HPV Vaccine Effectiveness Study in Rwandan Women Living With HIV

Study Overview
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Brief Summary
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Our study will assess and measure population effectiveness of prophylactic HPV vaccine in reducing cervical, anal, and/or oral prevalent and 6-month persistent infections among HPV-vaccinated and 757 HPV-unvaccinated Rwandan WLWH aged 18-26 years. Additional objectives include the quantification & examination of long-term antibody (into young adulthood) responses to HPV vaccination and to validate the performance (e.g., sensitivity and specificity) of a low-cost, POC (point-of-care) anti-HPV16 antibody test to determine/confirm HPV vaccination status. The findings for this study will provide necessary evidence regarding the long-term protection afforded by HPV vaccination in WLWH living in SSA, who are at the greatest risk of HPV-related cancers.

Detailed Description
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Cervical cancer is the 4th most common cancer and cause of cancer-related death in women globally; in many lower-resource settings, especially sub-Saharan Africa (SSA), it is the most common. Virtually all cervical cancer and precancer are caused by 12-15 high-risk human papillomavirus (HPV) types. HPV16 causes approximately 55-60% and HPV18 causes approximately 10-15% of cervical cancer while the remaining 12 HPV types cause the remaining 25-30% of cervical cancer. High-risk HPV, predominately HPV16, also causes most anal, vulvar, vaginal, and penile cancers and a significant proportion of oropharyngeal cancers. Prophylactic HPV vaccines have been developed and have been shown to be nearly 100% protective against incident HPV infection and related abnormalities in the general population. However, the evidence for the effectiveness of prophylactic HPV vaccines in women living with human immunodeficiency virus (HIV) (WLWH) is less clear. HIV infection increases the risk of cervical cancer due to an impaired immune response to HPV. Rwanda is a high-burden cervical cancer country where the prevalence of HIV is 3.7% among adult women, with higher HIV prevalence among young women (1). In 2011, Rwanda implemented a national HPV vaccination program with Gardasil®, which protects against HPV16 and HPV18, the two HPV types that cause  70% of cervical cancer, and HPV6 and HPV11, the two types that cause  90% of anogenital warts (HPV6/11/16/18). Their program has achieved >90% coverage of the target population, primarily girls aged 12 years, annually. The implementation of a highly successful HPV vaccination program and the high prevalence of HIV, in addition to the research and medical capacity that Albert Einstein College of Medicine (Einstein) has helped to build at the Rwanda Military Hospital (RMH) and University of Rwanda (UR), makes Rwanda the ideal locale to study the long-term effects of HPV vaccination in WLWH. To answer questions about HPV vaccine effectiveness and immunity in Rwandan WLWH, collaborators at Einstein, RMH, and UR will conduct an observational study of WLWH and HIV-negative (HIV[-]) women who did (birth cohorts 1997 and later) and WLWH who did not (birth cohorts before 1997) receive HPV vaccination through the national vaccination program. The investigators will compare cervicovaginal, anal, and oral prevalent and 6-month persistent HPV6/11/16/18 infections in 757 HPV-vaccinated WLWH to those in 757 unvaccinated WLWH and 757 HPV-vaccinated HIV[-] women. The investigators will also compare the HPV immune response in 548 HPV-vaccinated WLWH to 548 HPV-vaccinated HIV[-] women and the impact of switching from 3 doses to 2 doses of Gardasil® in 2015. Finally, the investigators will investigate the risk factors, including the cervicovaginal microbiome, for prevalent and 6-month persistent HPV infection in young WLWH and HIV[-] women. The long-term goal is to establish a cohort of WLWH in whom we can examine the long-term effectiveness of HPV vaccination in WLWH now and in the future. This contribution is significant as it will establish the population effectiveness of HPV vaccination in WLWH living in SSA, the group of women at the highest risk of cervical cancer, for which there is a dearth of evidence. The proposed research is innovative as it leverages and expands the local research and medical capacity in Rwanda to examine one of the critically unanswered questions about HPV vaccine effectiveness in the context of the World Health Organization's (WHO) call for the elimination of cervical cancer.

