Clinical trial NCT00798265: A Phase I Study of Quadrivalent Human Papilloma Virus (HPV) (Types 6, 11, 16, 18) Recombinant Vaccine in HIV-Infected and HIV-Negative Pre-Adolescents, Adolescents, and Young Adults
Official title: A Phase I Study of Quadrivalent Human Papilloma Virus (HPV) (Types 6, 11, 16, 18) Recombinant Vaccine in HIV-Infected and HIV-Negative Pre-Adolescents, Adolescents and Young Adults
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Human Immunodeficiency Virus
Human Papillomavirus- 6, 11, 16, 18
Adolescent
Papillomavirus Vaccines
Keywords: HPV Vaccination
HPV Immunogenicity
HIV Infection
HIV Negative
Adolescents and Young Adults
Healthy Volunteer
HV
Adolescent
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2008-11-26
Enrollment: 26
Sex: ALL
Minimum age (years): 12
Maximum age (years): 26
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Background:

* Human papilloma virus (HPV) is a common sexually transmitted disease. There are more than 100 different HPV types, and both males and females can get HPV infection. Most people do not have any symptoms when they become infected and are able to get rid of the infection on their own. However, they can still become re-infected with the same or a different HPV type, and in some people HPV infection persists.
* Persistent HPV infection is associated with the development of precancerous lesions and cancer. HPV types are classified as either high risk or low risk based on whether their persistence will lead to cancer.
* Patients who have suppressed immune systems are at a higher risk for HPV-related complications. They are more likely to contract multiple HPV types and have more persistent infection that can lead to precancerous lesions or cancer, which are then difficult to treat and often recur.
* A recently approved vaccine for HPV induces immunity to HPV 6, 11, 16, and 18. It was shown to be highly effective in preventing infection with these HPV types, and is approved for use in females 9 to 26 years of age. However, much less is known about the vaccines ability to induce immunity in males or individuals with suppressed immune systems.

Objectives:

- To investigate whether the HPV vaccine is safe to give and able to induce immunity in both female and male adolescents and young adults with HIV infection compared to healthy, human immunodeficiency virus (HIV)-negative persons of the same age.

Eligibility:

- Males and females, 12 to 26 years of age, divided into three groups: (1) Healthy and HIV-negative, (2) HIV-positive and on antiretroviral therapy, and (3) HIV-positive and not on antiretroviral therapy.

Design:

* Before beginning vaccination, participants will have a complete physical examination and blood drawn for routine blood tests, special tests of the immune system, antibody tests, and an HIV test.
* HPV vaccine will be given by injection into the muscle at 0, 2, and 6 months, according to the standard vaccination schedule.
* Patients with HIV infection will be monitored for a week following the first injection to test the level of HIV in the blood 3 days and 5 days after the first injection.
* Participants will also be asked to fill out a 10- to 15-minute Web-based survey about awareness, health behaviors, and personal choices related to risk factors for HIV, HPV, and other sexually transmitted diseases. Participants are not required to fill out the survey to receive the vaccine.
* The total duration of the study is 4 years. During the first year of the study, participants will return for six additional 1-day visits at months 1, 2, 3, 6, 7, and 12. Participants will return for 1-day visits every 6 months for the remaining 3 years.

Detailed description: Background:

Human papilloma virus (HPV) is one of the most common sexually transmitted diseases and a significant cause of cutaneous genital warts and anogenital cancer.

Infection with high-risk, oncogenic HPV types, most commonly types 16 and 18, is associated with low and high-grade cervical cellular abnormalities that are precursors to invasive cervical cancer, as well as vulvar and anal cancer, while HPV types 6 and 11 are associated with genital warts.

Persistence of HPV infection is more common in individuals with or at risk for chronic immunosuppression and HIV-infected individuals have a higher prevalence of HPV infection and HPV-associated anogenital disease compared to age-matched human immunodeficiency virus (HIV)-negative controls.

