A clinical textbook

Hepatology 2018

14. Management of adverse drug reactions

Martin Schaefer and Stefan Mauss

Introduction

Good adherence is a key factor in the successful treatment of chronic hepatitis C infection, just as for any other antiviral therapy of chronic viral disease. Good adherence was especially challenging for interferon-based treatments, which was the only available treatment option for the last two decades. By the end of 2013, the first interferon-free therapies based on direct acting antivirals (DAA) became available. These interferon-free regimens should have now replaced interferon based treatment as standard of care (EASL 2016). DAAs have much better efficacy, substantially improved tolerability and shorter treatment duration compared to interferon-based therapies (see Chapters 12 and 13).

However, interferon-based therapies will remain an option or even remain the standard of care for patients in resource limited settings. This is due to a high-cost strategy chosen by the pharmaceutical companies, which limits access to these direct acting antivirals (DAAs) in particular in medium income countries, with no access to generic drugs. In addition, prioritsing access for only people with most advanced HCV may limit access to DAAs in the US and some European countries. As a consequence, interferon-based therapies are still used to treat hepatitis C despite the lower efficacy and unfavourable adverse event profile.

Almost all patients on treatment with interferon plus ribavirin therapy will experience adverse events that can significantly influence their adherence. Therefore, proactive clinical management is crucial in order to avoid suboptimal therapy and/or unnecessary treatment discontinuations. In this chapter we will first discuss adverse events associated with dual therapy with interferon plus ribavirin, then address the adverse events associated with triple therapy that includes a DAA (simeprevir, daclatsvir or sofosbuvir), and finally interferon-free treatment regimens.

Interferon-based therapies

The most common adverse events in patients on treatment with pegylated interferon plus ribavirin are flu-like symptoms, myalgia, sleep disturbances, asthenia, gastrointestinal disorders and depressive episodes (Table 1).

For most adverse events, clinical trials with dose adjustment have not been carried out, and due to this, recommendations in this review are necessarily partially based on clinical experience.

Table 1. Common adverse events during therapy with peg-interferon α-2b or -2a plus ribavirin (McHutchinson 2009)
Common adverse events (≥25% incidence) Peg-interferon α-2b + ribavirin (n=1019) Peg-interferon α-2a + ribavirin (n=1035)
Fatigue 66% 63%
Headache 50% 42%
Nausea 43% 36%
Insomnia 39% 41%
Pyrexia 35% 23%
Anaemia (<10 g/dL) 34% 34%
Myalgia 27% 23%
Neutropenia (<1000 cells/µl) 26% 32%
Depression 26% 21%
Irritability 25% 25%
Rash 22% 28%

Flu-like symptoms, fever, arthralgia and myalgia

Flu-like symptoms, fever, arthralgia and myalgia appear a few hours after the injection of pegylated interferon (PEG-IFN) and may last for up to three days. One common approach is to use paracetamol or other NSAIDs immediately before or after the injection of interferon. Flu-like symptoms usually diminish spontaneously over the first weeks of treatment (Figure 1).

Low platelets are a contraindication for the use of acetylsalicylic acid, diclofenac or ibuprofen because of the inhibition of platelet aggregation. High doses of paracetamol may result in liver toxicity. Doses exceeding 2 g/day of paracetamol are therefore not recommended.

Figure 1. Time course of interferon-associated adverse events

Gastrointestinal disorders

Nausea can be mitigated by prokinetic agents such as metoclopramide or domperidone taken about 15 minutes before the intake of ribavirin, the usual cause of nausea with dual therapy. This may also positively influence the frequently observed loss of appetite.

Dry mouth has been reported as a result of inhibition of saliva production, a frequent complication of ribavirin, which may continue for weeks after discontinuation of therapy.

Weight loss

The average weight loss in interferon-based controlled studies is around 6–10% for a treatment period of 48 weeks (Seyam 2004). This may be predominantly due to loss of appetite and reduction in calorie intake. Weight loss is rapidly reversible upon discontinuation of therapy.

Asthenia and fatigue

Asthenia and fatigue are frequent complaints of patients that usually increase slowly in intensity over the first couple of weeks of therapy (Figure 1). In patients with marked anaemia these symptoms can be improved by raising low hemoglobin via the use of erythropoietin, reduction of ribavirin or red blood cell transfusion (Pockros 2004). Asthenia is also reported by patients without marked anaemia. In these patients hypothyroidism may be the explanation. Symptomatic treatment of asthenia and fatigue in patients without an underlying complication such as anaemia, depression or hypothyroidism is difficult.

Chronic fatigue has been successfully treated in individual cases with antidepressants or tryptophan (Sammut 2002, Schaefer 2008). One prospective randomised controlled trial showed superior effects of the 5-HT3 receptor antagonist ondansetron compared to placebo (Piche 2005). However, currently available data does not offer specific treatment recommendations.

Cough and dyspnoea

Cough while on therapy is frequently reported and is most probably due to edema of the mucosa of the respiratory system. Therefore, advanced, not well-controlled asthma bronchiale may be a contraindication for hepatitis C therapy. Dyspnoea is another frequent complaint with a more complex aetiology involving mucosa swelling, anaemia and asthenia.

Disorders of the thyroid gland

Hypothyroidism while on interferon-based therapy is reported with an incidence of 3–10% (Bini 2004, Tran 2005). Hyperthyroidism is less frequently observed with an incidence of 1–3% (Bini 2004, Tran 2005). The prevalence of thyroid dysfunction is higher in patients with the presence of liver/kidney microsomal antibodies (Manns 1999, Mauss 2012). Interferon-induced thyroiditis or the induction of thyroid antibodies is reported as an underlying mechanism. Hypothyroidism is treated via substitution of thyroid hormone whereas clinically symptomatic hyperthyroidism may be treated with ß-blockers or carbimazole. Premature termination of interferon-based therapy is usually not necessary. About half of the cases of hypothyroidism are reversible upon discontinuation of interferon-based therapy, although some cases may need prolonged periods of thyroid hormone replacement therapy.

Psychiatric adverse events

Incidence and profile of psychiatric adverse events

The most commonly emerging IFN α-induced psychiatric adverse events are outlined in Table 2. However, data on the frequency of psychiatric side effects differs depending on the design of the trial.

Table 2. Incidence of most reported IFN α-induced psychiatric side effects (modified from Schaefer 2012)
Psychiatric side effects Incidence
Fatigue 40–80%
Sleep disturbances 20–45%
Irritability 20–45%
Cognitive disturbances with impairments of concentration and memory 20–30%
Depressive episodes 20–70%
Mild 40–70%
Moderate 20–40%
Severe 5–20%
Delirium, psychosis, mania 1–3%
Suicidal thoughts 3–10%
Suicide attempts 0–0.02%

Most hepatological trials are only monitored for depression as a single symptom without using depression scales or diagnostic instruments, leading to an underreporting of mild to moderate depressive episodes. Most psychiatric trials used self-rating scales (e.g., SDS scale, BDI Scale) or monitor patients via expert rating scales (Hamilton Depression Scale [HAMDS] or Montgomery Asperg Depression Scale [MADRS]) to detect depressive syn scores did not fulfil DSM-IV criteria for a major depressive episode. Regarding these more sensitive psychiatric rating methods, over 50% of patients suffer from sleep disorders, chronic fatigue, irritability or cognitive disturbances (Schaefer 2012, Schaefer 2007, Schaefer 2002, Dieperink 2000, Renault 1987). Increased levels of anxiety may occur in up to 45% of patients, especially during the first 2–3 months of treatment. Mild depression with symptoms like reduced self-esteem, anhedonia, loss of interest, rumination, a diminished libido and spontaneous crying can be observed in 30–70% of the patients. 20–40% of treated patients develop moderate to severe depressive episodes (Schaefer 2012, Bonnaccorso 2002, Dieperink 2000, Renault 1987, Schaefer 2002, Malaguarnera 2002). Major depression has been reported in 15–55% (Schäfer 2007). Suicidal thoughts may occur in up to 10% of patients, while suicide attempts have been reported in single cases (Janssen 1994, Sockalingam 2010). Mania or psychosis has been reported as sporadically appearing side effects. Contrary to assumptions, patients with pre-existing psychiatric disturbances do not appear to have a greater risk for development of depression or attempting suicide (Schaefer 2012, Schaefer 2007, Schaefer 2003, Pariante 2002). However, patients with intravenous drug use not stabilised in a substitution treatment programme (e.g., methadone) seem more likely to discontinue treatment in the first three months compared to controls (Schaefer 2003, Mauss 2004, Schaefer 2007).

Antidepressants frequently used in trials are selective serotonin re-uptake inhibitors (SSRIs) such as citalopram, escitalopram, paroxetine or sertraline. The introduction of SSRIs and other current antidepressants has markedly improved the adverse event profile of antidepressants. Depending on the major symptoms, sedating or activating antidepressants, especially SSRIs, are treatment of choice for interferon-induced depressive mood disorders (Table 2). In patients with predominantly agitation and aggression, other strategies, e.g., the newer antipsychotics, may be added.

The efficacy of antidepressants for the treatment of interferon-induced depression has been shown in several open uncontrolled cohorts (Farah 2002, Gleason 2002, Kraus 2001, Schramm 2000, Hauser 2002, Gleason 2005). In the only prospective randomised controlled trial, an improvement of depressive symptoms after treatment of IFN-associated depression was shown with citalopram compared to placebo (Kraus 2008). In particular, because of the favourable adverse event profile, SSRIs seem to be most appropriate for treatment of IFN-associated depressive symptoms. However, antidepressants with different receptor profiles (i.e., mirtazapine) and classic antidepressants (i.e., nortriptyline) are also effective (Kraus 2001, Valentine 1995). Nevertheless, tricyclic antidepressants should be used as second choice because of pharmacological interactions, anticholinergic side effects, a higher risk for development of delirium, and liver or myocardial toxicity. To reduce early occurring adverse events of SSRIs (headache, nausea, agitation), treatment with antidepressants should be started at a low dose with subsequent dose increase depending on the effect and tolerability. In general, a therapeutically relevant antidepressive effect cannot be expected before day 8–14 of treatment. In case of non-response, the dose can be escalated. Treatment adherence should be assessed by monitoring serum levels before patients are switched to a different antidepressant.

Benzodiazepines can be given for a short period in cases of severe sleep disturbances, anxiety, agitation, irritability or severe depression. However, benzodiazepines should be avoided in patients with a history of IV drug or alcohol over-use because of their potential to induce addiction.

In the case of psychotic or manic symptoms, antipsychotics (e.g., risperidone, olanzapine) can be used at low doses together with benzodiazepines, but patients should be monitored carefully by a psychiatrist. One important risk factor for the development of psychotic symptoms is a history of drug use.

Although history of major depression or suicide attempts is considered a contraindication for interferon-based therapy, treatment of patients with pre-existing psychiatric disorders can be initiated in close collaboration with an experienced psychiatrist in a well-controlled setting (Schaefer 2004, Schaefer 2007).

Preemptive therapy with antidepressants

One double-blind randomised study with patients with malignant melanoma demonstrated that 14 days of pre-treatment with 20 mg paroxetine per day reduced the incidence of depression during interferon therapy significantly (Musselmann 2001). Pre-treatment with paroxetine also had a positive effect on the development of fears, cognitive impairments and pain during interferon treatment, but not on symptoms such as fatigue, sleep disturbances, anhedonia and irritability (Capuron 2002). A recent prospective controlled trial with HCV-infected patients demonstrated that pre-treatment with citalopram significantly reduced depression during the first 6 months of antiviral therapy in patients with psychiatric illness compared to controls (Schaefer 2005). Furthermore, prophylactic treatment with SSRIs was shown to reduce the severity of depressive symptoms in patients who had suffered from severe depression during previous treatment of hepatitis C with interferon α (Kraus 2005). A first randomised controlled trial confirmed a protective effect of preemptive initiation of treatment with antidepressants before starting interferon-based therapy in cases of elevated depression scores (Raison 2007). Two other trials using escitalopram for antidepressant pre-treatment found a significant reduction of depression during antiviral treatment with IFN plus ribavirin. In the largest trial so far, the overall incidence of depression, major depression and severe depression was significantly lower in patients who received a preemptive antidepressant therapy (Schaefer 2012). Another trial also resulted in less depressive symptoms in patients with escitalopram pre-treatment (De Knegt 2011). Three small trials did not show significant effects on reduction of depressive symptoms or overall incidence of major depression, although these trials were either small in size or had short observation times (Morasco 2007, Morasco 2010, Diez-Quevedo 2010). However, three meta-analyses showed that prophylactic SSRI antidepressants can significantly reduce the incidence of PEG-IFN+RBV-associated depression in patients with chronic hepatitis C, with good safety and tolerability, without reduction of sustained virologic response (Hou et al. 2013, Sarkar & Schaefer 2014, Udina et al. 2014). Regarding the decision making, patients who report sadness or mild depressive symptoms before antiviral treatment have an increased risk of developing depression and patients with mild cognitive disturbances have been shown to have an increased risk for severe depression and should receive a prophylactic antidepressant treatment (Sarkar et al. 2015).

In summary, current data support the view that patients with pre-existing depressive symptoms and/or mild cognitive disturbances should receive a prophylactic treatment with antidepressants. However, in patients without psychiatric risk factors, antidepressants can be given before antiviral plus interferon-based therapy on case-by-case basis.

Sleep disturbances

Patients who have difficulties falling asleep can be treated with zopiclone or trimipramine. Zolpidem may be used for patients with interrupted or shortened sleep patterns. Although the risk of addiction is markedly reduced compared with other benzodiazepines, only small amounts of zoplicone or zolpidem should be prescribed at a time and therapy should be limited to the period of interferon-based therapy. All sedatives in particular when taken late at night or in higher dose can impair the awareness and ability to concentrate the next morning, which may affect the ability to drive or work. Moreover, drug-drug interactions with the direct antiviral drugs, in particular the HCV protease inhibitors, have to be taken into account. As sleeping disorders can be an early symptom of depression, it is also important to assess the possible presence of other depressive symptoms when considering the use of sleeping aids.

Hematological and immunologic effects

In general, interferon-based therapy is accompanied by a marked drop in white blood cells. This includes absolute but not relative CD4+ cell count. This change of the cellular immune system does not result in an increased number of serious infections even in HIV-coinfected patients (Fried 2002, Manns 2001, Torriani 2004). In general, the incidence of serious infections is low (<5%) in patients on interferon-based therapy.

G-CSF increases neutrophils in patients treated with interferon-based therapies. However G-CSF has not been proven to have a clinical benefit in clinical trials and its use is off-label.

