Ignite Creation Date:
2024-05-19 @ 5:33 PM
Last Modification Date:
2024-10-26 @ 3:29 PM
Study NCT ID:
NCT06411938
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-05-14
First Post:
2024-04-03
Brief Title:
A Cervical Cancer Prevention Program in Kenya
Sponsor:
Indiana University
Organization:
Indiana University
Study Overview
Official Title:
A Community-based Cervical Cancer Prevention Program in Kenya Overcoming Obstacles to Care Promoting Understanding of HPV Natural History
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Merck-3
Brief Summary:
Cervical cancer is caused by oncogenic or high-risk HR human papillomavirus HPV and is the main cause of cancer-related death among Kenyan women This malignancy is theoretically preventable through a combination of screening of adult women and treating those with cervical premalignancies and vaccination of children and adolescents against HPV infection However only 5 of Kenyan women are regularly screened and only 14 have ever been screened which in Kenya is done by a method known as Visual Inspection with Acetic Acid VIA Possible obstacles to current screening include long travel to clinics high costs poor sensitivity and specificity of VIA the need for extensive training for VIA variability among providers in their interpretation of VIA lack of trained personnel and others In addition while safe and effective HPV vaccines have been available for 15 years very few 1 Kenyan children and adolescents have been vaccinated Obstacles to vaccination include high costs poor delivery infrastructure lack of education long travel to clinics and others The investigators began a community-based program to develop a framework for eradication of cervical cancer by screening adult women and vaccinating female children This program is becoming accepted in the Webuye region of Western Kenya but there is still a great deal to learn
Going forward this initiative will be known as the Kenya Mother-Daughter Cervical Cancer Eradication Program or the Mother-Daughter Program MDP for short The investigators propose a continuation of the MDP that will allow them to accumulate additional data needed to solidify the overall project and to answer additional questions as described below To accomplish this goal the investigators will first enroll an additional 300 adult women to the program This will increase the strength of the analysis of HR-HPV testing in detecting premalignant lesions of the cervix especially in HIV-infected women Second the investigators will identify the positive and negative features of the MDP from the viewpoint of both the adult women and the girls enrolled in the program Third because anogenital warts AGWs may serve as a reservoir for HR-HPV especially in women living with HIVAIDS the investigators will examine the prevalence HPV type distribution and treatment of these lesions among adult women participating in the MDP
Going forward this initiative will be known as the Kenya Mother-Daughter Cervical Cancer Eradication Program or the Mother-Daughter Program MDP for short The investigators propose a continuation of the MDP that will allow them to accumulate additional data needed to solidify the overall project and to answer additional questions as described below To accomplish this goal the investigators will first enroll an additional 300 adult women to the program This will increase the strength of the analysis of HR-HPV testing in detecting premalignant lesions of the cervix especially in HIV-infected women Second the investigators will identify the positive and negative features of the MDP from the viewpoint of both the adult women and the girls enrolled in the program Third because anogenital warts AGWs may serve as a reservoir for HR-HPV especially in women living with HIVAIDS the investigators will examine the prevalence HPV type distribution and treatment of these lesions among adult women participating in the MDP
Detailed Description:
Project Framework
The investigators will utilize a modification of the basic framework developed for the previous MISP Merck Investigator-Initiated Studies Program grant that began in 2018 This framework was successfully implemented in a rural Kenya community setting and combines screening of adult women ages 30 through 55 using HPV DNA testing of self-vaginal swabs with HPV vaccination of daughters ages 9 through 14 years of mothers attending community meetings
Rationale for conducting the proposed study
Strategies based on centralized care have been unsuccessful in preventing cervical cancer in Kenyan women HR-HPV DNA testing of self-collected vaginal swabs is acceptable and feasible and the investigators have now shown that such testing can occur in a community setting in rural Kenya other groups have demonstrated similar successes in Africa In studies funded by MISP awards the investigators have shown that essentially all women invited to community meetings agreed to enroll in the studies to receive education about cervical cancer and to provide a self-collected vaginal swab for HR-HPV DNA testing Nearly all women who attended the community meetings were willing to have their female children vaccinated against HPV The investigators have also shown that HPV vaccine can be delivered to western Kenya and can be administered to girls in a community setting The investigators wish to continue to use this framework in the next MISP to further study the utility of this strategy and to address research questions that will elucidate the barriers to participation and will begin to provide information about the impact of the program
The reasons the investigators want to enroll additional women are as follows First the investigators would also like to evaluate the educational aspect of the Mother-Daughter Project among women and girls regarding to cervical cancer awareness and prevention knowledge Second the investigators would like to intensively study the acceptability of the community-based program and define the obstacles of the program among women who are newly enrolled The investigators will interview women and randomly selected children and ask them to fill out detailed questionnaires related to these issues Second although the investigators expected to be able to address the issue of sensitivity and specificity of HR-HPV testing compared to VIA in the first MISP MISP-I the investigators noted an unexpectedly low rate of abnormal VIA in the original 200 women cohort The second cohort of 300 women is still undergoing evaluation and the investigators do not yet know the incidence of abnormal VIA examinations Thus additional women need to be enrolled in a third wave to address this important question Third this program has benefited the community by providing a cancer prevention program that includes HPV vaccination to which they have previously not had access to This program has engendered trust between the local population and caregivers Lastly the investigators hope to submit a larger application to an organization such as the Gates Foundation or the NIH for a larger award of several years duration based on as much preliminary data as can be generated from this project The same rationale applies to our desire to vaccinate additional girls via the MISP mechanism The investigators have vaccinated 2000 girls to date and as part of the second MISP MISP-II Because aflatoxin exposure represents a potential public health problem that could thwart efforts to control HPV-associated malignancies the investigators will study the serological response to vaccination in girls with chronic aflatoxin exposure once they have completed the vaccine regimen
The investigators will study the prevalence HPV type distribution and treatment response of AGWs in adult women living in Kenya AGWs cause considerable morbidity in women especially those who are HIV-infected Few comprehensive studies are available in women living in sub-Saharan Africa The investigators and others have previously showed that HR-HPV are frequently detected in AGWs from immunosuppressed people in the United States including some people living with HIV The investigators will determine the prevalence of AGWs in women participating in the community based program and test the hypothesis that the prevalence of AGW will be considerably higher in HIV-infected women The investigators will also test the hypothesis that HR-HPV types will be frequently detected in AGW from HIV-infected women suggesting that AGWs are a reservoir for HR-HPV and transmission The investigators will also explore an objective related to treatment of AGWs to determine if a higher failure rate in HIV-infected women may be related to poor control of HIV a higher HIV viral load and detection of HR-HPV in the AGWs
Thus these aims build on the infrastructure the investigators have created in the first two MISP award cycles The investigators believe the MDP a community based approach to cervical cancer can become the standard for western Kenya act as a framework for HPV-associated cancer control and can lead to a significant improvement in patient care as well as providing an opportunity for hypothesis driven research
The investigators propose a hypothesis driven study that expands our novel community-based approach to cervical cancer eradication in Kenya The investigators plan to enroll 300 additional Kenyan women between the ages of 30 to 55 years Self-collected vaginal swabs will be collected during the Community Meetings Swabs will be tested for HR-HPV DNA at Moi University using the Roche Cobas Assay Only women who have not previously participated in MISP I or II will be enrolled All women will be asked to travel to the Webuye Clinic for VIA and pelvic examination including careful inspection for AGWs Regardless of HIV status women with an abnormal positive VIA will undergo four-quadrant punch biopsy of the cervix 20 of women with normal negative VIA will also undergo cervical biopsy so that the sensitivity and specificity of HR-HPV testing and VIA can be determined using histologically proven CIN 23 as the gold standard
The investigators will enroll 2000 girls ages 9 through 14 into the study and administer the HPV vaccine at the community meetings The investigators have shown that vaccination is feasible in the community setting In the new study all women and girls will be asked to fill out questionnaires that will provide data about the educational aspects and overall acceptability of the MDP and obstacles related to its initiation In addition approximately 10 of women and girls will be interviewed at the end of the study to gain insights into the acceptability of the community-based program compared to the traditional methods of screening and vaccination The investigators wish to include the opinions and desires of the mothers and daughters in designing larger programs in the future This MISP if funded will help to build on current experiences as well as answering specific questions related to the hypotheses the investigators have proposed
Study strategies of the Mother Daughter Project MDP
Webuye is a community located in the western region of Kenya in Bungoma County on the highway to Uganda The total population of Webuye sub-county is approximately 25000 it is estimated that there are approximately 5000 to 6000 women between the ages of 30 and 55 years A community entry strategy has been utilized to introduce the prior studies and to invite women to community meetings Prior to study initiation a female Kenyan Counselor was trained about cervical cancer how to educate women about this malignancy and how to instruct women in performance of self-collected swabs Village chiefs village elders women deemed to be community leaders and leaders of the local churches were then approached by the Counselor and Study Coordinator to discuss the goals strategy and risks and benefits of the study Discussions have focused on the importance of early screening for cervical cancer the use of self-collected swabs for screening and vaccination of children against HPV
Community meetings and self-collected vaginal swabs
The Counselors will invite local women ages 30 through 55 years and their 9 through 14 year-old daughtersgrand-daughters to meetings in Webuye These meetings have been very successful approximately 30 to 40 women attend each meeting and many bring their daughters as well The instructional brochure that the investigators developed for the proper self-collection method available in both English and Swahili will again be shared with participants Women will obtain the swab in a private setting at the meeting Self-collected swabs will be gathered by the Counselor then a delivery person will transport the swabs dry no added medium at ambient temperature to Moi Teaching and Referral Hospital MTRH laboratories in Eldoret Kenya about 60 km away Swabs will be tested for HR-HPV DNA using the Roche Cobas Assay a test that provides specific HPV 16 or 18 detection as well as detection of any of 12 additional oncogenic types HPV types 31 33 35 39 45 51 52 56 58 59 66 68 Results of the Cobas Assay will be entered into a RedCap database that the investigators previously created for the first MISP Results of the Roche Cobas Assay will be delivered electronically to the Counselors tablet who will discuss these results with women at subsequent community meetings
VIA and cervical biopsy
All women will be asked to go to the Webuye Clinic for VIA which is the current standard of care for cervical cancer screening in Kenya Regardless of HIV status women with an abnormal positive VIA will undergo four-quadrant punch biopsy of the cervix 20 of women with normal negative VIA will also undergo cervical biopsy All women with abnormal VIA examinations will then be treated according to established local algorithms In the event of suspected cancer the participant will be sent to the Gynecologic Cancer Clinic at MTRH
In our vision for the future women will be triaged to the local clinic for VIA only if they have a positive Cobas Assay taking advantage of the high 99 negative predictive value of the Cobas Assay previously established in studies of HIV-uninfected women in the USA where the test is now FDA-approved for primary cervical cancer screening However the Roche Cobas Assay has not been adequately tested in HIV-infected women living in any country or in HIV-uninfected women living in sub-Saharan Africa utilizing self-collected vaginal swabs
Biopsy of AGWs
A pelvic examination will be performed and AGWs vulvar introital vaginal perineal perianal will be identified by clinical inspection A detailed anatomical chart will be utilized to document the location and size of suspected AGWs Women with lesions suspicious for AGW will be scheduled for gynecologist review If the gynecologist believes the lesions are consistent with AGW heshe will perform excision biopsy under local anesthesia with 1 lidocaine injected into the base of the lesion The entire lesion will be removed if smaller than 5 mm in diameter and the remaining lesions will be treated with cryotherapy per Kenya standard Following cleansing of the affected area lidocaine 1 will be injected into the base of the AGW the excision will be performed with sterile instruments generally scissors The sample will be place in buffered formalin and sent to the Pathology Department at Moi University where paraffin-embedded sections will be prepared One section from each biopsy specimen will be stained with hematoxylin and eosin for histological confirmation and additional sections will be used for DNA in situ hybridization assays Dako Laboratories or another suitable system using either a combined HPV 611 probe mix an HPV 1618 probe mix or an HPV 31333539455258 probe mix Sections will be scored positive or negative for each of the three probe mixes This work will likely be performed at Indiana University School of Medicine Indianapolis IN unless the investigators can train technicians at Moi University in this methodology
Follow-up visits for AGWs and cervical cancer screening
Women in the study who have AGWs biopsied and treated will be asked to return in six months to the Webuye Clinic to determine if warts have recurred Women will be asked to return to the Webuye Clinic for cervical cancer screening in one year if HIV-infected or in three years if HIV-uninfected
HPV vaccination of girls enrolled in the study
Women will be instructed at the community meetings in the efficacy safety and potential adverse effects of HPV vaccination Vaccination against HPV will be offered to girls 2000 in all ages 9 through 14 of women attending the community meetings The second dose of the HPV vaccine will be administered six to twelve months after the first dose at subsequent community meetings Careful records will be kept and all families will be given a record of the vaccine administration This is especially important because Kenya began a facility-based HPV vaccine program for 10 year-old girls in 2019 but few girls have been vaccinated to date Our approach is important because many girls will not be able to attend school to receive the vaccine or have the means to travel to local facilities for vaccination it is therefore important that community-based opportunities for vaccination are an option in Kenya In addition the government program vaccinates girls at age 10 and does not include 9-year-olds so our project will be important for these girls
Questionnaires
A detailed questionnaire in Swahili and English will be developed to 1 determine knowledge and beliefs of mothers about HPV and cervical cancer which will be administered at the beginning of the study and at the end of the study and 2 capture the opinions of mothers and daughters regarding all aspects of the program Mothers will be asked about the self-collected swabs travel to community meetings and the Clinic acceptability of HPV vaccination of daughters Daughters will be asked to answer questions related to vaccination how the community-based approach compared to a school-based program and other questions Children will fill out the questionnaire with help from their mothers
The aims of this project will be accomplished during a two-year period Key personnel will be trained in the first four months of the project The remainder of the first year and the second year will be devoted to community meetings vaccinations and VIA examinations AGW biopsy and treatments and follow up visits
The investigators Drs Brown Ermel Tong Tonui and Omenge will be responsible for analyzing the study data
Sample size consideration and analysis plan for Objective 1 Determine if High-Risk HR-HPV DNA testing of self-collected vaginal swabs collected in a community setting can be used as a triage step cervical cancer screening in HIV-infected Kenya women
Hypothesis HIV-infected women with negative HR-HPV DNA tests uniformly have either 1 normal VIA examinations or 2 falsely abnormal VIA examinations
The investigators will evaluate HR-HPV DNA testing of self-collected vaginal swabs as a triage step for VIA among HIV-infected rural Kenyan women Our hypothesis is that HIV-infected women with negative HR-HPV DNA tests will have normal VIA examinations or falsely-abnormal VIA examinations all women with abnormal VIA exams will undergo cervical biopsy
Sample size consideration The investigators will enroll 300 adult women in this study The investigators expect 30 90 women to be HIV-infected Of the 90 HIV-infected women the investigators expect 39 35 women to have a positive HR-HPV DNA test and 61 55 women to have a negative HR-HPV DNA test based on the data from the pilot study Of the 35 women with a positive HR-HPV DNA test the investigators expect that 30 11 women will have an abnormal VIA and of these 11 women 50 6 women will have biopsy proven CIN23 Of the 55 women with a negative HR-HPV DNA test the investigators expect that 4 2 women will have an abnormal VIA and of these 2 women 1 woman will have biopsy proven CIN 23 Thus the investigators expect among 90 HIV-infected women 17 women with positive HR-HPV DNA tests and 2 women with negative HR-HPV DNA tests will have biopsy proven CIN23
To analyze the test characteristics of HPV DNA testing of self-collected vaginal swabs the investigators will combine the data from the proposed sample of 300 women with the sample of 300 women that has been enrolled in the Merck Investigator Studies Program MISP II to a total sample of 600 women to test this hypothesis The enrollment and HPV DNA testing procedures are identical between the two studies which allows us to merge the two study populations to increase statistical power Of the 600 women the investigators expect 180 30 women to be HIV-infected Among the 180 HIV-infected women the investigators expect 70 women 39 to have a positive HR-HPV DNA test and among them 17 12 women to have biopsy proven CIN23 and 110 women 61 to have a negative HR-DNA test and among them 2 2 women to have biopsy proven CIN23
Our proposed sample size of 180 HIV-infected women 90 HIV-infected women from the current proposed sample of 300 women plus 90 HIV-infected women from the already enrolled 300 women in the MISP-II will provide 89 power to detect a significant difference in biopsy-proven CIN23 VIA abnormality between HR-HPV DNA positive and HR-HPV DNA negative HIV-infected women at a two-sided 005 significance level based on Fishers exact test
The investigators are requesting the HPV vaccine to vaccinate 2000 girls ages 9 through 14 two doses of vaccine will be required Thus the investigators request 4000 vaccine doses
Injection Site Reactions The protocol team should be contacted within 24 hours for any Grade 3 or 4 adverse experiences AE eg injection site reactions elevated temperatures following vaccination that occur at any point during study participation thought definitely possibly or probably related to vaccination Further vaccines should not be given to that participant prior to consultation with the Site Co- Investigator Dr Omenge Orango phone number 0722 609132 For injection reactions judged to be life-threatening the protocol team should be notified immediately The person receiving the vaccine should be brought to a clinic immediately for evaluation and treatment No additional vaccinations shall be given to that participant
Other Adverse Events
The following guidelines will be used for the management of AEs that are felt to be at least possibly related to vaccines
Grade 1 or 2 ToxicityAE Participants who develop a Grade 1 or 2 AE may continue study vaccine If a participant experiencing a Grade 1 or 2 AE chooses to permanently discontinue study treatment or study participation the AE will be documented
