AIDS-Related Human Papillomavirus Infection, High Grade Cervical Squamous Intraepithelial Neoplasia, HIV Infection
Conditions
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
Given IM
OTHERSaline
Given IM
Sponsors
AIDS Malignancy Consortium
National Cancer Institute (NCI)
University of Arkansas
AIDS and Cancer Specimen Resource
Merck Sharp & Dohme LLC
The Emmes Company, LLC
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
25 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Cervical High-grade Squamous Intraepithelial Lesions (HSIL) or Cervical Cancer | After week 4 study visit to week 52 post-randomization | For each arm (vaccine and placebo), the HSIL or cancer event rate will be estimated using its point estimate and 95% Poisson confidence intervals. Poisson regression analyses will be used to compare the two arms with respect to event rate. In addition, time to event from week 4 to 52 will be described using the Kaplan-Meier method for each arm, and the two arms will be compared with respect to time to event using the log-rank test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Cervical HSIL or Invasive Cancer From Weeks 52-104 | After week 52 to week 104 | The event rate for each arm from week 52 to week 104 for women who are event-free at 52 weeks will be estimated using its point estimate and 95% Poisson confidence interval. Poisson regression will be used to compare the two groups with respect to the event rate from week 52 to 104. |
| Predictors of Sustained Absence of Cervical HSIL Through Week 104 and HPV Clearance | At baseline through week 104 | Role of baseline types and quantity of HPV, presence of HSIL at baseline, cryotherapy vs. LEEP, CD4+ cell count, plasma HIV-1 RNA, ART use, age, sexual behavior, and vaccination use will be investigated. Poisson regression analyses will be used to determine if these factors are associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. These analyses will also control for use of LEEP or cryotherapy. |
| Incident Cervical Vaccine Type HPV Infections | Up to week 104 | Incident cervical vaccine type HPV infections are defined as HPV infections detected at 2 consecutive timepoints and assessed using type specific HPV DNA polymerase chain reaction (PCR) Vaccine and placebo participants will be compared with respect to these proportions using the chi-square test corrected for continuity. |
| Abnormal Cervical Cytology | Baseline, week 26, 52, and 104 | The proportion of women with abnormal cervical cytology at baseline, week 26, 52, and 104 will be reported and compared between arms. |
| Prevalent Vulvar HSIL or Cancer | Up to week 4 | The prevalence of vulvar HSIL or cancer at baseline will be estimated using the binomial proportion and its 95% confidence interval. |
| Incident Vulvar HSIL or Cancer | Up to week 104 | The proportion of women who acquire vulvar HSIL or cancer among those negative for vulvar HSIL or cancer at baseline for both intervention arms will be estimated as a binomial proportion for both groups. The chi-square test corrected for continuity will be used to compare arms with respect to the proportions who acquire vulvar HSIL during the study. |
| Number of Participants Stratified by the Presence or Absence of Incident Vulvar HSIL/Cancers. | Up to week 104 | Due to insufficient number of participants with outcome assessments, association (Logistic regression) analysis with clinical and demographic factors was not performed |
Countries
Kenya, Malawi, South Africa, Uganda, Zimbabwe
Contacts
PRINCIPAL_INVESTIGATORCarla Chibwesha
University of Witwatersrand, South Africa
Participant flow
Pre-assignment details
1256 patients underwent screening for determination of eligibility for the study. 535 patients were identified as eligible and enrolled
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 39.0 years |
| Age, Customized <=35 | 178 Participants |
| Age, Customized 35.1-45 | 241 Participants |
| Age, Customized 45.1-65 | 116 Participants |
| ART for at least 180 days prior to randomization | 270 Participants |
| CD4+ cells nadir at baseline <200 cells per cubic mm | 33 Participants |
| CD4+ cells nadir at baseline >=200 cells per cubic mm | 82 Participants |
| CD4+ cells nadir at baseline Not known | 305 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 179 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 176 Participants |
| History of Anal Sex | 29 Participants |
| History of anal SIL including anal condyloma? | 10 Participants |
| History of vulvar SIL including vulvar condyloma | 23 Participants |
| HIV viral load <200 copies/mL | 255 Participants |
| HIV viral load ≥200 copies/mL | 15 Participants |
| HIV viral load Missing data | 2 Participants |
| Karnofsky Performance Score 100 | 444 Participants |
| Karnofsky Performance Score 90 | 44 Participants |
| Median CD4+ nadir at baseline | 247.0 cells per cubic millimeters |
| New sex partner in the past 12 months | 63 Participants |
| Presence of High-risk HPV infection HPV 16 | 79 Participants |
| Presence of High-risk HPV infection HPV 18/45 | 71 Participants |
| Presence of High-risk HPV infection HPV 31/33/35/52/58 | 184 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 181 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 80 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex/Gender, Customized Female | 270 Participants |
| Tobacco used past month | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 265 | 3 / 270 |
| other Total, other adverse events | 20 / 265 | 22 / 270 |
| serious Total, serious adverse events | 16 / 265 | 20 / 270 |
Outcome results
None listed