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

• Sponsor: AIDS Clinical Trials Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01315353
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 467
• Locations: 13
• Arms: 3
• Actual Duration (Months): 58
• Patients Per Site: 35.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV-1 Infection	Procedure: Cervical Cryotherapy; Procedure: Loop Electrosurgical Excision Procedure (LEEP)	N/A

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

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 467 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 4, 2012
• Actual Primary Completion Date: Feb 1, 2017
• Actual Study Completion Date: Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: Immediate cryotherapy (HPV test-and-treat) 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; Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing.; Procedure: Loop Electrosurgical Excision Procedure (LEEP); 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.
Experimental: Arm B: cytology-based strategy 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); 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.
Experimental: Arm C : Ineligible for randomization to Arm A or B 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); 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.

Outcome Measures

Primary Outcome Measures

1. Cumulative Rate of Cervical Intraepithelial Neoplasia (CIN2+) (CIN2, CIN3 or Invasive Cancer) by Week 130 [Weeks 26, 52, 78, 104 and 130 post randomization]

   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.

Secondary Outcome Measures

1. Time to CIN2+ Diagnosis by Biopsy, as Determined by Local Review at a DAIDS-assessed Laboratory. [Weeks 26, 52, 78, 104 and 130 post randomization]

   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.

2. Cumulative Rate of CIN3+ (CIN3 or Invasive Cancer) by Week 130. [Weeks 26, 52, 78, 104 and 130 post randomization]

   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.

3. Number of Participants Who Discontinued Study Early. [0 to 130 weeks post randomization]

   The number of participants who did not complete the study.

4. Number of Participants With Abnormal Cytology Results at Study Visits. [Weeks 26, 52, 78, 104 and 130 post randomization]

   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.

5. Number of Participants With High Risk (hr)-HPV by the Abbott Real Time High-risk HPV Assay (aHPV) at Study Visits. [Weeks 26, 52, 78, 104 and 130 post randomization]

   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.

6. Number of Participants With High Risk (hr)-HPV by the Xpert HPV Assay at Study Visits. [Weeks 26, 52, 78, 104 and 130 post randomization]

   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.

7. Number of Participants With High Risk (hr)-HPV by the Roche Linear Array HPV Genotyping Test at Study Visits. [Weeks 26, 52, 78, 104 and 130 post randomization]

   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.

8. Percentage of Participants With Targeted Adverse Events (AEs) Reported Post Cryotherapy in Arm A. [4 weeks post cryotherapy]

   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.

9. Percentage of Participants With Targeted AEs Reported Post LEEP. [4 weeks 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Gaborone Prevention/Treatment Trials CRS (12701)	Gaborone		Botswana
2	Molepolole Prevention/Treatment Trials CRS (12702)	Molepolole		Botswana
3	Les Centres GHESKIO CRS (30022)	Port-au-Prince		Haiti	HT-6110
4	BJ Medical College CRS (31441)	Pune	Maharashtra	India	411001
5	National AIDS Research Institute Pune CRS (11601)	Pune	Maharashtra	India	411026
6	College of Med. JHU CRS (30301)	Blantyre		Malawi
7	University of North Carolina Lilongwe CRS (12001)	Lilongwe		Malawi
8	Investigaciones Medicas en Salud (INMENSA) (11302)	San Isidro	Lima	Peru
9	Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)	Lima		Peru	18 PE
10	Durban Adult HIV CRS (11201)	Durban		South Africa	4013 SF
11	Soweto ACTG CRS (12301)	Johannesburg		South Africa
12	Univ. of Witwatersrand CRS (11101)	Johannesburg		South Africa
13	UZ-Parirenyatwa CRS (30313)	Harare		Zimbabwe

Sponsors and Collaborators

• AIDS Clinical Trials Group
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Timothy J Wilkin, MD, MPH, Cornell Clinical Research Site

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 13, 2017
• Study Protocol - Jun 10, 2015

More Information

Additional Information:

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009.
• Addendum 1 Female Genital Grading Table for Use in Microbicide Studies
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Publications

None provided.

