Discontinuations and dose modification

The results of a large phase III clinical trial of peginterferon alfa-2a and ribavirin have been reported recently.⁸ More than 1,100 subjects were randomized to therapy with peginterferon alfa-2a and ribavirin, peginterferon alfa-2a and placebo, or standard interferon alfa-2b and ribavirin. Premature withdrawal from therapy due to laboratory abnormalities or adverse events in the combination arms with either peginterferon (10%) or standard interferon (11%) was comparable⁸ (Table 1).

Table 1. Frequency of discontinuations and dose modifications for peginterferon alfa-2a and ribavirin compared with standard interferon alfa-2b and ribavirin

		Peginterferon Alfa-2a and Ribavirin (%)			Interferon Alfa-2b and Ribavirin (%)
Discontinuation (total)		10			11
Adverse event		7			10
Laboratory abnormality		3			1
Dose modifications	Peginterferon (%)		Ribavirin (%)	Interferon (%)		Ribavirin (%)
Adverse event	11		22	11		21
Anemia	1		22	3		19
Neutropenia	20		1	5		<1
Thrombocytopenia	4		<1	<1		<1
Adapted from Fried et al.8

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Interestingly, this rate of discontinuation for either combination arm was lower than previously reported in earlier trials using standard interferon and ribavirin (approximately 20%),^4,9 suggesting improved strategies for managing side effects of therapy (see below).

Dose reductions (temporary or permanent) of peginterferon for any adverse event were required in 32% of patients compared with 27% in those treated with standard interferon.⁸ Laboratory abnormalities such as neutropenia, anemia, and thrombocytopenia were the most frequent indications for dose reduction. Thus, approximately 25% of patients required at least one dose reduction for laboratory abnormalities during therapy. The frequency of dose reduction for neutropenia was greater in the peginterferon combination arm compared with standard interferon (20% vs. 5%). Among these participants, approximately 5% experienced grade 4 neutropenia (<500 cells/mm³). Thrombocytopenia was also more common with peginterferon. The frequency of ribavirin dose reduction was similar in the combination arms of the study (40% and 37%). Despite the need for dose reductions, only a minority of patients discontinued therapy due to laboratory abnormalities (3% for peginterferon and ribavirin vs. 1% for standard interferon and ribavirin).

Frequency of adverse events

Table 2 shows the frequency of adverse events that were reported in at least 20% of participants in this trial.

 

Table 2. Frequency of adverse events for peginterferon alfa-2a and ribavirin compared with standard interferon alfa-2b and ribavirin (>20%)

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	Peginterferon Alfa-2a and Ribavirin	Interferon Alfa-2b and Ribavirin
Fatigue	54	55
Headache	47	52
Pyrexia	43	56
Myalgia	42	50
Rigors	24	35
Insomnia	37	39
Nausea	29	33
Alopecia	28	34
Irritability	24	28
Arthralgia	27	25
Anorexia	21	22
Dermatitis	21	18
Depression	22	30
Fatigue	54	55
Adapted from Fried et al.8

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The study design allowed for a comparison of the side effect profiles between combination therapies using peginterferon or standard interferon. In general, the adverse events were all predictable based on previous experience with interferon and ribavirin combination therapy, and no significant new classes of side effects were observed. Most adverse events in subjects treated with peginterferon and ribavirin were of similar frequency or significantly less frequent than for those treated with standard interferon and ribavirin. Thus, influenza-like symptoms (fever, myalgia, and rigors), headaches, and alopecia occurred less frequently (by at least 5%) in the peginterferon alfa-2a combination arm. Depression also occurred less frequently in those treated with peginterferon and ribavirin (22%) compared with standard interferon and ribavirin (30%).⁸
Peginterferon alfa-2b and ribavirin
A large phase III trial that compared the antiviral efficacy of 2 different regimens of peginterferon alfa-2b and ribavirin with standard interferon alfa-2b and ribavirin has also been reported and allows a comparison between side effect profiles.⁷ The frequency of treatment discontinuation due to any adverse event or laboratory abnormality was similar between the higher-dose (1.5 µg/kg) peginterferon combination arm and standard interferon (14% and 13%, respectively)⁷ (Table 3).

 

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Table 3. Frequency of discontinuations and dose modifications for peginterferon alfa-2b and ribavirin compared with standard interferon alfa-2b and ribavirin

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	Peginterferon Alfa-2b and Ribavirin (%)	Interferon Alfa-2b and Ribavirin (%)
Discontinuation (total)	14	13
Adverse event	12	12
Laboratory abnormality	2	1
Dose modifications
Adverse event	42	34
Anemia	9	13
Neutropenia	18	8
Adapted from Manns et al.7

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Most dose discontinuations resulted from adverse events (12% for each arm), whereas only a minority required discontinuation due to laboratory abnormalities (2% and 1%) (Janice Albrecht, personal communication, June 2002).