Official Title
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Long-Term Human Papillomavirus Vaccination Effectiveness and Immunity in Rwandan Women Living With and Without Human Immunodeficiency Virus

Conditions
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Cervical Cancer, Human Papilloma Virus, Human Immunodeficiency Virus, HPV-Related Carcinoma

Intervention / Treatment
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* Procedure: Blood collection
* Procedure: Oral, cervicovaginal and anal specimen collection
* Procedure: Anoscopy & Biopsy of Acetowhite Lesions
* Procedure: Colposcopy & Biopsy of Acetowhite Lesions
* Procedure: Ablative Treatment
* Procedure: LEEP (Loop Electrosurgical Excision Procedure)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female 18-28 years. The age of inclusion criteria will likely be restricted as age-specific enrollment goals are met. Physically and mentally able and willing to participate in the study. Willing to provide written and signed or thumb printed, informed consent. Known to be living with HIV (i.e., enrolled in a treatment program), or consent to HIV testing to confirm HIV status. Exclusion Criteria: Have positive pregnancy test or report to be pregnant at the time of visit or less than 6 weeks post-partum (will be asked to make an appointment 6 or more weeks post-partum) Report to be menstruating at the time of visit (will be asked to make new appointment) History of hysterectomy and no longer have a cervix History of treatment for cervical abnormalities after cervical screening History of cervical cancer Report no previous sexual activity HIV status is unknown, and date of birth is 12/31/1995 or earlier Because this study has age-specific enrollment goals for WLWH and HIV[-] women, once those enrollment goals are met for each study group, the respective cohorts will be closed and other eligible women will be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 28 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>HPV-vaccinated women living with HIV | Procedure: Blood collection<br>* Blood collection at enrollment visit<br>Procedure: Oral, cervicovaginal and anal specimen collection<br>* Oral, cervicovaginal and anal specimen collection at enrollment and follow-up visits<br>Procedure: Anoscopy & Biopsy of Acetowhite Lesions<br>* Used for management in follow-up visits of persistent anal HPV16/18+ in WLWH<br>Procedure: Colposcopy & Biopsy of Acetowhite Lesions<br>* Used for management in follow-up visits of persistent type-specific high-risk HPV cervicovaginal HPV<br>Procedure: Ablative Treatment<br>* Use for management in follow-up visits of persistent cervicovaginal HPV 16/18+ in WLWH, as identified in colposcopy and biopsy<br>Procedure: LEEP (Loop Electrosurgical Excision Procedure)<br>* Use for management in follow-up visits of persistent cervicovaginal HPV 16/18+ in WLWH, as identified in colposcopy and biopsy that ablation ineligible<br>|
| Group 2<br>HPV-unvaccinated women living with HIV | Procedure: Blood collection<br>* Blood collection at enrollment visit<br>Procedure: Oral, cervicovaginal and anal specimen collection<br>* Oral, cervicovaginal and anal specimen collection at enrollment and follow-up visits<br>Procedure: Anoscopy & Biopsy of Acetowhite Lesions<br>* Used for management in follow-up visits of persistent anal HPV16/18+ in WLWH<br>Procedure: Colposcopy & Biopsy of Acetowhite Lesions<br>* Used for management in follow-up visits of persistent type-specific high-risk HPV cervicovaginal HPV<br>Procedure: Ablative Treatment<br>* Use for management in follow-up visits of persistent cervicovaginal HPV 16/18+ in WLWH, as identified in colposcopy and biopsy<br>Procedure: LEEP (Loop Electrosurgical Excision Procedure)<br>* Use for management in follow-up visits of persistent cervicovaginal HPV 16/18+ in WLWH, as identified in colposcopy and biopsy that ablation ineligible<br>|
| Group 3<br>HIV[-] women who are HPV-vaccinated | Procedure: Blood collection<br>* Blood collection at enrollment visit<br>Procedure: Oral, cervicovaginal and anal specimen collection<br>* Oral, cervicovaginal and anal specimen collection at enrollment and follow-up visits<br>Procedure: Colposcopy & Biopsy of Acetowhite Lesions<br>* Used for management in follow-up visits of persistent type-specific high-risk HPV cervicovaginal HPV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in vaccine effectiveness of prophylactic HPV vaccine at 6 months | To measure population effectiveness of prophylactic HPV vaccine in reducing cervicovaginal, anal, and/or oral prevalent and 6-month persistent infections by HPV6/11/16/18 | Baseline and 6 months | 
| Change in long-term antibody responses to HPV vaccination at 6 months | To quantify, and examine the determinants of, long-term antibody (into young adulthood) responses to HPV vaccination | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HPV natural history study at 6 months | Conduct a natural history study to investigate determinants, including cervicovaginal microbiome (CVM), of short-term HPV persistence in young WLWH and HIV[-] women living in a SSA setting | Baseline and 6 months |