Safety of 4-valent human papillomavirus vaccine in males: a large observational post-marketing study

Figures & data

Figure 1. Day 1–60 male following the dosing schedule^a-c.

Table 1. Summary of the age distribution of 4vhpv vaccine recipients, October 2009 to December 2016.

Age at First Gardasil Dose (Years)	Regimen Initiator Cohort^a			Regimen Completer Cohort^b
	Dose 1	Dose 2	Dose 3	(3 Doses per Protocol)
	(N = 114,035)	(N = 58,552)	(N = 30,150)	(N = 20,693)
9	454	254	128	87
10	1,019	551	298	180
11	14,591	7,908	4,001	2,759
12	14,445	7,352	3,717	2,529
13	13,275	7,027	3,730	2,473
14	14,156	7,735	4,098	2,684
15	12,633	6,931	3,809	2,521
16	12,195	6,453	3,398	2,291
17	11,324	5,774	2,965	2,243
18	8,310	3,728	1,761	1,320
19	3,061	1,263	591	422
20	1,980	785	395	303
21	1,262	537	245	184
22	953	413	188	138
23	857	421	207	172
24	815	415	197	163
25	832	371	147	117
26	622	288	130	107
<9	202	22	10	0
>26	1,049	324	135	0
Total	114,035	58,552	30,150	20,693

^aRegimen Initiators include males any age with at least one dose of 4vHPV vaccine

^bRegimen Completers include males 9-26 years old, completing the 3 dose regimen of 4vHPV vaccine within 12 months with at least (per recommendations) 28 days between doses 1 and 2, 12 weeks between doses 2 and 3, and 24 weeks between doses 1 and 3.

Table 2. Summary of the Incidence Rates (IR) and Relative Rates (RR) for health outcomes significantly increased among 4vhpv vaccine recipients (N = 114,035) (All doses combined).

Abbreviations: ER, emergency room; HCUP, Healthcare Cost and Utilization Project; IR, incidence rate; RR, relative rate; CI, confidence interval; NC, Not calculated

^aIncidence rates per 1,000 person-years.

^bOnly HCUP categories with at least one increased RR (lower confidence limit >1.0) are presented. Results for HCUP categories with a significant decrease are located in Appendix Table A1. Bolded relative rate and confidence interval indicates the interval excludes 1.00. Bolded and highlighted relative rate and confidence interval indicates the double false-discovery rate adjusted p-value remains significant. Multiplicity adjustment limited to HCUP levels 1 and 2.

Table 3. Summary of the Incidence Rates (IR) and Relative Rates (RR) for health outcomes significantly increased among 4vhpv vaccine recipients (N = 114,035) (Dose 1 only).

Abbreviations: ER, emergency room; HCUP, Healthcare Cost and Utilization Project; IR, incidence rate; RR, relative rate; CI, confidence interval; NC, Not calculated ^a Incidence rates per 1,000 person-years.

^bOnly HCUP categories with at least one increased RR (lower confidence limit >1.0) are presented. Results for HCUP categories with a significant decrease are located in Appendix Table 1. Bolded relative rate and confidence interval indicates the interval excludes 1.00. Bolded and highlighted relative rate and confidence interval indicates the double false-discovery rate adjusted p-value remains significant. Multiplicity adjustment limited to HCUP levels 1 and 2.

Table 4. Rate of Venous Thromboembolism (VTE) Outcomes (per 10,000 Person-Years) among 4vhpv vaccine recipients in Risk Period versus Post-Vaccination Self-Control Period by Follow-up Window: All Doses Combined.

VTE Outcome	Risk Period			Self-Comparison Period			Relative Rate (95% CI)
	N Events	Person-Years	Rate	N Events	Person-Years	Rate
Day 1-14	1	7,679	1.3	0	6,824	0.00	.
Day 1-60	5	31,839	1.6	2	27,574	0.7	2.17(0.35–22.74)

Table 5. Rates of Emergent Outpatient, Emergency Room Visit, and Hospitalization Day 0 Outcomes among 4vhpv vaccine recipients and Concurrent Controls with Td/Tdap, Meningococcal, or Influenza Vaccine.

Dose sub-group (N doses)	Acute Event	Gardasil		Concurrent controls
		N Event	Rate^a(95%CI)	N Event	Rate^a(95%CI)
All doses (N = 160,867)^b	Syncope	88	5.47(4.39–6.74)	87	5.41(4.33–6.67)
	Epilepsy, Convulsions	91	5.66(4.55–6.95)	122	7.58(6.30–9.06)
	Head Trauma	126	7.83(6.52–9.33)	124	7.71(6.41–9.19)
	Allergic Reactions	339	21.07(18.89–23.44)	184	11.44(9.84–13.22)
	Total	644	40.03(37.00–43.25)	517	32.14(29.43–35.03)
Dose 1 (N = 109,864^b)	Syncope	85	7.74(6.18–9.57)	61	5.55(4.25–7.13)
	Epilepsy, Convulsions	68	6.19(4.81–7.85)	75	6.83(5.37–8.56)
	Head Trauma	104	9.47(7.73–11.47)	87	7.92(6.34–9.77)
	Allergic Reactions	242	22.03(19.34–24.98)	116	10.56(8.72–12.66)
	Total	499	45.42(41.52–49.59)	339	30.86(27.66–34.32)

a.Rate = Number of events per 10,000 doses.

b.Number of doses matched per comparison group.

Figure A1. 4vhpv doses by month* (2009–2016).

*Each month’s total represents the sum of years 2009-2016.

Table A1. Summary of the Incidence Rates (IR) and Relative Rates (RR) that are significantly decreased among regimen initiators (N = 114,035)^a,b in a risk period compared to a post-vaccination self-comparison period for potential combined ER/Hospital general safety outcomes by analysis category^c.

Abbreviations: ER, emergency room; HCUP, Healthcare Cost and Utilization Project; IR, incidence rate; RR, relative rate; CI, confidence interval.

^aPatient accrual 16-OCT-2009 through 31-DEC-2016.

^bRegimen Initiators include males any age with at least one dose of Gardasil.

^cOnly HCUP categories with at least one increased RR (lower confidence limit >1.0) are presented. Results for all HCUP categories are located in Table Sets 12-15.

^dIncidence rates per 1,000 person-years

^eBolded relative rate and confidence interval indicates the interval excludes 1.00. Bolded and highlighted relative rate and confidence interval indicates the double false discovery rate adjusted p-value remains significant.Multiplicity adjustment limited to HCUP levels 1 and 2.

^fMales with codes for the same HCUP category up to 12 months prior to and including the day of first vaccination in any health care setting (ER, hospitalization or physician office/outpatient) were excluded from the analysis for that HCUP category.

Table A2. Summary of the Incidence Rates (IR) and Relative Rates (RR) that are significantly decreased among regimen initiators (N = 114,035)^a,b in a risk period compared to a post-vaccination self-comparison period for combined potential hospital only general safety outcomes by analysis category^c.

Abbreviations: ER, emergency room; HCUP, Healthcare Cost and Utilization Project; IR, incidence rate; RR, relative rate; CI, confidence interval.

^aPatient Accrual 16-OCT-2009 through 31-DEC-2016.

^bRegimen Initiators include males any age with at least one dose of Gardasil.

^cOnly HCUP categories with at least one decreased RR (lower confidence limit > 1.0) are presented. Results for all HCUP categories are located in Table Sets 16-19.

^dIncidence rates per 1,000 person-years.

^eBolded RR and CI indicates the interval excludes 1.00. Bolded and highlighted RR and CI indicates the double false-discovery rate adjusted p-value remains significant. DFDR adjustment was at level 1 and 2.

^fMales with codes for the same HCUP category up to 12 months prior to and including the day of first vaccination in any healthcare setting (ER, hospitalization or physician office/outpatient) were excluded from the analysis for that HCUP category.