Background
Methods
Identification and Eligibility of Relevant Studies
Inclusion and Exclusion Criteria
Outcomes
Data Extraction
Statistical Analysis
Results
I. Selection of Studies
II. Characteristics of Included Trials and Trial Participants
Koutsky & | Harper | Villa | FUTURE I | FUTURE II | PATRICIA | Muñoz et al [18] | ||||||||
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Phase | III | III | II | III | III | III | III | |||||||
No. of study sites | 16 | 32 | 5 | 62 | 90 | 135 | 38 | |||||||
Countries included | 1 | 3 | 5 | 16 | 13 | 14 | 7 | |||||||
Year of study enrollment | 10/1998-11/1999 | 11/2003-07/2004 | Not reported | 01/2002-03/2003 | 06/2002-05/2003 | 05/2004-06/2005 | 06/2004-04/2005 | |||||||
Funding source | Merck | GlaxoSmithKline | Merck | Merck | Merck | GlaxoSmithKline | Merck | |||||||
Inclusion Criteria
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Age | 16-25 | 15-25 | 16-23 | 16-24 | 15-26 | 15-25 | 24-45 | |||||||
Lifetime no. of sexual partners | ≤ 5 | ≤ 6 | ≤ 4 | ≤ 4 | ≤ 4 | ≤ 6 | No restriction | |||||||
Exclusion Criteria
| Pregnancy, history of abnormal Pap smear | History of abnormal Pap smear, or ablative or excisional treatment of cervix; ongoing treatment for external condylomata; seropositive for HPV 16 or 18; DNA positive for any of 14 HR HPV in past 90 days | Pregnancy, history of abnormal Pap smear | Pregnancy, history of abnormal Pap smear or genital warts | Pregnancy, history of abnormal Pap smear | History of colposcopy, pregnancy, breastfeeding, autoimmune diseases or immunodeficiency | Pregnancy, history of genital warts, present or past cervical disease, immunocompromised | |||||||
Intervention & Comparator
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Vaccine component | HPV 16 VLPs | HPV 16, 18 VLPs | HPV 6, 11, 16, 18 VLPs | HPV 6, 11, 16, 18 VLPs | HPV 6, 11, 16, 18 VLPs | HPV 16, 18 VLPs | HPV 6, 11, 16, 18 VLPs | |||||||
VLP amount (μg) | 40 | 20/20 | 20/40/40/20 | 20/40/40/20 | 20/40/40/20 | 20/20 | 20/40/40/20 | |||||||
Vaccine adjuvant | 225 μg AAHS | AS04 (500 μg/50 μg) | 225 μg AAHS | 225 μg AAHS | 225 μg AAHS | AS04 (500 μg/50 μg) | 225 μg AAHS | |||||||
Comparator | Placebo | Placebo | Placebo | * Placebo/Placebo+Hepatitis B vaccine | Placebo | Hepatitis A vaccine | Placebo | |||||||
Comparator adjuvant | 225 μg AAHS | 500 μg aluminium hydroxide | 225 or 450 μg AAHS | 225 μg AAHS | 225 μg AAHS | 500 μg aluminium hydroxide | 225 μg AAHS | |||||||
Administration schedule | month 0, 2, 6 | month 0, 1, 6 | months 0, 2, 6 | month 0, 2, 6 | month 0, 2, 6 | month 0, 1, 6 | month 0, 2, 6 | |||||||
Clinical Protocol
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Frequency of HPV DNA test | 6 month interval | 6 month interval | 6 month interval | 6 month interval | 6 month interval | 6 month interval | 6 month interval | |||||||
Frequency of cytology test | 6 month interval | 6 month interval | 6 month interval | 6 month interval | 12 month interval | 12 month interval | 6 month interval | |||||||
Length of trial (months) | 41.0 | Initial trial: 27 Follow-up study: 53 | Initial trial: 36 Follow-up study: 60 | 36.0 (mean) | 36.0 (mean) | 39.4 (mean) | 26.4 (mean) | |||||||
Endpoints
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Primary | Persistent HPV 16 infection | Incidence infection with HPV 16, and/or 18. | Combined incidence of HPV 6, 11, 16 and/or 18-associated 6-month persistent infection, CIN1-3, AIS, VIN1-3, VaIN1-3, external genital warts and cervical, vulvar or vaginal cancer. | Incidence of HPV 6, 11, 16, and/or 18-associated genital warts, CIN1-3, VIN1-3, VaIN1-3, AIS, and cervical, vulvar or vaginal cancer | HPV 16 and/or 18-associated CIN 2-3, AIS and cervical cancer | HPV 16/18-associated CIN2+ | Combined incidence of 6-month persistent infection, CIN1-3, VIN1-3, VaIN1-3, AIS, cervical, vulvar or vaginal cancer, and genital warts associated with HPV 6, 11, 16 or 18, or with HPV 16 or 18 alone. | |||||||
Secondary | Transient or persistent HPV 16 infection | Persistent infection with HPV 16, 18 or 16/18; HPV 16/18-associated LSIL, HSIL, CIN1-3 and cancer | Combined incidence of HPV 6, 11, 16 and/or 18-associated CIN1-3, AIS and cancer; Persistent infection, CIN1-3 and AIS associated with HPV 31, 33, 45, 52, 58. | Persistent infection, CIN1-3 and AIS associated with HPV 31, 33, 45, 52, 58 | Persistent infection with HPV 16, 18 or other oncogenic types; HPV 16/18-associated CIN1+; immunogenicity and safety | Combined incidence of 6-month persistent infection, CIN1-3, VIN1-3, VaIN1-3, AIS, cervical, vulvar or vaginal cancer, or genital warts associated with HPV 6 or 11 | ||||||||
Populations for Efficacy Analysis
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Per-protocol population (PPP) | All subjects that received 3 doses of vaccine/placebo; DNA negative for HPV 16 in cervical swab and biopsy from day 1 to month 7; seronegative for HPV 16 on day 1; had no protocol violation; had a month 7 visit within 14-72 days after the third vaccination | All subjects that received 3 doses of vaccine/placebo; DNA negative for 14 HR HPV on day 1; cytologically negative and seronegative for HPV 16 and 18 on day 1; had no protocol violation | All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 6, 11, 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation | All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 6, 11, 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation.† | All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation.† | All subjects that received 3 doses of vaccine/placebo; seronegative to HPV 16 or 18 on day 1; DNA negative to HPV 16 or 18 on day1 and month 6; had normal or low-grade cytology at baseline, had no protocol violation | All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative in cervicovaginal swab and/or biopsy samples for HPV 6, 11, 16 or 18 on day 1; remained DNA negative to the same HPV type(s) through month 7; had no protocol violation; had one or more follow-up visits after month 7 | |||||||
Intention-to-treat (ITT)/Modified Intention-to-treat (MITT) population | MITT2: All subjects that received ≥1 dose of vaccine/placebo. | ITT: All subjects that received ≥1 dose of vaccine/placebo; DNA negative for 14 HR HPV on day 1; had data available for outcome measurement. | MITT: All subjects that received ≥1 dose of vaccine/placebo; seronegative and DNA negative to HPV 6, 11, 16 or 18 on day 1. | ITT: All subjects that had undergone randomization, regardless of their baseline HPV status or evidence of HPV-associated anogenital disease. | ITT: All subjects that had undergone randomization, regardless of their baseline HPV status or evidence of cervical neoplasia | ITT: All subjects that received ≥1 dose of vaccine/placebo; DNA negative to HPV 16 or 18 on day 1; had data available for outcome measurement. | ITT: All subjects that received ≥1 dose of vaccine/placebo; had one or more follow-up visits after day1. | |||||||
Methodological Quality
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Allocation concealment | Adequate | Adequate | Adequate | Adequate | Adequate | Adequate | Adequate | |||||||
Blinding | Adequate | Adequate | Adequate | Adequate | Adequate | Adequate | Adequate | |||||||
Dropout/loss-to-follow-up reported | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |||||||
Expected efficacy (1-RR) | 0.75 | 0.70 | 0.80 | 0.80 | 0.80-0.90 | 0.85 | 0.80 | |||||||
Sample size calculation performed | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |||||||
