HCV Rx

Managing Side Effects of HCV Treatment

Leah Molloy, PharmD 

Leah Molloy

Advances in hepatitis C virus therapy have brought forth new antiviral agents that are significantly less toxic than the traditional treatment backbone of interferon with ribavirin. However, as newly emerging agents are largely still used in concert with traditional antivirals, identification and management of treatment-related adverse effects continues to be of importance in clinical care. The most commonly reported adverse effects of interferon and ribavirin are hematologic toxicities, neuropsychiatric events, dermatological effects along with constitutional flu-like symptoms and fatigue.

Hematologic Effects

A well-described side effect of ribavirin is anemia, which occurs in up to 36% of patients. Ribavirin-induced anemia is caused by oxidative stress leading to red blood cell hemolysis. Dose reduction is recommended for all patients with hemoglobin of less than 10 g/dL. Drug discontinuation is recommended for patients whose hemoglobin falls below 8.5 g/dL. Recommended adjustments are more conservative for patients with cardiovascular disease who are more likely to experience adverse outcomes secondary to anemia.

Neutropenia is another important hematologic side effect of combination ribavirin and interferon treatment, and interferon dosage reductions are recommended for patients whose neutrophil counts fall below 0.75 × 109/L, with drug discontinuation advised when neutrophils are further reduced to less than 0.5 x 109/L. As neutropenia presents an important risk for serious infections, the recommendation for dose reduction may presumably be based on concern for opportunistic infections. The relationship between interferon-induced neutropenia and new infection in patients with HCV has been studied. In one such investigation, infections were common among these patients. However, data did not demonstrate a relationship between neutropenia and infection; rather, infections were more common among older patients.

The impact that the recommended antiviral dose reductions secondary to myelosuppression has on sustained virologic response has been evaluated. Reduced SVR achievement appears to occur primarily with substantial (60% to 80%) ribavirin dose reductions, when these dose reductions are made early in treatment, particularly during the first 12 weeks. Thus, there is interest in managing anemia to avoid reducing ribavirin doses early in therapy.

Epoetin alfa, a recombinant human erythropoietin product, is often used for anemia in other patient populations and has been considered in the setting of ribavirin-induced anemia. The efficacy of epoetin alfa was evaluated in a placebo-controlled study wherein anemic patients receiving interferon with ribavirin were randomly assigned to receive either placebo or weekly 40,000-unit doses of epoetin alfa. Significantly fewer patients assigned epoetin alfa required ribavirin dose reduction compared with those assigned placebo (88% vs. 60%; P<.001). Of note, patients with cardiovascular disease were excluded from this study. Similarly, the efficacy of granulocyte colony stimulating factor (G-CSF) in the management of ribavirin-induced neutropenia has been investigated, and has been confirmed to be a safe and effective means of maintaining maximum antiviral doses.

Epoetin alfa and G-CSF treatments appear to be effective in combating hematologic side effects of combination antiviral therapy and limiting dose reductions as recommended based on patient cell counts. However, the clinical importance of these measures as a means to safely achieve SVR, perhaps excluding those patients with special risk factors for poor outcomes from myelosuppression, remains a topic of discussion. Additionally, these growth factors present a significant expense and do not come without their own potentially adverse effects.

Interferon Ribavirin Effects 

 

 

Neuropsychiatric Effects

Neuropsychiatric events are a well-known serious side effect of interferon-based HCV treatment and can include major depression and suicidal or homicidal ideations. These effects, of varied severity, have been described in up to one-third of patients. One study observed an average time to onset of depression of 12 weeks after the start of interferon-based antiviral therapy.

Selective serotonin reuptake inhibitors (SSRIs) have emerged as an effective option to treat interferon-induced neuropsychiatric effects. In one study of patients who developed depression while on therapy, 85% were responsive to treatment with citalopram. A meta-analysis reviewing studies of SSRI prophylaxis to prevent depression among patients who received ribavirin and interferon identified significantly lower rates of depression and rescue treatment with an antidepressant among patients randomly assigned to receive SSRI prophylaxis. However, there was no difference in SVR attainment and rates of drug discontinuation between patients administered SSRI prophylaxis or placebo. Thus, SSRI prophylaxis does not appear to offer any benefit in terms of continuity or efficacy of hepatitis treatment, but may improve patient quality of life and be of particular utility among patients with underlying risk factors for serious neuropsychiatric events.

