HCV Treatment Complications Volume 20 Issue 4 October/November 2012 Perspective Managing Adverse Effects and Complications in Completing Treatment for Hepatitis C 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 thrombocytopenia; 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, paroxetine, 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. Platelet 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 epoetin alfa 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