HPV Test-and-Treat-Strategy Versus Cytology-based Strategy for Prevention of CIN2+ in HIV-Infected Women

Study Overview
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Brief Summary
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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
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The study had two components: 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 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.

Official Title
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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

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Procedure: Cervical Cryotherapy
* Procedure: Loop Electrosurgical Excision Procedure (LEEP)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Immediate cryotherapy (HPV test-and-treat)<br>Participants in Arm A (HPV test-and-treat) had cervical cryotherapy at entry. Post entry, participants in Arm A were seen at regular intervals for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP. | Procedure: Cervical Cryotherapy<br>* Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.<br>Procedure: Loop Electrosurgical Excision Procedure (LEEP)<br>* Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.<br>|
| Experimental: Arm B: cytology-based strategy<br>Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). | Procedure: Loop Electrosurgical Excision Procedure (LEEP)<br>* Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.<br>|
| Experimental: Arm C : Ineligible for randomization to Arm A or B<br>Participants were eligible for Arm C under the conditions noted in the inclusion criteria. Participants in Arm C had colposcopy and directed biopsies at entry. If CIN2+ was found by biopsy, then LEEP was performed and a follow-up visit 26 weeks after these procedures was scheduled for the collection of cervical specimens, cytology, and as needed, cervical colposcopy, directed biopsies, and LEEP. After the week 26 visit, Arm C participants went off study. | Procedure: Loop Electrosurgical Excision Procedure (LEEP)<br>* Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Rate of Cervical Intraepithelial Neoplasia (CIN2+) (CIN2, CIN3 or Invasive Cancer) by Week 130 | The Kaplan-Meier estimate of the cumulative rate of CIN2+ (CIN2, CIN3 or invasive cancer) by week 130. Time to CIN2+ was computed as the number of weeks between randomization and the week 26 to week 130 biopsy week when CIN2+ was first detected. For those who did not develop CIN2+, event time was censored at the latest among the following: time of last biopsy or last colposcopy or last pap smear. CIN2+ diagnosis by biopsy was determined by local review at a DAIDS-assessed laboratory. | Weeks 26, 52, 78, 104 and 130 post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to CIN2+ Diagnosis by Biopsy, as Determined by Local Review at a DAIDS-assessed Laboratory. | Time to CIN2+ was computed as the number of weeks between randomization and the week 26 to week 130 biopsy week when CIN2+ was first detected. For those who did not develop CIN2+, event time was censored at the latest among the following: time of last biopsy or last colposcopy or last pap smear. The 10th percentile of the time to CIN2+ (the number of weeks at which 10% of participants had had CIN2+ diagnosis) is presented in the data table below. | Weeks 26, 52, 78, 104 and 130 post randomization | 
| Cumulative Rate of CIN3+ (CIN3 or Invasive Cancer) by Week 130. | The Kaplan-Meier estimate of the cumulative rate of CIN3+ (CIN3 or invasive cancer) by week 130. Time to CIN3+ was computed as the number of weeks between randomization and the week 26 to week 130 biopsy week when CIN3+ was first detected. For those who did not develop CIN3+, event time was censored at the latest among the following: time of last biopsy or last colposcopy or last pap smear. CIN3+ diagnosis by biopsy was determined by local review at a DAIDS-assessed laboratory. | Weeks 26, 52, 78, 104 and 130 post randomization | 
| Number of Participants Who Discontinued Study Early. | The number of participants who did not complete the study. | 0 to 130 weeks post randomization | 
| Number of Participants With Abnormal Cytology Results at Study Visits. | Number of participants with abnormal (ASCUS: atypical squamous cells; undetermined significance, ASC-H: atypical squamous cells; favor high-grade squamous intra-epithelial lesion, LSIL: low-grade squamous intraepithelial lesion/mild dysplasia/HPV, HSIL: high-grade squamous intraepithelial lesion/moderate or severe dysplasia/carcinoma in situ/features of invasion; squamous cell carcinoma) cytology results. | Weeks 26, 52, 78, 104 and 130 post randomization | 
| Number of Participants With High Risk (hr)-HPV by the Abbott Real Time High-risk HPV Assay (aHPV) at Study Visits. | Number of participants with hr-HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) as detected by the Abbott Real Time high-risk HPV assay. Specimens for weeks 52, 78, 104 and 130 were not tested due to insufficient funding. | Weeks 26, 52, 78, 104 and 130 post randomization | 
| Number of Participants With High Risk (hr)-HPV by the Xpert HPV Assay at Study Visits. | Number of participants with hr-HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) as detected by the Xpert HPV assay. Specimens for weeks 52, 78, 104 and 130 were not tested due to insufficient funding. | Weeks 26, 52, 78, 104 and 130 post randomization | 
| Number of Participants With High Risk (hr)-HPV by the Roche Linear Array HPV Genotyping Test at Study Visits. | Number of participants with hr-HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) as detected by the Roche Linear Array HPV Genotyping test. Specimens for weeks 52, 78, 104 and 130 were not tested due to insufficient funding. | Weeks 26, 52, 78, 104 and 130 post randomization | 
| Percentage of Participants With Targeted Adverse Events (AEs) Reported Post Cryotherapy in Arm A. | Cryotherapy was performed in Arm A within 7 days of study entry. Targeted AEs four weeks after cryotherapy is provided in the data table below. The AE categories are not mutually exclusive. A participant may have experienced AEs and may be counted in more than one category. | 4 weeks post cryotherapy | 
| Percentage of Participants With Targeted AEs Reported Post LEEP. | LEEP was performed on participants who had CIN2+. For Arm A participants, LEEP was available starting at week 26; for Arms B and C, LEEP was available starting at study entry. Targeted AEs four weeks after LEEP is provided in the data table below. The AE categories are not mutually exclusive. A participant may have experienced AEs and may be counted in more than one category. | 4 weeks post LEEP |