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Immunogenicity and Safety of the Human Papillomavirus 6, 11, 16, 18 Vaccine in HIV-Infected Young Women
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Clinical Infectious Diseases Sept 1 2013
Jessica A. Kahn,1 Jiahong Xu,2 Bill G. Kapogiannis,3 Bret Rudy,4 Rene Gonin,2 Nancy Liu,2 Craig M. Wilson,5
Carol Worrell,3 and Kathleen E. Squires6
1Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Ohio; 2Westat, Inc, and 3Pediatric, Adolescent and
Maternal AIDS Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville,
Maryland; 4New York University School of Medicine, New York; 5School of Public Health, University of Alabama at Birmingham; and 6Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania
"Among 16- to 23-year-old human immunodeficiency virus-infected young women who were human papillomavirus (HPV) DNA and HPV seronegative at the time of vaccination with the quadrivalent HPV vaccine, immune responses to vaccination were generally robust and the vaccine was well tolerated."
"This was a phase 2, open-label, multicenter trial to evaluate the immunogenicity and safety of an HPV-6, -11, -16, -18 vaccine (Gardasil, Merck & Co, Inc, Whitehouse Station, New Jersey) in HIV-infected young women aged 16-23 years, conducted from July 2008 to February 2011. The trial was conducted through the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN); study subjects were recruited from 14 sites in the United States and Puerto Rico......Two groups of young women were recruited. Participants in group A were either naive to antiretroviral therapy (ART) or had not received ART for at least the 6 months prior to study entry (non-ART group), and those in group B had received ART for at least 6 months at the time of study entry, with 2 HIV type 1 (HIV-1) RNA plasma loads <400 copies/mL (ART group)."
"Seroconversion rates were approximately 100%, and immune responses were excellent and associated with high clinical efficacy (98%-100%) for preventing cervical, vaginal, and vulvar lesions associated with vaccine-type HPV [12-17].
However, immune responses to vaccination in HIV-infected individuals are often impaired; this may be due to defective primary immune responses, defects in generation of immunologic memory, or clonal deletion/depletion of memory T and B cells [18-22]. In one published study of immune responses to the quadrivalent HPV vaccine in 7- to 12-year-old children perinatally infected with HIV, seroconversion rates were excellent but immune titers to HPV-6 and HPV-18 were 30%-50% lower than those of controls [23].......
......Data are needed regarding the immunogenicity and safety of HPV vaccines in HIV-infected adolescent and young adult women to inform recommendations for vaccination in these individuals. Therefore, we designed a study to determine (1) the immunogenicity of the HPV-6, -11, -16, -18 vaccine and persistence of the immune response in HIV-infected young women, and (2) whether the HPV-6, -11, -16, -18 vaccine is well tolerated and safe in this population."
"Immune responses at week 28 and week 48 differed by HIV RNA load, but not by CD4, at baseline. Those with an RNA load <400 vs ≥400 had higher GMTs 4 weeks after vaccine dose 3 for all 4 vaccine types, although the differences only reached statistical significance for HPV-11 (P = .03) at 28 weeks.
Seroconversion rates were also higher for those with a viral load <400 vs ≥400, but the differences did not reach statistical significance."
"In this study, we examined the immunogenicity and safety of the quadrivalent HPV vaccine in HIV-infected young women. Immune responses were robust among those who were HPV DNA and HPV seronegative for vaccine-type HPVs at the time of vaccination and received all 3 vaccine doses within specified timeframes. Among HIV-infected young women on ART, GMTs and seroconversion rates did not differ significantly from those of a historical comparison group of HIV-uninfected young women in the same age range. These findings suggest that treatment with ART could have a positive influence on response to vaccination, and provide support for current recommendations of the Advisory Committee on Immunization Practices to vaccinate HIV-infected individuals [11]. Among young women not on ART, 3.6% did not seroconvert to HPV-16, 7.7% did not seroconvert to HPV-18, and GMTs for both HPV-16 and HPV-18 were significantly lower than those of the historical comparison group. Research is needed to examine the mechanisms for these lower response rates and to determine whether additional or higher doses of the vaccine could facilitate seroconversion, as was shown in a study of hepatitis B vaccine in HIV-infected individuals [29]. Nevertheless, most of the young women not on ART generated robust immune responses to vaccination that were shown in previous studies to be protective against persistent HPV infection and the development of HPV-related genital lesions, suggesting that even HIV-infected women not on ART may benefit from vaccination [12-17]."
Abstract
Background The objective of this study was to determine whether the 3-dose quadrivalent human papillomavirus (HPV) vaccine series (HPV-6, -11, -16, -18) is immunogenic and safe in young women infected with human immunodeficiency virus (HIV).
Methods We enrolled 99 women aged 16-23 years in a phase 2, open-label, multicenter trial, conducted from 2008 to 2011 by the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Outcome measures were immunogenicity 4 weeks after dose 3, measured by (1) geometric mean titers (GMTs) and (2) seroconversion rates for HPV-6, -11, -16, and -18, among those seronegative and HPV DNA negative for each type. Immune responses were compared to those of a historical comparison group of HIV-negative women (n = 267) using univariate methods. Clinical and laboratory adverse events were assessed after each dose.
Results The mean age of subjects was 21.4 years; 80% were non-Hispanic black, 69 were not taking antiretroviral therapy (ART), and 30 were taking ART. No differences in GMTs were noted among participants taking ART vs the comparison group, but GMTs were lower in participants not taking ART vs the comparison group for HPV-16 (2393 vs 3892 milli-Merck units per milliliter [mMU/mL], P = .012) and HPV-18 (463 vs 801 mMU/mL, P = .003). Seroconversion rates were 100% for HPV-6, -11, -16, and -18 among participants taking ART. Rates ranged from 92.3% (for HPV-18) to 100.0% (for HPV-6) among participants not taking ART. One severe adverse event (fatigue) was noted.
Conclusions In a sample of HIV-infected women who were HPV DNA and HPV seronegative, immune responses to HPV vaccination were generally robust and the vaccine was well tolerated.
Women infected with human immunodeficiency virus (HIV) are at significantly higher risk than HIV-uninfected women for persistent human papillomavirus (HPV) infection and progression to cervical precancers and invasive cervical cancer; in addition, the incidence of cervical cancer increases with more severe immunosuppression [1-5]. Recurrence of cervical precancers after treatment is common in HIV-infected individuals [6-8].
Two prophylactic HPV vaccines that are safe, well tolerated, and effective in healthy individuals are now recommended for girls and women aged 11-26 years: a bivalent (HPV-16, -18) vaccine and a quadrivalent (HPV-6, -11, -16, -18) vaccine [9]. The quadrivalent vaccine is also recommended for boys and men aged 11-21 years, and for men aged 22-26 years who have sex with men or who are immunocompromised [10, 11]. Despite the potential health benefits of HPV vaccination among HIV-infected individuals, little is known about its safety, immunogenicity, and efficacy in this population. Clinical trials demonstrated that healthy women who were previously uninfected with the HPV types targeted by the vaccines had a robust immune response to vaccination. Seroconversion rates were approximately 100%, and immune responses were excellent and associated with high clinical efficacy (98%-100%) for preventing cervical, vaginal, and vulvar lesions associated with vaccine-type HPV [12-17]. However, immune responses to vaccination in HIV-infected individuals are often impaired; this may be due to defective primary immune responses, defects in generation of immunologic memory, or clonal deletion/depletion of memory T and B cells [18-22]. In one published study of immune responses to the quadrivalent HPV vaccine in 7- to 12-year-old children perinatally infected with HIV, seroconversion rates were excellent but immune titers to HPV-6 and HPV-18 were 30%-50% lower than those of controls [23].
