Indian Pediatrics - Editorial

Letters to the Editor

Indian Pediatrics 2002; 39:701-702

The Effect of Thymosine 1 Alpha and Lamivudine Combination Therapy in Chronic Hepatitis B Patients

Recently, apart from INF-alpha, newer nucleoside analogues and other immunomodulatory therapies like thymosin alpha 1 (TA1) are being investigated for treatment of chronic hepatitis B (CHB) infection. We wish to share our experience of treating three cases of CHB with TA1.

Immunological studies have found that impaired HB virus-specific T cell reactivity is the major cause of chronic infection(1). The hepatitis B virus cytotoxic T lymphocyte (CTL) response in patients with chronic HBV infection is generally weak or totally undetectable. This effect may enhance the probability that T cell-based immune therapies delivered after lamivudine treatment can successfully reconstitute a protective CTL response able to cure chronic HBV infection(2). Thymosin alpha 1 is an oligopeptide hormone originally isolated from the thymus gland, and has been reported to have stimulating effects on the differentiation of T cells and NK cells(3).

We investigated the results of treatment with TA1 (0.9 mg/m2 twice a week sc) in combination with lamivudine (4 mg/kg/day max 100mg) in three patients with CHB infection for six months who were unresponsive to standard dose INF-alpha (5 MU/m2 3/week for six months) treatment regimen. Two patients were at 11 years of age and one patient at 10 years. All the patients were male and the duration after the cessation of the treatment was at least one year. At the onset of the combination therapy all patients had HBsAg and HBeAg seropositivity, negative anti-HBe and anti-HBs, HBV DNA over 2000 pg/ml by soluble hybridization technique, mean ALT values of 79 IU/L and mean histological activity index of 8.1 by Knodell classification. Early response at the end of six months of TA1 and lamivudine combination therapy and delayed response one year after discontinuation were determined.

Table I- The results of the end of the therapy and one year after the end of the therapy in three patients 
with chronic hepatitis B infections.

		Clearance of HBV-DNA	Seroconversion to HBeAg/anti-HBe		ALT (IU/L)
Case 1	End of the therapy	-		-		36
	After one year	+		-		80
Case 2	End of the therapy	-		-		28
	After one year	+		-		96
Case 3	End of the therapy	+		-		44
	After one year	+		-		75

When results were evaluated, two patients had HBV DNA clearance at the end of the treatment, but have relapsed during the follow-up period. In these two patients, ALT normalization was achieved <40 IU/L at the end of the treatment but raised again to the beginning levels. In one patient, there was no response by HBV DNA and ALT levels. HBeAg/anti-HBe seroconversion in all patients did not occur neither at the end of the six months of the treatment period nor after one year following the discontinuation of this combination therapy (Table 1). None of these patients had adverse effects during the treatment period and after discontinuation. In conclusion, combination therapy of TA1 and lamivudine was not found to be effective in our three patients with CHB infection.

Meta-analysis of 4 randomized controlled studies investigating the safety and efficacy of TA1 monotherapy for the treatment of chronic hepatitis B showed that six months treatment of TA1 (1.6 mg 2/week) almost doubled the sustained response rate compared with controls(4). In another study, six months after the end of the therapy with TA1, HBV-DNA was negative and ALT had normalized in 14% of treated cases and in 4.5% of control group(5).

A study from China has disclosed TA1, lamivudine and famciclovir combination to be safe and effective in patients with CHB infections(6). In that study group, within one year of total treatment, 64% of the patients experienced a seroconversion of HBeAg to negative with all patients having the ALT normalization. The HBV DNA became negative in all patients. However in our study group, HBeAg/antiHBe seroconversion, clearance of HBV DNA and normalization of ALT did not occur after one-year of the end of the therapy. This outcome may have resulted from the few number of patients in our study group. Large scaled numbers of studies with particularly priorly untreated patient groups are needed to determine more definite results.

Bunyamin Dikici,

Mehmet Bosnak,

Kenan Haspolat,

Dicle University Medical Faculty,

Department of Pediatric Gastroenterology,

Diyarbakir, Turkey

Correspondence to:

Bunyamin Dikici

Dicle University Medical Faculty,

Dept of Pediatrics, 21280 Diyarbakir/Turkey,

E-mail: [email protected]

References

1. Andreone P, Cursaro C, Gramenzi A, Margotti M, Ferri E, Talarico S, et al. In vitro effect of thymosin-alpha 1 and interferon-alpha on Th1 and Th2 cytokine synthesis in patients with chronic hepatitis C. J Viral Hepat 2001; 8: 194-201.

2. Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, et al. Lamivudine treatment can overcome cytotoxic T-cell hyporespon-siveness in chronic hepatitis B: new perspective for immune therapy. Hepatology 2001; 33: 963-971.

3. Ohmori H, Kamo M, Yamakoshi K, Nitta MH, Hikida M, Kanayama N. Restoration of immunocyte functions by thymosin alpha l in cyclophosphamide-induced immunodeficient mice. Immunopharmacol Immunotoxicol 2001; 23: 75-82.

4. Lau GK. Use of immunomodulatory therapy (other than interferon) for the treatment of chronic hepatitis B virus infection. J Gastro-enterol Hepatol 2000; 15 Suppl: E46-52.

5. Zavaglia C, Severini R, Tinelli C, Franzone JS, Airoldi A, Tempini S, et al. A randomized, controlled study of thymosin-alpha 1 therapy in patients with anti-HBe, HBV-DNA-positive chronic hepatitis B. Dig Dis Sci 2000; 45: 690-696.

6. Leung YK, SO T. Treatment of chronic hepatitis B using thymosin alpha 1 and a combination of two nucleoside analogs, lamivudine and famciclovir. AASLD Abst. Oct. 1998.