Clinical trial NCT00604175: Safety of and Immune Response to the Human Papillomavirus (HPV) Vaccine in HIV-Infected Women
Official title: A Phase II Study to Evaluate the Immunogenicity and Safety of a Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Females
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Sexually Transmitted Diseases
Keywords: HIV
HPV 6
HPV 11
HPV 16
HPV 18
Vaccine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: National Institute of Dental and Craniofacial Research (NIDCR)
First posted: 2008-01-30
Enrollment: 319
Sex: FEMALE
Minimum age (years): 13
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Human papillomavirus (HPV) is the most common sexually transmitted disease in the world. HPV infection can cause genital warts and certain cervical problems, including cervical cancer. HPV infection may be more severe and harder to treat in HIV-infected people. The purpose of this study was to determine whether the quadrivalent HPV vaccine is safe, tolerable, and effective in producing antibodies to HPV in HIV-infected women.

Detailed description: HPV is a DNA virus that affects both men and women. Approximately 90 types of HPV have been identified, 30 of which are sexually transmitted. The most common forms of HPV are types 6, 11, 16, and 18. The quadrivalent HPV vaccine that was tested in this study had been shown in previous studies to be effective in preventing infection with HPV 6, 11, 16, and 18 in healthy young women. According to a report by the Centers for Disease Control and Prevention (CDC), 80% of women will have acquired HPV by the age of 50. HIV infected women have been reported to have a higher prevalence and persistence of HPV infection, as well as an increased risk for abnormal Pap smears and cervical cancer. HPV types 16 and 18 cause the majority of cervical cancers worldwide, and types 6 and 11 are responsible for the majority of cases of genital warts. Vaccinations for preventable infections are particularly important among HIV infected people because people with HIV have compromised immune systems; therefore, any infection is very serious and can potentially be fatal. However, standard vaccination series have not been very successful because a compromised immune system may not produce the desired immune response to a vaccine. The HPV vaccine is designed to protect against infection with HPV types 6, 11, 16, and 18 and has been approved by the FDA for use in women between the ages of 9 and 26. The purpose of this study was to determine whether the quadrivalent HPV vaccine is safe, tolerable, and effective in producing antibodies to HPV in HIV infected females.

The study consisted of single arm evaluations of HPV vaccine immunogenicity and safety in 3 groups based on the study screening CD4 cell count as follows:

* Stratum A: CD4 cell count \>350 cells/mm\^3
* Stratum B: CD4 cell count \>200 to \<=350 cells/mm\^3
* Stratum C: CD4 cell count \<=200 cells/mm\^3

In Version 1.0 of the protocol, the target accrual was n=67 participants with screening HIV viral load \<=10,000 copies/mL and n=67 participants with HIV viral load \>10,000 copies/mL within each CD4 stratum, yielding n=134 in each CD4 stratum. In light of subsequent findings from completed HPV vaccine studies, the sample size was changed to n=94 participants per CD4 stratum in Version 2.0 of the protocol, and stratification by screening HIV viral load was removed. All Stratum A and Stratum B participants were enrolled under protocol Version 1.0.

The study duration was 72 weeks. All participants received HPV vaccine administered by intramuscular injection at baseline, and at Weeks 8 and 24. Following each injection, participants remained at the clinic for 30 minutes of observation for adverse events. A telephone follow-up or a home visit by study staff was performed within 2 days following each injection.

Participants returned to the clinic for visits at Weeks 4, 8, 12, 24, 28, 52, and 72. Most study visits included a physical exam, medication review, blood and urine collection, and answering questions about signs and symptoms since previous visit. Some visits included measurement of HIV viral load and CD4 cell count; collection of endocervical wick, cervical cytobrush and anal swab; and an oral exam. A subset of participants were asked to provide additional blood samples and oral cytobrush specimens.

Eligibility criteria: Inclusion Criteria:

* HIV infection
* CD4 count obtained within 45 days prior to study entry
* Karnofsky performance score \>=70 on at least one occasion within 45 days prior to study entry
* The following labs within 45 days prior to study entry:

  * hemoglobin \>8.0 g/dL
  * direct bilirubin \<2.5 x upper limit of normal (ULN)
  * alanine aminotransferase, ALT (SGPT) \<3 xULN
  * aspartate aminotransferase, AST (SGOT) \<3 xULN
  * platelet count \>=100,000 /mm\^3
* Willing to use acceptable forms of contraception for the duration of the study
* Written informed consent from participant or from parent or guardian, if applicable
* If on HAART, then the same regimen for at least 12 weeks prior to study entry with no change within 30 days prior to study entry. (This criterion was removed in Version 2.0 of the protocol.)
* HIV viral load obtained within 45 days prior to study entry (This criterion was removed in Version 2.0 of the protocol.)

Exclusion Criteria:

* Abnormal Pap test with confirmed biopsy results of cervical intraepithelial neoplasia (CIN) II or III or cervical cancer within 180 days prior to study entry
* Vulval intraepithelial neoplasia (VIN) II or III or cancer confirmed by biopsy results within 180 days prior to study entry
* Physician-diagnosed genital warts within 180 days prior to study entry
* Previous cervical dysplasia treatment, including loop electrosurgical excision procedure (LEEP), cervical cryotherapy, cone biopsy, and cervical laser vaporization within 180 days prior to study entry
* Use of any systemic antineoplastic or immunomodulatory treatment, systemic corticosteroids, investigational vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin (IVIG) within 45 days prior to study entry. Participants who had received standard of care (e.g., hepatitis B, influenza, and tetanus) vaccines were not excluded.
* Known allergy or hypersensitivity to yeast or any components of the vaccine or its formulation
* Current drug or alcohol use or dependence or any other condition that may interfere with study participation
* Serious illness requiring systemic treatment and/or hospitalization within 45 days prior to study entry
* Total hysterectomy. Participants who had undergone partial hysterectomy and had a cervix were not excluded.
* Hemophilia
* Currently on anticoagulation therapy other than acetylsalicylic acid
* Prior vaccination with an HPV vaccine
* Pregnant or breastfeeding