Study Objectives:

To assess the safety and immunogenicity of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in HIV-infected preadolescents, adolescents and young adults 12-26 years of age.

To determine whether there are differences in HPV vaccine immunogenicity between HIV-infected and HIV negative age-matched controls.

To determine whether there are differences in HPV vaccine immunogenicity between HIV-infected patients receiving highly active antiretroviral therapy (HAART) and those not receiving HAART with similar cluster of differentiation 4 (CD4) and viral load parameters at entry.

To determine whether HPV vaccination alters human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) levels.

To investigate the impact of CD4 count and HIV-1 RNA levels on HPV vaccine immunogenicity.

To characterize HPV deoxyribonucleic acid (DNA) positivity in the study cohort populations through oral/buccal and anogenital sampling at baseline.

To characterize HPV and HIV knowledge and risk and sexual behaviors in the study cohort populations.

Eligibility:

Individual Cohorts

Cohort 1: HIV-positive, CD4 cell count greater than or equal to 350 cells/mm\^3, HIV-1 RNA level by reverse transcription (RT) polymerase chain reaction (PCR) less than or equal to 20,000 copies/ml, on stable HAART regimen for greater than or equal to 6 months.

Cohort 2: HIV-infected, CD4 cell count greater than or equal to 500 cells/mm\^3, HIV-1 RNA level by RT PCR less than or equal to 20,000 copies/ml, on no antiretroviral treatment.

Cohort 3: healthy, HIV-negative controls All Cohorts

Females and males age 12 to 26 years

Patients must have a hemoglobin greater than or equal to 10.0 gm/dL, neutrophil count (ANC) greater than or equal to 1500/mm\^3, platelet count greater than or equal to 75,000/mm\^3 and prothrombin time (PT) or partial thromboplastin time (PTT) less than or equal to 1.5x upper limit of normal (ULN) (with the exception of patients with known clotting disorders or lupus anticoagulant); serum glutamic-pyruvic transaminase (SGPT)/Serum glutamic oxaloacetic transaminase (SGOT) \< 2/5x ULN, total bilirubin less than or equal to 1.5x ULN unless attributable to protease inhibitor therapy.

Patients must test negative for hepatitis B virus and hepatitis C virus, unless the result is consistent with prior vaccination or prior infection with full recovery.

No use of investigational agents within 4 weeks of study enrollment or use of immunosuppressive or immunomodulating agents within 8 weeks of study entry.

Study Design:

This is a non-randomized, prospective, phase I study of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine.

The study includes 3 cohorts of pre-adolescents, adolescents and young adults 12-26 years of age as outlined under Eligibility Criteria. Each cohort will enroll 35 patients.

All study subjects will receive three doses of HPV vaccine at 0, 2 and 6 months administered IM.

Study participants will be monitored at months 0, 1, 2, 3, 6, 7, and 12 (+/- 2 weeks for each visit, and every 6 months (+/- 30 days) thereafter for 48 months total.

Eligibility criteria: * ELIGIBILITY CRITERIA:

Cohort 1 Inclusion and Exclusion Eligibility Criteria:

INCLUSION CRITERIA:

2.1.1.1 Age 12 to 26 years

2.1.1.2 Females and males

2.1.1.3 Human immunodeficiency virus (HIV)-positive

2.1.1.4 Cluster of differentiation 4 (CD4) cell count and Human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) level parameters

* CD4 cell count greater than or equal to 350 cells/mm(3)
* HIV-1 RNA level by reverse transcription-polymerase chain reaction (RT PCR) less than or equal to 20,000 copies/ml

2.1.1.5 On stable highly active antiretroviral therapy (HAART) regimen for greater than or equal to 6 months with CD4 and viral load parameters as outlined in 2.1.1.4

2.1.1.6 Patients greater than or equal to 18 years willing to provide informed consent or parent/guardian willing to provide informed consent for minor children less than 18 years of age.

