Safety of and Immune Response to a Novel Human Papillomavirus Vaccine in HIV Infected Children

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety of and immune response to a new human papillomavirus (HPV) vaccine in HIV (Human immunodeficiency virus) infected children between the ages of 7 and 12 years.

Detailed Description
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Genital HPV infection is the most common sexually transmitted infection in the world and may lead to genital warts, anogenital dysplasias, and invasive cancers. HIV infected people and others with compromised immunity are at greater risk for HPV-related complications. In particular, researchers are concerned about the risk of HPV infection to women, who may be infected by their male partners, especially if these partners engage in anal intercourse. HIV infected women tend to have multiple types of HPV (associated with a greater risk of HPV-related disease), are less likely to clear HPV-related conditions, and are more likely to progress to HPV-related disease. The quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine to be tested in this study was safe and generally well tolerated in previous studies conducted in healthy and HPV-exposed adolescents, young adults, and older women. However, it is still unclear if the vaccine will be safe and will elicit a similar immune response in younger children. The purpose of this study is to evaluate the safety and immunogenicity of the novel quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine in HIV infected children 7 to 12 years of age. This study had two stages and lasted at least 108 weeks. In Stage I, participants were stratified by CD4 percentage (CD4%) nadir and CD4% at study screening (Stratum A: CD4% Nadir < 15 and CD4% ≥ 15 at screening, Stratum B: CD4% Nadir ≥ 15 and < 25 and CD4% ≥ 15 at screening, Stratum C: CD4% Nadir ≥ 25 and CD4% ≥ 25 at screening). Within each stratification group, they were randomly assigned to one of two arms. During Stage I, Arm A (QHPV:Quadrivalent human papillomavirus vaccine) participants received 3 doses of vaccine, while Arm B (Placebo/QHPV) participants received 3 doses of placebo. Participants did not know whether they were receiving vaccine or placebo. Participants received their assigned intervention at study entry and Weeks 8 and 24. At Week 96, Stage II began, and all study participants were told if they received vaccine or placebo in Stage I. Arm A participants received an additional dose of vaccine at Week 96; Arm B participants received doses of vaccine at Weeks 96, 104, and 120. Over the course of the study, there were at least 12 study visits. A physical exam and blood collection occurred at most visits; medical history occurred at selected visits. After each vaccination, participants were observed for at least 30 minutes to monitor for any allergic reactions possibly resulting from the vaccination. For 15 days following vaccination, parents or guardians were asked to complete a report card with details of each child's signs and symptoms. Three days after each vaccination, parents or guardians of study participants were contacted by telephone and asked about any adverse events that a child may have experienced.

Official Title
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Phase II Safety and Immunogenicity Study of Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine in HIV Infected Children 7 to 12 Years of Age

Conditions
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HIV Infections, Sexually Transmitted Diseases

