Skip to main content
NCBI home page
The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2017 Jan 6;2017(1):CD012496. doi: 10.1002/14651858.CD012496

Emtricitabine for adults with lamivudine‐resistant chronic hepatitis B virus infection

Shaffer Mok 1,✉, Sachin Mohan 2, Krystal M Hunter 3, Yize R Wang 1, Thomas A Judge 1
PMCID: PMC6464869

Abstract

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

To evaluate the benefits and harms of emtricitabine versus no intervention, placebo, and non‐emtricitabine interventions in adults with lamivudine‐resistant, chronic hepatitis B virus infection.

Background

Description of the condition

Hepatitis B is a viral infection that causes both acute and chronic disease, with widespread geographic distribution. On a global basis, hepatitis B is most commonly contracted by percutaneous and mucous membrane exposure to infectious body fluids (Mason 1993; Lee 1997). The primary route for transmission in East Asia is vertical transmission from mother to the newborn child, while the infection is usually contracted early in childhood in Sub‐Saharan Africa. In contrast, individuals in North America and Europe most commonly contract hepatitis B by sexual transmission, intravenous drug injection use, or tattoos.

Among the adult population exposed to hepatitis B, fewer than 5% will develop chronic infection (Hyams 1995). Though a small percentage of individuals develop long‐term illness, approximately 360 million people worldwide have evidence of chronic hepatitis B infection (WHO 2014). Among the individuals with chronic hepatitis B, approximately 780,000 people die annually due to the acute or chronic sequelae of this condition. In addition to this evident mortality risk, 15% to 40% of patients with chronic hepatitis B will develop significant morbidity such as cirrhosis as well as hepatocellular carcinoma (Bosch 2005; Goldstein 2005; McMahon 2005; WHO 2014). As a consequence of its disease‐related complication, hepatitis B is the reason for 5% to 10% of people requiring liver transplantation (Terrault 2005).    

Due to the high burden of disease, it is vital to establish effective therapy for chronic hepatitis B. Hepatitis B is a member of the hepadnaviridae family and is composed of a relaxed, circular, partially double‐stranded DNA configuration (Seeger 2000). In the hepatitis B viral genome, there are four open reading frames including the core, surface, X, and polymerase genes. Among these four components, the polymerase gene is composed of 800 amino acids. Within this complex gene is the code for the viral polymerase/reverse transcriptase which is the site for viral replication and nucleoside analogue therapy. 

Viral replication occurs when the viral DNA is converted to closed circular DNA (ccDNA) or circular formation. This covalently closed circular DNA (cccDNA) serves as the template for reverse transcriptase that binds adjacent the epsilon stem‐loop structure near the 5' end of its own messenger RNA (mRNA). This process facilitates packaging into nucleocapsids and initiates the protein‐priming mechanism using the tyrosine amino terminus of the reverse transcriptase.

During this process, four bases are synthesised, which anneal with the complementary sequences (Seeger 2000). In addition, mutation rates in this area of the hepatitis B viral genome are estimated at 1010 to 1011 point mutations per day, and are responsible for many of the viral therapy‐related resistant strains of hepatitis B virus (Nowak 1996).

In 1998, the first of these nucleoside analogues, lamivudine, was approved for chronic hepatitis B. Clinical trials showed virologic response and improvement of histologic activity (Lai 1998; Dienstag 1999). Various studies also showed the benefit of lamivudine therapy for inducing hepatitis B envelope antigen (HBeAg) loss and seroconversion of 17% to 32% at one year and 27% at two years (Lai 1998; Liaw 2000; Dienstag 2003). However, as clinical experience with lamivudine grew, the development of lamivudine‐resistant mutations came.

The most common mutation involves substitution of methionine in the tyrosine‐methionine‐aspartate (YMDD) motif of the DNA polymerase for valine or isoleucine, also known as rtM204V/I (Allen 1998; Stuyver 2001). As stated above, the area of the viral genome that codes for the polymerase is predisposed to numerous point mutations daily. Other such mutations include rtL180M and N263T, among numerous others. The presence of such resistant mutations has been described as 14% to 20% at one year, and 60% to 80% after five years of therapy (Lai 1998; Dienstag 1999; Liaw 2000; Schalm 2000; Leung 2001). The clinical manifestations of these mutations include asymptomatic viraemia, flaring of serum alanine transferase, worsening liver histology, symptomatic hepatic decompensation to hepatocellular carcinoma, and in rare cases, death (Bartholomew 1997; Liaw 1999; Bock 2002; Dienstag 2003; Andreone 2004; Lok 2009).

Description of the intervention

The various treatments for chronic hepatitis B include immunomodulator therapy such as interferon, encapsidation inhibitors, entry inhibitors, TLR7 agonists, and therapeutic vaccines (Petersen 2008; Kozlowska 2009; Lanford 2013; Fosdick 2014; Wang 2014; Yang 2014). With the exception of interferon, these therapies have yet to be evaluated in lamivudine‐resistant hepatitis B virus. At present, the most commonly used treatments include nucleoside and nucleotide analogues such at lamivudine, adefovir, entecavir, tenofovir, or telbivudine (Janssen 2005; Lau 2005; Hadziyannis 2006).

Among these therapies, emtricitabine has proven to be a potent inhibitor of viral replication. Emtricitabine is available alone, or in combination with tenofovir (trade name Truvada). Prior studies have evaluated emtricitabine therapy in the setting of hepatitis B virus infection, resulting in improved virologic (54% versus 2%), histologic (62% versus 25%) and biochemical (65% versus 25%) responses at week 48 compared with placebo (Lim 2006). Combination tenofovir and emtricitabine, with or without hepatitis B‐immunoglobulin (HBIG), has also been implicated in the setting of hepatitis B virus recurrence after orthotropic liver transplantation, demonstrating no cases with detectable hepatitis B virus DNA levels or graft rejection (Teperman 2010).

Other than those who have undergone orthotropic liver transplantation, individuals with HIV/hepatitis B virus co‐infection have shown a benefit with emtricitabine‐based therapy in achieving virologic response (Piroth 2008). Combination emtricitabine with tenofovir is a common medication prescribed as part of antiretroviral therapy for HIV (Benhamou 2006a). Overall, emtricitabine has been implicated as a potential therapeutic option for individuals co‐infected with HIV and hepatitis B virus (Benhamou 1999; Hoff 2001; Dore 2004; Rockstroh 2008; Tuma 2010). In another specialised population, HIV‐infected pregnant women, emtricitabine has shown considerable safety (Bzowej 2010; Benaboud 2011; INC Research 2012).

