Infection with human papillomavirus (HPV) has been clearly established as the central cause of cervical cancer. This Phase IV, observer-blind study is designed to evaluate the safety and immunogenicity of Cervarix in HIV infected females aged 15 to 25 years as compared to Merck's HPV vaccine (Gardasil). For comparative purposes, a group of HIV negative females will also be evaluated. All subjects will receive the HPV vaccine (either Cervarix or Gardasil) according to a three-dose schedule (Day 0, Week 6, Month 6).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
873
Subjects received three doses of the study vaccine administered intramuscularly according to a Day 0, Week 6, and Month 6 vaccination schedule.
Subjects received three doses of the study vaccine administered intramuscularly according to a Day 0, Week 6, and Month 6 vaccination schedule.
GSK Investigational Site
Porto Alegre, Rio Grande do Sul, Brazil
GSK Investigational Site
Ribeirão Preto, São Paulo, Brazil
GSK Investigational Site
Campinas, Brazil
GSK Investigational Site
Rio de Janeiro, Brazil
GSK Investigational Site
São Paulo, Brazil
GSK Investigational Site
Kohtla-Järve, Estonia
GSK Investigational Site
Tallinn, Estonia
GSK Investigational Site
Chennai, India
GSK Investigational Site
Kolkata, India
GSK Investigational Site
Mumbai, India
...and 5 more locations
Number of Human Immunodeficiency Virus Positive Subjects (HIV+) With Any and Grade 3 Solicited Local Symptoms
Assessed solicited local symptoms were pain, redness, swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = significant pain at rest, pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling with a maximum diameter greater than 50 millimeters (mm).
Time frame: During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses
Number of HIV+ Subjects With Any, Grade 3 and Related Solicited General Symptoms
Assessed solicited general symptoms were arthralgia, fatigue, gastrointestinal \[nausea, vomiting, diarrhoea and/or abdominal pain\], headache, myalgia, rash, temperature \[defined as axillary temperature higher than (\>) 37.5 degrees Celsius (°C)\] and urticaria. Any = occurrence of the symptom regardless of intensity grade and relationship. Grade 3 symptom = symptom that prevented normal activity. Grade 3 temperature = temperature \> 39.0 °C. Grade 3 urticaria = urticaria distributed on at least 4 body areas. Related = symptom assessed by the investigator as related to the vaccination.
Time frame: During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses
Number of HIV+ Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs)
An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Related = symptom assessed by the investigator as related to the vaccination.
Time frame: During the 30-day follow-up period (from the day of vaccination up to 29 subsequent days) after any vaccination
Number of HIV+ Subjects With Serious Adverse Events (SAEs)
SAEs assessed include any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or represented a congenital anomaly/birth defect in the offspring of a study subject.
Time frame: From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)
Number of HIV+ Subjects With Medically Significant Conditions (MSCs)
Medically significant conditions (MSCs) are defined as AEs prompting emergency room or physician visits that were not related to common diseases, or not related to routine visits for physical examination or vaccination, SAEs that were not related to common diseases.
Time frame: From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)
Number of HIV+ Subjects With Potential Immune-mediated Diseases (pIMDs)
Potential immune-mediated diseases are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.
Time frame: From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)
Number of HIV+ Subjects Reporting Pregnancies and Outcomes of Reported Pregnancies
Pregnancy related outcomes were: live infant no apparent congenital anomaly, live infant congenital anomaly, elective termination (termin.) no apparent congenital anomaly, elective termination (termin.) congenital anomaly, ectopic pregnancy, spontaneous abortion no apparent congenital (congen.) anomaly, stillbirth no apparent congenital anomaly, stillbirth congenital anomaly, lost to follow-up, pregnancy ongoing, missing.
Time frame: From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)
Number of HIV+ Subjects With Haematological and Biochemical Parameter Abnormalities
Among assessed haematological and biochemical parameters were: alanine aminotransferase \[ALAT\], basophilis \[BSPH\], creatinine \[CRT\], eosinophils \[ESPH\], haematocrit \[HTCR\], haemoglobin \[HGB\], lymphocytes \[LYMP\], monocytes \[MONO\], neutrophils \[NTPH\], platelets \[PLAT\], red blood cells \[RBC\] and white blood cells \[WBC\]. Unknown = value unknown for the specified visit and laboratory parameter; Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter.
Time frame: At Month 7 (30 days after the last vaccination dose at Month 6)
Cluster of Differentiation 4 (CD4+) Cell Count in HIV+ Subjects at Month 7
CD4+ cell count, expressed in cells/cubic millimeter (mm3), was assessed for HIV+ subjects.
Time frame: At Month 7 (30 days after the last vaccination dose at Month 6)
HIV Viral Load (VL) in HIV+ Subjects at Month 7
HIV VL, expressed in HIV copies/milliliter (mL), was assessed for HIV+ subjects.
Time frame: At Month 7 (30 days after the last vaccination dose at Month 6)
Number of HIV+ Subjects by World Health Organization (WHO) HIV Clinical Staging
HIV+ subjects were categorised into clinical stages 1 through 4, as per the WHO classification \[WHO, 2009\].
Time frame: At Month 7 (30 days after the last vaccination dose at Month 6)
Pseudovirion-Based Neutralization Assay (PBNA) Titers of Anti-HPV-16/18 Antibodies in HIV+ Subjects, Based on Adapted According-to-protocol (ATP) Cohort for Immunogenicity
Titers of anti-HPV-16/18 antibodies, expressed as Geometric Mean Titers (GMTs), with cut-offs greater than or equal to (≥) 40 estimated dose giving 50% signal reduction when compared to a control without serum (ED50), as assessed by the Pseudovirion-Based Neutralization Assay \[PBNA\], in HIV+ subjects. Between-group comparisons to assess non-inferiority were performed on the ATP cohort for immunogenicity (by PBNA, regardless of HPV serostatus at baseline).
Time frame: At Month 7 (30 days after the last vaccination dose at Month 6)
Pseudovirion-Based Neutralization Assay (PBNA) Titers of Anti-HPV-16/18 Antibodies in HIV+ Subjects, Based on Total Vaccinated Cohort (TVC)
Titers of anti-HPV-16/18 antibodies, expressed as Geometric Mean Titers (GMTs), with cut-offs greater than or equal to (≥) 40 estimated dose giving 50% signal reduction when compared to a control without serum (ED50), as assessed by the Pseudovirion-Based Neutralization Assay \[PBNA\], in HIV+ subjects. Between-group comparisons to assess superiority were performed on the TVC (by PBNA, regardless of HPV serostatus at baseline).
Time frame: At Month 7 (30 days after the last vaccination dose at Month 6)
Number of HIV- Subjects With Any and Grade 3 Solicited Local Symptoms
Assessed solicited local symptoms were pain, redness, swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = significant pain at rest, pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling with a maximum diameter greater than 50 millimeters (mm).
Time frame: During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses
Number of HIV- Subjects With Any, Grade 3 and Related Solicited General Symptoms
Assessed solicited general symptoms were arthralgia, fatigue, gastrointestinal \[nausea, vomiting, diarrhoea and/or abdominal pain\], headache, myalgia, rash, temperature \[defined as axillary temperature higher than (\>) 37.5 degrees Celsius (°C)\] and urticaria. Any = occurrence of the symptom regardless of intensity grade and relationship. Grade 3 symptom = symptom that prevented normal activity. Grade 3 temperature = temperature \> 39.0 °C. Grade 3 urticaria = urticaria distributed on at least 4 body areas. Related = symptom assessed by the investigator as related to the vaccination.
Time frame: During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses
Number of HIV- Subjects With Unsolicited Adverse Events (AEs)
An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Related = symptom assessed by the investigator as related to the vaccination.
Time frame: During the 30-day follow-up period (from the day of vaccination up to 29 subsequent days) after any vaccination
Number of HIV- Subjects With Serious Adverse Events (SAEs)
SAEs assessed include any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or represented a congenital anomaly/birth defect in the offspring of a study subject.
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Time frame: From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)
Number of HIV- Subjects With Medically Significant Conditions (MSCs)
Medically significant conditions (MSCs) are defined as AEs prompting emergency room or physician visits that were not related to common diseases, or not related to routine visits for physical examination or vaccination, SAEs that were not related to common diseases.
Time frame: From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)
Number of HIV- Subjects With Potential Immune-mediated Disease (pIMDs)
Potential immune-mediated diseases are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.
Time frame: From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)
Number of Subjects Reporting Pregnancies and Outcomes of Reported Pregnancies
Pregnancy related outcomes were: live infant no apparent congenital anomaly, live infant congenital anomaly, elective termination (termin.) no apparent congenital anomaly, elective termination (termin.) congenital anomaly, ectopic pregnancy, spontaneous abortion no apparent congenital (congen.) anomaly, stillbirth no apparent congenital anomaly, stillbirth congenital anomaly, lost to follow-up, pregnancy ongoing, missing.
Time frame: During the entire study period (from Day 0 up to Month 24)
Number of Subjects With Relevant Abnormalities in Alanine Aminotransferase, Basophils, Creatinine and Eosinophils Parameters
Among assessed haematological and biochemical parameters were: alanine aminotransferase \[ALAT\], basophils \[BSPH\], creatinine \[CRT\], eosinophils \[ESPH\]. Unknown = value unknown for the specified visit and laboratory parameter; Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter.
Time frame: At Day 0, Week 6, Week 10, Month 6, Month 7, Month 12, Month 18 and Month 24
Number of Subjects With Relevant Abnormalities in Haematocrit, Haemoglobin, Lymphocytes and Monocytes Parameters
Among assessed haematological parameters were: haematocrit \[HTCR\], haemoglobin \[HGB\], lymphocytes \[LYMP\] and monocytes \[MONO\]. Unknown = value unknown for the specified visit and laboratory parameter; Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter.
Time frame: At Day 0, Week 6, Week 10, Month 6, Month 7, Month 12, Month 18 and Month 24
Number of Subjects With Relevant Abnormalities in Neutrophils, Platelets, Red Blood Cells and White Blood Cells Parameters
Among assessed haematological parameters were: neutrophils \[NTPH\], platelets \[PLAT\], red blood cells \[RBC\] and white blood cells \[WBC\]. Unknown = value unknown for the specified visit and laboratory parameter; Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter.
Time frame: At Day 0, Week 6, Week 10, Month 6, Month 7, Month 12, Month 18 and Month 24
Number of Subjects With SAEs
SAEs assessed include any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or represented a congenital anomaly/birth defect in the offspring of a study subject.
Time frame: During the entire study period (from Day 0 up to Month 24)
Number of Subjects With Medically Significant Conditions (MSCs)
Medically significant conditions (MSCs) are defined as AEs prompting emergency room or physician visits that were not related to common diseases, or not related to routine visits for physical examination or vaccination, SAEs that were not related to common diseases.
Time frame: From Day 0 up to Month 18 (from Day 0 up to 12 months after the last vaccination dose at Month 6)
Number of Subjects With Potential Immune-mediated Diseases (pIMDs)
Potential immune-mediated diseases are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.
Time frame: From Day 0 up to Month 18 (from Day 0 up to 12 months after the last vaccination dose at Month 6)
Cluster of Differentiation 4 (CD4+) Cell Count in HIV+ Subjects at Months 12, 18 and 24
CD4+ cell count, expressed in cells/cubic millimeter (mm3), was assessed for HIV+ subjects.
Time frame: At Months 12, 18 and 24
HIV Viral Load (VL) in HIV+ Subjects at Months 12, 18 and 24
HIV VL, expressed in HIV copies/milliliter (mL), was assessed for HIV+ subjects.
Time frame: At Months 12, 18 and 24
Number of HIV+ Subjects by WHO HIV Clinical Staging
HIV+ subjects were categorised into clinical stages 1 through 4, as per the WHO classification \[WHO, 2009\].
Time frame: At Months 12, 18 and 24
Pseudovirion-Based Neutralization Assay (PBNA) Titers of Anti-HPV-16/18 Antibodies in HIV- Subjects, Based on TVC
Titers of anti-HPV-16/18 antibodies, expressed as Geometric Mean Titers (GMTs), with cut-offs greater than or equal to (≥) 40 estimated dose giving 50% signal reduction when compared to a control without serum (ED50), as assessed by the Pseudovirion-Based Neutralization Assay \[PBNA\], for HIV- subjects. Between-group comparisons to assess superiority were performed on the TVC (by PBNA, regardless of HPV serostatus at baseline).
Time frame: At Month 7 (30 days after the last vaccination dose at Month 6)
Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations by Enzyme-linked Immunosorbent Assay (ELISA) in Serum
Anti-HPV-16 and anti-HPV-18 antibody concentrations in serum, are presented as Geometric Mean Concentrations (GMCs), with cut-offs greater than or equal to (≥) 19 ELISA units per milliliter (EU/mL) and 18 EU/mL respectively, as assessed by Enzyme-linked immunosorbent assay (ELISA), in all (HIV+ and HIV-) subjects.
Time frame: At Day 0, Week 6, Week 10, Month 7, Month 12, Month 18 and Month 24
Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations by ELISA in Cervicovaginal Secretion (CVS)
Anti-HPV-16 and anti-HPV-18 antibody concentrations in CVS, are presented as Geometric Mean Concentrations (GMCs), with cut-offs greater than or equal to (≥) 0 EU/mL, as assessed by ELISA, in post-menarcheal subjects who volunteered for this procedure.
Time frame: At Day 0, Week 6, Week 10, Month 7, Month 12, Month 18 and Month 24
Frequency of Specific B-cells for HPV-16/18 Antigens
B-cell memory was assessed by Enzyme Linked Immuno Spot (ELISPOT) assay. The assay was performed in a subset of approximately 100 subjects (50 HIV+ and 50 HIV-).
Time frame: At Day 0, Week 6, Week 10, Month 7 and Month 12
Frequency of Cluster of Differentiation 4/8 [CD4+/CD8+] T-cell Response
The combinations of cytokines expressed were CD4/8-all doubles, CD4/8-d-cluster of differentiation 40 Ligand (CD40L), CD4/8-d-interferon gamma (IFNG), CD4/8-interleukin-2 (IL-2), CD4/8-d-tumour necrosis alpha (TNFA), as assessed by Intracellular cytokine staining (ICS). The assay was performed in a subset of approximately 100 subjects (50 HIV+ and 50 HIV-).
Time frame: At Day 0, Week 6, Week 10, Month 7 and Month 12