Clinical trial NCT01315353: HPV Test-and-Treat-Strategy Versus Cytology-based Strategy for Prevention of CIN2+ in HIV-Infected Women
Official title: A Randomized Trial To Compare An HPV Test-And-Treat Strategy To A Cytology-Based Strategy For Prevention Of CIN 2+ In HIV-Infected Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-03-15
Enrollment: 467
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Women sometimes develop cancer in an area called the cervix, which is the opening to the uterus, or womb. Women who have HIV are more likely to get this kind of cancer than women who do not have HIV. Nearly all of these cancers are caused by another virus, called human papilloma virus (or HPV). Other times, the cause of this cancer is not known.

The investigators are looking for a better way to prevent cervical cancer. This study is comparing two different methods to prevent cancer of the cervix in women who have HIV. This study will also see if these methods are safe and tolerable in women who have HIV.

Detailed description: The study had two components:

1. a randomized open-label comparison between immediate cryotherapy (test-and-treat strategy; Arm A) and cytology-based strategy (Arm B) in participants detected with high-risk HPV (hr-HPV), and
2. a brief cohort follow-up for participants for whom cryotherapy was inappropriate (Arm C).

The study's primary objective was to evaluate the effectiveness of immediate cryotherapy (Arm A) compared to the cytology-based strategy (Arm B).

The total target sample size was up to 450 (280 for Arms A and B, approximately 170 for Arm C). Randomization to Arms A and B was stratified by use of antiretroviral therapy (ART) at screening (taking any ART or not taking any ART) with institutional balancing.

All study participants were screened with the Abbott RealTime hr-HPV test (aHPV) to detect hr-HPV infection.

At screening, the examiner also performed a visual inspection and colposcopy without biopsies to determine whether the candidate's cervix was suitable for cryotherapy (see inclusion criteria for definition).

Participants with cervical lesions inappropriate for cryotherapy were not eligible for randomization (to Arms A or B) but were eligible to register to Arm C. Participants without hr-HPV (by aHPV) were also eligible to register to Arm C if lesions were seen on the screening colposcopy or if the screening cytology showed high-grade squamous intraepithelial lesions (HSIL). Arm C provided a larger number of participants for assessments of HPV genotypes found in CIN2+ (cervical intraepithelial neoplasia grade 2, 3, or invasive cancer) biopsy specimens and of the effect of LEEP on prevalent hr-HPV infections. In addition, Arm C provided important data for implementation of the HPV test-and-treat strategy including the role of HPV testing in the management of women with extensive cervical lesions inappropriate for cervical cryotherapy, hr-HPV negative women with cervical lesions or HSIL cytology.

Participants in Arm A undergo one or two cervical biopsies followed by immediate cervical cryotherapy at entry. Up to two visible lesions were biopsied. If no lesions were seen, then one normal-appearing area of the cervix was biopsied. Participants in Arm A received the results of the biopsy, but participants received cryotherapy treatment regardless of the results.

Participants in Arm B followed a cytology-based management plan involving three steps - cytology, colposcopy with directed biopsies, and loop electrosurgical excision procedure (LEEP), as needed.

Participants in Arms A and B were seen at weeks 26, 52, 78, 104 and 130 post entry for evaluation using aHPV, HPV DNA PCR, cervical cytology, and cervical colposcopy and directed biopsies for a total follow-up length of 130 weeks. Biopsies were expected for participants with abnormal cytology and with visible cervical lesions on colposcopy.

Participants in Arm C undergo colposcopy and directed biopsies. If CIN2+ was detected by biopsy, then LEEP was performed and a follow-up visit 26 weeks after these procedures was scheduled for evaluation using aHPV, HPV DNA PCR, Xpert HPV, cervical cytology, and cervical colposcopy and directed biopsies. After the week 26 visit, Arm C participants went off study.

All participants who had cryotherapy or LEEP were seen 4 weeks post-procedure to evaluate potential adverse events (AEs) from the procedure.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infection.
* Certain laboratory values obtained within 45 days prior to study entry (more information can be found in the protocol).
* For candidates suitable for cervical cryotherapy, hr-HPV detected by aHPV within 45 days prior to study entry.
* For women without hr-HPV detected by the aHPV assay, presence of lesions on visual inspection or HSIL cervical cytology. These participants are not eligible for randomization to Arms A or B and were followed in Arm C.
* Suitable candidate for cervical cryotherapy (as defined in the protocol): No visible cervical lesions, OR (a) any visible lesions were located entirely on the ectocervix and were no more than 2 to 3 mm. into the endocervical canal, AND (b) visible lesions covered less than 75% of the cervix, AND (c) all visible lesions were deemed appropriate for cryotherapy by the treating local health care provider.

NOTE: Participants with cervical lesions inappropriate for cryotherapy are not eligible for randomization to Arms A or B and were followed in Arm C.

* For participants of reproductive potential, negative pregnancy test within 48 hours prior to study entry.
* Must agree not to participate in a conception process (e.g. active attempt to get pregnant or in vitro fertilization), or use at least one reliable contraceptive if participating in sexual activity, from time of study entry until 12 weeks after study entry.
* If recently gave birth, must be at least 12 weeks postpartum.
* Ability and willingness of participant or legal guardian/representative to provide written informed consent.

Exclusion Criteria:

* Current or prior history of cervical, vaginal, or vulvar cancer.
* Prior cervical cryotherapy, LEEP, cervical conization, or total or partial hysterectomy.
* Cervical, vaginal, or vulvar lesions that are suspicious on clinical exam for cancer.
* Visual evidence of bacterial STIs (sexually transmitted infections) or suspicion of pelvic inflammatory disease.
* Prior vaccination with an HPV vaccine.
* Hemophilia.
* Currently on anticoagulation therapy other than acetylsalicylic acid.
* Serious illness requiring systemic treatment and/or hospitalization within 21 days prior to study entry.
* Active drug or alcohol use or dependence or any other condition that, in the opinion of the site investigator, would interfere with the participant's ability to adhere to study requirements.

Primary outcomes:
measure: Cumulative Rate of Cervical Intraepithelial Neoplasia (CIN2+) (CIN2, CIN3 or Invasive Cancer) by Week 130
timeFrame: Weeks 26, 52, 78, 104 and 130 post randomization
Secondary outcomes:
measure: Time to CIN2+ Diagnosis by Biopsy, as Determined by Local Review at a DAIDS-assessed Laboratory.
timeFrame: Weeks 26, 52, 78, 104 and 130 post randomization
measure: Cumulative Rate of CIN3+ (CIN3 or Invasive Cancer) by Week 130.
timeFrame: Weeks 26, 52, 78, 104 and 130 post randomization
measure: Number of Participants Who Discontinued Study Early.
timeFrame: 0 to 130 weeks post randomization
measure: Number of Participants With Abnormal Cytology Results at Study Visits.
timeFrame: Weeks 26, 52, 78, 104 and 130 post randomization
measure: Number of Participants With High Risk (hr)-HPV by the Abbott Real Time High-risk HPV Assay (aHPV) at Study Visits.
timeFrame: Weeks 26, 52, 78, 104 and 130 post randomization
measure: Number of Participants With High Risk (hr)-HPV by the Xpert HPV Assay at Study Visits.
timeFrame: Weeks 26, 52, 78, 104 and 130 post randomization
measure: Number of Participants With High Risk (hr)-HPV by the Roche Linear Array HPV Genotyping Test at Study Visits.
timeFrame: Weeks 26, 52, 78, 104 and 130 post randomization
measure: Percentage of Participants With Targeted Adverse Events (AEs) Reported Post Cryotherapy in Arm A.
timeFrame: 4 weeks post cryotherapy
measure: Percentage of Participants With Targeted AEs Reported Post LEEP.
timeFrame: 4 weeks post LEEP
Other outcomes:
Locations:
city: Gaborone
country: Botswana
facility: Gaborone Prevention/Treatment Trials CRS (12701)
city: Molepolole
country: Botswana
facility: Molepolole Prevention/Treatment Trials CRS (12702)
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO CRS (30022)
city: Pune
country: India
facility: BJ Medical College CRS (31441)
state: Maharashtra
city: Pune
country: India
facility: National AIDS Research Institute Pune CRS (11601)
state: Maharashtra
city: Blantyre
country: Malawi
facility: College of Med. JHU CRS (30301)
city: Lilongwe
country: Malawi
facility: University of North Carolina Lilongwe CRS (12001)
city: San Isidro
country: Peru
facility: Investigaciones Medicas en Salud (INMENSA) (11302)
state: Lima
city: Lima
country: Peru
facility: Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
city: Durban
country: South Africa
facility: Durban Adult HIV CRS (11201)
city: Johannesburg
country: South Africa
facility: Soweto ACTG CRS (12301)
city: Johannesburg
country: South Africa
facility: Univ. of Witwatersrand CRS (11101)
city: Harare
country: Zimbabwe
facility: UZ-Parirenyatwa CRS (30313)
Study officials:
affiliation: Cornell Clinical Research Site
name: Timothy J Wilkin, MD, MPH
role: STUDY_CHAIR
References: