Emtricitabine for adults with lamivudine‐resistant chronic hepatitis B virus infection
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:
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emtricitabine versus no intervention;
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emtricitabine versus placebo;
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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
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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.
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Health‐related quality of life (any valid assessment scale, filled out by the participant).
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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
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Hepatitis B‐related mortality (caused by morbidities or decompensation of the liver, such as liver cirrhosis or hepatocellular carcinoma).
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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.
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Proportion of participants without histological improvement.
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Proportion of participants with detectable HBsAg in serum or plasma.
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Proportion of participants with detectable hepatitis B virus DNA in serum or plasma.
Exploratory outcomes
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Proportion of participants with detectable HBeAg in serum or plasma (this outcome is only relevant for HBeAg‐positive participants).
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Proportion of participants without HBeAg seroconversion in serum or plasma (this outcome is only relevant for HBeAg‐positive participants).
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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
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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.
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Unclear risk of bias: the sequence generation method was not specified.
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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
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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).
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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.
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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
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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.
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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.
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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
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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.
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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.
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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
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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.
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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.
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High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting
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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.
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Unclear risk: not all predefined outcomes were reported fully, or it was unclear whether data on these outcomes were recorded or not.
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High risk: one or more predefined outcomes were not reported.
For‐profit bias
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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.
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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.
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High risk of bias: the trial was sponsored by industry or received other type of for‐profit support.
Other risk of bias
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Low risk of bias: the trial appeared to be free of other components that could put it at risk of bias.
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Unclear risk of bias: the trial may or may not be free of other components that could put it at risk of bias.
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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:
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likely not important: 0% to 40%;
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possible moderate heterogeneity: 30% to 60%;
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possible substantial heterogeneity: 50% to 90%; and
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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.
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Trials with low risk of bias compared to trials with high risk of bias.
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Parallel group trials compared to cluster‐randomised trials.
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Presence of cirrhosis compared to absence of cirrhosis.
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Compensated compared to decompensated cirrhosis.
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Presence of hepatocellular carcinoma compared to absence of hepatocellular carcinoma.
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Prior liver transplant recipients compared to non‐liver transplants.
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Different hepatitis B genotypes.
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Different hepatitis B genotypes (HBeAg‐positive compared to HBeAg‐negative).
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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.
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High certainty: this research provides a very good indication of the likely effect; the likelihood that the effect will be substantially different is low.
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Moderate certainty: this research provides a good indication of the likely effect; the likelihood that the effect will be substantially different is moderate.
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Low certainty: this research provides some indication of the likely effect; however, the likelihood that it will be substantially different is high.
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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.
