Thymosin α1 in liver disease: outcomes in hepatitis, cirrhosis, hepatocellular carcinoma and liver failure

Description of the potential effects of Thymosin α1 based on the literature. (This is not a product description, disclaimer at the bottom of the page)

Thymosin α1 (Tα1) is a 28-amino acid peptide that has a long history of safe use and well-established immunomodulatory effects. Thymosin α1 in liver diseases is the subject of numerous studies concerning chronic viral hepatitis B and C, liver cirrhosis, hepatocellular carcinoma (HCC), and acute liver failure. Importantly, it has gained approval in 35 developing countries for the treatment of chronic viral hepatitis B and C, demonstrating its recognised antiviral and immune-boosting properties. 

For hepatitis B and C (HBV/HCV), randomised trials and meta-analyses show that the addition of Tα1 can enhance virological and biochemical responses during treatment, especially when combined with standard treatment. In addition, several studies suggest that Tα1 may help maintain viral control after treatment, while being better tolerated than interferon alone. Tα1 has been tested alongside interferon-based regimens, where it reduced relapses and improved virological response at the end of treatment or sustained virological response in some difficult-to-treat patients. For HBV-related cirrhosis, the combination of Tα1 with nucleoside analogues such as entecavir appears safe, may accelerate early inhibition of viral replication and may slightly reduce the short-term risk of HCC, although long-term outcomes are often consistent with antiviral therapy alone.

In addition to chronic hepatitis, Tα1 has also been studied as an adjunct in HCC and ACLF. Early clinical studies indicate that administration of Tα1 in the perioperative period or during arterial chemoembolisation (TACE) can accelerate early immune recovery and delay tumour recurrence or improve survival. In addition, HBV Tα1-associated ACLF is associated with higher graft-free survival and fewer infections. Importantly, safety outcomes remained favourable across conditions. Overall, the evidence suggests that Tα1 is a generally well-tolerated immune enhancer that, when combined with standard therapy, can enhance or stabilise antiviral and antitumour effects. However, its benefits vary depending on disease stage, treatment regimen and duration of follow-up.

Thymosin α1 in liver diseases associated with cirrhosis

Thymosin α1 (Tα1) is an immune-enhancing peptide sometimes combined with the antiviral drug entecavir (ETV) to treat hepatitis B-related cirrhosis. In a pooled analysis of seven randomised trials involving 1144 patients, Peng et al (2020) found that the addition of Tα1 to ETV improved several early treatment outcomes: more patients achieved a complete clinical response, more had undetectable HBV DNA levels after 24 weeks, and more achieved HBeAg loss at this point. However, as therapy continued to 48-52 weeks, the differences in virological outcomes diminished and HBsAg loss remained similar in both groups. Some improvement in liver function tests and fibrosis scores was observed with combination therapy, although the magnitude of benefit varied between studies. Importantly, adverse effects occurred less frequently with the ETV + Tα1 combination than with ETV alone, indicating good tolerability. Overall, these results suggest a more rapid early inhibition of viral replication and a potential benefit to liver health, but it remains uncertain whether these short-term benefits translate into clear long-term clinical benefits [1].

Further evidence comes from a large multicentre study by Wu et al (2018) in patients with compensated cirrhosis. This compared ETV monotherapy with ETV in combination with Tα1 (1.6 mg administered subcutaneously twice weekly for 52 weeks). Over a median follow-up period of 38.2 months, the combined outcome of decompensation of liver function, hepatocellular carcinoma (HCC) or death was similar in both groups. At one year of Tα1 therapy, the incidence of HCC was slightly lower in the combination group (1.7% vs. 2.1%), and no new cases of HCC were reported in this group between weeks 39 and 77, suggesting a potential protective effect. At week 104, results for viral suppression, blood biomarkers and liver function were comparable in both treatment groups. Safety was favourable and both regimens were well tolerated. Overall, Tα1 in combination with ETV appears safe and may slightly reduce the risk of HCC in the near future [2].

Thymosin α1 (Tα1) and the treatment of hepatitis C

The addition of thymosin α1 (Tα1) to standard hepatitis C therapy may reduce the risk of recurrence and support the maintenance of virological response in patients in whom previous treatment has failed. Ciancio et al (2012) conducted a large randomised controlled trial involving 552 participants who had failed to respond to previous antiviral treatment regimens. Patients received Tα1 1.6 mg subcutaneously twice weekly along with standard peginterferon alfa-2a and ribavirin for 48 weeks. In the overall analysis, long-term viral clearance - measured as sustained virological response (SVR) - was similar in the Tα1 group and the control group (12.7% vs 10.5%; p = 0.407). However, among patients who completed a full course of treatment, SVR rates were significantly higher for Tα1 (41.0% vs 26.3%; p = 0.048). Importantly, this means that although Tα1 did not accelerate early viral clearance, it appeared to help maintain viral suppression and reduce the risk of relapse after therapy. Side effects were comparable in both groups, indicating that the addition of Tα1 was safe and well tolerated [3].

In another study, the combination of Tα1 with interferon showed more promising results. In an open-label study lasting 52 weeks, Kullavanuaya et al (2001) treated 12 patients with interferon alfa-2a (3 million units three times a week) in combination with Tα1 (1.6 mg twice a week). At week 24, one-third (33.3%) of the patients were virus-free and 41.7% had normal liver enzyme levels. By week 48, almost half of the patients (45.5%) had achieved both virus elimination and normalisation of ALT levels. Interestingly, four out of five patients who had never been treated before achieved a complete response, while previously treated patients showed less benefit. Laboratory results (AST, ALT and HCV RNA) decreased significantly compared with baseline values (p < 0.05). Side effects were mostly mild, such as muscle pain and slight hair thinning. These results suggest that Tα1 may enhance interferon therapy, especially in previously untreated patients, although longer follow-up is needed [4]. In addition, early randomised trials also suggested that adding thymalfascin (another name for Tα1) to peginterferon may help patients in whom previous treatment has failed. Rustgi (2004) summarised a randomised trial in which preliminary results favoured the combination with peginterferon over peginterferon alone and showed an acceptable safety profile [5]. Based on these results, Tα1 in combination with interferon-based therapy may reduce the risk of relapse and improve response at the end of treatment in some patients with hepatitis C, especially in those who are difficult to treat.

Furthermore, studies show that the addition of thymosin-α1 (Tα1) can enhance early response to treatment, although long-term cure rates are not always improved. Moscarella et al (1998) studied patients who had never received treatment before. One group was given interferon-α2b (3 million units, three times a week) plus Tα1 (1 mg, twice a week) for six months. The other group received interferon alone. At the end of treatment, the group receiving Tα1 had better early results. More patients showed improvement in liver enzyme tests (ALT) and hepatitis C virus RNA clearance (p < 0.05). However, after follow-up of patients for a further 12 months, long-term cure rates were only slightly higher for Tα1 [6]. Further analysis showed no clear benefit in patients with HCV-1b, but patients with HCV-2c seemed to respond better to treatment. Treatment was well tolerated and there were no unexpected side effects. Other studies have tested shorter Tα1 treatment regimens. Andreone et al (2004) conducted a pilot study with untreated patients using interferon-α2b with or without Tα1 (900 µg/m², twice weekly) for six months and then observing patients for a further six months. The addition of Tα1 significantly increased the number of patients in whom the virus was eliminated by the end of treatment (p = 0.03). However, six months after the end of therapy, there was no significant difference in sustained cure or improvement in liver enzymes between the groups. Both drugs were well tolerated [7]. The authors suggest that higher doses of Tα1, longer use or a combination with pegylated interferons may be necessary to convert the early benefit into a durable cure.

For difficult-to-treat patients, especially those with genotype 1 infection, triple therapy including thymalfascin (the Tα1 form) has shown more promising long-term results. Poo et al (2008) treated 40 patients of Hispanic origin who had not responded to previous treatment. Patients received thymalfascin (1.6 mg twice weekly), peginterferon-α2a (180 μg weekly) and ribavirin (800-1000 mg/day) for 48 weeks and were followed up to week 72. An early virological response occurred in 52.5% patients at week 12 and in 50% patients at week 24. At the end of treatment, 52.6% patients (according to the protocol) had shed their virus and had improved liver enzyme levels. Importantly, 21.1% achieved sustained virological response (SVR) at week 72, including 23.5% patients with genotype 1. Some patients required dose adjustment of peginterferon or ribavirin, but thymalfasin alone was well tolerated [8]. Early controlled studies also confirm that Tα1 enhances the hepatic and viral effects of interferon, although its long-term effect remains moderate. Sherman et al (1998) conducted a randomised, double-blind, placebo-controlled trial comparing Tα1 (1.6 mg twice weekly) in combination with interferon-α (3 million units three times weekly) with interferon alone or placebo. The combination of these drugs improved normalisation of liver enzymes (37.1% vs 16.2%), viral clearance (37.1% vs 18.9%) and liver tissue health (greater decrease in histological activity index). Virus levels declined significantly at weeks 8, 16 and 24 in the Tα1 group only. Nevertheless, the number of patients with sustained recovery after therapy remained low (14.2% vs 8.1%). Safety was good, with no unexpected adverse events reported [9].

In addition, thymalfascin (another name for thymosin α1, Tα1) in combination with peginterferon and ribavirin may help to reduce virus levels more rapidly in people with difficult-to-treat hepatitis C. In a 24-week pilot study, Poo et al (2004) subjected 23 patients, in whom previous therapy had failed, to triple therapy with peginterferon α-2a, ribavirin and thymalfascin. At week 12, 60.8% patients showed a decrease in viral titer and at week 24, 47.8% patients maintained this response. The treatment was generally safe and well tolerated. These preliminary results suggest that thymalfascin may enhance antiviral activity during treatment in difficult-to-treat cases of hepatitis C, although larger and longer studies are still needed to confirm a sustained benefit [10].

Thymosin α1 (Tα1) and the treatment of hepatitis B

Six-month treatment with thymosin α1 (Tα1) may provide more sustained improvement after treatment than interferon, although overall response rates remain moderate. You et al (2006) conducted a randomised controlled trial involving 62 patients who were positive for hepatitis B virus e antigen (HBeAg) and HBV DNA. Participants received Tα1 at a dose of 1.6 mg twice a week or interferon α for six months, and the results were also compared with a historical untreated control group. At the end of therapy, the complete response, defined as normalisation of ALT along with loss of HBV DNA and HBeAg, was 31.0% with Tα1 and 45.5% with interferon (the difference was not statistically significant). However, after six months of follow-up, the overall response increased to 48.3% in the Tα1 group compared with 27.3% in the interferon group (still not statistically significant). Sustained improvement in ALT and HBV DNA was almost three times more likely with Tα1. Both Tα1 and interferon performed better than the untreated control group. Importantly, Tα1 was well tolerated and no side effects were reported, whereas interferon caused typical flu-like symptoms and other expected side effects. These results suggest that Tα1 may help to maintain long-term benefits after treatment, although combination therapy may be required to increase the overall response rate [11].

It is noteworthy that the combination of thymosin α1 (Tα1) with interferon produced significantly better long-term results in terms of viral suppression and liver enzyme normalisation than interferon alone or interferon combined with lamivudine in HBeAg-negative chronic hepatitis B. Saruc et al (2003) conducted a study with 52 patients divided into three treatment groups: Tα1 in combination with interferon-α2b followed by interferon maintenance treatment, interferon alone or interferon in combination with lamivudine followed by lamivudine maintenance treatment. At 12 months follow-up, the sustained response, defined as normalisation of ALT with suppression of HBV DNA, was 70.3% in the Tα1 plus interferon group, compared with 20.0% with interferon alone and 26.6% with interferon combined with lamivudine (p = 0.036). After 18 months of follow-up, sustained response remained high at 71.4% for Tα1 in combination with interferon, but declined sharply to 10% and 20% in the other groups (p = 0.0003). The Tα1 combination was well tolerated and no unexpected safety issues were reported [12]. Overall, the use of Tα1 in combination with interferon provided significantly stronger and longer viral and liver enzyme control in HBeAg-negative chronic hepatitis B with a favourable safety profile.

