Protease inhibitors in combination with pegylated interferon and ribavirin for adult patients with chronic hepatitis C virus

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To systematically evaluate the beneficial and harmful effects of adding protease inhibitors to the current standard treatment of chronic hepatitis C with pegylated interferon and ribavirin.

Background

Description of the condition

Hepatitis C is an enveloped ribonucleic acid (RNA) virus. It is divided into 11 major genotypes, with six of the genotypes occurring more frequently (Foster 2009). An estimated 130 to 170 million people worldwide are infected with hepatitis C, and four million of them are in the United States (WHO 2011). Around 75% to 85% of patients who become infected with hepatitis C fail to clear the virus and become chronic carriers (Ghany 2009). Among these individuals, 5% to 20% are reported to develop cirrhosis over a period of approximately 20 to 25 years (Seeff 2002; Seeff 2009). Annually, approximately 2% to 4% of patients with advanced fibrosis or cirrhosis develop liver complications such as liver failure, portal hypertension, and hepatocellular carcinoma (Benvegnu 2001; Fattovich 2002). Chronic hepatitis C is the single most common indication for liver transplantation (OPTN 2005).

Description of the intervention

The goal of therapy in chronic hepatitis C is to prevent liver-related morbidity and mortality from the virus infection (Ghany 2009). The commonly used outcome for hepatitis C virus treatment is sustained virologic response (SVR) (Strader 2004). SVR is used as a surrogate measure for patient-relevant outcomes such as mortality, morbidity, and quality of life. A recent systemic review revealed that treatment-related SVR was associated with a substantially reduced risk of hepatocellular carcinoma (Morgan 2013). However, it has not been established whether achieving a SVR in chronic hepatitis C patients will have an impact on other final health outcomes, including mortality (Gluud 2007; Brok 2010; Koretz 2013).

Currently, the standard of care for patients with chronic hepatitis C is a 24 to 48-week course of pegylated interferon-alpha-2a (PEG-IFN-α2a) or pegylated interferon-alpha-2b (PEG-IFN-α2b) in combination with ribavirin. This therapy leads to a SVR in 42% to 52% of individuals infected with hepatitis C virus genotype 1, 65% to 85% in virus genotypes 4, 5, or 6, and 76% to 82% in virus genotypes 2 or 3 (Hoofnagle 2006).

The duration of therapy depends on the virologic response. The rapidity of virologic response appears to be an important predictor for a SVR. Multiple trials have attempted to shorten the duration of hepatitis C therapy based upon the patient's virologic response (Fried 2002). A shorter course of therapy is optimal, to decrease the cost of therapy and the associated adverse effects.

How the intervention might work

During the past 10 years, intensive efforts have been made to develop different compounds with antiviral activities against the hepatitis C virus, which are referred to as direct-acting antiviral agents. These antiviral agents are inhibitors of NS3 protein/NS4A cofactor complex which plays an important role in the final stages of the hepatitis C virus replication cycle (Simmonds 1993). Adding one of these direct-acting antiviral agents to standard treatment can increase the frequency of achieving SVR and may permit a shorter duration of therapy to achieve it (McGovern 2008).

The clinical development programme for the two hepatitis C virus nonstructural (NS) 3/4A protease inhibitors boceprevir and telaprevir has now been completed. A few reviews, including narrative reviews, and randomised clinical trials have been published so far (Hofmann 2011).

Why it is important to do this review

We aim to identify all randomised clinical trials to strengthen inferences about the benefits and harms of adding one of the protease inhibitors to the current standard treatment of pegylated interferon and ribavirin for adult patients with chronic hepatitis C.

Objectives

To systematically evaluate the beneficial and harmful effects of adding protease inhibitors to the current standard treatment of chronic hepatitis C with pegylated interferon and ribavirin.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomised clinical trials irrespective of language or publication status for the assessment of benefits and harms. We will include data from quasi-randomised or observational studies for assessment of harms only.

Types of participants

Adults over 18 years old, diagnosed with chronic hepatitis C: if anti-hepatitis C virus is present in the serum and serum aminotransferase activity remains elevated for more than six months (Ghany 2009); or there is evidence of necrosis or inflammation on liver biopsy (Strader 2004; Ghany 2009); or if the disease is suspected and it is confirmed by quantitative analysis of hepatitis C virus RNA through polymerase chain reaction (PCR) or transcription-mediated amplification testing (Ghany 2009); or by any other method used for diagnosis.

Participants may be treatment-naive (not previously treated with antiviral drugs), relapsers (participants with a transient response to previous antiviral treatment), or non-responders (participants without response to previous antiviral treatment).

Participants in the trials with any concomitant or preceding diseases, such as human immune deficiency virus (HIV), solid organ transplant recipients, or participants receiving haemodialysis, will be excluded. In addition, participants with other forms of liver disease that might be responsible for the liver problem, e.g., hepatitis B, alcoholism, iron overload, will also be excluded.

Types of interventions

Any of the currently approved protease inhibitors in combination with pegylated interferon and ribavirin at any dosage versus no intervention, placebo, or pegylated interferon and ribavirin.

Co-interventions will be allowed if administered equally to all groups of a trial. Dosages or dosing strategies that were shown to have much lower effectiveness (e.g., from phase II dosing trials) will be excluded as these cannot be used in practice due to the risk of resistance development.

Types of outcome measures

Primary outcomes
  1. All-cause mortality.

  2. Chronic hepatitis C-related mortality as defined by the authors of the trial.

  3. Morbidity: number of patients who have developed cirrhosis, ascites, variceal bleeding, hepatic encephalopathy, or hepatocellular carcinoma.

  4. Serious adverse events: Serious adverse events are defined according to the International Conference on Harmonisation (ICH) Guidelines (ICH-GCP 1997) as any event that leads to death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability, and any important medical event which may have jeopardised the patient or requires intervention to prevent it. All other adverse events will be considered non-serious.

Secondary outcomes
  1. Quality of life.

  2. Non-serious adverse events.

  3. Failure in virological response. Number of patients without sustained virological response (SVR): number of patients with detectable hepatitis C virus RNA (i.e., above the lower limit of detection) in the serum by a sensitive polymerase chain reaction-based assay (PCR-based) assay or by transcription-mediated amplification testing 24 weeks after the end of treatment.

  4. Proportion of patients without complete end of treatment virologic response (cEVR) defined as detectable hepatitis C virus RNA at weeks 12, 16, 20, and 24.

Search methods for identification of studies

Electronic searches

We will identify relevant randomised clinical trials by electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (Klingenberg 2011; Gluud 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003). The preliminary search strategies with the expected time spans of the searches are presented in Appendix 1. We will also search for randomised clinical trials on the web sites of the Food and Drug Administration (FDA) (www.fda.gov), the European Medicines Agency (EMA) (www.ema.europa.eu/ema), and the World Health Organization (WHO) Clinical Trials Portal (apps.who.int/trialsearch).

Relevant abstracts from EASL (European Association for the Study of the Liver), AASLD (American Association for the Study of Liver Disease), or any other meeting will also be included.

Searching other resources

We will check the bibliographic references of identified randomised clinical trials, textbooks, review articles, and meta-analyses in order to find randomised clinical trials not identified by the electronic searches. We will also contact principal authors of the identified randomised clinical trials to ask them for information regarding additional trials of which they are aware. We will contact pharmaceutical companies involved in the production of protease inhibitors in order to obtain unpublished randomised clinical trials.

Data collection and analysis

Selection of studies

The review authors will independently screen the titles and abstracts of identified articles for eligibility. MEA and PD will independently assess the inclusion criteria. We will retrieve the full text of articles to assess their potential eligibility for inclusion in the review. We will record excluded trials with reasons for exclusion. We will resolve disagreements by discussion with YFY.

Data extraction and management

We will develop and use a data collection form for extraction of data on methods, participants, interventions, and outcomes. If more than one publication on each randomised clinical trial is identified, we will compare data and consider one of the publications, usually the one providing the most pertinent information, to be primary. MEA and PD will extract data independently. Disagreements will be resolved by discussion with YFY.

We will also record whether sample size calculations were performed, the follow-up periods, and whether the trial was stopped early either due to benefit or harm.

Assessment of risk of bias in included studies

Initially, we will assess the risk of bias of all trials fulfilling the inclusion criteria at the trial level, using the Cochrane 'Risk of bias' tool with the domains below (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012a; Savović 2012b).

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 are adequate if performed by an independent person not otherwise involved in the trial.

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

  • High risk of bias: the sequence generation method was not random.

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 (for example, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).

  • Uncertain 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.

Blinding of participants, personnel, and outcome assessors
  • Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.

  • Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias in the results.

  • High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes was 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. Sufficient methods, such as multiple imputation, have been employed to handle missing data.

