Lamivudine for chronic hepatitis B in adults

Objectives

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

To evaluate the beneficial and harmful effects of lamivudine for patients with chronic hepatitis B.

Background

Hepatitis B virus (HBV) is a partially double‐strand circular DNA virus (Carman 1992). Chronic hepatitis B virus (HBV) infection is a serious global health problem. Of the two billion people who have been infected, more than 400 million have chronic hepatitis (Poland 2004). There are different models reported for estimation of HBV‐related problems. For the year 2000, the model estimated that 620,000 persons died worldwide from HBV‐related causes: 580,000 (94%) from chronic infection‐related cirrhosis and hepatocellular carcinoma and 40,000 (6%) from acute hepatitis B. Most HBV‐related deaths result from the chronic sequelae of infection acquired in the perinatal and early childhood periods (Goldstein 2005).

The presence of hepatitis B surface antigen (HBsAg) in the serum for six months or longer is indicative of chronic hepatitis B infection (Brechot 2001). Indicators for a good response to treatment include elevated serum aminotransferase levels (> 100 IU per millilitre), presence of HBV DNA in serum at a level of less than 200 pg per millilitre, and a liver biopsy suggesting moderate or severe inflammatory activity (Lee 1997). Patients with chronic HBV infection are divided into two groups based on the presence or the absence of hepatitis B e antigen (HBeAg) in their serum. These groups differ in their natural history and response to various drugs. Thus, HBeAg‐negative chronic hepatitis B, which is caused by a mutant form of virus that lacks the ability to synthesise HBeAg, is associated with worse prognosis and poorer response to treatment (Hadziyannis 2003; Milich 2003).

Interferon, lamivudine, adefovir dipivoxil, and entecavir are approved treatments for chronic hepatitis B (Marcellin 2005). Lamivudine and adefovir have significant antiviral activity, although viral rebound after cessation of therapy and development of resistance after long‐term lamivudine therapy pose major clinical limitations (D'Souza 2004). Entecavir is an orally administered cyclopentyl guanosine analogue that has been approved for treatment of chronic hepatitis B virus infection in adults. Interferon‐alpha has disadvantages due to the need for injections, frequent adverse effects, low response rate, and high cost. Its newer long‐acting preparations, pegylated interferon, are expected to have somewhat better response rates and are currently being studied (Cooksley 2003). In comparison, lamivudine is cheaper, has a more convenient oral route of administration, has few adverse effects, and a response rate similar to that of interferon‐alpha. However, the duration of administration of this drug remains unclear with many patients needing possibly life‐long treatment (Lai 2003a). Furthermore, with increasing duration of treatment, an increasing proportion of patients exhibit development of a mutation in the genome of the virus, which confers lamivudine resistance. The latter is associated with reappearance of viral replication and worsening of liver disease (Lai 2003b).

The active metabolite of lamivudine is a potent inhibitor of HBV‐DNA polymerase/reverse transcriptase activity (Zoulim 1998) and an increase in the strength of the T‐cell response to HBV antigens has been observed during lamivudine treatment (Boni 1998). In patients with chronic hepatitis B, lamivudine has been demonstrated to be effective in suppressing serum HBV‐DNA, in increasing the loss rate of serum HBeAg, in normalizing aminotransferases activities, and in decreasing necroinflammatory activity and fibrosis independently of HBeAg seroconversion (Honkoop 1997; Lai 1998; Dienstag 1999; Suzuki 1999). Similar responses have been observed in Asian patients (Lai 1998; Tassopoulos 1999). The use of lamivudine is associated with emergence of YMDD mutations, which have been detected in 14% at one year to 69% at five years after lamivudine treatment (Dienstag 1999; Lai 2003b). These mutations are involved in HBV resistance to lamivudine (Paik 2006).

We have not been able to identify a systematic review or a meta‐analysis evaluating the beneficial and harmful effects of lamivudine for chronic hepatitis B.

Objectives

To evaluate the beneficial and harmful effects of lamivudine for patients with chronic hepatitis B.

Methods

Criteria for considering studies for this review

Types of studies

Randomised trials will be included irrespective of language, publication status, and blinding. Observational and quasi‐randomised studies will be excluded.

Types of participants

Trials including adult patients (age more than 17 years) of either gender with chronic HBV infection with evidence of hepatitis (patients with normal and elevated ALT, both will be included but analysed separately) and of viral replication (detectable HBV DNA by DNA hybridisation method or polymerase chain reaction (PCR)). We will use the standardised methods for measurements of viral load based on the known techniques used (Kapke 1997; Saldanha 2001). Patients will be included irrespective of whether they are treatment‐naive or have previously been treated unsuccessfully for chronic HBV infection with another antiviral drug. Patients with cirrhosis and those with decompensated liver disease will also be included. Patients with evidence of concomitant human immunodeficiency virus (HIV) infection or hepatocellular carcinoma will also be included. Patients with prior liver transplantation or those with concomitant renal failure will also be included.

