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HCV Treatment Complications Volume 20 Issue 4 October/November 2012

Perspective Managing Adverse Effects and Complications in Completing Treatment for Virus Infection

The addition of direct-acting antivirals (DAAs) to hepatitis C virus (HCV) Psychiatric Complications treatment regimens has made treatment more effective and patient Depression is the most common psy- management more complex. Shepherding patients through a full course of chiatric complication encountered in HCV therapy requires motivation and involvement on the part of the patient HCV patients, with mild to moderate and the physician. Indeed, physician inexperience and lack of confidence in depression found in as much as 80% of guiding patients through the challenges of treatment appears to be a primary patients. Bipolar disorder and schizo- reason for early discontinuation of therapy. Among the many complications phrenia are also not infrequently en- of HCV treatment that must be managed efficiently and effectively are countered. depression and other psychiatric disorders; hematologic abnormalities There is little evidence to support including DAA- and ribavirin-associated anemia and peginterferon alfa- a benefit of preemptive antidepres- associated neutropenia and ; rash and drug eruptions, sant therapy in all patients undergo- including telaprevir-associated rash; and weight loss. Practical considerations ing HCV treatment, though a recent in management of these common complications are offered. This article randomized trial of HCV patients with- summarizes a presentation by Kenneth E. Sherman, MD, PhD, at the IAS–USA out psychiatric history suggested that live continuing medical education course held in New York in June 2012. major depression risk was decreased in a group of patients randomized to In clinical trials, treatment with a inexperience can result in a lack of receive escitalopram prior to interfer- direct-acting antiviral (DAA) in com- confidence in initiating and follow- on-based therapy.3 For patients who bination with peginterferon alfa and ing through with treatment. A recent are actively depressed, antidepressant ribavirin for 48 weeks produced a analysis in a study population receiv- treatment is likely to be required. Mild sustained virologic response (SVR) in ing peginterferon alfa and ribavirin and moderate depression can be as- approximately 65% to 75% of patients therapy showed that treatment was sessed by and readily treated by the with genotype 1 or 4 hepatitis C virus discontinued in 44% of patients, with HCV physician and in most cases, re- (HCV) infection. Peginterferon alfa and physician reasons accounting for 75% ferral to psychiatry is not necessary. ribavirin treatment for 24 weeks pro- of discontinuations and patient rea- The primary issue for the HCV physi- duced an SVR in approximately 70% sons accounting for 25%.1 cian is to determine whether the de- to 85% of patients with HCV genotype Whereas treatment futility account- pression is manageable in the con- 2 or 3 infection. SVR rates in clinical ed for 33% of physician discontinua- text of HCV treatment. The physician practice are not as high, in large part tions, no reason for discontinuation should become comfortable with the because early discontinuation of HCV was given for 39% of cases. Comorbidi- use and effects of several antidepres- therapy is frequent for reasons unre- ties and lack of adherence were cited sants, including sertraline, , lated to treatment futility (ie, stopping as reasons in 5% of cases each. Patients and mirtazapine. treatment for failure to achieve specific often cited adverse effects as a reason A thumbnail guideline for use of reductions in plasma HCV RNA level for stopping treatment, but some also these agents is to use sertraline if the by specific time points). Major reasons reported that they got the sense from depression is characterized by sadness for early discontinuation of anti-HCV their physician that they should stop or and crying episodes and paroxetine if it therapy are discussed herein. were encouraged to stop. In the WIN-R is characterized by anger. Mirtazapine (Weight-Based Dosing of