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

Phase 2

Completed

Conditions: HIV Infections
Sexually Transmitted Diseases

Interventions: Biological: Quadrivalent HPV vaccine

Registration Number: NCT00604175

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief 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.

Detailed 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 & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 319

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stratum B	Quadrivalent HPV vaccine	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.
Stratum A	Quadrivalent HPV vaccine	Participants with screening CD4 count \>350 cells/mm\^3 received 0.5mL of quadrivalent HPV vaccine at baseline and Weeks 8 and 24.
Stratum C	Quadrivalent HPV vaccine	Participants with screening CD4 count \<=200 cells/mm\^3 received 0.5mL of quadrivalent HPV vaccine at baseline and Weeks 8 and 24.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With HPV11 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series	Week 28	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.
Percentage of Participants With HPV16 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series	Week 28	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.
Percentage of Participants With HPV18 Antibody Development From the Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series	Week 28	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.
Percentage of Participants With HPV6 Antibody Development From Seronegative Status at Baseline to Seropositive Status a Month After Completion of HPV Vaccination Series	Week 28	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.

Secondary Outcome Measures

Name	Time	Method
Change in Log10 HPV16 Antibody Titers From Baseline Among Those Seropositive for HPV16 at Baseline	Weeks 0, 28, 72	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).
HPV11 Antibody Titers Among Those Seronegative for HPV11 at Baseline	Weeks 28, 72	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.
Change in Log10 HPV6 Antibody Titers From Baseline Among Those Seropositive for HPV6 at Baseline	Weeks 0, 28, 72	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).
Change in CD4 Cell Count From Baseline	Weeks 0, 4, 8, 12, 24, 28, 52 and 72	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.
Change in Log10 HPV11 Antibody Titers From Baseline Among Those Seropositive for HPV11 at Baseline	Weeks 0, 28, 72	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).
Number of Participants With Signs and Symptoms of Grade 3 or Higher	From baseline to up to Week 72	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.
Number of Participants With Laboratory Abnormalities of Grade 3 or Higher	From baseline to up to Week 72	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.
HPV6 Antibody Titers Among Those Seronegative for HPV6 at Baseline	Weeks 28, 72	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.
HPV16 Antibody Titers Among Those Seronegative for HPV16 at Baseline	Weeks 28, 72	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.
Change in Log10 HIV Viral Load (VL) From Baseline	Weeks 0, 4, 12, 28, 52, and 72	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.
HPV18 Antibody Titers Among Those Seronegative for HPV18 at Baseline	Weeks 28, 72	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.
Change in Log10 HPV18 Antibody Titers From Baseline Among Those Seropositive for HPV18 at Baseline	Weeks 0, 28, 72	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).

Trial Locations

Locations (61): Pediatric Perinatal HIV Clinical Trials Unit CRS
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Miami, Florida, United States
The Ponce de Leon Center CRS
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Atlanta, Georgia, United States
Mt. Sinai Hosp. Med. Ctr. - Chicago, Womens & Childrens HIV Program
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Chicago, Illinois, United States
Northwestern University CRS
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Chicago, Illinois, United States
Rush Univ. Med. Ctr. ACTG CRS
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Chicago, Illinois, United States
Massachusetts General Hospital CRS (MGH CRS)
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Boston, Massachusetts, United States
Ohio State University CRS
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Columbus, Ohio, United States
Penn Therapeutics, CRS
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Philadelphia, Pennsylvania, United States
Trinity Health and Wellness Center CRS
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Dallas, Texas, United States
Texas Children's Hospital CRS
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Houston, Texas, United States
Houston AIDS Research Team CRS
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Houston, Texas, United States
Wits Helen Joseph Hospital CRS (Wits HJH CRS)
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Johannesburg, Gauteng, South Africa
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
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Rio de Janeiro, Brazil
The University of Miami AIDS Clinical Research Unit (ACRU) CRS
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Miami, Florida, United States
Univ. of Florida Jacksonville NICHD CRS
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Jacksonville, Florida, United States
Johns Hopkins University CRS
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Baltimore, Maryland, United States
Howard Univ. Washington DC NICHD CRS
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Washington, District of Columbia, United States
University of Puerto Rico Pediatric HIV/AIDS Research Program CRS
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San Juan, Puerto Rico
San Juan City Hosp. PR NICHD CRS
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San Juan, Puerto Rico
South Florida CDTC Ft Lauderdale NICHD CRS
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Fort Lauderdale, Florida, United States
Puerto Rico AIDS Clinical Trials Unit CRS
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San Juan, Puerto Rico
Rush University CRS
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Chicago, Illinois, United States
UCSD Antiviral Research Center CRS
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San Diego, California, United States
Ucsf Hiv/Aids Crs
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San Francisco, California, United States
Duke Univ. Med. Ctr. Adult CRS
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Durham, North Carolina, United States
Vanderbilt Therapeutics (VT) CRS
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Nashville, Tennessee, United States
University of Colorado Hospital CRS
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Aurora, Colorado, United States
Denver Public Health CRS
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Denver, Colorado, United States
Henry Ford Hosp. CRS
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Detroit, Michigan, United States
Alabama Therapeutics CRS
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Birmingham, Alabama, United States
University of California, UC San Diego CRS
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La Jolla, California, United States
Usc La Nichd Crs
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Alhambra, California, United States
Miller Children's Hosp. Long Beach CA NICHD CRS
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Long Beach, California, United States
University of Southern California CRS
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Los Angeles, California, United States
Stanford AIDS Clinical Trials Unit CRS
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Palo Alto, California, United States
UCLA CARE Center CRS
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Los Angeles, California, United States
Georgetown University CRS (GU CRS)
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Washington, District of Columbia, United States
Tulane Univ. New Orleans NICHD CRS
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New Orleans, Louisiana, United States
IHV Baltimore Treatment CRS
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Baltimore, Maryland, United States
Bmc Actg Crs
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Boston, Massachusetts, United States
Beth Israel Deaconess Med. Ctr., ACTG CRS
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Boston, Massachusetts, United States
Washington University Therapeutics (WT) CRS
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Saint Louis, Missouri, United States
Cooper Univ. Hosp. CRS
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Camden, New Jersey, United States
New Jersey Medical School- Adult Clinical Research Ctr. CRS
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Newark, New Jersey, United States
Weill Cornell Chelsea CRS
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New York, New York, United States
NY Univ. HIV/AIDS CRS
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New York, New York, United States
Columbia P&S CRS
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New York, New York, United States
Univ. of Rochester ACTG CRS
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Rochester, New York, United States
Columbia IMPAACT CRS
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New York, New York, United States
Trillium Health ACTG CRS
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Rochester, New York, United States
Chapel Hill CRS
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Chapel Hill, North Carolina, United States
Greensboro CRS
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Greensboro, North Carolina, United States
Cincinnati CRS
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Cincinnati, Ohio, United States
Case CRS
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Cleveland, Ohio, United States
MetroHealth CRS
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Cleveland, Ohio, United States
The Research & Education Group-Portland CRS
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Portland, Oregon, United States
Thomas Jefferson Univ. Med. Ctr. CRS
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Philadelphia, Pennsylvania, United States
University of Pittsburgh CRS
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Pittsburgh, Pennsylvania, United States
The Miriam Hospital Clinical Research Site (TMH CRS) CRS
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Providence, Rhode Island, United States
University of Washington AIDS CRS
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Seattle, Washington, United States
Virginia Commonwealth Univ. Medical Ctr. CRS
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Richmond, Virginia, United States