  • Uncertain 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 in the results.

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

Selective outcome reporting
  • Low risk of bias: all outcomes were pre-defined and reported, or all clinically relevant and reasonably expected outcomes were reported.

  • Uncertain risk of bias: it is unclear whether all pre-defined and clinically relevant and reasonably expected outcomes were reported.

  • High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

For a trial to be assessed as having low risk of bias in the selective outcome reporting domain, the trial should have been registered either on the www.clinicaltrials.gov web site or a similar register, or there should be a protocol, e.g., published in a paper journal. In the case of trials run and published in the years when trial registration was not required, we will carefully scrutinise all publications reporting on the trial to identify the trial objectives and outcomes. If usable data on all outcomes specified in the trial objectives are provided in the publication's results section, then the trial can be considered to have low risk of bias for the selective outcome reporting domain.

For-profit bias
  • Low risk of bias: the trial appears to be free of industry sponsorship or other kinds of for-profit support that may manipulate the trial design, conductance, or results of the trial.

  • Uncertain risk of bias: the trial may or may not be free of for-profit bias as no information on clinical trial support or sponsorship is provided.

  • High risk of bias: the trial is sponsored by the industry or has received another kind of for-profit support.

If the risk of bias in a trial is judged as 'low' in all the domains listed above, the trial will fall in the 'low risk of bias' group of trials. If the risk of bias in the assessed trials is judged as 'uncertain' or 'high' in one or more of the specified domains, then the trial will fall in the group of 'high risk of bias' trials.

If disagreements among authors' evaluations occur, we will resolve them by discussion among all authors.

Measures of treatment effect

For dichotomous outcomes, we will express the results as risk ratio (RR) with 95% confidence intervals (CI).

For continuous outcomes, we will use the mean difference (MD), or if different scales had been used in the trials we will use the standardised mean difference (SMD) (Thompson 2002).

Unit of analysis issues

The unit of analysis will be the intervention group of participants in a randomised clinical trial.

Dealing with missing data

We plan to perform all analyses according to the intention-to-treat method, including all participants irrespective of compliance or follow-up.

Regarding the primary outcomes, we will include patients with incomplete or missing data in the sensitivity analyses by imputing them according to the following scenarios (Hollis 1999; Gluud 2013).

  • 'Best-worst' case scenario analyses: participants with missing outcome data are considered successes in the experimental group and failures in the control group. The denominator will include all the participants in the trial.

  • 'Worst-best' case scenario analyses: participants with missing outcome data are considered failures in the experimental group and successes in the control group. The denominator will include all the participants in the trial.

Assessment of heterogeneity

We will assess heterogeneity among trials by visual inspection of the forest plots, by using the Chi2 test (defining statistical heterogeneity as significant if P < 0.1), and by estimation of the percentage of heterogeneity between trials which cannot be explained by sampling variation (I2 statistic). If substantial heterogeneity, defined as more than 50%, is found, we will attempt to explore the possible reasons for it.

Assessment of reporting biases

We will use funnel plot asymmetry to assess publication bias provided that there are at least 10 included trials (Egger 1997).

Data synthesis

Meta-analyses

For the statistical analyses, we will use Review Manager 5.2 (RevMan 2012). For dichotomous data, we will calculate the RR separately for each trial and then calculate the trial results using both fixed-effect and random-effects model meta-analyses. In case of discrepancies between the results of the two models, we will report the results of both models; otherwise we will report the results only from the fixed-effect model. In our assessment of the imprecision achieved in our meta-analysis, we will follow the GRADE guidelines (Guyatt 2011).

Subgroup analysis and investigation of heterogeneity

We will consider the following subgroups.

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

  • Treatment-naive versus treatment-experienced participants.

  • Different protease inhibitors used in the trials.

  • Different doses of protease inhibitors.

  • Participants with different ethnic groups.

  • Participants with underlying liver cirrhosis compared to participants with no cirrhosis.

Sensitivity analysis

In addition to the sensitivity analyses specified under Dealing with missing data, we may perform other sensitivity analyses if deemed necessary during the review process.

'Summary of findings' tables

We will assess the quality of evidence at the outcome level across trials using the GRADE approach; all the outcomes will be included in the 'Summary of findings' table (GRADE table) (GRADEPro).

Acknowledgements

Special thanks to The Cochrane Hepato-Biliary Group for their help with data searching and full-text publications of some of the studies.

Thanks to the Case Western Reserve University and Louis Stokes VA Hospital, both in Cleveland, OH, USA.

Peer reviewers: Salvatore Madonia, Italy; Hirayuki Enomoto, Japan; Eric M Yoshida, Canada.

Contact editor: Ronlad L Koretz, USA.

Appendices

Appendix 1. search strategies

DatabaseTime spanSearch strategy
The Cochrane Hepato-Biliary Group Controlled Trials RegisterDate will be given at review stage('protease inhibitor*' OR telaprevir OR VX-950 OR incivek OR boceprevir OR INN OR victrelis) AND ('pegylated interferon' OR peg interferon OR peg-IFN OR Pegasus OR Pegasys OR peg intron OR 'viraferon peg') AND (ribavirin OR Copegus OR Rebetol OR Ribasphere OR Vilona OR Virazole) AND 'chronic hepatitis C'
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryLatest issue

#1 MeSH descriptor Protease Inhibitors explode all trees

#2 (protease inhibitor* OR telaprevir OR VX-950 OR incivek OR boceprevir OR INN OR victrelis)

#3 (#1 OR #2)

#4 pegylated interferon OR peg interferon OR peg-IFN OR Pegasus OR Pegasys OR peg intron OR viraferon peg

#5 MeSH descriptor Ribavirin explode all trees

#6 ribavirin OR Copegus OR Rebetol OR Ribasphere OR Vilona OR Virazole

#7 (#5 OR #6)

#8 MeSH descriptor Hepatitis C, Chronic explode all trees

#9 chronic hepatitis C

#10 (#8 OR #9)

#11 (#3 AND #4 AND #7 AND #10)

MEDLINE (Ovid SP)1950 to the date of search

1. exp Protease Inhibitors/

2. (protease inhibitor* or telaprevir or VX-950 or incivek or boceprevir or INN or victrelis).MP. [MP=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

3. 1 or 2

4. (pegylated interferon or peg interferon or peg-ifn or Pegasus or Pegasys or peg intron or viraferon peg).MP. [MP=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

5. exp Ribavirin/

6. (ribavirin or Copegus or Rebetol or Ribasphere or Vilona or Virazole).MP. [MP=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

7. 5 or 6

8. exp Hepatitis C, Chronic/

9. chronic hepatitis c.mp . [MP=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

10. 8 or 9

11. 3 and 4 and 7 and 10

12. (random* or blind* or placebo* or meta-analysis).MP. [MP=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

13. 11 and 12

EMBASE (Ovid SP)1980 to the date of search

1. exp proteinase inhibitor/

2. (protease inhibitor* or telaprevir or VX-950 or incivek or boceprevir or INN or victrelis).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. exp peg interferon/

5. (pegylated interferon or peg interferon or peg-ifn or Pegasus or Pegasys or peg intron or viraferon peg).MP. [MP=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

6. 4 or 5

7. exp ribavirin/

8. (ribavirin or Copegus or Rebetol or Ribasphere or Vilona or Virazole).MP. [MP=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

9. 7 or 8

10. exp hepatitis C/

11. chronic hepatitis c.mp . [MP=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

12. 10 or 11

13. 3 and 6 and 9 and 12

14. (random* or blind* or placebo* or meta-analysis).MP. [MP=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

15. 13 and 14

Science Citation Index Expanded (http://apps.isiknowledge.com)1900 to the date of search

# 7 #6 AND #5

# 6 TS=(random* or blind* or placebo* or meta-analysis)

# 5 #4 AND #3 AND #2 AND #1 

# 4 TS=(chronic hepatitis C)

# 3 TS=(ribavirin or Copegus or Rebetol or Ribasphere or Vilona or Virazole)

# 2 TS=(pegylated interferon or peg interferon or peg-ifn or Pegasus or Pegasys or peg intron or viraferon peg)

# 1 TS=(protease inhibitor* or telaprevir or VX-950 or incivek or boceprevir or INN or victrelis)

Contributions of authors

Mohammed Eyad Yaseen Alsabbagh drafted the protocol, Perica Davitkov helped in drafting the protocol, and Yngve Falck-Ytter revised the protocol. All authors agreed on the final protocol version.

Declarations of interest

None known.

Sources of support

Internal sources

  • Case Western Reserve University, Case Medical Center, Cleveland, OH, USA.

  • Louis Stokes VA Hospital, Cleveland, OH, USA.

External sources

  • No sources of support supplied

Ancillary