• Responsible Party: AIDS Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT01315353
• Other Study ID Numbers: ACTG A5282; 1U01AI068636
• First Posted: Mar 15, 2011
• Last Update Posted: May 11, 2018
• Last Verified: May 1, 2018

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from April 2012 to June 2014 from 7 different countries.

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy	Arm C : Ineligible for Randomization to Arm A or B
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	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+ is 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. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Period Title: Overall Study
STARTED	145	143	179
COMPLETED	116	120	166
NOT COMPLETED	29	23	13

Baseline Characteristics

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy	Arm C : Ineligible for Randomization to Arm A or B	Total
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	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+ is 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. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Total of all reporting groups
Overall Participants	145	143	177	465
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	145 100%	143 100%	175 98.9%	463 99.6%
>=65 years	0 0%	0 0%	2 1.1%	2 0.4%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	38	34	36	36
Sex: Female, Male (Count of Participants)
Female	145 100%	143 100%	177 100%	465 100%
Male	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Black Non-Hispanic	106 73.1%	107 74.8%	156 88.1%	369 79.4%
Hispanic (Regardless of Race)	11 7.6%	9 6.3%	6 3.4%	26 5.6%
Asian, Pacific Islander	28 19.3%	27 18.9%	15 8.5%	70 15.1%
Region of Enrollment (Count of Participants)
Haiti	3 2.1%	3 2.1%	16 9%	22 4.7%
Malawi	35 24.1%	37 25.9%	23 13%	95 20.4%
Botswana	8 5.5%	7 4.9%	45 25.4%	60 12.9%
South Africa	40 27.6%	41 28.7%	55 31.1%	136 29.2%
Zimbabwe	20 13.8%	19 13.3%	17 9.6%	56 12%
Peru	11 7.6%	9 6.3%	6 3.4%	26 5.6%
India	28 19.3%	27 18.9%	15 8.5%	70 15.1%
CD4+ T-cell Count (cells/mm^3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm^3]	529	479	568	521
Nadir CD4+ T-Cell Count (Count of Participants)
<=50 cells/mm^3	16 11%	15 10.5%	13 7.3%	44 9.5%
51-100 cells/mm^3	12 8.3%	19 13.3%	17 9.6%	48 10.3%
101-200 cells/mm^3	33 22.8%	34 23.8%	34 19.2%	101 21.7%
201-500 cells/mm^3	61 42.1%	57 39.9%	70 39.5%	188 40.4%
>500 cells/mm^3	12 8.3%	10 7%	33 18.6%	55 11.8%
HIV-1 RNA (Count of Participants)
<LLQ	93 64.1%	85 59.4%	116 65.5%	294 63.2%
>=LLQ	52 35.9%	58 40.6%	61 34.5%	171 36.8%
Antiretroviral Therapy (ART) Use (Count of Participants)
Not taking any ART	25 17.2%	22 15.4%	35 19.8%	82 17.6%
Taking any ART	120 82.8%	121 84.6%	142 80.2%	383 82.4%

Outcome Measures

1. Primary Outcome

Title	Cumulative Rate of Cervical Intraepithelial Neoplasia (CIN2+) (CIN2, CIN3 or Invasive Cancer) by Week 130
Description	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.
Time Frame	Weeks 26, 52, 78, 104 and 130 post randomization

Outcome Measure Data

Analysis Population Description

Intent to treat: All eligible participants were included in the analysis: participants were analyzed per original assigned randomized treatment. Analysis was limited to the two randomized study arms (Arms A and B).

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	145	143
Number (95% Confidence Interval) [Events per 100 persons]	24.9	26.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Treatment comparison was made using the difference (arm B - arm A) in the stratified Kaplan-Meier estimate for the week 130 cumulative rate of CIN2+ with 95% one-sided confidence interval.
	Type of Statistical Test	Superiority
	Comments	Confidence interval estimation was stratified by ART use at screening using Greenwood's variance with the inverse of this variance used for the stratum weights.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cumulative rate difference
	Estimated Value	1.7
	Confidence Interval	(1-Sided) 95%; -7.9 to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The lower bound of the (lower) one-sided 95% confidence interval was provided.