Peginterferon is especially useful in patients who are Physician Inexperience alfa-2b and Ribavirin) trial, which was suffering weight loss, because it is as- performed at 236 community and sociated with significant appetite stim- Treating HCV infection with available academic sites, 41.3% of subjects dis- ulation and weight gain. All of these regimens can be daunting to both continued therapy.2 Clinicians who are drugs have potential interactions with patient and physician, and physician inexperienced and not confident in telaprevir and boceprevir and should their ability to guide a patient through be started at the lowest possible ther- the treatment course may discontinue apeutic dose. Psychiatric assistance Dr Sherman is the Gould Professor of treatment early, depriving the patient is needed for patients with more se- Medicine and Director of the Division of Digestive Diseases at the University of of a chance for cure. As health care vere depression—eg, those with sui- Cincinnati College of Medicine in Ohio, providers, we need to move past any cidal ideation—and HCV treatment and a member of the IAS–USA Viral such hesitancy in order to provide ef- should be delayed until such patients Hepatitis Advisory Board. fective treatment and management. are stable. The most effective way to 125 IAS–USA Topics in Antiviral Medicine

manage such patients is not to refer to Protease Inhibitor Therapy 2) trial de- there is no increased risk of infection psychiatry and wait for clearance, but veloped anemia, compared with 29% associated with neutropenia, even to form a partnership with the psychia- of patients receiving peginterferon alfa when the absolute neutrophil count 7 trist throughout the duration of the pa- with ribavirin and placebo. Treatment (ANC) drops below 500/µL.10,11 Neutro- tient’s treatment. was discontinued because of anemia penia should be managed with filgras- Psychiatric expertise also usually is in 2% of each boceprevir group and tim (5-10 µg/kg) only when the ANC needed for patients with bipolar disor- in 1% of placebo patients. Dose re- drops below 500/µL and before any der or schizophrenia prior to starting ductions were implemented in 20% reduction in peginterferon alfa dose. HCV treatment. It is important that to 21% of boceprevir patients and in 13% of placebo patients, and epoetin these patients have a commitment to Thrombocytopenia psychiatric care. A contract with such alfa was used to treat anemia in 43% of patients sometimes ensures that they boceprevir patients and 24% of placebo Thrombocytopenia is a frequent cause will stay with their psychiatric care. patients. of treatment discontinuation in clini- With patients who have bipolar dis- Ribavirin dose reduction should be cal practice. counts plummet order, it is best to try to initiate HCV considered the first strategy for treat- during the first 6 weeks to 8 weeks treatment during a hypomanic phase. ing anemia in patients receiving DAA- in some patients, and physicians jus- It is difficult to start and maintain ther- containing regimens, because it does tifiably become alarmed. However, it apy in a manic or actively delusional not appear to compromise response, does not appear that a declining plate- patient even with the help of a psy- and is less expensive and safer than let count should prompt substantial chiatrist. There is evidence from sev- initiating treatment or concern until it reaches about 30,000/ eral small studies that partnering with other erythrocyte-stimulating growth µL. When platelet counts are in the psychiatry can help in getting patients factors. In a recent trial in 500 patients range of 20,000/µL to 30,000/µL, the with bipolar disorder or schizophrenia receiving boceprevir-containing regi- thrombocytopenia should be managed through an HCV treatment course. In mens, patients with hemoglobin lev- by peginterferon alfa dose reduction. one study, 22 patients with psychiat- els dropping below or about to drop In the absence of substantial ane- ric disorders and 17 control patients below 10 g/dL were randomized to mia, the ribavirin dose should not be were treated with peginterferon alfa receive a 200 mg/d to 400 mg/d re- changed, because ribavirin