Electronic health records to capture primary outcome measures: two case studies in HIV prevention research.

BACKGROUND: There is increasing interest in the use of electronic health records (EHRs) to improve the efficiency and cost-effectiveness of clinical trials, including the capture of outcome measures. MAIN TEXT: We describe our experience of using EHRs to capture the primary outcome measure - HIV infection or the diagnosis of HIV infection - in two randomised HIV prevention trials conducted in the UK. PROUD was a clinic-based trial evaluating pre-exposure prophylaxis (PrEP), and SELPHI was an internet-based trial evaluating HIV self-testing kits. The EHR was the national database of HIV diagnoses in the UK, curated by the UK Health Security Agency (UKHSA). In PROUD, linkage to the UKHSA database was performed at the end of the trial and identified five primary outcomes in addition to the 30 outcomes diagnosed by the participating clinics. Linkage also produced an additional 345 person-years follow-up, an increase of 27% over clinic-based follow-up. In SELPHI, new HIV diagnoses were primarily identified via UKHSA linkage, complemented by participant self-report through internet surveys. Rates of survey completion were low, and only 14 of the 33 new diagnoses recorded in the UKHSA database were also self-reported. Thus UKHSA linkage was essential for capturing HIV diagnoses and the successful conduct of the trial. CONCLUSIONS: Our experience of using the UKHSA database of HIV diagnoses as a source of primary outcomes in two randomised trials in the field of HIV prevention was highly favourable and encourages the use of a similar approach in future trials in this disease area.

"PROUD to have been involved": an evaluation of participant and community involvement in the PROUD HIV prevention trial.

BACKGROUND: The PROUD trial, a HIV prevention trial in men who have sex with men and trans women, set out to involve community representatives and trial participants in several ways. PROUD also aimed to evaluate participant involvement, to learn lessons and make recommendations for future clinical trials. METHODS: Two structured surveys, one of participant and community representatives involved in the PROUD study, and the other of researchers from the PROUD team, were carried out in 2017. The results from the surveys were reviewed quantitatively and qualitatively, and themes emerging from the data identified and synthesised. RESULTS: Survey invitations were sent to 88 involved participants, 11 community representatives and 10 researchers. The overall response rate was 55% (60/109). Overall, participants were younger than community representatives, and the majority were from Greater London. As expected, participants were predominantly involved in participant involvement meetings and community representatives in management committees.Participants and community representatives cited different motivations for getting involved in PROUD. Overall, participants were positive about their involvement; only two participants rated their experience unfavourably. Community representatives were also broadly positive. Most participants and all community representatives felt their involvement made a difference to the trial, themselves and / or the organisations they represented. However, some participant answers reflected the impact of participation in the trial rather than involvement in PPI activities.Researchers felt that PPI had positive impact across the entire trial cycle. Half felt they would have liked there to have been more PPI activity in PROUD. Researchers noted some challenges and recommendations for the future, including need for adequate funding, more engagement in PPI by all researchers, the need for PPI expertise to facilitate involvement activities and training and mentoring in PPI. CONCLUSIONS: Involving clinical trial participants and wider community representatives as active partners in PPI is feasible and valuable in trials. Researchers are encouraged to consider and appropriately resource participant involvement and prospectively evaluate all PPI within their trials.

The Context of Sexual Risk Behaviour Among Men Who Have Sex with Men Seeking PrEP, and the Impact of PrEP on Sexual Behaviour.

