Safety of and Immune Response to the Human Papillomavirus (HPV) Vaccine in HIV-Infected Women

HPV is a DNA virus that affects both men and women. Approximately 90 types of HPV have been
identified, 30 of which are sexually transmitted. The most common forms of HPV are types 6,
11, 16, and 18. The quadrivalent HPV vaccine that was tested in this study had been shown in
previous studies to be effective in preventing infection with HPV 6, 11, 16, and 18 in
healthy young women. According to a report by the Centers for Disease Control and Prevention
(CDC), 80% of women will have acquired HPV by the age of 50. HIV infected women have been
reported to have a higher prevalence and persistence of HPV infection, as well as an
increased risk for abnormal Pap smears and cervical cancer. HPV types 16 and 18 cause the
majority of cervical cancers worldwide, and types 6 and 11 are responsible for the majority
of cases of genital warts. Vaccinations for preventable infections are particularly important
among HIV infected people because people with HIV have compromised immune systems; therefore,
any infection is very serious and can potentially be fatal. However, standard vaccination
series have not been very successful because a compromised immune system may not produce the
desired immune response to a vaccine. The HPV vaccine is designed to protect against
infection with HPV types 6, 11, 16, and 18 and has been approved by the FDA for use in women
between the ages of 9 and 26. The purpose of this study was to determine whether the
quadrivalent HPV vaccine is safe, tolerable, and effective in producing antibodies to HPV in
HIV infected females.

The study consisted of single arm evaluations of HPV vaccine immunogenicity and safety in 3
groups based on the study screening CD4 cell count as follows:

- Stratum A: CD4 cell count >350 cells/mm^3

- Stratum B: CD4 cell count >200 to <=350 cells/mm^3

- Stratum C: CD4 cell count <=200 cells/mm^3

In Version 1.0 of the protocol, the target accrual was n=67 participants with screening HIV
viral load <=10,000 copies/mL and n=67 participants with HIV viral load >10,000 copies/mL
within each CD4 stratum, yielding n=134 in each CD4 stratum. In light of subsequent findings
from completed HPV vaccine studies, the sample size was changed to n=94 participants per CD4
stratum in Version 2.0 of the protocol, and stratification by screening HIV viral load was
removed. All Stratum A and Stratum B participants were enrolled under protocol Version 1.0.

The study duration was 72 weeks. All participants received HPV vaccine administered by
intramuscular injection at baseline, and at Weeks 8 and 24. Following each injection,
participants remained at the clinic for 30 minutes of observation for adverse events. A
telephone follow-up or a home visit by study staff was performed within 2 days following each
injection.

Participants returned to the clinic for visits at Weeks 4, 8, 12, 24, 28, 52, and 72. Most
study visits included a physical exam, medication review, blood and urine collection, and
answering questions about signs and symptoms since previous visit. Some visits included
measurement of HIV viral load and CD4 cell count; collection of endocervical wick, cervical
cytobrush and anal swab; and an oral exam. A subset of participants were asked to provide
additional blood samples and oral cytobrush specimens.

Inclusion Criteria:

- HIV infection

- CD4 count obtained within 45 days prior to study entry

- Karnofsky performance score >=70 on at least one occasion within 45 days prior to
study entry

- The following labs within 45 days prior to study entry:

- hemoglobin >8.0 g/dL

- direct bilirubin <2.5 x upper limit of normal (ULN)

- alanine aminotransferase, ALT (SGPT) <3 xULN

- aspartate aminotransferase, AST (SGOT) <3 xULN

- platelet count >=100,000 /mm^3

- Willing to use acceptable forms of contraception for the duration of the study

- Written informed consent from participant or from parent or guardian, if applicable

- If on HAART, then the same regimen for at least 12 weeks prior to study entry with no
change within 30 days prior to study entry. (This criterion was removed in Version 2.0
of the protocol.)

- HIV viral load obtained within 45 days prior to study entry (This criterion was
removed in Version 2.0 of the protocol.)

Exclusion Criteria:

- Abnormal Pap test with confirmed biopsy results of cervical intraepithelial neoplasia
(CIN) II or III or cervical cancer within 180 days prior to study entry

- Vulval intraepithelial neoplasia (VIN) II or III or cancer confirmed by biopsy results
within 180 days prior to study entry

- Physician-diagnosed genital warts within 180 days prior to study entry

- Previous cervical dysplasia treatment, including loop electrosurgical excision
procedure (LEEP), cervical cryotherapy, cone biopsy, and cervical laser vaporization
within 180 days prior to study entry

- Use of any systemic antineoplastic or immunomodulatory treatment, systemic
corticosteroids, investigational vaccines, interleukins, interferons, growth factors,
or intravenous immunoglobulin (IVIG) within 45 days prior to study entry. Participants
who had received standard of care (e.g., hepatitis B, influenza, and tetanus) vaccines
were not excluded.

- Known allergy or hypersensitivity to yeast or any components of the vaccine or its
formulation

- Current drug or alcohol use or dependence or any other condition that may interfere
with study participation

- Serious illness requiring systemic treatment and/or hospitalization within 45 days
prior to study entry

- Total hysterectomy. Participants who had undergone partial hysterectomy and had a
cervix were not excluded.

- Hemophilia

- Currently on anticoagulation therapy other than acetylsalicylic acid

- Prior vaccination with an HPV vaccine

- Pregnant or breastfeeding