increases and ribavirin in an interdisciplinary duction in ribavirin dose or to get an platelet count when compared with setting that included psychiatry. The addition of 40,000 U/wk of subcuta- use of peginterferon alfa alone.12 8 outcomes in the 2 groups were similar, neous epoetin alfa. SVR rates were Eltrombopag is a platelet growth with SVR being achieved in 50% and approximately 70% in both groups, factor that is very expensive, some- 58.6%, respectively.4 suggesting no difference between the times difficult to get insurance approv- 2 approaches with regard to compro- al for, and not widely used. However, mising response. In addition, a retro- its use can be considered in a patient Hematologic Toxicities spective analysis of outcomes in the who has a platelet count of 20,000/µL ADVANCE and ILLUMINATE telaprevir to 30,000/µL in whom no further pe- trials showed slightly, but not statisti- Anemia ginterferon alfa dose reductions can cally significantly lower SVR rates in be made and who is otherwise doing Anemia beyond that associated with patients with ribavirin dose reduced well. A study reported several years ribavirin alone is a major adverse ef- to a range of 800 mg/d to 1000 mg/d, ago showed that starting eltrombopag fect with both telaprevir and bocepre- or 600 mg/d, than in patients with no treatment in patients with low platelet vir. For example, anemia occurred in ribavirin dose reductions (all SVR rates counts prior to beginning HCV thera- 9 37% and 41% of patients receiving were between 74% and 79%). Similar py was successful in increasing plate- telaprevir in the ADVANCE (A New outcomes were observed in an analy- let counts such that they remained Direction in HCV Care: A Study of sis of previously treated patients in the at high levels throughout the course Treatment-Naive Hepatitis C Patients REVEAL (Risk Evaluation of Viral Load of therapy.13 This approach would be with Telaprevir)5 and ILLUMINATE (Il- Elevation and Associated Dis- very expensive and is not a US Food lustrating the Effects of Combination ease) study of telaprevir. and Drug Administration–approved Therapy with Telaprevir)6 trials, respec- use of eltrombopag, but the drug can tively, compared with 19% of patients Neutropenia be effective in adjunctive therapy for receiving peginterferon alfa and riba- thrombocytopenia. virin alone. No erythrocyte-stimulating Neutropenia is common during pegin- HCV treatment should be discontin- agents were used in the telaprevir tri- terferon alfa and ribavirin therapy and ued in most cases if the platelet count als, with anemia being managed by is attributed primarily to peginterferon drops below 20,000/µL. In patients ribavirin dose reduction. Similarly, alfa. Considerable anecdotal evidence, who have hemophilia, the threshold 49% of patients in each of the 2 bo- analyses of clinical trials, and one large for stopping therapy is much higher ceprevir arms in the SPRINT-2 (Serine single center experience indicate that (eg, about 50,000 cells/µL). 126 HCV Treatment Complications Volume 20 Issue 4 October/November 2012

Dermatologic Issues limited distribution in separate, isolated sites Peginterferon alfa, ribavirin, and tela- on the body.15 A mod- previr, but not boceprevir, are associ- erate eruption is a dif- ated with rash. Peginterferon alfa can fuse rash that involves cause dermatitis, local reactions, and less than 50% of body exacerbation of psoriasis. The local surface area. Severe reactions are rare but can be quite rash affects more than severe. Treatment should be stopped 50% of body surface in patients who develop a depression area or is accompanied or ulcer at the injection site; if treat- by substantial system- ment continues, the lesion will con- ic symptoms, muc- tinue to widen and deepen. Psoriasis ous membrane ulcera- may progress from tiny patches to that tion, target lesions, covering large portions of the body. or epidermal detach- In such cases, aggressive treatment ment. Severe cutaneous with topical steroids should be started adverse reaction (SCAR) in consultation with a dermatologist. comprises DRESS (usu- Light therapy sometimes helps. Treat- ally involving fever Figure 1. Drug rash with eosinophilia