Data are needed regarding the immunogenicity and safety of HPV vaccines in HIV-infected adolescent and young adult women to inform recommendations for vaccination in these individuals. Therefore, we designed a study to determine (1) the immunogenicity of the HPV-6, -11, -16, -18 vaccine and persistence of the immune response in HIV-infected young women, and (2) whether the HPV-6, -11, -16, -18 vaccine is well tolerated and safe in this population.
METHODS
Participants
This was a phase 2, open-label, multicenter trial to evaluate the immunogenicity and safety of an HPV-6, -11, -16, -18 vaccine (Gardasil, Merck & Co, Inc, Whitehouse Station, New Jersey) in HIV-infected young women aged 16-23 years, conducted from July 2008 to February 2011. The trial was conducted through the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN); study subjects were recruited from 14 sites in the United States and Puerto Rico. The institutional review board for each participating site approved the study.
Written informed consent was obtained for all participants ≥18 years of age, and participant assent and parent or guardian permission were obtained for participants <18 years of age.
Two groups of young women were recruited. Participants in group A were either naive to antiretroviral therapy (ART) or had not received ART for at least the 6 months prior to study entry (non-ART group), and those in group B had received ART for at least 6 months at the time of study entry, with 2 HIV type 1 (HIV-1) RNA plasma loads <400 copies/mL (ART group). All participants had acquired HIV through sexual exposure except one, who acquired HIV through a blood transfusion. Subjects were excluded if they had received an HPV vaccine; had recently received any vaccine, immune globulin, blood, or plasma products; were taking medications that could affect immune response; had a history of recent anogenital warts or any history of moderate or severe cervical dysplasia; were pregnant; reported active substance use or dependence; had an active opportunistic or serious bacterial infection; had thrombocytopenia or a coagulation disorder; or had a known or suspected malignancy or immune system disorder other than HIV.
Procedures
The vaccine administered was the quadrivalent HPV vaccine, which consists of 4 recombinant HPV type-specific vaccine-like particles, comprised of the L1 major capsid proteins of HPV-6, -11, -16, and -18. Vaccine doses were administered at day 1, week 8, and week 24 after documentation of a negative pregnancy test. HIV-1 RNA load, CD4+ T-cell count (CD4), complete blood count, and chemistry profile were obtained at each visit (day 1 and weeks 4, 8, 12, 24, 28, and 48).
Serologic testing for HPV-6, -11, -16, and -18 was done at day 1, week 24 (before dose 3), week 28 (4 weeks after dose 3), and week 48 (24 weeks after dose 3). Serology was measured using a competitive Luminex-based immunoassay (developed by Merck Research Laboratories) [24]. A clinician used a sterile Dacron swab to collect cervicovaginal samples for HPV DNA testing at day 1 and weeks 24 and 48 using a standardized method, during a speculum examination or using a blind vaginal swab. Swabs were tested for HPV DNA using an MY09/11 assay and dot blot method to detect 41 HPV types [25].
Solicitation of signs and symptoms to assess safety and tolerability were conducted by study staff 20 minutes, 3 days, and 7 days after each vaccine dose. Participants also recorded adverse events (AEs) daily for the first 7 days after each vaccine dose, using a vaccine report card or a telephone response system; these were reviewed and documented by study staff. The ATN's Supplemental Toxicity Table for Vaccine-Related Toxicities and Toxicity Table for Grading Severity of Adolescent Adverse Experiences (www.atnonline.org) were used to grade all clinical AEs and aberrant laboratory values, using a grading system of 1 to 4 (1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening). Toxicities were considered potentially vaccine associated if their onset occurred within 7 days after receipt of a study vaccine. In addition, any severe and unexplained toxicity was evaluated for possible vaccine association, regardless of the interval since vaccination. All toxicities and abnormal laboratory tests that were grade 3 or 4 and occurred between receipt of the first vaccine dose until 4 weeks after receipt of the third vaccine dose were reported to the protocol team within 48 hours for further assessment and monitoring. The protocol team made the final determination regarding association of an AE with the vaccine during monthly team calls. An independent data and safety monitoring board monitored the trial for safety.
