Appendix 1 (as supplied by the authors): Additional background … · Appendix 1 (as supplied by the authors): Additional background and results for a study of effectiveness and cost-effectiveness

Appendix to: Drolet M, Zhou Z, Sauvageau C, et al. Effectiveness and cost‐effectiveness of vaccination against herpes zoster in Canada: a modelling study. CMAJ 2019. DOI:10.1503/cmaj.190274. Copyright © 2019 Joule Inc. or its licensors

Appendix 1 (as supplied by the authors): Additional background and results for a study of effectiveness and cost-effectiveness of vaccination against herpes zoster

Table A1. Description of the 6 different functions of waning efficacy over time

Waning functions Equations

Linear VEi = β1 – β2 yearsi

Logarithmic VEi = β1 – β2 log(yearsi)

Power VEi = e–β1 yearsi

–β2

1-Power VEi = 1 – (e–β1 yearsi

β2)

Exponential VEi = β1e–β2yearsi

1-Exponential VEi = 1 – (β1eβ2yearsi)


Table A2. Parameters varied in sensitivity analysis of proportion of the burden among immunocompetent adults and for ophthalmic herpes zoster

Min Max References

Herpes zoster among immunocompetent adults

RR of HZ among immunocompetent

45 to 54 yrs old 91% 96%

Yawn 20071, Drolet 20102, Gialloreti 20103 55 to 64 yrs old 87% 97%

65 to 74 yrs old 87% 98%

75+ yrs old 91% 98%

RR of PHN among immunocompetent

45 to 54 yrs old 87% 98%

Drolet 20102, Gialloreti 20103 55 to 64 yrs old 84% 89%

65 to 74 yrs old 84% 96%

75+ yrs old 90% 100%

RR of hospitalization* among immunocompetent

Lin 20004, Brisson 20035

45 to 54 yrs old 69% 92%

55 to 64 yrs old 69% 92%

65 to 74 yrs old 69% 92%

75+ yrs old 69% 92%

RR of death among immunocompetent

Edmunds 20016, Brisson 2008 7 §

45 to 54 yrs old 100% 100%

55 to 64 yrs old 100% 100%

65 to 74 yrs old 100% 100%

75+ yrs old 100% 100%

Ophthalmic herpes zoster

% Ophthalmic herpes zoster 5% 25% Drolet 20102, Harpaz 20088, Cohen 20159, Lin 20004, Borkar 201310

Min: Minimum values identified in literature; Max: Maximum values identified in literature; RR: Relative Risk * Underlying conditions of immune suppression excluded: HIV, leukemia, other malignancies, other blood dyscrasia,

childhood immunodeficiency, pregnancy, radio/chemo/immunotherapy § The mortality rate used in the initial model already excluded conditions of immunosuppression Definitions of immunosuppression condition used in the different articles:

Yawn et al.15: Blood or solid malignancy in the 6 months before herpes zoster; hematopoietic cell transplant/solid organ transplant in the 12 months before herpes zoster; Low CD4 count or history of AIDS-related condition; autoimmune disease currently active and under therapy; long-term corticosteroids > 5mg/d in the 6 months before herpes zoster

Gialloreti et al.3: immunosuppressive or immunomodulating drugs for a period of more than 3 months, and those who had been given the following ICD9-CM codes indicative of immunodeficiency; 042 (HIV), 140-171, 174-208, and 235-239 (malignancies), 279 (congenital immunodeficiency) and V42 (organ or tissue replaced by transplant).

Drolet et al.2: taking oral corticosteroids at high dose (≥20 mg/d of prednisone or equivalent for an extended period); having invasive cancer or HIV/AIDS; currently receiving or having recently received cytotoxic or immunosuppressive treatment for cancer, organ transplant, or other (specify if other).

Lin et al.4 (underlying condition): HIV, leukemia, other malignancies, other blood dyscrasia, childhood immunodeficiencies, pregnancy, radio/chemo/ immunotherapy.


Table A3. Cost ($) per QALY gained comparing vaccination with the Live attenuated zoster vaccine or the Recombinant subunit vaccine to no vaccination (discount rate=3%)

Age at

vaccination/

Vaccine cost

Live attenuated zoster vaccine (LZV)

Percentiles of 30,000 model predictions

Recombinant subunit zoster vaccine (RZV)


5th 25th Median 75th 95th 5th 25th Median 75th 95th

50 yrs old

$100 CS CS 45 022 124 368 187 960 CS CS CS 39 074 185 908

$120 CS 3 537 61 145 158 733 238 030 CS CS 4 058 53 457 236 021

$140 CS 8 748 78 412 193 244 287 946 CS CS 9 381 67 865 287 163

$160 2 550 14 050 95 690 227 782 338 275 CS 3 026 14 962 82 456 337 790 $180 6 815 19 488 113 230 262 181 388 350 CS 7 020 20 450 97 039 387 996

