1. J. Kahn, J. Xu, B. Kapogiannis, B. Rudy, N. Liu, R. Gonin, C. Wilson, C. Worrell, K. Squires, and the Adolescent Medicine Trials Network for HIV/AIDS Interventions IMMUNOGENICITY AND SAFETY OF THE HPV-6, -11, -16, -18 VACCINE IN HIV-POSITIVE YOUNG WOMEN AIDS 2012 25 July 2012

2.  HIV-infected individuals are at increased risk for both HPV infection and progression to HPV-related malignancies such as invasive cervical cancer 1  Cancers in HIV-infected individuals often more aggressive, less responsive to treatment 2 HPV IN HIV-INFECTED INDIVIDUALS 1 Serraino Int J Cancer 1999, Mbulaiteye JAIDS 2003, Ellerbrock JAMA 2007 2 Holcomb Gyn Oncol 1999

3.  Two prophylactic HPV vaccines are FDA-approved  Quadrivalent and bivalent  In healthy individuals, vaccines safe, highly immunogenic, and effective  HPV vaccination could have a substantial public health impact, especially in regions with high burden of HIV  Benefit of vaccinating HIV-infected women uncertain  HPV prevalence is relatively high  Little known about safety and immunogenicity HPV VACCINATION IN HIV-INFECTED INDIVIDUALS

4. 1.To define immunogenicity of the quadrivalent (HPV-6, -11, -16, -18) vaccine in HIV-infected young women 2.To determine whether the quadrivalent vaccine is well-tolerated and safe in HIV-infected young women AIMS

5.  Study design  Phase II, open-label, multi-center trial  Study population  HIV-infected young women 16 to 23 years of age recruited from 14 sites  Study duration  48 weeks  Subjects received the vaccine at day 1, week 8, and week 24, then followed for 24 weeks  Sample size  99 subjects OVERVIEW OF THE STUDY

6. Inclusion  HIV infected after the age of 9 years  Two groups  Group A: ART naïve or no HAART for at least 6 months  Group B: receiving HAART for at least 6 months, with two HIV-1 RNA viral loads < 400 copies/mL Exclusion  Recent anogenital warts or history of CIN 2/3  Active opportunistic or serious bacterial infection  Immune globulin, blood/plasma products, steroids SELECTED INCLUSION/EXCLUSION CRITERIA

7.  Questionnaires  Laboratory testing  CD4+ count, HIV viral load, CBC, chemistry profile  STI and pregnancy testing  HPV testing (41 types)  Serum antibody titers  Before dose #1  Before and 4 weeks after dose #3  24 weeks after dose #3  Safety assessed after each vaccine dose  Self-reported AEs and laboratory AEs STUDY PROCEDURES

8.  GMTs  Titers (in mMU/mL) to HPV-6, -11, -16, -18, 4 weeks post vaccine dose #3  Seroconversion rates  Proportion with GMTs to HPV-6, -11, -16, and -18 > 20, 16, 20 and 24 mMU/mL, respectively, 4 weeks post vaccine dose #3  AE rates  Proportion of subjects experiencing local, systemic, laboratory AEs with each vaccine dose, graded 1 to 4  1=mild, 2=moderate, 3=severe, 4=life-threatening OUTCOME MEASURES

9.  Immunogenicity  Analyses conducted separately for 4 type-specific antibodies, and subjects seropositive or HPV DNA positive for each type excluded from analysis  One-sample t-test was used to compare GMTs, and Fisher’s exact test was used to compare seroconversion rates, of participants vs. HIV-uninfected historical controls  16-23 y/o women (N=267) recruited from Brazil, Europe and the U.S.: healthy, no history of abnormal Pap test, < 4 male sex partners (Villa, Vaccine 2006)  Safety and tolerability  Descriptives; evaluated for all participants ANALYSES

10. Characteristic%Mean Age21 Race/ethnicityNon-Hispanic White4 Non-Hispanic Black79 Hispanic16 CD4 (cells/mm 3 )> 35085 VL (copies/mL)*< 40040 HPV> 1 type75 PARTICIPANT CHARACTERISTICS BASELINE (N=99) *Subjects in group B vs. group A more likely to have an HIV VL < 400 copies/mL (p<0.0001)

11. % HPV-642 HPV-1168 HPV-1656 HPV-1874 SUBJECTS HPV SERONEGATIVE AND HPV DNA NEGATIVE AT BASELINE Immunogenicity results pertain only to these subjects

12. GMT GROUP A SUBJECTS VS. CONTROLS Group A mean Group B mean All mean Controls mean P value* HPV-654711397395820.78 HPV-1165514548966970.66 HPV-1621765037296138920.0003 HPV-184459635778010.0002 * Differences in mean GMTs for Group A subjects vs. controls No HAART

13. GMT GROUP B SUBJECTS VS. CONTROLS Group A mean Group B mean All mean Controls mean P value* HPV-65471139739582.12 HPV-116551454896697.07 HPV-162176503729613892.34 HPV-18445963577801.60 * Differences in mean GMTs for Group B subjects vs. controls HAART

14. SEROCONVERSION RATES GROUP A SUBJECTS VS. CONTROLS Group A % Group B % All % Controls % P value* HPV-696.310097.51000.11 HPV-1195.510096.81000.03 HPV-1694.610096.11000.03 HPV-1890.010092.51000.0002 * Differences in seroconversion rates for Group A subjects vs. controls No HAART

15. SEROCONVERSION RATES GROUP B SUBJECTS VS. CONTROLS Group A % Group B % All % Controls % P value* HPV-696.310097.5100- HPV-1195.510096.8100- HPV-1694.610096.1100- HPV-1890.010092.5100- * Differences in seroconversion rates for Group B subjects vs. controls HAART

16. GMT AT 28 AND 48 WEEKS GMT (mMU/mL) Study week 0 28 48 Group B Group A Overall HPV-6 10000 1000 100 10 0

17. SEROCONVERSION AT 48 WEEKS Group A % Group B % HPV-695.8100 HPV-1197.4100 HPV-1697.1100 HPV-1873.9*87.5* * P <.05

18. TOLERABILITY AND SAFETY Local reactions%Highest grade (N) Pain26.32 (1) Induration2.02 (2) Erythema0- Rash0- Abscess0- Subjects with > 1 AE, doses 1, 2, and 3 combined

19. TOLERABILITY AND SAFETY Systemic reactions%Highest grade (N) Fever (> 37.7 o C)12.12 (1)* Headache15.22 (4) Fatigue9.1 3 (1) Malaise8.12 (1) Anorexia4.02 (1) Arthralgia/myalgia4.02 (4) Weakness3.02 (1) Seizures0- Allergic reactions0- Subjects with > 1 AE, doses 1, 2, and 3 combined

20. LABORATORY TOXICITIES  No AEs > grade 3 evaluated as definitely related, probably related, or possibly related to vaccine  Qualitative evaluation demonstrated no concerning patterns in CD4+ count or VL

21.  Small N  Historical controls  Immunogenicity only examined among those seronegative and HPV DNA negative LIMITATIONS

22.  Among HIV-infected young women seronegative and HPV DNA negative at the time of vaccination, HPV type-specific immune responses to vaccination were generally robust; seroconversion rates > 90%  The vaccine was generally well-tolerated and safe  These data support recommendations to:  Vaccinate HIV-infected young women  Target vaccination to 11-12 year-olds, who are less likely to have acquired HIV behaviorally  Research needed re: women who did not seroconvert, long-term efficacy, efficacy in men CONCLUSIONS

23.  ATN supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), with supplemental funding from NIDA and NIMH (5 U01 HD 40533 and 5 U01 HD 40474)  Vaccine and HPV geometric mean titers provided by Merck & Co., Inc.  Scientific review by the TLG  Logistical support by ATN Coordinating Center  Analytic support by ATN DOC at Westat ACKNOWLEDGMENTS

24. 1.Children’s National Medical Center 2.Children’s Hospital of Philadelphia 3.John H. Stroger Jr. Hospital, Cook County 4.University of Puerto Rico 5.Montefiore Medical Center 6.Tulane University Health Sciences Center 7.University of Miami School of Med. 8.Children’s Diagnostic and Treatment Center 9.St. Jude’s Children’s Research Hospital 10.Children’s Memorial 11.University of South Florida 12.Children’s Hospital of Los Angeles 13.Mount Sinai Medical Center 14.University of Maryland PARTICIPATING ATN SITES

26. GMT GROUP A VS. GROUP B Group A mean Group B mean All mean Controls mean P value* HPV-654711397395820.05 HPV-1165514548966970.09 HPV-1621765037296138920.004 HPV-184459635778010.01 * Differences in mean GMTs for group A subjects vs. group B subjects