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 201225 July 2012

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

Two prophylactic HPV vaccines are FDA-approvedQuadrivalent 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 uncertainHPV prevalence is relatively high Little known about safety and immunogenicity

HPV VACCINATION IN HIV-INFECTED INDIVIDUALS

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

Study designPhase II, open-label, multi-center trial

Study populationHIV-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

InclusionHIV infected after the age of 9 yearsTwo 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

ExclusionRecent anogenital warts or history of CIN 2/3Active opportunistic or serious bacterial infection Immune globulin, blood/plasma products, steroids

SELECTED INCLUSION/EXCLUSION CRITERIA

Questionnaires Laboratory testing

CD4+ count, HIV viral load, CBC, chemistry profile STI and pregnancy testingHPV 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

GMTsTiters (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 ratesProportion 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

ImmunogenicityAnalyses 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

Characteristic % MeanAge 21Race/ethnicity Non-Hispanic White 4

Non-Hispanic Black 79Hispanic 16

CD4 (cells/mm3) > 350 85VL (copies/mL)* < 400 40HPV > 1 type 75

PARTICIPANT CHARACTERISTICSBASELINE (N=99)

*Subjects in group B vs. group A more likely to have an HIV VL < 400 copies/mL (p<0.0001)

%HPV-6 42HPV-11 68HPV-16 56HPV-18 74

SUBJECTS HPV SERONEGATIVE AND HPV DNA NEGATIVE AT BASELINE

Immunogenicity results pertain only to these subjects

GMTGROUP A SUBJECTS VS. CONTROLS

Group Amean

Group Bmean

Allmean

Controlsmean

P value*

HPV-6 547 1139 739 582 0.78HPV-11 655 1454 896 697 0.66HPV-16 2176 5037 2961 3892 0.0003HPV-18 445 963 577 801 0.0002

* Differences in mean GMTs for Group A subjects vs. controls

No HAART

GMTGROUP B SUBJECTS VS. CONTROLS

Group Amean

Group Bmean

Allmean

Controlsmean

P value*

HPV-6 547 1139 739 582 .12HPV-11 655 1454 896 697 .07HPV-16 2176 5037 2961 3892 .34HPV-18 445 963 577 801 .60

* Differences in mean GMTs for Group B subjects vs. controls

HAART

SEROCONVERSION RATESGROUP A SUBJECTS VS. CONTROLS

Group A%

Group B%

All%

Controls%

P value*

HPV-6 96.3 100 97.5 100 0.11HPV-11 95.5 100 96.8 100 0.03HPV-16 94.6 100 96.1 100 0.03HPV-18 90.0 100 92.5 100 0.0002

* Differences in seroconversion rates for Group A subjects vs. controls

No HAART

SEROCONVERSION RATESGROUP B SUBJECTS VS. CONTROLS

Group A%

Group B%

All%

Controls%

P value*

HPV-6 96.3 100 97.5 100 -HPV-11 95.5 100 96.8 100 -HPV-16 94.6 100 96.1 100 -HPV-18 90.0 100 92.5 100 -

* Differences in seroconversion rates for Group B subjects vs. controls

HAART

GMT AT 28 AND 48 WEEKS

GMT

(mM

U/m

L)

Study week 0 28 48

Group B Group A Overall

HPV-6 10000

1000

100

10

0

SEROCONVERSION AT 48 WEEKS

Group A%

Group B%

HPV-6 95.8 100HPV-11 97.4 100HPV-16 97.1 100HPV-18 73.9* 87.5*

* P <.05

TOLERABILITY AND SAFETY

Local reactions % Highest grade (N)Pain 26.3 2 (1)Induration 2.0 2 (2)Erythema 0 -Rash 0 -Abscess 0 -

Subjects with > 1 AE, doses 1, 2, and 3 combined

TOLERABILITY AND SAFETY

Systemic reactions % Highest grade (N)Fever (> 37.7o C) 12.1 2 (1)*Headache 15.2 2 (4)Fatigue 9.1 3 (1)Malaise 8.1 2 (1)Anorexia 4.0 2 (1)Arthralgia/myalgia 4.0 2 (4)Weakness 3.0 2 (1)Seizures 0 -Allergic reactions 0 -

Subjects with > 1 AE, doses 1, 2, and 3 combined

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

Small N Historical controls Immunogenicity only examined among those

seronegative and HPV DNA negative

LIMITATIONS

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 womenTarget vaccination to 11-12 year-olds, who are less likely

to have acquired HIV behaviorallyResearch needed re: women who did not

seroconvert, long-term efficacy, efficacy in men

CONCLUSIONS

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 TLGLogistical support by ATN Coordinating CenterAnalytic support by ATN DOC at Westat

ACKNOWLEDGMENTS

1. Children’s National Medical Center2. Children’s Hospital of Philadelphia3. John H. Stroger Jr. Hospital, Cook County4. University of Puerto Rico5. Montefiore Medical Center6. Tulane University Health Sciences Center7. University of Miami School of Med. 8. Children’s Diagnostic and Treatment Center9. St. Jude’s Children’s Research Hospital10.Children’s Memorial11.University of South Florida12.Children’s Hospital of Los Angeles13.Mount Sinai Medical Center14.University of Maryland

PARTICIPATING ATN SITES

GMTGROUP A VS. GROUP B

Group Amean

Group Bmean

Allmean

Controlsmean

P value*

HPV-6 547 1139 739 582 0.05HPV-11 655 1454 896 697 0.09HPV-16 2176 5037 2961 3892 0.004HPV-18 445 963 577 801 0.01

* Differences in mean GMTs for group A subjects vs. group B subjects