How to optimize HCV therapy in genotype 1 patients: management of side-effects
Dr S. S. Lee, 3330 Hospital Dr NW, Calgary, AB T2N 4N1, Canada
Fax: 1 403 270 0995
Antiviral therapy for chronic hepatitis C has dramatically changed with the advent of triple therapy incorporating direct-acting antivirals (DAAs) such as the protease inhibitors (PI) boceprevir and telaprevir. Such triple-therapy is associated with a new spectrum of side-effects which can hamper quality of life. These may lead to dosage reduction and sometimes discontinuation of therapy. This review presents practical tips to help manage adverse effects appropriately and efficiently. The main adverse effects causing discontinuation of therapy are varied. Although the most common adverse effects are the ‘flu’-like symptoms of fatigue, myalgia, fever and lassitude, these are usually easily managed and do not lead to treatment discontinuation. Cytopaenia, particularly anaemia, has emerged as perhaps the most troublesome side-effect. Cirrhotic patients are especially prone to moderate or severe anaemia with boceprevir and telaprevir triple-therapy regimens. Aggressive ribavirin dosage reductions, erythropoietin and blood transfusions are effective for managing anaemia. Skin rash can be controlled with moisturization and corticosteroid ointment. Rarely, dermatology consultation is required for further management. Anal discomfort, with or without diarrhoea, sometimes responds to barrier creams and haemorrhoidal ointments. Dysgeusia is treated by sipping water frequently, oral ointments and mouth washes to maintain salivary flow and oral hygiene. Successful adherence to treatment can be enhanced by a strong support network for the patient, including specially-trained hepatitis nurses and a multidisciplinary team incorporating pharmacists, counsellors and social workers.
hepatitis C virus
severe adverse effects
sustained virological response
Hepatitis C virus (HCV) infection affects approximately 170 million people world-wide, causing chronic hepatitis and liver-related mortality in a large number of patients . The previous ‘gold standard’ therapy, peginterferon-alpha (PEG-IFN) in combination with ribavirin (RBV) can eradicate HCV infection in approximately 40–50% of treatment-naïve patients infected with HCV genotype 1 . The success rate is substantially improved with the development and registration of two direct acting HCV protease inhibitors (boceprevir and telaprevir) in the second decade of the 21st century: about three-quarters of previously untreated, and more than half of previously unsuccessfully treated patients can achieve a sustained virological response (SVR) with PI-based triple therapies . A major barrier to treatment seems to be the many and sometimes very serious side-effects associated with PEG-IFN/RBV which can be increased and further burdened by PI. Eleven percent of subjects in the T12PR (telaprevir-triple therapy) arm of the ADVANCE study discontinued therapy at some point in the study caused by adverse effects, chiefly anaemia and rash . In the REALIZE trial of telaprevir-triple therapy for previously treated patients, up to 25% of subjects developed adverse effects, most commonly rash, anaemia and fatigue . In the SRINT-2 boceprevir-triple therapy study of naive patients , 12–16% of patients discontinued therapy because of adverse effects, although these discontinuation rates were not statistically different across the two triple-therapy groups compared with the PEG-IFN/RBV control group.
In this review, we will examine the major adverse effects of HCV antiviral therapy and suggested management recommendations, categorized by type of treatment or the specific adverse effect.
Peginterferon-alpha and ribavirin
Historically, the most predominant symptoms which patients have complained about when on treatment for HCV have consisted of the common ‘flu’-like symptoms: fatigue, lassitude, myalgia, fever, insomnia and weakness. In our experience, over 90% of patients complain of one or more of these symptoms. Feelings of generalized ‘tiredness’ are often confounded by anaemia and depression. If these confounders have been screened for, it is also important to identify psychological and social stressors, which may contribute to the fatigue. Important advice includes napping and resting when required, maintaining a regular daily schedule and keeping active. Often exercise is the last thing patients want to think about, but encouraging physical activity may help maintain emotional balance and promote energy levels. Maintaining hydration is also important in promotion of a sense of well-being. Symptomatic relief of the flu-like symptoms, as in typical cases of viral upper-respiratory tract infections, can be provided by moderate doses of acetaminophen. This drug is well-tolerated even in patients with cirrhosis, as long as doses do not exceed 2.5 g/24 h. To manage all adverse effects, we have found that providing a support network, such as ready access to nurses and an after-hours telephone health link, improves adherence to treatment and patient satisfaction with the treatment programme.