$200 10 979 24 939 130 587 296 714 438 604 3 633 11 031 25 881 111 571 438 928

60 yrs old

$100 CS CS 15 803 31 270 49 794 CS CS CS 1 756 34 677

$120 CS 2 424 23 476 42 471 65 752 CS CS CS 6 795 47 433

$140 CS 6 867 31 246 53 658 81 914 CS CS 404 11 830 60 185 $160 1 407 11 437 39 008 64 879 98 343 CS CS 3 899 16 920 72 748

$180 5 247 16 039 46 891 76 176 114 587 CS 1 222 7 409 22 021 85 490

$200 8 931 20 711 54 756 87 414 130 866 CS 4 303 10 951 27 164 98 133

65 yrs old

$100 CS CS 6 711 13 341 21 890 CS CS CS CS 10 924

$120 CS 677 12 732 20 365 31 105 CS CS CS CS 17 307

$140 CS 4 798 18 678 27 486 40 406 CS CS CS 2 051 23 727 $160 CS 8 904 24 600 34 605 49 903 CS CS CS 5 433 30 285

$180 3 471 13 093 30 468 41 753 59 338 CS CS 2 341 8 875 36 828

$200 7 048 17 253 36 335 48 963 68 976 CS 345 5 278 12 426 43 491

70 yrs old

$100 CS CS 5 329 11 000 17 696 CS CS CS CS 5 617

$120 CS 2 411 11 597 18 021 25 787 CS CS CS CS 11 162 $140 CS 7 203 17 905 25 070 34 113 CS CS CS 493 16 675

$160 1 487 12 014 24 145 32 177 42 573 CS CS CS 3 729 22 262

$180 5 666 16 746 30 334 39 374 51 071 CS CS 1 204 7 027 27 898

$200 9 751 21 502 36 566 46 584 59 635 CS CS 4 225 10 409 33 529

75 yrs old

$100 CS CS CS 5 020 13 331 CS CS CS CS CS

$120 CS CS 5 150 12 124 21 589 CS CS CS CS 1 181 $140 CS 3 654 11 558 19 400 30 062 CS CS CS CS 5 978

$160 CS 9 492 18 000 26 733 38 727 CS CS CS 197 10 899

$180 2 601 15 189 24 482 34 104 47 490 CS CS CS 3 830 15 976

$200 7 581 20 863 31 066 41 550 56 368 CS CS 781 7 466 21 072


Age at

vaccination/

Vaccine cost






80 yrs old

$100 CS CS 6 863 13 656 23 507 CS CS CS CS 128

$120 CS 7 255 14 939 22 709 34 194 CS CS CS CS 5 412

$140 2 852 14 684 23 049 31 852 45 069 CS CS CS 1 515 10 951 $160 9 504 21 993 31 194 41 072 56 103 CS CS CS 5 923 16 641

$180 15 982 29 202 39 380 50 435 67 269 CS CS 3 688 10 392 22 444

$200 22 322 36 507 47 524 59 823 78 606 CS 1 069 7 757 14 895 28 363

85 yrs old

$100 CS 11 119 18 948 27 124 40 098 CS CS CS CS 5 680

$120 8 769 20 673 29 490 39 033 54 403 CS CS CS 3 566 12 169 $140 17 523 30 198 40 086 51 151 69 046 CS CS 2 867 9 120 18 933

$160 25 944 39 639 50 717 63 344 83 878 CS 1 455 8 017 14 748 25 780

$180 34 159 49 057 61 337 75 529 98 890 CS 6 359 13 184 20 495 32 878

$200 42 196 58 391 71 943 87 857 113 915 841 11 183 18 360 26 256 39 904

CS: cost-saving; QALY: Quality-adjusted Life-years


Table A4. Cost ($) per QALY gained: Sensitivity analysis of epidemiological and economic parameters (vaccination vs no vaccination, vaccine cost=140$, age at vaccination=65 years old, discount rate=3%)