Dose modification for any adverse event was required in 42% of participants treated with peginterferon and 34% treated with standard interferon. Similar to the other peginterferon preparation, dose reduction for neutropenia was more common in those treated with peginterferon than standard interferon (18% vs. 10%). Four percent of patients treated with peginterferon and ribavirin experienced neutrophil counts less than 500 cells/mm³.

Frequency of adverse events

The frequency of adverse events reported by more than 20% of participants is shown in Table 4.

 

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Table 4. Frequency of adverse events for peginterferon alfa-2b and ribavirin compared with standard interferon alfa-2b and ribavirin (>20%)

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	Peginterferon Alfa-2b and Ribavirin (%)	Interferon Alfa-2b and Ribavirin (%)
Fatigue	64	60
Headache	62	58
Pyrexia	46	33
Myalgia	56	50
Rigors	48	41
Insomnia	40	41
Nausea	43	33
Alopecia	36	32
Irritability	35	34
Arthralgia	34	28
Anorexia/weight loss	32	27
Weight loss	29	20
Depression	31	34
Injection site reaction	58	36
Injection site inflammation	25	18
Adapted from Manns et al.7

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Compared with the standard combination arm, a number of adverse events were reported more frequently in those treated with the peginterferon combination.⁷ Thus, influenza-like symptoms (fevers, myalgias, and rigors) and several gastrointestinal disturbances (nausea, diarrhea, and weight loss) occurred with increased frequency (>5% difference) in those treated with peginterferon and ribavirin compared with the standard interferon combination. Injection site reactions and injection site inflammation were particularly common, although it was noted that these were generally mild and rarely dose limiting.⁷ Other adverse events, including depression, were reported with similar frequencies in both treatment groups.

 Uncommon serious adverse events

The previous discussion has focused on the most frequent dose-limiting side effects reported with peginterferon and ribavirin. Numerous case reports from patients treated with standard interferon with or without ribavirin show that more serious adverse events may occur with the potential to cause significant morbidity and end-organ damage. A partial list of severe adverse events is given in Table 5.

Among the infrequently reported (<1%) prominent serious adverse events associated with standard interferon therapy are retinopathy, retinal hemorrhage, visual loss, tinnitus, hearing loss, cardiac arrhythmias, congestive heart failure, interstitial pneumonitis, acute renal failure, bacterial infections (particularly in patients with cirrhosis), and induction or exacerbation of autoimmune diseases, hyperthyroidism, hypothyroidism, acute psychosis, panic attacks, severe depression, and suicide.^2,10-19 Healthcare providers should be aware that some of these isolated events have also been reported rarely in association with peginterferon therapy (see package inserts), so that appropriate aggressive investigations may be undertaken when warranted.


   Management of side effects

In the registration trials of peginterferon combination therapy, significant side effects often required dose reductions and occasionally discontinuation of therapy. Because most of the side effects associated with treatment are dose related, this strategy has been proven to be a safe and effective way to decrease adverse events and minimize serious, life-threatening sequelae. However, recent interest has focused on the importance of adherence to a prescribed medication regimen in maximizing response to antiviral therapy. Decreased adherence due to dose reductions or premature discontinuations could underestimate the true effect of combination therapy for hepatitis C. Indeed, retrospective analyses from 2 large trials of combination therapy with peginterferons suggested that participants who were able to maintain nearly all their prescribed therapy had significantly higher sustained virological response than those who required substantial dose reductions or early treatment withdrawal.^8,20,21 Thus, developing strategies that maximize adherence will likely further improve the efficacy of currently available antiviral agents.


   General strategies for management of side effects

Management of side effects can begin even before the first dose of medication is administered. Careful patient selection for entry into the registration trials previously described undoubtedly contributed to the low rates of serious adverse events and premature discontinuations of therapy. Thus, patients were excluded if they had significant psychiatric illnesses, active substance abuse, or comorbid medical conditions that could compromise tolerability of the agents under investigation. In clinical practice, proper selection of patients for therapy based on an understanding of the risks of adverse events remains an important safeguard for the use of these agents. However, it is likely that these agents will be used more frequently in patients who do not meet such rigorous standards, so the frequency and severity of adverse events may differ in the expanded treated population. Nevertheless, the concepts for managing adverse events remain applicable.

Before beginning therapy, patients should be educated about the expectations from treatment, particularly the likelihood of experiencing one or more adverse events that could impact transiently on their quality of life. Instructions in self-management techniques can enable a patient to play an active role. Simple interventions such as maintaining adequate hydration, altering dosing schedules to coincide with lighter workdays or weekend activities, maintaining mild to moderate exercise schedules, and judicious use of analgesics and antipyretics can ameliorate some of these side effects. Equally important is providing the patient with regular follow-up visits within a supportive environment. This will facilitate early detection of emerging adverse events and promote rapid intervention when warranted. Incorporation of physician extenders, such as nurse practitioners and physician assistants, and other support personnel such as nurse clinicians, pharmacists, and psychologists into a unified team will enhance greatly the experiences of patients on antiviral therapy.