How the intervention might work

Cross resistance has been described between lamivudine and entecavir, as well as telbivudine (Zoulim 2009). At the present time, resistant mutations do exist to emtricitabine therapy (Lok 2009; APASL 2012; EASL 2012; Terrault 2016). Resistance to emtricitabine shares a similar relation to lamivudine resistance, given the similar biochemical structure of these drugs (Lok 2009; APASL 2012; EASL 2012; Terrault 2016). In particular, one study of emtricitabine alone, demonstrated 13% selection for YMDD variants after 48 weeks of therapy (Lim 2006). On the other hand, the combination of tenofovir and emtricitabine used to treat co‐infected individuals with HIV/hepatitis B virus was shown to decrease the rates of selection for lamivudine‐resistance (Bani‐Sadr 2004).

Based upon this information, the present guidelines do recommend a potential switch to combination emtricitabine with tenofovir (Truvada), as a therapeutic option for lamivudine‐resistant hepatitis B virus (Lok 2009; APASL 2012; EASL 2012; Terrault 2016). Additionally, combination therapy is recommended in those with confirmed adefovir‐resistant mutations (Reijnders 2010). The addition of emtricitabine to tenofovir is also recommended by the European Association for the Study of the Liver (EASL) if tenofovir‐resistance exists; however, these findings are not based upon present clinical trials (EASL 2012).

Why it is important to do this review

In the setting of lamivudine‐resistant hepatitis B infection, various therapies have been recommended by expert societies (Kiyosawa 2001; Liaw 2007; Lok 2009; APASL 2012; EASL 2012; Terrault 2016). Recommended therapies include switching from lamivudine to another nucleoside and nucleotide analogue (emtricitabine plus tenofovir or tenofovir alone) and adding additional medications (adefovir or tenofovir) (Lok 2009; APASL 2012; EASL 2012; Terrault 2016). Studies have alluded to an improvement in hepatitis B virus DNA which is superior with tenofovir as compared to adefovir alone (Ristig 2002; Dore 2004; Kuo 2004; van Bömmel 2004; Peters 2006; Benhamou 2006a; Benhamou 2006b). However, all but two studies were in patients with HIV co‐infection, and present guidelines recommend combination therapy with lamivudine and adefovir, not adefovir alone (Ristig 2002; Dore 2004; Kuo 2004; van Bömmel 2004; Peters 2006; Benhamou 2006a; Benhamou 2006b).  

In addition, several meta‐analyses and reviews have been performed outside of Cochrane, evaluating various therapies for preventing development of viral‐resistant, mutant, and suppressing hepatitis B virus DNA (Chen 2009; Tang 2009; Ang 2010; Sheng 2011; Chen 2012; Tan 2012). However, many of these include non‐randomised studies in addition to randomised trials and each lacks proper assessment of methodological quality, including risk of bias, risk of random errors (imprecision), heterogeneity, external validity (directness), and risk of publication bias (Atkins 2004).

There are several Cochrane protocols and Reviews conducted within the Cochrane Hepato‐Biliary Group, which are related to our present review (Mumtaz 2007a; Mumtaz 2007b; Fisher 2009; Katz 2009; Katz 2010; Mumtaz 2010; Zhao 2010; Njei 2011; Ismail 2014). In addition, we have prepared four additional protocols specifically evaluating various therapies in patients with lamivudine‐resistant, chronic hepatitis B virus infection (Mok 2015; Mok 2016; Mok 2017a; Mok 2017b).

We could find no meta‐analyses or systematic reviews with randomised clinical trials of emtricitabine in patients with lamivudine‐resistant, chronic hepatitis B.

Objectives

To evaluate the benefits and harms of emtricitabine versus no intervention, placebo, and non‐emtricitabine interventions in adults with lamivudine‐resistant, chronic hepatitis B virus infection.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials regardless of publication type, publication status, and language assessing the benefits and harms of emtricitabine versus no intervention, placebo, and non‐emtricitabine interventions in people with lamivudine‐resistant, chronic hepatitis B virus infection.

If, during the selection of trials, we identify observational studies (i.e. quasi‐randomised studies; cohort studies; or patient reports) that report adverse events caused by or associated with emtricitabine, we will include these studies for a review of the adverse events. We will not specifically search for observational studies for inclusion in this review, which is a known limitation of our systematic review.

Types of participants

Adults (over 16 years of age) with chronic hepatitis B viral infection and documented phenotypic or genotypic resistance to lamivudine as documented by the study authors. The diagnosis of hepatitis B virus infection should have been determined based upon standard polymerase chain reaction methods or DNA hybridisation (Kapke 1997; Saldanha 2001). Included participants could also be those with HBeAg‐positive or ‐negative status, elevated alanine transferase or non‐elevated alanine transferase, or pregnant women with or without co‐infection with HIV, acquired immune deficiency syndrome (AIDS), hepatitis C, and hepatitis D (Siegfried 2006; Benhamou 2006b; Shey 2013). In addition, we will evaluate people with hepatitis B virus infection who had compensated or decompensated cirrhosis (i.e. hepatic encephalopathy, jaundice, ascites, spontaneous bacterial peritonitis, varices, or variceal haemorrhage), hepatocellular carcinoma, and those people who have undergone liver transplantation.

We will exclude from this review children (aged equal to/under 16 years), people without the lamivudine‐resistant mutation, people with acute or fulminant hepatitis B, and people who are treatment‐naïve.

Types of interventions

We will compare oral administration of continued:

  • emtricitabine versus no intervention;

  • emtricitabine versus placebo;

  • emtricitabine versus non‐emtricitabine intervention.

We will allow co‐interventions, provided they are used similarly in both comparison groups.

Types of outcome measures

Primary outcomes

  • All‐cause mortality or hepatitis B‐related morbidity (proportion of participants who developed cirrhosis, ascites, variceal bleeding, hepatorenal syndrome, hepatocellular carcinoma, or hepatic encephalopathy and who have not died). These two outcomes will be tested as a composite outcome as well as individually (mortality or morbidity). Such composite outcomes need to be interpreted with caution, especially if the components are influenced differently by the intervention.

  • Health‐related quality of life (any valid assessment scale, filled out by the participant).

