Modelling the economic value of cross- and sustained-protection in vaccines against cervical cancer

Figures & data

Figure 1. Model structure. CIN, cervical intraepithelial neoplasia; det, detected; HPVlr, human papillomavirus low-risk types; HPVonc, human papillomavirus oncogenic types.

Table 1.  Key model input data by country.

Parameter	France	Ireland	Italy
Transition probabilities
HPV-Onc to CIN 1	0.05^41	0.02^42	0.05^41
HPV-Onc to CIN 2/3	0 (>2 year needed for progression)
HPV-Onc clearance to normal	0.5^43–46	0.5^47–51	0.45^47–51
HPV‐LR clearance to normal	0.5^52	0.5^52	0.5^52
HPV‐LR to GW	0–0.03^53	0–0.26^54–56	0–0.03^53
HPV‐LR to CIN 1	0.04^57,[58]	0.04^57,[58]	0.04^57,[58]
% GW resistant to initial treatment	25%[53]	25%[53]	25%[53]
CIN 1 clearance	0.5^50,[57–59]	0.33^42	0.24^59–61
CIN 1 to CIN 2/3	0.09^59–61	0.09^59–61	0.09^59–61
% CIN 1 detected undergoing treatment	50%[54]	50%[54]	37%[62]
CIN 1 treatment success	95%[57],[63]	95%[57]	90%[64]
% CIN 2/3 detected undergoing treatment	100%[54]	100%[54]	100%[54]
CIN 2/3 treatment success	95%[57],[63]	95%[57]	90%[64]
CIN 2/3 cured	0.23^59,[60]	0.23^59,[60]	0.23^59,[60]
CIN 2/3 to CIN 1	0 (assumed that patients regress to clearance)
CIN 2/3 to persistent CIN 2/3	0.11^59,[60]	0.14^42	0.11^59,[60]
Persistent CIN 2/3 to cancer, annual probability of transition	0–0.3 (assumption)	0–0.3 (assumption)	0–0.06 (assumption)
Cancer to death from CC	7.5%[65–67]	8.5%[67],[68]	8.2%[67]
Cancer cured	20.0%[65]	18.5%[67],[68]	18.9%[65]
Screening effectiveness
CIN 1 detected	0.58^69	0.58^69	0.58^69
CIN 2/3 detected	0.61^69	0.61^69	0.61^69
% positive Pap smear	5%[70],[71]	5%[70],[71]	2.5%[56]
Treatment costs, euros
Regular screening and negative Pap test	48.57^63	140.00^42	13.74^62
Regular screening and positive Pap test	49.78^63	143.72^42	14.86^62
Treatment CIN 1 detected, year 1	270.52^63	507.50^42	296.32^72
Treatment CIN 2/3 detected, year 1	1064.08^63	685.00^42	902.87^72
Treatment CIN 1 detected, year 2	34.56^63	280.00^42	45.14^62
Treatment CIN 2/3 detected, year 2	34.56^63	280.00^42	90.28^62
GW treatment	482.70^53	366.00^73	132.80^74
Cancer stage I–IV treatment (annual costs)	13,508.51^75	18,160.00^42	3,141.52^76
Vaccine cost, (one dose, ex factory price)	90€	115€	90€
Utility: perfect health = 1, death = 0 (disutility score: decrement from 1 to calculate utility)
No HPV	1 (0)	1 (0)	1 (0)
HPV	1 (0)	1 (0)	1 (0)
GW	0.975 (0.025)[77–81]	0.975 (0.025)[77–81]	0.975 (0.025)[77–81]
CIN 1	1 (0)	1 (0)	1 (0)
CIN 1 detected	0.987 (0.013)[77–81]	0.987 (0.013)[77–81]	0.987 (0.013)[77–81]
CIN 2/3	1 (0)	1 (0)	1 (0)
CIN 2/3 detected	0.991 (0.009)[77–81]	0.991 (0.009)[77–81]	0.991 (0.009)[77–81]
Cancer	0.727 (0.273)[77–81]	0.727 (0.273)[77–81]	0.727 (0.273)[77–81]
Cancer cured	0.938 (0.062)[77–81]	0.938 (0.062)[77–81]	0.938 (0.062)[77–81]
Death, or death from CC	0 (1)	0 (1)	0 (1)
HPV presence by lesion type
% HPV‐16/18 in CC	73.6%[82] (European Region)	76.5%[82] (Northern Europe)	71.7%[82] (Italy)
% HPV‐6/11 in GW	76.2%[83]	76.2%[83]	76.2%[83]
% HPV‐16/18 in CIN 1	28.2^82 (European Region)	30.6%[82] (Northern Europe)	28%[82] (Italy)
% HPV‐16/18 in CIN 2/3	58.4%[82] (European Region)	64.2%[82] (Northern Europe)	55%[82] (Italy)
% HPV‐6/11 in CIN 1	2.2%[82] (European Region)	7.3%[82] (Northern Europe)	9%[82] (Italy)
Discount rate, costs/outcomes	3%/1.5%[54]	3.5%/3.5%[54]	3%/3%[54]
Screening	60% screened every 3 years from 25 to 65 years	40% screened every 3 years from 25 to 44 years	64% screened every 3 years from 25 to 60 years
		20% screened at 25, 30, 35 and 40 years

CIN, cervical intraepithelial neoplasia; GW, genital warts; HPV, human papillomavirus; HPV‐LR, human papillomavirus low-risk types, HPV-Onc, human papillomavirus oncogenic types.

Figure 2. Model validation: model output compared with observed data, invasive CC incidence, GW incidence for (a) France, (b) Italy (c) Ireland. CC, cervical cancer; GW, genital warts.

Table 2.  Lifetime modelled number of CC, GW and total costs (€) per 100,000 and per actual 12-year-old age cohort in France, Ireland and Italy pre-vaccination.

	France Per 370,000 (per 100,000) cohort	Ireland Per 30,000 (per 100,000) cohort	Italy Per 280,000 (per 100,000) cohort
CC cases	2703 (730)	191 (635)	1785 (638)
GW cases	31,837 (8605)	1313 (4377)	23,977 (8563)
Costs (€)	315,497,564 (85,269,612)	28,833,270 (96,110,901)	75,732,552 (27,047,340)

CC cervical cancer; GW, genital warts.

Table 3.  Incremental lifetime cost per QALY of vaccine A compared with B in each country (base case).

Country	Vaccine A	Vaccine B	A – B
France
Cost	€334,582,796	€327,223,141	−€7,359,654
QALY	26,479,425	26,479,737	313
ICER per QALY			B dominates A
Cost disc	€177,278,485	€172,541,597	−€4,736,888
QALY disc	16,239,694	16,239,937	243
ICER per QALY			B dominates A
Ireland
Cost	€32,845,682	€32,421,272	−€424,409
QALY	2,074,526	2,074,545	19
ICER per QALY			B dominates A
Cost disc	€20,686,293	€20,412,977	−€273,316
QALY disc	795,593	795,605	12
ICER per QALY			B dominates A
Italy
Cost	€145,341,189	€142,951,812	−€2,389,377
QALY	20,090,940	20,091,413	473
ICER per QALY			B dominates A
Cost disc	€107,932,571	€106,362,980	−€1,569,591
QALY disc	8,370,408	8,370,695	287
ICER per QALY			B dominates A

Disc, discounted; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Figure 3. Cost-effectiveness and dominance frontier for vaccine A compared with vaccine B by cross- and sustained-protection level with and without discounting in France, Ireland and Italy. VacA, vaccine A; X-protection, cross-protection (The dominance and cost effectiveness frontier lines determine the combined level of cross (x axe) and sustained (y axe) protection for vaccine A to dominate vaccine B (dominance frontier) and be cost effective compared with vaccine B (cost effectiveness frontier).

Table 4.  Minimum level of cross- and sustained-protection required alone for vaccine A to be cost-effective compared with vaccine B in each country without and with discounting.

	France	Ireland	Italy
Cost-effectiveness threshold (3 times the GDP per capita/1 time the GDP per capita)	€96,520/32,173	€142,611/47,537	€84,883/28,295
No discount rate
Minimum level of cross-protection (%) with 10 years sustained-protection for both vaccines	15/15%	13/15%	15/16%
Minimum duration of sustained-protection (years before waning begins); with no cross-protection for both vaccines	Never reached the cost-effectiveness threshold	16/17 years	29/32 years
Discounted
Minimum level of cross-protection (%) with 10 years sustained-protection for both vaccines	22/22%	44/48%	41/43%
Minimum duration of sustained-protection (years before waning begins); with no cross-protection for both vaccines	Never reached the cost-effectiveness threshold but cost-saving and lower QALY as of 41 years	Never reached the cost-effectiveness threshold	Never reached the cost-effectiveness threshold but cost-saving and lower QALY as of 18 years

GDP, gross domestic product; QALY, quality-adjusted life-year.

Figure 4. Sensitivity analysis on Italian undiscounted and discounted dominance and cost-effectiveness frontiers. Effect of uncertainty around cervical cancer and genital wart management cost and incidence related parameters under a + and − 50% of base-case value for HPV low-risk and HPVonc oncogenic types incidence, CC costs and GW cost. CC, cervical cancer; GW, genital warts; HPV‐LR, human papillomavirus low risk; HPVonc, human papillomavirus; VacA, vaccine A; X-protection, cross-protection.

Figure 5. Sensitivity analysis on Italian undiscounted and discounted dominance and cost-effectiveness frontiers. Effect of uncertainty on vaccines characteristics related parameters: vaccine type efficacy (VE) of 90% and 100%, booster duration of 10, 30 and 50 years and base-case duration of protection (BC) for vaccine B of 20, 30 and 50 years.

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