Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for HPV Vaccine for Males

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Methods for GRADE: HPV vaccine for Males

Evidence of benefits, harms, values and preferences, and cost-effectiveness were reviewed in accordance with GRADE methods (Ahmed F, et al). The primary policy question was "Should HPV4 be recommended for routine use in 11-12 year old boys." The benefits considered included prevention of genital warts, anal intraepithelial neoplasia (AIN), and anal cancer. The harms considered included serious adverse events (SAE), venous thromboembolism (VTE), syncope, and anaphylaxis.  Data on efficacy were from a randomized clinical trial of HPV4 in males; data on adverse effects were from randomized clinical trials of HPV4 in males and females, and post-licensure studies of HPV4 in females.  Evidence type for each study included a review of study design, risk of bias, inconsistency, indirectness, imprecision, and other considerations.

Recommendation Category A: Recommendation that applies to all persons in an age or risk-based group.  Recommendation Category B:  Recommendation for individual clinical decision making.  Evidence Type 1: Randomized controlled trials, or overwhelming evidence from observational studies. Evidence Type 2: Randomized controlled trials with important limitations, or exceptionally strong evidence from observational studies.  Evidence Type 3:  Observational studies. Evidence Type 4: Clinical experience and observations, observational studies, or randomized controlled trials with notable limitations. Source:  Ahmed F, Temte JL, Campos-Outcalt D, Schünemann HJ; for the ACIP Evidence Based Recommendations Work Group (EBRWG).  Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC).  Vaccine 29(49):9171-6, 2011.

Tables for GRADE: HPV Vaccine for Males

Table 1. Quadrivalent HPV Vaccine for Males: Benefits*

Outcome HPV 6-, 11-, 16-, 18- related	No. subjects (# studies)	Incidence in controls	Incidence in vaccinated	Vaccine efficacy (95% CI)	Risk difference per 1000 (95% CI)	Number needed to vaccinated
Population: Malesa
Genital warts	2798 (1 RCT)	1.99%	0.22%	89.3% (65.3, 97.9)	-18 (-13, -20)	56
Population: MSMb
Genital wartsc	402 (1 RCT)	4.33%	0.51%	88.1 (13.9, 99.7)	-38 (-6, -43)	26
AIN 1/2/3	402 (1 RCT)	11.5%	2.6%	77.5% (39.6, 93.3)	-89 (-46, -107)	11
AIN 2/3	402 (1 RCT)	6.3%	1.5%	74.9% (8.8, 95.5)	-48 (-6, -59)	21
AIN=anal intraepithelial neoplasia CI=confidence interval MSM=men who have sex with men RCT=randomized controlled trial aFollow-up 2.3 years bFollow-up 2.6 years cPersonal Communication, Carlos Sattler MD, August 2011 dFrequently reported as number needed to treat or NNT *Among those who received all 3 vaccine doses and were seronegative at day 1 and DNA-negative day 1 through month 7 to the respective HPV type (per protocol population)

Reference: from Package insert. Vaccine efficacy, risk difference, and number needed to vaccinate calculated with GRADEpro software

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Table 2. Quadrivalent HPV vaccine for Males: Evidence Type of Benefits

Outcome	Design (# studies)	Risk of Bias	Inconsistency	Indirectness	Imprecision	Other Considerations	Evidence Type
Population: Males
Genital warts	RCT (1)	No serious	No serious	No serious	No serious	None	1
Population: MSM
Genital warts	RCT (1)	No serious	No serious	No serious	No serious	None	1
AIN 1/2/3	RCT (1)	No serious	No serious	No seriousb	No serious	None	1
AIN2/3	RCT (1)	No serious	No serious	Yesa,b	No serious	None	2
AIN=anal intraepithelial neoplasia CI=confidence interval MSM=men who have sex with men RCT=randomized controlled trial a AIN2/3 considered anal precancer lesion (surrogate for anal cancer) downgraded by one level  for indirectness b Evidence in MSM available from clinical trial, no reason to suspect vaccine efficacy for boys aged 11-12 years would differ from that observed in MSM, not downgraded for indirectness

Reference:  Package insert Gardasil (quadrivalent human papillomavirus types 6, 11, 16 and 18 HPV)

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Table 3. Quadrivalent HPV Vaccine for Males:  Summary Harms from Prelicensure RCTs in Males and Females

Outcome	No. subjects  (# studies)	Incidence in vaccinated %	Incidence in controls %	Summary risk ratio (95% CI)
Malesa
SAE	4723 (2 RCTs)	0.4%	0.5%	0.88 (0.38, 2.06)
Syncope	4723 (2 RCTs)	0.04%	0.1%	0.50 (0.05, 5.52)
VTE	4723 (2 RCTs)	0	0	NE
Anaphylaxis	4722 (2 RCTs)	0	0	NE
Femalesb
SAE	18,893 (4 RCTs)	1.1%	1.1%	0.97 (0.74, 1.27)
Syncope	18,893 (4 RCTs)	0.2%	0.2%	0.84 (0.45, 1.55)
VTE	18,893 (4 RCTs)	0.03%	0.02%	1.33 (0.30, 5.96)
Anaphylaxis	18,893 (4 RCTs)	0	0.01	0.33 (0.01, 8.20)
NE= non estimable  VTE=venous thromboembolism RCT=randomized controlled trial CI=confidence interval SAE=serious adverse events:  FDA definition including death, hospitalization, life-threatening event, disability, congenital anomaly or birth defect, requiring intervention, or other serious event VTE = deep vein thrombosis, embolism, thrombophlebitis, thrombosis, or thrombophlebitis, superficial aFrom Merck protocols  018 (follow-up 2.5 years), 020 (follow-up 3 years) bFrom Merck protocols 007 (follow-up 3 years), 013 (follow-up 3.7 years), 015 (follow-up 3.7 years), 018 (follow-up 2.5 years) Summary risk ratio calculated using RevMan software, fixed effects

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Table 4. Quadrivalent HPV Vaccine for Males:  Harms from Postlicensure Vaccine Safety Datalink Observational Study in Females

Outcome, age group (yrs)	No. of doses administered	Incidence in vaccinated group (per 10,000 vaccinations)a	Incidence in comparison group (per 10,000 vaccinations)	Relative risk (95% CI)c
Syncopeb
9-18	351,630	17.35	21.72	0.86 (0.72, 1.02)
19-26	150,544	11.29	19.31	0.54 (0.42, 0.75)
VTEb
9-18	292,302	0.274	0.137	1.98d (0.86, 3.94)
19-26	176,194	0.624	0.851	0.73 (0.37, 1.31)
Anaphylaxise
9-26	600,558	0.017	0.015	N/A
VTE=venous thromboembolism CI=confidence interval N/A=not available a For syncope,observed rates presented and risk window was day 0.  For VTE, rates were adjusted by site and age. Risk window included days 1-42 b Comparison group for syncope was concurrent vaccinated group; for VTE was historical comparison group c Relative Risk adjusted by site and age; Simulated confidence intervals at the time upper limit was reached d Confirmed cases of VTE among 9-17 yr olds all had risk factors for VTE (smoking, obesity, oral contraceptive pill use, hypercoaguable disorders) e Comparison group from Bolkhe et al. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics 2003.

Reference: from Gee J, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine.  2011

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Table 5. Quadrivalent HPV Vaccine for Males:  Harms from Postlicensure Manufacturer Observational Study in Females

Outcome	No. of Persons	Incidence in vaccinated group (per 1,000 person years)	Incidence in comparison group (per 1,000 person years)	Relative risk (95% CI)a
Syncope	189,629	24.21	4.04	6.00 (3.91,9.21)b
VTE	189,629	6.32	4.97	1.27 (0.57,2.86)
Allergic reaction or Anaphylactic Shock	189,629	0.16	0.21	0.75 (0.32,1.78)c
VTE=venous thromboembolism CI=confidence interval aRelative risk is approximated by odds ratio, obtained from conditional logistic regression; bFor syncope, the relative risk elevation with lower bound CI greater than 1 suggests that syncope diagnosis codes are more likely to occur on day of vaccination than in self-comparison period; cFor allergic reaction/anaphylactic shock, external Safety Review Committee reviewed medical records of females with day 0 diagnosis codes & found no association between diagnosis & vaccination with quadrivalent HPV vaccine. VTE includes the following ICD-9 codes: 452 Portal vein thrombosis, 453.0 Budd-Chiari syndrome, 453.1 Thrombophlebitis migrans, 453.2 Embolism & thrombosis of inferior vena cava, 453.3 Embolism &  thrombosis of renal vein, 453.4-453.9 Acute and chronic venous embolism & thrombosis of deep or superficial vessels or veins at various sites or unspecified site, V12.51 Personal history of venous thrombosis & embolism. Outcome is defined as presence of diagnosis code in emergency room or hospital setting in vaccination risk period (day of vaccination for syncope & allergic reaction/anaphylactic shock, & 1-60 days after vaccination for VTE) or in post-vaccination self-comparison (i.e., “control”) period.  These codes could represent a new event, a pre-existing condition, a prior history of the condition, a “rule out” diagnosis, miscoding, or a misdiagnosis.  A diagnosis code also does not assume that the diagnosis is confirmed.  No validation of these codes was performed by medical record review.

Reference:  ACIP C. Velicer

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Table 6. Quadrivalent HPV vaccine for Males: Evidence Type of Harms

Outcome	Design (# studies, Sex)	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Evidence type
SAE	RCT (2,M; 4,F)	No serious	No serious	No seriousa	Yesb	None	2
VTE	RCT (2,M; 4,F)	No serious	No serious	No seriousa	Yesb	None	2
	O (2 F)	Yesd	No serious	Yesc	No serious	None	4
Syncope	RCT (2,M; 4,F)	No serious	No serious	No seriousa	Yesb	None	2
	O (2 F)	Yesd	No serious	Yesc	No serious	None	4
Anaphylaxis	RCT (2,M; 4,F)	No serious	No serious	No seriousa	Yesb	None	2
	O (2 F)	Yesd	No serious	Yesc	No serious	None	4
VTE=venous thromboembolism SAE=serious adverse events RCT=randomized controlled trial O=observational study aFemale data indirect, however male data available, not downgraded bRCTs with small sample size, downgraded one level for imprecision cStudies conducted in females, downgraded one level for indirectness dPossible uncontrolled confounding, downgraded one level for risk of bias Summary for Harm: No evidence of increased risk for anaphylaxis, VTE, or SAE from 5 RCTs in males and females (1 RCT in both males and females), and 2 observational studies in females. One of 7 studies found persons who were vaccinated with HPV4 were more likely to faint on the day they were vaccinated than another period in which vaccine was not administered, likely a result of injection-related syncope.

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Table 7. Summary Evidence Type for Benefits, Harms: Quadrivalent HPV Vaccine for Males

Comparison Group	Benefits and Harms	Outcome	Study design (# studies, sex)	Findings	Evidence type	Overall Evidence type b
HPV vaccination versus no HPV vaccination	Benefits	Genital warts	RCT (1,M)	Decreased risk among vaccinated	1	2
		AIN1/2/3	RCT (1,M)	Decreased risk among vaccinated	1	2
		AIN2/3	RCT (1,M)	Decreased risk among vaccinated	2	2
	Harms	SAE	RCT (2,M; 4,F)	No difference	2	2
		Syncope	RCT (2,M; 4,F)	No difference	2	2
		Syncope	O (2, F)	Increased risk among vaccinateda	4	2
		VTE	RCT (2,M; 4,F)	No difference	2	2
		VTE	O (2, F)	No difference	4	2
		Anaphylaxis	RCT (2,M; 4,F)	No difference	2	2
		Anaphylaxis	O (2, F)	No difference	4	2
RCT=randomized controlled trial O=observational study F=female M=male VTE=venous thromboembolism SAE=serious adverse events a One observational study found persons who were vaccinated with HPV4 were more likely to faint on the day they were vaccinated than another period in which vaccine was not administered b Overall evidence type 2 based on evidence from the strongest study design for critical harms and benefits

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Table 8. Considerations for Formulating Recommendations:  Quadrivalent HPV Vaccine for Males

Key factors	Comments
Balance between benefits and harms	Benefits are greater than potential harms
Evidence type for benefits and harms	Evidence Type 2 Benefit Evidence Type 2 Harm RCT Evidence Type 4 Harm O
Value	High value placed by ACIP HPV Work Group on prevention of cancer in males
Cost-effectiveness	HPV4 is most cost-effective if all HPV associated outcomes prevented, vaccine cost lower than current price, female coverage low (such as 30% 3-dose coverage at age 12 years)
RCT=randomized controlled trial O=observational study Summary for Benefits and Harms:  Benefits are greater than potential harms and overall evidence type is 2.  There is high value placed on prevention of cancer in males.  Quadrivalent HPV vaccine is most cost-effective if all HPV associated outcomes are prevented, vaccine cost is lower than current price, or female coverage is low. Recommendation for routine vaccination of males aged 11 or 12 years with HPV4 administered as a 3-dose series (recommendation category A; evidence type 2)

References

1. C Velicer. ACIP Presentation. Post-licensure Safety Study of Quadrivalent Human Papillomavirus Vaccine among 189,629 Females [336 KB, 20 pages] Presented at October 2011 ACIP Meeting.
2. Ahmed F, Temte JL, Campos-Outcalt D, Schünemann HJ, for the ACIP Evidence Based Recommendations Work Group (EBRWG).  Methods for developing evidence-based recommendations by the ACIP of the CDC.  Vaccine 2011;29(49):9171-76.
3. Bohlke K, Davis RL, DeStefano F, Marcy SM, Braun MM, Thompson RS; Vaccine Safety Datalink Team. Epidemiology of anaphylaxis among children and adolescents enrolled in a health maintenance organization. J Allergy Clin Immunol 2004;113:536-42.
4. Chesson HW, Ekwueme DU, Saraiya M, Dunne EF, Markowitz LE. The cost-effectiveness of male HPV vaccination in the United States. Vaccine 2011;29:8443-50.
5. Food and Drug Administration, Product approval information – licensing action, package insert: Gardasil (quadrivalent human papillomavirus types 6, 11, 16 and 18 HPV), Merck & Co.  Whitehouse  Station, NJ:  Food and Drug Administration; 2009.
6. Gee J, Naleway A, Shui I,et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011;29:8279-84.
7. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 2011;364:401-11.
8. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 2011;365:1576-85.