Hemolytic anaemia induced by ribavirin is further aggravated by the myelosuppressive effect of interferon inhibiting compensatory reticulocytosis (De Franceschi 2000). As a consequence, anaemia (<10 g/dL) is reported in up to 20% of patients (Hadziyannis 2004). In severe cases of anaemia dose reduction of ribavirin is required. In rare cases, red blood cell transfusion may be necessary. Erythropoietin can be successfully used to correct the ribavirin-induced anaemia at least partially and to avoid ribavirin dose reduction or red blood cell transfusions. In addition, erythropoietin use was associated with an improved quality of life. However, prospective controlled trials have not shown a positive effect on the efficacy of hepatits C therapy in patients who take erythropoietin (Afdahl 2004, Pockros 2004, Shiffman 2007). At present, erythropoietin is not approved for correction of ribavirin-induced anaemia in hepatitis C therapy and is reimbursed only in a small number of countries.

Mild to moderate thrombocytopenia is frequently seen in patients with advanced liver fibrosis and may complicate interferon-based therapy. Reduction of interferon dosing may be indicated to reverse severe thrombocytopenia. In studies eltrombopag has been used successfully to increase platelet count in patients with hepatitis C associated thrombocytopenia (McHutchinson 2007). In recent trials, eltrombopag increased the efficacy of hepatitis C treatment in cirrhotic patients, although the occurrence of portal vein thrombosis and thromboembolism was observed in about 5% of patients, which urges caution in widespread use (Afdhal 2011).

Skin disorders and hair loss

Some skin disorders such as lichen ruber planus, necrotising vasculitis or porphyrea cutanea tarda are associated with hepatitis C infection (see Chapter 15). The effects of hepatitis C therapy are often not well-studied and based only on information gathered through cohorts (Berk 2007).

Interferon and ribavirin therapy may have an effect on the skin itself including dry skin, itching, eczema and new or exacerbated psoriasis. Ointments with rehydrating components, urea or steroids can be used depending on the nature of the skin disorder. In severe cases a dermatologist should be involved. In particular, eczema and psoriasis may last substantially longer than the treatment period with interferon-based therapy.

Local skin reactions to the injection of pegylated interferon are common and usually present as red indurations lasting days to weeks. Repeated injections at the same site may cause ulcers and should be avoided. Hypersensitivity reactions to pegylated interferons are reported anecdotally.

Hair loss is frequent, usually appearing after the first months of therapy and continuing for some weeks after the cessation of therapy. Alopecia is very rare and hair loss is usually fully reversible, although the structure of the hair may be different after therapy.

Adverse events associated with combination therapy of pegylated interferon and ribavirin plus direct acting antiviral agents (DAAs)

Boceprevir and telaprevir

Triple combination therapy of pegylated interferon, ribavirin plus one of the first generation HCV protease inhibitors, telaprevir or boceprevir provided better efficacy for genotype 1 infection compared with pegylated interferon and ribavirin, while also offering new challenges for adherence and management of adverse events. In general all adverse events caused by interferon plus ribavirin remained, some were accentuated and/or new adverse events occurred (Table 3).

In a French cohort study including patients with compensated liver cirrhosis treated with telaprevir or boceprevir, an unexpected proportion of serious adverse events (in up to 50% of the patients) was observed including sepsis, hepatic decompensation and death (Hézode 2013). Preliminary data from other cohort studies presented at recent conferences suggest better safety outcomes in cirrhotic patients possibly due to a more cautious use of triple therapy.

Another unexpected adverse event seen in patients on triple therapy with telaprevir and bocepravir is clinically significant renal impairment (Mauss 2013, Karino 2013). The decline in renal function was seen mostly in patients with preexisting risk factors for renal insufficiency, associated with a more pronounced decline in hemoglobin and was reversible in most cases (Mauss 2013).

Due to the pronounced aggravation of the adverse event profile of interferon-based therapy telaprevir and boceprevir had only a limited period of use and production was discontinued after the approval of interferon free DAA regimen.

Table 3. Adverse event profile associated with telaprevir (Jacobson 2011) and boceprevir (Poordad 2011) in therapy-naïve patients in clinical studies
Telaprevir (ADVANCE study) Telaprevir + Peg-interferon α-2a + ribavirin Peg-interferon α-2a + ribavirin
Serious adverse event 11% 9%
Discontinuation due to adverse event 7% 4%
Anaemia (<10g/dL) 45% 16%
Rash 37% 24%
Itching 50% 36%
Anal discomfort/pruritis 17% 4%
Boceprevir (SPRINT-2 study) Boceprevir + Peg-interferon α-2b + ribavirin Peg-interferon α-2b + ribavirin
Serious adverse event 11% 9%
Discontinuation due to adverse event 12% 16%
Anaemia (<10 g/dL) 49% 29%
Dysgeusia 37% 18%

Simeprevir and daclatasvir as part of interferon-based therapy

Simeprevir is a second generation HCV protease inhibitor administered as one pill with once daily dosing and no specific food requirements and was approved in 2014 in the US and Europe. In addition, interactions with the cytochrome P450 system are less pronounced than first generation PIs, resulting in a smaller number of relevant drug-drug interactions (for details see www.hep-druginteractions.org). Simeprevir does not have an additive effect to interferon and ribavirin on the bone marrow. In particular, there was no increase in anaemia compared to dual therapy with interferon plus ribavirin (Fried 2013, Sulkowski 2013, Zeuzem 2013). However, skin toxicity remains an issue and in trials photosensitivity was reported in 3–4% of patients. Other adverse events that were more frequently seen in combinations with simeprevir are rash (25%), itching (20%) and jaundice due to inhibition of the UDP-glucuronyltransferase (Fried 2013, Zeuzem 2013). Jaundice as a result of drug-induced inhibition of the UDP-glucuronyltransferase is characterised by an increase of indirect bilirubin and is clinically innocuous. However, jaundice can also occur as a sign of liver toxicity usually caused by mixed hyperbilirubenia (conjugated and unconjugated) and an increase in liver transaminases, gamma-glutamyltransferase and alkaline phosphatase. Management of skin toxicity primarily includes sun protection and avoidance of tanning. Antihistamines such as cetirizine can be used.

Daclatasvir is an NS5a inhibitor, which was approved in Europe for the use with pegylated interferon and ribavirin in genotype 4. It can also be used in patients with genotype 1, when no interferon free DAA regimen nor sofosbuvir is available. The safety profile of daclatasvir in combination with peginterferon and ribavirin was similar to that seen with peginterferon and ribavirin alone, including some patients with compensated cirrhosis (summary of product characteristics European Medical Agency 2016).

Sofosbuvir as part of interferon-based therapy or as dual therapy with ribavirin

The main problem in assessing the adverse event profile of sofosbuvir is the lack of controlled trials for sofosbuvir as part of interferon based therapy. A comparator arm is essential to show a change in laboratory abnormalities or a difference in a frequently reported adverse event such as fatigue, nausea and headache due to the addition of sofosbuvir. Because of this, historic controls are used to infer conclusions about sofosbuvir side effects. Within these limitations sofosbuvir has not shown a specific adverse event profile when added to PEG-IFN and ribavirin (Lawitz 2013). However, most of these trials were carried out in relatively healthy patients with no substantial comorbidities or polypharmacy.

Studies with sofosbuvir and ribavirin have no ribavirin monotherapy arm as comparator, and the lack of meaningful historic controls make it difficult to draw conclusions on adverse events specific to sofosbuvir (Jacobson 2013). However, adverse events with sofosbuvir and ribavirin are infrequent and usually not serious (Jacobson 2013, Younossi 2013).

Sofosbuvir has no interaction with the cytochrome P450 system and is excreted mainly via the kidney as active metabolite. Potential interactions may involve the P-glycoprotein pathway as sofosbuvir is a substrate of this enzyme. Because of renal excretion of sofosbuvir and its main active metabolite in conjunction with the lack of conclusive studies in patients with advanced renal impairment, sofosbuvir is not recommended in patients with a glomerular filtration rate <30 mL/min (summary of product characteristics European Medical Agency 2016).

Adherence and interferon-based therapies

Adherence data from retrospective analyses suggest that at least 80% of the cumulative doses of ribavirin and interferon need to be taken by patients as a prerequisite for treatment success. Cumulative doses of less than 80% are associated with a steep drop in sustained virologic response (Camma 2005). Another surrogate of adherence is the premature treatment discontinuation rate, which usually ranges from 10–15% with pegylated interferon plus ribavirin (Fried 2002, Manns 2001).

Interferon-free regimens with DAAs

To date, the following combinations are approved for treating chronic hepatitis C: sofosbuvir plus ribavirin, sofusbuvir plus simeprevir +/- ribavirin, sofosbuvir plus daclatasvir +/- ribavirin, sofosbuvir plus ledipasvir +/- ribavirin, the “3D-combination” (ombitasvir + dasabuvir + paritaprevir/ritonavir +/- ribavirin), sofosbuvir plus velpatasvir +/- ribavirin and elbasvir plus grazoprevir +/- ribavirin. However, the indications differ in HCV genotypes covered, treatment duration and possible addition of ribavirin (see Chapter 12).

When ribavirin needs to be added, the main additional adverse events compared to placebo are fatigue, pruritus, asthenia, nausea, insomnia, dry skin, cough, dyspnoea and moderate anaemia (Zeuzem 2014). These side effects are all already reported for the combined use of ribavirin with interferon. However, the incidence and severity is lower when combining ribavirin with direct acting antivirals (DAAs).

For simeprevir, the main adverse events in the rather small COSMOS study (n=167) are skin photosensitivity, rash and jaundice as described above (Lawitz 2014). Incidence of these adverse events was about 10% of the study population or less. Due to the lack of a placebo control a more precise adverse event profile for simeprevir cannot be established. Data from large real world cohorts emerging so far confirm this safety profile for simeprevir in general. Due to accumulation of simeprevir in the liver, this drug should not be used in patients with advanced liver cirrhosis.

For daclatasvir, data from a phase 2 study (also n=167) reported the safety profile in combination with sofosbuvir (Sulkowski 2014). The most frequently reported adverse events were fatigue, headache and nausea, as in most chronic hepatitis C trials. Due to the lack of a placebo control the contribution of daclatasvir to this adverse event profile remains unclear.

For the fixed-dose combination of sofosbuvir and ledipasvir, safety data has been reported from more than 3000 patients treated in studies (e.g., Afdhal 2014, Afdahl 2014b). Due to the lack of published placebo controlled studies it is hard to quantify to what extent sofosbuvir and ledipasvir contribute to the adverse events reported. The most frequent complaints in the published profile are fatigue, headache, insomnia and nausea, but includes no new specific side effects which can be attributed to either sofosbuvir or ledipasvir. However, there have been recent case series of serious complications due to bradycardia and cardiac arrest including some deaths in patients taking antiarrhythmics, in particular amiodarone, in combination with sofosbuvir based DAA regimen (Fontaine 2015, Renet 2015). For this reason, sofosbuvir is contraindicated in patients taking amiodarone.

Another fixed dose combination is sofosbuvir and velpatasvir. The safety profile is very similar to sofosbuvir and ledipasvir. In clinical studies, headache, fatigue and nausea were the most common treatment associated adverse events reported in patients in >10% of patients. However, these and other adverse events were reported at a similar frequency in placebo treated patients compared with sofosbuvir and ledipasvir treated patients.

For the multidrug regimen of ombitasvir + dasabuvir + paritaprevir/RTV +/- ribavirin, the side effect profile is surprisingly good (Ferenci 2014). For this therapeutic strategy again more than 3000 patients were evaluated. In placebo-controlled trials nausea, pruritus, insomnia, diarrhoea and asthenia occurred in significantly more patients on the study drug regimen compared to placebo (Feld 2014). However, the difference in incidence compared to placebo was 10% or lower. Diarrhoea, observed in up to 15% of patients, is a known side effect of ritonavir. The moderate hyperbilirubinemic effect (3% of patients) is attributed to paritaprevir, an inhibitor of the bilirubin transporter OATP1B1. Serious adverse events were reported by 2% of patients in the study drug arm.

Ombitasvir + dasabuvir + paritaprevir/RTV should not be used in patients with decompensated cirrhosis according to the Summary of Product Characteristics as authorised by the European Medical Agency (SMPC European Medical Agency 2015). In contrast, ombitasvir + dasabuvir + paritaprevir/RTV do not accumulate in patients with advanced renal impairment and this combination has shown good efficacy and safety in these patients (Pockros 2016).

Due to boosting with ritonavir, drug-drug interactions with this regimen are frequent and need to be taken into account before initiating therapy.

Elbasvir and grazoprevir +/- ribavirin are approved for treatment of genotype 1 and 4. In clinical studies, the most commonly reported adverse reactions were fatigue and headache. Less than 1% of subjects treated with elbasvir and grazoprevir with or without ribavirin had serious adverse reactions. The frequency of serious adverse reactions and discontinuations due to adverse reactions in subjects with compensated cirrhosis were comparable to those seen in patients without cirrhosis (SMPC European Medical Agency 2016). Elbasvir and grazoprevir are metabolised in the liver mainly by cytochrome P450 3A and P-glycoprotein p. There is no accumulation in patients with renal impairment, no dose adjustment is necessary and elbasvir and grazoprevir showed good efficacy and tolerability in patients with end stage renal disease (Roth 2015).

Conclusion

In summary, the toxicity of interferon-based therapy plus ribavirin is considerable and requires active management and profound knowledge, particularly regarding the management of psychiatric adverse events.

The first generation of HCV protease inhibitors, boceprevir and telaprevir, did improve the efficacy of therapy, in particular in HCV genotype 1 patients, but at the cost of increased toxicities. These characteristics led to the replacement of these medications as soon as less toxic drugs with high efficacy became available.

Second generation protease inhibitors have an improved adverse event profile, are easier to take and have fewer drug-drug interactions.

At present, the first approved polymerase inhibitor, sofosbuvir, seems to have an advantageous adverse event profile when added to interferon-based therapy and has very limited drug-drug interactions.

Interferon and ribavirin free DAA combinations consisting of different combination of HCV-polymerase inhibitors, NS5a inhibitors or HCV-protease inhibitors have the best tolerability. However, ribavirin remains a necessity for specific patient populations.

References

Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004;126:1302-11.

Afdhal NH, Dusheiko G, Giannini EG, et al. Final Results of ENABLE 1, a Phase 3, Multicenter Study of Eltrombopag as an Adjunct for Antiviral Treatment of Hepatitis C Virus-Related Chronic Liver Disease Associated With Thrombocytopenia. Hepatology 2011; 54:1427-8.

Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370:1889-98.

Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:1483-93.

Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207-17.

Berk DR, Mallory SB, Keeffe EB, Ahmed A. Dermatologic disorders associated with chronic hepatitis C: effect of interferon therapy. Clin Gastroenterol Hepatol 2007;5:142-51.

Bini EJ, Mehandru S. Incidence of thyroid dysfunction during interferon alfa-2b and ribavirin therapy in men with chronic hepatitis C: a prospective cohort study. Arch Intern Med 2004; 164:2371-76.