   Management of specific adverse events

Certain adverse events associated with antiviral therapy have been responsible for most dose reductions and discontinuations and also have the greatest potential for altering the quality of life of individuals on antiviral therapy. Specific interventions may be available and deserve further discussion.

Anemia

Hemolytic anemia is a universal event associated with ribavirin combination therapy, although the extent of anemia can vary greatly between individuals. The mechanism of anemia due to ribavirin has recently been described.²² Ribavirin is taken up into erythrocytes and activated to ribavirin triphosphate. Erythrocytes are unable to hydrolyze ribavirin triphosphate, which therefore remains “trapped” within the erythrocyte, where concentrations can increase to levels 60-fold greater than plasma concentrations. The associated depletion of red blood cell adenosine triphosphate impairs antioxidant defense and induces red blood cell membrane oxidative damage, promoting extravascular hemolysis via the reticuloendothelial system.²²

During therapy with standard interferon and ribavirin, hemoglobin levels decreased within the first 2–4 weeks of therapy (Fig. 1) with a mean maximal decrease of approximately 3 g/dL.²

Fig. 1. Change in hemoglobin during a 48-week course of combination therapy with peginterferon alfa-2a and ribavirin (), peginterferon alfa-2a alone (), or standard interferon alfa-2b and ribavirin (×). Data courtesy of Hoffmann-La Roche.

Click on Image to view full size

When peginterferon alfa-2a and standard interferon alfa-2b combination regimens were compared, similar maximal decreases in hemoglobin were noted (3.7 vs. 3.6 g/dL). Nevertheless, 9% of participants treated with peginterferon and ribavirin required dose reductions due to decreased hemoglobin levels less than 10 g/dL.⁷ Fortunately these levels of anemia have not been associated with significant cardiovascular events, likely due to careful pretreatment patient selection and the exclusion from therapy of patients with cardiovascular risk factors. Hemoglobin levels promptly return to normal once therapy is discontinued.

Significant anemia associated with ribavirin therapy can increase fatigue, has a demonstrable effect on quality of life, and is a frequent indication for dose reduction of ribavirin.^7,8,23 A number of studies in patients undergoing cancer chemotherapy and a preliminary report from patients undergoing therapy for hepatitis C have suggested that epoetin alfa can relieve many of the symptoms related to chronic anemia.^24-27 Dieterich et al. randomized patients receiving standard interferon and ribavirin to epoetin alfa 40,000 U/wk or standard of care when hemoglobin levels decreased to 12 g/dL or less. After 16 weeks of study, hemoglobin levels were significantly higher in those treated with epoetin alfa compared with standard of care (14.2 vs. 11.2 g/dL; P < .05) and enabled maintenance of higher doses of ribavirin.²⁸ Although these results are of interest, what remains unclear are specific guidelines for using these medications to bolster hemoglobin levels. Additional studies are required to determine at what levels of hemoglobin should consideration be given to hematopoietic growth factors, which subgroups of patients would benefit most, whether treatment should be limited to symptomatic patients, and, ultimately, whether hematopoietic growth factors will have an impact on sustained virological response rates.

Neutropenia

Peginterferons induce neutropenia to a greater degree than standard interferons. Rapid decreases in neutrophil counts may be seen within the first 2 weeks of initiation of therapy and usually stabilize over the next 4 weeks as steady-state concentrations of peginterferon are achieved. Neutrophil counts rapidly return to baseline after therapy is discontinued (Fig. 2).

 

Fig. 2. Change in neutrophil count during a 48-week course of combination therapy with peginterferon alfa-2a with ribavirin (), peginterferon alfa-2a alone (), or standard interferon alfa-2b and ribavirin (×). Data courtesy of Hoffmann-La Roche.

Click on Image to view full size

All patients treated with peginterferon and ribavirin will experience some adverse events during therapy. However, most adverse events can be managed properly so that only a minority of patients will require premature discontinuation due to side effects. The adverse event profiles of peginterferons and ribavirin are similar to those seen with standard interferon, although the frequency of certain adverse events may vary by preparation. Hematologic abnormalities and depression are frequent indications for dose reductions.

Future studies should emphasize the importance of developing additional management strategies that will maximize adherence to antiviral therapy. Prospective studies of adherence could evaluate the impact of early versus late dose reductions and the effects on response in different genotypes. Additional information is required about the mechanisms of interferon-induced depression, which will facilitate the development of new therapeutic approaches. Prospective studies of hematopoietic growth factors to determine their effects on sustained virological response and quality of life and refining guidelines for dose reduction for neutropenia may also improve the management of adverse events during therapy with peginterferon and ribavirin for chronic hepatitis C.