  • Serious adverse events. We will use the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice's definition of a serious adverse event (ICH‐GCP 1997), that is, any untoward medical occurrence that results in death, is life‐threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. We will consider all other adverse events as non‐serious.

Secondary outcomes

  • Hepatitis B‐related mortality (caused by morbidities or decompensation of the liver, such as liver cirrhosis or hepatocellular carcinoma).

  • Non‐serious adverse events. We will define any untoward medical occurrence in a participant or clinical investigation participant that does not meet the criteria outlined in Primary outcomes for a serious adverse event as a non‐serious adverse event.

  • Proportion of participants without histological improvement.

  • Proportion of participants with detectable HBsAg in serum or plasma.

  • Proportion of participants with detectable hepatitis B virus DNA in serum or plasma.

Exploratory outcomes

  • Proportion of participants with detectable HBeAg in serum or plasma (this outcome is only relevant for HBeAg‐positive participants).

  • Proportion of participants without HBeAg seroconversion in serum or plasma (this outcome is only relevant for HBeAg‐positive participants).

  • Proportion of participants without normalisation of transaminases (i.e. biochemical response).

Search methods for identification of studies

Electronic searches

We will search the Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2016), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (latest issue), MEDLINE (OvidSP; from 1946), Embase (OvidSP; from 1974), and Science Citation Index EXPANDED (Web of Science; from 1900) (Royle 2003). We have provided preliminary search strategies for these databases with the expected time spans of the searches in Appendix 1.

Searching other resources

To include additional information, we will also evaluate the initial reference list for additional trials that may otherwise not be included in this Cochrane Review.

We will search online trial registries such as The Association of the British Pharmaceutical Industry, CenterWatch, Chinese and Hong Kong Clinical Trial Registries, ClinicalTrials.gov (clinicaltrials.gov), European Medicines Agency (EMA) (www.ema.europa.eu/ema/), World Health Organization (WHO) International Clinical Trial Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials.

We will also focus on literature in East‐Asian journals as well as East‐Asian trial registries to minimise location bias.

Data collection and analysis

We will conduct the Cochrane Review in accordance with the guidelines in The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), as well as the Cochrane Hepato‐Biliary Group Module (Gluud 2016). We will perform analyses using Review Manager 5 (RevMan 2014), and the Trial Sequential Analysis software program (Thorlund 2011a; TSA 2011).

Selection of studies

Two review authors (SM and SM) will independently select the trials and studies for inclusion and exclusion. If an unresolved discrepancy should exist, we will seek the opinion of a third review author (TAJ). We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009), and 'Characteristics of excluded studies' table. We will not impose any language restrictions.

Data extraction and management

The two review authors (SM and SM) will independently extract the data on all prespecified outcomes for both HBeAg‐positive and HBeAg‐negative participants from each randomised clinical trial. If an unresolved discrepancy should arise, we will seek the opinion of a third review author (TAJ).

Assessment of risk of bias in included studies

We will follow the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2016). According to empirical evidence (Schultz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012a; Savović 2012b), we will assess the risk of bias of the trials using the following 'Risk of bias' domains.

Allocation sequence generation

  • Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial.

  • Unclear risk of bias: the sequence generation method was not specified.

  • High risk of bias: the sequence generation method was not random. We will only use these studies for the assessments of harms and not for benefits.

Allocation concealment

  • Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (e.g. the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).

  • Unclear risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.

  • High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants. We will only use these studies for the assessments of harms and not for benefits.

Blinding of participants and personnel

  • Low risk of bias: any of the following: no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; or blinding of participants and key study personnel ensured, and it is unlikely that the blinding could have been broken.

  • Unclear risk of bias: any of the following: insufficient information to permit judgement of ‘low risk’ or ‘high risk’; or the trial did not address this outcome.

  • High risk of bias: any of the following: no blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

Blinded outcome assessment

  • Low risk of bias: any of the following: no blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; or blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.

  • Unclear risk of bias: any of the following: insufficient information to permit judgement of ‘low risk’ or ‘high risk’; or the trial did not address this outcome.

  • High risk of bias: any of the following: no blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.

Incomplete outcome data

  • Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. The trial used sufficient methods, such as multiple imputation, to handle missing data.

  • Unclear risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

  • High risk of bias: the results were likely to be biased due to missing data.

Selective outcome reporting

  • Low risk: the trial reported the following predefined outcomes: all‐cause mortality or hepatitis B‐related morbidity, serious adverse events, and hepatitis B‐related mortality. If the original trial protocol was available, the outcomes should be those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.clinicaltrials.gov), the outcomes sought should have been those enumerated in the original protocol if the trial protocol was registered before or at the time that the trial was begun. If the trial protocol was registered after the trial was begun, those outcomes will not be considered to be reliable.

  • Unclear risk: not all predefined outcomes were reported fully, or it was unclear whether data on these outcomes were recorded or not.

  • High risk: one or more predefined outcomes were not reported.

For‐profit bias

  • Low risk of bias: the trial appeared to be free of industry sponsorship or other type of for‐profit support that may manipulate the trial design, conductance, or results of the trial.

  • Unclear risk of bias: the trial may or may not be free of for‐profit bias as no information on clinical trial support or sponsorship was provided.

  • High risk of bias: the trial was sponsored by industry or received other type of for‐profit support.

Other risk of bias

  • Low risk of bias: the trial appeared to be free of other components that could put it at risk of bias.

  • Unclear risk of bias: the trial may or may not be free of other components that could put it at risk of bias.

  • High risk of bias: there were other factors in the trial that could put it at risk of bias.

We will judge trials at low risk of bias if assessed with low risk of bias in all the above domains. We will judge trials at high risk of bias if assessed with unclear risk of bias or high risk of bias in one or more of the above domains.

We will resolve any differences in opinion through discussion, and in the case of unsettled disagreements, we will ask a member of the Cochrane Hepato‐Biliary Group Editorial Team to adjudicate.

Measures of treatment effect

For dichotomous data, we will utilise risk ratios (RRs), number needed to treat for an additional beneficial outcome (NNTB) and number needed to treat for an additional harmful outcome (NNTH) with 95% confidence intervals (CIs). To do this, we will use both fixed‐effect and random‐effects meta‐analyses models (Jakobsen 2014). We will calculate P values using the Mantel‐Haenszel method.

We will evaluate continuous data using mean differences (MDs) with 95% CIs. We will use both fixed‐effect and random‐effects models with generic inverse variance. If the outcomes were measured in the same way, we will use pooled MDs. If the outcomes were measured using different methods, we will use standardised mean differences (SMDs). If the outcome is included in only one trial, we will report these data using traditional statistical analysis and descriptive discussion.

Unit of analysis issues

The unit of analysis will be the participants randomised into the trial groups. We will include parallel group randomised trials as well as cluster‐randomised trials in this review. We will assess these separately in subgroup analyses in the same meta‐analysis. We will meta‐analyse effect estimates and standard errors of these estimates in the cluster‐randomised trials using Review Manager 5 software inverse‐variance methods (RevMan 2014), and follow the guidelines set in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Using Review Manager 5, we will attempt to avoid unit of analysis errors (RevMan 2014). We will only include data from the first period of the trial in our meta‐analysis in cross‐over trials.

Dealing with missing data

If data are missing during our review, we will contact the primary author of the trial in order to obtain the required data. We will analyse missing data using the intention‐to‐treat principle that specifies that missing data in each group (experimental and control) is considered to be a treatment failure. We will include all randomised participants in the denominator. We plan to perform 'worst‐best' and 'best‐worst' scenario sensitivity analyses, including participants with missing data as treatment failures or successes.

Assessment of heterogeneity

To evaluate heterogeneity, we will use the Chi2 test with a P value of < 0.1 as the cut‐off value. Furthermore, we will use the I2 statistic which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) (Higgins 2011).

We will interpret I2 values as:

  • likely not important: 0% to 40%;

  • possible moderate heterogeneity: 30% to 60%;

  • possible substantial heterogeneity: 50% to 90%; and

  • considerable heterogeneity: 75% to 100%.

Assessment of reporting biases

We will handle different types of reporting biases (e.g. publication bias, time lag bias, outcome reporting bias, etc.) following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). 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 2011). For continuous outcomes with intervention effects measured as MDs, we will use the test proposed by Egger 1997 to test for funnel plot asymmetry (Egger 1997). For dichotomous outcomes with intervention effects we will use the arcsine test proposed by Rücker 2008 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

We will base our primary conclusions on the results of the primary outcomes at a low risk of bias.

Meta‐analysis

We will undertake the meta‐analysis according to the recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will use the statistical software Review Manager 5 provided by Cochrane to analyse data (RevMan 2014).

Assessment of significance

We will assess the intervention effects with both random‐effects model meta‐analysis and fixed‐effect model meta‐analysis and use the more conservative point estimate of the two (Jakobsen 2014). The more conservative point estimate is the estimate closest to zero effect. If the two estimates are equal, we will use the estimate with the widest CI. We will assess three primary outcomes; therefore, we will consider a P value of 0.025 or less as statistically significant (Jakobsen 2014). We will assess five secondary outcomes; therefore, we will consider a P value of 0.0166 or less as statistically significant (Jakobsen 2014). We will use the eight‐step procedure to assess if the thresholds for significance are crossed (Jakobsen 2014).

Trial Sequential Analysis

Trial Sequential Analysis adjusts the significance boundaries for sparse data and repetitive testing while acquiring data before a diversity adjusted required information size (DARIS) is reached in cumulative meta‐analyses (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010; Thorlund 2011a; Thorlund 2011b; TSA 2011). When evaluating each trial in our Cochrane Review, we will utilise Trial Sequential Analysis. For each Trial Sequential Analysis, we will use the event proportion in the control group, an a priori intervention effect of 20% RR reduction, a risk of type I error of 2.5%, and type II error of 20%, and utilise a heterogeneity adjustment factor (1/(1 ‐ D2) using the heterogeneity estimate diversity (D2) statistic among all trials to calculate DARIS (Jakobsen 2014). Subsequently, we will perform an analysis using 1% risk for type I errors and 10% for type II errors (Wetterslev 2009).

Subgroup analysis and investigation of heterogeneity

If data are available, we will evaluate the following subgroup analyses.

  • Trials with low risk of bias compared to trials with high risk of bias.

  • Parallel group trials compared to cluster‐randomised trials.

  • Presence of cirrhosis compared to absence of cirrhosis.

  • Compensated compared to decompensated cirrhosis.

  • Presence of hepatocellular carcinoma compared to absence of hepatocellular carcinoma.

  • Prior liver transplant recipients compared to non‐liver transplants.

  • Different hepatitis B genotypes.

  • Different hepatitis B genotypes (HBeAg‐positive compared to HBeAg‐negative).

  • Concomitant HIV or acquired immune deficiency syndrome (AIDS), hepatitis C, or hepatitis D infected compared to people without such co‐infections.

Sensitivity analysis

In addition to the specified sensitivity analysis described in Dealing with missing data, we may conduct additional sensitivity analyses on trials published in abstract form, full paper articles, and unpublished trials, if possible.

'Summary of findings' tables

We will assess confidence in the evidence using GRADE criteria (Atkins 2004). We will assess five factors referring to limitations in the study design and implementation of included studies that suggest the quality of the evidence: risk of bias; indirectness of evidence (population, intervention, control, outcomes); unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses); imprecision of results (wide CIs and as evaluated with our Trial Sequential Analyses (Jakobsen 2014); and a high probability of publication bias. We will define the levels of evidence as 'high', 'moderate', 'low', or 'very low'. These grades are defined as follows.

  • High certainty: this research provides a very good indication of the likely effect; the likelihood that the effect will be substantially different is low.

  • Moderate certainty: this research provides a good indication of the likely effect; the likelihood that the effect will be substantially different is moderate.

  • Low certainty: this research provides some indication of the likely effect; however, the likelihood that it will be substantially different is high.

  • Very low certainty: this research does not provide a reliable indication of the likely effect; the likelihood that the effect will be substantially different is very high.

Acknowledgements

We would like to thank Anat Fisher for initiating this protocol. We would like to thank Vijaya M. Musini and Ken Bassett for supervising this initial version. Also, we would like to acknowledge Dimitrinka Nikolova and Sarah Louise Klingenberg from the Cochrane Hepato‐Biliary Editorial Team office for their extensive guidance regarding this protocol and performance of search strategies. Also, we would like to acknowledge Susan Cavanaugh for her guidance in search strategies. Cochrane Review Group funding acknowledgement: The Danish State is the largest single funder of The Cochrane Hepato‐Biliary Group through its investment in The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark. Disclaimer: The views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or The Copenhagen Trial Unit.

Peer reviewers: Chavdar S Pavlov, Russia; Jane Linschou, Denmark. Contact and sign‐off editor: Christian Gluud, Denmark.

Appendices

Appendix 1. Search Strategy

Database Time span Search strategy
Cochrane Hepato‐Biliary Group Controlled Trials Register Date will be given at review stage. lamivudin* AND resistan* AND (chronic AND (hepatitis B OR hep B OR HBV))
Cochrane Central Register of Controlled Trials (CENTRAL) Latest issue #1 MeSH descriptor: [Lamivudine] explode all trees
#2 lamivudine
#3 #1 or #2
#4 resistan*
#5 MeSH descriptor: [Hepatitis B, Chronic] explode all trees
#6 (chronic and ('hepatitis B' or 'hep B' or HBV))
#7 #5 or #6
#8 #3 and #4 and #7
MEDLINE (Ovid SP) 1946 to the date of search. 1. exp Lamivudine/
2. lamivudine.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
3. 1 or 2
4. resistan*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
5. exp Hepatitis B, Chronic/
6. (chronic and ('hepatitis B' or 'hep B' or HBV)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
7. 5 or 6
8. 3 and 4 and 7
9. (random* or blind* or placebo* or meta‐analys*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
10. 8 and 9
Embase (Ovid SP) 1974 to the date of search. 1. exp lamivudine/
2. lamivudine.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
3. 1 or 2
4. resistan*.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
5. exp hepatitis B/
6. (chronic and ('hepatitis B' or 'hep B' or HBV)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
7. 5 or 6
8. 3 and 4 and 7
9. (random* or blind* or placebo* or meta‐analys*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
10. 8 and 9
Science Citation Index Expanded (Web of Science) 1900 to the date of search. #6 #5 AND #4
#5 TS=(random* or blind* or placebo* or meta‐analys*)
#4 #3 AND #2 AND #1
#3 TS=(chronic and ('hepatitis B' or 'hep B' or HBV))
#2 TS=(resistan*)
#1 TS=(lamivudine)
Open in a new tab

 

Contributions of authors

Shaffer RS Mok (SRSM) is the guarantor of the review. He was involved in conceiving, designing, and co‐ordinating the review. SRSM designed the search strategies, undertook the searches and organised retrieval of the papers. SRSM will also perform data management, enter data into RevMan, analyse, and interpret data. Both SRSM and Sachin Mohan (SM) were involved in data collection, screening the search results, screening retrieved papers against inclusion criterion, appraising the quality, extracting data, writing to authors for additional information, providing additional data, and obtaining screening data of unpublished studies. SRSM and SM will provide methodological, clinical, policy, and consumer perspectives. Both SRSM and SM will write the review. Thomas A Judge (TAJ) performed the duties of an unbiased third party if discrepancy arose, provided methodological, clinical, policy, and a consumer perspective, as well as general advice on the review. Yize R Wang (YRW) will assist with Chinese to English translation. Krystal M Hunter (KMH) will also perform analysis of the data. All review authors agreed to the submitted for publication protocol version in the Cochrane Database of Systematic Reviews in the Cochrane Library 2017.

Sources of support

Internal sources

  • Cooper University Hospital, USA.

    Library and Statistics

External sources

  • No sources of support supplied

Declarations of interest

Shaffer RS Mok: no known conflicts of interest to declare. Sachin Mohan: no known conflicts of interest to declare. Krystal M Hunter: no known conflicts of interest to declare. Yize R Wang: no known conflicts of interest to declare. Thomas A Judge: no known conflicts of interest to declare.

