Post-pandemic Review of anti-Influenza Drug Effectiveness (PRIDE - - PowerPoint PPT Presentation

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Post-pandemic Review of anti-Influenza Drug Effectiveness (PRIDE - - PowerPoint PPT Presentation

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Post-pandemic Review of anti-Influenza Drug Effectiveness (PRIDE Study): An investigation of the impact of neuraminidase inhibitor antiviral use on pneumonia and length of hospital stay in hospitalized influenza A(H1N1)pdm09 patients: an

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1/21/2015 The Fifth ESWI Influenza Conference , Riga, 17th September 2014

Post-pandemic Review of anti-Influenza Drug Effectiveness (PRIDE Study):

An investigation of the impact of neuraminidase inhibitor antiviral use

  • n pneumonia and length of hospital stay in hospitalized influenza

A(H1N1)pdm09 patients: an individual participant data meta-analysis

  • Dr Stella Muthuri
  • Dr Puja Myles
  • Dr Sudhir Venkatesan
  • Dr Jo Leonardi-Bee
  • Dr Wei Shen Lim
  • Professor Jonathan Van-Tam
  • PRIDE Research Consortium
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Conflict of interest

 This study is taking place through an unrestricted educational grant funding from F. Hoffmann-La Roche – The study is being undertaken fully independently of the

company, which has had/will have:

  • no input to the project design;
  • no access to any of the data;
  • no role in analysis or data interpretation;
  • no preview of the study results;
  • no opportunity to preview or comment on this presentation or any

manuscripts arising from the work.

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Authors’ declarations

  • JVT: Between October 2007 and September 2010,

ad hoc paid consultancy to both major NAI manufacturers (GlaxoSmithKline plc, F. Hoffman-La Roche). Former employee of SmithKline Beecham (now part of GSK) and Roche, 2000 - 2002. He has no outstanding interests related to shares, share options or accrued pension rights since 2004.

  • Other Nottingham authors: nil

1/21/2015 The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Background

  • Influenza-related pneumonia was a common severe

complication during the 2009-10 influenza pandemic

  • Prior to the 2009 pandemic, evidence of NAI effectiveness

in seasonal influenza was strongest in terms of symptom alleviation in healthy outpatients, but less robust for reductions in complications (such as pneumonia)

  • Since then, several studies support the potential benefit of

NAIs during 2009-10 but lack statistical power to be conclusive

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Journal of Infectious Diseases, 2013: 207 (15 February)

Study based on published manuscripts

Outcomes studied:

– Mortality

– Severe outcomes: admission to HDU/ICU or death – Influenza(AH1N1)pdm09 related Pneumonia

1/21/2015 The Fifth ESWI Influenza Conference , Riga, 17th September 2014

Preliminary work

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Key findings from meta-analysis of published studies

  • n Influenza-related pneumonia (Muthuri et al 2013)

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Limitations of meta-analysis:

  • High degree of heterogeneity between studies
  • Most studies did not provide adjusted risk estimates
  • Where adjusted risk estimates were available there were differences in the extent
  • f adjustment or confounders included in final models
  • Inability to adjust for propensity to receive treatment

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Objective

To carry out an individual patient data (IPD) meta- analysis to investigate the impact of NAI use on influenza-related pneumonia and hospital length of stay among patients admitted to hospital with influenza A(H1N1)pdm09

Prospero Registration: CRD42011001273

1/21/2015 The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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About the PRIDE Study

  • 80 Research groups* from 38 countries and 6 WHO

regions have provided data on 168,117 individual patient observations

* Two research groups provided exclusively outpatient data (excluded from current analysis).

  • Of these 29,259 patients with known data on NAI

treatment were hospitalised.

– Pneumonia analysis: 56 datasets (n=7,967; 27%) with data on

pneumonia status confirmed using radiographs – Length of hospital stay: 72 datasets (n=20,446; 70%) with data on duration of hospital stay

1/21/2015 The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Methodology

Standardisation of datasets

  • Standardised definitions created for confounder variables such as ‘comorbidity’,

‘disease severity’

  • Outcomes defined as:

– Influenza-related pneumonia: no pneumonia (normal on radiograph); pneumonia (positive for pneumonia on radiograph) – Length of hospital stay: duration in days between admission & discharge/ death

  • Exposure defined as:

– NAI treatment (at any time) vs no NAI treatment – Early NAI (≤2 days of symptom onset) treatment vs later NAI (>2 days after symptom onset) treatment – Early NAI (≤2 days of symptom onset) treatment vs no NAI treatment

  • Propensity scores (for receiving treatment) calculated using a regression model

with ‘treatment’ as the outcome variable and covariates (minimum model): age, sex, comorbidity (yes/no), disease severity at admission (yes/no)

