Randomised trial of HPV vaccination for the control of HPV-related diseases in HIV-positive African populations: Preparatory phase (PH01/14-39)

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

The development & rollout of bivalent, quadrivalent and nonavalent vaccines against high-risk oncogenic human papillomavirus (HPV) affords a tremendous opportunity to control and possibly eradicate the cancer with the highest incidence among female populations in Africa. Currently, HPV vaccines are recommended for use among sexually unexperienced women, typically young girls aged 14 years or younger, leaving a huge female population unprotected and at risk of developing cervical cancer and other HPV related diseases (genital warts, other genital & oropharyngeal cancers), for which few affordable and implementable screening options are available in resource-poor settings. The HPV vaccines afford high protection against the types they target, with some element of cross-protection against other genotypes, but it is assumed that no protection is offered if subjects have been infected by a vaccine type.

HIV+ women are at increased risk of acquisition and persistence of HPV leading on to the development of cervical cancer and other genital disease. We have conducted a study (called HARP) evaluating the performance of cervical cancer screening strategies among 1200 HIV+ women in South Africa (SA) and Burkina Faso (BF), which included HPV screening. We have found a huge burden of cervical precancer lesions (20% in SA, 5% on BF) and of high-risk HPV infection (>70% in SA, 55% in BF). We have recorded a good performance of HPV testing alone or in combination with cytology to detect these lesions. We would like to build upon this rich data source and the successful implementation of this study through the development of a clinical trial platform to develop the next phase of HARP, which will centre on the role of HPV control through screening and vaccination. We propose to develop a proposal for a randomised trial of HPV vaccination among HIV+ women to prevent cervical cancer lesions. There is currently no data on the efficacy of an HPV vaccine among HIV+ women, although a few trials have shown the safety and immunogenicity of the bivalent HPV vaccine in HIV+ populations, including one trial among SA women. The recent announcement by the SA government of the introduction of HPV vaccination countrywide offers the opportunity to explore the role of HPV vaccination in various sub groups.

The proposed study, in preparation of the vaccine trial, will assess the potential effectiveness and cost-effectiveness of HPV vaccination embedded in an HPV screening programme in reducing the incidence of HPV-related infection and disease (CIN, ano-genital warts) in the target populations. It will investigate the response to vaccination depending on HIV related factors (plasma viral load/CD4 count/antiretroviral therapy status) and HPV related factors (current infection as determined by presence of HPV in the genital tract, or prior exposure as determined by HPV serology) on various trial outcomes (histological, cytological and virological). Finally, it will investigate the potential acceptability of such trial.

Specifically, the PHINDS proposal will inform the development of an HPV vaccine study among HIV+ women in SA by:
1) Estimating the potential impact and sample size required for a vaccination study among HIV+ women recruited within a cervical cancer screening programme based on HPV testing (HARP study). Statistical & modelling methodology will be employed, using HARP & another Johannesburg based study datasets.
2) Evaluating the true exposure of the study population to HPV vaccine types by combining results of HPV genotyping (already done) & type-specific HPV serology (to be done).
3) Evaluating the feasibility, acceptability & costs of HPV vaccination in the target population, service providers & other national stakeholders.
4) Setting up a research network to implement the study through the recently awarded NIH Clinical Trials Unit at University of Witwatersrand, Johannesburg

Technical Summary

Vaccines against HPV hold great promise for the long term prevention of cervical cancer & anogenital warts (AGW). Two vaccines targeting the most frequent genotypes involved in the aetiology of cervical cancer (HPV16/18) & AGW (HPV6/11), in bivalent & quadrivalent forms, have been licensed. A nonavalent vaccine covering 90% of cancer types is being evaluated. HPV vaccination programmes typically target young girls. However, the relevance of extending vaccination to other groups, e.g. HIV+ women, is of public health importance since they are at higher risk of HPV infection, persistence & disease progression. Cervical cancer screening programmes can identify HIV+ women in need of CIN management treatment & prevention through vaccination. Although HPV vaccines have been shown to be safe & immunogenic in HIV+ populations in South Africa (SA), data is lacking on their efficacy against CIN & AGW. Our hypothesis is that HPV vaccination can decrease the incidence of HPV-related disease among HIV+ African women. The goal is to determine the likely effectiveness of adding vaccination to an HPV-based screening programme among HIV+ women in SA to inform the design of a phase III/IV individually randomized trial of the effectiveness of vaccination against CIN2+ & AGW endpoints. We will test HPV serology in stored serum samples taken from SA study cohorts that have also measured cervical HPV DNA & CIN prevalence & incidence to examine current & prior exposure to vaccine preventable HPV genotypes. The data will contribute to estimate & model the fraction of vaccine preventable types & the expected vaccine effectiveness with a bi/quadri/nonavalent vaccine against CIN2+, AGW & persistent HPV, & determine key trial parameters (e.g. sample size, trial duration, frequency of visits, eligibility criteria). We will also extend the analysis to predict the effectiveness on cancers prevented among HIV+ women. Qualitative research will determine the feasibility & acceptability of the trial.

