Thymosin alpha1 for chronic hepatitis B

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the beneficial and harmful effects of thymosin alpha1 in the treatment of chronic hepatitis B in adults and children.

Background

(Editorial comment: This protocol is written in the past tense in order to ease the transition into a Review, although the Review has yet not been performed.)

Hepatitis B virus (HBV) is a partially double‐strand circular DNA virus (Carman 1992). Approximately 300 million people are chronic carriers of HBV (Margolis 1991).

Sexual transmission (Alter 1986; Kingsley 1990), vertical transmission (Beasley 1977), and unsafe injections (Kane 1999), including intravenous drug addiction (Broers 1998), are important routes of infection. Household contact (Vegnente 1992) and occupational exposure, such as that of health care professionals (Lauer 1979; Hu 1991; Fernandes 1999), blood products (Colombo 1987; Saxena 1999) and haemodialysis (Williams 1974; Mioli 1992) are others risk factors.

The clinical manifestations and natural history of HBV infection vary with age. Clinical acute hepatitis B is more frequent in adults than children, and the probability of becoming a chronic carrier is greater in children than adults (McMahon 1985). Ninety five per cent of infected newborns will become asymptomatic carriers of hepatitis B surface antigen (HBsAg) compared to 30per cent of children infected after the neonatal period and of less than six years of age. Three to five per cent of the individuals that acquire the infection in adulthood will develop chronic hepatitis B (Lee 1997). The different patterns of the natural history of chronic HBV infection has recently been reviewed (Lok 2001).

Chronic hepatitis B is diagnosed in a patient, who has been serum HBsAg positive for at least six months associated with elevated levels of aminotransferases activity and liver biopsy revealing some degree of chronic hepatitis (Hoofnagle 1987; Lok 2001). Chronic hepatitis B can be subdivided into hepatitis B 'e' antigen (HBeAg)‐positive and HBeAg‐negative chronic hepatitis B (Lok 2001). It is important to distinguish chronic hepatitis B from the asymptomatic or inactive carrier status (Lok 2001). These patients also present HBsAg in the serum for more than six months, but do not present any symptoms of chronic liver disease, have normal levels of serum aminotransferases activity, and frequently do not present either HBeAg or HBV‐DNA in the serum, and whose liver biopsy is normal or with minimal alterations (Hoofnagle 1987; Lok 2001).

Chronic hepatitis B may progress to cirrhosis or hepatocellular carcinoma. After 10 years, about 20 per cent of patients with chronic hepatitis B have progressed to cirrhosis and about five per cent have progressed to hepatocellular carcinoma (Ikeda 1998).

Currently, alpha‐interferon or lamivudine are recommended for treatment of patients with chronic hepatitis B (Lok 2001). However, both interventions do not work in all patients, may give rise to adverse events, and are expensive (Lok 2001). Therefore, alternative interventions should be sought. Thymosin alpha1 has been demonstrated to be a potent immunologically active thymic polypeptide (Low 1979), inducing higher peripheral blood helper cell count, gamma‐interferon and interleukin‐2 production, and interleukin‐2 receptor expression on human lymphocytes (Svedersky 1982; Sztein 1986; Mutchnick 1991). In chronic hepatitis B, thymosin alpha 1 administration has been safe and effective resulting in a significantly higher HBV‐DNA clearance rate in the serum and the liver tissue and histological improvement (Mutchnick 1991; Chien 1998). There is no systematic review evaluating the beneficial and harmful effects of thymosin alpha1 in the treatment of chronic hepatitis B.

Objectives

To evaluate the beneficial and harmful effects of thymosin alpha1 in the treatment of chronic hepatitis B in adults and children.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) assessing beneficial and harmful effects of thymosin alpha1 for chronic hepatitis B. RCTs were included irrespective of publication status, language or blinding. Quasi‐randomised studies were excluded.

Types of participants

Patients with chronic HBV infection were included. Chronic hepatitis B was defined as described in the Background section. Patients infected with HBV mutants ('HBeAg minus mutants') or co‐infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) were also included.

Exclusion criteria were: ‐ asymptomatic HBV carriers, defined as patients with HBsAg in the serum for more than six months, but who did not present any symptoms of chronic liver disease, had normal levels of serum aminotransferase activity and did not present either HBeAg or HBV‐DNA in the serum, and whose liver biopsy was normal or with minimum alterations (Hoofnagle 1987; Lok 2001): ‐ hepatitis D virus positivity (HDV+); ‐ alcoholism; ‐ patients using immunosuppressive drugs; ‐ liver transplanted patients.

Types of interventions

• Any dosage of thymosin alpha 1 versus placebo, alpha‐interferon, anti‐viral drugs or no intervention.

• Thymosin alpha1 versus another regimen of thymosin alpha1.

• Thymosin alpha1 plus alpha‐interferon versus another regimen of thymosin alpha1 and alpha‐interferon or alpha‐interferon plus placebo or no intervention.

• Thymosin alpha1 plus other anti‐viral drugs versus thymosin alpha1 or alpha‐interferon or placebo or no intervention.

Co‐interventions were allowed as long as both arms of the RCT received the same co‐intervention(s).

Types of outcome measures

The outcome measures were evaluated at the end of treatment and at six months or more than six months after end of treatment. The RCTs needed to have assessed at least one of the outcome measures described below in order to be included in the review.

Primary outcomes: 1. Sustained virologic response: number of patients without disappearance of serum HBV DNA, HBsAg, HBeAg and/or development of antibodies to HBeAg (anti‐HbeAg) or to HbsAg (anti‐HbsAg) at six months and more than six months after treatment. 2. Number of patients with clinical or histological cirrhosis, liver failure, hepatocellular carcinoma, liver transplantation, and all‐cause mortality at six months and more than six months after treatment.

Secondary outcomes: 3. Biochemical response: number of patients without normalisation of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 4. Histological response: number of patients without improvement of inflammatory activity as assessed by liver biopsy according to Knodell or Desmet scores (Desmet 1994; Knodell 1981). 5. Quality of life using a validated general instrument or a validated liver disease‐specific instrument, e.g., The Chronic Liver Disease Questionnaire (CLDQ) (Younossi 1999). 6. Adverse events: Number and type of adverse events, defined as any untoward medical occurrence in a patient in any of the two intervention groups. This occurrence should not necessarily have a causal relationship with the treatment, but should have resulted in the discontinuation of treatment. We have defined serious adverse events according to the International Conference on Harmonisation (ICH) Guidelines (ICH‐GCP 1997) as any event that leads to death, is life‐threatening, requires in‐patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability, and any important medical event which may have jeopardised the patient or requires intervention to prevent it. All other adverse events will be considered non‐serious.

Search methods for identification of studies

Relevant RCTs were identified by electronic searching of The Cochrane Hepato‐Biliary Group Controlled Trials Register and The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 1, 2002), MEDLINE (1966‐2002), EMBASE (1980‐2002), and LILACS (1988‐2002).

The searches in The Cochrane Hepato‐Biliary Group Controlled Trials Register and The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library were performed using the search terms 'hepatitis B' and 'thymosin*'.

The Cochrane search strategy described in The Cochrane Collaboration Handbook was used for the MEDLINE database, using the specific terms 'hepatitis B' AND 'explode thymus hormones' OR 'thymosin [Text Word]'.

EMBASE was searched by the words 'hepatitis B' and 'thymosin*'.

For the LILACS database search we used the search strategy described by Castro et al. (Castro 1997), using the same search terms as those used with the MEDLINE database.

The bibliographic references of identified RCTs, textbooks, review articles, and meta‐analyses were checked in order to find RCTs not identified by the electronic searches. The principal authors of the identified RCTs were approached and inquired about additional RCTs they might know of. Pharmaceutical companies involved in the production of thymosin were contacted in order to obtain unpublished RCTs.

Data collection and analysis

Application of inclusion criteria Full articles were retrieved for assessment. Two reviewers independently and unblinded applied the inclusion criteria to all of these potential studies. When a discrepancy occurred in the trial selection, another reviewer was asked for an opinion in order to reach consensus. Data extraction The following prespecified characteristics of all included RCTs were extracted by two reviewers independently. In case of discrepancy, the opinion of a third reviewer was sought in order to reach consensus. The authors of the trials were approached to specify the following data, had they not been reported sufficiently in the article: Methods: diagnostic procedures, randomisation procedure, concealment of allocation, whether patients were blinded to treatment, whether investigators were blinded to treatment, adequate baseline assessment of primary outcome, reliability of outcome measures, protection against contamination, power calculation, sample representativeness, length of follow‐up. Participants: age, gender, ethnic origin, forms of transmission, presence or not of cirrhosis, criteria used to classify chronic hepatitis, HIV and HCV co‐infections, infection with HBV mutants, number of patients randomised, reasons for withdrawal from the study. Interventions: dosage and duration of therapy, and method of administration as well as co‐intervention in the control group. Outcomes: as listed above under outcome measures.

In case more that one publication on each RCT was identified, data were extracted from the most recent or most explicit publication.

Methodological quality The methodological quality, defined as the confidence that the design and report will restrict bias in the intervention comparison (Moher 1998), was evaluated independently and unblinded by two reviewers. According to empirical evidence (Jadad 1996; Jüni 2001; Kjaergard 2001; Moher 1998; Schulz 1995), we assessed the methodological quality using separate components, that is, generation of the allocation sequence, allocation concealment, and double blinding.

Generation of the allocation sequence Adequate: table of random numbers, computer generated random numbers, or similar. Unclear: the trial was described as randomised, but the generation of the allocation sequence was not described. Inadequate: quasi‐randomised trials (such studies were excluded).

Allocation concealment Adequate: concealed up to the point of treatment by central randomisation, sealed envelopes, or similar. Unclear: the allocation concealment was not described. Inadequate: open table of random numbers or similar.

Double blinding Adequate: using identical placebo or similar. Unclear: the trial was described as double blind, but the method of blinding was not described. Inadequate: tablets versus injections or similar. Not performed: the trial was not double blind.

The results of the methodological quality were used for sensitivity analysis and not as exclusion criteria. When a discrepancy occurred, a third reviewer was asked for an opinion in order to reach consensus.

Analysing and presenting the results The studies were stratified in subgroups according to:

• age of patients (adults and children);

• ethnicity;

• total dosage of thymosin alpha 1(low; intermediate; high);

• length of follow‐up (at the end of treatment and six months or more than six months);

• HBeAg status at entry;

• co‐infection by HIV or HCV at entry.

All analyses were performed according to the intention‐to‐treat method, using the last reported observed response ('carry forward') and including all patients irrespective of compliance or follow‐up. In addition, 'a worst case scenario' analysis was performed and patients with missing data were considered as treatment failures.

The software package (RevMan 4.1.) provided by The Cochrane Collaboration was used. For dichotomous variables, the relative risks with 95% confidence intervals (CI) were calculated by both fixed and random effects model (DerSimonian and Laird (DerSimonian 1986)).

Weighted mean differences with 95% CI were calculated for continuous outcome variables using both fixed and random effects models.

When overall results were statistically significant by both fixed and random effects models, relative risk reduction (RRR) and the number‐needed‐to‐treat (NNT) and the number‐needed‐to‐harm (NNH) were calculated.

Statistical heterogeneity was assessed both by inspection of graphical presentations ('funnel plot') (Egger 1997) and calculating standard Chi‐square test, defining significant as P < 0.1. Funnel plot asymmetry was also used to assess the existence of publication bias and other biases (Egger 1997). The possible reasons of heterogeneity were explored by performing sensitivity analyses using sustained virological response as the outcome measure. The following strategies were used for the sensitivity analyses:

A ‐ In relation to intervention: 1. To separate patients previously treated with thymosin alpha1 or other anti‐viral agents from those naive to previous treatment. 2. To separate RCTs using thymosin alpha 1 alone versus other interventions from RCTs using thymosin alpha1 in combination with other antiviral interventions versus the other antiviral interventions. 3. To separate RCTs according to the length of follow‐up.

B ‐ In relation to publication status: 1. To separate RCTs published as full paper articles, abstracts, and unpublished studies.

C ‐ In relation to methodological quality: 1. To separate RCTs in three groups according to their methodological quality: a) adequate randomisation (generation and concealment) and adequate double blinding; b) unclear randomisation and adequate double blinding or adequate randomisation and inadequate double blinding; c) unclear randomisation and inadequate double blinding. 2. To separate RCTs according to losses of follow‐up (studies without losses or minimal losses of follow‐up versus studies with high losses).

What's new

Date	Event	Description
10 October 2018	Amended	This protocol is withdrawn as it has never been developed in a systematic review.

History

Protocol first published: Issue 2, 2002

Date	Event	Description
5 November 2008	Amended	Converted to new review format.

Sources of support

Internal sources

• Centro de Aperfeiçoamento de Pessoal de Nível Superior, Brazil.

• Universidade Federal do Rio Grande do Norte, Brazil.

• Universidade Federal de São Paulo, Brazil.

External sources

• No sources of support supplied

Declarations of interest

None known.

Notes

This protocol is withdrawn as it has never been developed in a systematic review.

Withdrawn from publication for reasons stated in the review