Sheena McCormack

A mixed methods and triangulation model for increasing the accuracy of adherence and sexual behaviour data: the Microbicides Development Programme

Background The collection of accurate data on adherence and sexual behaviour is crucial in microbicide (and other HIV-related) research. In the absence of a “gold standard” the collection of such data relies largely on participant self-reporting. After reviewing available methods, this paper describes a mixed method/triangulation model for generating more accurate data on adherence and sexual behaviour in a multi-centre vaginal microbicide clinical trial. In a companion paper some of the results from this model are presented [1]. Methodology/Principal Findings Data were collected from a random subsample of 725 women (7.7% of the trial population) using structured interviews, coital diaries, in-depth interviews, counting returned gel applicators, focus group discussions, and ethnography. The core of the model was a customised, semi-structured in-depth interview. There were two levels of triangulation: first, discrepancies between data from the questionnaires, diaries, in-depth interviews and applicator returns were identified, discussed with participants and, to a large extent, resolved; second, results from individual participants were related to more general data emerging from the focus group discussions and ethnography. A democratic and equitable collaboration between clinical trialists and qualitative social scientists facilitated the success of the model, as did the preparatory studies preceding the trial. The process revealed some of the underlying assumptions and routinised practices in “clinical trial culture” that are potentially detrimental to the collection of accurate data, as well as some of the shortcomings of large qualitative studies, and pointed to some potential solutions. Conclusions/Significance The integration of qualitative social science and the use of mixed methods and triangulation in clinical trials are feasible, and can reveal (and resolve) inaccuracies in data on adherence and sensitive behaviours, as well as illuminating aspects of “trial culture” that may also affect data accuracy.

Microbicide clinical trial adherence: insights for introduction.

After two decades of microbicide clinical trials it remains uncertain if vaginally‐ delivered products will be clearly shown to reduce the risk of HIV infection in women and girls. Furthermore, a microbicide product with demonstrated clinical efficacy must be used correctly and consistently if it is to prevent infection. Information on adherence that can be gleaned from microbicide trials is relevant for future microbicide safety and efficacy trials, pre‐licensure implementation trials, Phase IV post‐marketing research, and microbicide introduction and delivery. Drawing primarily from data and experience that has emerged from the large‐scale microbicide efficacy trials completed to‐date, the paper identifies six broad areas of adherence lessons learned: (1) Adherence measurement in clinical trials, (2) Comprehension of use instructions/Instructions for use, (3) Unknown efficacy and its effect on adherence/Messages regarding effectiveness, (4) Partner influence on use, (5) Retention and continuation and (6) Generalizability of trial participants adherence behavior. Each is discussed, with examples provided from microbicide trials. For each of these adherence topics, recommendations are provided for using trial findings to prepare for future microbicide safety and efficacy trials, Phase IV post‐marketing research, and microbicide introduction and delivery programs.

Microbicides in HIV prevention

In 1999 about 5.4 million people were newly infected with HIV.1 In some countries public health programmes have achieved modest gains in reducing HIV transmission through behavioural change, but the worldwide picture is one of increasing rates of infection. Although the use of condoms has slowly increased in countries most severely affected by the HIV epidemic, many vulnerable women are unable to ensure they are used. An effective and affordable vaginal microbicide, whose use could be controlled by women, would represent an important addition to the armamentarium against HIV infection. In this article we examine current progress in microbicide development and discuss their future role in HIV control.nnWe searched Medline using the key words and phrases “microbicides,” “virucides,” and “vaginal microbicides.” We also obtained the latest product information from the Alliance for Microbicide Development (P Harrison, personal communication),2 and we asked scientific colleagues involved in microbicide research for their comments on products in preclinical development.nnMicrobicides act by disrupting or disabling organisms or block their entry into host cells by interfering with cell surface receptors. Chemical agents have a long history in the control of sexually transmitted infections and fertility. Penile antiseptics were widely promoted for controlling sexually transmitted disease in both world wars, although their efficacy and effectiveness remain uncertain.3 Intravaginal spermicides have been marketed for decades but have had limited popularity in the era of more reliable contraceptive methods.nnThe development of microbicides has drawn on existing contraceptive technology to develop safe, effective, acceptable, and accessible agents. As with HIV vaccines, progress with the development of effective microbicides has been slow, and the results of early trials of surfactants such as nonoxinol 9 were disappointing. The Microbicides 2000 conference in Washington, DC, provided new impetus to develop such compounds, and several promising products are …

Assessing the Accuracy of Adherence and Sexual Behaviour Data in the MDP301 Vaginal Microbicides Trial Using a Mixed Methods and Triangulation Model

Background Accurate data on adherence and sexual behaviour are crucial in microbicide (and other HIV-related) research. In the absence of a “gold standard” the collection of such data relies largely on participant self-reporting. The Microbicides Development Programme has developed a mixed method/triangulation model for generating more accurate data on adherence and sexual behaviour. Methodology/Principal Findings Data were collected from a random subsample of 725 women using structured case record form (CRF) interviews, coital diaries (CD) and in-depth interviews (IDI). Returned used and unused gel applicators were counted and additional data collected through focus group discussions and ethnography. The model is described in detail in a companion paper [1]. When CRF, CD and IDI are compared there is some inconsistency with regard to reporting of sexual behaviour, gel or condom use in more than half. Inaccuracies are least prevalent in the IDI and most prevalent in the CRF, where participants tend to under-report frequency of sex and gel and condom use. Women reported more sex, gel and condom use than their partners. IDI data on adherence match the applicator-return data more closely than the CRF. The main reasons for inaccuracies are participants forgetting, interviewer error, desirability bias, problems with the definition and delineation of key concepts (e.g. “sex act”). Most inaccuracies were unintentional and could be rectified during data collection. Conclusions/Significance The CRF – the main source of self-report data on behaviour and adherence in many studies – was the least accurate with regard to measuring sexual behaviour, gel and condom use. This has important implications for the use of structured questionnaires for the collection of data on sexual behaviour and adherence. Integrating in-depth interviews and triangulation into clinical trials could increase the richness and accuracy of behavioural and adherence data.

HIV prevention research: taking stock and the way forward.

Previous papers in this supplement have reviewed the evidence of the effectiveness of alternative HIV prevention methods from randomized controlled trials and other studies. This paper draws together the main conclusions from these reviews. A conceptual framework is presented that maps the proximal and distal determinants of sexual HIV transmission and helps to identify the stages in the causal pathway at which each intervention approach acts. The advances, gaps and challenges emerging from the reviews of individual intervention methods are summarized and cross-cutting themes identified. Approximately 90% of HIV prevention trials have found no effect on HIV incidence and we explore the alternative explanations for the large number of ‘flat’ trials. We conclude that there is no single explanation for these flat results, which may be due to interventions that are ineffective or inappropriately targeted or implemented, or to factors related to the design or conduct of trials. We examine the lessons from these flat results and provide recommendations on what should be done differently in future trials. HIV prevention remains of critical importance in an era of expanded delivery of antiretroviral therapy. In future HIV prevention research, it is important that resources are used as efficiently as possible to provide rigorous evidence of the effectiveness of a wider array of complementary prevention tools.

The potential for central monitoring techniques to replace on-site monitoring: findings from an international multi-centre clinical trial

Background Compliance with Good Clinical Practice (GCP) guidelines should ensure the safety of trial participants and the reliability of trial results. Over the last decade, increasing emphasis has been placed on the role of costly on-site monitoring and source data verification as processes to demonstrate that GCP is being followed, despite a lack of empirical evidence that these are effective. Purpose To assess whether findings from on-site monitoring of a recent international multi-centre clinical trial could have been identified using central data review and other centralised monitoring techniques. Methods Findings documented in a sample of site monitoring reports, and Programme Management Board Executive (PMBe) reports, from the Microbicides Development Programme (MDP) 301 trial – a randomised placebo-controlled trial of a microbicide gel to prevent vaginally acquired HIV infection conducted in four countries in East and Southern Africa – were extracted and individually assessed to determine whether they could have been detected in the trial database or through other central means. Results Four site visit reports contained 268 monitoring findings from a review of 104 participant files covering 324 study visits. Of the 268 findings, 76 (28.4%) were also identified in the study database. Central checks, had these been in place (such as central receipt and review of back-translated documents, enrolment and testing logs, informed consent, and more complex database queries), could have identified a further 179 (66.8%); 13 (4.9%) other findings (all minor) could have been identified through a review of the participant folder at site. The four PMBe reports reviewed included six major and three critical findings from a review of over 1000 participant files: only two of these (both major) were assessed as unlikely to be identified using central monitoring techniques. Limitations The study data used were not collected with this retrospective review in mind. It suggests that prospective work is needed to compare monitoring practices in real time. Conclusions While there may be some categories of findings that it is not possible to identify centrally, the very large majority of findings reviewed in this analysis could be identified using central monitoring strategies. These data suggest that with better central and targeted on-site monitoring, it should be possible to identify and address most protocol and procedural compliance issues without performing intensive and costly routine on-site data monitoring.

How informed is consent in vulnerable populations? Experience using a continuous consent process during the MDP301 vaginal microbicide trial in Mwanza, Tanzania

BackgroundHIV prevention trials conducted among disadvantaged vulnerable at-risk populations in developing countries present unique ethical dilemmas. A key concern in bioethics is the validity of informed consent for trial participation obtained from research subjects in such settings. The purpose of this study was to investigate the effectiveness of a continuous informed consent process adopted during the MDP301 phase III vaginal microbicide trial in Mwanza, Tanzania.MethodsA total of 1146 women at increased risk of HIV acquisition working as alcohol and food vendors or in bars, restaurants, hotels and guesthouses have been recruited into the MDP301 phase III efficacy and safety trial in Mwanza. During preparations for the trial, participatory community research methods were used to develop a locally-appropriate pictorial flipchart in order to convey key messages about the trial to potential participants. Pre-recorded audio tapes were also developed to facilitate understanding and compliance with gel-use instructions. A comprehension checklist is administered by clinical staff to all participants at screening, enrolment, 12, 24, 40 and 50 week follow-up visits during the trial. To investigate womens perceptions and experiences of the trial, including how well participants internalize and retain key messages provided through a continuous informed consent process, a random sub-sample of 102 women were invited to participate in in-depth interviews (IDIs) conducted immediately after their 4, 24 and 52 week follow-up visits.Results99 women completed interviews at 4-weeks, 83 at 24-weeks, and 74 at 52 weeks (a total of 256 interviews). In all interviews there was evidence of good comprehension and retention of key trial messages including that the gel is not currently know to be effective against HIV; that this is the key reason for conducting the trial; and that women should stop using gel in the event of pregnancy.ConclusionsProviding information to trial participants in a focussed, locally-appropriate manner, using methods developed in consultation with the community, and within a continuous informed-consent framework resulted in high levels of comprehension and message retention in this setting. This approach may represent a model for researchers conducting HIV prevention trials among other vulnerable populations in resource-poor settings.Trial registrationCurrent Controlled Trials ISRCTN64716212

HIV Incidence Among Non-Pregnant Women Living in Selected Rural, Semi-Rural and Urban Areas in Kwazulu-Natal, South Africa

The province of KwaZulu-Natal has the highest prevalence of HIV in South Africa, particularly among young women. In order to more closely examine the HIV prevalence and incidence in non-pregnant women from rural, semi-rural and urban areas, data from 5,753 women screened for enrolment into three HIV prevention studies were combined and analysed. The prevalence of HIV infection was 43% at screening. HIV incidence among the 2,523 enrolled HIV-negative women was determined every quarter, and sexual behaviour and socio-demographic data were collected as per respective protocols. During follow-up, 211 women seroconverted (6.6/100 women years). Multivariate analysis found that seroconversion rates were highest among women who were ≤24xa0years old, single and not cohabiting, and who had incident sexually transmitted infections. The epidemic in KwaZulu-Natal calls for targeted HIV prevention interventions among those at highest risk of acquiring or transmitting infection.

Controlling the HIV Epidemic with Antiretrovirals IAPAC Consensus Statement on Treatment as Prevention and Preexposure Prophylaxis

In the context of emerging evidence related to preexposure prophylaxis and HIV treatment as prevention, an evidence summit was held in mid-2012 to discuss the current state of the science and to provide a platform for consensus building around whether and how these prevention strategies might be implemented globally. Health care providers, researchers, policy makers, people living with HIV/AIDS, and representatives of government authorities, donor agencies, pharmaceutical companies, advocacy organizations, and professional associations attended from 52 countries. An international advisory committee was convened to identify key messages and recommendations based upon the data presented and discussed at the summit. The advisory committee further worked to develop this consensus statement meant to assist relevant stakeholders in taking stock and mapping out a route forward to enhance the HIV prevention armamentarium.

Microbicides development programme: engaging the community in the standard of care debate in a vaginal microbicide trial in Mwanza, Tanzania

BackgroundHIV prevention research in resource-limited countries is associated with a variety of ethical dilemmas. Key amongst these is the question of what constitutes an appropriate standard of health care (SoC) for participants in HIV prevention trials. This paper describes a community-focused approach to develop a locally-appropriate SoC in the context of a phase III vaginal microbicide trial in Mwanza City, northwest Tanzania.MethodsA mobile community-based sexual and reproductive health service for women working as informal food vendors or in traditional and modern bars, restaurants, hotels and guesthouses has been established in 10 city wards. Wards were divided into geographical clusters and community representatives elected at cluster and ward level. A city-level Community Advisory Committee (CAC) with representatives from each ward has been established. Workshops and community meetings at ward and city-level have explored project-related concerns using tools adapted from participatory learning and action techniques e.g. chapati diagrams, pair-wise ranking. Secondary stakeholders representing local public-sector and non-governmental health and social care providers have formed a trial Stakeholders Advisory Group (SAG), which includes two CAC representatives.ResultsKey recommendations from participatory community workshops, CAC and SAG meetings conducted in the first year of the trial relate to the quality and range of clinic services provided at study clinics as well as broader standard of care issues. Recommendations have included streamlining clinic services to reduce waiting times, expanding services to include the children and spouses of participants and providing care for common local conditions such as malaria. Participants, community representatives and stakeholders felt there was an ethical obligation to ensure effective access to antiretroviral drugs and to provide supportive community-based care for women identified as HIV positive during the trial. This obligation includes ensuring sustainable, post-trial access to these services. Post-trial access to an effective vaginal microbicide was also felt to be a moral imperative.ConclusionParticipatory methodologies enabled effective partnerships between researchers, participant representatives and community stakeholders to be developed and facilitated local dialogue and consensus on what constitutes a locally-appropriate standard of care in the context of a vaginal microbicide trial in this setting.Trial registrationCurrent Controlled Trials ISRCTN64716212