Statistical Analyses
We examined baseline demographic characteristics, behaviors, type-specific HPV serostatus, and type-specific cervicovaginal HPV DNA status by study group (non-ART and ART). The main outcome measures were geometric mean titers (GMTs, expressed as milli-Merck units per milliliter [mMU/mL]) and seroconversion rates for HPV-6, -11, -16, and -18, 4 weeks after vaccine dose 3. GMTs were analyzed as continuous variables. Seroconversion was defined, as in the clinical trials of the quadrivalent vaccine, as the proportion of participants with GMTs of ≥20, 16, 20, and 24 mMU/mL to HPV-6, -11, -16, and -18, respectively, and were analyzed as a series of dichotomous variables. Analyses were conducted separately for each of the 4 type-specific antibodies. Subjects seropositive or HPV DNA positive for each vaccine-type HPV at baseline were excluded from the analysis for that HPV type, and immunogenicity was measured in the per protocol population, that is, among participants who completed all 3 vaccine doses within the specified time frames. GMTs and seroconversion rates of participants vs an HIV-uninfected historical comparison group were compared using 1-sample t tests (with the null value of GMTs from the comparison group) and Fisher exact tests, respectively. The comparison group was comprised of healthy young women (n = 267) participating in a study of HPV vaccine immunogenicity [26], and who were chosen for comparison to our subjects because their age range (16-23 years) was the same, and immunogenicity is strongly associated with age. GMTs and seroconversion rates were also compared by group (non-ART vs ART), using a Kruskal-Wallis test and Fisher exact test, respectively. We assessed persistence of the immune response by comparing GMTs and seroconversion rates 4 and 24 weeks after vaccine dose 3. Finally, we examined whether GMTs and seroconversion rates differed by participant HIV RNA load and CD4 at baseline.
All participants who received at least 1 vaccine dose were included in the safety analysis. Safety and tolerability were assessed by determining the proportion of subjects experiencing local, systemic, or laboratory AEs, the proportion experiencing a grade 3 or 4 AE, and the relationship of any grade 3 or 4 AEs to study vaccine.
RESULTS
Of the 109 subjects screened for eligibility, 101 were determined to be eligible and 2 were subsequently unable to be contacted. Thus, 99 subjects were enrolled: 69 in the non-ART group and 30 in the ART group. Of these, 79 completed the study, and the remaining subjects were either discontinued from the study vaccine early but completed the follow-up visits or were prematurely discontinued from the study (Figure 1). Of the 99 subjects enrolled, 4 (4.0%) received 1 vaccine dose, 7 (7.1%) received 2 doses, 88 (88.9%) received 3 doses, and 76 (76.8%) received 3 doses within the scheduled time frames.
Information on subjects' baseline demographic, immunologic, and virologic characteristics, sexual behaviors, and sexually transmitted infection history have been previously published [27]. In brief, subjects' mean age was 21.4 years, and 79 (79%) described themselves as black or African-American, 10 (10.1%) as white, and 16 (16.2%) as Hispanic. Participants generally did not have advanced HIV infection: 85 (85.9%) had a CD4 count ≥350 cells/mm3 (Table 1). Forty participants (40.4%) had an HIV RNA load <400 copies/mL. Thirty-six (37.5%) reported >10 lifetime male sexual partners and 72 (72.7%) reported having used a condom during last sexual intercourse with their main partner. Participants in the non-ART and ART groups did not differ significantly by age, race, ethnicity, or CD4 (all P values >.05). Those in the ART group vs the non-ART group were more likely to have an HIV RNA load <400 copies/mL (93.3% vs 17.4%, P < .0001).
A summary of HPV serostatus and HPV DNA status at baseline by HPV type and study group is shown in Table 1 and described in detail in a previous paper [28].
