Evaluating the Effectiveness of the Quadrivalent Human Papillomavirus (HPV) Vaccine at Preventing Anal HPV Infection in HIV-Infected Men and Women

Anal HPV infection can be a risk factor for anal cancer, which is a common non-AIDS-defining
cancer among HIV-infected MSM. Screening for anal cancer is not widely available and can be
difficult to implement. People who receive the FDA-approved quadrivalent HPV vaccine,
Gardasil, may have a reduced risk of developing anal HPV infection, which may in turn reduce
the risk of developing anal cancer. The purpose of this study is to evaluate the
effectiveness of the quadrivalent HPV vaccine, Gardasil, at reducing the incidence of anal
HPV infections in HIV-infected MSM and HIV-infected women.

This study will enroll HIV-infected MSM and HIV-infected women. Participants will be
randomly assigned to receive the HPV vaccine or a placebo vaccine. At the screening study
visit, participants will undergo a physical examination, blood collection, anal swab
procedure, oral examination, questionnaires, a high-resolution anoscopy (HRA), and if
female, a pregnancy test, vaginal swab, and gynecologic exam. At the entry study visit,
participants will undergo most of the procedures performed at screening (with the exception
of an HRA and a gynecologic exam if female) plus a saliva test. Participants will receive
the HPV vaccine or placebo as an injection into their upper arm or thigh on Day 0 and Weeks
8 and 24. Study staff will call participants 2 to 3 days after each vaccination for
follow-up monitoring. Additional study visits and procedures will occur at Week 28, Week 52,
and every 26 weeks thereafter for at least 3 years and for a maximum of 4 years after the
last participant is enrolled in the study. Female participants will also have a gynecologic
exam at screening, Week 52, and every 52 weeks thereafter; a pregnancy test at screening,
baseline, Week 8, Week 24, and as indicated; and self-collected vaginal swabs at screening,
entry, Week 28, Week 52, and every 26 weeks thereafter. Peripheral blood mononuclear cells
(PBMCs) will be collected from some participants at entry, Week 28, and study exit.

Inclusion Criteria:

- HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
confirmed by a licensed Western blot or a second antibody test by a method other than
the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
More information on this criterion can be found in the protocol.

- Laboratory values obtained within 45 days prior to entry by any U.S. laboratory that
has a Clinical Laboratory Improvement Amendment (CLIA) certification or its
equivalent, or at any network-approved non-U.S. laboratory that operates in
accordance with Good Clinical Practices and participates in appropriate external
quality assurance programs:

1. Absolute neutrophil count (ANC) greater than 750 cells/mm^3

2. Hemoglobin greater than or equal to 9.0 g/dL

3. Platelet count greater than or equal to 75,000/mm^3

4. Serum creatinine less than or equal to three times the upper limit of normal
(ULN)

5. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase
[SGPT]) less than or equal to five times the ULN

6. Total or conjugated (direct) bilirubin less than or equal to 2.5 times the ULN

- For men, receptive anal sex (defined as receptive penile-anal sex or receptive
oral-anal sex with another man) within 1 year prior to entry

- Anal cytology result from specimen obtained within 45 days prior to entry

- HRA performed within 45 days prior to entry by a certified HRA provider with no
evidence of invasive or microinvasive anal cancer by anal biopsy or by visual
inspection if no biopsy was obtained. Note: refer to protocol for more information
about HRA certification process.

- For women, gynecologic examination (including screening for cervical disease by
exfoliative cytology with or without colposcopy) within 45 days prior to entry.

- For women of reproductive potential, a negative serum or urine pregnancy test within
45 days prior to study entry by any U.S. laboratory that has a CLIA certification or
its equivalent, or at any network-approved non-U.S. laboratory that operates in
accordance with Good Clinical Practices and participates in appropriate external
quality assurance programs. More information on this criterion can be found in the
protocol.

- Confirmation of the availability of the anal swab, vaginal swab (women only) and
Scope oral rinse specimens for HPV DNA PCR obtained at screening. The site must
confirm that these samples have been entered into the Laboratory Data Management
System (LDMS).

- Ability and willingness of participant or legal representative to provide informed
consent

Exclusion Criteria:

- History or current biopsy diagnosis of invasive or microinvasive cancer, i.e.:

- For all participants: anal or oropharyngeal cancer

- For men: penile cancer

- For women: cervical, vulvar, or vaginal cancer

- More information on this criterion can be found in the protocol.

- Anal, cervical, or vaginal cytological results suspicious for invasive carcinoma at
any point prior to entry

- Topical or surgical treatment for intra- or perianal intraepithelial neoplasia or
condyloma within 6 months prior to entry. More information on this criterion can be
found in the protocol.

- Prior receipt of one or more doses of an HPV vaccine

- Receipt of anticoagulants other than aspirin or nonsteroidal anti-inflammatory drugs
(NSAIDS) within 14 days prior to entry

- Known allergy/sensitivity or any hypersensitivity to yeast or any of the components
of the study product or its formulation. More information on this criterion can be
found in the protocol.

- Active drug or alcohol use or dependence or other condition that, in the opinion of
the site investigator, would interfere with adherence to study requirements

- Serious illness requiring systemic treatment and/or hospitalization within 21 days
prior to entry

- Hemophilia or other bleeding diatheses

- Use of any systemic antineoplastic or immunomodulatory treatment, systemic
corticosteroids other than inhaled corticosteroids or prednisone less than or equal
to 10 mg (or equivalent), investigational vaccines, interleukins, interferons, growth
factors, or intravenous immunoglobulin (IVIG) within 45 days prior to study entry.
NOTE: Routine standard-of-care vaccines (including hepatitis A, hepatitis B,
influenza, pneumococcal, and tetanus vaccines) are not exclusionary.

- Expected treatment of hepatitis B or hepatitis C virus with immunomodulatory agents
in the 7 months after entry

- Breastfeeding