We will exclude patients treated with adefovir dipivoxil and pegylated interferon alfa 2a as they are already under study by Aggarwal et al (Aggarwal 2006) and Mumtaz et al (Mumtaz 2007), respectively.

Types of interventions

We will compare:
(i) Lamivudine versus placebo or no intervention. 
(ii) Lamivudine versus standard interferon alfa.
(iii) Lamivudine versus other antiviral drugs, such as adefovir dipivoxil, entecavir, and emtricitabine.
(iv) High‐dose versus low dose lamivudine.
(v) Long duration versus short duration of lamivudine intervention.

Co‐interventions will be assessed if administered equally to both intervention arms.

Types of outcome measures

The following outcome measures will be used in HBeAg‐positive and HBeAg‐negative patients.

Among HBeAg‐positive patientsPrimary outcomes (1) Proportion with disappearance of HBeAg in the serum (at end of treatment and maximum post‐treatment follow‐up). 
(2) Proportions with suppression of HBV DNA level below 100,000 copies/ml (at end of treatment and maximum post‐treatment follow‐up).

Secondary outcomes (3) Mortality.
(4) Proportion with disappearance of serum HBV DNA (at end of treatment and at maximum post‐treatment follow‐up). 
(5) Proportion with decompensation of liver disease after lamivudine.
(6) Proportion with seroconversion from HBeAg‐positive status to anti‐HBe positive status (seroconversion). 
(7) Proportion with emergence of YMDD mutant on the phenotypic or genotypic basis.
(8) Proportion with any improvement in histologic activity index or fibrosis score. 
(9) Proportion with adverse events, according to the International Conference on Harmonisation (ICH) Guidelines (ICH‐GCP 1997).
(10) Proportion with discontinuation of treatment.
(11) Proportion with disappearance of HBsAg at maximal follow‐up.
(12) Quality of life.

Among HBeAg‐negative patientsPrimary outcomes (1) Proportion with suppression of HBV DNA level below 100,000 copies/ml (at end of treatment and maximum post‐treatment follow‐up).

Secondary outcomes (2) Mortality.
(3) Proportion with disappearance of serum HBV DNA (at end of treatment and maximum post‐treatment follow‐up) 
(4) Proportion with decompensation of liver disease. 
(5) Proportion with emergence of YMDD mutant on the phenotypic or genotypic basis.
(6) Proportion with any improvement in histologic activity index or fibrosis score. 
(7) Proportion with adverse events, according to the International Conference on Harmonisation (ICH) Guidelines (ICH‐GCP 1997).
(8) Proportion with discontinuation of treatment.
(9) Proportion with disappearance of HBsAg at maximal follow‐up.
(10) Quality of life.

Search methods for identification of studies

We will search The Cochrane Hepato‐Biliary Group Controlled Trials Register (at the review stage), the Cochrane Central Register of Controlled Trials in The Cochrane Library (latest issue), MEDLINE (1950 to the time the review is performed), EMBASE (1980 to the time when the review is performed), and Science Citation Index EXPANDED (1945 to the time when the review is performed) (Royle 2003). We will identify further trials by reviewing the reference lists and contacting the principal authors of the identified trials. We will also contact pharmaceutical companies that produce lamivudine to eventually obtain data from unpublished randomised clinical trials (Appendix 1).

Data collection and analysis

The review will be performed according to the recommendations of The Cochrane Collaboration (Higgins 2005) and The Cochrane Hepato‐Biliary Group Module (Gluud 2006).

Trial selection and data collection Two authors (KM and AS) will extract the prespecified characteristics of all included randomised clinical trials independently. In case of discrepancy, the opinion of the other two authors (SH and WJ) will be sought in order to reach consensus. The authors of the trials will be approached to specify data, had they not been reported sufficiently in the article. Two authors (KM and AS) will extract data on the patients characteristics and outcomes from the included trials.

Assessment of methodological quality Based on empirical evidence of bias risk (Schulz 1995; Moher 1998; Kjaergard 2001), the methodological quality of the trials will be assessed based on the generation of the allocation sequence, allocation concealment, blinding, and follow‐up. These quality components will be classified as follows:

Generation of the allocation sequence

• adequate (computer generated random numbers, table of random numbers, or similar);

• unclear (the trial was described as randomised, but the generation of the allocation sequence was not described); or

• inadequate (quasi‐randomised studies; such studies will be excluded).

Allocation concealment

• adequate (concealed up to the point of treatment by central randomisation, sealed envelopes, or similar);

• unclear (the allocation concealment procedure was not described); or

• inadequate (open table of random numbers or similar).

Blinding

• Adequate, if the trial was described as double blind and the method of blinding involved identical placebo or active drugs;

• Unclear, if the trial was described as double blind, but the method of blinding was not described;

• Not performed, if the trial was not double blind.

Follow‐up

• Adequate, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals;

• Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated;

• Inadequate, if the number or reasons for dropouts and withdrawals were not described.

We will also record whether the investigators have performed a sample size calculation and used an intention‐to‐treat analysis.

Data synthesis The analyses will be performed using Review Analyses (RevMan 2003) statistical software. Data will be analysed using the intention‐to‐treat principle, that is, patients with missing data will be considered as treatment failures. In the assessment of histological responses, a per protocol analysis will also be performed since the number of patients who undergo post‐treatment liver biopsies in trials of antiviral therapy in chronic hepatitis B is usually small. Binary outcomes will be expressed as relative risks (RR) and 95% confidence intervals (CI). The number needed to treat (NNT) will be calculated as 1/((1‐relative risk)*control group event rate), wherever applicable. For all analyses, both random‐effects (DerSimonian 1986) and fixed‐effect (DeMets 1987) models will be employed. All results will be reported using fixed‐effect models; however, when the two models give different results (one showing a significant intervention effect and the other no significant intervention effect), both results will be reported.

The following subgroup analyses will be performed to determine the impact of trial characteristics on the rate of sustained virologic response.

Methodological quality: comparison of the response rates in trials with adequate compared to inadequate or unclear generation of allocation sequence, allocation concealment, blinding, and follow‐up.
Publication status: comparison of the response rates in trials published as abstracts and letters compared to those published as full papers.
Co‐interventions: comparison of the response rates in trials with or without co‐interventions.
Patient characteristics: Trials involving treatment‐naive patients, relapsers, and non‐responders will be analysed separately. We will also analyse the patients with HIV infection, hepatocellular carcinoma, concomitant renal failure, and post‐liver transplantation status separately.

Bias will be assessed by looking for funnel plot asymmetry. We will perform the Begg and Mazumdar (Begg 1994) adjusted rank correlation test and the Egger (Egger 1997) regression asymmetry test for bias.

History

Protocol first published: Issue 2, 2007

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

Notes

This protocol for a Cochrane Review has been withdrawn as it is out of date.  The editorial group responsible for this previously published document has withdrawn it from publication as the authors have abandoned it.

Appendices

Appendix 1. Search strategies

Database	Time span	Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register	Date will be given at review status.	lamivudin* AND 'chronic hepatitis b'
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library	Latest issue.	#1 MeSH descriptor Lamivudine explode all trees in MeSH products #2 lamivudin* in All Fields in all products #3 (#1 OR #2) #4 MeSH descriptor Hepatitis B, Chronic explode all trees in MeSH products #5 chronic hepatitis b in All Fields in all products #6 (#4 OR #5) #7 (#3 AND #6)
MEDLINE (WinSPIRS 5.0)	1950 to the time when the review is performed.	#1 explode "Lamivudine"/ all subheadings #2 lamivudin* #3 #1 or #2 #4 explode "Hepatitis‐B‐Chronic"/ all subheadings #5 chronic hepatitis b #6 #4 or #5 #7 #3 and #6 #8 random* or blind* or placebo* or meta‐analysis #9 #7 and #8
EMBASE (WinSPIRS 5.0)	1980 to the time when the review is performed.	#1 explode "lamivudine"/ all subheadings #2 lamivudin* #3 #1 or #2 #4 explode "hepatitis‐B"/ all subheadings #5 explode "chronic‐hepatitis"/ all subheadings #6 chronic hepatitis b #7 #4 or #5 or #6 #8 #3 and #7 #9 random* or blind* or placebo* or meta‐analysis #10 #8 and #9
Science Citation Index EXPANDED (http://portal.isiknowledge.com/portal.cgi?DestApp=WOS&Func=Frame)	1945 to the time when the review is performed.	#1 TS=lamivudin* #2 TS=(chronic hepatitis b) #3 #2 AND #1 #4 TS=(random* or blind* or placebo* or meta‐analysis) #5 #4 AND #3

Contributions of authors

Khalid Mumtaz drafted the protocol and will perform the literature search, data extraction, and draft the final review. Amna Subhan and Saeed Hamid revised the protocol and will help in literature search, will review the trials, extract data, and help in writing the final review. 
Wasim Jafri revised the protocol and will help in reviewing the studies and revising the review.

Sources of support

Internal sources

• Aga Khan University Hospital, Departement of Medicine, Karachi, Pakistan

External sources

• Cochrane Hepato‐Biliary Group, Copenhagen, Denmark

Declarations of interest

None known.

Edited (no change to conclusions)