A critical review of cost-effectiveness analyses of vaccinating males against human papillomavirus

Figures & data

Table 1. Modeling aspects reviewed in this study

Aspects	Descriptions
Modeling approach	Dynamic vs. static; aggregate level vs. individual level; deterministic vs. stochastic.
Assumption on natural immunity	Susceptible-infectious-susceptible (SIS), susceptible-infectious-recovered (SIR) and susceptible-infectious-recovered-susceptible (SIRS)^1
Model calibration process	Method used for calibration, if any.
Diseases modeled	HPV-related diseases considered in the model.
HPV transmission patterns modeled	Heterosexual or homosexual.
Vaccination and screening strategies assessed	Vaccination strategy (initial vaccination, catch-up vaccination and booster), screening strategy and vaccine coverage rate.
Input parameters	Vaccine characteristics (efficacy, against infection and/or disease, waning function), transition probabilities, costs, utilities and discount rate.

¹ An SIR model assumes that, after recovery from infection, the individual will not be re-infected (i.e., natural immunity) whereas an SIS model assumes the individual can be re-infected immediately after recovery from infection (i.e., no natural immunity). An SIRS model assumes that natural immunity only exists for a period of time following recovery from infection.

Table 2. Items that should accompany the most rigorous model analyses (reproduced with permission from Garnett et al.³⁷)

Aspects	Descriptions
Diagrams that show model structure	To show how disease natural history is presented, process and determinants of disease acquisition, and how putative intervention could affect the system.
Complete list of model parameters	To include clear and precise descriptions of the meaning of each parameter, together with the values or ranges for each, with justification or the primary source cited, and important caveats about the use of these values noted. Where a parameter value comes from another modeling analysis, this caveat should be noted. Parameter values that are fit in this model (not independently measured) should be clearly marked.
Assessment of model predictions with data	Illustration of agreement between model (as used in the analyses) and data or observational information. Clear statement about how model was fitted to the data, including goodness-of-fit measure, the numerical algorithm used, which parameter varied, constraints imposed on parameter values, and starting conditions.
Presentation of results	Key modeling results to be presented with a scientifically based estimate of uncertainty. Presentation of uncertainty analyses should be accompanied with statement about the sources of uncertainties quantified and not quantified, and these sources can include parameter, data, and model structure.
Discussion of model structure	To include the scientific rationale for this choice of model structure and identify points where this choice would influence conclusion drawn. Also to describe the strength of the scientific basis underlying the key model assumptions.

Figure 1. PRISMA diagram.

Table 3. Cost-effectiveness studies of vaccinating males

	Elbasha et al.^40	Elbasha and Dasbach^45	Jit et al.^46	Kim and Goldie^47	Kim^43	Taira et al.^42	Zechmeister et al.^41	Olsen and Jepsen^48	Chesson et al.^49
Country	US	US	UK	US	US	US	Austria	Denmark	US
Modeling approach	Dynamic, aggregate, deterministic	Dynamic, aggregate, deterministic	Dynamic, aggregate, stochastic	Transmission and disease progression were modeled separately. For HPV 16/18 transmission: dynamic, aggregate, stochastic; for disease progression: static, individual-based, stochastic	Static, aggregate, stochastic	Two-part (transmission: dynamic, aggregate, deterministic; disease: static, aggregate, stochastic)	Dynamic, aggregate, deterministic	Agent-based (dynamic, individual, stochastic)	Dynamic, aggregate, deterministic
Diseases included	CC, GW	CC, VAG, VUL, PEN, ANA, H&N, JO/AORRP, GW	CC, GW	CC, VAG, VUL, PEN, ANA, H&N (oropharyngeal), JORRP, GW	ANA, GW	CC	CC	CC, GW	CC, VAG, VUL, PEN, ANA, H&N (oropharyngeal), JORRP, GW
Natural immunity	SIR	SIRS	SIRS	SIR	n/A	SIS	SIS	SIS	SIR
Coverage rate (as for ICER)	70%	F: 7–80% M: 4–48%	80%	75%	50%	70%	65%	70%	75%
Vaccine and booster price	$360	$400	£210 (incl. admin.)	$500	$500	$300; $100 (booster)	€360	€415	$500
Efficacy
Against infection	90%	F: 76–96% M: 41–62%	100%	F: 100%; M: 85%	90%	90%	90%	100%	F: 95%; M: 90%
Against disease outcome	100%	F: 98–100% M: 84–91%	-	F: 100%; M: 90%	90%	-	-	-
Protection duration (years)	Lifetime	32 (half life)	10, 20 or lifetime	Lifetime	Lifetime	10 after booster	10 after booster	Lifetime (?)	Lifetime
Discount rates (for both costs and benefits)	3.0%	3.0%	3.5%	3.0%	3.0%	3.0%	5.0%	3.0%	3.0%
Assessed strategy and ICER	12FM+CU12–24F vs. 12F+CU12–24F $41 803/QALYg ~€22 442/QALYg	9–26FM vs. 9–26F $25 664/QALYg ~€20 541/QALYg	12FM vs. 12F+CU12–25F £520 255/QALYg ~€650 319/QALYg	12FM vs. 12F $90 870/QALYg ~€72 696/QALYg	12M vs. NoVac $15 290/QALYg ~€12 232/QALYg	12FM +B22FM vs. 12F+B22F $422 039/QALYg ~€337 631/QALYg	12FM+B22FM vs. 12F+B22F €311 000/LYg	12FM vs. NoVac €18 677/QALYg	12FM+CU13–26F vs. 12F+CU13–26F $184 270/QALYg ~€147 416/QALYg

CC, cervical cancer; VAG, vaginal cancer; VUL, vulvar cancer; PEN, penile cancer; ANA, anal cancer; H&N, head and neck cancers; JO, juvenile-onset; AO, adult-onset; RRP, recurrent respiratory papillomatosis; GW, genital warts; F, female; M, male; CU, catch-up; B, booster; NoVac, no vaccination; QALYg, QALY gained; LYg, life year gained; SIS, Susceptible-Infectious-Susceptible; SIR, Susceptible-Infectious-Recovered; SIRS, Susceptible-Infectious-Removed-Susceptible. Exchange rate: €1 = $1.25 = £0.80 (as of May 2012)⁴⁴

Figure 2. HPV-related diseases and ICERs. (A) 9–26 FM vs. 9–26F. Reprinted with permission of Elbasha and Dasbach.⁴⁵ (B) 12FM vs. 12F. Reprinted with permission of Kim and Goldie.⁴⁷ For cervical cancer plus genital warts, estimated from the graph in the publication. (C) 12FM+CU13–26F vs. 12F+CU13–26F. Reprinted with permission of Chesson et al.⁴⁹ CC, cervical cancer; VAG, vaginal cancer; VUL, vulvar cancer; PEN, penile cancer; ANA, anal cancer; H&N, head and neck cancers; JORRP, juvenile-onset RRP, recurrent respiratory papillomatosis; GW, genital warts; F, female; M, male; CU, catch-up.

Figure 3. Vaccine coverage rate and ICERs. 12FM+CU13–26F vs. 12F+CU13–26F. Reprinted with permission of Chesson et al.⁴⁹

Table 4. Costs

	Elbasha et al.^40	Elbasha and Dasbach^45	Jit et al.^46	Kim and Goldie^47	Kim^43	Taira et al.^42	Zechmeister et al.^41	Olsen and Jepsen^48	Chesson et al.^49
Perspective	TPP (?)	n/a	TPP	Societal	n/a	n/a	TPP/Societal	TPP	Societal
Currency	USD	USD	GBP	USD	USD	USD	EUR	EUR	USD
Year	2005	2008	2006–7	2006	2006	2001	2007	2007	2008
Vaccine*	360	400	180–241.5	500	500	300 + 100(B)	330	415	500
Administration*			~13.11				30
Screening	Cytology: 99 Colpos.: 165 Colpos. +Biopsy: 318	Cytology: 112 Colpos.: 187	Cytology: 55 Colpos.: 216	Cytology: 32 HPV DNA:49 Colpos.: 364 Biopsy: 53	-	81	27.51	n/a	n/a
CIN 1	1554	1764	332	-	n/a	630 (LSIL)	2778	33	1959
CIN 2	3483	3955		3438		1218 (HSIL)		2676	3642
CIN 3									4135
Cervical cancer	Loc.: 26 470 Reg.: 28 330 Dist.: 45 376	Loc.: 30 059 Reg.: 32 171 Dist.: 51 527	S I: 13 339 S II: 22 386 S III: 21 269 S IV: 22 927	Loc.: 26 540 Reg.: 28 430 Dist.: 45 540	-	S I: 14 979 S II: 21 811 S III: 21 811 S IV: 24 004	S I: 16 536 S II: 26 724 S III: 27 611 S IV: 28 192	24 689	35 693
Other cancers	-	Ranging from 12 380 (loc. vulvar) to 40 463 (head and neck)	-	Ranging from 17 110 (penile) to 37 370 (oral)	31 300 (anal)	-	-	-	Ranging from 18 528 (penile) to 40 463 (oral)
Genital warts	489	♀: 515 ♂: 607	134	430	430	-	-	239	568
RRP	-	214 952	-	62 010	-	-	-	-	137 308

TTP, third-party payer; B, booster; Colpos., colposcopy; CIN, cervical intraepithelial neoplasia; CIS, carcinoma in situ; L/HSIL, low-/high-grade squamous intraepithelial leson; Loc., localized; Reg., regional; Dist., distant; S, stage; mo, months; RRP, recurrent respiratory papillomatosis; JO, juvenile-onset. * For a 3-dose course.

Table 5. Utility

	Elbasha et al.^40	Elbasha and Dasbach^45	Jit et al.^46	Kim and Goldie^47	Kim^43	Taira et al.^42	Zechmeister et al.^41	Olsen and Jepsen^48	Chesson et al.^49
Method	Multiplic.		Additive (?)	Multiplic.	n/a	n/a	Not used – life-years gained only	Multiplic. (?)	QALY loss per case
Baseline utility	Based on data from the US National Health Interview Survey and the Healthy People 2000 study		n/a	US Beaver Dam Study	n/a	US Beaver Dam Study		Unpublished Danish data (method not reported)	Not reported
CIN	CIN 1: 0.91 CIN 2/3: 0.87 CIS: 0.87		CIN 1: 0.012* CIN 2: 0.065* CIN 3: 0.054*	n/a	n/a	SIL: 0.97**		CIN 1: 0.9333 CIN 2/3: 0.8658	CIN 1/2: 0.03/0.07 for 18 mos CIN 3: 0.2 for 4 mos and 0.03 for 2 y
Cervical cancer	Loc.: 0.76 Reg.: 0.67 Dist.: 0.48		S I: 0.35* S II: 0.44* S III: 0.44* S IV: 0.52*	Loc.: 0.76 (over 5 y) Reg.: 0.67 (over 5 y) Dist.: 0.48 (lifetime)	-	S I: 0.79** S II-IV: 0.62**		S I: 0.7598 S II-IV: 0.6693	Loc., reg. and dist. = 0.36, 0.41 and 0.45 for 3 y, followed by death
Cervical cancer survivor	0.76		S I: 0.10* S II: 0.15* S III: 0.15* S IV: 0.38*		-	S I: 0.90** S II-IV: 0.62** Well: 1.00**		n/a	Loc.: 0.27 for 4 mos and then a further 0.07 Reg. and dist.: 0.37/0.45 for 3 y and then a further 0.1/0.24
Other cancers	-	Same as cervical cancer	-	0.68 (lifetime)	0.68 (Anal)	-		-	The same as cervical
Genital warts	0.91 (8.5 mo in average in Elbasha 2010)		0.039*	0.91 (3 mo)	0.91	-		0.9142	Sex-specific, combination of 3 decrements (0.05–0.15) and 2 duration (3 mos and 6 mos)
RRP	-	0.80	-	0.69 (JO, over 4 y)	-	-		-	1.05 QALYs per case

Multiplic, multiplicative; HALex, Health and Activities Limitation Index; QWB, Quality of Well-Being; TTO, time trade-off; CIN, cervical intraepithelial neoplasia; CIS, carcinoma in situ; SIL, squamous intraepithelial lesion; Loc., localized; Reg., regional; Dist., distant; S, stage; mo, months; RRP, recurrent respiratory papillomatosis; JO, juvenile-onset. *Utility decrement. ** Not clear if it is a decrement or a utility weight.

Table 6. Rigor of the studies

Studies	Diagram	Complete list of model parameters (including natural history parameters)	Assessment of model predictions with data (calibration details)	Presentation of results (including sensitivity analyses)*	Discussion of model structure	Quality regarding number of items
Elbasha et al. ^40	Yes	Yes (appendix)	No calibration	Yes One-way SA	No	3/5
Elbasha and Dasbach ^45	Yes	Yes (appendix)	Calibrated but method not reported	Yes PSA	Yes (appendix)	4/5
Jit et al. ^46	No	No	Yes	Yes One-way SA	No	2/5
Kim and Goldie ^47	No	Yes (incomplete)	Yes (in another paper)	Yes One-way SA	No	3/5
Kim ^43	No	No	Not calibrated	No sensitivity analyses	No	0/5
Taira et al. ^42	Yes	No	Calibrated but method not reported	Yes One-way SA	No	2/5
Zechmeister et al. ^41	Yes	Yes	Calibrated but method not reported	Yes	No	3/5
Olsen and Jepsen ^48	Yes (online appendix)	Yes	Calibrated but method not reported	One-way SA but results not shown	No	2/5
Chesson et al. ^49	Yes	Yes (appendix)	No calibration Based on published literatures	Yes	No	3/5

* Sensitivity analyses are conducted for vaccine parameters, cost and utilities. Natural history parameters such as the probability of transmission are not included in sensitivity analyses. Cross-protection has been included in some sensitivity analyses. SA, sensitivity analyses; PSA, probabilistic sensitivity analyses.

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