Occasionally, judicious timing of the PEG-IFN injection schedule can help the subgroup of patients who report a peak onset of symptoms 24–48 h after injection. For example, if peak onset occurs 1 day after injections, we recommend a Friday injection so that peak symptoms occur during the weekend when the patient is not working. Similarly, in the occasional patient who has onset of peak symptoms at a defined, predictable time interval post-injection, such as 14–18 h, we advise injection timed such that the peak flu-like symptoms occur at night while the patient sleeps.
Learning self-injection has been one of the minor challenges associated with interferon therapy. Patients are taught in a structured setting with a nurse prior to starting therapy with a ‘demo-pen’ to ensure proper technique. Automated self-injection syringes provided by the PEG-IFN manufacturers attempt to make injections easier to administer. Injection site irritation is common, more often with shorter needles in pen-like injections, which often also easily lock. It is important to teach the patient how to inject with sufficient force, beyond the superficial skin layer into subcutaneous tissue and rotate injection sites with each dose.
Anaemia is the dominant adverse effect leading to drug dose reductions with telaprevir and boceprevir triple therapies. Although troublesome with dual-therapy caused by the bone marrow suppression of interferon coupled with the RBV-induced haemolysis, adding boceprevir or telaprevir as triple-therapy has sharply exacerbated the extent of this side-effect. In the large registration trials of each triple-therapy regimen, anaemia was recognized as a major adverse effect (AE) of boceprevir but in the telaprevir studies, was overshadowed by the rash and gastrointestinal AEs. However, in clinical practice, with the widespread use of both drugs, it appears that the telaprevir rash is generally not a major problem, but that anaemia is frequently encountered with both DAAs.
Ribavirin is phosphorylated in erythrocytes, which leads to trapping and accumulation of metabolites, inducing haemolysis . This effect can be compounded by the bone marrow suppression of interferon and protease inhibitors. Anaemia has been reported in 49% of patients with boceprevir triple therapy vs 29% of the control group of patients treated with peginterferon + ribavirin alone . In that study, the magnitude of anaemia necessitated drug dose reductions in 21% of the triple-therapy group compared to 13% of controls. In the telaprevir ADVANCE study, anaemia was reported in 37% of the triple-therapy group compared to 19% in the dual-therapy controls .
Anaemia has also been cited as a surrogate for drug effectiveness in terms of SVR for dual-therapy with PEG-IFN/RBV, but this paradigm does not seem to apply to telaprevir triple-therapy [7, 8], although retrospective analysis indicates that SVR is still higher in boceprevir-treated patients who develop anaemia compared to those who did not .
The other major paradigm that needs reassessment in the age of DAA is the notion that maximizing RBV dosing during treatment is important for successful outcome. At least with telaprevir-triple therapy, preliminary evidence suggests that although some RBV is essential to improve the chance of SVR, even tiny doses that would be virtually useless as part of dual-therapy, can maintain high chances of SVR when used in triple-therapy. In 885 patients treated with telaprevir-triple therapy in the phase 2 and 3 studies, the SVR rate was 78% in those who received only 200–400 mg RBV daily vs 74% (P = NS) in those receiving 600–1200 mg . This suggests that even small doses of RBV can help sustain SVR; therefore aggressive RBV dose reductions can be made, at least during the first 12 weeks of triple-therapy.