Parameters varied






Main analysis CS 4 798 18 678 27 486 40 406 CS CS CS 2 051 23 727

Sensitivity analysis

Epidemiological

Proportion PHN

Min CS 8 238 26 743 38 151 53 677 CS CS CS 4 627 32 907

Max CS 2 573 13 959 20 597 30 055 CS CS CS 355 17 251

QALYs lost to PHN

Min CS 6 316 26 176 38 163 51 802 CS CS CS 2 759 32 488

Max CS 3 816 14 842 20 754 27 759 CS CS CS 1 669 17 081

HZ incidence

Min 1 960 10 850 27 248 37 198 52 476 CS CS 856 6 831 32 008

Max CS 327 12 746 20 309 30 435 CS CS CS CS 17 174

Hospitalizations

Min 5 379 11 626 24 095 32 362 45 705 CS CS 2 923 7 531 27 214

Max CS CS 13 087 22 752 35 297 CS CS CS CS 20 170

Immunocompetent

Min 5 831 14 581 31 980 43 557 61 301 CS CS 3 762 10 042 38 389

Max CS 6 782 21 306 30 644 44 516 CS CS CS 3 640 26 593

Economic

Treatment/PHN episode

Min CS 7 785 21 662 30 693 44 217 CS CS CS 4 808 27 176

Max CS 1 014 15 196 23 606 35 817 CS CS CS CS 19 666

Hospitalizations

Min 4 298 10 391 23 315 31 639 44 884 CS CS 1 867 6 567 26 877

Max CS CS 13 476 22 912 35 353 CS CS CS CS 20 343

Consultations

Min CS 6 271 20 621 29 549 42 903 CS CS CS 3 433 25 983

Max CS 2 024 15 231 23 565 35 295 CS CS CS CS 19 513

Treatment/HZ episode

Min CS 6 752 20 570 29 529 42 965 CS CS CS 4 430 26 698

Max CS 2 487 16 485 25 161 37 532 CS CS CS 105 20 559

Discount rate

0% CS CS 8 920 18 220 28 650 CS CS CS CS 17 412

5% 2 165 11 367 25 558 34 642 49 269 CS CS 789 6 564 28 203

CS: cost-saving; HZ: Herpes zoster; PHN: Post-herpetic neuralgia; QALY: Quality-adjusted Life-years


Table A5. Cost ($) per QALY gained: Sensitivity analysis of epidemiological and economic parameters (vaccination vs no vaccination, vaccine cost=200$, age at vaccination=65 years old, discount rate=3%)

Parameters varied


Percentiles of 30 000 model predictions

Recombinant subunit zoster vaccine

Percentiles of 30 000 model predictions


Main analysis 7 048 17 253 36 335 48 963 68 976 CS 345 5 278 12 426 43 491

Sensitivity analysis

Epidemiological

Proportion PHN

Min 11 254 23 981 49 846 65 705 89 462 CS 2 559 8 752 17 912 57 957

Max 4 363 12 716 28 477 37 833 52 657 CS CS 2 980 8 817 32 977

QALYs lost PHN

Min 9 143 22 330 51 371 67 593 86 787 CS 388 6 904 16 185 58 671

Max 5 525 13 504 29 074 36 761 46 495 CS 240 4 241 9 738 30 884

HZ incidence

Min 14 850 25 921 48 564 62 976 86 431 CS 6 278 11 496 19 585 55 514

Max 1 723 10 807 27 967 38 544 54 544 CS CS 771 6 947 33 945

Hospitalizations

Min 15 559 24 438 41 706 54 050 74 201 3 633 7 927 11 851 18 438 47 230

Max CS 9 870 30 841 44 091 63 363 CS CS CS 6 294 39 748

Immunocompetent

Min 18 871 30 671 54 740 71 653 98 353 3 366 9 594 15 021 23 862 64 545

Max 9 520 19 914 39 923 53 354 74 765 CS 2 318 7 274 14 703 47 631

Economic

Treatment/PHN episode

Min 10 105 20 268 39 291 52 221 72 752 CS 3 325 8 194 15 377 46 972

Max 3 522 13 426 32 879 45 075 64 270 CS CS 1 684 8 661 39 489

Hospitalizations

Min 14 502 23 250 41 005 53 319 73 537 2 483 6 852 10 795 17 414 46 787

Max CS 10 061 31 195 44 276 63 722 CS CS CS 6 313 39 979

Consultations

Min 8 435 18 734 38 225 51 176 71 491 CS 1 775 6 700 13 961 45 903

Max 4 545 14 374 32 941 45 037 63 807 CS CS 2 607 9 498 39 290

Treatment/HZ episode

Min 8 899 19 286 38 177 51 094 71 388 CS 2 889 7 754 15 008 46 629

Max 5 004 14 871 34 196 46 601 65 719 CS CS 2 401 9 397 40 379

Discount rate

0% CS 4 903 22 129 34 972 51 093 CS CS CS 3 704 33 769

5% 15 205 27 046 46 443 59 904 82 158 67 6 520 11 707 19 445 50 352

CS: cost-saving; HZ: Herpes zoster; PHN: Post-herpetic neuralgia; QALY: Quality-adjusted Life-years


