Human papillomavirus (HPV) vaccines have been shown to generate robust and sustained antibody responses and to prevent incident cervical infections in immunocompetent girls and women.1 As a consequence, reduction in precancerous cervical disease has also been observed among trial participants2,3 and in the general population of women postimplementation of population level vaccine programs.4 Although HPV and cervical cancer disproportionately affect women living with HIV5 and the World Health Organization recommends HPV vaccination in persons living with HIV,6 HPV vaccination data are very limited in females living with HIV in general and in girls in particular.
MATERIALS AND METHODS
This is a substudy of an open label, multicenter Canadian study evaluating the immunogenicity and safety of the qHPV vaccine (GARDASIL®; Merck and Co., Inc., Whitehouse Station, NJ), presenting the data on 35 girls living with HIV (9–13 years of age). Recruitment for the main study7 spanned November 2008 until December 2012 and enrolled 4420 women and girls living with HIV; data collection continues via a long-term follow-up study. This study was registered via the International Standard Registered Clinical/soCial sTudy Number (ISCTRN) trial registry (ISRCTN33674451).
The University of British Columbia Clinical Research Ethics Board provided ethical approval for local site and national study coordination (approval H08-00997); each of the 5 pediatric clinical sites obtained local approval.
Inclusion criteria for the overall study were: HIV positivity, age ≥ 9 years, not pregnant, willing to avoid pregnancy for the duration of the vaccination series and having a cervix. Exclusion criteria were: having an allergy to the vaccine or its components, history of receiving any HPV vaccine, current enrolment in a clinical trial using an investigational vaccine or drug and/or any condition deemed exclusionary by site investigator.
As it was not ethical to utilize a placebo arm, individual patient HPV serologic data from the 3-dose arm of a Canadian randomized controlled trial of 2 versus 3 doses of qHPV vaccine in girls without HIV, 9–13 years of age, were used as a comparator population.8 The same laboratory and methodology was used for HPV serology in both studies.
Baseline data were collected and participants were scheduled for 3 doses of qHPV vaccine intramuscularly at months 0/2/6. Adverse event (AE) data after each dose of vaccine were collected via telephone follow-up at 48 hours and participant completion of 30-day study diaries. Subjects were followed for 24 months with 8 planned study visits (−3/0/2/6/7/12/18/24 months). Serum concentrations of antibodies to HPV 6, 11, 16 and 18 were determined at each study visit using the Merck cLIA assay. Serotype-specific cut-offs for positivity were set as per licensure standards.9,10
The primary outcome was the seroconversion rate of HPV antibody for the 4 vaccine serotypes in girls living with HIV 9–13 years of age at month 7 (1 month postseries completion). Secondary outcomes included geometric mean titer (GMT) antibody responses at months 7 and 24.
GMTs and 95% confidence intervals were calculated by exponentiating the mean and confidence limits of the logarithm of the titer values. We compared baseline demographic characteristics between our cohort of girls living with HIV and the comparator cohort of girls without HIV, using Wilcoxon rank sum tests, χ2 tests or Fisher exact test, as appropriate. Linear regression models of log antibody levels were used to compare age-adjusted GMT ratios between the 2 cohorts of girls. Among girls living with HIV, we explored the relationship between clinical factors and antibody response at month 7 using linear regression. All statistical analyses were conducted in SAS 9.4 (Cary, NC).
Of 35 girls living with HIV, 33 received 3 doses of vaccine as per protocol (1 received 2 doses and 1 received 1 dose); 32 had month 7 serology data available. All but one study participant (97%) had acquired HIV perinatally, 24 (75%) were on antiretroviral therapy and 59% had a HIV viral load (VL) of <50 copies/ml at the time of first vaccine dose. Median and interquartile range nadir and baseline CD4 counts were 442 cells/mm3 (interquartile range, 246–594 cells/mm3) and 692 cells/mm3 (547–929 cells/mm3), respectively. Girls living with HIV were slightly younger and were predominantly Black, whereas the comparator girls were almost exclusively White (Table, Supplemental Digital Content 1, https://links.lww.com/INF/C908).
Of 32 girls living with HIV who received vaccine according to protocol and had antibody data at month 7, 31 were seronegative to all 4 HPV serotypes at baseline; 1 was seropositive for HPV 18. The majority (99%) of 252 girls without HIV used as comparators were also seronegative to all 4 serotypes at baseline: 2 of 252 (0.8%) were seropositive for HPV 6 and 1 of 252 (0.4%) was seropositive for both HPV 11 and HPV 16.
All girls living with HIV who were initially seronegative to an HPV serotype demonstrated seroconversion to all HPV serotypes at month 7. By month 24, among 26 patients with samples, the proportion maintaining seropositivity declined to 88.5%, 84.6% and 72.0% for serotypes 6, 11 and 18, respectively; 100% maintained seropositivity for serotype 16. By comparison, at month 24, all comparator girls maintained seropositivity for HPV 6, 11 and 16, and 93.6% (175/187) maintained titers for HPV 18. GMTs were significantly lower in girls living with HIV compared with girls without HIV at both 7 and 24 months (Table 1). This difference was maintained after adjusting for age with linear regression models. We considered the impact of missing data on the magnitude of difference in antibody response at month 24 between girls with HIV (missing 18%) and girls without HIV (missing 26%) and found that the difference between the 2 groups held under a variety of missing data scenarios.
Among girls living with HIV, GMTs for each HPV type were approximately 2- to 3-fold higher at month 7 and 2- to 6-fold higher at month 24 in those with a suppressed HIV VL at the time of initial vaccination compared with those without suppression. These differences were statistically significant for HPV 11, 16 and 18 at month 7, and for HPV 6, 11, and 18 at month 24 (Table, Supplemental Digital Content 2, https://links.lww.com/INF/C909). When compared with girls without HIV, GMTs of girls living with HIV who had a suppressed HIV viral load were significantly lower for HPV 6, 11 and 18 at month 7 and lower for HPV 6, 11 and 16 at month 24 (results not shown). In multivariable models, suppressed HIV VL was associated with higher antibody titers at month 7 for all 4 serotypes, while lower body mass index was associated with higher antibody response for HPV 6 (P = 0.05) and 11 (P = 0.01; Table, Supplemental Digital Content 3, https://links.lww.com/INF/C910).
Forty-nine percent of 35 participants who received at least 1 vaccine dose reported one or more vaccine-related AEs (Table, Supplemental Digital Content 4, https://links.lww.com/INF/C911). Almost half of the study participants reported some type of event, the majority being local injection site reactions. Four severe AEs were reported by 3 participants; none were classified by the study investigators as being attributable to the qHPV vaccine. All AEs were transient and resolved without consequence.
This study demonstrates that the qHPV vaccine was immunogenic, eliciting initial antibody seroconversion in all girls living with HIV 9–13 years of age, but that GMTs were significantly lower in girls living with HIV compared with girls without HIV. The rate of antibody loss and seroreversion was significantly higher in girls living with HIV, and this pattern was most notably observed with HPV 18. These results are consistent with the only other HPV vaccine trial published in children living with HIV under 13 years of age. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1085 trial11 reported high rates of seroconversion (>96%) among 7- to 12-year-old girls and boys living with HIV, but with lower GMTs than in published data for comparator populations not living with HIV. Seventy-two weeks after last vaccination >90% of IMPAACT participants maintained seropositivity for HPV 6, 11 and 16;12 76% remained above the seropositivity cut-off for HPV 18. In most vaccination programs, qHPV vaccination is targeted to be delivered between ages 9–12 years so that protection is achieved before sexual debut. Although an antibody titer value required for protection is unclear, if upwards of 20% of girls living with HIV serorevert within 24 months of vaccination, they may not be protected after initiation of sexual activity.
Long-term follow-up data from IMPAACT P1085 on 14 children living with HIV who received 3 doses of qHPV showed GMT decline of 50%–70%, with 93%, 86%, 86% and 64% continuing to meet seropositive cut-offs for HPV types 6, 11, 16 and 18 respectively at 4–5 years after vaccination. Seropositivity rates were greater, and GMTs were significantly higher, in the P1085 comparator arm of 58 children who received a 4th booster dose of qHPV at 96 weeks.13 Kahn et al,14 measuring qHPV antibodies in women living with HIV, compared GMTs using the cLIA and IgG LIA assay and concluded that lower type 18 titers may be a function of the cLIA assay and may not be reflective of immunogenicity. The relative importance of seropositivity and GMT are unclear as an immune correlate of protection remains unknown. While further assay comparison is warranted, assessments of efficacy will be paramount to understand the impact of lower HPV 18 titers as per cLIA assay. The optimal vaccination approach remains to be determined, but could include early vaccination to elicit an immune response followed by additional dose(s) in later adolescence to boost antibody titers closer to the time of sexual exposure.
As with previous vaccine studies among persons living with HIV,7 lack of HIV virologic suppression at the time of vaccination was associated with lower GMTs. This finding and lack of seroresponse correlation with CD4 count echo the IMPAACT P1085 cohort results. Power to detect differences based on CD4 count may have been limited because of sample size and limited range in CD4 count.
The qHPV vaccine was safe and well tolerated by pediatric participants with no serious vaccine–associated AEs considered by the care provider to be attributable to the qHPV vaccine. Although similar types of AEs were reported, these frequencies were lower than those in a cohort of 501 girls without HIV ages 10–15 years.15
In conclusion, this study demonstrates that the qHPV vaccine is immunogenic in girls living with HIV 9–13 years of age, but with lower peak GMT responses compared with a published cohort of similarly aged girls not living with HIV. Seroreversion was seen in 28% by 2 years after vaccination suggesting relatively rapid waning of antibody titer, which could potentially lead to lack of efficacy in preventing HPV infection by the age of sexual debut. Our results underscore potential differences in HPV vaccine response in girls living with HIV and provide data to support the maintenance of a 3-dose HPV vaccination schedule6 until research supports noninferiority of a 2-dose schedule in this population. Further, these findings highlight the importance of HIV virologic suppression before vaccination to optimize antibody response.
The authors acknowledge and thank all the clinicians and research staff at the clinical sites for their contribution to participant enrollment and follow-up as well as the additional HPV in HIV Study Group members who contributed to this study: Ms. Arezou Azampanah, Dr. Jeff Cohen, Dr. François Coutlée, Dr. Catherine Hankins, Dr. Marianne Harris, Dr. Angela Kaida, Dr. Marina Klein, Dr. Mel Krajden, Dr. Mona Loutfy, Dr. Jessica McAlpine, Dr. Neora Pick, Dr. Sandi Seigel, Dr. Joel Singer, Dr. Fiona Smaill, Dr. Sarah Stone, Ms. Marcie Summers, Dr. Sylvie Trottier, Dr. Dirk van Niekirk, Dr. Julie van Schalkwyk, Dr. Fatima Kakkar, Ms. Laura Vicol, Ms. Melissa Watt, Dr. Wendy Wobeser, Dr. Mark H. Yudin. The authors also thank all the girls and women living with HIV who shared their time, energy and insight while participating in this study.
1. Villa LL, Costa RL, Petta CA, et al.Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005;6:271278.
2. Muñoz N, Kjaer SK, Sigurdsson K, et al.Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst. 2010;102:325339.
3. Ferris D, Samakoses R, Block SL, et al.Long-term study of a quadrivalent human papillomavirus vaccine. Pediatrics. 2014;134:e657e665.
4. Hariri S, Bennett NM, Niccolai LM, et alHPV-IMPACT Working Group. Reduction in HPV 16/18-associated high grade cervical lesions following HPV vaccine introduction in the United States - 2008-2012. Vaccine. 2015;33:16081613.
5. Masur H, Brooks JT, Benson CA, et alNational Institutes of Health; Centers for Disease Control and Prevention; HIV Medicine Association of the Infectious Diseases Society of America. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:13081311.
6. World Health Organization. Human papillomavirus vaccines: WHO position paper, May 2017–Recommendations. Vaccine. 2017;35:57535755.
7. Money DM, Moses E, Blitz S, et alHPV in HIV Study Group. HIV viral suppression results in higher antibody responses in HIV-positive women vaccinated with the quadrivalent human papillomavirus vaccine. Vaccine. 2016;34:47994806.
8. Dobson SR, McNeil S, Dionne M, et al.Immunogenicity
of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA. 2013;309:17931802.
9. Joura EA, Kjaer SK, Wheeler CM, et al.HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine. Vaccine. 2008;26:68446851.
10. Villa LL, Costa RL, Petta CA, et al.High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006;95:14591466.
11. Levin MJ, Moscicki AB, Song LY, et alIMPAACT P1047 Protocol Team. Safety and immunogenicity
of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr. 2010;55:197204.
12. Weinberg A, Song LY, Saah A, et alIMPAACT/PACTG P1047 Team. Humoral, mucosal, and cell-mediated immunity against vaccine and nonvaccine genotypes after administration of quadrivalent human papillomavirus vaccine to HIV-infected children. J Infect Dis. 2012;206:13091318.
13. Levin MJ, Huang S, Moscicki AB, et alIMPAACT P1085 Protocol Team. Four-year persistence of type-specific immunity after quadrivalent human papillomavirus vaccination in HIV-infected children: effect of a fourth dose of vaccine. Vaccine. 2017;35:17121720.
14. Kahn JA, Xu J, Kapogiannis BG, et al.Brief report: antibody responses to quadrivalent HPV vaccination in HIV-infected young women as measured by total IgG and Competitive Luminex Immunoassay. J Acquir Immune Defic Syndr. 2017;75:241245.
15. Block SL, Nolan T, Sattler C, et alProtocol 016 Study Group. Comparison of the immunogenicity
and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics. 2006;118:21352145.