Overall, 42% were both seronegative and HPV DNA negative for HPV-6, 68% for HPV-11, 56% for HPV-16, 74% for HPV-18, 46% for both HPV-16 and -18, and 23% for all 4 vaccine types.
GMTs 4 weeks after vaccine dose 3 were approximately twice as high in the ART group than the non-ART group for all 4 HPV types; these differences were significant for HPV-16 and HPV-18 (Table 2). GMTs did not differ for any of the 4 HPV types in the ART group participants vs the historical comparison group. In contrast, GMTs were significantly lower in the non-ART group participants vs the historical comparison group for HPV-16 (2393 vs 3892 mMU/mL, P = .012) and HPV-18 (463 vs 801 mMU/mL, P = .003).
Seroconversion rates were 100% for all 4 HPV types among the ART group participants, and ranged from 92.3% (for HPV-18) to 100.0% (for HPV-6) for the non-ART group participants; differences between the non-ART and ART groups were not statistically significant (Table 2). Seroconversion rates were significantly lower in the non-ART group participants vs the historical comparison group for HPV-18 only (P = .003). The 3 participants who did not seroconvert for HPV-18 did seroconvert for HPV-16.
As shown in Figure 2, GMTs peaked 4 weeks after vaccine dose 3 (week 28) and then declined by 24 weeks after vaccine dose 3 (week 48). GMTs declined significantly (P ≤ .0005) for all 4 vaccine-type HPVs among non-ART and ART group participants. Seroconversion rates at week 48 remained at 100% for HPV-6, HPV-11, and HPV-16 among ART group participants (data not shown); the seroconversion rate fell from 100% to 86.7% for HPV-18. Seroconversion rates did not decline for HPV-6, HPV-11, or HPV-16 among the non-ART group participants, but declined from 92.3% to 67.6% for HPV-18. The difference in seroconversion rates between week 28 and week 48 for all participants was statistically significant only for HPV-18 (P = .0009).
Immune responses at week 28 and week 48 differed by HIV RNA load, but not by CD4, at baseline. Those with an RNA load <400 vs ≥400 had higher GMTs 4 weeks after vaccine dose 3 for all 4 vaccine types, although the differences only reached statistical significance for HPV-11 (P = .03) at 28 weeks.
Seroconversion rates were also higher for those with a viral load <400 vs ≥400, but the differences did not reach statistical significance.
The quadrivalent HPV vaccine was generally well tolerated (Table 3). Almost half of participants (48.5%) reported at least 1 local or systemic reaction for vaccine doses 1, 2, and 3 combined. A total of 26.3% of participants reported at least 1 local AE. The most common was pain, reported by 26.3% of participants: this was rated as mild (grade 1) by all participants except 1, who rated it moderate (grade 2). A total of 12.1% of participants reported fever. The highest fever was grade 2 (38.7°C-39.3°C), reported by 1 participant; the remainder had a temperature of ≤38.6°C. A total of 24.2% of participants reported another systemic reaction; the most common was headache (15.2%). One participant reported a severe systemic AE (grade 3), for fatigue. No severe or life-threatening (grade 3 or 4) laboratory AEs were evaluated by the team as definitely, probably, or possibly related to the vaccine. Although safety assessments differed in these subjects vs the historical comparison group, which precluded statistical comparisons, a general comparison demonstrated that the vaccine was as well tolerated-and in some cases better tolerated-in the HIV-infected subjects. Rates of AEs in subjects vs the historical comparison group were as follows: pain (26.3% vs 85.3%), erythema (0% vs 26.8%), rash (0% vs 1.1%), fever (12.1% vs 11.0%), headache (15.2% vs 40.4%), and fatigue (9.1% vs 5.5%).
CONCLUSIONS
In this study, we examined the immunogenicity and safety of the quadrivalent HPV vaccine in HIV-infected young women. Immune responses were robust among those who were HPV DNA and HPV seronegative for vaccine-type HPVs at the time of vaccination and received all 3 vaccine doses within specified timeframes. Among HIV-infected young women on ART, GMTs and seroconversion rates did not differ significantly from those of a historical comparison group of HIV-uninfected young women in the same age range. These findings suggest that treatment with ART could have a positive influence on response to vaccination, and provide support for current recommendations of the Advisory Committee on Immunization Practices to vaccinate HIV-infected individuals [11]. Among young women not on ART, 3.6% did not seroconvert to HPV-16, 7.7% did not seroconvert to HPV-18, and GMTs for both HPV-16 and HPV-18 were significantly lower than those of the historical comparison group. Research is needed to examine the mechanisms for these lower response rates and to determine whether additional or higher doses of the vaccine could facilitate seroconversion, as was shown in a study of hepatitis B vaccine in HIV-infected individuals [29]. Nevertheless, most of the young women not on ART generated robust immune responses to vaccination that were shown in previous studies to be protective against persistent HPV infection and the development of HPV-related genital lesions, suggesting that even HIV-infected women not on ART may benefit from vaccination [12-17].
GMTs declined for all 4 vaccine-type HPVs by 48 weeks after vaccine initiation, consistent with clinical trials of the quadrivalent HPV vaccine in healthy women. For most participants, however, GMTs at 48 weeks were still higher than after natural infection. Seroconversion rates declined significantly only for HPV-18. Long-term studies are needed to determine the duration of the immune response and the correlation between immune response and vaccine efficacy in HIV-infected young women. In a previous study of HIV-uninfected women in which declines in seropositivity were also greater for HPV-18 compared to other types, there were no breakthrough cases of HPV-18-related cervical intraepithelial neoplasia in quadrivalent vaccine recipients [30]. Furthermore, in prior studies of HPV vaccines, reexposure to the antigen resulted in a robust anamnestic response [26, 31]; such "boosting" through natural infection may translate to long-term efficacy.
Vaccines may have different safety profiles in HIV-infected vs HIV-uninfected individuals [20, 32-34]. In this study, the quadrivalent HPV vaccine was generally safe and well tolerated; only 1 grade 3 adverse event (fatigue) was reported. The AE rates reported by these participants were generally lower than those in published studies.
There are several limitations to this study. The relatively small number of participants limits the ability to make definitive conclusions about the safety and tolerability of the vaccine. In addition, these were generally healthy young women, with relatively high CD4, precluding the ability to examine the impact of a low CD4 and advanced HIV infection on immune response to vaccination. We were also unable to examine differences in immune response between women in the non-ART group who were ART naive vs those who had previously taken ART, because almost 90% of them had a baseline CD4 cell count ≥350 cells/mm3 and >92% seroconverted after vaccination. Furthermore, we compared immune responses of participants to a historical comparison group, precluding a direct comparison of AE rates because assessment of AEs differed in the 2 groups. Comparison group participants also differed from study participants in a number of ways that could impact immune response to vaccination. For example, although the age range was identical, the mean age of the comparison participants was approximately 1 year younger than those of the study participants. They also differed demographically from study participants and had had relatively few sexual partners (median, 2; range, 0-4). Furthermore, the results may not be generalizable to all young women with HIV. However, the clinical sites in the ATN are generally the largest of the clinics offering comprehensive services to HIV-positive youth in the United States, and therefore should be representative of youth in care. Finally, follow-up in our study was limited to 48 weeks, and we did not examine efficacy.
In conclusion, these data demonstrate that the quadrivalent HPV vaccine was immunogenic and was generally safe and well tolerated in HIV-infected adolescent and young adult women, supporting current recommendations to vaccinate HIV-infected individuals. Some young women not on ART had less robust immune responses than those on ART, suggesting that ART may improve response to vaccination in HIV-infected young women. Further studies are needed to examine factors predicting seroconversion and long-term efficacy in HIV-infected individuals.
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