Bonaccorso S, Marino V, Puzella, et al. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 2002; 22:86-90.

Cammà C, Licata A, Cabibbo G, Latteri F, Craxì A. Treatment of hepatitis C: critical appraisal of the evidence. Expert Opin Pharmacother 2005;6:399-408.

Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002;7:468-473.

De Franceschi L, Fattovich G, Turrini F, et al. Hemolytic anaemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000; 31:997-1004.

De Knegt RJ, Bezemer G, Van Gool AR, et al. Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C. Aliment Pharmacol Ther. 2011;34:1306-17.

Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review. Am J Psychiatry 2000;157:867-76.

Diez-Quevedo C, Masnou H, Planas R, et al. Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2011;72:522-8.

EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol (2016), http://dx.doi.org/10.1016/j.jhep.2016.09.001.

Farah A. Interferon-induced depression treated with citalopram. J Clin Psychiatry 2002; 63:166-7.

Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370:1594-603.

Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014;370:1983-92.

Fontaine H, Lazarus A, Pol S, et al. Bradyarrhythmias Associated with Sofosbuvir Treatment. N Engl J Med. 2015;373(19):1886-8.

Fried M, Shiffman M, Reddy R, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-82.

Fried MW, Buti M, Dore GJ, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: The randomized PILLAR study. Hepatology 2013;58:1918-29.

Gleason OC, Yates WR, Isbell MD, Philipsen MA. An open-label trial of citalopram for major depression in patients with hepatitis C. J Clin Psychiatry 2002;63:194-8.

Gleason OC, Yates WR, Philipsen MA. Major depressive disorder in hepatitis C: an open-label trial of escitalopram. Prim Care Companion J Clin Psychiatry 2005;7:225-30.

Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin in combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-55.

Hauser P, Khosla J, Aurora H, et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002;7:942-7.

Hézode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890. J Hepatol 2013;59:434-41.

Hou XJ, Xu JH, Wang J, Yu YY. Can antidepressants prevent pegylated interferon-α/ribavirin-associated depression in patients with chronic hepatitis C: meta-analysis of randomized, double-blind, placebo-controlled trials? PLoS One. 2013 Oct 30;8(10):e76799. doi: 10.1371/journal.pone.0076799. eCollection 2013.

Jacobson IM, McHutchinson JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-16.

Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;16;368:1867-77.

Janssen HL, Brouwer JT, van der Mast RC, Schalm SW. Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994;21:241-3.

Karino Y, Ozeki I, Hige S, et al. Telaprevir impairs renal function and increases blood ribavirin concentration during telaprevir/pegylated interferon/ribavirin therapy for chronic hepatitis C. J Viral Hepat 2013;20:167-73.

Kraus MR, Schafer A, Scheurlen M. Paroxetine for the prevention of depression induced by interferon alfa. N Engl J Med 2001;345:375-6.

Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C. Aliment Pharmacol Ther 2002;16:1091-9.

Kraus MR, Schafer A, Al-Taie O, Scheurlen M. Prophylactic SSRI during interferon alpha re-therapy in patients with chronic hepatitis C and a history of interferon-induced depression. J Viral Hepat 2005;12:96-100.

Kraus MR, Schafer A, Schottker K, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: A randomized, double-blind, placebo-controlled study. Gut 2008;57:531-6.

Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878-87.

Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naïve patients: the COSMOS randomised study. Lancet 2014;384:1756-65.

Malaguarnera M, Laurino A, Di F, et al. Neuropsychiatric effects and type of IFN-alpha in chronic hepatitis C. J Interferon Cytokine Res 2001;21:273-8.

Manns M, McHutchinson J, Gordon S, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-65.

Manns MP, Rambusch EG. Autoimmunity and extrahepatic manifestations in hepatitis C virus infection. J Hepatol. 1999;31 Suppl 1:39-42.

Mauss S, Berger F, Schober A, et al. Screening for autoantibodies in chronic hepatitis C patients has no effect on treatment initiation or outcome. J Viral Hepatitis 2013; 20:e72-7.

Mauss S, Berger F, Goelz J, Jacob B, Schmutz G. A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance. Hepatology 2004;40:120-4.

Mauss S, Hueppe D, Alshuth U. Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir. Hepatology. 2014,59(1):46-8.

McHutchinson JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007;357:2227-36.

McHutchinson JG, Lawitz EJ, Shiffman ML, et al. Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection. N Engl J Med 2009;361:580-593.

McHutchinson JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362: 1292-1303.

Morasco BJ, Rifai MA, Loftis JM, Indest DW, Moles JK, Hauser P. A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C. J Affect Disord 2007;103:83-90.

Morasco BJ, Loftis JM, Indest DW, et al. Prophylactic antidepressant treatment in patients with hepatitis C on antiviral therapy: a double-blind, placebo-controlled trial. Psychosomatics 2010;51:401-8.

Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344:961-6.

Pariante CM, Landau S, Carpiniello B. Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis. N Engl J Med 2002;347:148-9.

Piche T, Vanbiervliet G, Cherikh F, et al. Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study. Gut 2005;54:1169-73.