and systemic eruptions ment with injectable methylpredniso- and increased liver en- (DRESS). This patient’s skin is peeling off in layers, he had oral lone or other injectable steroids has lesions in his mouth with blisters, and his lips were swollen. He zymes); Stevens-Johnson had a high eosinophilic count. been successful at more advanced syndrome with toxic stages of psoriasis, but should not be epidermal necrolysis; used for initial treatment. Ribavirin is acute generalized exanthematous consists of calorie supplementation associated with drug eruption that of- pustulosis; and erythema multiforme. using milk shakes or nutrition drinks. ten occurs between 6 weeks and 16 Figure 1 illustrates DRESS. The pa- As noted above, the antidepressant weeks and up to 20 weeks of therapy. tient’s skin was peeling off in layers, mirtazapine is often effective in pro- It frequently overlaps with telaprevir- and he had lesions in the mouth, dra- moting weight gain. associated rash, which is the rash of matic swelling of the lips, and a very greatest concern. high eosinophil count. DRESS requires Telaprevir is associated with eczem- immediate hospitalization. Conclusion atous rash and drug rash with eosino- Mild rash developing in patients re- philia and systemic eruptions (DRESS). ceiving telaprevir should be managed With the availability of DAAs, the man- A summary of data from telaprevir conservatively with topical steroids. agement of HCV treatment has be- placebo-controlled phase II and III tri- For moderate rash without mucosal come more, not less, complex. Specific als indicates that rash occurred in ap- involvement, management includes management techniques are evolving proximately 56% of telaprevir patients stopping telaprevir, especially if the as we learn more about both safety compared with approximately 35% of patient has had more than 8 weeks and efficacy of the currently available control patients, with rash being mild of treatment, but continuing peginter- regimens. in severity in 37% of telaprevir patients, feron alfa and ribavirin. If the physi- The decision to initiate therapy 14 moderate in 14%, and severe in 5%. cian suspects that the rash is caused now, versus waiting for next-genera- Rash was typically pruritic and eczem- by ribavirin, the drug can be held for tion therapies that may not contain atous, covering less than 30% of the 1 week to 2 weeks and then restart- peginterferon alfa, is also complex. In total body surface area. Rash started ed at a lower dose. For patients with general, patients with stage 1 or 2 he- within the first 4 weeks of treatment severe rash or SCAR, all HCV treatment patic fibrosis are unlikely to progress to in approximately 50% of patients, but should be stopped. (stage 4) within 3 to 5 years was observed at any time during treat- and may choose to wait for newer ment. Progression of rash to greater therapies. However, these patients do severity occurred in less than 8% of Weight Loss represent a potential public health risk patients. to others, and there is no guarantee Grading of skin eruptions is impor- Weight loss associated with peginter- that newer therapies will truly be more tant. It was learned in the telaprevir feron alfa treatment is fairly com- efficacious with fewer adverse effects trials that even experienced clinicians mon. Body weight loss of more than than current therapy. overestimate the percentage of body 10% is considered serious. Serious In contrast, patients with stage 3 surface area affected by rash compared weight loss is more common among fibrosis and compensated cirrhosis with dermatologist findings. A mild patients who have HCV and HIV should probably be offered treatment eruption is a localized eruption with coinfection. Primary management now. Effective treatment may prevent

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hepatic decompensation. A patient 3. Schaefer M, Sarkar R, Knop V, et al. 10. Roomer R, Hansen BE, Janssen HL, de with decompensated disease (ascites, Escitalopram for the prevention of Knegt RJ. Risk factors for infection dur- peginterferon-alpha2a-associated de- ing treatment with peginterferon alfa and bleeding varices, encephalopathy) is pression in hepatitis C virus-infected ribavirin for chronic hepatitis C. Hepatol- not a candidate for the current genera- patients without previous psychiatric dis- ogy. 2010;52(4):1225-1231. ease: a randomized trial. Ann Intern Med. 11. Antonini MG, Babudieri S, Maida I, et al. tion of HCV antiviral therapies. 2012;157(2):94-103. Incidence of neutropenia and infections Management of treatment with the 4. Schaefer M, Hinzpeter A, Mohmand A, et during combination treatment of chronic next generation of DAAs may be eas- al. Hepatitis C treatment in "difficult-to- hepatitis C with pegylated al- treat" psychiatric patients with pegylated fa-2a or alfa-2b plus ribavirin. Infection. ier, but it is likely that challenges will interferon-alpha and ribavirin: response 2008;36(3):250-255. continue for decades to come. and psychiatric . Hepatology. 12. Thevenot T, Mathurin P, Moussalli J, et al. 2007;46(4):991-998. Effects of cirrhosis, interferon and azathi- 5. Jacobson IM, McHutchison JG, Dusheiko oprine on adverse events in patients with Financial Affiliations: Dr Sherman has G, et al. Telaprevir for previously untreat- chronic hepatitis C treated with ribavirin. served as a consultant to Abbott Molecular, ed chronic hepatitis C virus infection. N J Viral Hepat. 1997;4(4):243-253. Fibrogen Inc, Kadmon Corporation, and Mer- Engl J Med. 2011;364(25):2405-2416. 13. McHutchison JG, Dusheiko G, Shiffman 6. Sherman KE, Flamm SL, Afdhal NH, et al. ML, et al. Eltrombopag for thrombocy- ck Pharmaceuticals. He has served on data Response-guided telaprevir combination topenia in patients with cirrhosis as- and safety monitoring boards and endpoint treatment for hepatitis C virus infection. sociated with hepatitis C. N Engl J Med. adjudication committees for MedPace Inc N Engl J Med. 2011;365(11):1014-1024. 2007;357(22):2227-2236. and Janssen Therapeutics. His institution 7. Poordad F, McCone JJr, Bacon BR, et al. 14. Birnkrant D. FDA briefing documents on Boceprevir for untreated chronic HCV telaprevir NDA 201-917, prepared for the has received research support from Abbott genotype 1 infection. N Engl J Med. Antiviral Products Advisory Committee, Laboratories, Anadys Pharmaceuticals, BMS, 2011;364:1195-1206. April 1, 2011. http://www.fda.gov/down- Boehringer-Ingelheim Corp, Genentech Inc, 8. Poordad F, Lawitz EJ, Reddy KR, et al. loads/AdvisoryCommittees/Committees- Gilead Sciences, Inc, Norvartis, and Vertex A randomized trial comparing ribavirin MeetingMaterials/Drugs/AntiviralDrugs dose reduction versus for AdvisoryCommittee/UCM252561.pdf. Pharmaceuticals, Inc. (Updated 10/22/12) anemia management in previously un- Accessed October 9, 2012. treated patients with chronic hepatitis C 15. Cacoub P, Bourlière M, Lübbe J, et al. Der- receiving boceprevir plus peginterferon/ matological side effects of hepatitis C and References ribavirin. [Abstract 1419.] 47th Annual its treatment: patient management in the Meeting of the European Association for era of direct-acting antivirals. J Hepatol. 1. Clark BT, Garcia-Tsao G, Fraenkel L. Pat- the Study of the Liver (EASL). April 18-22, 2012;56(2):455-63. terns and predictors of treatment ini- 2012; Barcelona, Spain. tiation and completion in patients with 9. Sulkowski M, Roberts S, Afdhal N, et al. Additional Suggested Reading chronic hepatitis C virus infection. Patient Ribavirin dose modification in treatment- Prefer Adherence. 2012;6:285-295. naive and previously treated patients who Sherman KE. Therapeutic approach to the 2. Jacobson IM, Everson G, Gordon SC, et received telaprevir combination treat- treatment-naive patient with hepatitis C virus al. Interim analysis results from a phase ment: no impact on sustained virologic genotype 1 infection: a step-by-step approach. 2 study of telaprevir with peginterferon response in phase 3 studies. [Abstract Clin Infect Dis. 2012;55(9):1236-1241. alfa-2a and ribavirin in treatment-naive 1162.] 47th Annual Meeting of the Euro- subjects with hepatitis C. Hepatology. pean Association for the Study of the Liver Top Antivir Med. 2012;20(4):125-128 2007;46(4):315A. (EASL). April 18-22, 2012; Barcelona, Spain. ©2012, IAS–USA

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