2.1.1.7 Informed assent for patients 12-17 years of age (Optional at the discretion of the Principal Investigator and Parent/Guardian based on maturity level of minor)

2.1.1.8 Willing to use acceptable forms of contraception, if applicable, or abstinence to prevent pregnancy.

EXCLUSION CRITERIA:

2.1.1.9 Any of the following hematologic abnormalities

* Hemoglobin less than 10.0 g/dL
* Neutrophil count less than 1500/mm(3)
* Platelet count less than 75,000/mm(3)
* Prothrombin time (PT) or partial thromboplastin time (PTT) greater than or equal to 1.5 times upper limits of normal (ULN) (with the exception of patients with known clotting disorders or known lupus anticoagulant).

2.1.1.10 Any of the following hepatic abnormalities

* Alanine transaminase (ALT)/ serum glutamate-pyruvate transaminase (SGPT) and/or Aspartate aminotransferase (AST)/Serum glutamic oxaloacetic transaminase (SGOT) greater than 2.5 times ULN
* Total bilirubin greater than 1.5 times ULN unless attributable to protease inhibitor therapy.

2.1.1.11 Positive tests (antibody and/or antigen) for hepatitis B and hepatitis C viruses, unless the result is consistent with prior vaccination or prior infection with full recovery.

2.1.1.12 Acute infection requiring therapy at time of enrollment. Participants may be eligible for study after being on stable and appropriate anti-infective therapy.

2.1.1.13 Chemotherapy for active cancer.

2.1.1.14 Documented history of non-adherence to antiretroviral treatment regimen within 12 months of study entry.

2.1.1.15 Pregnancy or breastfeeding.

2.1.1.16 Use of immunosuppressive or immunomodulating agents within 8 weeks of study enrollment. Note: patients receiving oral corticosteroids for management of asthma or contact hypersensitivity for less than or equal to 14 days in duration will be allowed to enroll as long as it has been greater than or equal to 30 days since oral corticosteroid administration.

2.1.1.17 Known immediate hypersensitivity to yeast or any of the vaccine components.

2.1.1.18 Use of investigational agents within 4 weeks prior to study enrollment.

2.1.1.19 Active external genital warts requiring treatment or cervical intraepithelial neoplasia (CIN)2/3

2.1.1.20 Any clinically significant diseases (other than HIV infection) or findings during study screening that, in the opinion of the Principal Investigator or Lead Associate Investigator, may interfere with the study.

Cohort 2 Inclusion and Exclusion Eligibility Criteria:

Inclusion Criteria

2.1.2.1 Age 12 to 26 years

2.1.2.2 Females and males

2.1.2.3 HIV-positive

2.1.2.4 CD4 cell count and HIV-1 RNA level parameters

* CD4 cell count greater than or equal to 500 cells/mm(3)
* HIV-1 RNA level by RT PCR less than or equal to 20,000 copies/ml.

2.1.2.5 Not receiving antiretroviral treatment with CD4 and viral load parameters as outlined in 2.1.2.4.

2.1.2.6 Patients greater than or equal to 18 years willing to provide informed consent or parent/guardian willing to provide informed consent for minor children less than 18 years of age.

2.1.2.7 Informed assent for patients 12-17 years of age (Optional at the discretion of the Principal Investigator and Parent/Guardian based on maturity level of minor)

2.1.2.8 Willing to use acceptable forms of contraception, if applicable, or abstinence to prevent pregnancy.

EXCLUSION CRITERIA:

2.1.2.9 Any of the following hematologic abnormalities:

* Hemoglobin less than 10.0 g/dL
* Neutrophil count less than 1500/mm(3)
* Platelet count less than 75,000/mm(3)
* PT or PTT greater than or equal to 1.5 times ULN (with the exception of patients with known clotting disorders or known lupus anticoagulant).

