Thymosin α1 in liver disease: results of treatment of 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 extensive research for chronic hepatitis B and C virus infections, liver cirrhosis, hepatocellular carcinoma (HCC), and acute liver failure. Importantly, it has gained approval in 35 developing countries for the treatment of chronic hepatitis B and C, demonstrating its established antiviral and immunomodulatory activities. 

For hepatitis B and C (HBV/HCV), randomized trials and meta-analyses show that the addition of Tα1 can enhance virologic and biochemical responses during treatment, especially when combined with standard therapy. In addition, several studies suggest that Tα1 can help maintain viral control after treatment, while being better tolerated than interferon alone. Tα1 has been tested alongside interferon-based regimens, where it has reduced relapses and improved virologic response at the end of treatment or sustained virologic response in some difficult-to-treat patients. For HBV-related cirrhosis, the combination of Tα1 with nucleoside analogs such as entecavir appears safe, can accelerate early inhibition of viral replication and may slightly reduce short-term HCC risk, 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 chemoembolization (TACE) can accelerate early immune recovery and delay tumor recurrence or improve survival. In addition, HBV Tα1-associated ACLF is associated with higher graft-free survival and fewer infections. Importantly, safety outcomes remained favorable across conditions. Overall, the evidence suggests that Tα1 is a generally well-tolerated immune enhancer that, when combined with standard therapy, can enhance or stabilize antiviral and antitumor 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 randomized trials involving 1144 patients, Peng et al (2020) found that adding 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 that point. However, as therapy continued for up to 48-52 weeks, the differences in virologic 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 were less frequent 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 multicenter study by Wu et al (2018) in patients with compensated cirrhosis. It 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 liver function decompensation, 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 there were no new cases of HCC 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 favorable, 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 hepatitis C treatment

Adding thymosin α1 (Tα1) to standard hepatitis C therapy may reduce the risk of relapse and help maintain virological response in patients whose previous treatment has failed. Ciancio et al (2012) conducted a large randomized controlled trial involving 552 participants who had failed to respond to previous antiviral treatment regimens. Patients received Tα1 1.6 mg subcutaneously twice a week 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, combining 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, nearly half of the patients (45.5%) had achieved both virus elimination and normalization of ALT levels. Interestingly, four of five patients who had never been treated before achieved a complete response, while previously treated patients showed less benefit. Laboratory test results (AST, ALT and HCV RNA) decreased significantly compared to baseline values (p < 0.05). Side effects were mostly mild, such as muscle pain and minor 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 randomized trials also suggested that adding thymalfascin (another name for Tα1) to peginterferon may help patients whose previous treatment has failed. Rustgi (2004) summarized a randomized trial in which preliminary results favored 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 end-of-treatment response in some patients with hepatitis C, especially those who are difficult to treat.

In addition, 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 removal (p < 0.05). However, after observing patients for another 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 another six months. The addition of Tα1 significantly increased the number of patients whose 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 early benefits into durable cures.

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 Hispanic patients who had failed to respond 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 until week 72. An early virological response occurred in 52.5% patients at week 12 and in 50% 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 virologic 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 effects of interferon on the liver and virus, although its long-term effect remains moderate. Sherman et al (1998) conducted a randomized, double-blind, placebo-controlled study comparing Tα1 (1.6 mg twice a week) in combination with interferon-α (3 million units three times a week) with interferon alone or placebo. The combination of these drugs improved normalization of liver enzymes (37.1% vs. 16.2%), viral clearance (37.1% vs. 18.9%) and liver tissue health (greater decrease in histologic activity index). Virus levels dropped significantly at weeks 8, 16 and 24 in the Tα1 group only, yet 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 faster in people with difficult-to-treat hepatitis C. In a 24-week pilot study, Poo et al (2004) subjected 23 patients whose 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 effects 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 randomized 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 control group that received no treatment. At the end of therapy, the complete response, defined as normalization 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 to 27.3% in the interferon group (still not statistically significant). Sustained improvements in ALT and HBV DNA were almost three times more likely with Tα1, and both Tα1 and interferon performed better than the untreated control group. Importantly, Tα1 was well tolerated and no side effects were reported, while interferon caused typical flu-like symptoms and other expected side effects. These results suggest that Tα1 may help maintain long-term benefits after treatment, although combination therapy may be necessary 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 normalization of liver enzymes than interferon alone or interferon combined with lamivudine in HBeAg-negative chronic hepatitis B. Saruc et al (2003) conducted a study involving 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 normalization 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, the sustained response remained high at 71.4% for Tα1 in combination with interferon, but dropped 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 favorable safety profile.

Thymosin α1 (Tα1) may help reboot the body's antiviral defenses in HBeAg-positive hepatitis B patients by enhancing important immune signals. In a randomized 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 seen 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 the body's 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 along with Tα1 also helped patients who had previously failed interferon therapy, showing better control of the virus, 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 began 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 normalization of liver enzyme levels (ALT). Among patients who had previously failed to respond to treatment, 55% achieved improvement, and six patients completely lost HBsAg. 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 to interferon-α, thymosin α1 (Tα1) may provide longer post-therapy viral control, with better tolerability. You et al (2005) randomly assigned 56 anti-HBe positive and HBV DNA positive patients to a group receiving Tα1 (1.6 mg twice a week) 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 normalization 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, while Tα1 was better tolerated [15]. In short, Tα1 provided longer viral control after therapy and caused fewer side effects. In a number of randomized 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 randomized 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), normalization of liver enzymes (OR 3.12) and complete response (OR 2.69) compared to interferon. Since most of the included studies involved HBeAg-negative patients, the benefit appears to be strongest in this group [16]. These results indicate that Tα1 appears to promote sustained viral control after therapy, making it a valuable option for long-term immunotherapy of chronic HBV.