Grade 3 or 4 AE Participants who develop a Grade 3 or 4 AE that is at least possibly related to vaccine should be reevaluated for that toxicity until the AE returns to Grade 2 The study vaccine may be given at the discretion of the site investigator If the same Grade 3 or 4 AE recurs and is considered by the investigator to be possibly probably or definitely related to the study vaccine the study vaccine will be permanently discontinued If in the investigators opinion the AE has NOT been caused by the study vaccine or if the event is an asymptomatic laboratory abnormality study treatment may continue
Cryotherapy- and LEEP loop electro-excisional procedure-Related Complications These complications will be documented and reported to the PIs as well as Merck A brief summary of treatment for these complications is provided below
Vaginal Bleeding Bleeding post cervical biopsy will first be controlled with direct pressure using a dry swab If this is not sufficient then a swab with Monsels solution will be applied to stop the bleeding When postoperative bleeding occurs it usually appears 4-6 days after treatment and often from the posterior lip of cervix This bleeding can usually be controlled in the clinic by fulguration applying Monsels paste or using a silver nitrate applicator stick Rarely placement of a suture at the bleeding site is necessary The risk of post-treatment infection is very small and can likely be reduced even more by delaying surgical treatment until any woman with a likely diagnosis of pelvic inflammatory disease cervicitis vaginal trichomoniasis or bacterial vaginosis has been adequately treated and recovered
Vaginal Infection The chance of postoperative infection is lessened by 1 only performing cryotherapy or LEEP when there is no evidence of bacterial STIs sexually transmitted infections and 2 advising women to abstain from vaginal intercourse for 6 weeks post procedure
In addition participants are to be advised of the symptoms of infection and encouraged to return to the clinic if the symptoms occur If a participant presents postoperatively with a malodorous discharge it should be cultured if possible and empirical treatment prescribed with antibiotics that are effective for pelvic inflammatory disease
The investigators will utilize a modification of the basic framework developed for the previous MISP Merck Investigator-Initiated Studies Program grant that began in 2018 This framework was successfully implemented in a rural Kenya community setting and combines screening of adult women ages 30 through 55 using HPV DNA testing of self-vaginal swabs with HPV vaccination of daughters ages 9 through 14 years of mothers attending community meetings
Rationale for conducting the proposed study
Strategies based on centralized care have been unsuccessful in preventing cervical cancer in Kenyan women HR-HPV DNA testing of self-collected vaginal swabs is acceptable and feasible and the investigators have now shown that such testing can occur in a community setting in rural Kenya other groups have demonstrated similar successes in Africa In studies funded by MISP awards the investigators have shown that essentially all women invited to community meetings agreed to enroll in the studies to receive education about cervical cancer and to provide a self-collected vaginal swab for HR-HPV DNA testing Nearly all women who attended the community meetings were willing to have their female children vaccinated against HPV The investigators have also shown that HPV vaccine can be delivered to western Kenya and can be administered to girls in a community setting The investigators wish to continue to use this framework in the next MISP to further study the utility of this strategy and to address research questions that will elucidate the barriers to participation and will begin to provide information about the impact of the program
The reasons the investigators want to enroll additional women are as follows First the investigators would also like to evaluate the educational aspect of the Mother-Daughter Project among women and girls regarding to cervical cancer awareness and prevention knowledge Second the investigators would like to intensively study the acceptability of the community-based program and define the obstacles of the program among women who are newly enrolled The investigators will interview women and randomly selected children and ask them to fill out detailed questionnaires related to these issues Second although the investigators expected to be able to address the issue of sensitivity and specificity of HR-HPV testing compared to VIA in the first MISP MISP-I the investigators noted an unexpectedly low rate of abnormal VIA in the original 200 women cohort The second cohort of 300 women is still undergoing evaluation and the investigators do not yet know the incidence of abnormal VIA examinations Thus additional women need to be enrolled in a third wave to address this important question Third this program has benefited the community by providing a cancer prevention program that includes HPV vaccination to which they have previously not had access to This program has engendered trust between the local population and caregivers Lastly the investigators hope to submit a larger application to an organization such as the Gates Foundation or the NIH for a larger award of several years duration based on as much preliminary data as can be generated from this project The same rationale applies to our desire to vaccinate additional girls via the MISP mechanism The investigators have vaccinated 2000 girls to date and as part of the second MISP MISP-II Because aflatoxin exposure represents a potential public health problem that could thwart efforts to control HPV-associated malignancies the investigators will study the serological response to vaccination in girls with chronic aflatoxin exposure once they have completed the vaccine regimen
The investigators will study the prevalence HPV type distribution and treatment response of AGWs in adult women living in Kenya AGWs cause considerable morbidity in women especially those who are HIV-infected Few comprehensive studies are available in women living in sub-Saharan Africa The investigators and others have previously showed that HR-HPV are frequently detected in AGWs from immunosuppressed people in the United States including some people living with HIV The investigators will determine the prevalence of AGWs in women participating in the community based program and test the hypothesis that the prevalence of AGW will be considerably higher in HIV-infected women The investigators will also test the hypothesis that HR-HPV types will be frequently detected in AGW from HIV-infected women suggesting that AGWs are a reservoir for HR-HPV and transmission The investigators will also explore an objective related to treatment of AGWs to determine if a higher failure rate in HIV-infected women may be related to poor control of HIV a higher HIV viral load and detection of HR-HPV in the AGWs
Thus these aims build on the infrastructure the investigators have created in the first two MISP award cycles The investigators believe the MDP a community based approach to cervical cancer can become the standard for western Kenya act as a framework for HPV-associated cancer control and can lead to a significant improvement in patient care as well as providing an opportunity for hypothesis driven research
The investigators propose a hypothesis driven study that expands our novel community-based approach to cervical cancer eradication in Kenya The investigators plan to enroll 300 additional Kenyan women between the ages of 30 to 55 years Self-collected vaginal swabs will be collected during the Community Meetings Swabs will be tested for HR-HPV DNA at Moi University using the Roche Cobas Assay Only women who have not previously participated in MISP I or II will be enrolled All women will be asked to travel to the Webuye Clinic for VIA and pelvic examination including careful inspection for AGWs Regardless of HIV status women with an abnormal positive VIA will undergo four-quadrant punch biopsy of the cervix 20 of women with normal negative VIA will also undergo cervical biopsy so that the sensitivity and specificity of HR-HPV testing and VIA can be determined using histologically proven CIN 23 as the gold standard
The investigators will enroll 2000 girls ages 9 through 14 into the study and administer the HPV vaccine at the community meetings The investigators have shown that vaccination is feasible in the community setting In the new study all women and girls will be asked to fill out questionnaires that will provide data about the educational aspects and overall acceptability of the MDP and obstacles related to its initiation In addition approximately 10 of women and girls will be interviewed at the end of the study to gain insights into the acceptability of the community-based program compared to the traditional methods of screening and vaccination The investigators wish to include the opinions and desires of the mothers and daughters in designing larger programs in the future This MISP if funded will help to build on current experiences as well as answering specific questions related to the hypotheses the investigators have proposed
Study strategies of the Mother Daughter Project MDP
Webuye is a community located in the western region of Kenya in Bungoma County on the highway to Uganda The total population of Webuye sub-county is approximately 25000 it is estimated that there are approximately 5000 to 6000 women between the ages of 30 and 55 years A community entry strategy has been utilized to introduce the prior studies and to invite women to community meetings Prior to study initiation a female Kenyan Counselor was trained about cervical cancer how to educate women about this malignancy and how to instruct women in performance of self-collected swabs Village chiefs village elders women deemed to be community leaders and leaders of the local churches were then approached by the Counselor and Study Coordinator to discuss the goals strategy and risks and benefits of the study Discussions have focused on the importance of early screening for cervical cancer the use of self-collected swabs for screening and vaccination of children against HPV
Community meetings and self-collected vaginal swabs
The Counselors will invite local women ages 30 through 55 years and their 9 through 14 year-old daughtersgrand-daughters to meetings in Webuye These meetings have been very successful approximately 30 to 40 women attend each meeting and many bring their daughters as well The instructional brochure that the investigators developed for the proper self-collection method available in both English and Swahili will again be shared with participants Women will obtain the swab in a private setting at the meeting Self-collected swabs will be gathered by the Counselor then a delivery person will transport the swabs dry no added medium at ambient temperature to Moi Teaching and Referral Hospital MTRH laboratories in Eldoret Kenya about 60 km away Swabs will be tested for HR-HPV DNA using the Roche Cobas Assay a test that provides specific HPV 16 or 18 detection as well as detection of any of 12 additional oncogenic types HPV types 31 33 35 39 45 51 52 56 58 59 66 68 Results of the Cobas Assay will be entered into a RedCap database that the investigators previously created for the first MISP Results of the Roche Cobas Assay will be delivered electronically to the Counselors tablet who will discuss these results with women at subsequent community meetings
VIA and cervical biopsy
All women will be asked to go to the Webuye Clinic for VIA which is the current standard of care for cervical cancer screening in Kenya Regardless of HIV status women with an abnormal positive VIA will undergo four-quadrant punch biopsy of the cervix 20 of women with normal negative VIA will also undergo cervical biopsy All women with abnormal VIA examinations will then be treated according to established local algorithms In the event of suspected cancer the participant will be sent to the Gynecologic Cancer Clinic at MTRH
In our vision for the future women will be triaged to the local clinic for VIA only if they have a positive Cobas Assay taking advantage of the high 99 negative predictive value of the Cobas Assay previously established in studies of HIV-uninfected women in the USA where the test is now FDA-approved for primary cervical cancer screening However the Roche Cobas Assay has not been adequately tested in HIV-infected women living in any country or in HIV-uninfected women living in sub-Saharan Africa utilizing self-collected vaginal swabs
Biopsy of AGWs
A pelvic examination will be performed and AGWs vulvar introital vaginal perineal perianal will be identified by clinical inspection A detailed anatomical chart will be utilized to document the location and size of suspected AGWs Women with lesions suspicious for AGW will be scheduled for gynecologist review If the gynecologist believes the lesions are consistent with AGW heshe will perform excision biopsy under local anesthesia with 1 lidocaine injected into the base of the lesion The entire lesion will be removed if smaller than 5 mm in diameter and the remaining lesions will be treated with cryotherapy per Kenya standard Following cleansing of the affected area lidocaine 1 will be injected into the base of the AGW the excision will be performed with sterile instruments generally scissors The sample will be place in buffered formalin and sent to the Pathology Department at Moi University where paraffin-embedded sections will be prepared One section from each biopsy specimen will be stained with hematoxylin and eosin for histological confirmation and additional sections will be used for DNA in situ hybridization assays Dako Laboratories or another suitable system using either a combined HPV 611 probe mix an HPV 1618 probe mix or an HPV 31333539455258 probe mix Sections will be scored positive or negative for each of the three probe mixes This work will likely be performed at Indiana University School of Medicine Indianapolis IN unless the investigators can train technicians at Moi University in this methodology
Follow-up visits for AGWs and cervical cancer screening
Women in the study who have AGWs biopsied and treated will be asked to return in six months to the Webuye Clinic to determine if warts have recurred Women will be asked to return to the Webuye Clinic for cervical cancer screening in one year if HIV-infected or in three years if HIV-uninfected
HPV vaccination of girls enrolled in the study
Women will be instructed at the community meetings in the efficacy safety and potential adverse effects of HPV vaccination Vaccination against HPV will be offered to girls 2000 in all ages 9 through 14 of women attending the community meetings The second dose of the HPV vaccine will be administered six to twelve months after the first dose at subsequent community meetings Careful records will be kept and all families will be given a record of the vaccine administration This is especially important because Kenya began a facility-based HPV vaccine program for 10 year-old girls in 2019 but few girls have been vaccinated to date Our approach is important because many girls will not be able to attend school to receive the vaccine or have the means to travel to local facilities for vaccination it is therefore important that community-based opportunities for vaccination are an option in Kenya In addition the government program vaccinates girls at age 10 and does not include 9-year-olds so our project will be important for these girls
Questionnaires
A detailed questionnaire in Swahili and English will be developed to 1 determine knowledge and beliefs of mothers about HPV and cervical cancer which will be administered at the beginning of the study and at the end of the study and 2 capture the opinions of mothers and daughters regarding all aspects of the program Mothers will be asked about the self-collected swabs travel to community meetings and the Clinic acceptability of HPV vaccination of daughters Daughters will be asked to answer questions related to vaccination how the community-based approach compared to a school-based program and other questions Children will fill out the questionnaire with help from their mothers
The aims of this project will be accomplished during a two-year period Key personnel will be trained in the first four months of the project The remainder of the first year and the second year will be devoted to community meetings vaccinations and VIA examinations AGW biopsy and treatments and follow up visits
The investigators Drs Brown Ermel Tong Tonui and Omenge will be responsible for analyzing the study data
Sample size consideration and analysis plan for Objective 1 Determine if High-Risk HR-HPV DNA testing of self-collected vaginal swabs collected in a community setting can be used as a triage step cervical cancer screening in HIV-infected Kenya women
Hypothesis HIV-infected women with negative HR-HPV DNA tests uniformly have either 1 normal VIA examinations or 2 falsely abnormal VIA examinations
The investigators will evaluate HR-HPV DNA testing of self-collected vaginal swabs as a triage step for VIA among HIV-infected rural Kenyan women Our hypothesis is that HIV-infected women with negative HR-HPV DNA tests will have normal VIA examinations or falsely-abnormal VIA examinations all women with abnormal VIA exams will undergo cervical biopsy