Symptoms of anaemia include light-headedness, instability, presyncope and syncopal attacks. These and shortness of breath, visual blurring, and chest pain should be medically attended. Management strategies include RBV dosage reduction as the first step. If anaemia persists, blood transfusions and erythrocyte stimulating agents can be considered. We usually reserve transfusion for symptomatic patients whose haemoglobin has dropped to <8–9 g/l. In our province, obtaining third-party reimbursement for erythropoietin is extremely difficult owing to its high cost, and we suspect similar unavailability may also apply elsewhere in the world. In that respect, a large randomized controlled trial has conclusively demonstrated that the two strategies of RBV dose reduction (to a minimum of 600 mg/day) vs erythropoietin showed similar efficacy in achieving SVR (71% in both groups) . Thus erythropoietin appears to be unnecessary at least as far as boceprevir triple-therapy is concerned. It should be noted that, in contrast to the boceprevir studies, telaprevir trials did not permit the use of erythropoietin-stimulating agents in the management of anaemia, but required RBV dose reduction per protocol. However, as noted above, with telaprevir-triple therapy, ribavirin can be reduced in a very aggressive manner, and we currently have no hesitation in quickly dropping it to doses of 400–600 mg, even 200 mg daily during the 12 weeks of triple-therapy (Table 1).
Table 1. Common adverse effects and management
|Fatigue||Maintain active lifestyle, balanced diet, social support, rest as needed, caffeinated beverages (moderate), acetaminophen, nonsteroidal anti-inflammatory drugs|
|Fever/myalgia||Acetaminophen, change peginterferon dose timing|
|Insomnia||Regular evening schedule, avoid prebedtime stress or heavy exertion, hypnotics/sedatives|
|Anorexia/weight loss||No intervention usually needed; if severe, small frequent meals, nutritional supplements|
|Anaemia||Aggressive ribavirin dose reduction, blood transfusions, oral iron, erythropoieitin|
|Neutropaenia||Peginterferon dose reduction, granulocyte-stimulating factors if severe|
|Thrombocytopaenia||No intervention needed unless symptomatic or severe; peginterferon dose reduction, thrombopoietin if severe|
|Skin rash||Moisturizers, corticosteroid cream, anti-histamines, dermatology referral if severe|
|Diarrhoea/anal Discomfort||Corticosteroid ointment, barrier cream/paste, anti-diarrhoeals, increased dietary fibre, anti-histamines|
|Dysgeusia||Oral care, frequent water drinking, mouth washes, small frequent meals, plastic utensils, fruits and vegetables, lozenges, hard candies|
|Depression||Social support, psychology/psychiatry referral, SSRI antidepressants|
|Emotional lability/irritability||Social support especially spouse/partner/family, psychology/counselling Referral, SSRI anti-depressant if severe|
Special considerations in patients with cirrhosis
Similar to the higher rate of adverse effects and premature discontinuations with dual therapy in cirrhotic patients, triple therapies are associated with higher AEs in this subset. The French multicentre CUPIC study  offers a large, real-world cohort of patients with cirrhosis treated with either telaprevir-triple therapy (n = 296) or boceprevir-triple (n = 159). Although the study is nonrandomized and thus direct comparisons between the two triple-therapy regimens are not valid, some very clear trends have emerged from the dataset to date. In particular, the rates of serious adverse effects, especially anaemia, in this population are strikingly higher than those reported for noncirrhotic patients in the registration trials. SAEs in the telaprevir and boceprevir groups were reported at 49 and 38%, respectively, and overall treatment discontinuation rates were 26% and 24%. Premature discontinuations caused by AEs were 14% for telaprevir and 7% for boceprevir.
Anaemia categorized as mild-moderate (grade II) AE occurred in 20% (telaprevir) and 23% (boceprevir), and the rates of grade 3 or 4 AEs were 10% in both groups. Erythropoietin was used in a surprising 59% (telaprevir) and 66% (boceprevir) of this cirrhotic cohort.
Several deaths were reported and 4.4% of both groups experienced liver decompensation during treatment. Grade 3 or 4 neutropaenia was fortunately relatively uncommon, occurring in 5% of both groups.
The lessons we can draw from this important study are that this vulnerable subgroup must be monitored very carefully during treatment. In patients with cirrhosis, we routinely have them assessed by the liver transplant evaluation team before therapy in case of decompensation during treatment. Fortunately, severe neutropaenia remains uncommon, even in this population, but anaemia is common and must be aggressively managed with the entire gamut of treatments detailed earlier.
A spectrum of dermatological diseases has been described with HCV therapy, ranging from pruritis with or without urticaria to eczematous rashes, the majority of which seem to be self-limiting. In the CUPIC study severe rash (grade 3/4) occurred in 7.5% of patients treated with telaprevir . Both rash and pruritis regressed after withdrawal of telaprevir and administration of appropriate therapy, including topical treatments (ointments, anti-histamines) for symptoms and corticosteroids (in some cases, systemic corticosteroids). Although rash can affect any body part, it seems to be most commonly observed in the armpits, arms and legs. Diffuse and severe rash seems to be rare. The majority of cases are to be managed by moisturization; however, dermatologist consultations are not uncommon. Hydrocortisone 1% cream and avoidance of direct sun exposure also expedite healing.
Diarrhoea and anal discomfort have been reported in a significant minority of patients on HCV triple-therapy. While mild diarrhoea is not uncommon, especially with telaprevir, it is the anorectal ‘burning’ sensation with defecation that causes the most distress. Although in the ADVANCE study, only 13% of patients noted this side-effect , the real-world experience with telaprevir suggests higher prevalence. In our experience, approximately one-third of patients on telaprevir report anorectal discomfort. Such sensations are described by patients, especially those who are unaccustomed to eating spicy foods, like the ‘ring of fire’ with defecation in the morning after eating a very spicy meal. This sensation has not been described with boceprevir. The aetiology of these bowel disturbances remains unclear, but may have to do with the need for fatty food ingestion (20 g of fat is needed with each dose of telaprevir) and some peculiar gut or gut–flora interaction with the drug. In some but not all patients, the anorectal burning is associated with diarrhoea.
Management of this symptom includes several simple measures. It is important to assess hydration, and rule out infection with stool cultures in all cases. Corticosteroid ointment, barrier cream and sitz baths are used for preservation of anal integrity and relief of pain. Lidocaine ointments can also be tried for severe cases. Occasionally effective is a cold pack (such as a frozen sanitary napkin) and the addition of fibre to improve diarrhoea. Anti-diarrhoeals, such as loperamide, are also often given, with the caution that intestinal obstruction be avoided.
Altered or bad taste seems to be a consistent and common side-effect in patients treated with boceprevir; it is less commonly reported telaprevir. The SPRINT-1 study of boceprevir reported up to a 30–40% incidence of taste alterations in various patients . Patients describe that foods will start to taste different, or even metallic in nature. This can lead to decrease in appetite and rarely even put patients at risk for malnutrition. Symptoms seem to be exacerbated by decrease in saliva, i.e. lack of hydration. Common strategies used to tackle this difficult issue include instructing patients to drink plenty of fluids and the use of peppermint, candies and lozenges to increase saliva. For some patient switching from metal to plastic utensils helps. Others find that eating more tart foods lessens this symptom. Oral sprays or anaesthetics, such as commercially available lidocaine mouth gels and mouthwashes, may help.
Oral herpes, cheilitis and bleeding gums also seem to be more frequent on individuals on treatment. Proper oral care, using soft toothbrushes and avoiding alcohol-containing mouthwashes help prevent irritation and further gingival bleeding. A local preparation by the name of Akabutu's ‘swish and spit’ mouthwash is a prescription we give our patients to help combat oropharyngeal symptoms. This solution includes 62.5 ml of viscous lidocaine 2%, 10 ml of nystatin suspension (100 000 U/ml), 20 ml of cherry syrup, 200 ml Normal saline for irrigation and a 10 mg hydrocortisone tablet at the time of dispension.
Development of ‘new’ depression has been quoted up to 16%  in patients treated with interferon. Patients with past history of drug addiction tended to have a greater incidence of depression, although milder, whereas the severity of depressive episodes in patients with a psychiatric history tended to be moderate or severe. Suicidal thoughts were reported in 4–6% of patients. True suicidal ideation requires immediate discontinuation of interferon-based treatment and urgent referrral to a psychiatrist. Suicides and attempted suicides are infrequent but well-reported with IFN-based therapy and thus treating centres need to ‘err on the side of caution’.