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Statistical analysis

  • Pneumonia analysis: Multilevel logistic regression modelling†
  • Length of stay analysis: Multilevel mixed-effects negative binomial

regression†

  • Adjustment carried out for: propensity score (by quintile), steroid use in

hospital, antibiotic treatment

  • Stratified analyses: by age group (adults, children), pregnant women,

and laboratory confirmed A(H1N1)

  • Analyses conducted using Stata™ V.13

† baseline outcome rates were allowed to vary between the studies through using a random intercept

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Characteristics of hospitalised patients included in analyses

Characteristics

Overall sample (All hospitalised patients) n= 29,259 (100%) Pneumonia analysis n= 7,967 (27%) Length of stay (LOS) analysis n=20,446 (70%)

Age, years; median (IQR) 26 (11- 44) 29 (13 - 48) 27 (11-46) Males 14,442 (49%) 4268(54%) 10,219 (50%) Population groups Adults (ages ≥16 years) Children (ages <16 years) Pregnant women (ages:13-54 years)§ Laboratory confirmed A(H1N1)pdm09 Clinically diagnosed A(H1N1)pdm09 19,834 (68%) 9,225 (32%) 2,167 (23%) 25,026 (86%) 4,233 (14%) 5,692 (71%) 2,258 (28%) 374 (16%) 7,603 (95%) 364 (5%) 14,169 (69%) 6,205 (30%) 1,348 (21%) 16,710 (82%) 3,736(18%) Symptom onset to hospital admission; days, median (IQR) 2 (1-5) 3 (1 - 5) 3 (1-5) NAI (at any time) Early NAI (≤2 days) 18,811 (64%) 5,996 (20%) 6,764 (85%) 1,782 (22%) 13,722 (67%) 4,060(20%) Mortality 2,784 (10%) 706 (9%) 2,229 (11%)

§ proportions based on women between ages 13 & 54 years

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Results: Influenza-related pneumonia

Characteristics of pooled sample of hospitalised patients (N= 7,967)

Characteristics

Total in pneumonia analysis No pneumonia n= 3446 Pneumonia n=4521 Population groups Adults (ages ≥16 years) Children (ages <16 years) Pregnant women (ages:13-54 years)§ Laboratory confirmed A(H1N1)pdm09 Clinically diagnosed A(H1N1)pdm09 5,692 (71%) 2,258 (28%) 374 (16%) 7,603 (95%) 364 (5%) 2,371 (69%) 1,066 (31%) 192 (19%) 3,238(94%) 208 (6%) 3,321 (73%) 1,192 (26%) 182 (14%) 4365 (97%) 156 (3%) Males 4268(54%) 1852 (54%) 2416 (53%) Age, years; median (IQR) 29 (13 - 48) 25 (11 - 45) 33 (14 - 50) Symptom onset to hospital admission; days, median (IQR) 3 (1 - 5) 2 (1 - 4) 3 (1-6) Mortality 706 (9%) 92 (3%) 614 (14%)

§ proportions based on women between ages 13 & 54 years

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Treatment characteristics of hospitalised patients included in pneumonia analysis

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

Exposure definition

Total in pneumonia analysis n= 7,967 No pneumonia n= 3,446 Pneumonia n=4,521

NAI (at any time) 6,764 (85%) 2,760 (80%) 4,004 (89%) Oseltamivir (at any time) 6,705 (99%) 2,713 (98%) 3,992 (100%) Zanamivir (at any time) 129 (2%) 65(2%) 64 (2 %) Peramavir (at any time) 47 (0.6%) 5 (0.2%) 42 (1%) Time of treatment after symptom onset Early NAI (≤2 days) 1782 (26%) 1,027 (37%) 755 (19%) Later NAI (>2 days) 2829 (42%) 968 (35%) 1861 (46%) NAI timing data missing 2153 (32%) 765 (28%) 1,388 (35%) Symptom onset to antiviral treatment; days, median (IQR)

3 (2-6) 2 (1-4) 4 (2-7)

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Outcome: Influenza related pneumonia

Exposure: NAI treatment at anytime vs. none

*

Radiologically confirmed pneumonia vs no pneumonia on CXR

†Adjusted for propensity score quintile, steroid use in hospital, antibiotic treatment in hospital

Statistically significant results in bold

Population Subgroups Crude OR (95% CI) Adjusted† OR (95% CI) Lab confirmed cases (all ages) 1.62 (1.35 – 1.94) 1.28 (1.05 - 1.55) Lab confirmed and clinical diagnoses (all ages) 1.65 (1.39 - 1.96) 1.31 (1.09 - 1.58) Adults (16 years and above) 1.56 (1.26 – 1.94) 1.25 (1.00 - 1.57) Children (under 16 years) 1.42 (1.03 – 1.98) 1.30 (0.93 – 1.83) Pregnant (13 - 54 years) 1.19 (0.52 – 2.71) 0.80 (0.31 - 2.07) ICU patients Adults (16 years and above) 1.62 (1.02 – 2.59) 1.49 (0.92 – 2.42) Children (under 16 years) 1.55 (0.95 – 2.52) 1.47 (0.89 – 2.40)