Given the potential severity of these effects, patients with risk factors such as underlying depression or drug abuse have historically been excluded from many drug trials, which may lead some of these patients to go untreated in clinical practice per drug warnings and contraindications. This is particularly concerning as injection drug use continues to be among the most common risk factors of HCV acquisition. Some research has been conducted in these populations, and recommendations support proceeding with antiviral therapy in this patient population with diligent multidisciplinary monitoring and treatment along with prophylactic antidepressant therapy. 

Dermatologic Effects

The incidence and severity of dermatologic side effects of HCV treatment are varied. Injection-site reactions may be observed with interferon, and both ribavirin and interferon are associated with rash, dermatitis and potential exacerbation of underlying psoriasis. Dermatologic effects of traditional antiviral therapy are typically mild and self-limiting, warranting only supportive care, or topical steroids may be considered in severe reactions. Conversely, telaprevir (Incivek, Vertex) carries a black-box warning for rare but potentially fatal skin reactions including Stevens Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and toxis epidermal necrolysis, which warrant immediate medical attention.

Optimizing Safe and Effective Treatment

While side effects of HCV treatment are common and often severe, they are also well understood and management strategies are well described. Identifying adverse effects early and providing appropriate care promptly within the setting of a strong interdisciplinary patient support network should enhance patient quality of life and increase successful continuation and completion of therapy.

References:
Afdhal NM. Gastroenterology. 2004;126:1302-1311.
Antonini MG. Infection. 2008;36:250-255.
Hauser P. Mol Psychology. 2002;7:942-947.
Hou X. PLoS One. 2013;8:e76799.
Maddock C. J Psychopharm. 2004;18:41-46.
McHutchison JG. Gastroenterology. 2002;123:1061-1069.
Nicholas RM. Aliment Pharmacol Ther. 2010;31:929-937.
Pegintron [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
Rebetol [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
Russmann S. Curr Med Chem. 2006;13:3351–3357.
Schaefer M. Clin Infect Dis. 2013;57:S111-S117.
Shiffman ML. Gastroenterology. 2004;126:1015-1023.
Talal AH. J Acquir Immune Defic Syndr. 2011;58:261-268.
For more information:
Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.
Leah Molloy, PharmD 

Leah Molloy

Advances in hepatitis C virus therapy have brought forth new antiviral agents that are significantly less toxic than the traditional treatment backbone of interferon with ribavirin. However, as newly emerging agents are largely still used in concert with traditional antivirals, identification and management of treatment-related adverse effects continues to be of importance in clinical care. The most commonly reported adverse effects of interferon and ribavirin are hematologic toxicities, neuropsychiatric events, dermatological effects along with constitutional flu-like symptoms and fatigue.

Hematologic Effects

A well-described side effect of ribavirin is anemia, which occurs in up to 36% of patients. Ribavirin-induced anemia is caused by oxidative stress leading to red blood cell hemolysis. Dose reduction is recommended for all patients with hemoglobin of less than 10 g/dL. Drug discontinuation is recommended for patients whose hemoglobin falls below 8.5 g/dL. Recommended adjustments are more conservative for patients with cardiovascular disease who are more likely to experience adverse outcomes secondary to anemia.

Neutropenia is another important hematologic side effect of combination ribavirin and interferon treatment, and interferon dosage reductions are recommended for patients whose neutrophil counts fall below 0.75 × 109/L, with drug discontinuation advised when neutrophils are further reduced to less than 0.5 x 109/L. As neutropenia presents an important risk for serious infections, the recommendation for dose reduction may presumably be based on concern for opportunistic infections. The relationship between interferon-induced neutropenia and new infection in patients with HCV has been studied. In one such investigation, infections were common among these patients. However, data did not demonstrate a relationship between neutropenia and infection; rather, infections were more common among older patients.

The impact that the recommended antiviral dose reductions secondary to myelosuppression has on sustained virologic response has been evaluated. Reduced SVR achievement appears to occur primarily with substantial (60% to 80%) ribavirin dose reductions, when these dose reductions are made early in treatment, particularly during the first 12 weeks. Thus, there is interest in managing anemia to avoid reducing ribavirin doses early in therapy.