It often remains unclear if treatment unmasks latent but untreated depression or whether the stress and burden of disease and treatment creates it. Aggression and irritability are also seen to significantly increase on treatment, as mood fluctuations and tolerability decrease. These individuals are important to identify and multidisciplinary support and treatment with nurses, psychologists and psychiatrists is key. Social work support and various networks, such as distress centre information and available counselling, must be available to the patient upfront and prior to treatment. Citalopram (a serotonin selective reuptake inhibitor) is the most common pharmacotherapy we use. Dosages are started at 20 mg orally daily and titrated upwards. Having a working collaboration with psychiatry services is essential. Patients need to be taught coping strategies, and daily activities, meditation, biofeedback measure, journal writing and a tight social support network need strong encouragement. In particular, the spouse or partner must be an integral part of the social support network. Those lacking a partner/spouse are encouraged to involve one or more other family members or close friends.
Thyroid dysfunction occurs in about 5% of patients during or shortly after a course of antiviral treatment, and appears to be an interferon-related adverse effect. As this is approximately the same prevalence of thyroid dysfunction in the general population, it has been suggested that this is not a de novo complication induced by interferon, but rather that this immune-activating drug somehow triggers the onset of thyroiditis in patients who have latent or as yet-undeclared autoimmune thyroid disease. Hyper and hypothyroidism either clinical or biochemical have been observed and need to be monitored. Some individuals require thyroid replacement during treatment, with normalization of thyroxine levels as the goal.
Many patients on antiviral treatment complain of hair loss or thinning. They can be reassured that such thinning is transient and the hair will grow back after cessation of therapy. We advise several simple measures to minimize this side-effect. These include avoiding harsh chemicals in hair such as dyes, using satin pillow cases to avoid friction and minimizing washing of hair. Very few patients require wigs or hair pieces for cosmetic reasons.
Vitamin D deficiency, particularly in northern countries is a common occurrence, and this seems to be even more frequent in our HCV patients for unclear reasons . Many patients are on replacement with oral vitamin D tablets or solutions. Levels can be monitored periodically.
A chronic dry cough is commonly described with triple therapy. The pathogenesis remains unclear, but may be related to drying of secretions and decreased hydration, and seems to be especially associated with ribavirin. Patients must understand the importance of water and fluid intake and can consider lozenges and the use of humidifiers. If these measures are not successful and the cough is disabling, reduction in RBV dosage seems to abate symptoms. Patients may complain of a polyuria during their treatment course. Urine analysis and urine cultures are often negative, and this may be associated with increased fluid intake. This seems to be more common in males, and is of unclear significance.
Patients may complain of confusion, decreased concentration ability or a certain ‘fogginess’. It is important that they be counselled not to drive or operate heavy machinery as they may cause harm to themselves and others if this occurs. For the same reasons, it is strongly recommended to completely abstain from alcohol during treatment duration.
Successful treatment and attaining a SVR may be enhanced by a strong support network for patients including trained nurses and a multidisciplinary team that includes knowledgeable pharmacists (many more drug interactions now occur with the DAAs), psychologist/counsellors, ready access to psychiatrists, and social workers. We believe that the top three factors associated with successful adherence and treatment completion include: (i) adequate hydration at all times; (ii) patients recognizing the correct time for treatment in their life, and during treatment they must try to minimize all other stressors which may interfere with drug administration and side-effects; (iii) patients must recognize that they may need to stop or reduce work hours if side-effects are disabling, so having a financial and emotional security net is essential prior to treatment of their hepatitis C.
SSL has consulted for, received speaker honoraria and research funds from Merck, Vertex and Hoffman-LaRoche. PLK and TD have received honoraria for nursing advisory boards from Merck, Vertex and Hoffmann-LaRoche. AC has no disclosure.