Publications

10 25 50

publication icon
Kelly H (2015) Concomitant Infection of HIV and HPV: What Are the Consequences? in Current Obstetrics and Gynecology Reports

 
Description National SA Cervical cancer screening policy
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact In South Africa, Wits RHI have been engaging with the National Department of Health (NDOH) for many years on the issue of cervical cancer screening and prevention (including through vaccination). During a DFID-funded research Consortium (2005-2010), we conducted a national level consultation with DOH and the Deputy Minister at the time in defining the research agenda that would be required to support the introduction and evaluation of HPV vaccination in the country. A number of research projects have been written which then led to the collection of data that have increased the awareness of policy makers and service providers to the need for improved cervical cancer screening in the country. Since then, senior researchers from Wits RHI have been providing direct inputs into Policy/Guidelines for screening of cervical cancer, which influence practitioners. 2016 guidelines are currently being revised utilising research outputs from the HARP Study (direct head to head comparison of cervical cancer screening methods among HIV+ women conducted between 2010-14). This will result in improvements of clinical service delivery, increases in detection rates and hopefully decreases in cervical-cancer morbidity and mortality. Other findings from our research have highlighted the need, feasibility and acceptability to provide HPV vaccination to girls, as well as potentially other groups such as older women, HIV+ women, boys and men (HIM study 2009-2014). As a result, the NDOH has contracted Wits RHI to undertake an evaluation of the Pilot study of HPV vaccination of young girls in KwaZulu Natal (2014/15). The recommendations will serve to improve the vaccination campaign at national level with potentially huge benefits regarding decreased incidence of cervical cancer and thus economic and societal impacts. As part of the PHINDS study (2014/15), we have engaged with the Deputy Director of NDOH on the trial design fo an HPV vaccination study among HIV+ women in Johannesburg. The DD has provided support to the study, which has now been submitted for GHT funding (2016). I am revising the policy document as we speak (it's open on my computer) but because it is not yet published we don't have a weblink. Our names are in the list of advisory committee members that contributed
 
Description AFRAVIH Conference 2016
Amount £900 (GBP)
Organisation Francophone Alliance of Health Actors against HIV (AFRAVIH) 
Sector Charity/Non Profit
Country France
Start 04/2016 
End 04/2016
 
Description CANSA grant
Amount R 250,000 (ZAR)
Organisation Cancer Association of South Africa 
Sector Charity/Non Profit
Country South Africa
Start  
 
Description CARTA PhD fellowship
Amount $100,000 (USD)
Organisation Consortium for Advanced Research Training in Africa 
Sector Public
Country Kenya
Start  
 
Description International HPV Conference 2015 travel award
Amount £740 (GBP)
Organisation International Papillomavirus Society 
Sector Charity/Non Profit
Country Unknown
Start 09/2015 
End 09/2015
 
Description Marie Curie Fellowship
Amount € 100,000 (EUR)
Organisation Marie Curie 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 08/2024
 
Title Modelling 
Description Mathematical modelling to predict effect of HPV vaccination in HIV+ women Development and evaluation of different algorithms to assess attribution /contribution of different HPV genotypes to cervical intraepithelial neoplasia in HIV+ women 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Mathematical modelling was used in the PHINDS study by the team at Imperial College to inform the design of a clinical trial of HPV vaccination among HIV+ women. It has informed on the choice of trial outcomes; the size of impact with several epidemiological assumptions; the duration of follow-up; the choice of vaccine for the maximise effectiveness. This was used directly for the Research proposal submitted to GHT in 2016 and will also be submitted as manuscript for publication. As part of this work, some developmental work was required to update/modify algorithms for attribution of HPV genotypes to cervical intraepithelial neoplasia in HIV+ women. This is leading to a manuscript for publication.. 
 
Title Modelling impact of HPV vaccination 
Description This is reported in the Research Tools and Methods section 
Type Of Material Computer model/algorithm 
Provided To Others? No  
Impact This is reported in the Research Tools and Methods section 
 
Description CAB Feedback 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Wits RHI in Johannesburg have organised feedback to CAB (Community Advisory Board) on findings from HARP study (cervical cancer screening) and follow up PHINDS study (preparation for HPV vaccination)
Year(s) Of Engagement Activity 2015
 
Description Community Radio Programme 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Wits RHI have organised 4 radio sessions with the Alexandra Community Radio station in Johannesburg to disseminate information about the high prevalence of CIN2+ disease in the population, encourage women to undergo pap smear testing and the importance of adhering to the follow-up appointments for further treatment.
Year(s) Of Engagement Activity 2015