WHO/HIV/2014.42 © World Health Organization 2014
Global Hepatitis Programme Guideline development for Hepatitis C virus Screening, Care and Treatment in low- and middle-income countries PICO 7 Treatment (Simeprevir) – Decision Making Table
Evidence to recommendation framework
Should simeprevir be used to treat chronic hepatitis C? Problem: HCV genotype 1 infection Option: simprevir + peg-INF + ribavirin Comparison: peg-INF + ribavirin Setting: ambulatory care Perspective: WHO CRITERIA JUDGEMENTS
Background: [Background]
RESEARCH EVIDENCE
ADDITIONAL CONSIDERATIONS
P RO B LE M
Is the problem a priority?
No
Probably No
Uncertain
Probably Yes
Yes X
Varies
HCV affects 170 million people around the world; 3% of the world’s population.
Date: 2013-12-07 1 EtR – Confidential – do not share or cite 1
Problem: HCV genotype 1 infection
Option: SMV+peg-INF+RBV
Comparison: peg-INF+RBV
Setting: ambulatory care
CRITERIA What is the overall certainty of this evidence? Is there important uncertainty about how much people value the main outcomes?
JUDGEMENTS No included studies
RESEARCH EVIDENCE
ADDITIONAL CONSIDERATIONS
Very low
Low
Moderate
High X
Possibly Important important uncertainty uncertainty or variability or variability
Probably no No important important No known uncertainty uncertainty undesirable or variability or variability outcomes X
Summary of findings: simeprevir (12 weeks)/PR (24-48 weeks) vs. PR Outcome Without SMV (per 1000) With SMV (per 1000) Difference (per 1000 (95%CI) Relative effect (RR) (95%CI) RR 0.39 (0.33 to 0.45) RR 1.13 (0.5 to 2.55
B E NE F IT S & HA RM S O F T HE O P T IO NS
Certainty of the evidence (GRADE) HIGH MODERATE due to imprecision
Patients with HCV genotype 1a should be screened for the genetic mutation Q80K polymorphism (30% of genotype 1a patients in the studies), as the response in those patient is not much higher than with peg-IFN alone. The response rate in HIV co-infected patients was 74% (78/106) [Dietrich et al; EACS 2013; not included in this analysis as no peg-INF/RBV comparator group was included], similar to what was observed in non-HIV co-infected patients. The findings can therefore be applied to a HIV coinfected population without rating down for indirectess.
Are the desirable anticipated effects large?
No
Probably No
Uncertain
Probably Yes
Yes X
Varies
Failure of SVR SAE leading to treatment discontinuation
544 17
212 19
332 less 2 more
Are the undesirable anticipated effects small?
No
Probably No
Uncertain
Probably Yes X
Yes
Varies
Link to detailed evidence profile
Are the desirable effects large relative to undesirable effects?
No
Probably No
Uncertain
Probably Yes
Yes X
Varies
Date: 2013-12-07 2 EtR – Confidential – do not share or cite 2
Problem: HCV genotype 1 infection
Option: SMV+peg-INF+RBV
Comparison: peg-INF+RBV
Setting: ambulatory care
CRITERIA Are the resources required small? Is the incremental cost small relative to the net benefits? What would be the impact on health inequities?
JUDGEMENTS No Probably No Uncertain X Probably Yes Yes Varies
RESEARCH EVIDENCE
ADDITIONAL CONSIDERATIONS
RE S O URCE US E
At the time of deliberations, detailed pricing information was unavailable for countries covered in this guideline.
No
Probably No
Uncertain X
Probably Yes
Yes
Varies
E Q UIT Y
Increased Probably Uncertain Probably Reduced Varies increased reduced X
A CCE P T A B ILIT Y
Is the option acceptable to key stakeholders?
No
Probably No
Uncertain
Probably Yes
Yes X
Varies
F E A S IB ILIT Y
Is the option feasible to implement?
No
Probably No
Uncertain
Probably Yes
Yes X
Varies
No refrigeration necessary; once daily dosing
Date: 2013-12-07 3 EtR – Confidential – do not share or cite 3
Problem: HCV genotype 1 infection
Option: SMV+peg-INF+RBV
Comparison: peg-INF+RBV
Setting: ambulatory care
Balance of consequences
Undesirable consequences clearly outweigh desirable consequences in most settings
Undesirable consequences probably outweigh desirable consequences in most settings
The balance between desirable and undesirable consequences is closely balanced or uncertain
Desirable consequences probably outweigh undesirable consequences in most settings
Desirable consequences clearly outweigh undesirable consequences in most settings X
Type of recommendation
We recommend against offering this option
We suggest not offering this option
We suggest offering this option
We recommend offering this option X
Recommendation (text)
Simeprevir (12 weeks), given in combination with pegylated interferon and ribavirin (for 24 weeks) is recommended in genotype 1 HCV infection without Q80K polymorphism (non-HIV co-infected and HIV co-infected populations) rather than pegylated interferon and ribavirin alone. Strong recommendation, high quality of evidence Note: This recommendation was made without explicit resource use considerations as detailed pricing information was unavailable for countries covered in this guideline at the time of deliberations.
Justification Subgroup considerations Implementation
[to follow] none [to follow]
considerations
Monitoring and evaluation [to follow] Research priorities [to follow]
Date: 2013-12-07 4 EtR – Confidential – do not share or cite 4
Problem: HCV genotype 1 infection
Option: SMV+peg-INF+RBV
Comparison: peg-INF+RBV
Setting: ambulatory care
Evidence profile title: Should simeprevir/ribavirin/peg-INF vs. peg-IFN/ribavirin be used for HCV genotype 1 infection*? Author(s): YFY Date: 2013-12-09
Question: Should simeprevir (12 weeks)/ribavirin/peg-INF (24 weeks) vs. peg-IFN/ribavirin be used for HCV genotype 1 infection*? Quality assessment Participants (studies) Follow up Risk of bias Inconsistency Indirectness Imprecision Publication bias Overall quality of Study event rates (%) evidence With PegWith IFN/ribavirin Simeprevir/ribavirin/ peg-INF
Summary of Findings Relative effect (95% CI) Anticipated absolute effects Risk with PegIFN/ribavirin Risk difference with Simeprevir/ribavirin/peg-INF (95% CI)
Failure of SVR (CRITICAL OUTCOME) 1464 (5 RCT) no serious risk of bias no serious inconsistency no serious indirectness no serious imprecision undetected ⊕⊕⊕⊕ HIGH large effect present 294/540 (54.4%) 193/924 (20.9%) RR 0.39 (0.33 to 0.45) 544 SVR failures per 1000 332 fewer SVR failures per 1000 (from 299 fewer to 365 fewer)
SAE leading to treatment discontinuation (initial 12 weeks) (IMPORTANT OUTCOME) 1464 (5 RCT) (data from FDA briefing) 1
no serious risk of bias
no serious inconsistency
no serious indirectness
serious1
undetected
9/540 ⊕⊕⊕⊝ MODERATE1 (1.7%) due to imprecision
15/924 (1.6%)
RR 1.13 (0.5 to 2.55)
17 SAE per 1000
2 more SAE per 1000 (from 8 fewer to 26 more)
Estimate crosses one; large confidence interval (fails to exclude relative harms as well as benefits)
* Patients with HCV genotype 1a should be screened for the genetic mutation Q80K polymorphism (30% of genotype 1a patients in the studies), as the response in those patient is not much higher than with peg-IFN alone. The response rate in HIV co-infected patients was 74% (78/106) [Dietrich et al; EACS 2013; not included in this analysis as no peg-INF/RBV comparator group included], similar to what was observed in non-HIV co-infected patients.
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Date: 2013-12-07 5 EtR – Confidential – do not share or cite 5
Problem: HCV genotype 1 infection
Option: SMV+peg-INF+RBV
Comparison: peg-INF+RBV
Setting: ambulatory care
References (To make references appear here, place cursor in any text above this page and choose: Insert > Footnote…> Endnote > End of section)
Date: 2013-12-07 6 EtR – Confidential – do not share or cite 6
Explanations
Definitions for ratings of the certainty of the evidence (GRADE)** Ratings Definitions This research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different* is low. This research provides a good indication of the likely effect. The likelihood that the effect will be substantially different4 is moderate. This research provides some indication of the likely effect. However, the likelihood that it will be substantially different4 is high. This research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different4 is very high. Implications This evidence provides a very good basis for making a decision about whether to implement the intervention. Impact evaluation and monitoring of the impact are unlikely to be needed if it is implemented. This evidence provides a good basis for making a decision about whether to implement the intervention. Monitoring of the impact is likely to be needed and impact evaluation may be warranted if it is implemented. This evidence provides some basis for making a decision about whether to implement the intervention. Impact evaluation is likely to be warranted if it is implemented. This evidence does not provide a good basis for making a decision about whether to implement the intervention. Impact evaluation is very likely to be warranted if it is implemented.
High
Moderate Low Very low
*Substantially different: large enough difference that it might have an effect on a decision **The Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group began in the year 2000 as an informal collaboration of people with an interest in addressing the shortcomings of present grading systems in health care. The working group has developed a common, sensible and transparent approach to grading quality of evidence and strength of recommendations. Many international organizations have provided input into the development of the approach and have started using it.
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Generic EtR framework
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