Pockros PJ, Shiffman ML, Schiff ER, et al. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology 2004; 40:1450-8.

Pockros PJ, Reddy KR, Mantry PS, et al. Efficacy of Direct-Acting Antiviral Combination for Patients With Hepatitis C Virus Genotype 1 Infection and Severe Renal Impairment or End-Stage Renal Disease. Gastroenterology. 2016;150(7):1590-8.

Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-206.

Raison CL, Woolwine BJ, Demetrashvili MF, et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharmacol Ther 2007;25:1163-74.

Renault PF, Hoofnagle JH, Park Y, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987;147:1577-80.

Renet S, Chaumais MC, Antonini T, et al. Extreme Bradycardia After First Doses of Sofosbuvir and Daclatasvir in Patients Receiving Amiodarone: 2 Cases Including a Rechallenge. Gastroenterology. 2015;149(6):1378-1380.

Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537-45.

Sammut S, Bethus I, Goodall G, Muscat R. Antidepressant reversal of interferon-alpha-induced anhedonia. Physiol Behav 2002;75:765-72.

Sarkar S, Sarkar R, Berg T, Schaefer M. Sadness and mild cognitive impairment as predictors for interferon-alpha-induced depression in patients with hepatitis C. Br J Psychiatry. 2015 Jan;206(1):45-51.

Sarkar S, Schaefer M. Antidepressant pretreatment for the prevention of interferon alfa-associated depression: a systematic review and meta-analysis. Psychosomatics. 2014 May-Jun;55(3):221-34.

Schaefer M, Engelbrecht MA, Gut O, et al. Interferon alpha [IFNalpha] and psychiatric syndromes: a review. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:731-46.

Schaefer M, Schmidt F, Folwaczny C, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology 2003;37:443-51.

Schaefer M, Heinz A, Backmund M. Treatment of chronic hepatitis C in patients with drug dependence: time to change the rules? Addiction 2004;99:1167-75.

Schafer A, Wittchen HU, Seufert J, Kraus MR. Methodological approaches in the assessment of interferon-alfa-induced depression in patients with chronic hepatitis C – a critical review. Int J Methods Psychiatr Res 2007;16:186-201.

Schaefer M, Hinzpeter A, Mohmand A, et al. Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: Response and psychiatric side effects. Hepatology 2007;46:991-8.

Schaefer M, Schwaiger M, Garkisch AS, et al. Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C. J Hepatol 2005;42:793-8.

Schaefer M, Capuron L, Friebe A, et al. Hepatitis C infection, antiviral treatment and Mental Health: A European Expert Consensus Statement. J Hepatol, 2012; 57:1379-90.

Schaefer M, Sarkar S, Knop V, et al. Escitalopram for the Prevention of Peginterferon-α2a–Associated Depression in Hepatitis C Virus–Infected Patients Without Previous Psychiatric Disease. A Randomized Trial. Ann Intern Med, 2012; 157:94–103.

Schafer A, Wittchen HU, Seufert J, Kraus MR. Methodological approaches in the assessment of interferon-alfa-induced depression in patients with chronic hepatitis C – a critical review. Int J Methods Psychiatr Res 2007;16:186-201.

Schramm TM, Lawford BR, Macdonald GA, Cooksley WG. Sertraline treatment of interferon-alfa-induced depressive disorder. Med J Aust, 2000;173:359-61.

Seyam MS, Freshwater DA, O’Donnell K, Mutimer DJ. Weight loss during pegylated interferon and ribavirin treatment of chronic hepatitis C. J Viral Hepat 2005;12:531-5.

Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology 2007;46:371-9.

SMPC Viekirax 2015: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Product_Information/human/003839/WC500183997.pdf (as accessed Jan 18 2016)

Sulkowski MS, Poordad F, Manns MP, et al. Anaemia during treatment with peginterferon alfa-2b/ribavirin and boceprevir: Analysis from the sprint-2 trial. Hepatology 2013; 57:974-84.

Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211-21.

Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-50.

Tran HA, Jones TL, Batey RG.The spectrum of thyroid dysfunction in an Australian hepatitis C population treated with combination Interferon-alpha 2-beta and Ribavirin. BMC Endocr Disord 2005;5:8.

Udina M, Hidalgo D, Navinés R, et al. Prophylactic antidepressant treatment of interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2014 Oct;75(10):e1113-21.

Valentine AD, Meyers CA. Successful treatment of interferon-alpha-induced mood disorder with nortriptyline. Psychosomatics 1995;36:418-9.

Younossi ZM, Stepanova M, Henry L, et al. Minimal Impact of Sofosbuvir and Ribavirin on Health Related Quality of Life in Chronic Hepatitis C (CH-C). J Hepatol 2014;60:741-7.

Zeuzem S, Berg T, Gane E, et al. Simeprevir Increases Rate of Sustained Virologic Response Among Treatment-Experienced Patients With HCV Genotype-1 Infection: A Phase IIb Trial. Gastroenterology 2014;146:430-441.

Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014;370:1993-2001.

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