Primary outcomes:
measure: Percentage of Participants With HPV6 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series
timeFrame: Week 28
measure: Percentage of Participants With HPV11 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series
timeFrame: Week 28
measure: Percentage of Participants With HPV16 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series
timeFrame: Week 28
measure: Percentage of Participants With HPV18 Antibody Development From the Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series
timeFrame: Week 28
Secondary outcomes:
measure: HPV6 Antibody Titers Among Those Seronegative for HPV6 at Baseline
timeFrame: Weeks 28, 72
measure: HPV11 Antibody Titers Among Those Seronegative for HPV11 at Baseline
timeFrame: Weeks 28, 72
measure: HPV16 Antibody Titers Among Those Seronegative for HPV16 at Baseline
timeFrame: Weeks 28, 72
measure: HPV18 Antibody Titers Among Those Seronegative for HPV18 at Baseline
timeFrame: Weeks 28, 72
measure: Change in Log10 HPV6 Antibody Titers From Baseline Among Those Seropositive for HPV6 at Baseline
timeFrame: Weeks 0, 28, 72
measure: Change in Log10 HPV11 Antibody Titers From Baseline Among Those Seropositive for HPV11 at Baseline
timeFrame: Weeks 0, 28, 72
measure: Change in Log10 HPV16 Antibody Titers From Baseline Among Those Seropositive for HPV16 at Baseline
timeFrame: Weeks 0, 28, 72
measure: Change in Log10 HPV18 Antibody Titers From Baseline Among Those Seropositive for HPV18 at Baseline
timeFrame: Weeks 0, 28, 72
measure: Number of Participants With Signs and Symptoms of Grade 3 or Higher
timeFrame: From baseline to up to Week 72
measure: Number of Participants With Laboratory Abnormalities of Grade 3 or Higher
timeFrame: From baseline to up to Week 72
measure: Change in Log10 HIV Viral Load (VL) From Baseline
timeFrame: Weeks 0, 4, 12, 28, 52, and 72
measure: Change in CD4 Cell Count From Baseline
timeFrame: Weeks 0, 4, 8, 12, 24, 28, 52 and 72
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Alhambra
country: United States
facility: Usc La Nichd Crs
state: California
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS
state: California
city: Long Beach
country: United States
facility: Miller Children's Hosp. Long Beach CA NICHD CRS
state: California
city: Los Angeles
country: United States
facility: University of Southern California CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford AIDS Clinical Trials Unit CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Denver
country: United States
facility: Denver Public Health CRS
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS)
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: South Florida CDTC Ft Lauderdale NICHD CRS
state: Florida
city: Jacksonville
country: United States
facility: Univ. of Florida Jacksonville NICHD CRS
state: Florida
city: Miami
country: United States
facility: Pediatric Perinatal HIV Clinical Trials Unit CRS
state: Florida
city: Miami
country: United States
facility: The University of Miami AIDS Clinical Research Unit (ACRU) CRS
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS
state: Georgia
city: Chicago
country: United States
facility: Mt. Sinai Hosp. Med. Ctr. - Chicago, Womens & Childrens HIV Program
state: Illinois
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Chicago
country: United States
facility: Rush University CRS
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ. New Orleans NICHD CRS
state: Louisiana
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS)
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hosp. CRS
state: Michigan
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: Camden
country: United States
facility: Cooper Univ. Hosp. CRS
state: New Jersey
city: Newark
country: United States
facility: New Jersey Medical School- Adult Clinical Research Ctr. CRS
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: New York
country: United States
facility: Columbia IMPAACT CRS
state: New York
city: Rochester
country: United States
facility: Trillium Health ACTG CRS
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Greensboro
country: United States
facility: Greensboro CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Columbus
country: United States
facility: Ohio State University CRS
state: Ohio
city: Portland
country: United States
facility: The Research & Education Group-Portland CRS
state: Oregon
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ. Med. Ctr. CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital Clinical Research Site (TMH CRS) CRS
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics (VT) CRS
state: Tennessee
city: Dallas
country: United States
facility: Trinity Health and Wellness Center CRS
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital CRS
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth Univ. Medical Ctr. CRS
state: Virginia
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: Rio de Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico Pediatric HIV/AIDS Research Program CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
city: Johannesburg
country: South Africa
facility: Wits Helen Joseph Hospital CRS (Wits HJH CRS)
state: Gauteng
Study officials:
affiliation: Department of Immunology/Infectious Disease, The Miriam Hospital, Brown University
name: Erna Milunka Kojic, MD
role: STUDY_CHAIR
affiliation: Obstetrics-Gynecology and Medicine, The Miriam Hospital, Brown University
name: Susan Cu-Uvin, MD
role: STUDY_CHAIR
References:
citation: Cameron JE, Hagensee ME. Human papillomavirus infection and disease in the HIV+ individual. Cancer Treat Res. 2007;133:185-213. doi: 10.1007/978-0-387-46816-7_7.
citation: Chaturvedi AK, Goedert JJ. Human papillomavirus genotypes among women with HIV: implications for research and prevention. AIDS. 2006 Nov 28;20(18):2381-3. doi: 10.1097/01.aids.0000253366.94072.b4. No abstract available.
citation: De Vuyst H, Franceschi S. Human papillomavirus vaccines in HIV-positive men and women. Curr Opin Oncol. 2007 Sep;19(5):470-5. doi: 10.1097/CCO.0b013e3282c8c8fc.
citation: Kojic EM, Cu-Uvin S. Update: human papillomavirus infection remains highly prevalent and persistent among HIV-infected individuals. Curr Opin Oncol. 2007 Sep;19(5):464-9. doi: 10.1097/CCO.0b013e3282c8c84c.
citation: Palefsky J. Human papillomavirus infection in HIV-infected persons. Top HIV Med. 2007 Aug-Sep;15(4):130-3.
citation: Kojic EM, Kang M, Cespedes MS, Umbleja T, Godfrey C, Allen RT, Firnhaber C, Grinsztejn B, Palefsky JM, Webster-Cyriaque JY, Saah A, Aberg JA, Cu-Uvin S. Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in HIV-1-infected women. Clin Infect Dis. 2014 Jul 1;59(1):127-35. doi: 10.1093/cid/ciu238. Epub 2014 Apr 9.
citation: Kang M, Umbleja T, Ellsworth G, Aberg J, Wilkin T. Effects of Sex, Existing Antibodies, and HIV-1-Related and Other Baseline Factors on Antibody Responses to Quadrivalent HPV Vaccine in Persons With HIV. J Acquir Immune Defic Syndr. 2022 Apr 1;89(4):414-422. doi: 10.1097/QAI.0000000000002891.
citation: Cespedes MS, Kang M, Kojic EM, Umbleja T, Godfrey C, Webster-Cyriaque JY, Masih R, Firnhaber C, Grinsztejn B, Saah A, Cu-Uvin S, Aberg JA. Anogenital human papillomavirus virus DNA and sustained response to the quadrivalent HPV vaccine in women living with HIV-1. Papillomavirus Res. 2018 Dec;6:15-21. doi: 10.1016/j.pvr.2018.08.002. Epub 2018 Aug 16.