of hepatitis C (Butt et al., 2006; Fultz et al., 2003; Grebely et al., 2009). However, recent studies have shown that HCV treatment results are acceptable in HIV/HCV coinfected patients with comorbid psychiatric and substance disorders (Aspinall et al., 2013; Dimova et al., 2013). In order to avoid dose reduction or treatment discontinuation, a range of different strategies concerning acute management or prevention of mental disorders have been developed. An approach that integrates the expertise of a variety of disciplines, including specialists in addiction medicine, hepatology, infectious diseases, primary care, and psychiatry, has been advocated for the treatment of HCV infection among PWID (Bonner et al., 2012). The availability of simple, well-tolerated, and highly effective interferon-free direct-acting antivirals will promote adherence among these patients. 2. Methods This is a narrative review. Data for this paper was sourced from electronic databases PUBMED, Google Scholar, and Scopus and was not limited by language or date of publication. Articles were chosen for citation on the basis of the relevance of its contents without any bias toward author or journal. Key words were as follows: HIV, Hepatitis C, coinfection, mental disorders, interferon-alpha, ribavirin, management, psychiatric adverse events, antiviral agents, interactions. 3. Results 3.1. Psychiatric comorbidity in HCV/HIV coinfection In the Western world, the most common risk factor for HCV infection is parenteral drug use (Ghany et al., 2009). Considering that 10% of HIV-infected patients are coinfected with HCV, the coinfection rates among PWID rise from 50% to 90% (Walsh and Maher, 2012). Some studies have shown that HIV/HCV coinfected individuals tend to be older, more likely to be male and to have a history of alcohol abuse or illicit drug use than monoinfected patients. HCV and HIV are overlapping epidemics with opioid dependence (Taylor et al., 2013). Moreover, heavy alcohol use is a risk factor for contagion of HCV. It has been reported that chronic alcohol consumption has an immunosuppressive effect, which could account for an increased susceptibility to HCV infection (Befrits et al., 1995). To our knowledge there are no data concerning epidemiology of alcohol use disorders and HIV/HCV coinfection, but between 8% and 43% of patients who suffer from an alcohol use disorder and comorbid liver disease have evidence of HCV infection (Befrits et al., 1995). Alcohol misuse is therefore a risk factor for transmission of HCV and it increases the rate of liver disease progression (Loftis et al., 2006). People with psychiatric disorders are more often coinfected than general population. The prevalence of HIV among individuals with a psychiatric disorder ranges between 1% and 23% and the prevalence of HCV ranges between 8.5% and 30% (Himelhoch et al., 2011). Moreover, it is now known that the rates of psychiatric illness within the group of HIV-positive persons who are coinfected with HCV are the highest (Weiss and Gorman, 2006). Goulet et al. conducted a study to determine the prevalence of mental disorders in all veterans receiving care for HIV during the years 1997–2002. From all the veterans who were in care, the 18% were coinfected with HCV. The coinfected group had higher rates of drug use disorders (58% vs 22%), alcohol use disorders (56% vs 24%), depression (43% vs 28%), posttraumatic stress disorder (18% vs 8%), bipolar disorder (12% vs 6%) and schizophrenia

3.2. Interferon-α-induced neuropsychiatric side effects 3.2.1. Effects Antiviral combined treatments that include standard or pegylated IFN-α are usually related to significant neuropsychiatric side effects, which are estimated to occur in up to 30%–80% of all chronic hepatitis C patients who receive (Schaefer et al., 2012). Depression and asthenia are the most common of these side effects. Asthenia is the most prominent symptom, since it occurs in up to 80% of the patients. Overall, depression develops in 30%–70% of patients during IFN-α treatment, with mild to moderate depression developing 174

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in 45%–70%, whereas major depressive episodes occur in 15%–45%. Wide ranges of prevalence depend greatly on the use of different assessment methods (clinical assessments, self-reports, diagnostic interviews) (Schaefer et al., 2012). In addition to depression and asthenia, IFN-α is also linked to a wide range of other neuropsychiatric symptoms. Anger or irritability affect up to 50% of patients, most of them in relation to depression, but in some cases related to manic or psychotic features. Sleep disorders (usually insomnia), anxiety, and cognitive disturbances may occur in up to 50% of the patients. In contrast, mania and psychosis represent more rare adverse events, developing in up to 3% of the patients (Schaefer et al., 2012). Finally, whereas suicidal thoughts have been reported in up to 10% of the patients, case reports of suicide or suicidal attempts are rare (Sockalingam et al., 2011). It is usually thought that in HIV-coinfected individuals the proportion of IFN-α-induced depression may be higher. However, data so far show a similar prevalence of depression in HIV/HCV coinfected patients. Laguno et al. found that 40% of a sample of 113 coinfected patients developed symptoms of depression during antiviral treatment (Laguno et al., 2004). Fumaz et al. found 59% of patients affected by mild to moderate depressive symptoms and 14% with moderate to severe episodes (Fumaz et al., 2007). Alavi et al. assessed mental health during treatment of recently acquired HCV in a predominantly PWID population (76%). Only 16% of the patients were found to be depressed at baseline, and 35% developed a de novo depressive episode during antiviral treatment. Depression at baseline was more frequent in HCV monoinfected than in coinfected patients. De novo depression during treatment was equally represented in both groups of patients (Alavi et al., 2012). It should be noticed that some patients with a history of drug use disorders may confound early side effects of IFN-α with withdrawal symptoms. Cravings might also be secondary to IFN-α–driven mood changes or be related to needles that are used for IFN-α therapy. However, rates of relapse in injection drug users seem to be relatively low (0%–17%) (Sasadeusz et al., 2011). Regarding the time course of the neuropsychiatric side effects, some studies have shown that neurovegetative and somatic symptoms tend to occur at early stages of therapy, often during the first weeks of the treatment, while mood and cognitive symptoms, tend to appear at later stages, usually after week 4 of treatment (Capuron and Miller, 2011; Schaefer et al., 2012). Similarly in HIV/HCV coinfected populations, depressive symptoms appeared in the first 3 months after initiation of IFN-α treatment (Fumaz et al., 2007; Laguno et al., 2004).

Table 1 Risk factors for interferon-induced depression. Female gender Baseline subthreshold depression Personal History of Major Depression Personal History of Psychiatric Disorder High baseline IL-6 levels Abbreviations: IL=interleukin.

influence on compliance (Lo Re et al., 2011; Rodis and Kibbe, 2010). However, data in coinfected patients are contradictory. Indeed, HIV/ HCV coinfection by itself seems to have a positive influence on adherence (Lo Re et al., 2011), and psychiatric comorbidity is not associated with lower adherence, treatment completion, sustained virological response (SVR), or depression during PegIFNα treatment (Alavi et al., 2012; Hauser et al., 2009). 3.2.3. Risk factors Clinical, genetic and biological markers have been proposed in an effort to predict the occurrence of IFN-α neuropsychiatric adverse effects (Table 1) (Udina et al., 2014). Several studies have demonstrated that patients with higher levels of baseline depressive symptoms have higher depression scores during IFN-α therapy, and therefore are more likely to develop clinically significant depression (Schaefer et al., 2012), and this is also true in coinfected patients (Alavi et al., 2012). Some studies have shown that high baseline inflammation predicts the occurrence of IFN-α-induced depression. For instance, higher baseline levels of some cytokines predict depression: interleukin-6 (Prather et al., 2009; Wichers et al., 2006), soluble interleukin-2 receptor (Wichers et al., 2006), interleukin-10 (Wichers et al., 2006), soluble tumor necrosis factor-receptor-1 (Friebe et al., 2007), and levels of soluble interleukin-6 receptor (Friebe et al., 2007). Both brain- and immune-related genes have also been proved as predictors of IFN-α induced psychopathology. Two studies have shown an association between the allele of the short/long polymorphism in the serotonin transporter and depression (Lotrich et al., 2009). The apolipoprotein E e4 has been shown to predict depression, irritability and anxiety during IFN-α therapy (Gochee et al., 2004). Recently, Rasimas et al. found in a gene expression analysis a total of twenty-four genes (16 upregulated and 8 downregulated) that were differentially expressed at baseline in patients who afterwards developed IFNα neuropsychiatric side effects (Rasimas et al., 2012).

3.2.2. Consequences IFN-α neuropsychiatric side effects are thought to have a high impact on treatment compliance, and consequently on response rates. Furthermore, they are an important barrier to access antiviral treatment, especially in coinfected individuals. The proportion of coinfected HIV/HCV individuals who initiate HCV therapy remained less than 25% in Western countries, in spite of availability of dual therapy with PegIFNα and ribavirin (Scott et al., 2009). Mild neuropsychiatric symptoms along with controlled HIV infection are the strongest independent predictors of HCV treatment initiation in different samples of coinfected patients (Butt et al., 2006; Cachay et al., 2013; Scott et al., 2009). When compared with HCV monoinfection, hepatitis C therapy is less effective in coinfected individuals due, in part, to high rates of treatment discontinuation. In monoinfected patients rates of discontinuation secondary to adverse events ranged from 7% to 21% (Fried, 2002) while in HIV/HCV coinfected patients therapy discontinuation occurred in 12%–50% (Carrat et al., 2004; Torriani et al., 2004; Voigt et al., 2006). However, if treated in multidisciplinary settings, discontinuation rates are low 4%–6% (Fumaz et al., 2007). Treatment adherence is a crucial point for successful treatment of HCV (Lo Re et al., 2011), and mental disorders have a strong negative

3.2.4. Neurobiology Although multiple pathways have been proposed to explain the neuropsychiatric toxicity of IFN-α, two mechanisms emerge from the others: modifications in monoamine metabolism and impaired neuroendocrine functioning. IFN-α has the ability to alter the synthesis, transport and turnover of monoamines (Capuron and Miller, 2011). 3.3. Direct-acting antivirals (DAA) The treatment available for HCV has changed significantly over recent decades, from IFN monotherapy to IFN and ribavirin combination therapy to PegIFN with ribavirin. Recently, direct antivirals such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to improve efficacy of PegIFN and ribavirin (Kamal, 2014). Results to date indicate that SVR rates with alloral DAA regimens in HIV/HCV co-infected patients are comparable to those of HCV monoinfected patients (Bichoupan and Dieterich, 2014). However, some drug–drug interactions between antiretroviral agents and DAAs may cause toxicity, lower the likelihood of SVR, and lead to development of antiretroviral resistance (Grebely et al., 2015) (Table 2). Drug-drug interactions based on the metabolization of medications 175

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Table 2 Drug-drug interactions between HCV DAAs and HIV antiretrovirals.

Simeprevir

Sofosbuvir

Telaprevir

Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Efavirenz Etravirine Nevirapine Rilpivirine Atazanavir; Atazanavir/Ritonavir Darunavir/Ritonavir Fosamprenavir Lopinavir Saquinavir Dolutegravir Elvitegravir/Cobicistat Maraviroc Raltegravir - Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. Red: These drugs should not be coadministered. - The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool).

3.3.1. Drug-drug interactions between DAAs and psychoactive drugs (Table 3)

are uncommon with PegIFN and ribavirin dual therapy. However, interactions were most often observed with the HAART. For example, zidovudine may enhance hemoglobin decrease and thus, lead to a dose reduction in ribavirin (Bräu et al., 2004). Didanosine is associated with cases of hepatic decompensation in patients with liver cirrhosis (Mauss and Klinker, 2013). Telaprevir and boceprevir are the first-generation oral protease inhibitors. Both drugs are mainly metabolized by cytochrome P450 3A4 and inhibit 3A4 and 3A5 isoenzymes. Additionally, both drugs inhibit P-glycoprotein (Ghosal et al., 2011). The majority of psychiatric drugs is also metabolized via cytochrome P450 and may show substantial interactions when administered simultaneously. Simeprevir and faldaprevir are second-generation protease inhibitors and are currently being evaluated. They can also interact with the cytochrome P450 system but to a lesser extent than their predecessors (Asselah and Marcellin, 2014). Sofosbuvir is a nucleoside analog inhibitor and has recently been approved by regulatory authorities to be used in clinical practice. One major feature of sofosbuvir is its pan-genotypic antiviral effect (Kamal, 2014). Sofosbuvir does not seem to interact with the cytochrome P450 system and has not substantial interactions with the majority of psychiatric drugs. Sofosbuvir is taken once daily and it is recommended to be used in combination with IFN-α and ribavirin. Besides, it allows reduction in the duration of the IFN-α treatment to 12 weeks. Hence, the European Association for the Study of the Liver (EASL) considers it as the standard of care for co-infected patients (European Association for Study of Liver, 2015) (Table 3).

3.3.1.1. Antidepressants. Antidepressants are frequently used for depression treatment in HIV/HCV coinfected persons. SSRIs are the most often recommended for this specific population and among them, citalopram and escitalopram may be the most frequently used. Both are metabolized via cytochrome P450, especially by 3A4 and 2D6 isoenzymes. Studies with sofosbuvir or simeprevir and escitalopram have shown no major interactions between them. Hence, escitalopram can be use with both HCV protease inhibitors. Since citalopram has a similar degradation pathway, it can be considered safe too (Mauss and Klinker, 2013). Fluoxetine and paroxetine are primarily metabolized by CYP2D6 and therefore considered to be safe when combined with sofosbuvir and simeprevir.

3.3.1.2. Benzodiazepines. In general, sedatives should be avoided since its concentration can increase substantially when administered with boceprevir and telaprevir (Garg et al., 2012). However, sofosbuvir can be co-administered with the majority of benzodiazepines with no significant interactions expected. Zolpidem shows a concentration diminution when administered with telaprevir and can be given safely (Luo et al., 2012).

3.3.1.3. Antipsychotics. Pymozide should not be administered with boceprevir and telaprevir since there is an increased risk of cardiac 176

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Table 3 Drug-drug interactions between HCV DAAs and psychoactive drugs.

Simeprevir

Sofosbuvir

Telaprevir

Antidepressants amitriptyline citalopram duloxetine escitalopram fluoxetine paroxetine sertraline trazodone venlafaxine Antipsychotics amisulpiride aripiprazole chlorpromazine clozapine haloperidol olanzapine paliperidone quetiapine risperidone Benzodiazepines alprazolam bromazepam clonazepam diazepam lorazepam lormetazepam - Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. Red: These drugs should not be coadministered. - The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool).

arrhythmia (Mauss and Klinker, 2013). The majority of second generation antipsychotics (SGA) are metabolized by cytochrome P450 3A4. In opposition, olanzapine is metabolized by the cytochrome P450 1A2 isoenzyme and thus, can be considered safe. Paliperidone is the SGA with lowest hepatic metabolism and considered of choice in HIV patients under antiviral treatment by some authors (Cachay et al., 2013).

3.3.1.6. Opioid substitution treatment. Methadone and buprenorphine have not shown major interactions with boceprevir and telaprevir in clinical studies (Hulskotte et al., 2013). Dose adjustment of methadone is neither necessary with sofosbuvir.

3.3.1.4. Anticonvulsivants. Older anticonvulsivants such as phenytoin, carbamazepine and phenobarbital are strong inductors of cytochrome P450 and are likely to reduce the drug concentrations of all new antivirals. Newer anticonvulsivants such as pregabalin, gabapentin and levetiracetam have no significant hepatic metabolism and can be given without the risk of interactions (Mauss and Klinker, 2013).

Since HCV infection is one of the leading causes of morbidmortality for HIV-infected people in Western countries, HCV eradication should be a priority. PWID and psychiatric patients are among the most predisposed to be coinfected with HIV/HCV but are the least likely to receive HCV treatment. Therefore, there is an urgent need to enhance mechanisms through which this subset of patients can be treated. Research has shown that patients with histories of current or past psychiatric disorders can successfully complete a course of IFN therapy and that sustained virologic response (SVR) rates are similar to those without these comorbid disorders (Ho et al., 2001; Sylvestre, 2005; Sylvestre et al., 2004). Some authors have already proposed a change of paradigm from a HCV treatment focused on antiviral therapy to a broader concept including the management of the comorbidities (Loftis et al., 2006;

3.4. Mental health management of HIV/HCV coinfected patients before antiviral treatment

3.3.1.5. Lithium. Lithium is not metabolized by the cytochrome P450 system and can therefore, be considered safe when used with antivirals. However, it has shown toxicity in HIV patients with nephropathy and it is not recommended in this specific population.

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Overall, if psychiatric complications arise during IFN-α-treatment, acute pharmacological intervention becomes necessary. Psychopharmacological approaches are useful to treat IFN-α-induced neuropsychiatric side effects, specially depression, irritability and insomnia (Schaefer et al., 2012). Several uncontrolled studies and one randomized, double-blind, placebo control trial (Kraus et al., 2008) have shown that antidepressants are highly effective in treating IFN-α-induced depression, specially the selective serotonin reuptake inhibitors (SSRI) (Schaefer et al., 2012). Adverse effects associated with SSRIs are comparable to those in patients not coinfected. Current data do not indicate negative longterm effects on SVR or an increase of treatment discontinuation because of side effects of antidepressants (Raison et al., 2007; Schaefer et al., 2013a). If patients respond to acute pharmacological treatment the antidepressant should be continued through antiviral therapy and for 6–12 weeks after discontinuation because persistence or recurrence of depression has been described after the end of antiviral treatment (Schaefer et al., 2012). In case of nonresponse, Baraldi et al. have summarized a range of other alternatives that were successfully used in single cases (Baraldi et al., 2012). For other IFN-α related psychiatric symptoms, no specific trial data are available and symptomatic treatment should be individualized. Fatigue may be ameliorated by antidepressant treatment. However, it can also be distinct from depression and related to basal ganglia alterations and decreased dopaminergic function (Capuron and Miller, 2011). One prospective and controlled trial showed a positive effect of ondansetron (Piche et al., 2005), but data have not been confirmed so far. Single case reports also indicate some partial positive effects of tryptophan, bupropion or modafinil (Martin et al., 2007; Schaefer et al., 2005). Concerning cognitive disturbances associated to depressive symptoms, antidepressants can be regarded as first line treatment. However, no specific treatment is known for acute or long-lasting cognitive symptoms unrelated to depression. For insomnia, benzodiazepines or related hypnotics should be avoided if possible because of the risk of addiction. Sedative antidepressants (mirtazapine, trazodone) or antipsychotics may be used instead (Schaefer et al., 2013a). Irritability is a difficult-to-treat symptom, which can have many causes such as sleep disturbance, depression, mixed state, mania, psychosis, or worsening of agitation and impulsivity in patients with personality disorders. Irritability as a symptom of depression might respond to antidepressant treatment. However, if irritability is related to mania, antidepressants may exacerbate the symptom, and a case series study has suggested that a small dose of antipsychotic medication can help (Maddock et al., 2004). In case of manic or psychotic symptoms, confusional state, or suicidal thoughts, patients should immediately be referred to a psychiatrist. The decision to reduce dose or discontinue IFN-α treatment should be made by the multidisciplinary team (Schaefer et al., 2012). Since the detection of early IFN-α-related depressive symptoms relies on close observation and may be missed, the prophylactic use of antidepressants has been proposed. There are three open label trials focused on this topic. In all three studies, antidepressants were able to reduce the incidence of IFN-α-induced depression. Six prospective, randomized, placebo-controlled trials have been published up to date (Raison et al., 2013; Sarkar and Schaefer, 2014). In four of them, antidepressant pre-treatment with paroxetine, citalopram or escitalopram did not reduce the incidence of IFN-α induced major depressive episodes or the overall severity of depressive symptoms. However, the largest trial to date by Schaefer et al. demonstrated a positive effect of escitalopram on the incidence and severity of depression. A metaanalysis of these studies concluded that antidepressant pretreatment

Schaefer et al., 2013b). This implies a co-management model of care in the frame of a multidisciplinary team (Loftis et al., 2006). It is very important to intensively inform the patients about HCV and its treatment, as well as the possible neuropsychiatric symptoms associated with IFN. The risk for severe psychiatric disorders might be higher in patients who are not aware of their association with antiviral treatment and may lead to lack of adherence. First of all, a screening for substance use disorders and psychiatric disorders should be done to all HIV/HCV coinfected patients. It is recommended that patients with a psychiatric history receive psychiatric consultation and a psychiatric symptom rating scale should be used before beginning antiviral treatment (Loftis and Hauser, 2003; Schaefer et al., 2013b). Besides, an optimization of the psychiatric treatment will be needed in order to stabilize the patients and to prevent possible drug interactions. The resolution to offer antiviral therapy should be individualized in current users of illicit drugs or alcohol. These patients should be referred to an addiction specialist for a suitable handling. An opiate substitution program should be provided, for patients suffering from opioid dependence (Loftis and Hauser, 2003; Robaeys et al., 2013). It is also important to confirm that patients abstain from regular alcohol consumption given its effects on liver fibrosis and treatment response reduction. In case they cannot, treatment for alcohol dependence should be provided (Schaefer et al., 2013b). Furthermore, there are some psychosocial issues that can entangle antiviral therapy and reduce compliance. They include subclinical psychiatric symptoms, general life instability and inadequate resources (Schaefer et al., 2013b). Measurement of social functioning before antiviral treatment is needed because it may predict who can be at risk of developing psychiatric side effects during HCV treatment. Additionally, strategies to improve psychological adaptation to chronic medical illness, develop adaptative coping skills, increase social support and promote a healthy lifestyle should be implemented (Schaefer et al., 2012). 3.5. Mental health management and prevention of IFN-α associated psychiatric problems In the course of IFN-α therapy, the patient's mental state should be regularly evaluated in order to detect treatment-related symptoms. A program for HIV/HCV coinfected patients would be monthly visits during the first 12 weeks of treatment, followed by visits at 8- to 12week intervals from there on until the end of therapy (Ghany et al., 2009). In contrast, patients with a history of psychiatric or drug use disorders, monitoring should be done every 2–4 weeks during the first 3 months, and then every 4–6 weeks until 12–24 weeks after antiviral treatment (Schaefer et al., 2012). It is also suggested to use validated screening scales to assess the severity of psychiatric symptoms (Leutscher et al., 2010). Still, they are not diagnostic instruments, and a diagnosis of depression should be confirmed by a psychiatrist (Schaefer et al., 2013b). In some cases, psychiatric referral should be needed; if the treating physician is unable to diagnose correctly or to manage psychiatric problems; the initial management has failed; the psychiatric situation is complex or uncertain; there is an identified or suspected risk of suicide, alcohol, or substance abuse; there is a complex and difficult social situation; multiple psychotropic drugs are necessary; or psychotherapeutic treatment is required (Schaefer et al., 2013b). In severe cases such as high suicide risk, lack of response to treatment, psychotic symptoms or disorientation, psychiatric hospitalization may be considered (Schaefer et al., 2012). Discontinuation of antiviral treatment because of psychiatric complications should be decided individually, but in most cases treatment can be continued without dose reduction or discontinuation if an adequate therapeutic management of the psychiatric side effects is offered (Loftis et al., 2006). 178

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reduced the overall incidence of major depression during IFN treatment in all patients and was associated with lower mean depression scores after 12 and 24 weeks of IFN treatment (Sarkar and Schaefer, 2014). 4. Discussion HCV infection is a major cause of morbi-mortality in HIV-infected patients. Thus, HCV management has become a priority in the care of HIV-infected patients in Western countries. Antiviral therapy based on PegIFNα is usually associated with significant psychiatric side effects, which may reduce treatment adherence and constitute risk factors for treatment failure. Furthermore, they are an important barrier to access treatment, especially in HIV/ HCV coinfected patients. However, data so far indicate that IFNαinduced psychiatric side effects have a similar prevalence in HIV/HCV coinfected patients than in monoinfected patients and they can be managed and even prevented successfully with psychopharmacological strategies. In addition, treatment for HCV infection has changed significantly over recent decades, with the appearance of new antivirals and treatment combinations without IFNα. New antivirals seem to be safer regarding psychiatric side effects, but new drug-drug interactions should be considered. In general, HCV/HIV co-infected individuals should be considered as a population in high need for treatment of hepatitis C with the new DAAs. Hence, coinfected patients can complete a course of therapy with similar SVR rates than no-coinfected individuals. Nonetheless, this goal can only be achieved if a co-management model of care is implemented in the frame of a multidisciplinary team, which would include hepatologists, nurse practitioners, psychiatrists and substance use specialists. Conflicts of interest None. References Alavi, M., Grebely, J., Matthews, G.V., Petoumenos, K., Yeung, B., Day, C., Lloyd, A.R., Van Beek, I., Kaldor, J.M., Hellard, M., Dore, G.J., Haber, P.S., 2012. Effect of pegylated interferon-α−2a treatment on mental health during recent hepatitis C virus infection. J. Gastroenterol. Hepatol. 27, 957–965. http://dx.doi.org/10.1111/ j.1440-1746.2011.07035.x. Alberti, A., Vario, A., Ferrari, A., Pistis, R., 2005. Review article: chronic hepatitis C– natural history and cofactors. Aliment. Pharmacol. Ther. 22 (Suppl. 2), 74–78. http://dx.doi.org/10.1111/j.1365-2036.2005.02602.x. Aspinall, E.J., Corson, S., Doyle, J.S., Grebely, J., Hutchinson, S.J., Dore, G.J., Goldberg, D.J., Hellard, M.E., 2013. Treatment of hepatitis C virus infection among people who are actively injecting drugs: a systematic review and meta-analysis. Clin. Infect. Dis. 57 (Suppl. 2), S80–S89. http://dx.doi.org/10.1093/cid/cit306. Asselah, T., Marcellin, P., 2014. Second-wave IFN-based triple therapy for HCV genotype 1 infection: simeprevir, faldaprevir and sofosbuvir. Liver Int. 34, 60–68. http:// dx.doi.org/10.1111/liv.12424. Baraldi, S., Hepgul, N., Mondelli, V., Pariante, C.M., 2012. Symptomatic treatment of interferon-α-induced depression in hepatitis C: a systematic review. J. Clin. Psychopharmacol. 32, 531–543. http://dx.doi.org/10.1097/ JCP.0b013e31825d9982. Befrits, R., Hedman, M., Blomquist, L., Allander, T., Grillner, L., Kinnman, N., Rubio, C., Hultcrantz, R., 1995. Chronic hepatitis C in alcoholic patients: prevalence, genotypes, and correlation to liver disease. Scand. J. Gastroenterol. 30, 1113–1118. Berenguer, J., Alvarez-Pellicer, J., Martín, P.M., López-Aldeguer, J., Von-Wichmann, M.A., Quereda, C., Mallolas, J., Sanz, J., Tural, C., Bellón, J.M., González-García, J., 2009. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 50, 407–413. http://dx.doi.org/10.1002/ hep.23020. Bichoupan, K., Dieterich, D.T., 2014. Pegylated-IFNα2a for HIV/hepatitis C virus coinfected patients: out with the old, in with the new. Expert Opin. Biol. Ther. 14, 1369–1378. http://dx.doi.org/10.1517/14712598.2014.943180. Bonner, J.E., Barritt, A.S., Fried, M.W., Evon, D.M., 2012. Time to rethink antiviral treatment for hepatitis C in patients with coexisting mental health/substance abuse issues. Dig. Dis. Sci. 57, 1469–1474. http://dx.doi.org/10.1007/s10620-012-21414.

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