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

HIV Infections Clinical Trial

Official title:

A Phase II Study to Evaluate the Immunogenicity and Safety of a Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Females

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00604175
• Other study ID #: A5240
• Secondary ID: 10393ACTG A5240
• Status: Completed
• Phase: Phase 2
• Start date: February 2008
• Est. completion date: November 2012

Study information

• Verified date: August 2015
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Human papillomavirus (HPV) is the most common sexually transmitted disease in the world. HPV infection can cause genital warts and certain cervical problems, including cervical cancer. HPV infection may be more severe and harder to treat in HIV-infected people. 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 women.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 319
• Est. completion date: November 2012
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 13 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections
• Sexually Transmitted Diseases

Intervention

Biological:
• Quadrivalent HPV vaccine
Quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine. All participants received the vaccine via intramuscular injection at baseline, Week 8 and Week 24.

Locations

Country	Name	City	State
Brazil	Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS	Rio de Janeiro
Puerto Rico	Puerto Rico AIDS Clinical Trials Unit CRS	San Juan
Puerto Rico	San Juan City Hosp. PR NICHD CRS	San Juan
Puerto Rico	University of Puerto Rico Pediatric HIV/AIDS Research Program CRS	San Juan
South Africa	Wits Helen Joseph Hospital CRS (Wits HJH CRS)	Johannesburg	Gauteng
United States	Usc La Nichd Crs	Alhambra	California
United States	The Ponce de Leon Center CRS	Atlanta	Georgia
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	IHV Baltimore Treatment CRS	Baltimore	Maryland
United States	Johns Hopkins University CRS	Baltimore	Maryland
United States	Alabama Therapeutics CRS	Birmingham	Alabama
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts
United States	Bmc Actg Crs	Boston	Massachusetts
United States	Massachusetts General Hospital CRS (MGH CRS)	Boston	Massachusetts
United States	Cooper Univ. Hosp. CRS	Camden	New Jersey
United States	Chapel Hill CRS	Chapel Hill	North Carolina
United States	Mt. Sinai Hosp. Med. Ctr. - Chicago, Womens & Childrens HIV Program	Chicago	Illinois
United States	Northwestern University CRS	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS	Chicago	Illinois
United States	Rush University CRS	Chicago	Illinois
United States	Cincinnati CRS	Cincinnati	Ohio
United States	Case CRS	Cleveland	Ohio
United States	MetroHealth CRS	Cleveland	Ohio
United States	Ohio State University CRS	Columbus	Ohio
United States	Trinity Health and Wellness Center CRS	Dallas	Texas
United States	Denver Public Health CRS	Denver	Colorado
United States	Henry Ford Hosp. CRS	Detroit	Michigan
United States	Duke Univ. Med. Ctr. Adult CRS	Durham	North Carolina
United States	South Florida CDTC Ft Lauderdale NICHD CRS	Fort Lauderdale	Florida
United States	Greensboro CRS	Greensboro	North Carolina
United States	Houston AIDS Research Team CRS	Houston	Texas
United States	Texas Children's Hospital CRS	Houston	Texas
United States	Univ. of Florida Jacksonville NICHD CRS	Jacksonville	Florida
United States	University of California, UC San Diego CRS	La Jolla	California
United States	Miller Children's Hosp. Long Beach CA NICHD CRS	Long Beach	California
United States	UCLA CARE Center CRS	Los Angeles	California
United States	University of Southern California CRS	Los Angeles	California
United States	Pediatric Perinatal HIV Clinical Trials Unit CRS	Miami	Florida
United States	The University of Miami AIDS Clinical Research Unit (ACRU) CRS	Miami	Florida
United States	Vanderbilt Therapeutics (VT) CRS	Nashville	Tennessee
United States	Tulane Univ. New Orleans NICHD CRS	New Orleans	Louisiana
United States	Columbia IMPAACT CRS	New York	New York
United States	Columbia P&S CRS	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	Weill Cornell Chelsea CRS	New York	New York
United States	New Jersey Medical School- Adult Clinical Research Ctr. CRS	Newark	New Jersey
United States	Stanford AIDS Clinical Trials Unit CRS	Palo Alto	California
United States	Penn Therapeutics, CRS	Philadelphia	Pennsylvania
United States	Thomas Jefferson Univ. Med. Ctr. CRS	Philadelphia	Pennsylvania
United States	University of Pittsburgh CRS	Pittsburgh	Pennsylvania
United States	The Research & Education Group-Portland CRS	Portland	Oregon
United States	The Miriam Hospital Clinical Research Site (TMH CRS) CRS	Providence	Rhode Island
United States	Virginia Commonwealth Univ. Medical Ctr. CRS	Richmond	Virginia
United States	Trillium Health ACTG CRS	Rochester	New York
United States	Univ. of Rochester ACTG CRS	Rochester	New York
United States	Washington University Therapeutics (WT) CRS	Saint Louis	Missouri
United States	UCSD Antiviral Research Center CRS	San Diego	California
United States	Ucsf Hiv/Aids Crs	San Francisco	California
United States	University of Washington AIDS CRS	Seattle	Washington
United States	Georgetown University CRS (GU CRS)	Washington	District of Columbia
United States	Howard Univ. Washington DC NICHD CRS	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	National Institute of Dental and Craniofacial Research (NIDCR)