Figure A1. Flow diagram of the model

HZ: Herpes zoster; PHN: Post-herpetic neuralgia


Figure A2. Calibration results of the predicted vaccine efficacy to vaccine efficacy from randomized clinical trials for the Live attenuated zoster vaccine (LZV) and Recombinant subunit zoster vaccine (RZV)

A) Efficacy against herpes zoster by age B) Efficacy against herpes zoster over time since vaccination*

C) Efficacy against post-herpetic neuralgia by age

&: Fitted vaccine efficacy using methods developed by Brisson 20087 and Bilcke 201211; 6 functions were used (Linear 1-Exponential Power Exponential Log 1-Power); For LZV, vaccine efficacy against post-herpetic neuralgia was estimated to be higher than vaccine efficacy against herpes zoster (for individuals older than 70 years old (as in Brisson et al). For RZV, the trials did not show any significant difference in vaccine efficacy against herpes zoster and post-herpetic neuralgia and therefore we assumed that both initial vaccine efficacy and waning efficacy were the same for both herpes zoster and post-herpetic neuralgia endpoints. * Efficacy data over time obtained from randomized trials (adults ≥ 70 years old for RZV12 and adults ≥ 60 years old for LZV13)


Figure A3. Cost-effectiveness acceptability curve of vaccinating adults aged 65 years against herpes zoster (assuming vaccine cost of $140 and $200) QALY: Quality-adjusted Life-years; Results from the 30,000 simulations; Vaccine costs are for the complete series


Figure A4. Cost difference between the Recombinant subunit zoster vaccine (RZV) and the Live Attenuated zoster vaccine (LZV) to consider RZV as a cost-effective intervention at the $45 000/QALY gained threshold compared to LZV

Boxplots represents the 5th, 25th, 50th, 75th, and 95th percentiles taken from the 30,000 simulations results.


Figure A5. Sensitivity analysis: Cost ($) per QALY gained of vaccination with the Recombinant subunit zoster vaccine (RZV) and the Live attenuated zoster vaccine (LZV) vs no vaccination, by vaccine cost (complete series) and waning function (for adults aged 65 years).

QALY: Quality-adjusted Life-years Boxplots represents the 5th, 25th, 50th, 75th, and 95th percentiles taken from the 30,000 simulations results Predictions by age groups are presented for vaccine costs (complete series) varying from $100 to $200


REFERENCES

1. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the

incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc.

2007;82:1341-9.

2. Drolet M, Brisson M, Schmader KE, et al. The impact of herpes zoster and postherpetic neuralgia on

health-related quality of life: a prospective study. CMAJ. 2010;182:1731-6.

3. Gialloreti LE, Merito M, Pezzotti P, et al. Epidemiology and economic burden of herpes zoster and

post-herpetic neuralgia in Italy: a retrospective, population-based study. BMC infectious diseases.

2010;10:230.

4. Lin F, Hadler JL. Epidemiology of primary varicella and herpes zoster hospitalizations: the pre-

varicella vaccine era. J Infect Dis. 2000;181:1897-905.

5. Brisson M, Edmunds WJ. Epidemiology of Varicella-Zoster Virus in England and Wales. J Med Virol.

2003;70 Suppl 1:S9-14.

6. Edmunds WJ, Brisson M, Rose JD. The epidemiology of herpes zoster and potential cost-effectiveness

of vaccination in England and Wales. Vaccine. 2001;19:3076-90.

7. Brisson M, Pellissier JM, Camden S, Quach C, De Wals P. The potential cost-effectiveness of

vaccination against herpes zoster and post-herpetic neuralgia. Hum Vaccin. 2008;4:238-45.

8. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the

Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57:1-30; quiz CE2-4.

9. Cohen EJ. Management and Prevention of Herpes Zoster Ocular Disease. Cornea. 2015;34 Suppl 10:S3-

8.

10. Borkar DS, Tham VM, Esterberg E, et al. Incidence of herpes zoster ophthalmicus: results from the

Pacific Ocular Inflammation Study. Ophthalmology. 2013;120:451-6.

11. Bilcke J, Ogunjimi B, Hulstaert F, Van Damme P, Hens N, Beutels P. Estimating the age-specific

duration of herpes zoster vaccine protection: a matter of model choice? Vaccine. 2012;30:2795-800.

12. Cunningham AL, Lal H, Kovac M, et al. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70

Years of Age or Older. N Engl J Med. 2016;375:1019-32.

13. Merck. Zoster vaccine live (Oka/Merck) Zostavax. FDA clinical briefing document for Merck and Co.;

Available at

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.177.2250&rep=rep1&type=pdf. Accessed

June 10 2019. 2005.

Documents

Appendix 1 (as supplied by the authors): Additional background … · Appendix 1 (as supplied by the authors): Additional background and results for a study of effectiveness and cost-effectiveness