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Cochrane Database of Systematic Reviews Protocol - Intervention

Antiviral treatments for lamivudine‐resistant chronic hepatitis B adult patients

Authors' declarations of interest

Version published: 07 October 2009 Version history

https://doi.org/10.1002/14651858.CD008178

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Abstract

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

To evaluate the benefits and harms of antiviral treatments in adult patients with lamivudine‐resistant chronic hepatitis B.

Background

Description of the condition

Chronic hepatitis B disease is caused by the host immune response to hepatitis B virus infection. Globally, an estimated 350 million people are infected with hepatitis B (WHO 2000; Lavanchy 2004). Around 1.5% to 3.3% of the patients infected with hepatitis B fail to clear the virus and become chronic carriers (Liaw 2009). Among these patients, 2% to 3% are reported to develop cirrhosis (Liaw 2009). Hepatic cancer develops in 3% to 6% of patients with cirrhosis (Liaw 2009). Chronic hepatitis B results in 0.5 to 1.2 million deaths per year mainly due to hepatocellular carcinoma, cirrhosis, or chronic hepatitis (Lavanchy 2004).

Hepatitis B virus has a high mutation rate due to the absence of the 'proof‐reading' in the viral polymerase (Brown 1992; Ghany 2007). This rapid mutation rate, combined with a high viral loads (up to 1012 copies/ml) and a high turn‐over rate (1 to 2 days, with 1012 virions produced per day) leads to multiple quasi‐species existing within a host (Ghany 2007).

Chronic hepatitis B treatment involves two classes of drugs: nucleoside or nucleotide analogues (such as lamivudine, adefovir, entecavir, and telbivudine), and immunomodulatory agents (interferons alfa 2b and pegylated interferon alfa 2a).

Nucleoside or nucleotide analogues all work by inhibiting the synthesis of the viral DNA, mainly by inhibiting the reverse transcriptase enzymes (Leemans 2007), while immunomodulatory agents work by enhancing the host immune response through induction enzymes that inhibit virus replication, suppress cell proliferation, enhance the phagocytic activity of macrophages, and augment cytotoxicity of lymphocytes for target cells (Haria 1995).

The nucleoside or nucleotide analogues cause selective resistant variants of hepatitis B virus (Ghany 2007). Resistance to lamivudine emerges in 14% to 22% of the patients during the first year of treatment and up to 80% after five years of treatment (Lok 2002;Lai 2003).The most common mutant associated with lamivudine resistance is the mutation of methionine to valine or isoleucine at position rt204 (rtM204V/I) in the tyrosine‐methionine‐aspartate‐aspartate (YMDD) motif of the C subdomain of hepatitis B virus polymerase (Chayama 1998; Hussain 1999; Hunt 2000). Other mutations include replacement of leucine by methionine at position 528 and the replacement of valine, leucine, or methionine by isoleucine at position 555 (Gunther 1999; Pichoud 1999).

Why it is important to do this review

Lamivudine is the most common drug used in the nucleotide inhibitor class, with rising number of patients developing viral resistant mutant. The effect of lamivudine‐resistance is unpredictable, as the mutant may have a lower replication rate compared to the wild virus. Lamivudine resistance ranges from asymptomatic viraemia, flaring of serum alanine transferase (ALT), worsening liver histology, symptomatic hepatic decompensation, to hepatocellular carcinoma (Liaw 1999; Bock 2002; Dienstag 2003; Lok 2003; Anderson 2004). Rare instances of death in lamivudine‐resistant infection have been reported, mainly in immunosuppressive patients and in patients with cirrhosis (Liaw 2001).

Several treatments have been suggested in lamivudine‐resistant chronic hepatitis B virus patients. Treatment with newer nucleotide or nucleoside analogues, such as adefovir or entecavir, are hypothetically effective, because lamivudine viral mutants are not resistant to these drugs. However, it is not known whether to discontinue lamivudine or to combine it with other drugs. Continued lamivudine may decrease the emergence of hepatitis B strains resistant to the new drugs.

Previous systematic reviews included patients with chronic hepatitis B virus infection without known resistance to lamivudine who were treated with either lamivudine, adefovir, dipivoxil, entecavir, or pegylated interferon alfa 2a (Aggarwal 2006; Mumtaz 2007; Woo 2007; Mumtaz 2008). This systematic review will focus exclusively on the lamivudine‐resistant chronic hepatitis B patients.

Objectives

To evaluate the benefits and harms of antiviral treatments in adult patients with lamivudine‐resistant chronic hepatitis B.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials will be included regardless of language, publication status, or blinding.

Types of participants

Chronic hepatitis B patients (17 years or older) of either sex with genotypic or phenotypic resistance to lamivudine (as defined by the authors of the study) and with normal or elevated ALT will be included. The diagnosis of chronic hepatitis B will be based on the presence of detectable HBV DNA by DNA hybridisation method or polymerase chain reaction (PCR). Standardised methods for measurement of viral load should be used (Kapke 1997; Saldanha 2001).

Patients with cirrhosis, decompensated liver disease, hepatocellular carcinoma or prior liver transplantation, as well as patients with evidence of concomitant human immunodeficiency virus (HIV) infection or concomitant renal failure will be included. We will exclude studies of patients with chronic hepatitis B without known resistance to lamivudine as well as studies of patients with acute hepatitis B virus infection.

Types of interventions

We will compare:

  1. Continuing treatment with lamivudine versus placebo or no intervention.

  2. Continuing treatment with lamivudine versus interferons or nucleoside or nucleotide analogue monotherapy.

  3. Combination therapies including lamivudine versus continuing lamivudine monotherapy.

  4. Any combination therapy versus monotherapy (for example lamivudine plus peginterferon versus monotherapy with peginterferon).

Types of outcome measures

Primary outcomes

  1. All cause mortality.

  2. Nonfatal serious adverse events: Serious adverse events are defined according to the International Conference on Harmonisation (ICH) Guidelines (ICH 1996) as any event that 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.

  3. Liver‐related morbidity (proportion of patients with newly diagnosed hepatocellular carcinoma, cirrhosis, symptomatic hepatitis, liver decompensation, flaring of ALT, or deterioration in Child‐Turcotte‐Pugh [CTP] score).

Secondary outcomes

  1. Quality of life, using standardised validated scores.

  2. Proportion without any improvement in histologic activity index or fibrosis score.

  3. Viral responses defined as the proportion of patients without seroconversion to anti‐HBs negative status; without seroconversion to anti‐HBe positive status in HBeAg negative patients; and without disappearance of serum HBV DNA.

  4. Biochemical response defined as the proportion of patients without normalisation of ALT in those patients with elevated ALT levels at trial entry.

  5. Drug tolerability: proportion of withdrawals due to adverse events and patients with any adverse events.

  6. Proportion of patients discontinuing treatment for any reason.

  7. Proportion of patients with emergence of YMDD mutant on phenotypic or genotypic basis.

Search methods for identification of studies

Electronic searches

We will search The Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index EXPANDED (Royle 2003). We have given preliminary search strategies in Appendix 1 with the time span for the searches.

Searching other resources

We will identify additional trials by reviewing the reference lists of trials meeting the inclusion criteria as well as bibliography of other reviews on lamivudine‐resistant chronic hepatitis B patients.

Data collection and analysis

Selection of studies

Two authors (AF and VM) will independently select which studies will be included. In case of unresolved discrepancy, the opinion of the third author (KB) will be sought in order to reach consensus.

Data extraction and management

Two authors (AF and VM) will independently extract the data on all prespecified outcomes from all randomised clinical trials meeting the inclusion criteria, both at the end of treatment and at maximum post‐treatment follow up. In case of unresolved discrepancy, the opinion of the third author (KB) will be sought in order to reach consensus.

Assessment of risk of bias in included studies

The methodological quality of the trials and hence risk of bias will be assessed based on seven domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, baseline imbalance, early stopping (Higgins 2008; Wood 2008; Gluud 2009). For each domain, we will describe the methodology as reported in the publication and judge the risk of bias. Authors of each study will be contacted to obtain additional information if necessary. The bias risk components are classified as follows:

Sequence generation 

  • Adequate, sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards and throwing dice are adequate if performed by an independent adjudicator.

  • Unclear, the trial is described as randomised but the method of sequence generation was not specified.

  • Inadequate, the sequence generation method is not, or may not be, random. Quasi‐randomised studies, those using dates, names, or admittance numbers in order to allocate patients are inadequate and will be excluded for the assessment of benefits but not for harms.

Allocation concealment

  • Adequate, allocation was controlled by a central and independent randomisation unit, serially numbered, opaque and sealed envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment.

  • Unclear, the trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.

  • Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised. Quasi‐randomised studies will be excluded for the assessment of benefits but not for harms.

Blinding

  •  Adequate, the trial was described as double blind and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. 

  • Unclear, the trial was described as double blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial.

  • Inadequate, blinding not performed, the trial was not double blind, so that the allocation was known during the trial.

Incomplete outcome data

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

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

Selective outcome reporting

  • Adequate, pre‐defined, or clinically relevant and reasonably expected outcomes are reported on.

  • Unclear, not all pre‐defined, or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not.

  • Inadequate, one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded.

Baseline imbalance

  • Adequate, if there was no baseline imbalance in important characteristics.

  • Unclear, if the baseline characteristics were not reported.

  • Inadequate, if there was a baseline imbalance due to chance or due to imbalanced exclusion after randomisation.

Early stopping

  • Adequate, if sample size calculation was reported and the trial was not stopped, or the trial was stopped early by formal stopping rules at a point where the likelihood of observing an extreme intervention effect due to chance was low.

  • Unclear, if sample size calculation was not reported and it is not clear whether the trial was stopped early or not.

  • Inadequate, if the trial was stopped early due to informal stopping rules or the trial was stopped early by a formal stopping rule at a point where the likelihood of observing an extreme intervention effect due to chance was high.

Measures of treatment effect

Dichotomous data will be presented as relative risks (RR) with 95% confidence intervals (CI). Wherever applicable, the number needed to treat will be derived from the risk difference (RD), calculated as (1/RD). Continuous variables will be expressed as mean difference (MD) with 95% CI.

Dealing with missing data

In case of missing data, the primary author of the trial will be contacted with a request to provide the required data. Data will be analysed using the intention‐to‐treat principle, that is, patients with missing data (in both treatment groups) will be considered as treatment failures and all randomised patients will be included in the denominator. Additionally, a sensitivity analysis will be performed, counting patients with incomplete or missing data alternately as treatment failures or successes (four scenario analysis).

Assessment of heterogeneity

Heterogeneity will be assessed using the I2 statistics, which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) (Higgins 2002; Higgins 2003) .

Assessment of reporting biases

To assess possible publication bias, we will search on‐line trial registries (such as The Association of the British Pharmaceutical Industry, CenterWatch, Chinese and Hong Kong Clinical Trial Registries, ClinicalTrial.gov, European Medicine Agency, International Clinical Trial Registry Platform). We will specifically focus on literature in East‐Asian journals as well as trial registries to minimise location bias.

Different types of reporting biases (eg, publication bias, time lag bias, outcome reporting bias, etc) will be handled following the recommendations of The Cochrane Collaboration (Higgins 2008). For all types of outcomes, we will test for funnel plot asymmetry when there is a sufficient number of trials included in the meta‐analysis (Higgins 2008). For continuous outcomes with intervention effects measured as mean difference, the test proposed by Egger 1997 will be used to test for funnel plot asymmetry (Egger 1997). For dichotomous outcomes with intervention effects measured as odds ratios, the arcsine test proposed by Rücker 2008 will be used to test for funnel plot asymmetry. Nevertheless, asymmetric funnel plots are not necessarily caused by publication bias, and publication bias does not necessarily cause asymmetry in a funnel plot (Egger 1997).

Data synthesis

The analyses will be performed using Review Analyses statistical software (RevMan 2008). Effect size will be examined using both fixed‐effect model (DeMets 1987) and random‐effects model (DerSimonian 1986). If the results of the two analyses lead to the same conclusion, only the results of the fixed‐effect model analysis will be reported. In case heterogeneity between trials is significant, the possible reasons for heterogeneity will be explored.

Subgroup analysis and investigation of heterogeneity

If data are available, subgroup analyses based on other existing co‐morbidities at baseline (such as cirrhosis, decompensated liver disease, hepatocellular carcinoma, prior liver transplantation, concomitant human immunodeficiency virus (HIV) infection, or concomitant renal failure) will be performed.

Sensitivity analysis

We will perform sensitivity analyses as follows (if number of studies permitted):
‐ excluding studies with inadequate concealment of allocation.
‐ excluding unblinded studies.
‐ excluding studies with less than 80% of randomised patients undergoing post‐treatment liver biopsies.