Countries where clinical trial is conducted

United States,  Brazil,  Puerto Rico,  South Africa, 

References & Publications (6)

Cameron JE, Hagensee ME. Human papillomavirus infection and disease in the HIV+ individual. Cancer Treat Res. 2007;133:185-213. Review. — View Citation

Chaturvedi AK, Goedert JJ. Human papillomavirus genotypes among women with HIV: implications for research and prevention. AIDS. 2006 Nov 28;20(18):2381-3. — View Citation

De Vuyst H, Franceschi S. Human papillomavirus vaccines in HIV-positive men and women. Curr Opin Oncol. 2007 Sep;19(5):470-5. Review. — View Citation

Kojic EM, Cu-Uvin S. Update: human papillomavirus infection remains highly prevalent and persistent among HIV-infected individuals. Curr Opin Oncol. 2007 Sep;19(5):464-9. Review. — View Citation

Kojic EM, Kang M, Cespedes MS, Umbleja T, Godfrey C, Allen RT, Firnhaber C, Grinsztejn B, Palefsky JM, Webster-Cyriaque JY, Saah A, Aberg JA, Cu-Uvin S. Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in HIV-1-infected women. Cl — View Citation

Palefsky J. Human papillomavirus infection in HIV-infected persons. Top HIV Med. 2007 Aug-Sep;15(4):130-3. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With HPV6 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series	Percentage of participants with HPV6 antibody development from seronegative status (HPV6 antibody titers <20 mMU/mL) at baseline to seropositive (HPV6 antibody titers >=20 mMU/mL) status a month after the completion of HPV vaccination series. HPV serotyping was performed centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum.	Week 28
Primary	Percentage of Participants With HPV11 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series	Percentage of participants with HPV11 antibody development from seronegative status (HPV11 antibody titers <16 mMU/mL) at baseline to seropositive (HPV11 antibody titers >=16 mMU/mL) status a month after the completion of HPV vaccination series. HPV serotyping was performed centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum.	Week 28
Primary	Percentage of Participants With HPV16 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series	Percentage of participants with HPV16 antibody development from seronegative status (HPV16 antibody titers <20 mMU/mL) at baseline to seropositive (HPV16 antibody titers >=20 mMU/mL) status a month after the completion of HPV vaccination series. HPV serotyping was performed centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum.	Week 28
Primary	Percentage of Participants With HPV18 Antibody Development From the Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series	Percentage of participants with HPV18 antibody development from seronegative status (HPV18 antibody titers <24 mMU/mL) at baseline to seropositive (HPV18 antibody titers >=24 mMU/mL) status a month after the completion of HPV vaccination series. HPV serotyping was performed centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum.	Week 28
Secondary	HPV6 Antibody Titers Among Those Seronegative for HPV6 at Baseline	HPV antibody titers to type 6 were measured centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum. The results below the lower limit of detection (LLD) were assigned the values of half the LLD (7 mMU/mL, and after assay change in December 2012, 11 mMU/mL for HPV6). Geometric mean HPV6 titers with 95% CIs were calculated among the subset of participants who were seronegative for HPV6 (<20 mMU/mL) at baseline.	Weeks 28, 72
Secondary	HPV11 Antibody Titers Among Those Seronegative for HPV11 at Baseline	HPV antibody titers to type 11 were measured centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum. The results below the lower limit of detection (LLD) were assigned the values of half the LLD (8 mMU/mL for HPV11). Geometric mean HPV11 titers with 95% CIs were calculated among the subset of participants who were seronegative for HPV11 (<16 mMU/mL) at baseline.	Weeks 28, 72
Secondary	HPV16 Antibody Titers Among Those Seronegative for HPV16 at Baseline	HPV antibody titers to type 16 were measured centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum. The results below the lower limit of detection (LLD) were assigned the values of half the LLD (11 mMU/mL for HPV16). Geometric mean HPV16 titers with 95% CIs were calculated among the subset of participants who were seronegative for HPV16 (<20 mMU/mL) at baseline.	Weeks 28, 72
Secondary	HPV18 Antibody Titers Among Those Seronegative for HPV18 at Baseline	HPV antibody titers to type 18 were measured centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum. The results below the lower limit of detection (LLD) were assigned the values of half the LLD (10 mMU/mL for HPV18). Geometric mean HPV18 titers with 95% CIs were calculated among the subset of participants who were seronegative for HPV18 (<24 mMU/mL) at baseline.	Weeks 28, 72
Secondary	Change in Log10 HPV6 Antibody Titers From Baseline Among Those Seropositive for HPV6 at Baseline	Change in log10 HPV6 antibody titers was calculated as log10 HPV6 antibody titers at a later timepoint (Week 28, Week 72) minus log10 HPV6 antibody titers at baseline among those seropositive for HPV6 (>=20 mMU/mL) at baseline. HPV antibody titers to type 6 were measured centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum. The results below the lower limit of detection (LLD) were assigned the values of half the LLD (7 mMU/mL, and after assay change in December 2012, 11 mMU/mL for HPV6).	Weeks 0, 28, 72
Secondary	Change in Log10 HPV11 Antibody Titers From Baseline Among Those Seropositive for HPV11 at Baseline	Change in log10 HPV11 antibody titers was calculated as log10 HPV11 antibody titers at a later timepoint (Week 28, Week 72) minus log10 HPV11 antibody titers at baseline among those seropositive for HPV11 (>=16 mMU/mL) at baseline. HPV antibody titers to type 11 were measured centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum. The results below the lower limit of detection (LLD) were assigned the values of half the LLD (8 mMU/mL for HPV11).	Weeks 0, 28, 72
Secondary	Change in Log10 HPV16 Antibody Titers From Baseline Among Those Seropositive for HPV16 at Baseline	Change in log10 HPV16 antibody titers was calculated as log10 HPV16 antibody titers at a later timepoint (Week 28, Week 72) minus log10 HPV16 antibody titers at baseline among those seropositive for HPV16 (>=20 mMU/mL) at baseline. HPV antibody titers to type 16 were measured centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum. The results below the lower limit of detection (LLD) were assigned the values of half the LLD (11 mMU/mL for HPV16).	Weeks 0, 28, 72
Secondary	Change in Log10 HPV18 Antibody Titers From Baseline Among Those Seropositive for HPV18 at Baseline	Change in log10 HPV18 antibody titers was calculated as log10 HPV18 antibody titers at a later timepoint (Week 28, Week 72) minus log10 HPV18 antibody titers at baseline among those seropositive for HPV18 (>=24 mMU/mL) at baseline. HPV antibody titers to type 18 were measured centrally using the competitive Luminex ImmunoAssay (HPV-4, cLIA) on stored serum. The results below the lower limit of detection (LLD) were assigned the values of half the LLD (10 mMU/mL for HPV18).	Weeks 0, 28, 72
Secondary	Number of Participants With Signs and Symptoms of Grade 3 or Higher	Number of participants who experienced a sign or symptom of Grade 3 or higher at any time after baseline while on study. Grading of signs and symptoms was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.	From baseline to up to Week 72
Secondary	Number of Participants With Laboratory Abnormalities of Grade 3 or Higher	Number of participants who experienced a laboratory abnormality of Grade 3 or higher at any time after baseline while on study. Grading of laboratory abnormalities was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.	From baseline to up to Week 72
Secondary	Change in Log10 HIV Viral Load (VL) From Baseline	A blood sample was drawn for local testing to determine the HIV VL. Change in log10 HIV VL was calculated as log10 HIV VL at a later time point (Weeks 4, 12, 28, 52 and 72) minus log10 HIV VL at baseline.	Weeks 0, 4, 12, 28, 52, and 72
Secondary	Change in CD4 Cell Count From Baseline	A blood sample was drawn for local testing to determine the CD4 cell count. Change in CD4 cell count was calculated as CD4 cell count at a later time point (Weeks 4, 8, 12, 24, 28, 52 and 72) minus CD4 cell count at baseline.	Weeks 0, 4, 8, 12, 24, 28, 52 and 72

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