Thymosin α1 (Tα1) may help reboot the body's antiviral defence in HBeAg-positive hepatitis B patients by enhancing important immune signals. In a randomised trial, Jiang et al (2010) assigned 25 patients to groups receiving 1.6 mg or 3.2 mg of recombinant Tα1 for 52 weeks. Over time, Tα1 increased levels of key cytokines, including IFN-γ, IL-2, TNF-α and IL-4. It also increased the number of immune cells producing these protective signals, often restoring and sometimes exceeding levels observed in healthy subjects. The higher dose of 3.2 mg elicited a stronger immune response than the 1.6 mg dose [13]. These results show that Tα1 enhances antiviral immunity in a dose-dependent manner, making it a promising immune therapy for chronic HBV. In addition, the use of low doses of interferon together with Tα1 also helped patients in whom interferon therapy had previously failed, showing better viral control, improved liver enzymes and tissue regeneration. Rasi et al (1996) treated 15 patients with chronic HBV DNA-positive infection, including 11 who had previously failed to respond to interferon. The treatment regimen started with Tα1 (1 mg daily for four days) combined with low-dose interferon-α lymphoblastic (3 MU), followed by twice-weekly administration of Tα1 and interferon for 25 weeks. A total of 60% (9/15) patients experienced elimination of HBV DNA and normalisation of liver enzyme levels (ALT). Among patients who had previously failed to respond to treatment, 55% improved and six patients completely lost HBsAg. The biopsy also showed improvement in liver tissue (lower Knodell index). The treatment was well tolerated with no unexpected safety issues [14]. These results suggest that the addition of Tα1 to low-dose interferon may help achieve a response in difficult-to-treat HBV cases.

Compared with interferon-α, thymosin α1 (Tα1) may provide longer post-therapy viral control, with better tolerability. You et al (2005) randomly allocated 56 anti-HBe positive and HBV DNA positive patients to a group receiving Tα1 (1.6 mg twice weekly) or interferon-α for six months and compared the two groups with 30 untreated patients. At the end of treatment, the overall response, defined as normalisation of ALT and loss of HBV DNA, was 30.8% with Tα1 and 46.7% with interferon (a statistically insignificant difference). Six months later, the situation had changed: 42.3% of Tα1-treated patients maintained a complete response compared to 23.3% of interferon-treated patients. Both groups performed better than the untreated control group (3.3%, p < 0.0001). Importantly, delayed viral responses were significantly more frequent with Tα1 (42.9% versus 0% with interferon). Patients treated with interferon experienced more relapses, whereas Tα1 was better tolerated [15]. In short, Tα1 provided longer viral control after therapy and caused fewer side effects. In a number of randomised trials, thymosin α1 (Tα1) is not superior to interferon during active treatment, but achieves better post-therapy outcomes, especially for HBeAg-negative hepatitis B. Yang et al (2008) conducted a meta-analysis of four randomised controlled trials (n = 199) comparing Tα1 with interferon-α. After six months of treatment, there were no significant differences between the two drugs in terms of viral, biochemical or cumulative response rates. However, at six-month follow-up, Tα1 provided a higher probability of sustained viral suppression (OR 3.71), normalisation of liver enzymes (OR 3.12) and complete response (OR 2.69) compared with interferon. As most of the included studies involved HBeAg-negative patients, this benefit appears to be strongest in this group [16]. These results indicate that Tα1 appears to promote sustained control of the virus post-therapy, making it a valuable option for long-term immunotherapy of chronic HBV.

Furthermore, thymosin α1 (Tα1) in combination with interferon can improve both short- and long-term outcomes in HBeAg-positive hepatitis B patients, without increasing side effects. Mao and Shi (2011) analysed seven randomised trials involving 535 patients. They found that Tα1 in combination with interferon achieved better outcomes than interferon alone at the end of therapy and during follow-up. More patients using the combination became HBV-DNA negative (54.9% versus 36.3% at the end of treatment; 58.6% versus 30.7% during follow-up). Normalisation of ALT was also higher (74.5% versus 60.9% at the end of treatment; 74.0% versus 55.6% during follow-up). HBeAg loss (56.9% vs. 36.7% at the end of treatment; 62.2% vs. 33.2% during follow-up) and seroconversion (40.1% vs. 29.0% at the end of treatment; 47.0% vs. 29.5% during follow-up) occurred more frequently with Tα1. Furthermore, HBsAg loss during follow-up was greater with Tα1 (9.8% vs. 3.7%). Importantly, safety was similar in both groups. Overall, this combination provided stronger and more sustained improvements in virus, liver enzymes and immune markers [17].

Thymosin α1 (Tα1) alone can also help patients with chronic hepatitis B, and higher doses appear to be particularly useful for those with advanced liver fibrosis. Iino et al (2005) randomly assigned 316 Japanese patients to a group receiving Tα1 at a dose of 0.8 mg or 1.6 mg twice a week for 24 weeks, and then followed them for 12 months. At the end of therapy, ALT levels normalised in approximately 36% patients receiving the higher 1.6 mg dose, with similar rates at the 0.8 mg dose. HBV DNA clearance reached approximately 30% in the bDNA assay and 15% in the TMA assay, while HBeAg was cleared in 22.8% patients. Interestingly, patients with more severe liver fibrosis responded better to the higher dose of 1.6 mg. Side effects were mild and comparable for both doses. These results show that Tα1 provides significant liver and viral improvement with a good safety profile, and that higher doses may be beneficial for patients with advanced disease [18]. In daily clinical practice, thymosin α1 (Tα1) appears safe and may provide moderate but sustained benefit, even for patients in whom interferon therapy has failed. Amarapurkar and Das (2002) studied 20 patients from India, 15 with chronic hepatitis and five with cirrhosis. All received Tα1 at a dose of 1.6 mg twice weekly for six months. At the end of treatment, four patients had responded to therapy; two more achieved a delayed response within six months after the end of therapy; one patient had a relapse after one year. Overall, the sustained response was 25% (5/20). Although no patient experienced HBsAg resolution, ALT levels decreased significantly and remained at improved levels after one year. No serious side effects were observed. Although efficacy was moderate, Tα1 showed good safety and provided stable improvement in liver status, even in patients who did not respond to interferon [19].

