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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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HIV Infections, Sexually Transmitted Diseases

Intervention / Treatment
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* Biological: Quadrivalent HPV vaccine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum A<br>Participants with screening CD4 count >350 cells/mm^3 received 0.5mL of quadrivalent HPV vaccine at baseline and Weeks 8 and 24. | Biological: Quadrivalent HPV vaccine<br>* Quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine. All participants received the vaccine via intramuscular injection at baseline, Week 8 and Week 24.<br>* Other names: GARDASIL;|
| Experimental: Stratum B<br>Participants with screening CD4 count >200 to <=350 cells/mm^3 received 0.5mL of quadrivalent HPV vaccine at baseline and Weeks 8 and 24. | Biological: Quadrivalent HPV vaccine<br>* Quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine. All participants received the vaccine via intramuscular injection at baseline, Week 8 and Week 24.<br>* Other names: GARDASIL;|
| Experimental: Stratum C<br>Participants with screening CD4 count <=200 cells/mm^3 received 0.5mL of quadrivalent HPV vaccine at baseline and Weeks 8 and 24. | Biological: Quadrivalent HPV vaccine<br>* Quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine. All participants received the vaccine via intramuscular injection at baseline, Week 8 and Week 24.<br>* Other names: GARDASIL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, HPV 6, HPV 11, HPV 16, HPV 18, Vaccine