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Outcome : Influenza related pneumonia

Exposure: Early NAI (≤2 days) vs. none

* P =0.050; ** P = 0.045

†Adjusted for propensity score quintile, steroid use in hospital, antibiotic treatment in hospital

Population Subgroups Crude OR (95% CI) Adjusted† OR (95% CI) Lab confirmed cases (all ages) 1.02 (0.80 – 1.31) 0.77 (0.59 – 1.00)* Lab and clinically confirmed (all ages) 1.03 (0.81 – 1.30) 0.77 (0.60 – 0.99)** Adults (16 years and above) 0.92 (0.70 – 1.20) 0.69 (0.52 – 0.93) Children (under 16 years) 1.11 (0.66 – 1.89) 0.88 (0.50 – 1.56) Pregnant (13 - 54 years) 0.66 (0.20 – 2.22) 0.56 (0.20 – 1.53) ICU patients Adults (16 years and above) 0.91 (0.48 – 1.72) 0.91 (0.46 – 1.82) Children (under 16 years) 1.35 (0.53 – 3.43) 1.17 (0.43 – 3.19)

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Outcome: Influenza related pneumonia

Exposure: ‘early’ NAI (≤2 days) vs. ‘later’ NAI (>2 days)

†Adjusted for propensity score quintile, steroid use in hospital, antibiotic treatment

Statistically significant results in bold

Population Subgroups Crude OR (95% CI) Adjusted† OR (95% CI) Lab confirmed cases (all ages) 0.36 (0.31 – 0.43) 0.44 (0.37 – 0.53) Lab and clinically confirmed (all ages) 0.36 (0.30 – 0.42) 0.43 (0.37 – 0.51) Adults (16 years and above) 0.34 (0.28 – 0.40) 0.41 (0.34 – 0.50) Children (under 16 years) 0.53 (0.36 – 0.78) 0.55 (0.36 – 0.83) Pregnant (13 - 54 years) 0.29 (0.14 – 0.60) 0.40 (0.16 – 0.97) ICU patients Adults (16 years and above) 0.38 (0.25 – 0.59) 0.41 (0.26 – 0.64) Children (under 16 years) 0.38 (0.17 – 0.79) 0.36 (0.16 – 0.86)

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Summary of main findings: Association between NAI treatment and influenza related pneumonia†

† Radiologically confirmed pneumonia 1/21/2015 The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Results: Length of hospital stay (LOS)

1/21/2015 The Fifth ESWI Influenza Conference , Riga, 17th September 2014

*Adjusted for propensity score quintile, corticosteroid and/ or antibiotic treatment in hospital, death

Exposure LOS Median (IQR)

No NAI 4 (2-8) NAI anytime 6 (3-12) Early (≤2 days) NAI 4 (3-8) Late (>2 days) NAI 7 (3 – 14) Population Subgroups Crude RR (95% CI) Adjusted† RR (95% CI)

  • 1. Antiviral anytime vs none

Lab confirmed cases (all ages) 1.21 (1.18 – 1.25) 1.15 (1.11 – 1.18) Lab and clinically confirmed (all ages) 1.19 (1.15 – 1.22) 1.24 (1.21 – 1.28)

  • 2. Early (≤2 days) vs none

Lab confirmed cases (all ages) 1.11 (1.06 – 1.16) 0.96 (0.91 – 1.01) Lab and clinically confirmed (all ages) 1.09 (1.05 – 1.13) 1.07 (1.01 – 1.13)

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Conclusions

  • Our data suggest differential effects depending on the timing and use of

NAIs.

  • NAIs given early reduced the likelihood of pneumonia compared with no

treatment

  • NAIs prescribed in response to the development of pneumonia/ during

hospitalisation explain increased likelihood of pneumonia & LOS, for comparisons of ‘NAI treatment (at any time) vs none’

  • In patients requiring NAI therapy our findings confirm the importance of

early treatment in reducing influenza-related pneumonia and length of hospital stay during the 2009-10 pandemic.

  • Further work is needed to investigate the optimal timing for NAI

treatment from symptom onset, duration of treatment, dosing schedule and use of combination NAI regimens in relation to severe influenza

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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PRIDE Study Consortium members

  • Dr. Abdullah Al Mamun et al.
  • Dr. Ahmadreza Moradi et al.
  • Dr. Alejandro H. Rodriguez /SEMICYUC
  • Dr. Allison McGeer et al.
  • Dr. Anjarath Lorena Higuera Iglesias et al.
  • Dr. Anna Seale et al.
  • Dr. Annelies van Zwol et al.
  • Dr. Arthur Kwan et al.
  • Dr. Auksė Mickienė et al.
  • Dr. Barbara Bertisch et al.
  • Dr. Barbara Rath et al.
  • Dr. Bin Cao et al.
  • Dr. Bin Du et al.
  • Prof. Bojana Beović et al.
  • Dr. Bunyamin Sertogullarindan et al.
  • Dr. Carlos Bantar et al.
  • Dr. Catia Cilloniz Campos et al.
  • Dr. Dashti-Khavidaki et al.
  • Dr. Dat Tran et al.
  • Prof. Dragan Mikić et al.
  • Dr. Eduard Langenegger et al.
  • Dr. Dr Eduardo Azziz-Baumgartner
  • Dr. Elena Beatriz Sarrouf et al.
  • Dr. Elga Mayo Montero et al.
  • Dr. Elvira Čeljuska-Tošev et al.
  • Dr. Ewa Talarek et al.
  • Prof. Fang Gao Smith et al.
  • Dr. Faris Madanat et al.
  • Prof. Fernando P. Polack et al.
  • Dr. Frank Stephan et al.
  • Dr. Gal Dubnov-Raz et al.
  • Dr. Gerben Keijzers et al.
  • Dr. Gokhan Metan et al.
  • Prof. Heinz Burgmann et al.
  • Prof. Idriss Lahlou Amine et al.
  • Dr. Isabelle Bonmarin /InVS
  • Dr. Jethro Herberg et al.
  • Dr. Joanna Skręt-Magierło et al.
  • Prof. Jonathan Nguyen-Van-Tam /FLUCIN
  • Dr. Jordi Carratalà /REIPI
  • Dr. Julian W. Tang et al.
  • Dr. Julie Bettinger et al.
  • Dr. Justin Denholm et al.
  • Dr. Kelvin To et al.
  • Dr. Kristin Mohn et al.
  • Dr. Kusznierz Gabriela et al.
  • Prof. Lankarani et al.
  • Assoc. Prof. Leo Yee Sin et al.
  • Lic. Clarisa Báez et al.
  • Dr. Maddalena Gianella et al.
  • Dr. Marcela Echavarría et al.
  • Dr. Marian Knight et al.
  • Dr. Matteo Bassetti et al.
  • Dr. Mehpare Özkan et al.
  • Dr. Mical Paul et al.
  • Dr. Mirela Foresti Jiménez et al.
  • Prof. P. Nymadawa et al.
  • Dr. Patrick Gérardin et al.
  • Dr. Paul Zarogoulidis et al.
  • Dr. Péricles A. D. Duarte et al.
  • Prof. Peter Höger et al.
  • Dr. Renata Yokota et al.
  • Prof. Robert Booy et al.
  • Dr. Rita Linko et al.
  • Dr. Samir Refay et al., MoH, Egypt
  • Dr. Samuel Dominguez et al.
  • Dr. Selda Hançerli Törün et al.
  • Dr. Sergio Fanella et al.
  • Dr. Sophie Gubbels et al.
  • Prof. Quazi Tarikul Islam et al.
  • Dr. Tariq Al Khuwaitir et al.
  • Dr. Tim Uyeki / NHLBI ARDS Network
  • Dr. Tim Uyeki / PALISI Network
  • Dr. Thiago Moreno L. Souza et al.
  • Dr. Tjasa Vidmar et al.
  • Dr. Toshie Manabe et al.
  • Dr. C. B. Tripathi et al.
  • Dr. Victor Hugo Borja Aburto /IMSS
  • Dr. Wei Cui et al.
  • Prof. Zhancheng Gao et al.
  • Prof. Ziad Memish et al., MoH, Saudi Arabia

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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For more information about the PRIDE STUDY:

http://www.nottingham.ac.uk/research/groups/healthprotection /projects/pride.aspx

Email : stella.muthuri@nottingham.ac.uk puja.myles@nottingham.ac.uk

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THANK YOU!

The Fifth ESWI Influenza Conference , Riga, 17th September 2014

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Study flow diagram: Influenza related pneumonia

1/21/2015 XV International Symposium on Respiratory Viral Infections, Rotterdam, 15th March, 2013

Hospitalised patients with NAI status known; 78 studies, n=29,259

Exclude 8 datasets with no info on pneumonia status, n= 8,878

70 studies (NAI status known & pneumonia info

  • n), n=20,381

Radiological evidence of pneumonia, n= 7,967 (27%) Pneumonia, n=4,521 No pneumonia, n=3,446 Clinical evidence of pneumonia, n=8,589 (29%) Pneumonia, n=6847 No pneumonia, n=2708

Exclude pneumonia status unknown, n= 3,825