Early placebo-controlled studies also support the potential of thymosin α1 (Tα1) in restoring immune control and promoting long-term remission. Mutchnick et al (1991) randomly assigned 12 patients with chronic HBV to receive thymosin (fraction 5 or Tα1) or placebo twice weekly for six months. After one year, patients treated with thymosin showed a greater improvement in ALT and significantly higher HBV-DNA clearance (86% [6/7] vs 20% [1/5], p < 0.04). Liver biopsies showed a reduction in replicative HBV DNA (1/7 vs 4/5, p < 0.04). Immune activity also improved, with increases in lymphocyte counts, CD3/CD4 cells and interferon-γ production. The benefits persisted for an average of 26 months and there were no significant side effects. These results indicate that thymosin can enhance antiviral immunity, reduce viral replication and maintain long-term remission without compromising safety [20].

Thymosin α1 (Tα1) in combination with interferon may increase hepatitis B virus e antigen (HBeAg) loss, but the overall benefit beyond interferon alone remains uncertain. Lim et al (2006) conducted a double-blind study involving 98 HBeAg-positive patients with no prior treatment. All participants received interferon; half also received Tα1 (1.6 mg three times a week) for 24 weeks. At week 72, HBeAg loss was greater with the combination (45.8% vs 28.0%). However, this difference (17.8%, 95% CI -1.2%-35.3%; p = 0.067) did not reach statistical significance. Other outcomes - including HBeAg seroconversion, ALT normalisation, HBV DNA clearance and liver histology - were similar in both groups. The treatment regimen was well tolerated. In conclusion, Tα1 showed a favourable trend for HBeAg loss, but did not show a significant overall advantage [21]. Tα1 may also favour longer viral control and better improvement in laboratory results compared with interferon, with fewer side effects. You et al (2001) randomly assigned 81 patients with chronic hepatitis B to receive Tα1 (1.6 mg twice weekly for six months), interferon-α (standard six-month regimen) or a historical untreated control group. At the end of treatment, HBV DNA clearance was 55.6% for Tα1, 66.7% for interferon and 6.7% for no treatment. After six months of follow-up, the Tα1 group showed further improvement and HBV DNA clearance increased to 72.2%, outperforming the interferon (39.4%) and control group (6.7%). HBeAg seroconversion after the observation period was 55.6% for Tα1, 27.3% for interferon and 3.3% in the control group. Normalisation of ALT reached 61.1% for Tα1, 30.3% for interferon and 10% in the control group. The complete response (normalisation of ALT and loss of HBV DNA and HBeAg) was also higher with Tα1 (55.6%) than with interferon (27.3%). Tα1 caused only mild discomfort at the injection site, while interferon induced flu-like symptoms. Overall, Tα1 provided a stronger and longer-lasting response with better tolerability [22].

Short cycles of thymosin α1 (Tα1) treatment may help some patients with hepatitis B, especially those with a lower baseline viral titer or a transient increase in ALT during treatment. Arase et al (2003) conducted a randomised pilot study with 16 patients. They compared two dosing strategies: 0.8 mg vs 1.6 mg Tα1 (given intensively for a fortnight, then twice weekly for up to 24 weeks). After 24 months, 37.5% had achieved a complete response (HBeAg clearance, HBV DNA negativity and ALT normalisation). Patients who experienced a temporary ALT elevation above 300 IU/l during therapy were more likely to achieve a response (p = 0.0029). Patients who started treatment with lower HBV DNA levels (<100 Meq/ml) also had better results (p = 0.0063). There was no significant difference between the two Tα1 doses (p = 0.608). The treatment was well tolerated. These results suggest that Tα1 may be most effective in patients with a certain baseline profile and immune activity during therapy [23]. 

Nucleic acid polymers (NAPs) can significantly inhibit hepatitis B virus and may work even better in combination with thymosin α1 (Tα1). Al-Mahtab et al (2016) published the results of two studies in HBeAg-positive, previously untreated patients. REP-2055 monotherapy (n = 8) and REP-2139-Ca monotherapy (n = 12) significantly reduced hepatitis B virus surface antigen (HBsAg) levels by 2-7 log and HBV DNA by 3-9 log, while inducing anti-HBs antibody production (10-1712 mIU/ml). Nine patients subsequently received short-term immune therapy with pegylated interferon or Tα1. Following the addition of these immunological agents, 8 of 9 patients lost HBsAg, and all had a strong increase in anti-HBs antibodies before the end of treatment. Persistence varied: in some, very low HBV DNA levels persisted for 52-290 weeks, while others relapsed within 12-123 weeks. REP-2139-Ca was better tolerated than REP-2055, although side effects such as hair loss, difficulty swallowing and taste changes were reported. In summary, these results show that NAPs cause a significant reduction in viral protein and DNA levels, and combining them with Tα1 or pegylated interferon further enhances HBsAg elimination and antibody response [24]. 

In addition, thymosin α1 (Tα1) can match the short-term effects of interferon and may maintain the effects longer, causing fewer side effects. Andreone et al (1996) randomly assigned 33 chronic hepatitis B patients with HBe antigen and HBV-DNA to a group receiving Tα1 or interferon-α (IFN-α) for six months. Fifteen untreated patients constituted the control group. At the end of therapy, the overall response, defined as normal ALT levels and HBV-DNA loss, was 29.4% for Tα1 and 43.8% for IFN-α. After six months of follow-up, persistence was more favourable for Tα1, where 41.2% patients maintained a complete response compared to 25% for IFN-α. Both active drugs achieved better results than no therapy. Side effects also differed: IFN-α caused typical flu-like symptoms, while Tα1 was well tolerated, causing only mild discomfort at the injection site. Based on the results, Tα1 provided safer treatment and more durable post-treatment control [25]. In addition, the use of thymosin α1 (Tα1) together with famcyclovir may help patients with immune tolerance to achieve immune control. Lau et al (2002) randomly allocated 96 HBeAg-positive patients in the immune tolerance phase to a group receiving Tα1 together with famcyclovir, famcyclovir alone or no treatment for 26 weeks and then followed up for up to 52 weeks. At week 26, HBV-DNA levels fell more with the combination treatment (-0.94 log10) than with famciclovir alone (-0.70 log10; p < 0.001). At week 52, HBeAg seroconversion occurred in 15.6% patients receiving the combination treatment, compared with 0% patients receiving famciclovir alone or no treatment (p = 0.053, strong trend). Patients who responded to treatment also showed stronger HBV-specific CD4⁺ (Th1) T-cell activity, indicating improved immune function. Safety was similar in all groups. Overall, Tα1 in combination with famcyclovir resulted in a more profound inhibition of viral replication and early seroconversion through reactivation of the immune response [26].

In a research study, some patients with hepatitis B responded better to thymosin α1 (Tα1) therapy. Chien et al (2006) randomly assigned 98 patients with chronic HBV to receive Tα1 for 26 weeks (T6), Tα1 for 52 weeks (T12) or no treatment. Complete response (normal ALT levels with HBeAg and HBV-DNA clearance) was strongly associated with Tα1 use (OR 12.05), genotype B versus genotype C (OR 3.75) and precore mutations (OR 6.29). Patients with genotype B responded better than patients with genotype C (52% vs 24%; p = 0.036). Cases with the precore mutation also showed a better response than wild-type cases (64% vs 19%; p = 0.002). However, the extension of Tα1 use from 26 to 52 weeks ( ) did not result in a significant advantage over genotype or mutation status. These results show that selecting patients based on viral genotype and mutation can improve Tα1 treatment outcomes [27]. In addition, a 26-week treatment with thymosin α1 (Tα1) can produce delayed and sustained improvements while remaining safe. Chien et al (1998) randomly assigned 98 patients with chronic HBV to a group receiving Tα1 for 26 weeks (T6), Tα1 for 52 weeks (T12) or to an observation group. After 18 months, the overall virological response, defined as HBV-DNA and HBeAg clearance, was 40.6% for T6, 26.5% for T12 and 9.4% for no treatment. The difference between T6 and the control group was statistically significant (p = 0.004), while a strong trend was observed for T12 (p = 0.068). The response persisted after treatment, suggesting a gradual restoration of immunity. Liver biopsies showed improvement in inflammation, especially in the lobules, although there was less reduction in fibrosis. There was no clearance of HBsAg. Safety was excellent, with no serious adverse events reported. Overall, Tα1 was effective, well tolerated and appeared to help the immune system to control the virus even after the end of therapy [28].

Thymosin α1 (Tα1) in liver cancer and severe hepatitis B

Importantly, the use of thymosin α1 together with lamivudine after hepatectomy can inhibit hepatitis B virus and slow the recurrence of liver cancer. Cheng et al (2006) followed 33 patients with hepatitis B virus-associated hepatocellular carcinoma (HCC) after surgery, comparing surgery alone with surgery in combination with lamivudine and Tα1. After one year, the combination achieved 100% inhibition of HBV-DNA compared with only 6% in the surgery alone group (p = 0.0016). In addition, HBeAg seroconversion was higher (62.5% vs 5.9%, p = 0.0157). Tumour recurrence also occurred later with treatment (median 7.0 vs 5.0 months, p = 0.0052). Furthermore, the median overall survival time was higher (10.0 vs 7.0 months, p = 0.1005), suggesting a potential survival benefit worthy of further study [29]. Similarly, another randomised trial confirmed this benefit. Cheng et al (2005) again compared surgery alone with surgery in combination with lamivudine and Tα1 in 33 patients with active HBV-related HCC. After one year, combination therapy achieved 100% suppression of HBV-DNA compared with 6% for surgery alone (p < 0.01), and HBeAg seroconversion reached 62.5% compared with 5.9% (p < 0.05). In addition, tumours recurred less frequently (81.3% vs 95.5%) and later (median 7.0 vs 5.0 months, p < 0.01). As a result, survival improved from 7.0 to 10.0 months (p < 0.01). These results support the addition of antiviral and immunomodulatory therapy after surgery to suppress HBV, delay recurrence and prolong survival [30].

It is worth noting that the addition of thymosin-α1 after transcatheter chemoembolisation (TACE) may enhance short-term immune regeneration in advanced HCC. Fang et al (2017) randomly assigned 30 patients to receive TACE alone or TACE in combination with Tα1 (1.6 mg subcutaneously twice weekly for four weeks). Compared to TACE alone, the combination of these therapies raised immune cell levels. After four weeks, CD4⁺ T-cell counts were higher than p u (43.2% vs 31.2%, p < 0.05), and CD3⁺ and CD8⁺ T-cell counts also increased. Additionally, autophagy markers (Beclin-1 and LC3) increased early on, but returned to baseline levels after three months. Importantly, no new safety issues were reported, confirming that Tα1 is a safe treatment for early immune recovery after TACE [31]. Furthermore, the use of thymosin-α1 together with TACE may improve long-term outcomes by enhancing immune system activation. Stefanini et al (1998) studied 12 patients with advanced HCC treated with Tα1 (900 μg/m² twice weekly for six months) in combination with TACE and compared them with a matched control group treated with TACE alone. The combination was well tolerated and improved overall survival time, with benefits becoming significant from the seventh month onwards (p < 0.05). In addition, immunological analysis showed an increase in CD3⁺ and CD8⁺ T cells after three months and higher levels of NK cells (CD16⁺/CD56⁺) after one month, indicating a stronger activation of the immune system in combination with TACE [32].

Thymosin-α1 may accelerate recovery and reduce complications in life-threatening acute liver failure associated with chronic hepatitis B (ACLF). Chen et al (2022) randomly assigned 120 patients to receive standard care or standard care combined with Tα1 (1.6 mg daily for one week, then twice weekly until week 12). After 90 days, transplant-free survival was higher with Tα1 (75.0% vs 53.4%, p = 0.030). In addition, new infections occurred less frequently (32.1% vs 58.6%, p = 0.005), as did hepatic encephalopathy (8.9% vs 24.1%, p = 0.029) and infection-related deaths (8.9% vs 24.1%, p = 0.029). Importantly, treatment was well tolerated, confirming that Tα1 is a valuable immune booster for HBV-related severe liver failure [33].

Typical clinical dosage of thymosin α1 (Tα1)

Most clinical trials of thymosin-α1 (Tα1) used a subcutaneous (SC) dose of 1.6 mg twice weekly, usually for 24-52 weeks. Some studies have tested a dose of 0.8 mg SC twice weekly or a dose based on body surface area (approximately 900 µg/m² SC twice weekly). Short 'loading' regimens (daily dosing for 1 week before switching to twice-weekly dosing) have been reported in selected acute cases, such as HBV-related liver failure.

In chronic hepatitis B (HBV), both HBeAg-positive and HBeAg-negative patients were usually treated with a dose of 1.6 mg SC twice weekly for 6-12 months; a Japanese study showed a better response to the 1.6 mg dose than to the 0.8 mg dose. Combination therapy with antiviral drugs (e.g. entecavir, famciclovir, interferon) also tended to use a dose of 1.6 mg twice weekly. For HBV-induced cirrhosis, a dose of 1.6 mg subcutaneously twice weekly for approximately 52 weeks was added to standard nucleoside analogue therapy (t) in large studies. For HBV-associated acute liver failure (ACLF), a dose of 1.6 mg daily for the first week and then twice weekly until week 12 was administered in one study. Following liver surgery or transcatheter chemoembolisation (TACE) for HBV-associated hepatocellular carcinoma (HCC), Tα1 was also administered at a dose of 1.6 mg subcutaneously twice a week, while some previous studies used a dose of 900 µg/m² subcutaneously twice a week.

In chronic hepatitis C (HCV), Tα1 was combined with interferon-based therapy at 1-1.6 mg subcutaneously twice weekly for 24-48 weeks; monotherapy at 900 µg/m² twice weekly for 6 months was ineffective. Dose-response studies have shown a stronger immune effect at a dose of 3.2 mg subcutaneously twice weekly compared with 1.6 mg, but the 1.6 mg dosing regimen remains the most commonly used.

Practical conclusions

For hepatitis B and C, the most commonly used and best studied regimen is a dose of 1.6 mg subcutaneously twice a week for 24 to 52 weeks. Adjustments are dependent on the patient's condition:

• Daily for 1 week and then twice weekly for HBV-related severe liver failure (ACLF).
• Short cycles twice weekly after TACE for liver cancer.
• Dosage based on body surface area (~900 µg/m²) in older studies.

In general, 1.6 mg twice a week is the standard basis for most clinical applications.

Disclaimer

This article has been written for educational purposes and is intended to raise awareness of the substance under discussion. It is important to note that the article is about the substance in general - it is not a description of a specific product (chemical reagent). We are not suggesting the use of chemical reagents on humans - this is prohibited by law, for a product to be used for treatment it must be registered as a medicine. The information contained in the text is based on available scientific research and is not intended as medical advice or to promote self-medication. The reader should consult with a qualified health professional for all health and treatment decisions.

References

1. Peng, D., Xing, H. Y., Li, C., Wang, X. F., Hou, M., Li, B. and Chen, J. H. (2020). Clinical efficacy and adverse effects of entecavir and thymosin alfa-1 combination therapy compared with entecavir monotherapy in HBV-related cirrhosis: a systematic review and meta-analysis. BMC Gastroenterology, 20(1), 348. https://doi.org/10.1186/s12876-020-01477-8https://pubmed.ncbi.nlm.nih.gov/33076834/ 
2. Wu, X., Shi, Y., Zhou, J., Sun, Y., Piao, H., Jiang, W., Ma, A., Chen, Y., Xu, M., Xie, W., Cheng, J., Xie, S., Shang, J., Cheng, J., Xie, Q., Ding, H., Zhang, X., Bai, L., Zhang, M., Wang, B., Chen, S., Ma, H., Ou, X., Jia, J. and You, H. (2018). Combination of entecavir with thymosin alfa-1 in compensated HBV-related cirrhosis: a prospective, multicentre, randomised open-label study. Expert Opinion on Biological Therapy, 18(sup1), 61-69. https://doi.org/10.1080/14712598.2018.1451511 https://pubmed.ncbi.nlm.nih.gov/30063860/
3. Ciancio, A., Andreone, P., Kaiser, S., Mangia, A., Milella, M., Solà, R., Pol, S., Tsianos, E., De Rosa, A., Camerini, R., McBeath, R. and Rizzetto, M. (2012). Thymosin alfa-1 with peginterferon alfa-2a/ribavirin in the treatment of IFN/ribavirin-insensitive chronic hepatitis C: role of an adjuvant? Journal of Viral Hepatitis, 19(Suppl 1), 52-59. https://doi.org/10.1111/j.1365-2893.2011.01524.x https://pubmed.ncbi.nlm.nih.gov/22233415/
4. Kullavanuaya, P., Treeprasertsuk, S., Thong-Ngam, D., Chaermthai, K., Gonlachanvit, S. and Suwanagool, P. (2001). Combination treatment with interferon alfa-2a and thymosin alfa 1 in chronic hepatitis C: results after 48 weeks of treatment. Journal of the Medical Association of Thailand, 84(Suppl 1), S462-S468. PMID: 11529376 https://pubmed.ncbi.nlm.nih.gov/11529376/
5. Rustgi, V. (2004). Combination treatment with thymalfascin (thymosin alfa-1) and peginterferon alfa-2a in patients with chronic hepatitis C who have not responded to standard treatment. Journal of Gastroenterology and Hepatology, 19(Suppl 6), S76-S78. https://doi.org/10.1111/j.1440-1746.2004.03632.x https://pubmed.ncbi.nlm.nih.gov/15546255/
6. Moscarella, S., Buzzelli, G., Romanelli, R. G., Monti, M., Giannini, C., Careccia, G., Marrocchi, E. M. and Zignego, A. L. (1998). Combination therapy with interferon and thymosin in previously untreated patients with chronic hepatitis C: preliminary results. Liver, 18(5), 366–369. https://doi.org/10.1111/j.1600-0676.1998.tb00819.x. PMID: 9831367. https://pubmed.ncbi.nlm.nih.gov/9831367/
7. Andreone, P., Gramenzi, A., Cursaro, C., Felline, F., Loggi, E., D'Errico, A., Spinosa, M., Lorenzini, S., Biselli, M., Bernardi, M. (2004). Thymosin alfa 1 in combination with interferon alfa in previously untreated patients with chronic hepatitis C: results of a randomised controlled pilot study. Journal of Viral Hepatitis, 11(1), 69-73. https://doi.org/10.1046/j.1365-2893.2003.00470.xhttps://pubmed.ncbi.nlm.nih.gov/14738560/ 
8. Poo, J. L., Sánchez Avila, F., Kershenobich, D., García Samper, X., Torress-Ibarra, R., Góngora, J., Cano, C., Parada, M. and Uribe, M. (2008). Efficacy of triple therapy with thymalfascin, peginterferon alfa-2a and ribavirin in the treatment of Spanish patients with non-responders to chronic hepatitis C. Annals of Hepatology, 7(4), 369-375. PMID: 19034238. https://pubmed.ncbi.nlm.nih.gov/19034238/
9. Sherman, K. E., Sjogren, M., Creager, R. L., Damiano, M. A., Freeman, S., Lewey, S., Davis, D., Root, S., Weber, F. L., Ishak, K. G. and Goodman, Z. D. (1998). Combination therapy with thymosin alpha1 and interferon for the treatment of chronic hepatitis C: a randomised, placebo-controlled, double-blind study. Hepatology, 27(4), 1128-1135. https://doi.org/10.1002/hep.510270430 【PMID: 9537454】https://pubmed.ncbi.nlm.nih.gov/9537454/ 
10. Poo, J. L., Sánchez-Avila, F., Kershenobich, D., García-Samper, X., Gongora, J. and Uribe, M. (2004). Triple combination of thymalfascin, peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C whose previous treatment with interferon and ribavirin failed: 24-week intermediate results of a pilot study. J Gastroenterol Hepatol, 19(Suppl 6), S79-S81. doi:10.1111/j.1440-1746.2004.03634.x. PMID: 15546256 https://pubmed.ncbi.nlm.nih.gov/15546256/
11. You, J., Zhuang, L., Cheng, H. Y., Yan, S. M., Yu, L., Huang, J. H., Tang, B. Z., Huang, M. L., Ma, Y. L., Chongsuvivatwong, V., Sriplung, H., Geater, A., Qiao, Y. W. and Wu, R. X. (2006). Efficacy of thymosin alfa-1 and interferon alfa in the treatment of chronic hepatitis B: a randomised controlled trial. World Journal of Gastroenterology, 12(41), 6715-6721. https://doi.org/10.3748/wjg.v12.i41.6715 https://pubmed.ncbi.nlm.nih.gov/17075991/
12. Saruc, M., Ozden, N., Turkel, N., Ayhan, S., Hock, L. M., Tuzcuoglu, I. and Yuceyar, H. (2003). Long-term results of combination therapy with thymosin alfa 1 and interferon alfa-2b in patients with chronic hepatitis B without HBeAg antigen. Journal of Pharmaceutical Sciences, 92(7), 1386-1395. https://doi.org/10.1002/jps.10401 https://pubmed.ncbi.nlm.nih.gov/12820143/
13. Jiang, Y. F., Ma, Z. H., Zhao, P. W., Pan, Y., Liu, Y. Y., Feng, J. Y. and Niu, J. Q. (2010). Effects of thymosin-α1 on cytokine synthesis of T helper 1 cells and T helper 2 cells in chronic hepatitis B patients with positive hepatitis B virus e antigen test. Journal of International Medical Research, 38(6), 2053–2062. https://doi.org/10.1177/147323001003800620https://pubmed.ncbi.nlm.nih.gov/21227010/ 
14. Rasi, G., Mutchnick, M. G., Di Virgilio, D., Sinibaldi-Vallebona, P., Pierimarchi, P., Colella, F., Favalli, C. and Garaci, E. (1996). Treatment of chronic hepatitis B with a combination of low-dose lymphoblastic interferon and thymosin alpha 1. Journal of Viral Hepatitis, 3(4), 191–196. https://doi.org/10.1111/j.1365-2893.1996.tb00094.x https://pubmed.ncbi.nlm.nih.gov/8871880/
15. You, J., Zhuang, L., Cheng, H. Y., Yan, S. M., Qiao, Y. W., Huang, J. H., Tang, B. Z., Ma, Y. L., Wu, G. B., Qu, J. Y. and Wu, R. X. (2005). Randomised controlled clinical trial comparing thymosin alfa-1 with interferon alfa in patients with chronic hepatitis B without HBeAg in China. Journal of the Chinese Medical Association, 68(2), 65-72. https://doi.org/10.1016/s1726-4901(09)70137-6 https://pubmed.ncbi.nlm.nih.gov/15759817/
16. Yang, Y. F., Zhao, W., Zhong, Y. D., Yang, Y. J., Shen, L., Zhang, N. and Huang, P. (2008). Comparison of the efficacy of thymosin alfa-1 and interferon alfa in the treatment of chronic hepatitis B: a meta-analysis. Antiviral Research, 77(2), 136-141. https://doi.org/10.1016/j.antiviral.2007.10.014 https://pubmed.ncbi.nlm.nih.gov/18078676/
17. Mao, H. Y. and Shi, T. D. (2011). [Treatment with interferon and alpha-1 thymosin versus interferon monotherapy for HBeAg-positive chronic hepatitis B: a meta-analysis]. Zhonghua Gan Zang Bing Za Zhi, 19(1), 29–33. https://doi.org/10.3760/cma.j.issn.1007-3418.2011.01.009 https://pubmed.ncbi.nlm.nih.gov/21272455/
18. Iino, S., Toyota, J., Kumada, H., Kiyosawa, K., Kakumu, S., Sata, M., Suzuki, H. and Martins, E. B. (2005). Efficacy and safety of thymosin alfa-1 in Japanese patients with chronic hepatitis B; results of a randomised clinical trial. Journal of Viral Hepatitis, 12(3), 300-306. https://doi.org/10.1111/j.1365-2893.2005.00633.x https://pubmed.ncbi.nlm.nih.gov/15850471/
19. Amarapurkar, D. and Das, H. S. (2002). Thymosin alfa in the treatment of chronic hepatitis B: an uncontrolled open-label study. Indian Journal of Gastroenterology, 21(2), 59-61. PMID: 11990327https://pubmed.ncbi.nlm.nih.gov/11990327/ 
20. Mutchnick, M. G., Appelman, H. D., Chung, H. T., Aragona, E., Gupta, T. P., Cummings, G. D., Waggoner, J. G., Hoofnagle, J. H., & Shafritz, D. A. (1991). Treatment of chronic hepatitis B with thymosin: a pilot placebo-controlled study. Hepatology, 14(3), 409-415. https://doi.org/10.1002/hep.1840140305. PMID: 1874487. https://pubmed.ncbi.nlm.nih.gov/1874487/
21. Lim, S. G., Wai, C. T., Lee, Y. M., Dan, Y. Y., Sutedja, D. S., Wee, A., Suresh, S., Wu, Y. J., Machin, D., Lim, C. C., Fock, K. M., Koay, E., Bowden, S., Locarnini, S. and Ishaque, S. M. (2006). Randomised, placebo-controlled trial of thymosin alfa-1 and lymphoblastic interferon in the treatment of HBeAg-positive chronic hepatitis B. Antiviral Therapy, 11(2), 245-253. PMID: 16640105 https://pubmed.ncbi.nlm.nih.gov/16640105/
22. You, J., Zhuang, L., Tang, B. Z., Yang, W. B., Ding, S. Y., Li, W., Wu, R. X., Zhang, H. L., Zhang, Y. M. and Yan, S. M. (2001). Randomized controlled clinical trial of treatment with thymosin-α1 versus interferon-α in patients with hepatitis B. World Journal of Gastroenterology, 7(3), 411-414. https://doi.org/10.3748/wjg.v7.i3.411https://pmc.ncbi.nlm.nih.gov/articles/PMC4688733/ 
23. Arase, Y., Tsubota, A., Suzuki, Y., Suzuki, F., Kobayashi, M., Someya, T., Akuta, N., Hosaka, T., Saitoh, S., Ikeda, K., Kobayashi, M. and Kumada, H. (2003). Pilot study on thymosin alpha-1 therapy in patients with chronic hepatitis B. Internal Medicine, 42(10), 941-946. https://doi.org/10.2169/internalmedicine.42.941 https://pubmed.ncbi.nlm.nih.gov/14606705/
24. Al-Mahtab, M., Bazinet, M. and Vaillant, A. (2016). Safety and efficacy of nucleic acid polymers in monotherapy and in combination with immunotherapy in previously untreated Bangladeshi patients with HBeAg+ chronic hepatitis B . PLoS One, 11(6), e0156667. https://doi.org/10.1371/journal.pone.0156667https://pubmed.ncbi.nlm.nih.gov/27257978/
25. Andreone, P., Cursaro, C., Gramenzi, A., Zavagliz, C., Rezakovic, I., Altomare, E., Severini, R., Franzone, J. S., Albano, O., Ideo, G., Bernardi, M. and Gasbarrini, G. (1996). Randomised controlled trial comparing thymosin alfa-1 treatment with interferon alfa treatment in patients with chronic hepatitis B with antibodies to hepatitis B virus e antigen and hepatitis B virus DNA. Hepatology, 24(4), 774-777. https://doi.org/10.1002/hep.510240404 https://pubmed.ncbi.nlm.nih.gov/8855175/
26. Lau, G. K. K., Nanji, A., Hou, J., Fong, D. Y. T., Au, W.-S., Yuen, S.-T., Lin, M., Kung, H.-F. and Lam, S.-K. (2002). Combination therapy with thymosin alpha-1 and famcyclovir activates T-cell responses in patients with chronic hepatitis B virus infection in the immune tolerance phase. Journal of Viral Hepatitis, 9(4), 280–287. https://doi.org/10.1046/j.1365-2893.2002.00361.x https://pubmed.ncbi.nlm.nih.gov/12081605/ 
27. Chien, R.-N., Lin, C.-Y., Yeh, C.-T. and Liaw, Y.-F. (2006). Hepatitis B virus genotype B is associated with better response to thymosin alpha1 therapy than genotype C. Journal of Viral Hepatitis, 13(12), 845-850. https://doi.org/10.1111/j.1365-2893.2006.00761.x (PMID: 17109685) https://pubmed.ncbi.nlm.nih.gov/17109685/
28. Chien, R. N., Liaw, Y. F., Chen, T. C., Yeh, C. T. and Sheen, I. S. (1998). Efficacy of thymosin alfa1 in patients with chronic hepatitis B: a randomised controlled trial. Hepatology, 27(5), 1383-1387. https://doi.org/10.1002/hep.510270527 (PMID: 9581695) https://pubmed.ncbi.nlm.nih.gov/9581695/
29. Cheng, S., Wu, M., Chen, H., Shen, F., Yang, J., Cong, W., Yin, Z., Zhao, Y. and Wang, P. (2006). Antiviral therapy with lamivudine and thymosin alfa1 for hepatocellular carcinoma coexisting with chronic hepatitis B virus infection. Hepatogastroenterology, 53(68), 249-252. PMID: 16608033. https://pubmed.ncbi.nlm.nih.gov/16608033/
30. Cheng, S., Wu, M., Chen, H., Shen, F., Yang, J., Cong, W., Zhao, Y. and Wang, P. (2005). Antiviral therapy with lamivudine and thymosin is helpful in preventing recurrence of hepatocellular carcinoma with coexisting active hepatitis B. Zhonghua Zhong Liu Za Zhi, 27(2), 114-116. PMID: 15946554. https://pubmed.ncbi.nlm.nih.gov/15946554/
31. Fang, S. J., Zheng, L. Y., Zhao, Z. W., Fan, X. X., Xu, M. and Ji, J. S. (2017). [Effects of transcatheter arterial chemoembolization combined with thymosin alpha 1 on immune cell autophagy in advanced hepatocellular carcinoma]. Zhonghua Yi Xue Za Zhi, 97(25), 1942-1946. https://doi.org/10.3760/cma.j.issn.0376-2491.2017.25.005 https://pubmed.ncbi.nlm.nih.gov/28693071/
32. Stefanini, G. F., Foschi, F. G., Castelli, E., Marsigli, L., Biselli, M., Mucci, F., Bernardi, M., Van Thiel, D. H. and Gasbarrini, G. (1998). Alpha-1-thymosin and transcatheter arterial chemoembolisation in patients with hepatocellular carcinoma: preliminary experience. Hepatogastroenterology, 45(19), 209-215. PMID: 9496515 https://pubmed.ncbi.nlm.nih.gov/9496515/
33. Chen, J. F., Chen, S. R., Lei, Z. Y., Cao, H. J., Zhang, S. Q., Weng, W. Z., Xiong, J., Lin, D. N., Zhang, J., Zheng, Y. B., Gao, Z. L. and Lin, B. L. (2022). Safety and efficacy of thymosin α1 in the treatment of hepatitis B virus-related acute liver failure: a randomized controlled trial. Hepatology International, 16(4), 775–788. https://doi.org/10.1007/s12072-022-10335-6 https://pubmed.ncbi.nlm.nih.gov/35616850/