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
Phase: NA
Conditions: HIV-1 Infection
Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

A5282 
A Randomized, Phase II Trial to Compare an HPV Test-and-
Treat Strategy to a Cytology-based Strategy for Prevention 
of CIN 2+ in HIV-infected Women 
A Limited Center Trial of the AIDS Clinical Trials Group 
(ACTG) 
DAIDS ES # 10845 
This file contains the current ACTG A5282 protocol, which 
includes the following documents:  
Letter of Amendment #3, dated 10 June 2015
Clarification Memorandum #2, dated 2 January 2014
Clarification Memorandum #1, dated 5 February 2013
Letter of Amendment #2, dated 9 August 2012
Letter of Amendment #1, dated 21 September 2011
Protocol Version 1.0, dated 16 November 2010

Letter of Amendment #3 
          Page  1 of 5 
10 June 2015 
ACTG A5282 Protocol Version 1.0 
Letter of Amendment #3 for: 
A5282 
A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 10845 
Letter of Amendment Date: 10 June 2015 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
Fax: 
(301) 628-3302 
Silver Spring, MD  20910 
LETTER OF AMENDMENT 
DATE: 
June 10, 2015 
TO: 
Non-US ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS 
Coordinators Participating in the A5282 Study 
FROM: 
A5282 Protocol Team  
SUBJECT: 
Letter of Amendment #3 for Protocol A5282, Version 1.0, 11/16/2010, entitled “A 
Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women” 
The following information impacts the A5282 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This must be approved by your IRB/EC before 
implementation.  
The following information may also impact the Sample Informed Consent. Your IRB/EC will 
be responsible for determining the process of informing subjects of the contents of this 
Letter of Amendment (LOA). 

Letter of Amendment #3 
          Page 2 of 5 
10 June 2015 
ACTG A5282 Protocol Version 1.0 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit a LOA 
registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory 
Support Center. Sites will receive a registration notification for the LOA once the DAIDS 
PRO verifies that all the required LOA registration documents have been received and are 
complete. A LOA registration notification from the DAIDS PRO is not required prior to 
implementing the LOA. A copy of the LOA registration notification along with this letter and 
any IRB/EC correspondence should be retained in the site’s regulatory files. 
The following are changes to A5282, Version 1.0, 11/16/2010 (new language is in bold text and 
deleted language is in strikethrough): 
1.
All references to “careHPV” were replaced with “xpert hrHPV” since the former test is not
available for the study (item a). Additional information about the xpert hrHPV test was
provided (items b and c).
a.
The schema (design and figure 1) and the following sections now read “xpert
hrHPV’ wherever “careHPV” used to appear: 1.3.5, 1.3.7, 3.0, 6.1, 6.3.10,
9.2.2.3, 9.2.2.8, 9.6.2.1, 9.6.2.2, and Appendix I/Attachment A.
b.
The background was revised to delete the 5th section “careHPV, low-cost testing
for hr-HPV.” The following section was added in its place and the associated
reference is provided:
Background:  
Xpert hrHPV Assay 
The Cepheid Xpert HPV Assay (Xpert hrHPV) is a new, qualitative, real-time 
Polymerase Chain Reaction (PCR) assay for the detection of hrHPV DNA. 
The assay is formatted in a single-use GeneXpert Test cartridge and is run 
on the Cepheid GeneXpert® System, a multi-analyte, random access, 
molecular-diagnostic platform ranging in capacity from 1 to 80 test 
processing modules. Importantly, a single hrHPV DNA test can be 
completed in one hour, permitting same-day screening, diagnosis, and 
treatment which reduces the potential for lost to follow-up in lower-
resource settings and permits decentralized, clinic-based (versus lab-
based) testing. It uses ThinPrep (CytoLyt) media. Xpert gives five separate 
results: a) HPV16, b) HPV18/45, c) P3-HPV 31/33/35/52/58, d) P4-HPV51/59, 
and e) P5-HPV39/68/56/66. Xpert was compared to two validated hrHPV 
tests, cobas4800 (cobas, Roche Molecular Diagnostics) and hc2, and to 
histologic outcomes using specimens from colposcopic referral 
populations at 7 clinical sites in the US (n = 697) [26]. Xpert was equally 
sensitive for HSIL (n = 141) as cobas (90.8% vs. 90.8%) and more sensitive 
than hc2 (90.8% vs. 81.6%, p = 0.004). Xpert was more specific than cobas 
(42.6% vs. 39.6%, p = 0.02) and less specific than hc2 (42.6% vs. 47.7%, p < 
0.001). hrHPV detection by the Xpert demonstrated excellent clinical 
performance for identifying women with HSIL that was comparable to 
currently available clinically-validated tests.  

Letter of Amendment #3 
          Page 3 of 5 
10 June 2015 
ACTG A5282 Protocol Version 1.0 
Reference:  
26. Qiao YL, Sellors JW, Eder PS, et al. A new HPV-DNA test for cervical-cancer
screening in developing regions: a cross-sectional study of clinical accuracy in 
rural China. Lancet Oncol 2008;9(10):929-36. Einstein MH, Smith KM, Davis 
TE, et al. Clinical evaluation of the cartridge-based GeneXpert human 
papillomavirus assay in women referred for colposcopy. J. Clin. Microbiol. 
Jun 2014;52(6):2089-2095. 
c.
The 3rd section of the rationale, “PEPFAR objectives,” now reads:
Part of this study is being funded by a supplement from the U.S. NIH to conduct
implementation science research of interest to the President’s Emergency Plan
for AIDS Relief (PEPFAR). The PEPFAR objectives in section 1.3 will use
screening and baseline evaluations from all women who give consent for this
study. The availability of the xpert hrHPV careHPV test should broaden access
to cervical cancer screening through the HPV test-and-treat strategy. It will be
critical to understand how this test performs in HIV-infected women. Although this
assay has been conformité européenne (CE)-marked, it will not be widely
available until late 2011. This study will compare xpert hrHPV careHPV results 
to two other HPV tests: HPV DNA PCR and aHPV. Cryotherapy is not 
recommended for women with extensive cervical lesions. Data from our Zambian 
investigators suggest that 15-20% of HIV-infected women will have such lesions 
and that half of these women will have CIN2/3 or invasive/microinvasive cancer 
on histology [40, 41]. Algorithms for cervical cancer screening must address 
treatment of these women to maximally impact mortality from cervical cancer. 
2.
Per the March 2015 interim DSMB review, biopsies are being added to study follow-up
visits for all participants, regardless of preceding colposcopy results.
a.
Section 3.0, fourth paragraph, now reads: Participants in Arms A and B will be
seen at regular intervals post entry for aHPV, HPV DNA PCR, cervical cytology,
and cervical colposcopy and directed biopsies for a total follow-up length of 130
weeks. At least two cervical biopsies should be performed at the week 78
and week 130 visits. Visible lesions should be biopsied preferentially. If no
visible lesions are seen, then two random biopsies should be obtained.
b.
Section 6.3.10, subsection on colposcopy and directed biopsies, now reads:
Post entry:

Participants in Arms A and B will undergo colposcopy and directed biopsies
at the weeks 26, 78, and 130 clinic visits. At least two cervical biopsies
should be performed at the week 78 and week 130 visits. Visible lesions
should be biopsied preferentially. If no visible lesions are seen, then
two random biopsies should be obtained.

Participants in Arm C who undergo LEEP post-entry will undergo colposcopy

Letter of Amendment #3 
          Page 4 of 5 
10 June 2015 
ACTG A5282 Protocol Version 1.0 
and directed biopsies at the week 26 clinic visit. 
Digital images and colposcopic impression will be submitted for review, along 
with location of cervical biopsies. 
(The following paragraph supersedes Clarification Memo [CM] #2, dated 
01/02/1014.) Directed biopsies will be obtained from areas suspicious for CIN. 
Biopsies are taken only if lesions are seen upon colposcopy. In the event lesions 
are not seen upon colposcopy but the cytology specimens show presence of 
HSIL, then the participant should return to the study clinic for repeat colposcopy 
and other diagnostics procedures such as endocervical curettage (ECC), random 
cervical biopsies (if not already done), or diagnostic LEEP. Results of these 
diagnostic tests must be recorded on the appropriate CRF. Slides from biopsies 
of CIN2+ and biopsies without CIN2+ will be submitted for review. If CIN2+ is 
detected by biopsy, the participant will undergo LEEP. 
c.
Sample Informed Consent, What do I have to do if I am in this Study?, Groups A
and B: At the study visit about 6, 18, and 30 months after the entry visit you will
also have a colposcopy and biopsies if any abnormal areas are seen. At months
18 and 30, you will have two biopsies performed whether or not abnormal
areas are seen.
3.
Additional clarifications were made to Section 6.3.10.
a.
The subsection, “Diagnoses,” now reads:
Diagnoses
(Per CM #1, dated 02/05/1013.) After entry, record any new diagnoses made
since the last visit using the ACTG criteria for clinical events and other diseases.
(Per CM #1, dated 02/05/1013.) Except for invasive cancer, cervical cytology and
histology results do not need to be recorded as events; these results will be
entered on study-specific CRFs only.
(New language) Record all histology results from procedures for the
diagnosis or treatment of cervical HSIL (such as cervical conization or
hysterectomy) and from biopsies performed related to the presence or
absence of squamous intraepithelial lesions on the appropriate CRFs.
b.
The subsection, “LEEP,” now reads:
(The following paragraph supersedes item 4b in LoA #2, dated 08/09/1012.)
LEEP
Participants found to have CIN2+ by biopsy at any point during the study will be
offered LEEP or other excisional treatment (except for participants in Arm A
prior to week 26 who have CIN2+ on pre-cryotherapy biopsy at entry). If the
participant had a prior LEEP, treatment of recurrent or incompletely treated

Letter of Amendment #3 
          Page 5 of 5 
10 June 2015 
ACTG A5282 Protocol Version 1.0 
CIN2+ is at the discretion of the site investigator. These participants will continue 
on study. 
(No changes to the remainder of this subsection.) 
4.
Section 7.3, Other Diseases/Conditions, has been modified to request diagnostic slides
for participants diagnosed with invasive cancer. A sentence has been added at the end
of this section, reading: “The diagnostic slides from any women diagnosed with
invasive cancer should be submitted for central review as soon as possible.”
The above information will be incorporated into the next protocol version as necessary if the 
protocol is amended. 

Clarification Memorandum #2 
          Page 1 of 2 
2 January 2014 
ACTG A5282 Protocol Version 1.0 
Clarification Memorandum #2 for: 
A5282 
A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 10845 
Clarification Memorandum Date: 2 January 2014 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
Fax:  
(301) 628-3302 
Silver Spring, MD 20910 
CLARIFICATION MEMO 
DATE: 
January 2, 2014 
TO: 
Non-US ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS 
Coordinators Participating in the A5282 Study 
FROM: 
A5282 Protocol Team  
SUBJECT: 
Clarification Memo # 2 to the A5282 Protocol, Version 1.0, 11/16/2010, entitled 
“A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women” 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your IRB; however, 
as always, you must follow your IRB's policies and procedures. If IRB review of 
clarification memos is required at your site, please submit this document for review. 
Each site should file a copy of this clarification memo with the protocol for reference. 
The protocol clarifications contained in this memo should be implemented immediately.  
These updates will be included in the next version of the A5282 protocol if it is amended 
at a future date. 

Clarification Memorandum #2 
          Page 2 of 2 
2 January 2014 
ACTG A5282 Protocol Version 1.0 
The following is a clarification to protocol A5282, Version 1.0, 11/16/2010 –  
Section 6.3.10 now reads: “Directed biopsies will be obtained from areas suspicious for CIN. 
Biopsies are taken only if lesions are seen upon colposcopy. In the event lesions are not seen 
upon colposcopy but the cytology specimens show presence of HSIL, then the participant 
should return to the study clinic for endocervical curettage (ECC) repeat colposcopy and 
other diagnostics procedure such as endocervical curettage (ECC), random cervical 
biopsies, or diagnostic LEEP. Results of these diagnostic tests must be recorded on the 
appropriate CRF. Slides from biopsies of CIN2+ and biopsies without CIN2+ will be submitted 
for review. If CIN2+ is detected by biopsy, the participant will undergo LEEP. 

Clarification Memorandum #1 
          Page 1 of 2 
5 February 2013 
ACTG A5282 Protocol Version 1.0 
Clarification Memorandum #1 for: 
A5282 
A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 10845 
Clarification Memorandum Date: 5 February 2013 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
Fax:  
(301) 628-3302 
Silver Spring, MD 20910 
CLARIFICATION MEMO 
DATE: 
February 5, 2013 
TO: 
Non-US ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS 
Coordinators Participating in the A5282 Study 
FROM: 
A5282 Protocol Team  
SUBJECT: 
Clarification Memo # 1 to the A5282 Protocol, Version 1.0, 11/16/2010, entitled 
“A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women” 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your IRB; however, 
as always, you must follow your IRB's policies and procedures. If IRB review of 
clarification memos is required at your site, please submit this document for review. 
Each site should file a copy of this clarification memo with the protocol for reference. 
The protocol clarifications contained in this memo should be implemented immediately.  
These updates will be included in the next version of the A5282 protocol if it is amended 
at a future date. 

Clarification Memorandum #1 
          Page 2 of 2 
5 February 2013 
ACTG A5282 Protocol Version 1.0 
The following are clarifications to A5282, Version 1.0, 11/16/2010: 
1.
Section 6.3.2, “Medical History” now reads:
The medical history must document any history of genital condyloma; any AIDS-
defining illness or condition as defined by the Centers for Disease Control and
Prevention; any history of cervical, vaginal, or vulvar LSIL or HSIL on cytology or
histology; and menstrual history. The medical history must also include all diagnoses
identified by the ACTG criteria for clinical events and other diagnoses within 45 days
prior to study entry. For current criteria, refer to the appendix identified in the study CRF.
Any allergies to any medications and their formulations should be documented in the
source documents only.
2.
Language in three subsections of Section 6.3.6, “Clinical Assessments,” has been changed.
a.
Subsection “Signs/Symptoms” now reads:
At entry, all signs and symptoms Grade ≥ 3 that occurred within 45 days prior to
entry must be recorded on the CRF.
Post entry, signs and symptoms Grade ≥ 3 must be recorded on the CRF.
In addition, post entry, all grades of signs and symptoms related to cervical
cryotherapy or LEEP treatments that are contained within the DAIDS “Female
Genital Grading Table for Use in Microbicide Studies” will be captured
(http://rsc.tech-res.com/safetyandpharmacovigilance/). Grade 1 or 2 signs and
symptoms should be recorded on study-specific CRFs only. Grade ≥ 3 should
be recorded on study-specific CRFs as well as on the generic event CRFs.
b.
Subsection “Diagnoses” now reads:
After entry, record any new diagnoses made since the last visit using the ACTG
criteria for clinical events and other diseases.
Except for invasive cancer, cervical cytology and histology results do not need
to be recorded as events; these results will be entered on study-specific CRFs
only.
c.
Subsection “Concomitant Medications” now reads:
Concomitant Medications
Record ART medications (including start and stop dates) and receipt of HPV
vaccines, and receipt of medical or surgical treatment for genital warts, vulvar
intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VAIN). Any
antibiotics, hormonal treatment, or prescribed or over-the-counter treatments for
gynecological conditions should be recorded.
These updates will be included in the next version of the A5282 protocol if it is amended. 

Letter of Amendment #2 
          Page 1 of 3 
9 August 2012 
ACTG A5282 Protocol Version 1.0 
Letter of Amendment #2 for: 
A5282 
A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 10845 
Letter of Amendment Date: 9 August 2012 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
Fax: 
(301) 628-3302 
Silver Spring, MD  20910 
LETTER OF AMENDMENT 
DATE: 
August 9, 2012 
TO: 
Non-US ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS 
Coordinators Participating in the A5282 Study 
FROM: 
A5282 Protocol Team  
SUBJECT: 
Letter of Amendment #2 for Protocol A5282, Version 1.0, 11/16/2010, entitled “A 
Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women” 
The following information impacts the A5282 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This must be approved by your IRB/EC before 
implementation.  
The following information may also impact the Sample Informed Consent. Your IRB/EC will 
be responsible for determining the process of informing subjects of the contents of this 
Letter of Amendment (LOA). 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit a LOA 
registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory 
Support Center. Sites will receive a registration notification for the LOA once the DAIDS 

Letter of Amendment #2 
          Page 2 of 3 
9 August 2012 
ACTG A5282 Protocol Version 1.0 
PRO verifies that all the required LOA registration documents have been received and are 
complete. An LOA registration notification from the DAIDS PRO is not required prior to 
implementing the LOA. A copy of the LOA registration notification along with this letter and 
any IRB/EC correspondence should be retained in the site’s regulatory files. 
The following are changes to A5282, Version 1.0, 11/16/2010: 
1.
Figure 1, Overview of Study Design
2.
Clarification of contraception requirements if using Efavirenz (EFV)
a.
Section 4.1.7, Contraception Requirements
NOTES: If participating in sexual activity that could lead to pregnancy, study participants
taking efavirenz should conform to local or WHO guidelines regarding prevention
of pregnancy while on efavirenz.
b.
Sample Informed Consent, “What do I need to know about pregnancy and
contraceptives?”
If you are taking certain anti-HIV drugs (Efavirenz), you and your partner may need to
follow additional guidelines to prevent pregnancy while using Efavirenz.  The study
staff will discuss this with you.
3.
Clarification of the definition of cervicitis
a.
Eligibility Criterion 4.2.4, Visual evidence of bacterial STIs or suspicion of pelvic
inflammatory disease.
NOTE: Visually apparent cervicitis thought to be related to STIs or suspected pelvic
inflammatory disease must be treated with appropriate antibiotics at least 7 days prior to
entry.
b.
Section 7.2, Cryotherapy- and LEEP-related Complications
The risk of postoperative infection is very small and can probably be reduced even more
by delaying surgical treatment until any woman with a likely diagnosis of pelvic
inflammatory disease or cervicitis thought to be related to clinically treatable STIs,
vaginal trichomoniasis, or bacterial vaginosis has been adequately treated and has
recovered.  
4.
Clarification of LEEP for Participants in Arm A
a.
Section 6.1, Schedule of Events
Visual colposcopic 
inspection shows extensive 
lesions inappropriate for 
cryotherapy  
(n~105) 
Visual colposcopic inspection shows lesions 
appropriate for cryotherapy or no lesions 
(n~595) 

Letter of Amendment #2 
          Page 3 of 3 
9 August 2012 
ACTG A5282 Protocol Version 1.0 
LEEP -- if CIN2+ is found on biopsy (except the pre-cryotherapy biopsy results at 
entry for participants in Arm A) 
b.
Section 6.3.10, Other Laboratory Studies and Procedures
Colposcopy and Directed Biopsies
If CIN2+ is detected by biopsy post-entry, the participant will undergo LEEP.
LEEP
Participants found to have CIN2+ by biopsy at any point during the study will be offered
LEEP (except for participants in Arm A who have CIN2+ on pre-cryotherapy biopsy
at entry).
5.
Screening Window and Lab Testing Timeframe Extended from 30 Days to 45 Days
a.
Section 6.2.1, Screening Evaluations
Screening evaluations to determine eligibility must be completed within 45 days prior to
study entry, unless otherwise specified.
b.
Eligibility Criterion 4.1.2, The following laboratory values obtained within 45 days prior to
study entry:

Absolute neutrophil count (ANC)  750/mm3

Platelet count  75,000/mm3

Hemoglobin (HgB) > 8 gm/dL
c.
Eligibility Criterion 4.1.3, For candidates suitable for cervical cryotherapy (as defined in
section 4.1.5 below), hr-HPV detected by aHPV within 45 days prior to study entry.
6.
Section 6.3.10, Other Laboratory Studies and Procedures
Participants should refrain from any kind of sexual activity, douching, and inserting any
intravaginal products for at least 48 hours prior to the collection of vaginal/cervical
specimens.
The above information will be incorporated into the next protocol version as necessary if the 
protocol is amended. 

Letter of Amendment #1 
          Page 1 of 4 
21 September 2011 
ACTG A5282 Protocol Version 1.0 
Letter of Amendment #1 for: 
A5282 
A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 10845 
Letter of Amendment Date: 21 September 2011 
ACTG Operations Center 
Social & Scientific Systems, Inc. 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
Fax: 
(301) 628-3302 
Silver Spring, MD  20910 
LETTER OF AMENDMENT 
DATE: 
September 21, 2011 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5282 Protocol Team  
SUBJECT: 
Letter of Amendment #1 for Protocol A5282, Version 1.0, 11/16/2010 entitled “A 
Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a 
Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women” 
The following information impacts the A5282 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review.  This must be approved by your IRB/EC before 
implementation.  
The following information may also impact the Sample Informed Consent. Your IRB/EC will 
be responsible for determining the process of informing subjects of the contents of this 
Letter of Amendment. 
Upon receiving final IRB/EC and any other applicable regulatory entity (RE) approvals for 
this LoA, sites should implement the LoA immediately. Sites are still required to submit a 
LoA registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory 
Support Center (RSC). Sites will receive a registration notification for the LoA once the 
DAIDS PRO verifies that all the required LoA registration documents have been received 
and are complete. A LoA registration notification from the DAIDS PRO is not required prior 

Letter of Amendment #1 
          Page 2 of 4
21 September 2011 
ACTG A5282 Protocol Version 1.0 
to implementing the LoA. A copy of the LoA registration notification along with this letter 
and any IRB/EC correspondence should be retained in the site’s regulatory files. 
The following are changes to A5282, Version 1.0, 11/16/2010 (changes in bold text or 
strikethrough): 
1.
Schema, Figure 1 Overview of Study Design
The Arm A box now reads: Cervical biopsies + Immediate cryotherapy (N=140)
2.
Section 1.3, Secondary Objectives
1.3.6 To evaluate baseline/screening characteristics (detection of various HPV types, CD4,
CD4 nadir, HIV RNA, sexual history, and recent sexual activity) associated with 
cytological abnormalities at baseline. 
1.3.8 To report the proportion of HIV-infected women with extensive cervical lesions 
inappropriate for cryotherapy and examine possible factors associated with these 
lesions, including CD4 count, plasma HIV-1 RNA, ART use, HPV types detected, 
sexual history, and recent sexual activity. 
3.
Section 2.2, Rationale, PEPFAR Objectives
The PEPFAR objectives in section 1.3.5 will use screening and baseline evaluations from all
women who give consent for this study.
4.
Section 3.0, Study Design, 4th Paragraph
All participants in Arm A (HPV test-and-treat) will undergo one or two cervical biopsies
followed by immediate cervical cryotherapy at entry. Up to two visible lesions should be
biopsied. If no lesions are seen, then one normal-appearing area of the cervix should
be biopsied at a location of the investigator’s choosing to ensure that at least one
biopsy is collected. Participants in Arm A will receive the results of the cytology, but
participants will receive cryotherapy treatment regardless of the results.
5.
Section 4.1.3
For candidates suitable for cervical cryotherapy (as defined in section 4.1.5 below), hr-HPV
detected by aHPV within 30 days prior to study entry.
6.
Section 5.1.1, Cervical Cryotherapy
One or two cervical biopsies will be performed. This will be followed by cervical
cryotherapy: Two 3-minute freezes separated by 5 minutes of thawing. Refer to the A5282
MOPS for a detailed description of this procedure.
7.
Section 6.1, Schedule of Events
The row “Cryotherapy (Arm A only)” now reads “Cervical biopsies/cryotherapy (Arm A
only).”

Letter of Amendment #1 
          Page 3 of 4
21 September 2011 
ACTG A5282 Protocol Version 1.0 
8.
Section 6.3.10, Other Laboratory Studies and Procedures
Colposcopy and Directed Biopsies
At entry:

Participants in Arm A will not have colposcopy and directed biopsies; these women will
instead undergo have one or two cervical biopsies performed followed by
immediate cervical cryotherapy.
LEEP 
All specimens obtained by LEEP will be fixed in formalin and submitted for local review. 
Cryotherapy (Arm A Only) 
Participants in Arm A will undergo cervical cryotherapy within 7 days after entry. Please see 
the A5282 MOPS for details. All women in Arm A should undergo one or two cervical 
biopsies immediately prior to cervical cryotherapy. Up to two visible lesions should 
be biopsied. If no lesions are seen, then one normal-appearing area of the cervix 
should be biopsied at a location of the investigator’s choosing. At least one biopsy is 
collected. Digital images obtained immediately prior to and following cryotherapy will be 
submitted for review. 
9.
Section 7.3, Other Diseases/Conditions, Invasive Cervical, Vaginal, or Vulvar Cancer, Last
Paragraph
Participants who are diagnosed with cervical, vaginal, or vulvar cancer after enrolling into
the study will continue to be followed on study. These participants will come into the clinic
per the time points in Section 6.1 for study evaluations. These participants will receive
additional treatments as indicated in the site-specific clinical management plan. Any women
in Arm A diagnosed with invasive cervical cancer on the biopsies obtained
immediately prior to cryotherapy should be seen as soon as possible for evaluation
by a local specialist and treated as per standard of care in that country.
10. Section 9.2.2, Secondary Endpoints
9.2.2.11 Sexual history at baseline (age at first vaginal sex and lifetime number of
vaginal sex partners) and recent sexual activity (number of vaginal sex 
partners and condom use within the previous 6 months). 
11. Section 9.6, Analyses
9.6.1  Comparison of CIN2+ between Arms A and B
New text added as the second paragraph: Participants in Arm A will undergo one 
or two cervical biopsies immediately prior to cryotherapy. If any of these 
biopsies show invasive cancer, then these participants will be considered as 
failures for the primary endpoint. Please note that CIN2 or CIN3 on the pre-
cryotherapy biopsies will not be considered endpoints. 
Third paragraph now reads: Participants in Arm B may have biopsy done prior to 
week 26 based on the evaluation of baseline abnormal cervical cytology, and 

Letter of Amendment #1 
 Page 4 of 4 
21 September 2011 
ACTG A5282 Protocol Version 1.0 
whereas participants in Arm A will not have one or two cervical biopsies 
immediately prior to cryotherapy until week 26. Participants in Arm A or Arm B 
diagnosed prior to their week 26 visit with CIN2+ that is cleared according to the 
biopsy at their week 26 will not be considered failures for the primary endpoint 
analysis. They are counted as meeting the primary endpoint only if CIN2+ is found at 
week 26 or later. Unplanned biopsies in Arm A that occur prior to the week 26 visit 
will not be considered for the primary endpoint. 
9.6.2.1 Arms A and B Only 
Third paragraph now reads: These models will explore nadir CD4 count and 
baseline/screening characteristics (e.g., HIV RNA level, current CD4 count, sexual 
history, and cytology outcome) and recent sexual activity (time-updated 
variable) as independent variables. 
9.6.2.2 Arms A, B, and C  
First paragraph now reads: Logistic regression models will be developed to explore 
the factors associated with cytological abnormalities at entry or screening, e.g., HPV 
types, CD4, nadir CD4, HIV RNA level, sexual history, and recent sexual activity. 
Third paragraph now reads: We will assess the relationship of CD4 cell count (<200, 
200-349, 350-499, ≥500), ART use (yes or no), plasma HIV RNA, sexual history, 
and recent sexual activity to the presence of these lesions. We will also relate 
these variables to the presence or absence of CIN2+ at the month 6 visit 
among women in Arm C. 
12. Sample Informed Consent, “What do I have to do if I am in this study?”
Groups A and B
If you are in Group A, the study doctor or nurse will tell you when to come back to the
clinic again to receive the results of the Pap test from screening or will give the
results of the Pap test to you at this visit (if available). Regardless of the test results,
you will have one or two biopsies of your cervix immediately followed by cryotherapy of
your cervix. The biopsies and cryotherapy will happen at the entry visit or within one
week of the entry visit. The study doctor or nurse will tell you when to come back to the
clinic again to receive the results of the biopsies.
All Groups
To help ensure the quality of study procedures, medical experts other than the study doctor
and nurse will review:
1.
Pictures taken of the cervix right before and right after cryotherapy, colposcopy, and
LEEP.
2.
Some of the biopsy specimens.
3.
A portion of the specimen collected during LEEP.
The above information will be incorporated into the next protocol version as necessary if the 
protocol is amended. 

A5282 
A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a Cytology-
based Strategy for Prevention of CIN 2+ in HIV-infected Women 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
Sponsored by: 
The National Institute of Allergy 
and Infectious Diseases 
Non-IND Protocol 
The ACTG Optimization of Co-Infection and 
Co-Morbidity Management (OpMAN) Committee:  
Thomas B. Campbell, M.D., Chair 
Protocol Chair:   
Timothy Wilkin, M.D., M.P.H.  
Protocol Co-Vice Chairs: 
Cynthia Firnhaber, M.D. 
Vikrant Sahasrabuddhe, M.B.B.S., 
M.P.H., Dr.P.H  
DAIDS Clinical Representative: 
Catherine Godfrey, M.D. 
Clinical Trials Specialist: 
Reena T. Allen, M.A. 
FINAL Version 1.0 
November 16, 2010 

A5282 
FINAL Version 1.0 
11/16/10 
CONTENTS 
Page 
SITES PARTICIPATING IN THE STUDY ..................................................................................... 4 
PROTOCOL TEAM ROSTER ....................................................................................................... 5 
STUDY MANAGEMENT ............................................................................................................... 8 
GLOSSARY OF TERMS ............................................................................................................. 10 
SCHEMA ..................................................................................................................................... 12 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES .................................................................... 14 
1.1 
Hypothesis ........................................................................................................... 14 
1.2 
Primary Objective ................................................................................................ 14 
1.3 
Secondary Objectives ......................................................................................... 14 
1.4 
Tertiary Objectives (contingent on future funding) ............................................... 15 
2.0 
INTRODUCTION ............................................................................................................. 15 
2.1 
Background ......................................................................................................... 15 
2.2 
Rationale ............................................................................................................. 21 
3.0 
STUDY DESIGN ............................................................................................................. 22 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................. 23 
4.1 
Inclusion Criteria .................................................................................................. 23 
4.2 
Exclusion Criteria ................................................................................................ 25 
4.3 
Study Enrollment Procedures .............................................................................. 26 
4.4 
Coenrollment Guidelines ..................................................................................... 27 
5.0 
STUDY TREATMENT ..................................................................................................... 27 
5.1 
Intervention, Administration, and Duration .......................................................... 27 
5.2 
Study Product Formulation and Preparation ....................................................... 28 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................... 28 
5.4 
Concomitant Medications .................................................................................... 28 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................ 29 
6.1 
Schedule of Events ............................................................................................. 29 
6.2 
Timing of Evaluations .......................................................................................... 30 
6.3 
Instructions for Evaluations ................................................................................. 31 
7.0 
CLINICAL MANAGEMENT ISSUES ............................................................................... 36 
7.1 
Grade 3 or Higher Events .................................................................................... 36 
7.2 
Cryotherapy- and LEEP-related Complications ................................................... 37 
7.3 
Other Diseases/Conditions .................................................................................. 37 
7.4 
Pregnancy ........................................................................................................... 38 

A5282 
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CONTENTS (Cont’d) 
Page 
8.0 
CRITERIA FOR STUDY DISCONTINUATION ............................................................... 38 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................ 38 
9.1 
General Design Issues ........................................................................................ 38 
9.2 
Endpoints ............................................................................................................ 39 
9.3 
Randomization and Stratification ......................................................................... 40 
9.4 
Sample Size and Accrual .................................................................................... 40 
9.5 
Monitoring ............................................................................................................ 41 
9.6 
Analyses .............................................................................................................. 42 
10.0 
PHARMACOLOGY PLAN ............................................................................................... 44 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 44 
11.1 
Records to Be Kept ............................................................................................. 44 
11.2 
Role of Data Management .................................................................................. 44 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 44 
11.4 
Expedited Adverse Event (EAE) Reporting to DAIDS ......................................... 45 
12.0 
HUMAN PARTICIPANTS ................................................................................................ 46 
12.1 
IRB/EC Review and Informed Consent ............................................................... 46 
12.2 
Participant Confidentiality .................................................................................... 46 
12.3 
Study Discontinuation .......................................................................................... 46 
13.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 46 
14.0 
BIOHAZARD CONTAINMENT ........................................................................................ 47 
15.0 
REFERENCES ................................................................................................................ 48 
APPENDIX I: SAMPLE INFORMED CONSENT 
APPENDIX I, ATTACHMENT A: A5282 DEFINITIONS OF SCREENING PROCEDURES FOR 
CERVICAL CANCER 

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SITES PARTICIPATING IN THE STUDY 
A5282 is limited to select sites outside of the United States that have prior experience with and 
capacity to perform cervical cancer screening and treatment procedures. The list of eligible sites 
can be found on the A5282 protocol-specific web page (PSWP). 