New

References

Additional references

  1. Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology (Baltimore, Md.) 1998;27(6):1670‐7. [DOI] [PubMed] [Google Scholar]
  2. Andreone P, Gramenzi A, Cursaro C, Biselli M, Cammà C, Trevisani F, et al. High risk of hepatocellular carcinoma in anti‐HBe positive liver cirrhosis patients developing lamivudine resistance. Journal of Viral Hepatitis 2004;11(5):439‐42. [DOI] [PubMed] [Google Scholar]
  3. Ang EL, Banez V, Flores H, Estanislao N, Velasquez M. Entecavir in lamivudine‐refractory chronic hepatitis B infection: a meta‐analysis. Hepatology International 2010;4(1):143. [Google Scholar]
  4. Liaw YF, Kao JH, Piratvisuth T, Chan H, Chien RN, Liu CJ, et al. Asian‐Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatology International 2012;6:531‐6. [DOI] [PubMed] [Google Scholar]
  5. Atkins D, Best D, Briss PA, Eccles M, Falck‐Ytter Y, Flottorp S, et al. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ (Clinical Research Ed.) 2004;328(7454):1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bani‐Sadr F, Palmer P, Scieux C, Molina JM. Ninety‐six‐week efficacy of combination therapy with lamivudine and tenofovir in patients coinfected with HIV‐1 and wild‐type hepatitis B virus. Clinical Infectious Diseases 2004;39(7):1062‐4. [DOI] [PubMed] [Google Scholar]
  7. Bartholomew MM, Jansen RW, Jeffers LJ, Reddy KR, Johnson LC, Bunzendhal H, et al. Hepatitis‐B‐virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet 1997;349(9044):20‐2. [DOI] [PubMed] [Google Scholar]
  8. Benaboud S, Pruvost A, Coffie PA, Ekouevi DK, Urien S, Arrive E, et al. Concentrations of tenofovir and emtricitabine in breast milk of HIV‐1‐infected women in Abidjan, Cote d’Ivoire, in the ANRS 12109 TEmAA Study, Step 2. Antimicrobial Agents and Chemotherapy 2011;55:1315‐7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Benhamou Y, Bochet M, Thibault V, Martino V, Caumes E, Bricaire F, et al. Long‐term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus‐infected patients. Hepatology (Baltimore, Md.) 1999;30(5):1302‐6. [DOI] [PubMed] [Google Scholar]
  10. Benhamou Y, Fleury H, Trimoulet P, Pellegrin I, Urbinelli R, Katlama C, et al. Anti‐hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV‐infected patients. Hepatology (Baltimore, Md.) 2006;43(3):548‐55. [DOI] [PubMed] [Google Scholar]
  11. Benhamou Y. Treating chronic lamivudine‐resistant hepatitis B in HIV co‐infected patients. Gastroenterology Clinics and Biology 2006;30(10):3S22‐5. [PubMed] [Google Scholar]
  12. Bock CT, Tillmann HL, Torresi J, Klempnauer J, Locarmi S, Manns MP, et al. Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation. Gastroenterology 2002;122(2):264‐73. [DOI] [PubMed] [Google Scholar]
  13. Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clinical Liver Disease 2005;9(2):191‐211. [DOI] [PubMed] [Google Scholar]
  14. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta‐analyses. Journal of Clinical Epidemiology 2008;61(8):763‐9. [DOI] [PubMed] [Google Scholar]
  15. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta‐analyses may be inconclusive – trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently. Conclusive neonatal meta‐analyses. International Journal of Epidemiology 2009;38(1):287‐98. [DOI] [PubMed] [Google Scholar]
  16. Bzowej NH. Hepatitis B. Therapy in pregnancy. Current Hepatitis Reports 2010;9:197‐204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chen E, Wang L, Lei J, Xu L, Tang H. Meta‐analysis: Adefovir dipivoxil in combination with lamivudine in patients with lamivudine‐resistant hepatitis B virus. Virology Journal 2009;6:163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chen Y, Ju T. Comparative meta‐analysis of adefovir dipivoxil monotherapy and combination therapy of adefovir dipivoxil and lamivudine for lamivudine‐resistant chronic hepatitis B. International Journal of Infectious Diseases 2012;16(3):e152‐8. [DOI] [PubMed] [Google Scholar]
  19. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. New England Journal of Medicine 1999;341(1256):1263. [DOI] [PubMed] [Google Scholar]
  20. Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long‐term lamivudine therapy. Gastroenterology 2003;124(1):105‐17. [DOI] [PubMed] [Google Scholar]
  21. Dore GJ, Cooper DA, Pozniak AL, DeJesus E, Zhong L, Miller MD, et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy‐naive and ‐experienced patients coinfected with HIV‐1 and hepatitis B virus. Journal of Infectious Diseases 2004;189(7):1185‐92. [DOI] [PubMed] [Google Scholar]
  22. European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis B. Journal of Hepatology 2012;57:167–85. [DOI] [PubMed] [Google Scholar]
  23. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphic test. BMJ (Clinical Research Edition) 1997;315(7109):629‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Fisher A, Musini JV, Bassett K. Antiviral treatments for lamivudine‐resistant chronic hepatitis B adult patients. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD008178] [DOI] [Google Scholar]
  25. Fosdick A, Zheng J, Pflanz S, Frey CR, Hesselgesser J, Halcomb RL, et al. Pharmacokinetic and pharmacodynamic properties of GS‐9620, a novel Toll‐like receptor 7 agonist, demonstrate interferon‐stimulated gene induction without detectable serum interferon at low oral doses. Journal of Pharmacology and Experimental Therapeutics 2014;348(1):96‐105. [DOI] [PubMed] [Google Scholar]
  26. Gluud C, Nikolova D, Klingenberg SL. Cochrane Hepato‐Biliary Group. About Cochrane (Cochrane Review Groups (CRGs)) 2016, Issue 7. Art. No.: LIVER. [PubMed]
  27. Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. International Journal of Epidemiology 2005;34:1329‐39. [DOI] [PubMed] [Google Scholar]
  28. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Long‐term therapy with adefovir dipivoxil for HBeAg‐negative chronic hepatitis B for up to 5 years. Gastroenterology 2006;131(6):1743‐51. [DOI] [PubMed] [Google Scholar]
  29. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
  30. Hoff J, Bani‐Sadr F, Gassin M, Raffi F. Evaluation of chronic hepatitis B virus (HBV) infection in coinfected patients receiving lamivudine as a component of anti‐human immunodeficiency virus regimens. Clinical Infectious Diseases 2001;32(6):963‐9. [DOI] [PubMed] [Google Scholar]
  31. Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clinical Infectious Diseases 1995;20:992‐1000. [DOI] [PubMed] [Google Scholar]
  32. International Conference on Harmonisation Expert Working Group. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1, Philadelphia (PA): Barnett International/PAREXEL, 1997. [Google Scholar]
  33. INC Research. Antiretroviral Pregnancy Registry. www.apregistry.com (accessed prior to 17 August 2016).
  34. Ismail MH, Wiysonge CS, Ricaforte‐Campos JD, Clarke MJ. Entecavir for chronic hepatitis B. Cochrane Database of Systematic Reviews 2014, Issue 7. [DOI: 10.1002/14651858.CD011233] [DOI] [Google Scholar]
  35. Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta‐analytic methods. BMC Medical Research Methodology 2014;14:120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Janssen HL, Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Rotterdam Foundation for Liver Resarch. Pegylated interferon alfa‐2b alone or in combination with lamivudine for HBeAg‐positive chronic hepatitis B: a randomized trial. Lancet 2005;365(9454):123‐9. [DOI] [PubMed] [Google Scholar]
  37. Kapke GE, Watson G, Sheffler S, Hunt D, Frederick C. Comparison of the Chiron Quantiplex branched DNA (bDNA) assay and the Abbott Genostics solution hybridization assay for quantification of hepatitis B viral DNA. Journal of Viral Hepatitis 1997;4(1):67‐75. [DOI] [PubMed] [Google Scholar]
  38. Katz LH, Fraser A, Leibovici L, Tur‐Kaspa R. Lamivudine for preventing reactivation of hepatitis B infection in patients planned to undergo immunosuppressive therapy. Cochrane Database of Systematic Reviews 2009, Issue 2. [DOI: 10.1002/14651858.CD005264.pub2] [DOI] [Google Scholar]
  39. Katz LH, Tur‐Kaspa R, Guy DG, Paul M. Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation. Cochrane Database of Systematic Reviews 2010, Issue 7. [DOI: 10.1002/14651858.CD006005.pub2] [DOI] [PubMed] [Google Scholar]
  40. Kiyosawa K, Tanaka E. Strategy for lamivudine‐resistant YMDD mutant‐associated chronic hepatitis B. Journal of Gastroenterology 2001;36(2):139‐41. [DOI] [PubMed] [Google Scholar]
  41. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9. [DOI] [PubMed] [Google Scholar]
  42. Kozłowska J, Jabłońska J, Wiercińska‐Drapało A. Toll‐like receptors in viral hepatitis. Postepy Higieny i Medycyny Doswiadczalnej 2009;21(63):351‐4. [PubMed] [Google Scholar]
  43. Kuo A, Dienstag JL, Chung RT. Tenofovir disoproxil fumarate for the treatment of lamivudine‐resistant hepatitis B. Clinical Gastroenterology and Hepatology 2004;2(3):266‐72. [DOI] [PubMed] [Google Scholar]
  44. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one‐year trial of lamivudine for chronic hepatitis. New England Journal of Medicine 1998;339:61‐8. [DOI] [PubMed] [Google Scholar]
  45. Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM, et al. GS‐9620, an oral agonist of Toll‐like receptor‐7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 2013;144(7):1508‐17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon Alfa‐2a, lamivudine,and the combination for HBeAg‐positive chronic hepatitis B. New England Journal of Medicine 2005;352(26):2682‐95. [DOI] [PubMed] [Google Scholar]
  47. Lee WM. Hepatitis B virus infection. New England Journal of Medicine 1997;337:1733‐45. [DOI] [PubMed] [Google Scholar]
  48. Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology (Baltimore, Md.) 2001;33(6):1527‐32. [DOI] [PubMed] [Google Scholar]
  49. Liaw YF, Chien RN, Yeh CT, Tsai SL, Chu CM. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology (Baltimore, Md.) 1999;30(2):567‐72. [DOI] [PubMed] [Google Scholar]
  50. Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000;119:172‐80. [DOI] [PubMed] [Google Scholar]
  51. Liaw Y. Rescue therapy for lamivudine‐resistant chronic hepatitis B: when and how?. Hepatology (Baltimore, Md.) 2007;45(2):266‐8. [DOI] [PubMed] [Google Scholar]
  52. Lim SG, Ng TM, Kung N, Krastev Z, Volfova M, Husa P, et al. A double‐blind placebo‐controlled study of emtricitabine in chronic hepatitis B. Archives of Internal Medicine 2006;166(1):49‐56. [DOI] [PubMed] [Google Scholar]
  53. Lok A, McMahon B. American Academy for the study of Liver Diseases (AASLD) Practice Guidelines: chronic hepatitis B. Hepatology (Baltimore, Md.) 2009;50(3):1‐35. [Google Scholar]
  54. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.MR000033.pub2] [DOI] [PubMed] [Google Scholar]
  55. Mason A, Wick M, White H, Perrillo R. Hepatitis B virus replication in diverse cell types during chronic hepatitis B virus infection. Hepatology (Baltimore, Md.) 1993;18:781‐9. [DOI] [PubMed] [Google Scholar]
  56. McMahon BJ. Epidemiology and natural history of hepatitis B. Seminar in Liver Disease 2005;Suppl 1(25):3‐8. [DOI] [PubMed] [Google Scholar]
  57. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta‐analyses? . Lancet 1998;352(9128):609‐13. [DOI] [PubMed] [Google Scholar]
  58. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. BMJ (Clinical Research Ed.) 2009;339:B2535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Adefovir dipivoxil for adults with lamivudine‐resistant chronic hepatitis B virus infection. Cochrane Database of Systematic Reviews 2015, Issue 12. [DOI: 10.1002/14651858.CD011981] [DOI] [Google Scholar]
  60. Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Interferon for people with lamivudine‐resistant chronic hepatitis B virus infection. Cochrane Database of Systematic Reviews 2016, Issue 4. [DOI: 10.1002/14651858.CD012138] [DOI] [Google Scholar]
  61. Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Telbivudine for adults with lamivudine‐resistant chronic hepatitis B virus infection. Cochrane Database of Systematic Reviews 2017 (in press).
  62. Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Entecavir for patients with lamivudine‐resistant chronic hepatitis B virus infection. Cochrane Database of Systematic Reviews 2017, Issue 1. [DOI: 10.1002/14651858.CD012495] [DOI] [Google Scholar]
  63. Mumtaz K, Subhan A, Hamid S, Jafri W. Lamivudine for chronic hepatitis B in adults. Cochrane Database of Systematic Reviews 2007, Issue 2. [DOI: 10.1002/14651858.CD006547] [DOI] [Google Scholar]
  64. Mumtaz K, Hamid S, Brok J, Jafri W. Pegylated interferon for chronic hepatitis B. Cochrane Database of Systematic Reviews 2007, Issue 1. [DOI: 10.1002/14651858.CD006303] [DOI] [Google Scholar]
  65. Mumtaz K, Ahmed US, Zuberi NF, Salamat S, Jafri W. Lamivudine during pregnancy for preventing hepatitis B virus infection in newborns. Cochrane Database of Systematic Reviews 2010, Issue 9. [DOI: 10.1002/14651858.CD008718] [DOI] [Google Scholar]
  66. Njei B, Kumar S, Kongnyuy EJ. Adefovir dipivoxil for chronic hepatitis B. Cochrane Database of Systematic Reviews 2011, Issue 12. [DOI: 10.1002/14651858.CD009521] [DOI] [Google Scholar]
  67. Nowak MA, Bonhoeffer S, Hill AM, Boehme R, Thomas HC, McDade H. Viral dynamics in hepatitis B virus infection. Proceedings of the National Academy of Sciences of the United States of America 1996;93:4398‐402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Peters MG, Andersen J, Lynch P, Liu T, Alston‐Smith B, Brosgart CL, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology (Baltimore, Md.) 2006;44(5):1110‐6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Petersen J, Dandri M, Mier W, Lütgehetmann M, Volz T, Weizsäcker F, et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nature Biotechnology 2008;26(3):335‐41. [DOI] [PubMed] [Google Scholar]
  70. Piroth L, Pol S, Lacombe K, Miailhes P, Rami A, Rey D, et al. Management and treatment of chronic hepatitis B virus infection in HIV positive and negative patients: the EPIB 2008 study. Journal of Hepatology 2010;53(6):1006‐12. [DOI] [PubMed] [Google Scholar]
  71. Reijnders JG, Deterding K, Petersen J, Zoulim F, Santantonio T, Buti M, et al. Antiviral effect of entecavir in chronic hepatitis B: influence of prior exposure to nucleos(t)ide analogues. Journal of Hepatology 2010;52:493‐500. [DOI] [PubMed] [Google Scholar]