Intervention / Treatment
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* Biological: Quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle (VLP) or Quadrivalent human papillomavirus vaccine (QHPV)
* Other: Placebo/QHPV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Children ages ≥ 7 to < 12 years of age. A confirmed diagnosis of HIV infection, defined as two positive assays from two different samples. The two results may be in any combination of the following: at any age: Deoxyribonucleic acid (DNA) polymerase chain reaction (PCR), Ribonucleic acid (RNA) PCR age > 4 weeks: p24 antigen detection age >18 months: licensed ELISA (Enzyme-linked immunosorbent assay) with confirmatory Western Blot CD4% ≥ 15 at the time of screening is required (Note that this is a minimum requirement, and that for Stratum C the CD4% needs to be ≥ 25). For Strata A and B: Currently stable (≥ 3 months) on highly active antiretroviral therapy (HAART) regimen, defined as three or more antiretrovirals from at least two different therapeutic classes, or therapy with the combination of azidothymidine, lamivudine, and abacavir. For stratum C no antiretroviral therapy is required. Parent or legal guardian able and willing to provide signed informed consent. Negative urine pregnancy test sensitive to 25 International Unit (IU) beta-human chorionic gonadotropin (HCG) for girls who are menstruating (child bearing potential). Female study volunteers who are participating in sexual activity that could lead to pregnancy must agree to use two reliable methods of contraception, one of which must be a barrier method. A barrier method of contraception (condoms or cervical cap) together with another reliable form of contraception (condoms a , with a spermicidal agent; a diaphragm or cervical cap with spermicide; an intrauterine device [IUD]; or hormonal-based contraception) must be used while on this study. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV-1 transmission Males participating in the study must not attempt to impregnate a woman, or participate in sperm donation programs. Males engaging in sexual activity that could lead to pregnancy must use a condom. Exclusion Criteria Body temperature ≥ 101 F or ≥ 38.3 C, orally determined, within 72 hours prior to the first and each subsequent injection. Subjects may be vaccinated any time in the next seven days thereafter, provided that the site investigator is satisfied that the febrile illness has ended. Total bilirubin ≥ 5 x Upper Limit of Normal (ULN) at screening. Alanine transaminase (ALT) or serum glutamic pyruvic transaminase (SGPT) ≥ 5 x ULN at screening in the absence of other explained causes (as determined by the site investigator) at screening. Serum creatinine ≥ 1.5 mg/dL at screening. Absolute neutrophil count ≤ 750 cells/mm3 at screening. Hemoglobin ≤ 9.9 g/dL at screening. Platelet count ≤ 75,000 cells/mm³ at screening. Presence of an acute opportunistic non-bacterial or bacterial infection requiring therapy at the time of enrollment; the subject may be entered once he/she is stable on appropriate anti-infective therapy. Chemotherapy for active malignancy. Other known or suspected disease of the immune system, or immunosuppressive therapy. Prior treatment with immunosuppressive or immunomodulation therapy within 60 days of screening. Prior treatment with three or more week-long courses of corticosteroids (≥ 2.0 mg/kg or ≥ 20 mg total of prednisone-equivalent) within one year of screening; or any systemic (oral or parenteral) steroids (≥ 2.0 mg/kg or ≥ 20 mg total of prednisone-equivalent for ≥ 3 days) within 30 days of study entry. Prior vaccinations with inactivated vaccines received within two weeks of any dose of study vaccine, and no other vaccinations may be planned for two weeks after each dose of study vaccine. Prior vaccinations with live vaccines received within three weeks before any dose of study vaccine, and no other vaccinations may be planned for two weeks after each dose of study vaccine. Prior diagnosis of sexually transmitted infections (STIs), genital warts, or juvenile recurrent papillomatosis. History of any severe allergic reaction (e.g., swelling of the mouth and throat, difficulty breathing, hypotension, or shock) that required medical intervention. Known allergies to any vaccine component, including aluminum, yeast, or BENZONASE™ (nuclease, Nycomed [used to remove residual nucleic acids from this and other vaccines]). Previous treatment with any immune globulin preparation or blood-derived products within the six months prior to the first injection and none may be planned during the study. Known coagulation disorder that would contraindicate Intramuscular (IM) injections. Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study. Breastfeeding.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: QHPV<br>QHPV at week 0, 8, 24, 96. | Biological: Quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle (VLP) or Quadrivalent human papillomavirus vaccine (QHPV)<br>* QHPV at week 0, 8, 24 and 96.<br>* Other names: QHPV;|
| Other: Arm B: Placebo/QHPV<br>Placebo at week 0, 8, 24; QHPV at week 96, 104, 120. | Other: Placebo/QHPV<br>* Placebo at week 0, 8, 24 and QHPV at week 96, 104, 120.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Developing Grade 3 or 4 Adverse Events (AEs) | Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (December 2004). The grades used are: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening. All grade 3 and higher signs, symptoms, and laboratory toxicities were included. | Within 14 days of first three doses of vaccination | 
| Percent of Participants Developing Grade 3 or 4 Adverse Events (AEs) Attributed to Study Treatment | Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (December 2004). All grade 3 and higher signs, symptoms, and laboratory toxicities attributed to study treatment were included. The relationship between the Adverse Events and the vaccination were evaluated by study team and assigned to, for example, Treatment related, Non-treatment related, Baseline, Possibly treatment related. | Within 14 days of first three doses of vaccination | 
| Percent of Participants With Human Papillomavirus (HPV) Type-Specific Seroconversion | Serum anti-HPV 6, 11, 16, and 18 antibody was measured using a competitive Luminex immunoassay (cLIA; reported in milli-Merck Units [mMU]/mL). Sero-positivity was defined as an anti-HPV titer ≥20, 16, 20, and 24 mMU/mL, for HPV types 6, 11, 16, and 18, respectively. | At week 28 after beginning the vaccination series | 
| Serum Anti-HPV Antibody Titers (cLIA) | Geometric means of Type-specific Serum anti-HPV antibody titers (cLIA) | Arm A week 0, 28, 72, 96, 97, 100; Arm B week 0, 28, 72, 96, 97, 100, 124. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD4 Count Over Time |  | Arm A week 0, 8, 12, 24, 28, 72, 96, 100 and 108; Arm B week 0, 8, 12, 24, 28, 72, 96, 100, 104, 108, 120, and 124. | 
| CD4 Percent Over Time |  | Arm A week 0, 8, 12, 24, 28, 72, 96, 100 and 108; Arm B week 0, 8, 12, 24, 28, 72, 96, 100, 104, 108, 120, and 124. | 
| HIV-1 Viral Load (Ribonucleic Acid [RNA] Copies/ml) Over Time |  | Arm A week 0, 8, 12, 24, 28, 72, 96, 100 and 108; Arm B week 0, 8, 12, 24, 28, 72, 96, 100, 104, 108, 120, and 124. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV