Interferon is the mainstay of therapy for chronic HCV infection. The standard interferon- regimen is 3 million U three times weekly for 12 months. Unfortunately, this regimen results in sustained eradication of HCV in only 15% to 20% of cases [3]. In addition, many persons cannot tolerate interferon therapy because of its numerous adverse effects. Many patients with chronic HCV infection resort to the use of untested and unregulated over-the-counter agents that claim to be medically beneficial.

Several oral thymic preparations are available over the counter. When we began this study, a substantial number of patients at our institution were taking or had inquired about a dietary supplement called Complete Thymic Formula (Preventive Therapeutics, Inc., Duluth, Georgia). The components of this supplement include bovine glandular extracts of thymosin, thymopoietin, and thymic humoral factor as well as various herbs, vitamins, enzymes, and minerals [4]. Although no study of Complete Thymic Formula has been done, statements on the Internet claim that this product is beneficial for the treatment of chronic HCV infection. The immunologic properties of thymic factors include stimulation of interferon production after a viral challenge, enhancement of T-cell-dependent antibody response and helper T-cell activity, production of suppressor T cells, and modulation of natural killer cell activity [5-7].

We did a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of Complete Thymic Formula in patients with chronic HCV infection who did not respond to or were intolerant of interferon monotherapy.

Methods

Top Methods Results Discussion Author & Article Info References

Patients

The Human Investigative Committee of the University of Alabama at Birmingham, Birmingham, Alabama, approved our study protocol. All participants gave written informed consent.

Patients followed at the University of Alabama at Birmingham Liver Center were recruited and were eligible for enrollment if they were positive for HCV RNA on serologic testing after at least 3 months of interferon therapy. Patients who could not tolerate interferon because of severe side effects, such as fatigue, neuropsychiatric disturbances, or thrombocytopenia, were also included. Patients were excluded if they were pregnant, were currently abusing drugs or alcohol, had hepatoma, were seropositive for HIV, had an absolute granulocyte count less than 1000 cells/mm³, or had a coexistent cause of liver disease.

Patients were randomly assigned in a double-blinded manner to receive either Complete Thymic Formula or a placebo (provided by Preventive Therapeutics, Inc.) that was identical in shape, color, and packaging to the active drug. Physicians and patients were blinded to treatment assignments. Patients were instructed to take six tablets twice daily with meals (the regimen recommended by the manufacturer) for 12 weeks. At the end of 3 months, patients were unblinded and those who had been receiving placebo were offered therapy with Complete Thymic Formula. All patients, if they chose, could receive Complete Thymic Formula for a total of 6 months after the end of the randomized phase of the study.

Patients were evaluated monthly for compliance, which was assessed by pill count, and for the development of adverse reactions. Each month, a complete blood count was done and serum levels of electrolytes, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, and total bilirubin were measured. Titers of HCV RNA were assessed before enrollment, 3 months after randomization, and after 6 months of active therapy by using a qualitative multicycle reverse transcription polymerase chain reaction method (National Genetics Institute, Culver City, California). Titers were calculated up to 5 million copies/mL; if a titer was greater than 5 million copies/mL, it was simply reported as such and the exact value was not given. The primary end point with respect to efficacy was an undetectable HCV RNA titer at the end of treatment. Secondary end points were a significant decrease in viral load (arbitrarily defined as a 10-fold decrease in HCV RNA titer) and normalization of elevated aminotransferase levels.

Statistical Analysis

Point estimates and 95% CIs were used for all comparisons. Data were analyzed by using the unpaired Student t-test, the Fisher exact test, and the Wilcoxon nonparametric test for differences in groups, as appropriate. All measurements are expressed as the mean ±SD. Statistical significance was designated as a P value less than 0.05.

Role of the Funding Source

The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication.

Results

Top Methods Results Discussion Author & Article Info References

Thirty-eight patients-36 who did not respond to interferon and 2 who were intolerant of interferon (1 had severe fatigue and headaches, and 1 had hallucinations)-were enrolled in our study. The duration of interferon therapy in these patients had ranged from 3 to 17 months (mean duration, 7 months). Eighteen patients received placebo, and 20 received Complete Thymic Formula. Thirty-two patients (84%) (13 receiving placebo and 19 receiving Complete Thymic Formula) completed 3 months of their regimens. Six patients were excluded from analysis because of noncompliance with follow-up appointments and because serum samples for HCV RNA analysis were not available. Nineteen patients (13 from the treatment group and 6 from the placebo group) received 6 months of open-label treatment with Complete Thymic Formula. Thirteen patients (6 from the treatment group and 7 who had crossed over from the placebo group to receive Complete Thymic Formula) did not return for follow-up visits and did not provide serum samples for the open-label analysis. Among patients completing the 3-month randomized phase of the trial and 6 months of open-label treatment, 96% of pills were taken.

Baseline clinical characteristics for all patients are shown in Table 1. The study groups did not differ in age, sex, HCV viral load, elevated aminotransferase levels, or presence of cirrhosis. Thirty-one patients (82%) had HCV genotype 1, and 13 (34%) had cirrhosis confirmed by liver biopsy.

After the 3-month randomized phase of the trial, HCV had not been eliminated in any patient. No significant differences were seen in the placebo group (n = 13) compared with the treatment group (n = 19) in mean HCV RNA levels (4.06 ± 1.52 x 10⁶ copies/mL compared with 3.48 ± 1.92 x 10⁶ copies/mL; mean change, –0.55 x 10⁶ copies/mL [95% CI, –1.86 to 0.75 x 10⁶ copies/mL]; P > 0.2), mean alanine aminotransferase levels (130 ± 98 U/L compared with 156 ± 80 U/L; mean change, 25 U/L [CI, –38 to 90 U/L]; P > 0.2), or mean aspartate aminotransferase levels (98 ± 74 U/L compared with 103 ± 59 U/L; mean change, 5 U/L [CI, –43 to 53 U/L]; P > 0.2).

The data for patients who completed 6 months of open-label treatment with Complete Thymic Formula are shown in Table 2. All patients had persistent HCV viremia. Treatment did not result in a significant difference in mean HCV RNA titers compared with titers at baseline (2.78 ± 1.96 x 10⁶ copies/mL compared with 3.12 ± 1.94 x 10⁶ copies/mL; mean change, –0.34 x 10⁶ copies/mL [CI, –1.63 to 0.95 x 10⁶ copies/mL]; P > 0.2). In addition, no significant changes were seen in mean alanine aminotransferase levels (137 ± 19 U/L compared with 121 ± 19 U/L; mean change, –16U/L [CI, –78 to 46 U/L]; P > 0.2) or mean aspartate aminotransferase levels (98 ± 78 U/L compared with 81 ± 69 U/L; mean change, –15U/L [CI, –63 to 33 U/L]; P > 0.2).

One patient developed severe thrombocytopenia (platelet count, 4 x 10⁹/L) during the fifth month of therapy with Complete Thymic Formula. The patient was receiving only one other medication, naproxen, which is associated with a reported incidence of thrombocytopenia of less than 1% [8]. The patient's antiplatelet antibody levels were elevated and, after a short course of steroids and discontinuation of therapy with both Complete Thymic Formula and naproxen, the platelet count returned to baseline. No other hematologic, renal, or gastrointestinal adverse effects were noted.

Discussion

Top Methods Results Discussion Author & Article Info References

In our study, patients with chronic hepatitis C who did not respond to or were intolerant of interferon therapy had no significant differences in serum HCV RNA titers or hepatic aminotransferase levels after receiving Complete Thymic Formula for 3 to 6 months. In no patient was HCV successfully eradicated. One patient developed severe thrombocytopenia that may have been due to use of Complete Thymic Formula.

Recent studies have investigated an injectable thymosin extract alone or in combination with interferon for the treatment of chronic HCV infection. Because the bioavailability of Complete Thymic Formula is undefined, comparisons with the injectable form of thymosin are limited. Nevertheless, a recent preliminary study [9] reported that no benefit was seen after 6 months of treatment with injectable thymosin-₁ in 10 patients with chronic HCV infection. In contrast, an open-label study investigating standard interferon therapy plus thymosin-₁ showed that 5 of 11 interferon-naive patients and 1 of 4 patients who did not respond to interferon had sustained eradication of HCV RNA [10]. In addition, a preliminary report of a cohort from a randomized, placebo-controlled trial [11] suggests that the combination of interferon and thymosin-₁ resulted in a greater biochemical response than did interferon monotherapy. Whether the combination of Complete Thymic Formula and interferon is beneficial is unknown.

Limitations of our study include the small number of patients investigated and the fact that almost all of our patients had not previously responded to interferon therapy. In addition, most of our patients had HCV genotype 1 and one third had cirrhosis: These factors are considered to be predictors of poor response to interferon therapy [12, 13] and, taken together, may explain our sample's poor response to Complete Thymic Formula. No conclusions can be drawn from our study about the use of Complete Thymic Formula therapy by HCV-infected patients who have never received interferon or who have predictors of better response to interferon therapy.

Patients whose diseases are not treated effectively by conventional methods often seek alternative therapies and may be vulnerable to claims made by providers of these treatments, even in the absence of scientific investigation about efficacy and safety. In the United States in 1990, expenditures on unconventional medicine for all health problems exceeded $13 billion [14]. The implications of our negative study underscore several reasons why it is important to investigate unconventional therapies and to report both positive and negative study results. First, many alternative treatments are available over the counter; this facilitates their use and the potential substitution of them for conventional methods with proven efficacy and safety. Second, when counseling patients about alternative treatment options, physicians are often hindered by a lack of information about the efficacy and safety of those options. Our results suggest that patients with HCV infection who have received interferon should be advised of the lack of efficacy and the potential risks of Complete Thymic Formula. Finally, the U.S. Food and Drug Administration recently approved consensus interferon and the combination of interferon- 2b and ribavirin for persons who do not respond to interferon and persons who have relapse after receiving interferon monotherapy [15, 16]. It is hoped that new studies of HCV enzyme inhibitors will provide promising alternatives for patients who cannot tolerate interferon.

Dr. Raymond: University of Alabama at Birmingham Liver Center, Division of Gastroenterology and Hepatology, 633 Zeigler Research Building, 703 South 19th Street, Birmingham, AL 35294.