  72. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  73. Ristig MB, Crippin J, Aberg JA, Powderly WG, Lisker‐Melman M, Kessels L, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus‐coinfected individuals for whom interferon‐alpha and lamivudine therapy have failed. Journal of Infectious Diseases 2002;186(12):1844‐7. [DOI] [PubMed] [Google Scholar]
  74. Rockstroh JK, Bhagani S, Benhamou Y, Bruno R, Mauss S, Peters L, et al. European AIDS Clinical Society (EACS) guidelines for the clinical manage‐ment and treatment of chronic hepatitis B and C coinfection in HIV‐infected adults. HIV Medicine 2008;9:82‐8. [DOI] [PubMed] [Google Scholar]
  75. Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603. [DOI] [PubMed] [Google Scholar]
  76. Rücker G, Schwarzer G, Carpenter J. Arcsine test for publication bias in meta‐analyses with binary outcomes. Statistics in Medicine 2008;27:746‐63. [DOI] [PubMed] [Google Scholar]
  77. Saldanha J, Gerlich W, Lelie N, Dawson P, Heermann K, Heath A, et al. An international collaborative study to establish a World Health Organization international standard for hepatitis B virus DNA nucleic acid amplification techniques. Vox Sanguinis 2001;80(1):63‐71. [DOI] [PubMed] [Google Scholar]
  78. Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Annals of Internal Medicine 2012;157(6):429‐38. [DOI] [PubMed] [Google Scholar]
  79. Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Health Technology Assessment 2012;16(35):1‐82. [DOI] [PubMed] [Google Scholar]
  80. Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000;46(4):562‐8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Schultz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408‐12. [DOI] [PubMed] [Google Scholar]
  82. Seeger C, Mason WS. Hepatitis B Virus Biology. Microbiology and Molecular Biology Reviews : MMBR 2000;64(1):51‐68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Sheng YJ, Liu JY, Tong SW, Hu HD, Zhang DZ, Hu P, et al. Lamivudine plus adefovir combination therapy versus entecavir monotherapy for lamivudine‐resistant chronic hepatitis B: a systematic review and meta‐analysis. Virology Journal 2011;8:393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Shey MS, Kongnyuy EJ, Alobwede SM, Wiysonge CS. Co‐formulated abacavir‐lamivudine‐zidovudine for initial treatment of HIV infection and AIDS. Cochrane Database of Systematic Reviews 2013, Issue 3. [DOI: 10.1002/14651858.CD005481.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Siegfried N, Deventer PJU, Mahomed FA, Rutherford GW. Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD004535.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Stuyver LJ, Locarnini SA, Lok A, Richman DD, Carman WF, Dienstag JL, et al. Nomenclature for antiviral‐resistant human hepatitis B virus mutations in the polymerase region. Hepatology (Baltimore, Md.) 2001;33(3):751‐7. [DOI] [PubMed] [Google Scholar]
  87. Tan Y, Ding K, Su J, Trinh X, Peng Z, Gong Y, et al. The naturally occurring YMDD mutation among patients chronically infected HBV and untreated with lamivudine: a systematic review and meta‐analysis. PLoS One 2012;7(3):e32789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Tang H, Chen E, Wang L, Lei J, Xu L. Meta‐analysis: adefovir dipivoxil in combination with lamivudine in patients with lamivudine‐resistant hepatitis B virus. Hepatology (Baltimore, Md.) 2009;50:495A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Teperman L, Spivey J, Poordad F, Schiano T, Bzowej N, Pungpapong S, et al. Emtricitabine/tenofovir DF combination +/HBIG post‐orthotopic liver transplantation to prevent hepatitis B recurrence in patients with normal to moderate renal impairment: interim results. Journal of Hepatology 2010;52:512‐3. [Google Scholar]
  90. Terrault N, Roche B, Samuel D. Management of the hepatitis B virus in the liver transplantation setting: a European and an American perspective. Liver Transplantation 2005;11:7716‐32. [DOI] [PubMed] [Google Scholar]
  91. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Mudar MH, et al. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology (Baltimore, Md.) 2016;63(1):261‐83. [DOI: 10.1002/hep.28156] [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Thorlund K, Dewvereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta‐analyses?. International Journal of Epidemiology 2009;38(1):276‐86. [DOI] [PubMed] [Google Scholar]
  93. Thorlund K, Anema A, Mills E. Interpreting meta‐analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV‐infected individuals. Clinical Epidemiology 2010;2:57‐66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). ctu.dk/tsa/files/tsa_manual.pdf (accessed 5 November 2016).
  95. Thorlund K, Imberger G, Walsh M, Chu R, Gluud C, Wetterslev J, et al. The number of patients and events required to limit the risk of overestimation of intervention effects in meta‐analysis ‐ a simulation study. PLoS One 2011;6(10):e25491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Copenhagen Trial Unit. TSA ‐ Trial Sequential Analysis. Version 0.9 Beta. Copenhagen: Copenhagen Trial Unit, 2011.
  97. Tuma P, Medrano J, Resino S, Vispo E, Madejon A, Sanchez‐Piedra C, et al. Incidence of liver cirrhosis in HIV‐infected patients with chronic hepatitis Bor C in the era of highly active antiretroviral therapy. Antiviral Therapy 2010;15(6):881‐6. [DOI] [PubMed] [Google Scholar]
  98. Bömmel F, Wünsche T, Mauss S, Reinke P, Bergk A, Schürmann D, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine‐resistant hepatitis B virus infection. Hepatology (Baltimore, Md.) 2004;40(6):1421‐5. [DOI] [PubMed] [Google Scholar]
  99. Wang Y, Chen K, Wu Z, Liu Y, Liu S, Zou Z, et al. Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen‐specific immune responses in HBV‐transgenic mice. International Journal of Infectious Diseases 2014;23(29C):31‐6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta‐analysis. Journal of Clinical Epidemiology 2008;61(1):64‐75. [DOI] [PubMed] [Google Scholar]
  101. Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random effects model meta‐analyses. BMC Medical Research Methodology 2009;9:86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. World Health Organization. Fact sheet N°204 – Hepatitis B. www.who.int/mediacentre/factsheets/fs204/en/ (accessed 23 March 2015).
  103. Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed) 2008;336(7644):601‐5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Yang L, Shi LP, Chen HJ, Tong XK, Wang GF, Zhang YM, et al. Isothiafludine, a novel non‐nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation. Acta Pharmacologica Sinica 2014;35(3):410‐8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Zhao S, Tang L, Fan X, Chen L. Telbivudine for chronic hepatitis B. Cochrane Database of Systematic Reviews 2010, Issue 9. [DOI: 10.1002/14651858.CD008715] [DOI] [Google Scholar]
  106. Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 2009;137:1593‐608. [DOI] [PubMed] [Google Scholar]

Articles from The Cochrane Database of Systematic Reviews are provided here courtesy of Wiley

RESOURCES