2.1.2.10 Any of the following hepatic abnormalities

* ALT/SGPT and/or AST/SGOT greater than 2.5 times ULN
* Total bilirubin greater than 1.5 times ULN unless attributable to protease inhibitor therapy.

2.1.2.11 Positive tests (antibody and/or antigen) for hepatitis B and hepatitis C viruses, unless the result is consistent with prior vaccination or prior infection with full recovery.

2.1.2.12 Acute infection requiring therapy at time of enrollment. Participants may be eligible for study after being on stable and appropriate anti-infective therapy.

2.1.2.13 Chemotherapy for active cancer.

2.1.2.14 Pregnancy or breastfeeding.

2.1.2.15 Use of immunosuppressive or immunomodulating agents within 8 weeks prior to study enrollment. Note: patients receiving oral corticosteroids for management of asthma or contact hypersensitivity for less than or equal to 14 days in duration will be allowed to enroll as long as it has been greater than or equal to 30 days since oral corticosteroid administration.

2.1.2.16 Known immediate hypersensitivity to yeast or any of the vaccine components.

2.1.2.17 Use of investigational agents within 4 weeks prior to study enrollment.

2.1.2.18 Active external genital warts requiring treatment or CIN2/3

2.1.2.19 Any clinically significant diseases (other than HIV infection) or findings during study screening that, in the opinion of the Principal Investigator or Lead Associate Investigator may interfere with the study.

Cohort 3 Inclusion and Exclusion Eligibility Criteria:

INCLUSION CRITERIA:

2.1.3.1 Age 12 to 26 years

2.1.3.2 Females and males

2.1.3.3 HIV-negative

2.1.3.4 Patients greater than or equal to 18 years willing to provide informed consent or parent/guardian willing to provide informed consent for minor children less than 18 years of age.

2.1.3.5 Informed assent for patients 12-17 years of age (Optional at the discretion of the Principal Investigator and Parent/Guardian based on maturity level of minor)

2.1.3.6 Willing to use acceptable forms of contraception, if applicable, or abstinence to prevent pregnancy.

EXCLUSION CRITERIA:

2.1.3.7 Any of the following hematologic abnormalities:

* Hemoglobin less than 10.0 g/dL
* Neutrophil count less than 1500/mm(3)
* Platelet count less than 75,000/mm(3)
* PT or PTT greater than or equal to 1.5 times ULN (with the exception of patients with known clotting disorders or known lupus anticoagulant).

2.1.3.8 Any of the following hepatic abnormalities

* ALT/SGPT and/or AST/SGOT greater than 2.5 times ULN
* Total Bilirubin greater than 1.5 times ULN unless attributable to protease inhibitor therapy.

2.1.3.9 Positive tests (antibody and/or antigen) for HIV, hepatitis B and hepatitis C viruses, unless the result is consistent with prior vaccination or prior infection with full recovery.

2.1.3.10 Acute infection requiring therapy at time of enrollment. Participants may be eligible for study after being on stable and appropriate anti-infective therapy.

2.1.3.11 Chemotherapy for active cancer.

2.1.3.12 Pregnancy or breastfeeding

2.1.3.13 Use of immunosuppressive or immunomodulating agents within 8 weeks prior to study enrollment. Note: patients receiving oral corticosteroids for management of asthma or contact hypersensitivity for less than or equal to 14 days in duration will be allowed to enroll as long as it has been greater than or equal to 30 days since oral corticosteroid administration.

2.1.3.14 Known immediate hypersensitivity to yeast or any of the vaccine components.

2.1.3.15 Use of investigational agents within 4 weeks prior to study enrollment.

2.1.3.16 Active external genital warts requiring treatment or carcinoma in-situ 2/3 (CIN2/3)

2.1.3.17 Any clinically significant diseases or findings during study screening that, in the opinion of the Principal Investigator or Lead Associate Investigator may interfere with the study.

Primary outcomes:
measure: Immunogenicity of the Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine in Human Immunodeficiency Virus (HIV)-Infected Preadolescents, Adolescents and Young Adults 12-26 Years of Age
timeFrame: Up to 36 months
Secondary outcomes:
measure: Human Papilloma Virus (HPV) Vaccine Immunogenicity Between Human Immunodeficiency Virus (HIV)-Infected Participants Receiving Highly Active Antiretroviral Therapy (HAART) & Those Not Receiving HAART With Similar T-lymphocytes (CD4) & Viral Load Parameters
timeFrame: At study entry
measure: Number of Participants With Log Change in Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels After Human Papilloma Virus (HPV) Vaccination
timeFrame: Baseline, and months 1, 3, 7 and 12
measure: Fold Change in Anti-Human Papilloma Virus (HPV) Titer and T-lymphocytes (CD4) Count (Only at Baseline)
timeFrame: Months 7, 12, 24 and 36
measure: T-lymphocytes (CD4) Count (Only at Baseline)
timeFrame: Baseline
measure: Number of Participants With Human Papilloma Virus (HPV) Deoxyribonucleic Acid (DNA) Positivity by Oral/Buccal Swabs at Baseline in the Study Cohort Populations
timeFrame: Baseline
measure: Number of Participants With Human Papillomavirus (HPV) Deoxyribonucleic Acid (DNA) Positivity by Anogenital Swabs
timeFrame: Up to 36 months
measure: Number of Participants Who Completed The Youth Risk Behavior Surveillance System (YRBSS)
timeFrame: Baseline
measure: Number of Participants With Serum for Human Papilloma Virus (HPV) Antibody Titers Performed by Merck (Competitive Luminex Assay)
timeFrame: 0, 1, 2, 3, 6, 7, 12, 18, 24, 30, 36, 42, and 48 hours
measure: Functional Human Papilloma Virus (HPV) Antibody Neutralization Assays
timeFrame: At 7 months
measure: Cryopreserved Peripheral Blood Mononuclear Cells (PBMCs) for Human Papilloma Virus (HPV) & Human Immunodeficiency Virus (HIV) Lymphocyte Proliferation Assays, Cytokine Induction Assay, Luminex Multi-cytokine Profiling of PBMCs
timeFrame: 0, 1, 3, 7, 12, 24, 36, and 48 hours
measure: Extended Fluorescence Activated Cell Sorting (FACS)/Quantitative Lymphocyte Subpopulation Studies
timeFrame: 0, 1, 3, 7, 12, 18, 24, 30, 36, 42, and 48 hours
measure: Quantitative Measurement of Human Immunodeficiency Virus (HIV)-Related Chemokines Macrophage Inflammatory Proteins (MIP)-1 Alpha (α), MIP-1 Beta (β) and Regulated Upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)
timeFrame: 0, 1, 2, 3, 6, 7, 12, 18, 24, 30, 36, 42, and 48 hours
measure: Cryopreserved Whole Blood for Human Papilloma Virus (HPV) Deoxyribonucleic Acid (DNA) Testing
timeFrame: 0, 7, 12, 24, 36, and 48 Months
measure: Research Assays Immunologic Responses for Human Immunodeficiency Virus (HIV) Infected Subjects Only
timeFrame: Month 0 only
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0)
timeFrame: Date treatment consent signed to date off study, up to 43 months and 8 days
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Hoyoung M Maeng, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev. 1988;10:122-63. doi: 10.1093/oxfordjournals.epirev.a036020.
citation: Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003 Feb 6;348(6):518-27. doi: 10.1056/NEJMoa021641.
citation: Koshiol JE, Laurent SA, Pimenta JM. Rate and predictors of new genital warts claims and genital warts-related healthcare utilization among privately insured patients in the United States. Sex Transm Dis. 2004 Dec;31(12):748-52. doi: 10.1097/01.olq.0000145851.76025.ad.