Evaluation of Safety and Immunogenicity of a Human Papillomavirus (HPV) Vaccine in Human Immunodeficiency Virus (HIV) Infected Females

Study Overview
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Brief Summary
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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).

Official Title
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Safety and Immunogenicity of Cervarix™ in Human Immunodeficiency Virus Infected Females

Conditions
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Infections, Papillomavirus, Papillomavirus Vaccines

Intervention / Treatment
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* Biological: GSK Biologicals' HPV vaccine 580299
* Biological: Merck's Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine (Gardasil)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they and/or their parent(s)/legally acceptable representative(s) (LAR) can and will comply with the requirements of the protocol. A female between, and including, 15 and 25 years of age at the time of the first vaccination. Written informed consent obtained from the subject and/or from the subject's parent or LAR. Subjects willing to undergo HIV Voluntary Counseling and Testing (VCT) and willing to be informed of their HIV infection status. For HIV seropositive subjects: Subjects must be HIV seropositive according to World Health Organization (WHO) case definition. Subject must be asymptomatic (or only have persistent generalized lymphadenopathy). Subjects should have a CD4 cell count > 350 cells/mm3. If currently taking antiretrovirals (ARVs), subjects must be on compliant to triple therapy (highly active ART) and have undetectable viral load on two previous clinical visits within the six months prior to study entry. For HIV seronegative subjects: Subjects confirmed as HIV seronegative at the screening visit. For non-virgin female subjects: Subjects must have no history of abnormal cytology or CIN 1/2/3. Subjects must have had no more than six life-time sexual partners prior to enrollment. Subjects must have no history of congenital malformations of the uterine cervix, or history of cauterization or surgical procedures involving damage to the transformation zone of the cervix or stenosis. Female subjects of non-childbearing potential may be enrolled in the study. Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test at screening and on the day of vaccination, and has agreed to continue adequate contraception during the entire treatment period and for two months after completion of the vaccination series. Exclusion Criteria: Previous vaccination against HPV, or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period (Day 0 to Month 24). ART not compliant with the National Guidelines. Active tuberculosis (TB) visit (criteria mandatory only for HIV+ subjects). Current TB therapy. Hemoglobin < 8.0 g/dL at the screening visit. Creatinine > 1.5-fold the upper limit of normal (ULN) at the screening visit. Alanine aminotransferase (ALT) > 2.5-fold ULN at the screening visit. Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period (Day 0 to Month 24). Chronic administration (defined as more than 14 consecutive days) of immunosuppressants or other immune-modifying drugs (with the exception of ART) within six months prior to the first vaccine dose. Administration of a vaccine not foreseen by the study protocol within 30 days (Days 0 - 29) before the first dose of study vaccine/control. Enrollment will be postponed until the subject is outside the specified window. Planned administration of a vaccine not foreseen by the study protocol within 30 days before or 30 days after (i.e., Days 0 - 29) any dose of study vaccine. Previous administration of components of the investigational vaccine. Cancer or autoimmune disease under treatment. Hypersensitivity to latex. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine/control. Acute disease and/or fever at the time of enrollment. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory testing performed at the screening visit. History of any neurological disorders or seizures. Pregnant or breastfeeding female. A subject planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the study period, up to two months after the last vaccine dose (i.e., up to Month 8). Concurrently participating in another clinical study, at any time during the study period (Day 0 to Month 24), in which the subject has been or will be exposed to an investigational or a non-investigational product. Any medically diagnosed or suspected immunodeficient condition (other than HIV for HIV seropositive subjects), based on medical history, physical examination and/or laboratory tests results. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine/control or planned administration during the study period. Enrollment will be postponed until the subject is outside the specified window. Administration of trimethoprim/sulphamethoxazole within seven days before the first dose of study vaccine/control, or planned administration of trimethoprim/sulphamethoxazole within seven days after the first dose of study vaccine/control. Current drugs or alcohol abuse. Child in care.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIV+/Cervarix Group<br>HIV seropositive female subjects, between and including 15 and 25 years of age, who received 3 doses of Cervarix vaccine, administered intramuscularly in the deltoid muscle of the non-dominant arm, according to a three-dose schedule: at Day 0, Week 6, Month 6. | Biological: GSK Biologicals' HPV vaccine 580299<br>* Subjects received three doses of the study vaccine administered intramuscularly according to a Day 0, Week 6, and Month 6 vaccination schedule.<br>* Other names: Cervarix;|
| Active Comparator: HIV+/Gardasil Group<br>HIV seropositive female subjects, between and including 15 and 25 years of age, who received 3 doses of Gardasil vaccine, administered intramuscularly in the deltoid muscle of the non-dominant arm, according to a three-dose schedule: at Day 0, Week 6, Month 6. | Biological: Merck's Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine (Gardasil)<br>* Subjects received three doses of the study vaccine administered intramuscularly according to a Day 0, Week 6, and Month 6 vaccination schedule.<br>* Other names: Gardasil;|
| Experimental: HIV-/Cervarix Group<br>HIV seronegative female subjects, between and including 15 and 25 years of age, who received 3 doses of Cervarix vaccine, administered intramuscularly in the deltoid muscle of the non-dominant arm, according to a three-dose schedule: at Day 0, Week 6, Month 6. | Biological: GSK Biologicals' HPV vaccine 580299<br>* Subjects received three doses of the study vaccine administered intramuscularly according to a Day 0, Week 6, and Month 6 vaccination schedule.<br>* Other names: Cervarix;|
| Active Comparator: HIV-/Gardasil Group<br>HIV seronegative female subjects, between and including 15 and 25 years of age, who received 3 doses of Gardasil vaccine, administered intramuscularly in the deltoid muscle of the non-dominant arm, according to a three-dose schedule: at Day 0, Week 6, Month 6. | Biological: Merck's Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine (Gardasil)<br>* Subjects received three doses of the study vaccine administered intramuscularly according to a Day 0, Week 6, and Month 6 vaccination schedule.<br>* Other names: Gardasil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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]. | 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). | 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). | At Month 7 (30 days after the last vaccination dose at Month 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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]. | 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). | 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. | 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. | 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-). | 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-). | At Day 0, Week 6, Week 10, Month 7 and Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervarix, Gardasil, Immunogenicity, Cervical cancer, Safety, HPV vaccine