Clinical trial NCT03284866: HPV Vaccine Therapy in Reducing High-Grade Cervical Lesions in Patients With HIV and HPV
Official title: A Randomized, Placebo-Controlled Trial of HPV Vaccination to Reduce Cervical High-Grade Squamous Intraepithelial Lesions Among HIV-Infected Women Participating in an HPV Test-and-Treat Program (COVENANT)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: AIDS-Related Human Papillomavirus Infection
High Grade Cervical Squamous Intraepithelial Neoplasia
HIV Infection
Lead sponsor: AIDS Malignancy Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: University of Arkansas
name: AIDS and Cancer Specimen Resource
name: Merck Sharp & Dohme LLC
name: The Emmes Company, LLC
name: University of California, Los Angeles
First posted: 2017-09-15
Enrollment: 536
Sex: FEMALE
Minimum age (years): 25
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This randomized phase III trial studies how well human papillomavirus (HPV) vaccine therapy works in reducing high-grade cervical lesions in patients with human immunodeficiency virus (HIV) and HPV. Vaccines made from HPV peptides or antigens may help the body build an effective immune response to kill the HPV virus and prevent cervical lesions from developing or coming back after being removed.

Detailed description: At screening, potential participants will be tested for cervical human papillomavirus (HPV) infection (GeneXpert hrHPV assay and HPV DNA PCR) and undergo cervical colposcopy to confirm the absence of cervical cancer. If eligible, the participant will be randomized to receive either the 9-valent HPV vaccine or saline placebo.

Participants will return 4 and 26 weeks later for the second dose of vaccine or placebo. At week 4, participants will have cervical colposcopy and undergo cryotherapy or loop electrosurgical excisional procedure (LEEP) as appropriate. Participants undergoing cervical cryotherapy will have cervical biopsies before the treatment. Participants will be followed with HPV testing (Gene Xpert and HPV DNA PCR) at weeks 26, 52, 78, and 104, and will have cervical cytology and colposcopy with biopsies at weeks 26, 52, and 104.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load, or documentation of receipt of antiretroviral therapy; Note: the term "licensed" refers to a kit that has been certified or licensed by an oversight body within the participating country and validated internally; WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment; a reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a western blot or a plasma HIV-1 RNA viral load
* HPV positive by the GeneXpert hrHPV assay with HPV16, HPV 18/45, or HPV31/33/35/52/58 detected; Note: participants who are hrHPV positive with only HPV51/59 or HPV 39/68/56/66 detected are not eligible
* Receipt of ART for at least 180 days prior to randomization
* Participants of childbearing potential, defined as a sexually mature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy or (2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months), must have a negative urine or serum pregnancy test within 3 weeks prior to enrollment and agree to use an effective form of contraception (e.g., barrier contraception or hormonal contraception), delaying pregnancy for at least 12 months and ideally for the duration of the study; Note: those willing to participate delay pregnancy for at least 6 months, while receiving the recombinant human papillomavirus nonavalent (9vHPV) vaccine (or placebo)
* If the participant is of childbearing potential, she should be at least 3 months postpartum
* Karnofsky score \>= 70%
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Current sexually transmitted infection (STI) requiring treatment (women may participate after adequate treatment, at the discretion of the treating provider)
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to Gardasil or Gardasil 9
* Uncontrolled intercurrent illness that would limit compliance with study requirements
* Prior hysterectomy with removal of the cervix
* Prior treatment for cervical HSIL
* Prior history of cervical, vulvar, or vaginal cancer
* Cervical, vulvar, or vaginal lesions suspicious for cancer based on clinical appearance (e.g. necrotic, ulcerated, and/or fungating masses), unless biopsies show no invasive cancer
* Known bleeding diathesis
* Prior HPV vaccination
* Current or planned use of anticoagulants other than aspirin or non-steroidal anti-inflammatory agents

Primary outcomes:
measure: Occurrence of cervical high-grade squamous intraepithelial lesions (HSIL) or cervical cancer
timeFrame: After week 4 study visit to week 52 post-randomization
Secondary outcomes:
measure: Occurrence of cervical HSIL from weeks 52-104
timeFrame: After week 52 to week 104
measure: Role of baseline types and quantity of HPV as predictors of sustained absence
timeFrame: At baseline and week 4
measure: Role of presence of HSIL at baseline as a predictor of sustained absence
timeFrame: At baseline and week 4
measure: Role of CD4+ cell count as a predictor of sustained absence
timeFrame: At baseline and week 4
measure: Role of plasma HIV-1 RNA as a predictor of sustained absence
timeFrame: At baseline and week 4
measure: Role of ART use as a predictor of sustained absence
timeFrame: At baseline and week 4
measure: Role of age as a predictor of sustained absence
timeFrame: At baseline and week 4
measure: Role of sexual behavior as a predictor of sustained absence
timeFrame: At baseline and week 4
measure: Role of vaccination use as a predictor of sustained absence
timeFrame: At baseline and week 4
measure: Incident cervical vaccine type HPV infections defined as infections at 2 consecutive timepoints and assessed using type specific HPV DNA polymerase chain reaction (PCR)
timeFrame: Up to week 104
measure: Abnormal cervical cytology
timeFrame: Baseline, week 26, 52, and 104
measure: Prevalent vulvar HSIL or cancer
timeFrame: Up to week 4
measure: Incident vulvar HSIL or cancer
timeFrame: Up to week 104
measure: Clinical and demographic factors associated with incident vulvar HSIL or cancer
timeFrame: Up to week 104
Other outcomes:
measure: HPV type distributions
timeFrame: Up to week 104
measure: HPV strain variant analysis of cervical and vulvar HSIL specimens
timeFrame: Up to week 104
measure: Tissue microarray library of cervical specimens for biomarker analysis and discovery
timeFrame: Up to week 104
measure: hrHPV type distribution in the anus
timeFrame: Up to week 104
measure: hrHPV type prevalence in the anus
timeFrame: Up to week 104
measure: Vaccine-induced antibody titers
timeFrame: Up to week 104
Locations:
city: Eldoret
country: Kenya
facility: Moi University School of Medicine
city: Lilongwe
country: Malawi
facility: UNC Project Malawi
city: Cape Town
country: South Africa
facility: African Cancer Institute at Stellenbosch
city: Johannesburg
country: South Africa
facility: University of the Witwatersrand
city: Kampala
country: Uganda
facility: Uganda Cancer Institute
city: Harare
country: Zimbabwe
facility: University of Zimbabwe
Study officials:
affiliation: University of Witwatersrand, South Africa
name: Carla Chibwesha
role: PRINCIPAL_INVESTIGATOR
References: