Report of 6 Cases of Complete HCV Remission in Prior Non-Responders Treated with Pegylated Interferon Plus Ribavirin Plus Thalidomide

By Ronald Baker, PhD

Summary

Although it represents the current standard of care for chronic hepatitis C virus (HCV) infection, combination therapy with pegylated interferon plus ribavirin does not provide optimal treatment for this debilitating and life-threatening disease, which impacts a significant portion of the world's population.

The present article reviews a recent Brazilian paper published in Revista do Instituto de Medicina Tropical de Sao Paulo. This report describes 6 chronic HCV patients who failed initial combination therapy with pegylated interferon/ribavirin (Peg-IFN/RBV). After the addition of thalidomide to Peg-IFN/RBV therapy, all 6 experienced complete remission of their chronic hepatitis C infection and presented with negative HCV RNA, according to the author of these case reports.

The use of thalidomide in a triple combination regimen with pegylated interferon and ribavirin for the treatment of hepatitis C is described in these Brazilian case reports for the first time in the medical literature.

Introduction

With greater than 170 million people infected with HCV worldwide, treatment and care for chronic hepatitis C must be considered one of the most important public health issues. HCV infection ranks as the principal cause of death in individuals with chronic liver diseases, according to the World Health Organization.

In developed countries, the current standard of care for chronic hepatitis C is combination therapy with pegylated interferon plus ribavirin, which is the only FDA-approved therapy for this debilitating and life-threatening condition.

The standard treatment recommendation is 24 weeks of combination therapy with Peg-IFN plus ribavirin for patients with HCV genotypes 2 or 3, and 48 weeks for those with genotypes 1 or 4.

Studies have shown that approximately 42% of HCV genotype 1 patients receiving pegylated interferon alfa-2b (PegIntron) plus ribavirin achieve a sustained virological response (SVR). SVR is defined as maintaining an undetectable HCV viral load 6 months following the end of treatment. Patients who achieve durable SVR are widely regarded as "cured" of their HCV infection, although there are rare reports of individuals who relapse following achievement of SVR.

Study results suggest that patients with genotypes 2 or 3 receiving PegIntron plus ribavirin experience an SVR rate of approximately 82% (Manns et al. Lancet 358. 2001). SVR rates in individuals undergoing treatment with pegylated interferon alfa-2a (Pegasys) plus ribavirin are approximately 46% and 76% for genotype 1 and genotype 2 or 3 patients, respectively (Fried et al. NEJM 347. 2002; Hadziyannis et al. Ann Intern Med 140. 2004).

Clearly the success rates of pegylated interferon/ribavirin therapy are far from optimal, especially for patients with genotype 1. Clinical trials of new experimental drugs for chronic hepatitis C patients with genotype 1 are underway, but FDA approval of these agents is not assured, and there are as yet no certainties about their effectiveness or long-term safety.

Experimental Treatment Regimens Reported in the Medical Literature

A number of experimental therapeutic approaches to the treatment of chronic hepatitis C among prior non-responders to both conventional IFN and Peg-IFN/RBV have been documented in the medical literature. These include the combinations of IFN + ribavirin + amantadine, IFN + phlebotomy, IFN + prednisolone, IFN + cimetidine, IFN + N-acetylcysteine, and IFN + vitamin E.

In addition to these combinations, other adjuvant therapies for chronic hepatitis C include levorin, glycyrrhizin, ursodeoxycholic acid, Maxamine, pentoxifylline, isoprinosine, colchicine, histamine, IL-1229, IL-28, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and thymosin alpha.

More recent experimental approaches presented at recent major research conferences include Actimmune (IFN gamma), Albuferon (albumin interferon), BILN-2061 (discontinued due to toxicity in early studies), consensus interferon, merimepodib, milk thistle (silymarin), NM283 (valopicitabine, an HCV polymerase inhibitor), pegylated interferon plus viramidine (also known as taribavirin, a prodrug of ribavirin), SCH 503034 (an HCV protease inhibitor), and telaprevir (VX-950), another HCV protease inhibitor). For a review of these experimental anti-HCV agents, see the collection of articles on HIV and Hepatitis.com.

Case Reports of Remission in 6 Patients in Brazil Receiving Peginterferon + Ribavirin + Thalidomide

The present case report study by Marcos Montani Caseiro, MD, published in Revista do Instituto de Medicina Tropical de Sao Paulo, describes the use of thalidomide and Peg-IFN/ribavirin combination therapy for chronic hepatitis C in prior nonresponders to Peg-IFN/ribavirin.