2. Secondary Outcome

Title	Time to CIN2+ Diagnosis by Biopsy, as Determined by Local Review at a DAIDS-assessed Laboratory.
Description	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.
Time Frame	Weeks 26, 52, 78, 104 and 130 post randomization

Outcome Measure Data

Analysis Population Description

Intent to treat: All eligible participants were included in the analysis. Analysis was limited to the two randomized study arms (Arms A and B).

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	145	143
Number (95% Confidence Interval) [weeks]	31	30

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between Arm A and Arm B with respect to time to CIN2+.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments	The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Log Rank
	Comments	Log-rank test was stratified by ART use at screening.

3. Secondary Outcome

Title	Cumulative Rate of CIN3+ (CIN3 or Invasive Cancer) by Week 130.
Description	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.
Time Frame	Weeks 26, 52, 78, 104 and 130 post randomization

Outcome Measure Data

Analysis Population Description

Intent-to-treat: All eligible participants were included in the analysis: participants were analyzed per original assigned randomized treatment. Analysis was limited to the two randomized study arms (Arms A and B).

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	145	143
Number (95% Confidence Interval) [Cumulative rate of events/100 persons]	12.7	17.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Treatment comparison was made using the difference (arm B - arm A) in the stratified Kaplan-Meier estimate for the week 130 cumulative rate of CIN3+ with 95% two-sided confidence interval.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cumulative rate difference
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; -4.8 to 13.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval estimation was stratified by ART use at screening using Greenwood's variance with the inverse of this variance used for the stratum weights.

4. Secondary Outcome

Title	Number of Participants Who Discontinued Study Early.
Description	The number of participants who did not complete the study.
Time Frame	0 to 130 weeks post randomization

Outcome Measure Data

Analysis Population Description

Intent to treat: All eligible participants were included in the analysis. Analysis was limited to the two randomized study arms (Arms A and B).

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	145	143
Count of Participants [Participants]	29 20%	23 16.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null hypothesis: There is no difference between Arm A and Arm B with respect to rate of premature study discontinuation.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.445
	Comments	The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Number of Participants With Abnormal Cytology Results at Study Visits.
Description	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.
Time Frame	Weeks 26, 52, 78, 104 and 130 post randomization

Outcome Measure Data

Analysis Population Description

Included participants with available cytology results.

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	145	143
Week 26: With Abnormal Cytology	80 55.2%	75 52.4%
Week 52: With Abnormal Cytology	80 55.2%	72 50.3%
Week 78: With Abnormal Cytology	63 43.4%	64 44.8%
Week 104: With Abnormal Cytology	57 39.3%	62 43.4%
Week 130: With Abnormal Cytology	33 22.8%	46 32.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 26.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	P-value for the week 26 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between the Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 52.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.279
	Comments	P-value for the week 52 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 78.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.781
	Comments	P-value for the week 78 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 104.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.375
	Comments	P-value for the week 104 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with abnormal cervical cytology results at week 130.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.444
	Comments	P-value for the week 130 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

6. Secondary Outcome

Title	Number of Participants With High Risk (hr)-HPV by the Abbott Real Time High-risk HPV Assay (aHPV) at Study Visits.
Description	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.
Time Frame	Weeks 26, 52, 78, 104 and 130 post randomization

Outcome Measure Data

Analysis Population Description

Includes participants with results for Abbott Real Time high-risk HPV assay

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	122	111
Week 26: With hr-HPV Detected	74 51%	78 54.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with hr-HPV at week 26.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.132
	Comments	P-value for the week 26 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	Number of Participants With High Risk (hr)-HPV by the Xpert HPV Assay at Study Visits.
Description	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.
Time Frame	Weeks 26, 52, 78, 104 and 130 post randomization

Outcome Measure Data

Analysis Population Description

Includes participants with results for Xpert HPV assay

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	119	109
Week 26: With hr-HPV Detected	64 44.1%	68 47.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with hr-HPV at week 26.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.227
	Comments	P-value for the week 26 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Number of Participants With High Risk (hr)-HPV by the Roche Linear Array HPV Genotyping Test at Study Visits.
Description	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.
Time Frame	Weeks 26, 52, 78, 104 and 130 post randomization

Outcome Measure Data

Analysis Population Description

Includes participants with results for the Roche Linear Array HPV Genotyping test.

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	92	91
Week 26: With hr-HPV Detected	74 51%	73 51%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Immediate Cryotherapy (HPV Test-and-treat), Arm B: Cytology-based Strategy
	Comments	Null Hypothesis: There is no difference between Arm A and Arm B with respect to the proportion of participants with hr-HPV at week 26.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	P-value for the week 26 comparison. The p-value is not adjusted for multiple comparisons. The a priori threshold for statistical significance used for the two-sided test was 0.05.
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Percentage of Participants With Targeted Adverse Events (AEs) Reported Post Cryotherapy in Arm A.
Description	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.
Time Frame	4 weeks post cryotherapy

Outcome Measure Data

Analysis Population Description

Included Arm A participants who had cryotherapy.

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	142
Profuse watery vaginal discharge	20 13.8%
Mild cervical bleeding	15 10.3%
Heavy odorous discharge	13 9%
Cervical infection	5 3.4%
Mild watery vaginal discharge	4 2.8%
Lower Abdominal Pain	3 2.1%
Severe cramps or abdominal pain requiring parenter	3 2.1%
Moderate Watery Vaginal Discharge	2 1.4%
Pelvic inflammatory disease	1 0.7%
Abdominal Pain, Mild, No Medicine Taken	1 0.7%
Had Intermittent Blood Spotting Per Vagina	1 0.7%
Heavy cervical bleeding	1 0.7%
Light Watery Vaginal Discharge	1 0.7%
Mild Odour	1 0.7%
Mild P.V. Spotting	1 0.7%
Mild Vaginal Bleeding	1 0.7%
Mild Vaginal Bleeding Moderate Watery Vaginal Disc	1 0.7%
Minimal Watery Discharge	1 0.7%
Mod Watery Non Offensive Vag Discharge & Mod Yello	1 0.7%
Moderate Offensive Vaginal Watery Discharge	1 0.7%
Moderate Vaginal Discharge	1 0.7%
Moderate Vaginal Watery Discharge And Minimal Yell	1 0.7%
Moderate Vaginal Discharge & Minimal Yellowi	1 0.7%
Post Coital Bleeding	1 0.7%
Moderate Vaginal Watery & Brown Smelly Discharge	1 0.7%
Slight Pv Discharge	1 0.7%
Trichomonas Vaginitis	1 0.7%

10. Secondary Outcome

Title	Percentage of Participants With Targeted AEs Reported Post LEEP.
Description	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.
Time Frame	4 weeks post LEEP

Outcome Measure Data

Analysis Population Description

Participants in each arm who had LEEP were included in the analysis.

Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)	Arm B: Cytology-based Strategy	Arm C : Ineligible for Randomization to Arm A or B
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.	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+ is 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. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
Measure Participants	24	34	54
Cervical bleeding	50 34.5%	21 14.7%	22 12.4%
Vaginal discharge	12 8.3%	15 10.5%	31 17.5%
Cramps or abdominal pain requiring parenteral meds	12 8.3%	6 4.2%	13 7.3%
Vaginal Bleeding	4 2.8%	3 2.1%	13 7.3%
Cervical infection	0 0%	3 2.1%	2 1.1%
Metrorrhagia	4 2.8%	0 0%	0 0%
Pelvic inflammatory disease	0 0%	3 2.1%	0 0%

Adverse Events

Time Frame	AEs reported from entry visit to off study visit (at week 130 or earlier).
Adverse Event Reporting Description	At entry, all signs/symptoms (s/s) and lab values Grade >=3 that occurred within 45 days prior to entry were recorded; post entry, s/s and lab values Grade >=3 were recorded. Post entry, all grades of s/s related to cervical cryotherapy or LEEP treatments included in Addendum 1 were reported. SUSAR Reporting Category in DAIDS EAE Manual V2.0 was used. Grading was based on DAIDS AE Grading Table (V1.0) and Addendum 1.
Arm/Group Title	Arm A: Immediate Cryotherapy (HPV Test-and-treat)		Arm B: Cytology-based Strategy		Arm C: Ineligible for Randomization to Arm A or B
Arm/Group Description	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. Cervical Cryotherapy: Participants had cervical cryotherapy within 7 days after study entry. The cryotherapy consists of two 3-minute freezes separated by 5 minutes of thawing. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy post-entry had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.		Participants in Arm B followed a cytology-based management plan involving three steps- cytology, colposcopy with directed biopsies, and LEEP (as needed). Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.		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+ is 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. Loop Electrosurgical Excision Procedure (LEEP): Participants found to have CIN2+ by biopsy at any point during the study had LEEP, an electro-surgical procedure used to treat high-grade cervical dysplasia.
All Cause Mortality
	Arm A: Immediate Cryotherapy (HPV Test-and-treat)		Arm B: Cytology-based Strategy		Arm C: Ineligible for Randomization to Arm A or B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/145 (1.4%)		1/143 (0.7%)		0/177 (0%)
Serious Adverse Events
	Arm A: Immediate Cryotherapy (HPV Test-and-treat)		Arm B: Cytology-based Strategy		Arm C: Ineligible for Randomization to Arm A or B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/145 (3.4%)		2/143 (1.4%)		5/177 (2.8%)
Infections and infestations
Localised infection	1/145 (0.7%)		0/143 (0%)		0/177 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma	1/145 (0.7%)		1/143 (0.7%)		0/177 (0%)
Cervix carcinoma stage 0	1/145 (0.7%)		0/143 (0%)		0/177 (0%)
Squamous cell carcinoma of the cervix	0/145 (0%)		0/143 (0%)		1/177 (0.6%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/145 (0.7%)		0/143 (0%)		0/177 (0%)
Foetal death	0/145 (0%)		1/143 (0.7%)		0/177 (0%)
Reproductive system and breast disorders
Cervical dysplasia	1/145 (0.7%)		0/143 (0%)		1/177 (0.6%)
Cervix haemorrhage uterine	0/145 (0%)		0/143 (0%)		1/177 (0.6%)
Vaginal haemorrhage	0/145 (0%)		0/143 (0%)		2/177 (1.1%)
Other (Not Including Serious) Adverse Events
	Arm A: Immediate Cryotherapy (HPV Test-and-treat)		Arm B: Cytology-based Strategy		Arm C: Ineligible for Randomization to Arm A or B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/145 (41.4%)		49/143 (34.3%)		38/177 (21.5%)
Gastrointestinal disorders
Abdominal pain lower	14/145 (9.7%)		3/143 (2.1%)		3/177 (1.7%)
Infections and infestations
Bacterial vaginosis	25/145 (17.2%)		27/143 (18.9%)		9/177 (5.1%)
Cervicitis	29/145 (20%)		20/143 (14%)		27/177 (15.3%)
Cervicitis trichomonal	9/145 (6.2%)		5/143 (3.5%)		2/177 (1.1%)
Vulvovaginal candidiasis	9/145 (6.2%)		10/143 (7%)		3/177 (1.7%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	9/145 (6.2%)		8/143 (5.6%)		3/177 (1.7%)
Reproductive system and breast disorders
Cervical dysplasia	12/145 (8.3%)		13/143 (9.1%)		18/177 (10.2%)
Vaginal discharge	39/145 (26.9%)		15/143 (10.5%)		15/177 (8.5%)
Vaginal haemorrhage	10/145 (6.9%)		3/143 (2.1%)		5/177 (2.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.