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PROTOCOL TEAM ROSTER 
Chair 
Timothy Wilkin, M.D., M.P.H. 
Cornell Clinical Research Site  
119 W. 24th Street, Ground floor  
New York, NY  10011 
Phone:  +1-212-746-7202 
FAX: 
+1-212-746-7203 
 
E-Mail: tiw2001@med.cornell.edu  
Co-Vice Chairs 
Cynthia Firnhaber, M.D. 
University of Witwatersrand  
Perth Road  
Westdene  
Johannesburg 
SOUTH AFRICA 
Phone: 271 127-68800 
FAX:  
271 148-22130 
E-Mail:  cfirnhaber@witshealth.co.za 
Vikrant Sahasrabuddhe, M.B.B.S., M.P.H., 
Dr.P.H 
Vanderbilt Institute for Global Health  
2525 West End Avenue, Suite 750  
Nashville, TN  37203-1738 
Phone: +1-615-525-5033 
FAX:  
+1-615-343-7797 
E-Mail:  vikrant.sahasrabuddhe@ 
vanderbilt.edu  
DAIDS Clinical Representative  
Catherine Godfrey, M.D.  
HIV Research Branch 
TRP, DAIDS, NIAID, NIH 
6700-B Rockledge Drive 
Bethesda, MD  20892-7624 
Phone:  +1-301-496-1540 
FAX: 
+1-301-432-9282 
E-Mail: cgodfrey@niaid.nih.gov  
Clinical Trials Specialist 
Reena T. Allen, M.A. 
ACTG Operations Center 
Social & Scientific Systems 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: +1-301-628-3000 
FAX: 
+1-301-628-3302 
E-Mail: rallen@s-3.com  
Statisticians 
John Spritzler, Sc.D.  
SDAC/Harvard School of Public Health  
Center for Biostatistics in AIDS Research  
651 Huntington Avenue  
FXB Building, 5th floor  
Boston, MA  02115-6017 
Phone: +1-617-432-3171 
FAX: 
+1-617-432-3163 
E-Mail: spritz@sdac.harvard.edu   
Roy Matining, M.S. 
SDAC/Harvard School of Public Health  
Center for Biostatistics in AIDS Research  
651 Huntington Avenue  
FXB Building, 5th floor  
Boston, MA  02115-6017 
Phone: +1-617-432-3025 
FAX: 
+1-617-432-3163 
E-Mail: rmatining@sdac.harvard.edu  
Data Manager 
Ann Walawander, M.A. 
HIV Section  
Frontier Science & Technology Research 
Foundation 
4033 Maple Road  
Amherst, NY 14226-1056 
Phone:   +1-716-834-0900x7290 
FAX: 
+1-716-834-8432 
E-Mail:   walawander.ann@fstrf.org 

 
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PROTOCOL TEAM ROSTER (Cont’d) 
 
Investigators 
Ramesh Bhosale, M.D. 
Obstetrics and Gynecology  
Byramjee Jeejeebhoy Medical College  
A1, Doctors' Quarters 
Vishnu Sadashiv Campus  
Opp. Zilla Parishad  
Pune  411001 
INDIA 
Phone:  91 20 2613 3367 
FAX:  
91 20 2612 6868 
E-Mail:  drrameshbhosale@yahoo.com  
 
Beatriz Grinsztejn, M.D., Ph.D. 
Instituto de Pesquisa Clinica Evandro 
Chagas Fiocruz  
Infectious Diseases Department  
Fundacao Oswaldo Cruz  
Avenida Brasil 4365, Manguinhos  
Rio de Janeiro  21045--900 
BRAZIL 
Phone: 55 21 2270 7064 
FAX:  
55 21 2564 4933 
E-Mail: gbeatriz@unisys.com.br  
 
Mulindi Mwanahamuntu, M.B.B.S., M.Med.  
University Teaching Hospital Campus 
AIDC Building  
Nationalist Road 
P.O. Box 34681 
Lusaka, ZAMBIA  
Phone: 260 211 253359  
FAX:   
260 211 253359  
E-Mail:  mulindim@hotmail.com  
 
Field Representatives 
Christina Megill, P.A.-C. 
Cornell CRS  
Weill Medical College of Cornell University  
119 West 24th Street, 1st floor  
P.O. Box 248  
New York, NY  10011 
Phone:  +1-212-746-7183 
FAX:  
+1-212-746-7203 
E-Mail:  chm2029@med.cornell.edu 
 
Field Representatives, Cont’d 
Janet Nicotera, R.N., B.S.N.  
Vanderbilt Institute for Global Health & 
Les Centres GHESKIO 
2525 West End Ave, Suite 750 
Nashville, TN 37232 
Phone:  +1-615-322-9374 
FAX:  
+1-615-343-7797 
E-Mail:  janet.nicotera@vanderbilt.edu  
 
Laboratory Technologist 
Laura Blair, B.S., M.T. (A.S.C.P.) 
Washington University School of Medicine  
Retrovirus Laboratory  
4320 Forest Park Boulevard  
Room 209, Cortex Building  
St. Louis, MO  63108 
Phone: +1-314-454-8032 
Fax:  
+1-314-454-8020 
 
 
E-Mail: blair_l@wustl.edu  
 
Community Scientific Subcommittee (CSS) 
Representative 
Morenike Giwa, B.A. 
Houston AIDS Research Team CRS  
P.O. Box 711403  
Houston, TX  77271 
Phone: +1-281-236-6109 
Fax:  
+1-713-777-7942 
 
 
E-Mail: morenikegiwa@yahoo.com 
 
Protocol Virologist 
Robert W. Coombs, M.D., Ph.D. 
Virology Division  
Department of Laboratory Medicine  
Department of Medicine 
University of Washington  
Harborview Medical Center, Box 359690  
325 9th Avenue  
Seattle, WA  98104-2499 
Phone: +1-206-341-5200 x5205 
FAX:  
+1-206-341-5203 
E-Mail:  bcoombs@u.washington.edu 

 
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PROTOCOL TEAM ROSTER (Cont’d) 
 
Laboratory Data Coordinators 
Travis Behm, B.S. 
HIV Section  
Frontier Science & Technology Research 
Foundation 
4033 Maple Road  
Amherst, NY 14226-1056 
Phone:   +1-716-834-0900x7377 
FAX: 
+1-716-833-0655 
E-Mail:   tbehm@fstrf.org  
 
Derek Weibel 
HIV Section  
Frontier Science & Technology Research 
Foundation  
4033 Maple Road  
Amherst, NY 14226-1056 
Phone:   +1-716-834-0900 
FAX: 
+1-716-833-0655 
E-Mail:   weibel@fstrf.org  
 
Consultant 
Groesbeck Parham, M.D.  
University of Alabama at Birmingham  
Department of Medicine Room 126  
Bevill Research Building  
Birmingham, AL  35294 
Phone:  +1-205-934-1917 
E-Mail:  gparham@cidrz.org  
 
International Program Specialist  
Christina Blanchard-Horan, Ph.D., M.A., 
C.C.R.P 
ACTG Operations Center 
Social & Scientific Systems 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: +1-301-628-3000 
FAX: 
+1-301-628-3302 
E-Mail: cblanchardhoran@s-3.com   
 
 

 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.coreA5282@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to actg.coreA5282@fstrf.org.  A 
response should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites that are planning to register to this study must contact the Computer Support Group at the 
Data Management Center (DMC) as soon as possible to have the relevant personnel at the site 
added to the actg.protA5282 e-mail group. Include the protocol number in the email subject line. 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol chair and co-vice chairs. Send an e-mail message to 
actg.coreA5282@fstrf.org (ATTN: Drs. Wilkin, Firnhaber, and Sahasrabuddhe). Include the 
protocol number, patient identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to laboratory tests, send an e-mail message to 
actg.coreA5282@fstrf.org. 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), 
the CRF schedule of events, randomization/participant registration, delinquencies, and other 
data management issues, contact the data manager.  
 
For transfers, reference the Patient Transfer from Site to Site SOP 119, and contact Ann 
Walawander directly.  
 
For other questions, send an e-mail message to actg.coreA5282@fstrf.org (ATTN: Ann 
Walawander).   
 
Include the protocol number, PID, and a detailed question. 
 
Randomization (Arms A and B)/Participant Registration (Arm C)  
For randomization/participant registration questions or problems and study identification number 
(SID) lists, send an e-mail message to rando.support@fstrf.org or call the Statistical and Data 
Analysis Center (SDAC)/DMC Randomization Desk at +1-716-898-7301. 
 
Computer and Screen Problems  
Contact the SDAC/DMC programmers. Send an e-mail message to actg.support@fstrf.org or 
call +1-716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist. Send an e-
mail message to actg.coreA5282@fstrf.org (ATTN: Reena Allen). 
 

 
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STUDY MANAGEMENT (Cont'd) 
 
Copies of the Protocol 
To request hard copies of the protocol, send a message to ACTGOpsCenter@s-3.com (ATTN: 
Diane Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site 
(https://www.actgnetwork.org). 
 
Protocol Registration 
Send an e-mail message to Protocol@tech-res.com or call +1-301-897-1707.  
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or +1-301-897-1709; or fax 1-800-275-7619 or +1-301-897-1710.  
 
Phone Calls 
Any phone calls must be documented by e-mail to actg.coreA5282@fstrf.org. This will be the 
site’s responsibility. 
 
Protocol-Specific Web Page 
Additional information concerning the general study management of ACTG studies can be found 
on the ACTG web site and specific information about A5282 can be found on the study’s PSWP 
(https://www.actgnetwork.org).

 
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GLOSSARY OF TERMS 
 
ACTG  
AIDS Clinical Trials Group 
AE 
 
adverse event 
aHPV  
Abbott RealTime hr-HPV (assay) 
ANC 
 
absolute neutrophil count 
aOR 
 
adjusted odds ratio 
ART 
 
antiretroviral therapy 
AGUS  
atypical glandular cells of undetermined significance 
ASCUS 
atypical squamous cells of undetermined significance 
CDC 
Center for Disease Control and Prevention  
CE 
 
conformité européenne (marked) 
CI 
 
confidence interval 
CIN 
 
cervical intraepithelial neoplasia 
CIN2+  
cervical intraepithelial neoplasia grade 2, 3, or invasive cancer 
CLIA  
Clinical Laboratory Improvement Amendments (certification) 
CSS 
 
Community Scientific Subcommittee 
CRF 
 
case report form 
CRS 
 
clinical research site 
DAERS 
DAIDS Adverse Experience Reporting System  
DAIDS  
Division of AIDS 
DMC  
Data Management Center 
DSMB  
Data and Safety Monitoring Board 
E/CIA 
enzyme or chemiluminescence immunoassay 
EAE 
 
expedited adverse event 
EC 
 
ethics committee 
ECC 
endocervical curettage 
HC2 
(Digene) Hybrid Capture-2™ 
HgB 
hemoglobin 
HERS  
HIV Epidemiology Research Study  
hr-HPV 
high risk human papillomavirus 
HR 
 
hazards ratio 
HSIL/LSIL 
high-grade (H) or low-grade (L) squamous intraepithelial lesions 
IATA  
International Air Transport Association 
IC 
 
internal control 
ICF 
 
informed consent form 
ICH 
 
International Conference on Harmonisation 
IRB 
 
institutional review board  
IRIS 
 
immune reconstitution inflammatory syndrome 
LEEP  
loop electrosurgical excision procedure 
MOPS  
manual of procedures 
NIAID  
National Institute of Allergy and Infectious Diseases 
NIH 
 
National Institutes of Health 
OHRP  
Office for Human Research Protections 
PATH  
Program for Appropriate Technologies in Health  
PEPFAR 
(U.S.) President’s Emergency Plan for AIDS Relief 
PCR 
 
polymerase chain reaction 

 
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GLOSSARY OF TERMS (Cont'd) 
 
PID 
 
patient identification number 
PSWP  
protocol-specific web page 
RE 
 
regulatory entity 
RSC 
 
(DAIDS) Regulatory Support Center 
SCC 
 
squamous cell carcinoma 
SID 
 
study identification number 
SIL 
 
squamous intraepithelial lesions 
STI 
 
sexually transmitted infection  
SUSAR 
suspected, unexpected serious adverse reaction 
VAIN 
vaginal intraepithelial neoplasia  
VIA  
visual inspection (of the cervix) aided by acetic acid  
VIN 
vulvar intraepithelial neoplasia 
WHO 
World Health Organization 
WIHS  
Women’s Interagency HIV Study  

 
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SCHEMA 
 
A5282 
 
A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a Cytology-based 
Strategy for Prevention of CIN 2+ in HIV-infected Women 
 
DESIGN 
 
A5282 is a randomized clinical trial that will compare a human papillomavirus (HPV) test-and-
treat-strategy with a cytology-based strategy. All participants will be screened with the Abbott 
RealTime high-risk HPV test (aHPV) to detect high-risk HPV (hr-HPV) infection.  
 
If hr-HPV is detected, participants will be randomized to Arm A, immediate cryotherapy (HPV 
test-and-treat), or Arm B, cytology-based strategy. Participants will be eligible for Arm C under 
the following conditions: (i) if cervical lesions are seen that are inappropriate for cryotherapy or 
(ii) if hr-HPV is not detected but visual inspection shows lesions or cervical cytology results 
show high-grade squamous intraepithelial lesions (HSIL). Once on study, all participants will 
have cervical colposcopy and directed biopsies, cervical cytology, aHPV, HPV DNA polymerase 
chain reaction (PCR), and careHPV tests as part of their study follow-up. 
 
DURATION 
 
 
Participants in Arms A and B will be on study for 130 weeks (about 2.5 years). Participants in 
Arm C will be on study for up to 26 weeks (about 6 months). 
 
SAMPLE SIZE    
 
The study will randomize 280 hr-HPV-positive women to Arms A and B and enroll approximately 
170 women in Arm C for a total study sample size of up to 450 participants. 
 
POPULATION  
 
HIV-infected women 18 years of age or older. Eligible participants should have no history of 
major cervical procedures or suspicion of cervical, vaginal, or vulvar cancer. See Section 4.0 for 
specific eligibility criteria. 
 
STRATIFICATION 
 
Randomization will be stratified by current use of antiretroviral therapy (ART) (i.e., any ART or 
no ART) with institutional balancing. 
 
TREATMENTS  
 
 
Cervical cryotherapy.  
 
Loop electrosurgical excision procedure (LEEP) for biopsy-proven cervical intraepithelial 
neoplasia (CIN) 2+ (i.e., CIN2, CIN3, or invasive cancer). 

 
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SCHEMA (Cont’d) 
 
Figure 1: Overview of Study Design 
 
 
 
 
  
Cervical hr-HPV 
positive women will 
be randomized 
(n=280) 
Arms A and B have the same evaluations from 
weeks 26 to 130: 
-- Colposcopy and directed biopsies at weeks   
26, 78, and 130 
-- aHPV, HPV DNA PCR, and cytology every 26 
weeks 
-- careHPV at week 26 
Arm B 
Cytology-based 
strategy 
(n=140)
Arm A 
Immediate 
cryotherapy 
(n=140) 
Visual inspection shows 
extensive lesions 
inappropriate for cryotherapy  
(n~105) 
Colposcopy and 
directed biopsies if 
cytology abnormal 
Arm C 
Ineligible for 
randomization 
(n~170) 
Visual inspection shows lesions appropriate 
for cryotherapy or no lesions 
(n~595) 
aHPV test
HIV-infected women ages 18 or older 
(n~700) 
aHPV test
Cervical hr-HPV negative women 
will not be randomized (n~315).  
 
A subset of these women will be 
followed in Arm C (n~65). 
If CIN2+ on biopsy, 
then LEEP 
Colposcopy and 
directed biopsies 
If CIN2+ on biopsy, 
then LEEP 
If LEEP, then will have 
colposcopy and directed 
biopsies, aHPV, HPV 
DNA PCR, careHPV, and 
cytology 26 weeks post 
entry. 

 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
1.1 
Hypothesis    
 
In HIV-infected women with high-risk human papillomavirus (hr-HPV), immediate 
cryotherapy results in a lower probability of cervical intraepithelial neoplasia (CIN)2+ 
than a cytology-based strategy. 
 
1.2 
Primary Objective  
 
To evaluate the effectiveness of immediate cryotherapy in HIV-infected women with hr-
HPV compared to a cytology-based strategy by comparing cumulative CIN2+ rates. 
 
1.3 
Secondary Objectives 
 
1.3.1 To evaluate the safety and tolerability of cervical cryotherapy (Arm A) in HIV-
infected women. 
 
1.3.2 To compare between arms the presence of cervical cytological abnormalities 
during the study. 
 
1.3.3 To assess study discontinuation rates and reasons for discontinuation between 
arms. 
 
1.3.4 To compare time to development of CIN2+ between those women with and 
without detection of hr-HPV by aHPV at 26 weeks, and those women with and 
without cervical cytological abnormalities after cervical cryotherapy in Arm A. 
 
1.3.5 To assess detection frequencies of cervical HPV types (by DNA PCR) and the 
rates of hr-HPV by careHPV at study entry. 
 
1.3.6 To evaluate baseline/screening characteristics (detection of various HPV types, 
CD4, CD4 nadir, and HIV RNA) associated with cytological abnormalities at 
baseline. 
 
 
PEPFAR Objectives  
 
1.3.7 To evaluate the sensitivity and specificity of careHPV for hr-HPV detection as 
measured by aHPV and HPV DNA PCR at study screening and the agreement 
beyond chance between these measures. 
 
1.3.8 To report the proportion of HIV-infected women with extensive cervical lesions 
inappropriate for cryotherapy and examine possible factors associated with these 
lesions including CD4 count, plasma HIV-1 RNA, ART use and HPV types 
detected. 
 

 
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1.4 
Tertiary Objectives (contingent on future funding) 
 
1.4.1 To compare between arms the presence of hr-HPV by aHPV and HPV DNA PCR 
during the study. 
 
1.4.2 To assess the HPV types detected (by DNA PCR) at the time of CIN2+ detection 
by cervical swab and in histopathology specimens. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Cervical Cancer and HIV 
Cervical cancer is the second most common cancer among women worldwide [1, 2]. The 
most recent compilation of global data indicates that an estimated 490,000 new cases of 
and 275,000 deaths due to cervical cancer occur annually among women worldwide. 
Nearly 80% of these cases are in developing countries where screening programs are 
not well established and awareness about the disease is low. HIV-infected women 
appear to be at increased risk of cervical cancer both in resource rich and resource 
limited areas [3, 4]. See Figure 2 below for the current model for cervical cancer 
pathogenesis.  
 
Compared with HIV-uninfected women, women with HIV are more often infected with 
multiple types of hr-HPV [5], are more likely to have persistent hr-HPV infections [6], and 
respond less well to treatments of cervical intraepithelial neoplasia (CIN) [7, 8]. With 
improved access to antiretroviral therapy (ART) and improved longevity, HIV-infected 
women are living longer allowing time for persistent hr-HPV infections and high-grade 
CIN2+ to progress to invasive cancer.  
 
Figure 2: Model of Cervical Cancer Pathogenesis [9]  
 
 

 
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HPV types 16 and 18 account for 70% of cervical cancer cases worldwide [10, 11]. It is 
not clear whether that proportion is different in HIV-infected women [12]. A recent meta-
analysis of epidemiologic studies of HPV infections in HIV-infected women suggested 
that HPV 16 was less likely to be found with cervical high-grade squamous intraepithelial 
lesions (HSIL) in HIV-infected women compared with HIV-uninfected women (32% vs. 
45%), but HPV 18 was somewhat higher (13% vs. 7%) [13].   
 
Cytology-based Cervical Cancer Screening 
Cervical cancer screening programs are traditionally based on cervical cytology as the 
initial screening test. A cytology-based screening program is a three-visit process: 1) 
women have a speculum exam during which cervical cytology samples are obtained, 2) 
women with abnormal results undergo cervical colposcopy with directed biopsies of 
visible lesions, and 3) lesions with CIN2+ on histopathology are treated with excisional or 
ablative treatment [14, 15]. However, cervical cytology has an irreducible false negative 
rate of 30% [16]. Multiple cervical cytological assessments are necessary to achieve an 
acceptably high sensitivity for CIN2+. In resource rich settings, some have advocated for 
primary screening with hr-HPV testing instead of cytology [17].  
 
HPV Test-and-Treat Strategies 
It is challenging to establish and sustain cytology-based screening programs in resource 
limited settings [15, 18]. Such programs require trained cytotechnologists and qualified 
pathologists to interpret the results. An alternative strategy that has been proposed relies 
on testing for cancer-causing or “high-risk” types of HPV (hr-HPV) as the screening test 
for cervical cancer [9]. The underlying principle is that hr-HPV infection is a necessary 
cofactor for the vast majority of cervical cancers [19, 20]. If hr-HPV is present, women 
undergo ablative treatment of the transformation zone with same-visit cryotherapy to 
treat presumptive CIN2+ and/or areas of hr-HPV infection without actual CIN2+.   
 
The HPV test-and-treat strategy was evaluated in a three-arm study comparing hr-HPV 
testing, VIA (visual inspection of the cervix after a wash of acetic acid) without the aid of 
a colposcope, and a control arm of delayed evaluation in a large clinical trial of South 
African women [21]. Women aged 35-65 received a test for hr-HPV (Digene Hybrid 
Capture-2 [HC2]™, Qiagen, Gaithersburg, MD) and VIA at baseline. They returned to 
the clinic 2-6 days later for randomization to either cryotherapy if HPV-infected (n=2163), 
cryotherapy if VIA is abnormal (n=2227), or a 6-month delayed evaluation (n=2165). 
Women returned 6 months later for colposcopy with biopsy of suspicious lesions. 
Women who were either hr-HPV infected or had an abnormal VIA at entry and a subset 
of women who were hr-HPV uninfected or had a normal VIA at entry returned at 12 
months for a second colposcopy. 
 
The investigators found that the rate of CIN2+ was higher in the delayed evaluation 
group (3.55%, 95%CI [2.71%-4.39%]) compared to the VIA group (2.23%, 95% CI 
[1.57%-2.89%]) or HPV test-and-treat group (0.80%, 95% CI [0.40%-1.20%]). The HPV 
test-and-treat strategy was the most effective at preventing CIN2+. These differences 
persisted at the 12-month visit. Complications were minor with only one serious adverse 
event (AE), cervical bleeding, reported.   
 

 
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The HPV-based approach appeared to work particularly well among HIV-infected 
women [22]. Among approximately 300 HIV-infected women randomized to the HPV 
test-and-treat arm, 3.4% developed CIN2+ through 3 years of follow-up compared with 
19.8% of approximately 300 HIV-infected women randomized to the control arm 
(p<.001). Nearly all CIN2+ (34/36 or 94%) developed among women infected with hr-
HPV at baseline. When restricting the analysis to women with hr-HPV at baseline, the 
rate of CIN2+ was 40% among HPV-infected women randomized to the delayed 
evaluation arm compared with 7% among HPV-infected women in the HPV test-and-
treat arm from follow-up visits month 6 through month 36. These results suggest that an 
HPV test-and-treat strategy is efficacious in HIV-infected women and should be 
considered as a cervical cancer prevention strategy.  
 
Investigators recently published results from a large, cluster-randomized trial conducted 
in India of three cervical cancer screening tests compared to a control group with no 
screening [23]. HIV status was not reported. The three screening tests were testing for 
hr-HPV (Digene HC2), VIA, and cervical cytology. If the screening test was abnormal, 
then women were referred for cervical colposcopy and directed biopsy of lesions. All 
women with CIN2+ were offered treatment with LEEP. Only one screening test was 
performed for each woman. Fifty-two clusters with a total of 131,746 women were 
randomly assigned to the four groups. The death rate from cervical cancer was .52 that 
of the control group during 8 years of follow-up (95% CI [.33–.83]). There was no 
significant difference between the VIA or the cytology groups compared to the control 
group. This suggests that hr-HPV testing was the most effective screening test when 
performed at a single time point.   
 
Abbott RealTime High Risk-HPV Test 
The Abbott RealTime hr-HPV (aHPV) test detects 14 high-risk HPV types (16, 18, 31, 
33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) in cervical specimens. Abbott has 
completed European certification for this assay. It is an automated test that utilizes real-
time polymerase chain reaction (PCR) technology. By using a multi-color detection 
system, this test differentiates signals from HPV 16, HPV 18, and the non-HPV 16/18 
high-risk types in the same reaction, giving 3 results for each test. The test also features 
an internal control (IC) for specimen adequacy by detecting an endogenous human b-
globin sequence. In addition, external positive and negative controls are included in each 
run to assess run validity. Test results are automatically reported by assay software that 
evaluates key characteristics of real-time PCR data against quality assurance 
parameters to assess result validity [24]. 
 
The aHPV assay was compared with Digene HC2 in a clinical trial enrolling 702 women 
who underwent testing using both assays, HPV DNA PCR, cytology, and colposcopy 
with directed biopsies [25]. The aHPV was positive in 100/100 (100%) of women with 
CIN3+ compared to 97% for Digene HC2. The aHPV was positive in 224/229 (97.8%) of 
women with CIN2+ compared with 219/229 (95.6% for Digene HC2). The specificity, 
positive and negative predictive values were similar for the two assays. The 
concordance was 92%, and the agreement beyond chance was excellent, Cohen’s 
κ=0.77 (95% CI 0.72-0.83). When using HPV DNA PCR as the gold standard, the 
accuracy of aHPV in detecting high-risk HPV was significantly higher than that of Digene 
HC2 (98.7% versus 92.9%, P <0.0001). 

 
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careHPV: Low-cost Testing for hr-HPV  
With support from the Gates Foundation, the Program for Appropriate Technologies in 
Health (PATH) has partnered with Qiagen Inc., Gaithersburg, MD (formerly Digene Inc.) 
to adapt the Digene HC2 assay for use in resource limited settings [careHPV website]. 
The resulting careHPV™ test has been field-tested yielding comparable results to the 
Digene HC2 performed in developed countries [26]. The careHPV detects the presence 
of 14 hr-HPV types without distinguishing between the types. Qiagen will commercially 
distribute careHPV in 2010 priced at approximately $5US per sample [careHPV 
website]. Results of the careHPV are available within 2 hours, multiple samples can be 
run at one time, and samples can be analyzed in basic laboratory facilities. The current 
prototype is portable and can be powered by a battery in areas where electricity is 
unreliable. The reagents used in this test are in dry form and heat-stabilized so that they 
do not require storage at specific temperature or humidity. Samples are not read by a 
luminometer but by exposure of a strip of film.  
 
careHPV was evaluated in a cross-sectional study of 2388 HIV-negative women age 30-
54 in China [26]. Samples for careHPV, Digene HC2, and cervical cytology were 
collected and VIA performed and compared against colposcopy with directed biopsies. 
Seventy women were diagnosed with CIN2+. The careHPV had a sensitivity and 
specificity of 90% and 84.2%, respectively, for CIN2+. Digene HC2 had a sensitivity and 
specificity of 97.1% and 85.6%, respectively. Of note, VIA was only 41% sensitive for 
CIN2+. Qiagen has completed European certification for the careHPV assay. 
 
Outcomes to Treatment of Cervical Cancer Precursors 
HIV-infected women are at greater risk for recurrent CIN2+ after treatments [7, 8, 27]. 
Continued detection of HPV post treatment is a strong predictor of recurrent disease in 
HIV-uninfected women and likely for HIV-infected women as well [14, 15]. Few studies 
have investigated the effect of ablative (e.g., cryotherapy) or excisional (e.g., LEEP) 
treatments on HPV clearance in HIV-infected women. Massad and colleagues [27] 
reported on 170 HIV-infected women from the Women’s Interagency HIV Study (WIHS) 
and HIV Epidemiology Research Study (HERS) cohorts who underwent cervical 
treatment for CIN. They found that HPV was commonly detected among women who 
had abnormal cervical cytology after treatment. Half of the women had recurrent CIN 
through 3 years of follow-up post procedure. However, much of the recurrent disease 
was low-grade CIN. Recurrence was more common among HIV-infected women with hr-
HPV detected after treatment (HR=2.5, 95% CI [1.3-6.5]) and among those treated for 
CIN2+ (HR=2.4, 95% CI [1.4-4.8]).  
 
More data are available for HIV-uninfected women. Elfgren and colleagues [28] reported 
on 109 women treated for CIN with either cervical conization or cryotherapy. Eighty-four 
(81%) were positive for HPV. Thirty-one women were treated with cervical cryotherapy; 
15 (48%) were positive for at least one of the same types 3 months later and 
approximately 20% 12 months after cervical cryotherapy. Of note, HPV clearance was 
greater for women who underwent cervical conization. Aerssens and colleagues 
reported on 122 women who underwent either cervical cryotherapy (n=55) or LEEP 
(n=67) [29]. Forty-four percent of women who underwent cryotherapy had the same type 
of HPV detected 6 weeks after treatment compared with 25% in the LEEP group. The 
efficacy of cryotherapy for clearing HPV infection in the absence of CIN is not known. 

 
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Prevalence of hr- HPV and CIN at Select ACTG Sites 
Johannesburg, South Africa. Firnhaber and colleagues of the University of 
Witswatersrand recently published data on the prevalence of HPV infections and cervical 
squamous intraepithelial lesions (SIL) on cytology in HIV-infected women in 
Johannesburg, South Africa recruited from the government outpatient HIV clinic [30]. 
One thousand and ten HIV-infected women with a median age of 34 and CD4 count of 
231 cells/µL were screened with cervical cytology and a subset screened with HPV DNA 
PCR. Five hundred and three (50%) of these women had an abnormal cervical cytology: 
84 (8%) had atypical squamous cells, 237 (23%) low-grade lesions and 182 (18%) had 
high grade lesions. Among the 191 women with HPV DNA PCR results, 138 (72%) had 
one or more types of hr-HPV detected by PCR and 51% had more than one hr-HPV type 
detected. Among 90 women with normal cytology, 54 (60%) had one or more types of 
hr-HPV detected. HPV 16 was detected in 42% of women with HSIL and HPV 18 in 3%. 
High risk-HPV by DNA PCR was related to current CD4 count: 72 (82%) of women with 
a CD4 <200 cells/mm3 had hr-HPV by PCR compared with 7 (41%) of women with a 
CD4 >500 cells/mm3.  
 
Pune, India. Investigators have shown that in a cross-sectional assessment of 303 HIV-
infected women, 83 (27.7%) had colposcopic-histopathological evidence of CIN1+ 
lesions and 50 (16.5%) had evidence of advanced CIN2+ neoplastic disease [31]. High 
risk-HPV by Digene HC2 was detected in 41.7% (124/297) of participants. On 
multivariable ordinal logistic regression, the independent predictors of increasing severity 
of CIN included (i) receiving ART [adjusted odds ratio (aOR): 2.16 (1.15, 4.04), p=0.02] 
and (ii) being hr-HPV positive [aOR: 1.91 (1.12, 3.26), p=0.02].  
 
Port-au-Prince, Haiti. Cervical cancer is the leading cause of cancer death in Haitian 
women, with an estimated 1300 deaths annually [32]. After the introduction of ART for 
HIV-infected patients in Haiti in 2003, malignancies became the third leading cause of 
AIDS mortality, behind wasting syndrome and tuberculosis. Colleagues from GHESKIO 
have examined treatment outcomes in a cohort of 910 adults with AIDS who started ART 
in 2003 at the GHESKIO center. In HIV-infected women receiving ART in Haiti, cervical 
cancer was the most common cause of cancer death occurring at a rate of 3 deaths per 
1000 patient-years [33]. Investigators have screened 500 women enrolled in a 
randomized clinical trial of early versus delayed ART (sponsored by the U.S. National 
Institutes of Health [NIH], U01 AI058257). The median age is 36 years. The median CD4 
cell count at enrollment was 312 cells/µL. The median follow-up is over 2 years with 96% 
retention. This trial was interrupted by the Data and Safety Monitoring Board (DSMB) 
after an interim review showed the mortality was 76% lower in the early treatment group 
[34]. Four hundred and seventy women were studied. Per the baseline Pap test, 53 
women (11%) had ASC-US, 100 (22%) had low-grade squamous intraepithelial lesions 
(LSIL), and 35 (7%) had HSIL. By HPV testing with the Digene assay, 268 (57%) had a 
hr-HPV type detected. By colposcopy, 45 (10%) of the 470 women were diagnosed with 
a high grade CIN2+ lesions. 
 

 
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Lusaka, Zambia. In a cross-sectional study in Lusaka, Zambia, HSIL and cytology 
suggestive of squamous cell carcinoma (SCC) were detected in 52% of HIV-infected 
women accessing ART [35]. The prevalence of cervical hr-HPV by PCR was 85.3% 
(128/150 women). High risk-HPV by PCR was significantly greater among women with 
CD4 cell counts less than 200 cells/µL: 44/53 (83%) versus 87/91 (96%), p=.001, and 
the only hr-HPV types significantly associated with HSIL or SCC by cytology were HPV 
31 and HPV 58. HPV 16 was detected in 22% of women with HSIL, and HPV 18 was 
detected in 13%. Multiplicity of HPV types (median was 4 high-risk types) and 
heterogeneity (36 of 37 detectable types by PCR were found) were prominent [36].  
 
Table 1: Data on hr-HPV and CIN in HIV-infected Women from Select Clinical Research 
Sites (CRSs) Participating in A5282 
 
* PCR performed on a subset of women (n=191) in South Africa. 
 
Potential Risks of Study Treatments 
 
Cervical biopsies 
o Common, not serious 
 
Pain during biopsy 
 
Mild bleeding  
o Rare  
 
Heavy bleeding requiring treatment to stop the bleeding 
 
Infection of the cervix requiring antibiotics  
 
Possible increased risk of miscarriage after multiple cervical biopsies 
 
 
Cervical cryotherapy 
o Common, not serious 
 
Pain and cramping during the procedure (1%) 
 
Profuse watery vaginal discharge (>10%) 
 
Heavy, odorous discharge (1%) 
 
Mild cervical bleeding (2%) 
 
Cervical infection (1-2%) 
 
Retraction of squamocolumnar junction into cervical canal, which makes 
subsequent exams more difficult 
 
Country (City) 
CRS 
Sample 
Size 
Median 
CD4 
(cells/µL)
Hr-HPV 
Prevalence
Any SIL 
on 
Cytology
HSIL+ 
Cytology 
CIN+ by 
Histology 
Reference
Haiti  
(Port-au-
Prince) 
GHESKIO 
470 
312 
57% by  
Digene 
HC2 
40% 
7% 
10% 
Un-
published 
India  
(Pune) 
NARI 
303 
343 
41% by  
Digene 
HC2 
34% 
6% 
16.5% 
38 
South Africa 
(Johannesburg) 
WITS 
1010 
231 
72% by 
PCR * 
50% 
18% 
Not 
assessed
30, 39 
Zambia  
(Lusaka) 
University 
Teaching 
Hospital 
150 
165 
90% by 
PCR 
76% 
52% 
Not 
assessed
36 

 
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o Rare 
 
Severe cramps and abdominal pain requiring parenteral medications (<1%) 
 
Pelvic inflammatory disease (<1%) 
 
Heavy cervical bleeding (very rare, potentially serious) 
 
Cervical stenosis (very rare, potentially serious) 
 
Vaginal injury from unintentional freezing (very rare, not serious) 
 
Vasovagal reactions during procedure (<1%) 
 
Potential increased risk of transmitting HIV to sexual partners post-procedure 
 
 
LEEP 
o Common, not serious  
 
Transitory pain from local anesthetic into the cervix  
 
Blood tinged, dark brown mucus for 1-2 weeks post LEEP 
 
Dull ache/cramping during procedure 
 
Postoperative cramping/pain (common, relived by analgesics) 
o Uncommon, serious:  
Intraoperative/perioperative 
 
Anesthetic reaction/vasovagal syncope <1% 
 
Severe intra/perioperative bleeding <2% 
 
Electrical injury of vaginal wall (rare)  
 
Perforation of uterus <1% 
Postoperative 
 
Moderate to severe postoperative bleeding <2% 
 
Cervical or endometrial infection/pelvic inflammatory disease (rare, mostly if 
not treated perioperatively by antibiotics) 
 
Cervical stenosis, due to scarring: <1-2%: more in menopausal women  
 
Cervical incompetence: resulting in miscarriage or pre-term labor <2%  
 
Infertility (rare) 
 
Potential increased risk of transmitting HIV to sexual partners post procedure 
[37] 
 
2.2 
Rationale 
 
Age Range 
HPV testing is used in the screening algorithm of HIV-uninfected women age 30 or older. 
HPV testing has not been traditionally used for younger women because of the high-
incidence of transient, insignificant HPV infections. However, HIV-infected young people 
have been noted to have a high prevalence of CIN2/3 as well as cases of invasive 
cancer. Therefore, the protocol team has opted to include younger women in this study. 
 
Arm C 
Women falling into either of the following two categories will be followed in Arm C: (i) 
women who have extensive cervical lesions that are inappropriate for cervical 
cryotherapy and (ii) high-risk HPV negative women with cervical lesions or a HSIL 
cytology. In a large screen-and-treat evaluation from Zambia, approximately 15% of 
women undergoing evaluation were thought to have lesions inappropriate for 
cryotherapy and were referred for LEEP [40]. In a recent presentation from Zambia, 20% 
of HIV-infected women had lesions inappropriate for cryotherapy. Of these women, 15% 

 
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had invasive cancer and another 33% had CIN2 or 3. Inclusion of this category of 
women in the present study will yield a larger number of participants for assessment of 
the HPV genotypes found in CIN2+ biopsy specimens (possible future study) and for the 
effect of LEEP on prevalent hr-HPV infections. In addition, these study populations will 
provide important data for implementation of the HPV test-and-treat strategy, as outlined 
in section 1.3.8, including the role of HPV testing in the management of women 
presenting with such conditions.   
 
PEPFAR Objectives 
Part of this study is being funded by a supplement from the U.S. NIH to conduct 
implementation science research of interest to the President’s Emergency Plan for AIDS 
Relief (PEPFAR). The PEPFAR objectives in section 1.3.5 will use screening and 
baseline evaluations from all women who give consent for this study. The availability of 
the careHPV test should broaden access to cervical cancer screening through the HPV 
test-and-treat strategy. It will be critical to understand how this test performs in HIV-
infected women. Although this assay has been conformité européenne (CE)-marked, it 
will not be widely available until late 2011. This study will compare careHPV results to 
two other HPV tests: HPV DNA PCR and aHPV. Cryotherapy is not recommended for 
women with extensive cervical lesions. Data from our Zambian investigators suggest 
that 15-20% of HIV-infected women will have such lesions and that half of these women 
will have CIN2/3 or invasive/microinvasive cancer on histology [40, 41]. Algorithms for 
cervical cancer screening must address treatment of these women to maximally impact 
mortality from cervical cancer. 
 
Summary 
An HPV test-and-treat strategy may become the standard of care for cervical cancer 
screening in resource limited settings because it is safe, effective, and inexpensive. A 
phase II study that randomizes women with hr-HPV was chosen because these women 
are at highest risk for CIN2+ and maximizes the efficiency of the study. Although limited 
data suggest an HPV test-and-treat strategy is effective in HIV-infected women, further 
study is needed before it can be broadly applied in this population. The protocol team 
proposes a proof-of-concept study in HIV-infected women to compare the effectiveness 
of immediate cryotherapy in women identified with high-risk HPV in screening to 
cytology-based strategy. It is imperative to understand how to apply an HPV test-and-
treat strategy in HIV-infected women to reduce the morbidity and mortality due to 
cervical cancer. 
 
 
3.0 
STUDY DESIGN 
 
A5282 is a randomized clinical trial of an HPV test-and-treat-strategy compared to 
cytology-based strategy. The study population is composed of HIV-1-infected women 
ages 18 years or older. No restrictions are in place for ART regimens, which will be 
initiated or continued according to the local standard of care. Sites should strongly 
consider initiating ART in women with a CD4 <350 cells/µL, if feasible. ART is not 
provided by the study. To be eligible, participants must have no history of cervical, 
vaginal, or vulvar cancer; no prior cervical cryotherapy, cervical conization, or 
hysterectomy; and no prior receipt of HPV vaccines.  

 
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The screening laboratory evaluations include CD4 cell count, plasma HIV-1 RNA viral 
load, and complete blood count. All participants will undergo a speculum examination at 
screening to obtain cervical specimens for cytology, aHPV, and HPV DNA PCR. 
Participants will be screened for hr-HPV with aHPV. This test semi-quantitatively detects 
the presence of type 16, type 18, or the presence of any of the other 12 types of hr-HPV 
(31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). A separate specimen will be 
collected and stored for careHPV testing, which detects the 14 types listed above.  
 
At screening, the examiner will also perform a visual inspection and colposcopy without 
biopsies to determine whether the candidate’s cervix is suitable for cryotherapy. 
Participants with cervical lesions inappropriate for cryotherapy (as defined in Section 
4.1.8) are not eligible for randomization but will be eligible to register to Arm C. 
Participants without hr-HPV (by aHPV) will also be eligible to register to Arm C if lesions 
were seen on the screening colposcopy or if the screening cytology shows HSIL. 
 
The study will randomize 280 participants with hr-HPV (by aHPV) to Arm A or Arm B. 
Randomization will be stratified by current use of ART (i.e., any ART or no ART) with 
institutional balancing. Participants in Arm A (HPV test-and-treat) will undergo cervical 
cryotherapy at entry. Participants in Arm A will receive the results of the cytology, but 
participants will receive cryotherapy treatment regardless of the results.  Participants in 
Arm B will follow a cytology-based management plan involving three steps – cytology, 
colposcopy with directed biopsies, and LEEP (as needed). Participants in Arms A and B 
will be seen at regular intervals post entry for aHPV, HPV DNA PCR, cervical cytology, 
and cervical colposcopy and directed biopsies for a total follow-up length of 130 weeks. 
A separate specimen will be collected 26 weeks post entry and stored for careHPV 
testing. 
 
Participants in Arm C will undergo colposcopy and directed biopsies. If CIN2+ is found 
by biopsy, then LEEP will be performed and a follow-up visit 26 weeks after these 
procedures will be scheduled for aHPV, HPV DNA PCR, careHPV, cervical cytology, 
and cervical colposcopy and directed biopsies. After the week 26 visit, Arm C 
participants will go off study.  
 
All participants undergoing cryotherapy or LEEP will be seen 4 weeks post-procedure to 
assess for AEs from the procedure. Quality assurance procedures are in place for 
reviews of digital impressions rendered during colposcopies (no lesions seen, lesions 
seen/appropriate for cryotherapy or lesions seen/not appropriate for cryotherapy). Slides 
from biopsies with and without CIN2+ will be reviewed regionally or centrally (see the 
A5282 Manual of Procedures [MOPS] for details). HPV DNA PCR and careHPV will be 
performed on stored specimens and results will not be used for clinical management. 
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 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 

 
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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. 
 
NOTE:  For sites located in countries other than the United States, the term 
“licensed” refers to a kit that has been certified or licensed by an 
oversight body within that country and validated internally.  
 
World Health Organization (WHO) and Centers for Disease Control and 
Prevention (CDC) 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. 
 
4.1.2 The following laboratory values obtained within 30 days prior to study entry:  
 
Absolute neutrophil count (ANC)  750/mm3  
 
Platelet count  75,000/mm3 
 
Hemoglobin (HgB) > 8 gm/dL 
 
4.1.3 For candidates suitable for cervical cryotherapy (as defined in section 4.1.8 
below), hr-HPV detected by aHPV within 30 days prior to study entry. 
 
NOTE:  Participants with a visual inspection showing extensive lesions 
inappropriate for cryotherapy do not require an aHPV test result prior to 
enrollment.  
 
4.1.4  For women without hr-HPV detected by aHPV, presence of lesions on visual 
inspection or HSIL cervical cytology. 
 
4.1.5 Suitable candidate for cervical cryotherapy, defined as: 
 
No visible cervical lesions. 
-- OR -- 
 
Any visible lesions are located entirely on the ectocervix and are no more 
than 2 to 3 mm into the endocervical canal, AND 
 
visible lesions cover less than 75% of the cervix, AND 
 
all visible lesions are deemed appropriate for cryotherapy by the treating 
health care provider. 
 
NOTE:  Participants with cervical lesions inappropriate for cryotherapy are not 
eligible for randomization and should be followed in Arm C. 
 
4.1.6 For participants of reproductive potential, negative serum or urine pregnancy test 
with a sensitivity of <25 mlU/mL within 48 hours prior to study entry. 
 
NOTE:   Reproductive potential is defined as women who have not been 
postmenopausal for at least 24 consecutive months (i.e., who have had 

 
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menses within the preceding 24 months) or women who have not 
undergone surgical sterilization (e.g., hysterectomy, bilateral 
oophorectomy, tubal ligation, or salpingectomy).  
 
4.1.7 Contraception requirements 
 
 
 
All study participants must agree not to participate in a conception process (e.g., 
active attempt to become pregnant or in vitro fertilization) from the time of study 
entry until 12 weeks after study entry. 
 
If participating in sexual activity that could lead to pregnancy, the study 
participant must agree to use at least one reliable form of contraceptive from the 
time of study entry until 12 weeks after study entry. At least one of the following 
contraceptives MUST be used appropriately: 
 
Condoms (male or female) with or without a spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
IUD 
 
Hormone-based contraceptive 
 
NOTE:   If participating in sexual activity that could lead to pregnancy, study 
participants taking efavirenz must use two forms of contraceptives.  
 
Study participants who are not of reproductive potential (defined as 
women who have been postmenopausal for at least 24 consecutive 
months or have undergone surgical sterilization [e.g., hysterectomy, 
bilateral oophorectomy, or salpingectomy]) are eligible without requiring 
the use of contraceptives. Participant-reported history is acceptable 
documentation of sterilization, menopause, and a female’s reproductive 
potential. 
 
4.1.8 If recently gave birth, must be at least 12 weeks postpartum. 
 
4.1.9 Females ≥ 18 years of age at study entry.  
 
4.1.10 Ability and willingness of participant or legal guardian/representative to provide 
written informed consent. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Current or prior history of cervical, vaginal, or vulvar cancer. 
 
4.2.2 Prior cervical cryotherapy, LEEP, cervical conization, or total or partial 
hysterectomy. 
 
4. 2.3 Cervical, vaginal, or vulvar lesions that are suspicious on clinical exam for 
cancer. 
 
4. 2.4 Visual evidence of bacterial STIs or suspicion of pelvic inflammatory disease.  

 
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NOTE:   Cervicitis or suspected pelvic inflammatory disease must be treated with 
appropriate antibiotics at least 7 days prior to entry. 
 
4.2.5 Prior vaccination with an HPV vaccine. 
 
4.2.6 Hemophilia. 
 
4.2.7 Currently on anticoagulation therapy other than acetylsalicylic acid. 
 
4.2.8 Serious illness requiring systemic treatment and/or hospitalization within 21 days 
prior to study entry. 
 
4.2.9 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. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
Division of AIDS (DAIDS) Protocol Registration Office (PRO) at the Regulatory 
Support Center (RSC). The DAIDS PRO will review the submitted protocol 
registration packet to ensure that all of the required documents have been 
received.  
 
For studies at non-US sites, protocol activation is required prior to enrolling 
participants into the study. 
 
Site-specific informed consent forms (ICFs) will be reviewed and approved by the 
DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals of an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICF(s) 
will not be reviewed and approved by the DAIDS PRO, and sites will receive an 
Amendment Registration Notification when the DAIDS PRO receives a complete 
registration packet. A copy of the Amendment Registration Notification should be 
retained in the site's regulatory files. 
 

 
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For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant or legal guardian/representative 
will be asked to read and sign the approved ICF.  
 
For participants from whom a signed ICF has been obtained, an ACTG 
Screening Checklist must be entered through the Data Management Center 
(DMC) Subject Enrollment System.  
 
4.3.2 Randomization (Arms A and B)/Participant Registration (Arm C) 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
 
4.4 
Coenrollment Guidelines 
 
Sites are strongly encouraged to coenroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-U.S. Clinical Research Sites for Currently 
Unspecified Genetic Analyses.” Coenrollment in A5243 does not require permission from 
the A5282 protocol chairs.  
 
Participants cannot be coenrolled in A5240, “A Phase II Study to Evaluate the 
Immunogenicity and Safety of a Quadrivalent Human Papillomavirus Vaccine in HIV-1-
Infected Females.” 
 
Sites should consult the A5282 PSWP for other studies in which participants can be 
coenrolled, or contact the protocol chair and co-vice chairs via e-mail as described in the 
Study Management section for permission to enroll participants who are being followed 
in other clinical trials. 
 
 
5.0 
STUDY TREATMENT 
 
5.1 
Intervention, Administration, and Duration 
 
5.1.1 Cervical Cryotherapy 
 
Two 3-minute freezes separated by 5 minutes of thawing. Refer to the A5282 
MOPS for a detailed description of this procedure. 
 
5.1.2 LEEP 
 
 
Refer to the A5282 MOPS for a detailed description of this procedure. 
 

 
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5.2 
Study Product Formulation and Preparation 
 
 
 
Not applicable. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
 
Not applicable. 
 
5.4 
Concomitant Medications 
 
5.4.1 Required Medications 
 
If participating in sexual activity that could lead to pregnancy, participants must 
agree to use at least one reliable form of contraceptive (as defined in section 
4.1.10) from the time of study entry until 12 weeks after study entry. 
 
5.4.2 Prohibited Medications 
 
None. 
 
5.4.3 Precautionary Medications 
 
 
Participants who require anticoagulation medication other than acetylsalicylic 
acid should not undergo cervical biopsies, LEEP, or cryotherapy.  
 
Site investigators are encouraged, but not required, to delay HPV vaccinations 
for participants in Arms A and B until 24 weeks post entry.  

 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
6.1 
Schedule of Events  
 
Evaluation 
Screening 
Entry 
(day 0) 
Post Entry Evaluations 
4 weeks 
post cervical 
treatment  
Week 26  
(Final Visit for 
Arm C) 
Week 
52 
Week 
78 
Week 
104 
Week 130 
(Final Visit for Arms A 
and B) / Disc Evals 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
Medical history / Medication history 
X 
 
 
 
 
 
 
 
Nadir CD4 cell count 
X 
 
 
 
 
 
 
 
Complete physical examination (PE) 
X 
 
 
 
 
 
 
 
Clinical assessments 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
 
 
 
 
 
 
 
Pregnancy test 
within 48 hours prior to entry 
whenever suspected, prior to cryotherapy and prior to LEEP 
 
CD4 cell count  
X 
 
 
 
 
 
 
 
Plasma HIV-1 RNA  
X 
 
 
 
 
 
 
 
Speculum examination and colposcopy  
X 
 
 
 
 
 
 
 
Real-time aHPV and Stored HPV DNA PCR  
X 
 
 
 
 
 
 
 
Stored aHPV and Stored HPV DNA PCR 
 
 
X 
X 
X 
X 
X 
 
Stored careHPV 
X 
 
X 
 
 
 
 
 
Cervical cytology  
X 
 
X 
X 
X 
X 
X 
 
Colposcopy and directed biopsies  
 
See Section 
6.3.10 
X 
 
X 
 
X 
 
LEEP 
 
only if CIN2+ is found on biopsy 
 
Cryotherapy (Arm A only) 
 
X 
 
 
 
 
 
 
Assessment of targeted AEs  
 
X 
 
 
 
 
 
X 
Sociodemographic and sexual behavior 
questionnaire 
 
X 
X 
X 
X 
X 
X 
 

 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant’s starting any study 
treatment. Screening evaluations to determine eligibility must be completed 
within 30 days prior to study entry, unless otherwise specified.  
 
The cytology and HPV evaluations cannot be performed while the participant is 
menstruating. If a participant has visual evidence of bacterial STIs or an 
examination consistent with pelvic inflammatory disease, then samples for 
cytology and HPV testing should not be obtained. The participant should be 
treated according to the local standard of care, in which case screening 
evaluations can be performed a minimum of 7 days after initiating treatment.  
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database. 
Cytology, colposcopic visual impression, and HPV testing on screening failures 
will also be captured on a case report form (CRF) and entered into the ACTG 
database.  
 
6.2.2 Entry Evaluations 
 
Participants should receive study treatment within 7 days after 
randomization/registration, unless contraindicated (see Section 6.3.10). 
 
6.2.3 Post Entry Evaluations 
 
 
Post Entry Evaluations  
Study visits will be conducted in the clinic at week 26 +/- 6 weeks for participants 
in all arms and at weeks 52, 78, and 104 +/- 6 weeks for participants in Arms A 
and B only. Additional visits will be necessary between these time points to 
discuss cytology and/or histology test results and subsequent management plans 
with participants.     
 
Post Cervical Treatment Evaluations  
Participants will be seen in the clinic 4 weeks +/- 10 days after cryotherapy or 
LEEP for assessment of procedure-related AEs. 
 
Study Completion Evaluations  
The final study visit will occur at week 26 +/- 6 weeks for participants in Arm C 
and at week 130 +/- 12 weeks for participants in Arms A and B. The off-study 
CRF must be completed and keyed into the database for each participant after 
completing the evaluations required at the final study visit unless CIN2+ is found, 
in which case the off-study CRF should be completed and keyed into the 
database after the participant undergoes LEEP and completes the 4-week post 
treatment assessment of procedure-related AEs.  

 
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6.2.4 Discontinuation Evaluations 
 
Evaluations for Randomized/Registered Participants Who Do Not Undergo Study 
Treatment 
Participants who are randomized to Arm A or B or registered to Arm C but do not 
undergo study treatment will not be discontinued from study. Instead, these 
participants will be followed on study and should complete the study evaluations 
as per Section 6.1 up to week 130 (Arms A and B) or week 26 (Arm C).  
 
Premature Study Discontinuation Evaluations 
Participants who discontinue study participation prior to the final study visit will be 
asked to come into the clinic to complete the study evaluations as noted in the 
“Week 130 (Final Visit) / Disc Evals” column of Section 6.1. The participant will 
discontinue from the study after completing these evaluations. Refer to Section 
8.0 for criteria for discontinuation.  
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
web site for information about what must be included in the source document: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced
ocappndx.pdf. 
 
All stated evaluations are to be recorded on the CRF and entered into the ACTG 
database unless otherwise specified. This includes events that meet the International 
Conference on Harmonisation (ICH) definitions for a serious adverse event: 
 
 
Results in death 
 
Life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/in capacity  
 
Congenital anomaly/birth defect 
 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the events listed above.   
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to 
the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009) 
and Addendum 1-Female Genital Grading Table for Use in Microbicide Studies, 
which can be found on the DAIDS RSC web site: http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
 6.3.1 Documentation of HIV-1 
 
 
Refer to Section 4.1.1 regarding assay requirements for HIV-1 documentation. 
HIV-1 documentation is not recorded on the CRF. 

 
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6.3.2 Medical History 
 
The medical history must include all diagnoses identified by the ACTG criteria for 
clinical events and other diagnoses, and menstrual history. For current criteria, 
refer to the appendix identified in the study CRF. Any allergies to any 
medications and their formulations must be documented.  
 
6.3.3 Medication History 
 
A medication history of ART use must be present, including start dates of all ART 
agents currently being received, and date of first ART. 
 
6.3.4 Nadir CD4 Cell Count 
 
The participant’s prior nadir CD4 cell count (absolute value and date) should be 
documented when possible with a copy of the nadir CD4 cell count report. If this 
documentation is not available, then participant recollection will suffice. For 
participants who do not know the exact nadir value and for whom there is no 
source documentation, then recall of the categorical nadir (e.g., <50, <100, <200 
cells/mm3) will suffice. 
 
6.3.5 Complete Physical Examination 
 
A complete physical examination should be done prior to entry and is to include 
at a minimum an examination of the skin, head, mouth, and neck; auscultation of 
the chest; cardiac exam; abdominal exam; examination of the lower extremities 
for edema; Karnofsky performance test; and assessment of WHO clinical staging 
of HIV/AIDS. 
 
The complete physical exam will also include signs and symptoms, diagnoses, 
and vital signs (temperature, pulse, and blood pressure). 
 
6.3.6 Clinical Assessments 
 
Targeted Physical Examination 
Post entry, a targeted physical examination is to include vital signs (temperature, 
pulse, and blood pressure) and is to be driven by any previously identified or new 
signs or symptoms including diagnoses that the participant has experienced 
since the previous visit. 
 
Signs and Symptoms  
At entry, all signs and symptoms Grade ≥ 3 that occurred within 45 days prior to 
entry must be recorded; post entry, signs and symptoms Grade ≥ 3 must be 
recorded. Post entry, all grades of signs and symptoms related to cervical 
cryotherapy or LEEP treatments that are contained within the DAIDS “Female 
Genital Grading Table for Use in Microbicide Studies” will be captured 
(http://rsc.tech-res.com/safetyandpharmacovigilance/).  
 

 
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Diagnoses 
Record all diagnoses identified by the ACTG criteria for clinical events and other 
diseases.  
 
Concomitant Medications 
Record ART medications (including start and stop dates), receipt of HPV 
vaccines, and receipt of medical or surgical treatment for genital warts, vulvar 
intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VAIN). Any 
antibiotics, hormonal treatment, or prescribed or over-the-counter treatments for 
gynecological conditions should be recorded.  
 
Adherence Assessment 
The site should discuss and encourage ongoing adherence to ART at each study 
visit if the participant is receiving ART. Any concerns about adherence should be 
communicated to the participant’s primary care provider. This should be 
documented in the source documents only. 
 
6.3.7 Laboratory Evaluations 
 
At screening, entry, and post entry record all Grade ≥ 3 laboratory values.  
 
Hematology 
ANC, platelet count, and HgB. 
 
Pregnancy Test 
For women with reproductive potential, a negative serum or urine -HCG (urine 
test must have a sensitivity of <25 mIU/mL) pregnancy test must be performed 
within 48 hours prior to study entry, prior to cryotherapy and LEEP (if done), and 
post entry whenever pregnancy is suspected. (See section 7.4 for the 
management of study participants who become pregnant after entry.) 
 
6.3.8 Immunologic Studies 
 
CD4 Cell Count 
Obtain absolute CD4 cell count and percentage from a DAIDS-approved 
laboratory. These results should be communicated to the participant’s primary 
care provider to assist in the management of her HIV infection, including the 
initiation of ART as indicated, and the site must document this communication in 
the source documents. 
 
6.3.9 Virologic Studies 
 
Plasma HIV-1 RNA 
Obtain HIV-1 RNA viral load levels from a DAIDS-approved laboratory. These 
results should be communicated to the participant’s primary care provider to 
assist in the management of her HIV infection, and the site must document this 
communication in the source documents. 
 

 
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6.3.10 Other Laboratory Studies and Procedures 
 
Refer to the A5282 MOPS for detailed instructions on how to perform colposcopy 
and biopsies, collect specimens for aHPV, HPV DNA PCR, and careHPV, 
perform cervical cytology, cryotherapy, and LEEP, and detailed plans for the 
quality assurance of clinical procedures. 
 
Participants must refrain from any kind of sexual activity, douching, and inserting 
any intravaginal products for at least 48 hours prior to the collection of 
vaginal/cervical specimens. 
 
Speculum Examination and Colposcopy 
Participants will undergo a speculum examination at screening to obtain cervical 
specimens for HPV testing and cytology. If participants have visual evidence of 
bacterial STIs or an examination consistent with pelvic inflammatory disease, 
then samples for HPV testing and cytology should not be obtained. Instead, 
these women should be treated according to the local standard of care, in which 
case screening evaluations can be performed a minimum of 7 days after initiating 
treatment. 
 
A trained examiner will also perform colposcopy at screening to determine 
whether the participant’s cervix is suitable for cryotherapy and for visual 
impression only. Digital images will be taken using a video colposcope provided 
to sites by the study, and submitted for review along with the colposcopic 
impression provided by the examiner as to the degree of CIN (no lesions seen, 
lesions seen appropriate for cryotherapy, lesions seen not appropriate for 
cryotherapy). Refer to the A5282 MOPS for detailed procedures. 
 
No biopsies are to be obtained at screening unless the examiner is suspicious of 
invasive cervical, vaginal, or vulvar cancer, in which case the participant will not 
be enrolled into the study and will be managed as per section 7.3.   
 
aHPV  
A cervical specimen will be obtained at screening for real-time aHPV testing. 
Post-entry, specimens will be obtained for aHPV and stored locally (refer to the 
A5282 MOPS).   
 
HPV DNA PCR 
Specimens will be stored for HPV DNA PCR. Testing will be performed on the 
same specimen as the aHPV. Specimens may be shipped to the U.S. for HPV 
typing at a central laboratory, if permitted by in-country regulations, or batch 
tested at a local or regional laboratory. Specimens obtained by LEEP will also be 
stored locally for possible future testing by HPV DNA PCR. 
 
careHPV 
A cervical cytobrush specimen will be obtained for careHPV and stored locally in 
the appropriate media (refer to the A5282 MOPS). 
 

 
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Cytology 
Cervical cytology specimens will be obtained and processed locally in real-time 
(refer to the A5282 MOPS). Pap smears will be interpreted locally. Results 
should be communicated to the participant’s primary care provider, and the site 
must document this communication in the source documents.  
 
Colposcopy and Directed Biopsies 
At entry: 
 
Participants in Arm A will not have colposcopy and directed biopsies; these 
women will instead undergo cryotherapy. 
 
Participants in Arm B will undergo colposcopy with directed biopsies if the 
screening cytology is abnormal, i.e., the result reveals atypical squamous 
cells of undetermined significance (ASCUS), atypical glandular cells of 
undetermined significance (AGUS), low grade squamous intraepithelial lesion 
(LSIL), or HSIL. 
 
Participants in Arm C will undergo colposcopy and directed biopsies if the 
screening cytology shows HSIL or if cervical lesions were seen upon visual 
inspection.  
 
Post entry: 
 
Participants in Arms A and B will undergo colposcopy and directed biopsies 
at the weeks 26, 78, and 130 clinic visits. 
 
Participants in Arm C who undergo LEEP post-entry will undergo colposcopy 
and directed biopsies at the week 26 clinic visit. 
 
Digital images and colposcopic impression will be submitted for review, along 
with location of cervical biopsies. 
 
Directed biopsies will be obtained from areas suspicious for CIN. Biopsies are 
taken only if lesions are seen upon colposcopy. In the event lesions are not seen 
upon colposcopy but the cytology specimens show presence of HSIL, then the 
participant should return to the study clinic for endocervical curettage (ECC). 
Slides from biopsies of CIN2+ and biopsies without CIN2+ will be submitted for 
review. If CIN2+ is detected by biopsy, the participant will undergo LEEP. 
 
LEEP 
Participants found to have CIN2+ by biopsy at any point during the study will be 
offered LEEP. If the participant had a prior LEEP, treatment of recurrent CIN2+ is 
at the discretion of the site investigator. These participants will continue on study. 
All specimens obtained by LEEP will be fixed in formalin and submitted for 
review. Digital images obtained immediately prior to and following LEEP will also 
be submitted for review.  
 
Participants will be advised to abstain from vaginal intercourse and douching for 
6 weeks after a LEEP, or the use of condoms during this period will be advised. 
Participants will return to the site for an assessment of AEs 4 weeks after LEEP, 
or sooner if significant AEs occur. 
 

 
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LEEP should not be performed while the participant is menstruating. Additionally, 
if a participant has visual evidence of bacterial STIs or an examination consistent 
with pelvic inflammatory disease, then LEEP should be deferred. The participant 
should be treated according to the local standard of care, in which case LEEP 
can be performed a minimum of 7 days after initiating treatment.  
 
Cryotherapy (Arm A Only) 
Participants in Arm A will undergo cervical cryotherapy within 7 days after entry. 
Digital images obtained immediately prior to and following cryotherapy will be 
submitted for review.  
 
Participants will be advised to abstain from vaginal intercourse and douching for 
6 weeks after cryotherapy, or the use of condoms during this period will be 
advised. Participants will return to the site for an assessment of targeted AEs 4 
weeks after cryotherapy, or sooner if significant AEs occur.  
 
 
Cryotherapy should not be performed while the participant is menstruating. 
Additionally, if a participant has visual evidence of bacterial STIs or an 
examination consistent with pelvic inflammatory disease, then cryotherapy 
should be deferred. The participant should be treated according to the local 
standard of care, in which case cryotherapy can be performed a minimum of 7 
days after initiating treatment.  
 
6.3.11 Questionnaires  
 
Assessment of Targeted AEs 
AEs related to cryotherapy or LEEP will be recorded and graded according to the 
DAIDS “Female Genital Grading Table for Use in Microbicide Studies,” which can 
be found on the DAIDS RSC web site: http://rsc.tech-
res.com/safetyandpharmacovigilance/.   
 
Sociodemographic and Sexual Behavior Questionnaire 
A standardized questionnaire will be used to collect data on sociodemographic 
indicators as well as sexual behavior indicators (e.g., age at first sexual 
intercourse, lifetime number of sexual partners, frequency of vaginal intercourse 
in the preceding 6 months, and number of partners in the preceding 6 months). 
After entry, only recent sexual activity will be assessed. 
 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
7.1 
Grade 3 or Higher Events 
 
If the site investigator considers a Grade 3 or higher event to be related to the study 
procedure(s), it is left to the discretion of site investigator to determine whether the 
procedure(s) should be repeated. 
 

 
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7.2 
Cryotherapy- and LEEP-related Complications  
 
Vaginal Bleeding 
Bleeding post cervical biopsy will first be controlled with direct pressure using a dry 
swab. If this is not sufficient, then a swab with Monsel’s solution will be applied to stop 
the bleeding. 
 
When postoperative bleeding occurs, it usually appears 4-6 days after treatment and 
often from the posterior lip of cervix. This bleeding can usually be controlled in the clinic 
by fulguration, applying Monsel’s paste, or using a silver nitrate applicator stick. Rarely, 
placement of a suture at the bleeding site is necessary. The risk of postoperative 
infection is very small and can probably be reduced even more by delaying surgical 
treatment until any woman with a likely diagnosis of pelvic inflammatory disease, 
cervicitis, vaginal trichomoniasis, or bacterial vaginosis has been adequately treated and 
recovered.  
 
Vaginal Infection 
The chance of postoperative infection is lessened by (1) only performing cryotherapy or 
LEEP when there is no evidence of bacterial STIs and (2) advising women to abstain 
from vaginal intercourse for 6 weeks post procedure.   
 
In addition, participants are to be advised of the symptoms of infection and encouraged 
to return to the clinic if the symptoms occur. If a participant presents postoperatively with 
a malodorous discharge, it should be cultured if possible and empirical treatment 
prescribed with antibiotics that are effective for pelvic inflammatory disease.  
 
7.3 
Other Diseases/Conditions 
 
Invasive Cervical, Vaginal, or Vulvar Cancer 
Each clinical research site conducting A5282 will develop its own plan for the clinical 
management of invasive cervical, vaginal, or vulvar cancer. Plans will be submitted to 
the A5282 protocol team for review prior to the enrollment of women at the site. 
 
Participants with visual evidence for cervical, vaginal, or vulvar cancer at the screening 
visit will not be enrolled into the study. After it is determined that these women are 
ineligible, biopsies of lesions suspicious for cancer are recommended to confirm the 
diagnosis. Although these women will not be enrolled into the study, all of the screening 
results with the exception of HPV DNA PCR results will be provided to the participants 
and their health care providers. These women will then be followed as per the site-
specific clinical management plan. 
 
Participants who are diagnosed with cervical, vaginal, or vulvar cancer after enrolling 
into the study will continue to be followed on study. These participants will come into the 
clinic per the time points in Section 6.1 for study evaluations. These participants will 
receive additional treatments as indicated in the site-specific clinical management plan.  
 

 
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Other Gynecological Conditions 
Cervical polyps, VIN, VAIN and vulvovaginal warts will be managed according to local 
standard of care.  
 
7.4 
Pregnancy  
 
Participants who become pregnant after study entry will continue to be followed on 
study. These participants will come into the clinic to complete study evaluations as per 
the schedule in Section 6.1 but will not undergo LEEP, cryotherapy, or cervical biopsy 
until 6 weeks after the pregnancy is completed. If there is suspicion of invasive cancer, 
clinical management is left to the discretion of the site investigator. 
 
Pregnancy outcome for the participant and the infant will be recorded on a CRF at the 
end of the pregnancy.  
 
If pregnancy occurs for a participant on study who is on ARVs, sites are strongly 
encouraged to register the pregnancy with The Antiretroviral Pregnancy Registry as 
soon as the site becomes aware of it.  More information is available at 
www.apregistry.com. 
 
 
8.0 
CRITERIA FOR STUDY DISCONTINUATION 
 
 
Request by the participant to withdraw. 
 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 
 
Clinical reasons believed life threatening by the physician, even if not addressed in 
Section 7.0 of the protocol. 
 
At the discretion of the ACTG, IRB/EC, the U.S. Office for Human Research 
Protections (OHRP), the U.S. National Institute of Allergy and Infectious Diseases 
(NIAID), or investigator. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
The study has two components: (1) a randomized open label comparison between 
immediate cryotherapy (Arm A) and cytology-based strategy (Arm B) in participants 
detected with hr-HPV and (2) a brief cohort follow-up for participants for whom 
cryotherapy is inappropriate (Arm C). 
 
The study sample size is driven by the randomized component of the study, which is 
primary for the study. It is a proof-of-concept study to evaluate if a “test-and-treat” 
strategy for HPV is promising in HIV-infected women in resource limited settings. As 
such, the primary analysis will be conducted with a one-sided test to assess if immediate 
cryotherapy (Arm A) reduces the week 26 through week 130 cumulative rate of CIN2+ 
(CIN 2, CIN 3, or invasive cancer) compared to the cytology-based strategy (Arm B). 

 
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Should immediate cryotherapy be worse than the cytology-based strategy, the proposed 
“test-and-treat” strategy will not be pursued. Therefore, it is not important to have formal 
statistical evidence for the negative result. The study is powered well at 90% so that the 
chances of missing a positive result, thereby missing an opportunity to pursue a 
promising cervical screening strategy, are small. 
 
Approximately 105 participants for whom cryotherapy is inappropriate will be followed in 
the study for 26 weeks (Arm C). Type-specific HPV detections and cervical cytology and 
biopsy outcomes will be assessed. 
 
9.2 
Endpoints 
 
9.2.1 Primary Endpoint 
 
CIN2+ (CIN2, CIN3 or invasive cancer) by biopsy 26 weeks post randomization 
through 130 weeks post randomization, as determined by local review at a 
DAIDS-assessed laboratory.  
 
9.2.2 Secondary Endpoints 
 
9.2.2.1  Targeted AEs reported post cryotherapy (Arm A).  
 
9.2.2.2  Targeted AEs reported post LEEP. 
 
9.2.2.3 Detection of hr-HPV by careHPV at study visits.  
 
9.2.2.4  Cervical cytology results at study visits. 
 
9.2.2.5  Time to CIN2+ diagnosis by biopsy, as determined by local review at a 
DAIDS-assessed laboratory. 
 
9.2.2.6  Early study discontinuation rates and reasons. 
 
 
9.2.2.7  Nadir CD4 and CD4 count and HIV RNA levels at screening. 
 
9.2.2.8   careHPV results, HPV DNA PCR results, and aHPV results. 
 
9.2.2.9 Colposcopic impression from screening (no lesions seen, lesions seen 
that are appropriate for cryotherapy, lesions seen that are NOT 
appropriate for cryotherapy). 
 
9.2.2.10 CIN3+ (CIN3 or invasive cancer) by biopsy 26 weeks post 
randomization through 130 weeks post randomization, as determined 
by local review at a DAIDS-assessed laboratory. 
 
9.2.3 Tertiary Endpoints (contingent on future funding) 
 
9.2.3.1 Detection of type-specific HPV by DNA PCR at study visits. 

 
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9.2.3.2 Confirmed detection of type-specific HPV by DNA PCR at two 
consecutive study visits. 
 
9.3 
Randomization and Stratification 
 
The participants with hr-HPV by aHPV, and for whom cryotherapy is appropriate, will be 
randomized with equal probability to Arm A or B to receive immediate cryotherapy at 
study entry (Arm A) or to follow the cytology-based strategy (Arm B). Randomization to 
Arms A and B will be stratified by the current use of ART (any ART or no ART). There 
will also be institutional balancing to help ensure roughly equal sizes of Arms A and B at 
a given site. Enrollment will continue until the study has accrued at least 140 participants 
in each of Arms A and B. Approximately 170 participants will be enrolled in Arm C. There 
is no required minimum number of participants to be enrolled in Arm C. Randomization 
will be by permuted blocks with institutional balancing. 
 
9.4 
Sample Size and Accrual 
 
For the primary analysis, cumulative occurrence of CIN2+ on biopsy from week 26 to 
week 130 will be compared between Arms A and B. 
     
The study reported by Kuhn et al [22] implies about a 43% cumulative rate of CIN2+ 
among women infected with HIV at entry in the delayed evaluation arm compared to 
about 7% in the HPV test-and-treat arm (comparable to Arm A) for HIV-infected and hr-
HPV positive women with 3-year follow-up. However, unlike the delayed evaluation arm 
in Kuhn’s study, some of the women in Arm B in the current study may be diagnosed 
with CIN2+ based on the abnormal baseline cervical cytology that leads to colposcopy 
and possibly successful treatment within 26 weeks. Hence, the CIN2+ rate in Arm B is 
likely to be less than 43% approximated from the delayed evaluation arm in Kuhn’s 
study. It is approximated that 24% of the hr-HPV-positive, HIV-infected women will be 
diagnosed with CIN2+ at the first colposcopy, based on the baseline HPV prevalence 
and the month 6 colposcopy results reported by Kuhn et al [22]. Assuming that the 
sensitivity of cervical cytology is approximately 80% and the efficacy of the treatment is 
90%, it is approximated that 17% of the HPV-infected women in Arm B will be diagnosed 
with CIN2+ and treated successfully prior to week 26. Taking into account that these 
CIN2+ events will not count as events in the A5282 study, using an assumed 
exponential distribution for time to event to adjust for the shorter follow up time in A5282 
compared to the Kuhn study, and using the three year cumulative event rates of 7% and 
43% in the Kuhn study’s HPV-and-treat arm and delayed evaluation arm, respectively, 
we estimate the cumulative CIN2+ event rate from week 26 to week 130 in Arm A and 
Arm B to be about 6% and 20%, respectively. 
 
As a proof-of-concept study, the protocol team plans to conduct a one-sided test using 
time-to-event methods that adjust for interval censored data at a type 1 error rate of 5% 
to show improvement with immediate cryotherapy (Arm A) with at least 90% power. 
Assuming a 20% rate in Arm B and 6% rate in Arm A leads to a study sample size of 
111 in each arm. Table 2 below presents a conservative estimate [42] of the power to 
detect various rate differences between the study arms with the sample size of 111 in 

 
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each arm using a Fischer’s exact test. Based on simulations, the actual analysis method 
will have at least as much power as presented in Table 2.   
 
Table 2: Assumed Rates and Sample Sizes 
Arm B Rate Arm A Rate 
Arm Difference
Power
0.22 
0.07 
0.06 
0.05 
0.15
0.16 
0.17
 91%
 95% 
 97%
0.20 
0.07 
0.06 
0.05 
0.13
0.14 
0.15
 84%
 90% 
 94%
0.18 
0.07 
0.06 
0.05 
0.11
0.12 
0.13
 74%
 82% 
 88%
 
Accounting for up to 20% overall for loss to follow-up (assumed to be not associated with 
the endpoint), the study will enroll 140 participants in each study arm. The protocol team 
expects about 40% of the participants screened for this study to be detected with hr-HPV 
and eligible for randomization to Arms A and B. It is approximated that screening about 
700 participants will lead to 280 participants for Arms A and B. The remaining 
participants, approximated to be about 170, will be followed in Arm C. Not more than 170 
participants will be enrolled in Arm C for follow-up in this study. 
 
We anticipate accrual to be completed 15 months from the time the protocol is released 
to the sites. 
 
9.5 
Monitoring 
 
The study will be reviewed at least annually by the NIAID Co-Infections and 
Complications DSMB, starting 6-12 months after the accrual of the first participant. As a 
proof-of-concept study in comparison between Arms A and B, formal interim analyses to 
conclude early superiority of immediate cryotherapy in reducing the cumulative rate of 
CIN2+ over 2 years will not occur. To consider futility, the DSMB will review the rates 
and predicted confidence bounds using the accumulated data and the simulated data for 
the unobserved remainder under the observed trend and under the design assumptions. 
The DSMB will review the AEs related to cryotherapy and overall reported AEs in the 
study arms. The DSMB will also review early discontinuation rates in the study arms and 
the reasons for discontinuation. The DSMB will also review baseline data critical to our 
sample size calculations including proportion diagnosed with CIN2+ in the control arm at 
entry which we assume to be 17%. 
 
Reports on toxicity events will be provided to the DAIDS Medical Officer following the 
standard schedule for DSMB-monitored studies. Frequent reports on accrual and the 
conduct of the study will be provided to the protocol team. The schedules and formats of 
these reports will be outlined in the study monitoring plan. 
 

 
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9.6 
Analyses 
 
9.6.1  Comparison of CIN2+ between Arms A and B 
 
For the primary analysis, time-to-event methods will be used to estimate the 
cumulative rate of the primary endpoint (from week 26 to week 130 after  
study entry) to account for lost to follow-up. The protocol team plans to use the 
Turnbull estimation for the proportions of participants without CIN2+ diagnosis by 
the end of the study, stratified by the study stratification factors [43]. The 
generalized Greenwood’s formula for the standard error will be used for the 
variance and inverse variance method to account for strata [44]. The proportions 
in Arms A and B will be compared using asymptotic normal distributions. A one-
sided 95% upper confidence bound on the difference (Arm B proportion minus 
Arm A proportion) between these proportions will also be provided. A stratified 
log-rank test will be conducted as a secondary analysis to compare the time to 
development of CIN2+ between Arms A and B. The primary analysis will be 
conducted as intent-to-treat on all participants randomized to the study Arms A 
and B. In other words, participants will be included in the analyses even if 
cryotherapy is not performed in Arm A and participants do not adhere to the 
strategy in Arm B. Per-protocol analysis will also be performed on only the 
participants who adhere to the specified procedures in Arms A and B, as 
secondary analysis. Participants without complete biopsy data will be censored 
at their last visit with a biopsy result (i.e., weeks 26, 78, 130). 
 
Participants in Arm B may have biopsy done prior to week 26 based on the 
evaluation of baseline abnormal cervical cytology, whereas participants in Arm A 
will not have biopsies until week 26. Participants in Arm B diagnosed prior to their 
week 26 visit with CIN2+ that is cleared according to the biopsy at their week 26 
will not be considered failures for the primary endpoint analysis. They are 
counted as meeting the primary endpoint only if CIN2+ is found at week 26 or 
later. Unplanned biopsies in Arm A that occur prior to the week 26 visit will not be 
considered for the primary endpoint. 
 
The pathologic classification for the primary endpoint will be the determination by 
the local review at a DAIDS-assessed laboratory. Central review will be done for 
quality assurance. 
 
9.6.2  Analyses of Secondary Endpoints 
 
Secondary objectives will be evaluated with 2-sided tests or 2-sided confidence 
intervals with a significance level of 5%. The study is not powered to test the 
secondary study objectives formally, and no adjustment will be made to the type I 
error rates to account for multiple testing. 
 

 
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9.6.2.1  Arms A and B Only 
 
The primary endpoint analysis method will be applied using an endpoint 
of CIN3+ (CIN3 or invasive cancer), as determined by local review at a 
DAIDS-assessed laboratory. 
 
The targeted AEs reported after cryotherapy (Arm A) will be described 
separately. The study discontinuation rates will be compared between 
Arms A and B, using Fisher’s exact tests, and time to discontinuation 
will be compared using a log-rank test. The reasons for study 
discontinuations will also be summarized. 
 
The proportions of participants with hr-HPV detection by aHPV will be 
compared between Arms A and B at each study visit after study entry 
using Fisher’s exact tests. Logistic mixed effects models will be 
developed for the longitudinal data on detection of hr-HPV at post entry 
visits to make a comparison between Arms A and B. These models will 
explore nadir CD4 count and baseline/screening characteristics (e.g., 
HIV RNA level and cytology outcome) as independent variables. Similar 
analyses will be conducted to assess cytological abnormalities. 
 
Within Arm A, cryotherapy outcomes will be assessed using McNemar’s 
test for correlated proportions. Proportions of participants with and 
without cytological abnormalities at baseline and at 26 weeks after 
cryotherapy will be estimated. The HPV types detected at the time of 
abnormalities will also be summarized. 
 
Time to CIN2+ diagnosis will be compared between those with and 
without detection of hr-HPV by aHPV and by careHPV at 26 weeks after 
cryotherapy, using a log-rank test in Arm A. It will also be compared 
between those with and without cervical cytological abnormality at 26 
weeks after cryotherapy.   
 
9.6.2.2  Arms A, B and C 
 
The frequencies of HPV types by DNA PCR and the rate of hr-HPV by 
aHPV and careHPV detected at screening will be summarized. 
Detection rates of multiple HPV types will also be described. Logistic 
regression models will be developed to explore the factors associated 
with cytological abnormalities at entry or screening, e.g., HPV types, 
CD4, nadir CD4, and HIV RNA level.  
 
The sensitivity and specificity of careHPV for hr-HPV detection will be 
assessed based on aHPV results and HPV DNA PCR results on the 
types included in careHPV, using the screening data. The agreement 
between the careHPV and aHPV, and careHPV and HPV DNA PCR 
methods for categorizing the HPV type, beyond what would be 
expected by chance, will be estimated with Cohen’s Kappa statistic [45]. 

 
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The targeted AEs reported after LEEP in all study arms will be 
described.  
 
We will report the proportion of women with cervical lesions 
inappropriate for cryotherapy. We will report the prevalence of CIN2+, 
hr-HPV test results, and cytological abnormalities in these women. 
Specifically, we will assess the sensitivity, specificity, positive and 
negative predictive value of hr-HPV detection by careHPV and aHPV for 
CIN2+ in this subgroup. We will explore the inter-rater reliability of such 
assessments by blinded review of digital colposcopic images. We will 
assess the relationship of CD4 cell count (<200, 200-349, 350-499, 
≥500), ART use (yes or no), and plasma HIV RNA to the presence of 
these lesions. 
 
 
10.0 
PHARMACOLOGY PLAN 
 
Not applicable. 
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
CRFs will be provided for each participant. Participants must not be identified by name 
on any CRFs. Participants will be identified by the patient identification number (PID) 
and study identification number (SID) provided by the ACTG DMC upon 
randomization/participant registration. 
11.2 
Role of Data Management 
 
11.2.1 Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
11.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
11.3 
Clinical Site Monitoring and Record Availability 
 
11.3.1 Site monitors under contract to the U.S. NIAID will visit participating CRSs to 
review the individual participant records, including consent forms, CRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 

 
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11.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB/EC, the site monitors, the U.S. NIAID, or the U.S. 
OHRP for confirmation of the study data. 
 
11.4 
Expedited Adverse Event (EAE) Reporting to DAIDS  
 
11.4.1  Adverse Event Reporting to DAIDS 
 
 
Requirements, definitions, and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS Expedited Adverse Event (EAE) Manual, 
which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS. In the 
event of system outages or technical difficulties, expedited AEs may be 
submitted via the DAIDS EAE Form. For questions about DAERS, please contact 
DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also be sent 
from within the DAERS application itself. 
 
 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech-
res.com/safetyandpharmacovigilance/. For questions about EAE reporting, 
please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2  Reporting Requirements for this Study 
 
 
The suspected, unexpected serious adverse reaction (SUSAR) Reporting 
Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used 
for this study. 
 
 
There are no study agents for this protocol. All Grade 3 and 4 SAEs that are 
related to study procedures should be reported. 
 
 
In addition to the SUSAR Reporting Category identified above, other AEs that 
must be reported in an expedited manner are cervical, vaginal, and vulvar 
cancers and miscarriages.  
  
11.4.3  Grading Severity of Events 
 
 
The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification August 
2009) and Addendum 1-Female Genital Grading Table for Use in Microbicide 
Studies are used and available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 

 
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11.4.4 Expedited AE Reporting Period 
 
 
The expedited AE reporting period for this study is as per the EAE manual. 
 
 
After the protocol-defined AE reporting period, unless otherwise noted, 
SUSARs, as defined in Version 2.0 of the EAE Manual, will be reported to 
DAIDS if the study staff become aware of the events on a passive basis (from 
publicly available information). 
 
 
12.0 
HUMAN PARTICIPANTS 
 
12.1 
IRB/EC Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB/EC responsible for oversight of 
the study. A signed consent form will be obtained from the participant or legal 
guardian/representative. The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. A copy of the 
consent form will be given to the participant or legal guardian/representative and this fact 
will be documented in the participant’s record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by ACTG, IRB/EC, the U.S. NIAID, the 
U.S. OHRP, or any host country regulatory entities. 
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, the U.S. NIAID, the 
U.S. OHRP, or other government agencies as part of their duties to ensure that research 
participants are protected.  
 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies.   
 
 

 
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14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the U.S. NIH. 
 
All dangerous goods materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  

 
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15.0 
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APPENDIX I 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
 
For protocol: 
A5282, FINAL Version 1.0, Dated 11/16/10, 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 
 
SHORT TITLE FOR THE STUDY: A5282, FINAL Version 1.0, Dated 11/16/10, Comparison of 
Two Strategies for the Prevention of Cervical Cancer in HIV-infected Women 
 
 
INTRODUCTION 
 
You are being asked to take part in the research study named above because you are a woman 
infected with HIV (the virus that causes AIDS).  This study is sponsored by the National 
Institutes of Health.  The doctor in charge of this study at this site is: (insert name of Principal 
Investigator).  Before you decide if you want to be a part of this study, we want you to know 
about the study.  
 
This is a consent form.  It gives you information about this study.  The study staff will talk with 
you about this information.  You are free to ask questions about this study at any time.  If you 
agree to take part in this study, you will be asked to sign this consent form.  You will get a copy 
to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
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.   
  
We 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.  
  
First, a test for HPV will be done.  HPV is the virus that usually causes cervical cancer.  Some 
types of HPV are more likely to cause cervical cancer than others.  These types are called high 
risk.  Women with high risk types of HPV virus in their cervix will be assigned to one of two 
different approaches.  In the standard approach, two procedures are done to check for cancer 
cells in the cervix.  The first procedure is called a Pap test.  For this test, a sample of cells is 
collected from the cervix and looked at under a microscope.  If there are signs of abnormal cells, 
another sample is taken with a biopsy, which is when a small piece of cervical tissue is removed 

 
 
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to be looked at more closely.  If the biopsy shows abnormal cells, one more procedure, called 
LEEP, will be done to remove the abnormal cells.  The purpose of removing the cells is to 
prevent cervical cancer from developing. 
  
The second approach is experimental and involves a freezing procedure called cryotherapy.  
During this procedure, cells in the cervix that have the HPV high risk virus will be frozen and 
killed.  This approach to preventing cervical cancer is called "test and treat."   
  
In this study, women will be assigned at random to one of two methods to prevent cancer.  The 
first method is the standard method, using the Pap test, biopsy, and if needed LEEP (which is 
used only when abnormal cells are found).  The second method is experimental, using the 
cryotherapy (freezing) procedure for all women who have high risk types of HPV virus. 
 
Cryotherapy is not the preferred option for all women.  Women who are not eligible for 
cryotherapy will be followed in the study and receive other standard treatments appropriate for 
them.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Definitions 
This consent form includes specific terms used to describe screening procedures for cervical 
cancer that will be done in this study.  These terms are defined in Attachment A of this consent 
form and include:  
1. Speculum exam 
2. Pap test and HPV testing 
3. Cervical colposcopy 
4. Cervical biopsy 
5. Cervical cryotherapy 
6. LEEP 
 
Before the study starts 
If you agree to join this study, you will be asked to sign this consent form.  After you have signed 
this form, you will be asked to come to the clinic for a screening visit.  Tests will be done at the 
screening visit to make sure you meet the requirements for joining the study.  The study doctor 
or nurse will tell you how long the screening visit may take.   
 
The screening visit will include:  
 
Proof of your HIV infection.  If there is no record available, another HIV test will be done.  
You may have to sign a separate consent form before this is done. 
 
A complete physical exam.  You will also be asked to answer questions about your medical 
history, medications you are taking now and have taken in the past, and how you have been 
feeling.  You will be asked a question about your lowest ever CD4 cell count (the number of 
white blood cells that fight infection) unless a record of this is already available. 
 
A speculum exam, colposcopy without biopsy, and collection of cervical samples using a 
small brush.  A picture will be taken of the cervix during the colposcopy.  The study doctor or 

 
 
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nurse will insert three (3) small brushes in and around the cervix for a Pap test and three (3) 
different tests for HPV.         
 
A complete blood count. You will have about 1 teaspoon of blood drawn from a vein in your 
arm for these tests. 
 
A blood or urine pregnancy test, if you are able to become pregnant.  About 1 teaspoon of 
blood will be drawn from a vein in the arm or you will give a urine sample at the clinic for the 
pregnancy test.  You will not be able to enroll in this study if you are pregnant. 
 
A CD4 cell count and an HIV viral load test (a measure of how much HIV is in your blood).  
About 4 teaspoons of blood will be drawn from a vein in your arm. 
 
The study staff will discuss test results with you throughout your participation in this study. The 
results of the complete blood count, CD4 count, and HIV viral load will be provided to your 
medical providers to assist in the treatment of your HIV infection. 
 
Depending on the results of the screening tests, the study doctor or nurse will tell you when to 
come back to the clinic for the entry visit or will tell you if this study is not a good fit for you. You 
cannot take part in this study if the screening tests show signs of cervical cancer. Instead, you 
will have biopsies done for confirmation.  The study doctor or nurse will talk to you about your 
choices and connect you to the appropriate medical care. 
 
If you do NOT enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use the information we collect from you.  As part of this screening visit, some 
demographic (e.g., age, gender, race), clinical (e.g., disease condition, diagnosis, HPV test 
results, pictures from colposcopy), and laboratory (e.g., CD4 cell count, HIV viral load) 
information is being collected from you so that ACTG researchers may help determine whether 
there are patterns or common reasons why people do not join a study. This information may 
also help to understand what puts women with HIV at higher risk for abnormal Pap tests and to 
understand how well the HPV tests work in women with HIV. 
 
Entry visit 
If cryotherapy is a good option for you, at entry you will be assigned into Group A or Group B.  
You will be assigned by chance (as if by the toss of a coin [or the site may insert a culturally-
appropriate description of randomization]).  Your chance of being assigned to either of these 
groups is equal.  You, your doctor, and the study staff will be told which group you are in.   
 
If cryotherapy is not a good option for you, you will be eligible for Group C.  If the test for high-
risk HPV is negative but there are areas that might be damaged by HPV or the screening Pap 
test is very abnormal, you will also be eligible for Group C.   
 
All of the groups are as follows: 
 
Group A:  HPV test-and-treat  
 
Group B:  Pap-screening  
 
Group C:  Women not eligible for cryotherapy  
 
Groups A and B 
At entry:  

 
 
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 
You will be asked about any medicine changes you have had since the screening visit.   
 
You will be asked to complete a questionnaire about your sexual behavior, family, and living 
arrangements. 
 
You will be asked how you have been feeling.  You may have a physical exam depending 
on how you feel.   
 
If you are in Group A, you will have cryotherapy of your cervix at or within one week of the entry 
visit.   
 
If you are in Group B, the study doctor or nurse will tell you when to come back to the clinic to 
receive your Pap test result or will give the result of the Pap test to you at this visit.  If the Pap 
test is abnormal, you will have cervical colposcopy and biopsies of areas that look abnormal.  
The study doctor or nurse will then tell you when to come back to the clinic again to receive the 
results of the biopsies.  If the biopsies show HPV-damaged areas, you will undergo LEEP, a 
procedure to remove these areas. 
 
For both groups, you will return to the clinic about 6, 12, 18, 24, and 30 months after the entry 
visit. At these visits: 
 
You will have a Pap test and cervical samples collected using a small brush for high-risk 
HPV tests. 
 
You will be asked about any medicine changes you have had since your last study visit.   
 
You will be asked to complete a questionnaire about sex you have had recently. 
 
You will be asked how you have been feeling.  You may have a physical exam depending 
on how you feel.   
 
At the study visit about 6, 18, and 30 months after the entry visit you will also have a colposcopy 
and biopsies if any abnormal areas are seen. 
 
You will have a pregnancy test done (blood or urine): 
 
At anytime throughout the study if you think you may be pregnant. 
 
Before you have cryotherapy, if scheduled. (If you are pregnant, cryotherapy will not be 
done.) 
 
Before you have a LEEP, if done.  
 
The study doctor or nurse will tell you how long each visit may take.  The study visit at 130 
weeks (about 2 ½ years) is the last study visit for Groups A and B. 
 
Group C 
At entry, you will have the same tests done as mentioned above for Groups A and B.  Also, you 
will have colposcopy and biopsies at entry if any abnormal areas are seen.  If these tests show 
HPV-damaged areas, then you will have a LEEP.  
 
If you have a LEEP, you will be asked to return to the clinic about 6 months after entry. At this 
visit: 
 
You will be asked about any medicine changes you have had since your last study visit.   
 
You will be asked to complete a questionnaire about sex you have had recently. 

 
 
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 
You will be asked how you have been feeling.  You may have a physical exam depending 
on how you feel.   
 
You will have a colposcopy and biopsies if any abnormal areas are seen. 
 
You will have a Pap test and cervical samples collected using a small brush for high-risk 
HPV tests. 
 
The study doctor or nurse will tell you how long each visit may take.  The study visit at about 6 
months is the last study visit for Group C. 
 
All groups 
You should not have vaginal sex, douche, or place anything inside the vagina for 48 hours (2 
days) before the following procedures:  speculum exam, Pap test, HPV testing, cervical 
colposcopy, cervical biopsy, cryotherapy, and LEEP. 
 
Whenever you have a Pap test or cervical biopsy during the study, you will return to the clinic to 
discuss the results with the study doctor or nurse.  The study doctor or nurse will tell you how 
long this may take.  The study doctor or nurse may ask you to complete additional procedures 
depending on the results.  These additional procedures may include colposcopy with biopsies or 
LEEP.  You will be given instructions on how to prepare for these procedures and what to 
expect after the procedures are completed (such as normal side effects).   
 
Throughout the study, whenever you have cryotherapy or LEEP:  
 
You will return to the clinic about one month later to complete a questionnaire about how 
you have been feeling since the procedure.  
 
We ask that you not have vaginal sex or douche for 6 weeks after the procedure.  There are 
two reasons for not having sex.  First, there is a small chance this procedure may cause an 
infection of the cervix.  Second, there is a possibility of the presence of more blood and HIV 
in the vagina after the procedure.  These things could place your partner at higher risk for 
getting HIV.  To be safer, it is recommended that if you have vaginal sex, your sexual 
partner uses a condom. 
 
To help ensure the quality of study procedures, medical experts other than the study doctor and 
nurse will review: 
 
Pictures taken of the cervix right before and right after cryotherapy, colposcopy, and LEEP.   
 
Some of the biopsy specimens. 
 
A portion of the specimen collected during LEEP. 
 
The study doctor or nurse will share the results of these reviews with you when they become 
available. 
 
At anytime throughout the study, if tests reveal the presence of cervical cancer, the study doctor 
or nurse will talk to you about your choices and connect you to the appropriate medical care.  
You will be asked to stay in the study.  If you decide to stay in the study, you will continue to 
come to the clinic for study visits and receive all tests for your group.     
 
 
 

 
 
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If you do not have cryotherapy or LEEP at the start of the study 
If you do not have cryotherapy (Group A only) or LEEP at the start of the study, you will still be 
asked to continue in the study. If you decide to stay in the study, you will come to the clinic for 
the study visits and receive all tests for your group.  
 
If you do not complete study visits up to week 130 (Groups A and B) or week 26 (Group C) 
If you end your participation in the study before the last study visit for your group, you will be 
asked to come to the clinic for one last visit before going off study.  At this visit: 
 
You will be asked about any medicine changes you have had since your last study visit.   
 
You will be asked to complete a questionnaire about sex you have had recently. 
 
You will be asked how you have been feeling.  You may have a physical exam depending 
on how you feel.   
 
You will have colposcopy and biopsies if any abnormal areas are seen.  
 
You will have a Pap test and cervical samples collected using a small brush for high-risk 
HPV tests. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 450 people will join Groups A, B, and C.  
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 2 ½ years if you are in Group A or B and about 6 months if 
you are in Group C. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
continuing the study may be harmful to you. 
 
the study is stopped or cancelled. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Use of certain medications 
If you are taking a drug used to stop blood from clotting (including aspirin and ibuprofen), tell 
your study doctor or nurse.  Some of these medications may prevent you from having cervical 
biopsies, cryotherapy, or LEEP done. 
 
Completing questionnaires 
Answering questions about sexual behaviors may cause embarrassment.   
 
 
 

 
 
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Blood draw 
Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the 
body, lightheadedness; and in rare cases, fainting or infection. 
 
Cervical colposcopy, speculum exam, Pap test, and HPV testing 
These tests can be uncomfortable.  Occasionally there can be some bleeding, a tingling feeling, 
or slight stinging.  These tests may cause embarrassment.  Some people may feel anxiety while 
waiting for the test results.  
 
Cervical biopsy 
 
Pain during biopsy 
 
Mild bleeding similar to a menstrual period 
 
Rarely, the following problems can occur 
 
Heavy bleeding can occur requiring treatment to stop the bleeding 
 
Infection of the cervix requiring antibiotics (drugs used to stop or slow down the growth 
of bacteria and germs) 
 
Damage to the cervix making it more difficult to carry a pregnancy  
 
Cervical cryotherapy 
 
Pain and cramping during the procedure  
 
Heavy, watery discharge from the vagina for 1 to 2 weeks 
 
Heavy, foul-smelling discharge from the vagina 
 
Mild bleeding similar to a menstrual period  
 
Infection of the cervix requiring antibiotics  
 
Rarely, the following problems can occur 
 
Severe cramps and stomach pain requiring pain medications  
 
Infection of your uterus and surrounding areas  
 
Heavy bleeding requiring treatment to stop the bleeding 
 
Narrowing of the cervix making it difficult for menstrual bleeding to occur 
 
Accidental freezing of the vagina during the procedure 
 
Dizziness or fainting during the procedure 
 
Damage to the cervix making it more difficult to carry a pregnancy  
 
Damage to the cervix making it difficult to become pregnant 
 
LEEP 
 
Pain from injections of numbing medication into the cervix  
 
Blood tinged or dark brown mucus from the vagina for 1 or 2 weeks  
 
Dull ache or cramping during the procedure 
 
Pain or cramping after the procedure 
 
Infection of the cervix requiring antibiotics 
 
Rarely, the following reactions can occur 
 
Dizziness, fainting or allergic reaction to the numbing medications  
 
Severe bleeding of the cervix requiring sewing of the cervix 
 
Accidental damage of the vagina 
 
Accidental damage of the uterus  
 
Infection of the uterus and surrounding areas  
 
Narrowing of the cervix making it difficult for menstrual bleeding to occur 

 
 
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 
Damage to the cervix making it more difficult to carry a pregnancy  
 
Damage to the cervix making it difficult to become pregnant 
 
Spreading HIV 
For some time after you have cryotherapy or LEEP, it is possible the condition of the cervix may 
make it more likely to spread HIV to a sexual partner.  For this reason, we ask that you not have 
vaginal sex for 6 weeks after the procedure.  If you choose to have vaginal sex, we ask that 
your sexual partner use a condom. 
 
 
WHAT DO I NEED TO KNOW ABOUT PREGNANCY AND CONTRACEPTIVES? 
 
If you can become pregnant, you must have a pregnancy test before you enter this study.  The 
test must show that you are not pregnant.  If you think you may be pregnant at any time during 
the study, tell the study doctor or nurse right away.  The study staff will talk to you about your 
choices. 
 
You and your partner must use at least one reliable method of birth control that you discuss with 
the study staff for at least a portion of the time that you are in the study.  You must use at least 
one method of birth control from the day of the entry visit until 12 weeks (3 months) after the 
entry visit.  You must choose at least one of the birth control methods listed below: 
 
 
Condoms (male or female) with or without a spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
Intrauterine device (IUD) 
 
Hormone-based contraceptive 
 
If you are taking certain anti-HIV drugs (Efavirenz), you and your partner must use at least two 
of these methods of birth control.  The study staff will discuss this with you. 
 
If you become pregnant during the study, you will be asked to stay in the study.  If you decide to 
stay in the study, you will continue to have most of the study tests.  There are three (3) study 
tests that you will not have until 6 weeks after the pregnancy is completed:  cervical biopsy, 
cervical cryotherapy, and LEEP.  If you agree, study staff will contact you to ask you about the 
outcome of the pregnancy, even if it is after you stop taking part in the study. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made.  A possible benefit is receiving cervical treatments that reduce the risk of developing 
cervical cancer.  It is also possible that you may receive no benefit from being in this study.  
Information learned from this study may help others who have HIV and/or HPV. 
 
 
 
 

 
 
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WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
 
Having screening tests for cervical cancer from your doctor 
 
Not having screening tests for cervical cancer 
 
Participating in another study, if you qualify 
 
Please talk to your doctor about these and other choices available to you.  Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to help keep your personal information confidential.  We cannot guarantee 
absolute confidentiality.  Your personal information may be disclosed if required by law.  Any 
publication of this study will not use your name or identify you personally.  
 
Your records may be reviewed by (insert name of site) IRB/EC, the U.S. National Institutes of 
Health, U.S. Office for Human Research Protections (OHRP), (insert any host country 
regulatory entities to review study documents), study staff, and study monitors. 
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company.  In some 
cases it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study.   
 
If you are diagnosed with cancer of the cervix, then you will be referred for appropriate 
treatment.  This is not a part of the study and is not paid for by the study.   
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Sites may insert language about remuneration or delete this section if not applicable.] 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries.  The cost for this treatment will be charged to you or your insurance company.  
There is no program for compensation either through this institution or the U.S. National 
Institutes of Health.  You will not be giving up any of your legal rights by signing this consent 
form. 
 
 

 
 
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WHAT ARE MY RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary.  You may choose not to take part in this study 
or leave this study at any time.  Your decision will not have any impact on your participation in 
other studies conducted by U.S. National Institutes of Health, and will not result in any penalty 
or loss of benefits to which you are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study.  If you want the results of the study, let the study 
staff know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
 
name of the investigator or other study staff 
 
telephone number of above  
 
For questions about your rights as a research subject, contact: 
 
 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
 
telephone number of above 

 
 
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SIGNATURE PAGE 
 
PART A. CONSENT TO JOIN THE STUDY 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to take part in this study, please print and sign your name below. 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Participant’s Legally Authorized  
 
Legally Authorized Representative’s Signature  
Representative (as appropriate) (print)  
and Date 
 
 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 
PART B. LEFTOVER SAMPLES 
 
Some of your cervical specimens that are left over after all required study testing and quality 
assurance reviews are done may be stored locally (with usual protectors of identity) and used 
for ACTG-approved HIV-related research locally or in the United States.  These 
leftover samples may be stored for an indefinite length of time.  We cannot ensure that you will 
be told the results of the research done on these samples. 
 
Storage of leftover samples is not necessary to participate in the study.  Even if you agree now, 
you may withdraw your approval for the storage of your leftover samples at anytime in the 
future.  Please indicate with your initials below whether or not you approve the use of your 
leftover samples. 
 
 
________ YES                     ________ NO 
 

 
 
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APPENDIX I 
ATTACHMENT A 
A5282 Definitions of Screening Procedures for Cervical Cancer 
  
1. Speculum exam 
 
A speculum is an instrument that a doctor or nurse inserts into the vagina to gently stretch 
the opening.  This allows the doctor or nurse to examine the cervix, collect specimens from 
the cervix, and do the procedures mentioned below.   
 
2. Pap test and HPV testing 
 
This is a procedure in which a doctor or nurse uses a small brush and a small wooden 
spatula to gently scrape cells from the cervix.  It will take about 5 minutes to collect these 
specimens.  For a Pap test, the cells are looked at under a microscope to check for any 
problems.  For HPV testing, the cells are tested to see if HPV is present and which of the 30 
types of HPV are present.  The three (3) types of HPV tests used in this study are: 
 
Abbott RealTime test for high-risk types of HPV -- This test is approved for use in 
Europe. You will receive the results of this test. 
 
careHPV -- This is an investigational test for high risk HPV.  This will be done at a later 
point.  You will not receive the results of this test. 
 
HPV DNA PCR -- This test identifies the specific types of HPV that are present.  This will 
be done at a later point.  You will not receive the results of this test.  
 
  
3. Cervical colposcopy 
 
This is a speculum exam in which acetic acid (such as common table vinegar) is placed on 
the cervix.  This causes cervical cells that are not normal to appear white in color.  A doctor 
or nurse then uses a colposcope to look at the cervix.  A colposcope is a large microscope 
that is positioned approximately 30 centimeters from the vagina.  A bright light on the end of 
the colposcope lets the doctor or nurse clearly see the cervix.  It will take about 15 minutes 
to do this procedure.  
 
4. Cervical biopsy 
 
This is done during a cervical colposcopy.  A doctor or nurse gently removes a small amount 
of skin from areas of the cervix that appear to be damaged by HPV.  It will take about 5 
minutes to do this procedure.  
 
If it appears to the doctor or nurse that the HPV-damaged area is going inside the cervix, 
then a probe will be placed inside the cervix to gently scrape cells to test for abnormal cells 
(this process of gently scraping cells is called endocervical curettage, or ECC).  It will take 
about 5 minutes to do this procedure.  
 
The tissue sample (or biopsy) is sent to the laboratory to look for abnormal cells. 
 

 
 
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5. Cervical cryotherapy 
 
This is a treatment that freezes a section of the cervix.  A doctor or nurse will insert a 
speculum into the vagina.  For this treatment, the doctor or nurse will not inject the cervix 
with medication to numb the cervix.  A special instrument called a probe will be inserted to 
reach the parts of the cervix that are abnormal.  A freezing material in the probe will allow 
the doctor or nurse to freeze and destroy the affected skin on the cervix. For this study, 
freezing will occur for 3 minutes, the cervix will be allowed to thaw for 5 minutes, and 
freezing will be repeated for another 3 minutes.   
 
6. LEEP 
 
LEEP is short for loop electrosurgical excision procedure.  This procedure uses a thin wire 
loop to remove abnormal areas from the cervix.  A doctor or nurse will insert a speculum into 
the vagina and will inject the cervix with medication to numb the cervix.  The wire loop is 
attached to a machine that gives off small electric current.  The wire is passed under the 
areas damaged by HPV to remove them.  It will take about 20 minutes to do this procedure.