In addition, 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) analyzed seven randomized 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). ALT normalization 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) were more common with Tα1. In addition, 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 durable improvements in virus, liver enzymes and immune markers [17].

Thymosin α1 (Tα1) alone can also help patients with chronic hepatitis B, and higher doses seem 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 observed them for 12 months. At the end of therapy, ALT levels normalized in some 36% patients receiving the higher 1.6-mg dose, with similar rates for the 0.8-mg dose. HBV DNA clearance reached about 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 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 a week 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 a resolution of HBsAg, ALT levels dropped 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 liver improvement, 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 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 can 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 who had not received 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 normalization, HBV DNA clearance and liver histology-were similar in both groups. The treatment regimen was well tolerated. In conclusion, Tα1 showed a favorable trend in HBeAg loss, but did not show a significant overall advantage [21]. Tα1 may also promote longer viral control and better improvement in laboratory results compared to interferon, with fewer side effects. You et al (2001) randomly assigned 81 patients with chronic hepatitis B to a group receiving Tα1 (1.6 mg twice a week 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. Normalization of ALT reached 61.1% for Tα1, 30.3% for interferon and 10% in the control group. The complete response (normalization 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 lower baseline viral titers or a transient increase in ALT during treatment. Arase et al (2003) conducted a randomized pilot study involving 16 patients. They compared two dosing strategies: 0.8 mg vs. 1.6 mg of Tα1 (given intensively for two weeks, then twice weekly for up to 24 weeks). After 24 months, 37.5% achieved a complete response (HBeAg clearance, HBV DNA negativity and ALT normalization). 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 outcomes (p = 0.0063). There was no significant difference between the two doses of Tα1 (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 when combined with thymosin α1 (Tα1). Al-Mahtab et al (2016) published the results of two studies conducted on 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 later received short-term immune therapy with pegylated interferon or Tα1. After the addition of these immune agents, 8 of the 9 patients lost HBsAg, and all had a strong increase in anti-HBs antibodies before the end of treatment. Persistence varied: some had very low HBV DNA levels 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 can 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 complete 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 favorable 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) along with famcyclovir can help immunologically tolerant patients achieve immune control. Lau et al (2002) randomly assigned 96 HBeAg-positive patients in the immune tolerance phase to a group receiving Tα1 together with famciclovir, famciclovir alone or no treatment for 26 weeks, and then followed them 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 drug combination, 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 combined with famcyclovir resulted in deeper 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 cases with the wild type (64% vs 19%; p = 0.002). However, extending 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 virologic response, defined as clearance of HBV-DNA and HBeAg, 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 control the virus even after therapy ended [28].

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

Importantly, the use of α1-thymosin 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 combined with lamivudine and Tα1. After one year, the combination achieved 100% inhibition of HBV-DNA compared to only 6% in the surgery alone group (p = 0.0016). In addition, HBeAg seroconversion was higher (62.5% vs. 5.9%, p = 0.0157). Tumor relapse also occurred later with treatment (median 7.0 vs 5.0 months, p = 0.0052). Moreover, 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 randomized 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 to 6% for surgery alone (p < 0.01), and HBeAg seroconversion reached 62.5% compared to 5.9% (p < 0.05). In addition, tumor 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 noteworthy that the addition of thymosin-α1 after transcatheter chemoembolization (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 a week for four weeks). Compared to TACE alone, the combination of these therapies raised immune cell levels. After four weeks, the number of CD4⁺ T cells was higher than p u (43.2% vs. 31.2%, p < 0.05), and the number of CD3⁺ and CD8⁺ T cells also increased. In addition, autophagy markers (Beclin-1 and LC3) increased early, but returned to baseline levels after three months. Importantly, no new safety issues were reported, confirming that Tα1 is a safe way for early immune recovery after TACE [31]. Moreover, the use of thymosin-α1 along 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 onward (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 can speed 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, graft-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 a week, usually for 24-52 weeks. Some studies have tested a dose of 0.8 mg SC twice a week or a dose based on body surface area (approximately 900 µg/m² SC twice a week). 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 a week 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 typically used a dose of 1.6 mg twice a week. For HBV-induced cirrhosis, a dose of 1.6 mg subcutaneously twice a week for about 52 weeks was added to standard therapy with nucleoside analogs (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. After liver surgery or transcatheter chemoembolization (TACE) for HBV-associated hepatocellular carcinoma (HCC), Tα1 was also administered at a dose of 1.6 mg subcutaneously twice a week, while some earlier 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 a dose of 1-1.6 mg subcutaneously twice a week for 24-48 weeks; monotherapy at 900 µg/m² twice a week for 6 months was ineffective. Dose-response studies have shown stronger immune effects at a dose of 3.2 mg subcutaneously twice a week compared to 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 depend on the patient's condition:

• Daily for 1 week, then twice weekly for severe HBV-related liver failure (ACLF).
• Short cycles twice a week 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 was 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 do not suggest 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 drug. The information contained in the text is based on available scientific research and is not intended to serve as medical advice or promote self-medication. The reader should consult any health and treatment decisions with a qualified health professional.

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