Design: SiVETs nested within longitudinal observational cohorts of fisherfolk (FF) and female sex worker (FSW) in Uganda.
Setting: The fisherfolk observational cohorts (OBC) recruited from fishing communities on the shoreline of Lake Victoria in Entebbe and Masaka, about 40 kilometers South and 100 kilometers West of Kampala, Uganda’s capital respectively and the SiVET in this population was nested in the OBC in Masaka. The main economic activity is fishing but other occupations such as fish processing, small-scale businesses, entertainment etc. support the fishing activity. This population is characterised by very high HIV prevalence, 20-30% [18] and annual incidence, 3-11% [19], with more than 50% reporting frequent high risk sexual behaviour [20].
The FSW population’s OBC was located within Kampala city; on Mengo hill near the Kampala city center. Women in sex work operate from HIV hotspots defined as nightclubs, entertainment facilities, restaurants/hotel, lodges and bars conducive for meeting male clients. Similarly, the prevalence and annual incidence of HIV are reported to be very high 37% [21] and 3% [8] respectively and > 90% of these women report frequent high risk sexual behaviour [20].
Description of OBCs
Data from three OBCs; two-FF and one-FSW conducted respectively from February 2009 to April 2015 and from April 2008-April 2017 were used in this analysis, Figure1. In the first FF cohort (February 2009 to December 2011), study staff provided HIV counselling and testing (HCT) to potential participants and those found to be HIV negative, aged 18-49 years were enrolled into an OBC at a clinic established in each of five participating fishing communities. Repeat HCT was performed every 6-months for 18 months. The primary aims of this OBC was to determine the feasibility of enrolling and following FF in an observational cohort and to determine HIV incidence. The second FF cohort, (January 2012 to April 2015) was similar to the first FF cohort with the following exceptions: (i) participants had to travel from the landing sites to the research clinic in Masaka Town, a distance of approximately 40km, to attend study visits; (ii) repeat HCT was conducted quarterly; (iii) extra aim of maintaining a pool of participants for future HIV prevention trials.
The FSW cohort initially recruited women from one administrative (Makindye) division of Kampala city until 2014 when the protocol was amended to include all the city’s five divisions. Trained study fieldworkers visited HIV hotspots, provided study information to prospective participants, and invited them to the study clinic for screening and possible enrolment. At the clinic, women received HCT and those found to be HIV negative were enrolled. The aims of this cohort and participant follow up schedules were similar to those of the second FF cohort above. Details of the FF & FSW cohorts have been published previously [8, 19, 21-23].
Description of SiVETs
To prepare the research teams for the rigors of clinical trials, SiVETs were nested in the OBCs described above (one in each of FF and FSW), administering hepatitis B vaccine (ENGERIX-BTM GlaxoSmithKline Biologicals Rixensart, Belgium) as a proxy for an experimental HIV vaccine. Participants that had been enrolled in the OBCs ≥ 3 months and ≤ 18 months were consecutively screened and enrolled into SiVET, from July 2012 to April 2014 in the second FF cohort and from August 2014 to April 2017 in the FSW cohort. SiVET participants received a Hepatitis B vaccine injection at 0, 1 and 6 months mimicking a possible schedule for an actual HIV vaccine efficacy trial. They also underwent HCT every quarter for one year. SiVETs details have also been previously published [22, 24].
Data stratification: We divided the OBC data into two periods (a) the Pre-SiVET OBC (non-SiVET data) made up of enrollment and follow up data before rollout of the SiVET protocol in both the FF and FSW communities and (b) the SiVET concurrent OBC (non-SiVET data); comprising all the data collected in the 12 months of OBC in the SiVET period, mutually exclusive, Figure 1.
Key evaluations
(i) We compared baseline characteristics of the participants in the SiVET to those in OBC (non-SiVET cohort); (a) in the pre-SiVET period, (b) in the SiVET period, all before PSM.
(ii) Repeated evaluation (i) above after PSM.
(iii) We compared HIV incidence in the SiVET to that in the non-SiVET; (c) in the pre-SiVET period, (d) in the SiVET period, all before PSM.
(iv) Repeated evaluation (iii) above after PSM.
HIV testing: Largely, HIV testing was performed using a single antibody rapid test by Alere Determine TM HIV-1/2 (Alere Medical Co Ltd, Matsuhidai, Matsudo-shi, Chiba, Japan). Samples that turned out positive underwent a confirmation test using two parallel enzyme linked immunosorbent assay (ELISA) tests (Murex Biotech Limited, Dartford, United Kingdom, and Vironostika, BioMérieux boxtel, The Netherlands). Discordant HIV results were confirmed by either Statpak (Chembio Diagnostic Systems Inc., USA) or Western Blot (Cambridge Biotech, USA).
Data management and statistical methods
Observational cohort data and SiVET in the FF were captured in MS Access 2003 database (Microsoft Corporation, Redmond, WA), while SiVET data in the FSW were managed using OpenClinica 3.5 (Waltham, MA). All data were analysed in STATA 15.0 (Stata Corp, College Station, TX, USA). The OBC datasets were stratified into two periods, (i) non-SiVET (OBC) in the pre-SiVET period; data collected from the date of initiation of OBC to the date of initiation of SiVET protocol in a given source population (FF or FSW). (ii) non-SiVET (OBC) in the SiVET concurrent; data collected from the date SiVET began enrolling to the date of the last SiVET participant clinic visit.
Variable categorizations: We categorized source population as fisherfolk (FF) or female sex work (FSW), religion categorized as Christian (including Catholic, Anglicans, Pentecostals, seventh day Adventists) or Muslims, Marital status categorized as single never married (if one has never lived with a partner in any sexual relationship) or currently/previously married (including married polygamous, monogamous, widowed or separated).
Calculating the PS: Logit models, in which SiVET assignment status was regressed on measured baseline characteristics were fitted to determine the propensity scores (probability of selection into SiVET conditional on measured baseline characteristics) stratified by period (pre-SiVET or SiVET concurrent). We matched on the following variables; source population, sex, age group, ethnicity, education level, marital status, duration of stay in the community, number of sexual partners in the last three months and alcohol use. We performed 1:1 PSM without replacement within a caliper width of 0.2 between SiVET and non-SiVET in the pre-SiVET, and in the SiVET concurrent periods to ensure a balance in baseline characteristics. Matching using a caliper width of 0.2 of the pooled standard deviation of the logit of the propensity score is considered to afford superior performance in the estimation of treatment effects [25]. We considered less than 20% difference in covariates after matching as indicative of good matching [26]. Participants in SiVET for whom there was no match in the non-SiVET OBCs were excluded from the PS matched analysis. We used Chi-square tests to compare the baseline characteristics of participants in SiVET to those in OBCs before and after PSM stratified by the period. We estimated the standardized differences before and after PSM comparing covariate values for participants in SiVET to those in non-SiVET in either period and illustrated these graphically. We compared HIV incidence between SiVET and non-SiVET in each period before and after PSM. HIV incidence was determined as number of HIV positive cases divided by person years at risk (PYAR) expressed as per 100 PYAR. PYAR were calculated as sum of the time from study specific participant enrolment date to the date of the last HIV seronegative result or an estimated date of HIV infection. The date of HIV infection was defined as a random (multiple imputation) date between last HIV-negative and the first HIV-positive result dates.