Sample size consideration The investigators will enroll 300 adult women in this study The investigators expect 30 90 women to be HIV-infected Of the 90 HIV-infected women the investigators expect 39 35 women to have a positive HR-HPV DNA test and 61 55 women to have a negative HR-HPV DNA test based on the data from the pilot study Of the 35 women with a positive HR-HPV DNA test the investigators expect that 30 11 women will have an abnormal VIA and of these 11 women 50 6 women will have biopsy proven CIN23 Of the 55 women with a negative HR-HPV DNA test the investigators expect that 4 2 women will have an abnormal VIA and of these 2 women 1 woman will have biopsy proven CIN 23 Thus the investigators expect among 90 HIV-infected women 17 women with positive HR-HPV DNA tests and 2 women with negative HR-HPV DNA tests will have biopsy proven CIN23
To analyze the test characteristics of HPV DNA testing of self-collected vaginal swabs the investigators will combine the data from the proposed sample of 300 women with the sample of 300 women that has been enrolled in the Merck Investigator Studies Program MISP II to a total sample of 600 women to test this hypothesis The enrollment and HPV DNA testing procedures are identical between the two studies which allows us to merge the two study populations to increase statistical power Of the 600 women the investigators expect 180 30 women to be HIV-infected Among the 180 HIV-infected women the investigators expect 70 women 39 to have a positive HR-HPV DNA test and among them 17 12 women to have biopsy proven CIN23 and 110 women 61 to have a negative HR-DNA test and among them 2 2 women to have biopsy proven CIN23
Our proposed sample size of 180 HIV-infected women 90 HIV-infected women from the current proposed sample of 300 women plus 90 HIV-infected women from the already enrolled 300 women in the MISP-II will provide 89 power to detect a significant difference in biopsy-proven CIN23 VIA abnormality between HR-HPV DNA positive and HR-HPV DNA negative HIV-infected women at a two-sided 005 significance level based on Fishers exact test
The investigators are requesting the HPV vaccine to vaccinate 2000 girls ages 9 through 14 two doses of vaccine will be required Thus the investigators request 4000 vaccine doses
Injection Site Reactions The protocol team should be contacted within 24 hours for any Grade 3 or 4 adverse experiences AE eg injection site reactions elevated temperatures following vaccination that occur at any point during study participation thought definitely possibly or probably related to vaccination Further vaccines should not be given to that participant prior to consultation with the Site Co- Investigator Dr Omenge Orango phone number 0722 609132 For injection reactions judged to be life-threatening the protocol team should be notified immediately The person receiving the vaccine should be brought to a clinic immediately for evaluation and treatment No additional vaccinations shall be given to that participant
Other Adverse Events
The following guidelines will be used for the management of AEs that are felt to be at least possibly related to vaccines
Grade 1 or 2 ToxicityAE Participants who develop a Grade 1 or 2 AE may continue study vaccine If a participant experiencing a Grade 1 or 2 AE chooses to permanently discontinue study treatment or study participation the AE will be documented
Grade 3 or 4 AE Participants who develop a Grade 3 or 4 AE that is at least possibly related to vaccine should be reevaluated for that toxicity until the AE returns to Grade 2 The study vaccine may be given at the discretion of the site investigator If the same Grade 3 or 4 AE recurs and is considered by the investigator to be possibly probably or definitely related to the study vaccine the study vaccine will be permanently discontinued If in the investigators opinion the AE has NOT been caused by the study vaccine or if the event is an asymptomatic laboratory abnormality study treatment may continue
Cryotherapy- and LEEP loop electro-excisional procedure-Related Complications These complications will be documented and reported to the PIs as well as Merck A brief summary of treatment for these complications is provided below
Vaginal Bleeding Bleeding post cervical biopsy will first be controlled with direct pressure using a dry swab If this is not sufficient then a swab with Monsels solution will be applied to stop the bleeding When postoperative bleeding occurs it usually appears 4-6 days after treatment and often from the posterior lip of cervix This bleeding can usually be controlled in the clinic by fulguration applying Monsels paste or using a silver nitrate applicator stick Rarely placement of a suture at the bleeding site is necessary The risk of post-treatment infection is very small and can likely be reduced even more by delaying surgical treatment until any woman with a likely diagnosis of pelvic inflammatory disease cervicitis vaginal trichomoniasis or bacterial vaginosis has been adequately treated and recovered
Vaginal Infection The chance of postoperative infection is lessened by 1 only performing cryotherapy or LEEP when there is no evidence of bacterial STIs sexually transmitted infections and 2 advising women to abstain from vaginal intercourse for 6 weeks post procedure
In addition participants are to be advised of the symptoms of infection and encouraged to return to the clinic if the symptoms occur If a participant presents postoperatively with a malodorous discharge it should be cultured if possible and empirical treatment prescribed with antibiotics that are effective for pelvic inflammatory disease
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None