α = 0.05 (one-sided) | β = 0.10 | α = 0.05 (two-sided) | β = 0.20 | α = 0.05 (two-sided) | β = 0.10 | α = 0.0125 (one-sided) | β = 0.09 | α = 0.02055 (one-sided) | β = 0.10 | α = 0.05 (two-sided) | β = 0.06 | -- | β = 0.13 |
Characteristics, n (%) | Koutsky & Mao et al. § | Harper et al. | Villa et al. | FUTURE I | FUTURE II | PATRICIA | Muñoz et al. | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Vaccine (n = 768) | Control (n = 765) | Vaccine (n = 560) | Control (n = 553) | Vaccine (n = 277) | Control (n = 275) | Vaccine (n = 2723) | Control (n = 2732) | Vaccine (n = 6087) | Control (n = 6080) | Vaccine (n = 9319) | Control (n = 9325) | Vaccine (n = 1911) | Control (n = 1908) | |
Age, mean (SD) | 20.0 (1.6) | 20.1 (1.6) | 20.4 (2.8) | 20.5 (2.7) | 20.2 (1.7) | 20.0 (1.7) | 20.2 (1.8) | 20.3 (1.8) | 20.0 (2.2) | 19.9 (2.1) | 20.0 (3.1) | 20 (3.1) | 34.3 (6.3) | 34.3 (6.3) |
HPV 16 Positivity | ||||||||||||||
DNA | -- | -- | -- | -- | 49 (17.7)†
| 51(18.5)†
| 238 (8.9) | 227 (8.4) | 543 (9.1) | 545 (9.1) | 516 (5.6) | 478 (5.2) | -- | -- |
Serology | 143 (12.0) | 166 (13.9) | -- | -- | 312 (11.5) | 319 (11.7) | 652 (10.7) | 688 (11.3) | 1544 (16.7) | 1552 (16.8) | -- | -- | ||
HPV 18 Positivity | ||||||||||||||
DNA | -- | -- | -- | -- | 17 (6.1)†
| 21 (7.6)†
| 86 (3.2) | 83 (3.1) | 230 (3.8) | 242 (4.0) | 215 (2.3) | 216 (2.3) | -- | -- |
Serology | -- | -- | -- | -- | 93 (3.4) | 90 (3.3) | 227 (3.7) | 236 (3.9) | 1076 (11.7) | 1070 (11.6) | ||||
Lifetime no. of sexual partners | ≤ 5 | ≤ 6 | ≤ 4 | ≤ 4 | ≤ 4 | ≤ 6 | No restriction | |||||||
None | 38 (5) | 34 (4) | 90 (16) | 85 (16) | 17 (6) | 16 (6) | -- | -- | -- | -- | 294 (3)††
| 292 (3)††
| 0 (0) | 2 (0.1) |
One | 218 (28) | 200 (26) | 197 (35) | 188 (35) | 80 (29) | 88 (32) | -- | -- | -- | -- | 5862 (63)††
| 5869 (63)††
| 719 (38) | 751 (39) |
Two/Two to five | 173 (23) | 173 (23) | 259 (46) | 242 (45) | 73 (26) | 75 (27) | -- | -- | -- | -- | 1114 (12)††
| 1161 (13)††
| 385 (20) | 362 (19) |
Three/Three or more | 138 (18) | 131 (17) | -- | -- | 67 (24) | 50 (18) | -- | -- | -- | -- | 636 (7)††
| 595 (6)††
| 229 (12) | 223 (12) |
Four/Four or more | 105 (14) | 144 (19) | -- | -- | 40 (14) | 46 (17) | -- | -- | -- | -- | -- | -- | 142 (7) | 130 (7) |
Five/Five or more | 96 (13) | 83 (11) | 14 (3) | 18 (3) | -- | -- | -- | -- | -- | -- | 433 (23) | 437 (23) | ||
Smoking status | ||||||||||||||
Never smoker | -- | -- | 102 (18) | 85 (16) | -- | -- | -- | -- | -- | -- | 6401 (69)* | 6388 (69)* | 923 (48) | 935 (49) |
Former smoker | -- | -- | 164 (30) | 138 (26) | -- | -- | -- | -- | -- | -- | 2706 (29)* | 2726 (29)* | 159 (8) | 148 (8) |
Current smoker | 183 (24) | 190 (25) | 294 (52) | 310 (58) | -- | -- | 696 (26) | 716 (26) | -- | -- | -- | -- | 339 (18) | 332 (17) |
Chlamydia trachomatis | ||||||||||||||
Negative | -- | -- | -- | -- | -- | -- | 2565 (94) | 2545 (93) | 5723 (94) | 5737 (94) | 8155 (88) | 8188 (88) | -- | -- |
Positive | 24 (3) | 19 (3) | -- | -- | -- | -- | 118 (4) | 135 (5) | 258 (4) | 224 (4) | 478 (5) | 475 (5) | -- | -- |
Contraceptive use | ||||||||||||||
Barrier | -- | -- | -- | -- | 63 (23) | 76 (28) | 872 (32) | 874 (32) | -- | -- | -- | -- | 441 (23) | 425 (22) |
Hormonal | -- | -- | -- | -- | 161 (58) | 157 (57) | 1568 (58) | 1539 (57) | 3613 (60) | 3614 (60) | 5544 (59) | 5662 (61) | 596 (31) | 591 (31) |
Behavioral | -- | -- | -- | -- | 48 (17) | 48 (17) | 487 (18) | 498 (18) | -- | -- | -- | -- | 165 (9) | 184 (10) |
Other | -- | -- | -- | -- | 21 (8) | 17 (6) | 125 (5) | 138 (5) | -- | -- | -- | -- | 748 (39) | 749 (39) |
Cytological status at entry | ||||||||||||||
Normal | 656 (88) | 655 (87) | -- | -- | -- | -- | 2360 (89) | 2326 (88) | 5222 (87) | 5242 (89) | 8395 (90) | 8450 (91) | -- | -- |
Abnormal | 84 (11) | 96 (13) | -- | -- | -- | -- | 288 (11) | 316 (12) | 697 (12) | 654 (11) | 908 (10) | 860 (10) | -- | -- |