Epoetin alfa, a recombinant human erythropoietin product, is often used for anemia in other patient populations and has been considered in the setting of ribavirin-induced anemia. The efficacy of epoetin alfa was evaluated in a placebo-controlled study wherein anemic patients receiving interferon with ribavirin were randomly assigned to receive either placebo or weekly 40,000-unit doses of epoetin alfa. Significantly fewer patients assigned epoetin alfa required ribavirin dose reduction compared with those assigned placebo (88% vs. 60%; P<.001). Of note, patients with cardiovascular disease were excluded from this study. Similarly, the efficacy of granulocyte colony stimulating factor (G-CSF) in the management of ribavirin-induced neutropenia has been investigated, and has been confirmed to be a safe and effective means of maintaining maximum antiviral doses.

Epoetin alfa and G-CSF treatments appear to be effective in combating hematologic side effects of combination antiviral therapy and limiting dose reductions as recommended based on patient cell counts. However, the clinical importance of these measures as a means to safely achieve SVR, perhaps excluding those patients with special risk factors for poor outcomes from myelosuppression, remains a topic of discussion. Additionally, these growth factors present a significant expense and do not come without their own potentially adverse effects.

Interferon Ribavirin Effects 

 

 

Neuropsychiatric Effects

Neuropsychiatric events are a well-known serious side effect of interferon-based HCV treatment and can include major depression and suicidal or homicidal ideations. These effects, of varied severity, have been described in up to one-third of patients. One study observed an average time to onset of depression of 12 weeks after the start of interferon-based antiviral therapy.

Selective serotonin reuptake inhibitors (SSRIs) have emerged as an effective option to treat interferon-induced neuropsychiatric effects. In one study of patients who developed depression while on therapy, 85% were responsive to treatment with citalopram. A meta-analysis reviewing studies of SSRI prophylaxis to prevent depression among patients who received ribavirin and interferon identified significantly lower rates of depression and rescue treatment with an antidepressant among patients randomly assigned to receive SSRI prophylaxis. However, there was no difference in SVR attainment and rates of drug discontinuation between patients administered SSRI prophylaxis or placebo. Thus, SSRI prophylaxis does not appear to offer any benefit in terms of continuity or efficacy of hepatitis treatment, but may improve patient quality of life and be of particular utility among patients with underlying risk factors for serious neuropsychiatric events.

Given the potential severity of these effects, patients with risk factors such as underlying depression or drug abuse have historically been excluded from many drug trials, which may lead some of these patients to go untreated in clinical practice per drug warnings and contraindications. This is particularly concerning as injection drug use continues to be among the most common risk factors of HCV acquisition. Some research has been conducted in these populations, and recommendations support proceeding with antiviral therapy in this patient population with diligent multidisciplinary monitoring and treatment along with prophylactic antidepressant therapy. 

Dermatologic Effects

The incidence and severity of dermatologic side effects of HCV treatment are varied. Injection-site reactions may be observed with interferon, and both ribavirin and interferon are associated with rash, dermatitis and potential exacerbation of underlying psoriasis. Dermatologic effects of traditional antiviral therapy are typically mild and self-limiting, warranting only supportive care, or topical steroids may be considered in severe reactions. Conversely, telaprevir (Incivek, Vertex) carries a black-box warning for rare but potentially fatal skin reactions including Stevens Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and toxis epidermal necrolysis, which warrant immediate medical attention.

Optimizing Safe and Effective Treatment

While side effects of HCV treatment are common and often severe, they are also well understood and management strategies are well described. Identifying adverse effects early and providing appropriate care promptly within the setting of a strong interdisciplinary patient support network should enhance patient quality of life and increase successful continuation and completion of therapy.

References:
Afdhal NM. Gastroenterology. 2004;126:1302-1311.
Antonini MG. Infection. 2008;36:250-255.
Hauser P. Mol Psychology. 2002;7:942-947.
Hou X. PLoS One. 2013;8:e76799.
Maddock C. J Psychopharm. 2004;18:41-46.
McHutchison JG. Gastroenterology. 2002;123:1061-1069.
Nicholas RM. Aliment Pharmacol Ther. 2010;31:929-937.
Pegintron [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
Rebetol [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
Russmann S. Curr Med Chem. 2006;13:3351–3357.
Schaefer M. Clin Infect Dis. 2013;57:S111-S117.
Shiffman ML. Gastroenterology. 2004;126:1015-1023.
Talal AH. J Acquir Immune Defic Syndr. 2011;58:261-268.
For more information:
Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.