Interferon therapy dosing

While there are no FDA-approved treatments for hepatitis D, interferon has been shown to be effective.46 48 Various doses have been evaluated, with the most effective treatment being 9 million units three times weekly.47 Seventy-one percent of patients who were treated with this regimen for 48 weeks had normalized ALT levels.47 Adverse effects and monitoring parameters for interferon therapy are similar to treatment for hepatitis C. In some situations, patients infected with hepatitis D who develop hepatic decompensation and ESLD may need to undergo liver transplantation. 

Flulike symptoms, including fever, chills, weakness, fatigue, myalgia, and arthralgia, are the most common side effects of interferon therapy. These symptoms occur in more than 50% of patients given injections of interferons either intravenously, intramuscularly, or subcutaneously. Intralesional injection may produce milder flulike symptoms with somewhat less frequency. Tolerance to these symptoms generally develops with repeated dosing. 

Subsequent analysis of stored serum samples showed reduction of HCV RNA levels during treatment and durable eradication of virus in some cases [38]. These early results were confirmed by randomized controlled trials in patients with chronic hepatitis C [39-41]. Durable viral eradication (termed sustained virologic response, or SVR) was achieved in 6% to 15% of patients after six months of treatment with recombinant interferon at doses of 3 to 6 MU administered subcutaneously three times per week. SVR increased to 13% to 25% if treatment was extended to 12 months [41]. The combination of the oral nucleoside analogue ribavirin with recombinant interferon increased SVR to 41% [42-44]. Ribavirin, however, is potentially embryotoxic and induces a dose-dependent hemolytic anemia, a situation that calls for close monitoring during therapy. 

Therapy becomes problematic when antibodies and markers of HCV infection are evident. It is imperative to complete the unambiguous identification of HCV antibodies by determination of HCV RNA. (The positivity of HCV antibodies may well be a methodologically related false-positive result.). If HCV RNA is detected, i. e. in florid HCV infection, interferon therapy (or a combination with ribavirin) should be considered. This antiviral therapy may be indicated despite positivity of LKM 1 following critical evaluation and close-meshed controls. There is a possibility of AIH activation under antiviral therapy. In this case, INF therapy has to be stopped as quickly as possible. It is not currently known whether this risk can be avoided by simultaneous administration of low-dose prednisolone. The same problem arises in the (very rare) combination of AIH with coexistent florid HBV infection. 

Cotier SJ, Wartelle CF, Larson AM, Gretch DR, Jensen DM, Carithers RL Jr. Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C. J Viral Hepat 2000 7(3) 211-17. 

Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M, Nishioji K, Katagishi T, Nakagawa Y, Tada H, Sawa Y, Mizuno M, Kagawa K, Kashima K. Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996 25(3) 283-91. 

Because a-interferon therapy can exacerbate autoimmune disorders, it is important to exclude autoimmune diagnoses before initiating therapy. Thrombocytopenia and granulocytopenia are more common in patients with cirrhosis and hypersplenism. The psychiatric complications are especially severe in those with severe liver disease, occur in up to 20% of patients, and are the most common dose-limiting side effects. Therapy should be discontinued if serious complications occur. The dose of a-interferon must be reduced in 10% to 40% of patients. Treatment must be discontinued because of adverse effects in 5% to 10% of patients. For many patients, reassurance that the side effects are therapy related, not severe, and will disappear when therapy is stopped is sufficient. It is always important to reassure both patient and family, especially when psychiatric side effects are evident. These points are critical given that patient adherence is crucial to the ultimate success of HCV treatment. ... 

Toxicities for the interferon therapy were common and severe in a majority of the patients at some point during therapy and necessitated dose reductions and/or delays during both the induction and maintenance phases of the study. Dose modifications were required for dose-limiting constitutional symptoms, hematologic toxicity, and hepatic toxicities, but 74% of the patients were able to complete the year of therapy in an outpatient setting. 

In an attempt to provide the benefit of aldesleukin therapy without the serious side effects, a number of studies have evaluated continuous-infusion aldesleukin therapy, and lower-dose aldesleukin alone or with chemotherapy and interferon therapy. Response rates have been promising, but survival has not been significantly affected. At this time, direct head-to-head comparisons of various dosing schedules and regimens are needed to determine the optimum approach to aldesleukin therapy in metastatic melanoma. The coadministration of LAK cells with aldesleukin does not appear to significantly improve clinical response. Although some studies have suggested improved response with coadministration of TILs with recombinant IL-2, the therapy is technically difficult and costly, and the overall clinical benefit has not been clearly demonstrated. 

Nordmann R, Ribiere C, Rouach H (1992) Implication of free radical mechanisms in ethanol-induced cellular injury. Free Radical Biol Med 112 219-240 Oh KW, Qian T, Brenner DA, Lemasters JJ (2003) Salicylate enhances necrosis and apoptosis mediated by the mitochondrial permeability transition. Toxicol Sci 73 44—52 Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M, Nishioji K, Katagishi T, Nakagawa Y, Tada H, Sawa Y, Mizuno M, Kagawa K, Kashima K (1996) Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 25 283-291 Oleinick NL, Corcoran JW (1969) Two types of binding of erythromycin to ribosomes Ifom antibiotic-sensitive and resistant Saci/te suhtilis 168. J Biol Chem 244 727-735 Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Diff 11 381-389... 

Balan V Nelson DR, Sulkowski MS, Everson GT, Lambiase LR, Wiesner RH, Dickson RC, Post AB, Redfleld RR, Davis GL, Neumann AU, Osborn BE, Ereimuth WW, Subramanian GM (2006) A Phase I/II study evaluating escalating doses of recombinant human albumin-interferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy, Antivir Ther 11 35 5... 

Fischl MA, Richman DD, Saag M, Meng TC, Squires KE, Holden-Wiltse J, Meehan PM (1997) Safety and antiviral activity of combination therapy with zidovudine, zalcitabine, and two doses of interferon-alpha2a in patients with HIV. J Acquit Immune Deflc Syndr Hum Retrovirol 16 247-253... 

Wolters LM, van Nunen AB, Honkoop P, Vossen AC, Niesters HG, Zondervan PE, de Man RA (2000) Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus. J Viral Hepat 7 428 34 Wong DK, Cheung AM, O Rourke K, Naylor CD, Detsky AS, Heathcote J (1993) Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A metaanalysis. Ann Intern Med 119 312-323... 

Adherence to therapy is another important factor in increasing and maintaining SVR. Patients who were adherent with interferon and ribavirin therapy (taking more than 80% of doses for more than 80% of the treatment duration) had an SVR of 52% whereas those who were not compliant had an SVR of 44% 42... 

Choosing Therapy There is no consensus on the best medication for initial therapy. Comparative beta interferon trials indicate better efficacy with more frequent and/or higher dosing.37 This consideration must be balanced with neutralizing antibody development and patient acceptance and tolerance. 

Interferon-a2b has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.42 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.42 Interferon-a2b is currently approved by the Food and Drug Administration (FDA) as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stage IIB, IIC, or III disease.43 It is controversial if interferon-a2b (IFN) should be offered as adjuvant therapy for every high-risk MM patient. The reason is because clinical trials with different doses of IFN have not proved definitively that IFN improves overall patient survival. 

Fever, rigors, chills, malaise headaches, myalgia Nausea, emesis Neutropenia Hepatic enzyme elevation Cutaneous—alopecia, transient, mild rashlike reaction Acetaminophen (APAP). NSAID if APAP is not effective. Meperidine for severe chills and rigors. Bedtime administration. 5-HT3 antagonist, prochlorperazine, metoclopramide, fluids Weekly complete blood count reduce dose by 30-50% Liver function tests (LFTs) weekly withhold treatment until LFTs normalize restart at 30-50% dose reduction reversible on dose reduction or cessation. Interferon is contraindicated in patients with psoriasis because exacerbation of psoriasis has been noted during IFN therapy. 

Kirkwood JM, Bender C, Agarwala S, et al. Mechanisms and management of toxicities associated with high dose interferon-a2b therapy. J Clin Oncol 2002 20 3703-3718. 

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