The use of thalidomide for various pathologies is well known. These include AIDS-related pharyngeal ulceration (aphthous ulcers), leprosy, tuberculosis, and AIDS-related wasting. The drug has properties as a sedative-hypnotic, immunomodulatory, anti-inflammatory, and antiangiogenic agent.

Because it can cause severe congenital abnormalities, thalidomide is generally only available in specialty cancer treatment centers where research trials are taking place and specialist doctors have experience in its use.

It is most commonly used to treat a type of cancer known as myeloma, and may be given to help keep the myeloma in remission after treatment, or if the myeloma recurs after treatment.

To the best of our knowledge, the case reports summarized here represent the first documented use of thalidomide for the treatment of chronic hepatitis C infection.

First Case Report

Following is a summary of the first case report described by Dr. Caseiro:

A 44-year-old male patient with genotype 1 chronic HCV infection identified in November 1996 came to the San Paulo clinic for medical assessment in October 1999. His liver function tests showed ALT 86 U/L, AST 178 U/L, and HCV RNA 340,463 U/mL by PCR. Liver biopsy revealed structural lesion (level 3) and steatosis.

In May 2001, the patient initiated therapy with weekly injections of Peg-IFN 3,000,000 U and oral ribavirin 500 mg twice daily for a total of 12 months. At the end of this treatment, HCV RNA was 1,309,317 U/mL, with ALT 151 U/L and AST 272 U/L. The patient was then referred to the San Paulo clinic for re-evaluation. As of October 2002, the patient received 1.5 ?g/kg of PegIntron once weekly and 500 mg of ribavirin twice daily for a total of 12 weeks.

In January 2003, the PCR test showed HCV RNA of 2,126,000 U/mL. The patient complained of multiple ulcers, pain, and difficulty eating. No response to local therapy or anesthetics and other medications was observed.

In addition to IFN and ribavirin, a dose of 100 mg twice-daily thalidomide was prescribed for 30 days to treat the patient's mouth ulcers. At the follow-up appointment 1 month later, the patient presented with remission of the symptoms, and reported that the ulcers had disappeared in 1 week.

His liver function tests showed a decrease in AST (32 U/L) and ALT (40 U/L). Thalidomide administration was maintained for 30 days. In May 2003, his HCV RNA viral load was undetectable. In August 2003, a qualitative PCR test was negative, and it remained negative in October, at the end of the treatment.

Five More Cases of Remission in Pegylated Interferon/Ribavirin Nonresponders

Five additional patients who presented no decrease in HCV viral load after 12 weeks of weekly treatment with 1.5 ?g/kg PegIntron and 500 mg of ribavirin twice daily were treated at the San Paulo clinic with 100 mg twice-daily thalidomide for 30 days.

Four patients presented negative HCV PCR and 1 patient, who weighed 130 kg, had a decrease in HCV viral load of 1 log at the follow-up appointment 30 days after initiation of thalidomide.

Five patients achieved sustained virological response at Weeks 48 and 72.

Discussion

First, no conclusions can be drawn about the potential effectiveness of thalidomide for the treatment of chronic HCV based on these 6 case reports. More data from a randomized study would be required to evaluate the utility of thalidomide in combination with pegylated interferon and ribavirin.

Various theories have been presented concerning the mechanism of the efficacy of thalidomide, for instance, as an immunomodulatory, anti-inflammatory agent which inhibits tumor necrosis factor alpha (TNF-alpha), and the effects of thalidomide on lymphocytes, increasing interferon gamma secretion.

Many questions remain. It is still unknown whether thalidomide has any effect on HCV replication, whether it modulates cytokines that affect the inflammatory process of HCV-related liver diseases, or whether thalidomide might benefit HCV patients not receiving pegylated interferon and ribavirin.

Other questions to consider are the appropriate dose of thalidomide, the duration of treatment, and the time to initiate therapy.

In conclusion, Dr. Caseiro writes, "Only a randomized clinical trial can provide us with the answers. We have already begun a pilot trial which will soon allow us to present more consistent data."

FDA Warnings on Use of Thalidomide

It must be emphasized that thalidomide use can be harmful, in particular when used by pregnant women, since the drug may cause severe birth defects. While studies have demonstrated that thalidomide can treat mouth ulcers very effectively in people with HIV infection, it is not FDA-approved for any other indication in the U.S.

Do not take thalidomide if there is any possibility that you are, or may become, pregnant. A single dose can cause severe birth defects.

Thalidomide was first marketed in Europe in the late 1950s. It was used as a sleeping pill and to treat morning sickness during pregnancy. At that time, no one knew thalidomide caused birth defects.

Thalidomide is not approved for general sale in the United States. However, the FDA allows it to be used in studies of certain severe or life-threatening diseases for which there may be no other treatment.

If you become pregnant, you must immediately stop taking thalidomide. You should contact your doctor to discuss whether or not to continue your pregnancy.

Warning for Male Patients

You must abstain from sexual intercourse or use a condom during intercourse while, and for one month after, taking thalidomide. It is not known if thalidomide is present in male ejaculate (semen).

Thalidomide Use Guidelines for All Patients

Be sure to take your medication as prescribed by your doctor. If there is anything you do not understand, ask your doctor to explain it to you.
Thalidomide often causes drowsiness. You should avoid drinking alcohol or taking other medications that also make you sleepy. Thalidomide can reduce your ability to drive or operate machinery. It can also reduce your alertness and ability to think clearly.

Thalidomide might cause damage to your nerves. It is not known whether this nerve damage is reversible after the drug is stopped. Symptoms of nerve damage include burning, numbness, or tingling of your arms, hands, legs, or feet. Call your doctor if you have any questions, or experience any of these or other troubling symptoms.

Your doctor may do special laboratory tests to check for nerve damage. If nerve damage is found, you and your doctor can decide whether the benefit that you might be receiving from thalidomide outweighs the risk of possible permanent damage to your nerves if you continue taking thalidomide.
Check with your doctor before taking any other prescription or over-the-counter medication.

If you develop a skin rash with or without a fever, fast heart beat, or low blood pressure, immediately stop taking thalidomide and contact your doctor.

Any side effect should be reported to your doctor. The following list contains additional side effects that may occur while you are taking thalidomide:

- mood changes
- dry mouth
- headache
- nausea
- constipation
- increased appetite
- puffiness of the face and limbs (edema)
- dry skin
- itching
- irregular menstrual period
- low white blood cell count
- thyroid problems
- blood sugar that is too high or lowslow heart beat

12/08/06

Source

M M Caseiro. Treatment of chronic hepatitis C in non-responsive patients with pegylated interferon associated with ribavirin and thalidomide: report of six cases of total remission. Revista do Instituto de Medicina Tropical de Sao Paulo 48(2): 109-112. April 2006.

Bibliography

Diggle, G E. Thalidomide: 40 years on. Int J Clin Prac 55: 627-631. 2001.

Dolev, E. The thalidomide story and its lessons. Harefuah 140: 663-667. 2001.

Fried, M W, Shiffman, M L, Reddy, K R, and others. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. NEJM 347: 975-982. 2002.

Hadziyannis, S J, Sette Jr, H, Morgan, T R, and others. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 140: 346-355. 2004.

Manns, M P, McHutchison, J G, Gordon, SC, and others. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358: 958-965. 2001.

Matthews, S J and J A McCoy. Thalidomide: a review of approved and investigational uses. Clinical Therapy 25: 342-395. 2003.

Meierthofer, C, Dunzendorfer, S, and Wiederman, CJ. Theoretical basis for the activity of thalidomide. BioDrugs 15: 681-703. 2001.

Nasca, M R, Micali, G, Cheigh, N H, and others. Dermatologic and nondermatologic uses of thalidomide. Annals of Pharmacotherapy 37: 1307-1320. 2003.

Reyes-Teran, G, Sierra-Madero, J G, Martinez del Cerro, V, and others.  Effects of thalidomide on HIV-associated wasting syndrome: a randomized, doubleblind, placebo-controlled clinical trial. AIDS 10: 1501-1507. 1996.

Verbon, A, Juffermans, N P, Speelman, P, and others. A single oral dose of thalidomide enhances the capacity of lymphocytes to secrete gamma interferon in healthy humans. Antimicrobial Agents and Chemotherapy 44: 2286-2290. 2000.

Walker, M P, Appleby, T C, Zhong, W, and others. Hepatitis C virus therapies: current treatments, targets and future perspectives. Antivir Chem Chemother    14: 1-21. 2003.

Wu, K L and Sonneveld, P. Thalidomide: new uses for an old drug. Ned Tijdschr Geneeskd 146: 1438-1441. 2002.

Youle, M, Clarbour, J, Farthing, C, and others. Treatment of resistant aphthous ulceration with thalidomide in patients positive for HIV antibody. British Medical Journal 298: 432. 1989.