There are still important gaps in our understanding of how people will incorporate PrEP into their existing HIV prevention strategies. In this paper, we explore how PrEP use impacted existing sexual risk behaviours and risk reduction strategies using qualitative data from the PROUD study. From February 2014 to January 2016, we conducted 41 in-depth interviews with gay, bisexual and other men who have sex with men (GBMSM) enrolled in the PROUD PrEP study at sexual health clinics in England. The interviews were conducted in English and were audio-recorded. The recordings were transcribed, coded and analysed using framework analysis. In the interviews, we explored participants' sexual behaviour before joining the study and among those using or who had used PrEP, changes to sexual behaviour after starting PrEP. Participants described the risk behaviour and management strategies before using PrEP, which included irregular condom use, sero-sorting, and strategic positioning. Participants described their sexual risk taking before initiating PrEP in the context of the sexualised use of drugs, geographical spaces linked with higher risk sexual norms, and digitised sexual networking, as well as problematic psychological factors that exacerbated risk taking. The findings highlight that in the main, individuals who were already having frequent condomless sex, added PrEP to the existing range of risk management strategies, influencing the boundaries of the 'rules' for some but not all. While approximately half the participants reduced other risk reduction strategies after starting PrEP, the other half did not alter their behaviours. PrEP provided an additional HIV prevention option to a cohort of GBMSM at high risk of HIV due to inconsistent use of other prevention options. In summary, PrEP provides a critical and necessary additional HIV prevention option that individuals can add to existing strategies in order to enhance protection, at least from HIV. As a daily pill, PrEP offers protection in the context of the sex cultures associated with sexualised drug use, digitised sexual applications and shifting social norms around sexual fulfilment and risk taking. PrEP can offer short or longer-term options for individuals as their sexual desires change over their life course offering protection from HIV during periods of heightened risk. PrEP should not be perceived or positioned in opposition to the existing HIV prevention toolkit, but rather as additive and as a tool that can and is having a substantial impact on HIV.

Acceptability of an open-label wait-listed trial design: Experiences from the PROUD PrEP study.

BACKGROUND: PROUD participants were randomly assigned to receive pre-exposure prophylaxis (PrEP) immediately or after a deferred period of one-year. We report on the acceptability of this open-label wait-listed trial design. METHODS: Participants completed an acceptability questionnaire, which included categorical study acceptability data and free-text data on most and least liked aspects of the study. We also conducted in-depth interviews (IDI) with a purposely selected sub-sample of participants. RESULTS: Acceptability questionnaires were completed by 76% (415/544) of participants. After controlling for age, immediate-group participants were almost twice as likely as deferred-group participants to complete the questionnaire (AOR:1.86;95%CI:1.24,2.81). In quantitative data, the majority of participants in both groups found the wait-listed design acceptable when measured by satisfaction of joining the study, intention to remain in the study, and interest in joining a subsequent study. However, three-quarters thought that the chance of being in the deferred-group might put other volunteers off joining the study. In free-text responses, data collection tools were the most frequently reported least liked aspect of the study. A fifth of deferred participants reported 'being deferred' as the thing they least liked about the study. However, more deferred participants disliked the data collection tools than the fact that they had to wait a year to access PrEP. Participants in the IDIs had a good understanding of the rationale for the open-label wait-listed study design. Most accepted the design but acknowledged they were, or would have been, disappointed to be randomised to the deferred group. Five of the 25 participants interviewed reported some objection to the wait-listed design. CONCLUSION: The quantitative and qualitative findings suggest that in an environment where PrEP was not available, the rationale for the wait-listed trial design was well understood and generally acceptable to most participants in this study.

Comparative Immunogenicity of HIV-1 gp140 Vaccine Delivered by Parenteral, and Mucosal Routes in Female Volunteers; MUCOVAC2, A Randomized Two Centre Study.

BACKGROUND: Defining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses. METHODS: In this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel. RESULTS: Three IM immunizations of CN54 gp140 at either 20 or 100 µg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization. CONCLUSIONS: These data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming. CLINICAL TRIALS REGISTRATION: EudraCT 2010-019103-27 and the UK Clinical Research Network (UKCRN) Number 11679.

EV02: a Phase I trial to compare the safety and immunogenicity of HIV DNA-C prime-NYVAC-C boost to NYVAC-C alone.

The aim of this randomised controlled trial was to see if the addition of 4 mg/ml DNA-C priming given by the intramuscular route at weeks 0 and 4 to NYVAC-C at weeks 20 and 24, safely increased the proportion of participants with HIV-specific T-cell responses measured by the interferon (IFN)-gamma ELISpot assay at weeks 26 and/or 28 compared to NYVAC-C alone. Although 2 individuals discontinued after the first DNA-C due to adverse events (1 vaso-vagal; 1 transient, asymptomatic elevation in alanine transaminase), the vaccines were well tolerated. Three others failed to complete the regimen (1 changed her mind; 2 lost to follow-up). Of the 35 that completed the regimen 90% (18/20) in the DNA-C group had ELISpot responses compared to 33% (5/15) that received NYVAC-C alone (p=0.001). Responses were to envelope in the majority (21/23). Of the 9 individuals with responses to envelope and other peptides, 8 were in the DNA-C group. These promising results suggest that DNA-C was an effective priming agent, that merits further investigation.