Simulated Vaccine Efficacy Trials Research Articles

Feasibility of conducting HIV prevention trials among key populations in Nairobi, Kenya

ObjectiveTo assess the feasibility of conducting HIV prevention trials among key populations in Nairobi, Kenya.BackgroundHIV prevention trials require the inclusion of those at high risk of HIV infection and their informed decision to take part and remain in the clinical trial to the end is crucial. In Kenya key populations including men who have sex with men (MSM) and female sex workers (FSW) are, disproportionately, at high risk of HIV infection when compared to the general population. Few trials testing biomedical prevention products against HIV have enrolled Kenyan FSW and MSM.MethodsWe performed simulated vaccine efficacy trial (SiVET) using licensed hepatitis B vaccines as substitutes for a HIV vaccine candidate and included randomization for those immune to hep B. The SiVET was an observational study designed to mimic the rigors of a clinical trial; we assessed HIV risk, provided risk counselling and prevention tools and performed HIV testing at baseline and periodically until the end of the trial. MSM and FSW were enrolled at a ratio of 4:1. Volunteers were assigned to either hepatitis B vaccine or placebo.ResultsRecruitment took approximately 24 months between Sep 2015 and Sep 2017. Of the 368 volunteers screened, 250 (200 MSM and 50 FSW) were enrolled. Reasons for exclusion at screening included: being positive for HIV (n = 7), hepatitis (n = 14), other pre-existing medical conditions (n = 41), eligible but chose not to enrol (n = 47). Most of the volunteers adhered to study procedures and attended their study visits within the study window. These include volunteers who received the second vaccination 244 (98%), the third vaccination 228 (91%) and, the final study visit 217 (87%). The reasons volunteers discontinued from the study early included: relocation and loss to follow up (n = 14). A total of 8 cases of HIV infection were observed in 174.5 Person Years at Risk (PYAR), all among MSM, including 5 seroconversions identified at the last study visit, for a HIV incidence of 4.58 cases/ 100 PYAR, among MSM enrolled in the study.ConclusionOur findings suggest that it is possible to conduct HIV prevention trials among key populations in Nairobi with a good adherence to a vaccine efficacy trial schedule. Despite HIV prevention efforts, we also noted a high incidence of HIV infection. This demonstrates the need for effective HIV prevention products in these populations.

Use of propensity score matching to create counterfactual group to assess potential HIV prevention interventions

The design of HIV prevention trials in the context of effective HIV preventive methods is a challenge. Alternate designs, including using non-randomised ‘observational control arms’ have been proposed. We used HIV simulated vaccine efficacy trials (SiVETs) to show pitfalls that may arise from using such observational controls and suggest how to conduct the analysis in the face of the pitfalls. Two SiVETs were nested within previously established observational cohorts of fisherfolk (FF) and female sex workers (FSW) in Uganda. SiVET participants received a licensed Hepatitis B vaccine in a schedule (0, 1 and 6 months) similar to that for a possible HIV vaccine efficacy trial. All participants received HIV counselling and testing every quarter for one year to assess HIV incidence rate ratio (IRR) between SiVET and non-SiVET (observational data). Propensity scores, conditional on baseline characteristics were calculated for SiVET participation and matched between SiVET and non-SiVET in the period before and during the SiVET study. We compared IRR before and after propensity score matching (PSM). In total, 3989 participants were enrolled into observational cohorts prior to SiVET, (1575 FF prior to Jul 2012 and 2414 FSW prior to Aug 2014). SiVET enrolled 572 participants (Jul 2012 to Apr 2014 in FF and Aug 2014 to Apr 2017 in FSW), with 953 non-SiVET participants observed in the SiVET concurrent period and 2928 from the pre-SiVET period (before Jul 2012 in FF or before Apr 2014 in FSW). Imbalances in baseline characteristics were observed between SiVET and non-SiVET participants in both periods before PSM. Similarly, HIV incidence was lower in SiVET than non-SiVET; SiVET-concurrent period, IRR = 0.59, 95% CI 0.31–0.68, p = 0.033 and pre-SiVET period, IRR = 0.77, 95% CI 0.43–1.29, p = 0.161. After PSM, participants baseline characteristics were comparable and there were minimal differences in HIV incidence between SiVET and non-SiVET participants. The process of screening for eligibility for efficacy trial selects participants with baseline characteristics different from the source population, confounding any observed differences in HIV incidence. Propensity score matching can be a useful tool to adjust the imbalance in the measured participants’ baseline characteristics creating a counterfactual group to estimate the effect of interventions on HIV incidence.

Willingness of female sex workers in Kampala, Uganda to participate in future HIV vaccine trials: a case control study

BackgroundWe anticipate large efficacy trials of novel HIV vaccines that have shown acceptable safety profiles. We determined willingness to participate (WTP) in future HIV vaccine efficacy trials among HIV negative female sex workers (FSWs) in Kampala Uganda.MethodsWe conducted a case control study in the Good Health for Women Project cohort. Cases received HIV prevention services and, enrolled in a 12-month simulated vaccine efficacy trial (SiVET) that used Hepatitis B vaccine; they underwent vaccine trial procedures as would be in an actual trial. Controls received similar health services but did not enroll in SiVET. We matched cases and controls (ratio 2:1) for age and duration in the cohort. We described a hypothetical HIV vaccine trial to cases (after 9 months in SiVET) and controls including trial attributes: randomization, delaying pregnancy, frequent blood draws (80-100mls) and study visits for 3 years. We compared WTP and willingness for vaccine trial attributes by case/control using chi-squared or Fisher’s exact tests and fitted conditional logistic regression models to determine independent predictors of WTP.ResultsWe analyzed data for 311 volunteers (219 cases, 92 controls); median age 27 years (IQR: 23–32), 39.9% had ≥secondary education, 57.9% had sex work as their main job and 81.9% used illicit drugs. Compared to controls, more cases had lived in the community for > 1 year, (85.4% vs 64.1%; p < 0.001) and fewer cases reported illicit drug use in the past 3 months, (79.0% vs 89.1%; p = 0.03). Overall, 278 (89.4%) volunteers expressed WTP in an HIV vaccine trial, the most common reason being hope of protection against HIV. More cases than controls (58.2% vs 44.7%) did not need to consult anyone before trial participation (p = 0.03); cases were more willing to delay pregnancy (99.0% vs 94.0%; p = 0.03). Combining vaccine trial attributes, 249 (89.6%) of the 278 accepted all attributes. After controlling for case/ control status women with secondary education or higher expressed less WTP (aOR 0.17; 95% CI 0.04–0.80).ConclusionFSWs in Kampala demonstrated high WTP. Prior experience with trial requirements like contraception may improve their uptake during actual trials. Family involvement is important for those without prior trial experience.

Willingness to participate in future HIV vaccine trials among men who have sex with men and female sex workers living in Nairobi, Kenya.

To evaluate factors associated with willingness to participate in future HIV vaccine trials among men who have sex with men and female sex workers living in Nairobi, Kenya. Working with 'key populations', those at elevated risk of HIV acquisition, is important to conduct efficient HIV prevention trials. In Nairobi Kenya, HIV infection is higher in men who have sex with men (MSM) and female sex workers (FSW) than in the general adult population, hence the need to establish if they would be willing to participate in future HIV vaccine trials. We administered a structured questionnaire to MSM and FSW enrolled in a simulated vaccine efficacy trial (SiVET). The SiVET was an observational study designed to mimic the rigors of a clinical trial to assess HIV risk characteristics at baseline. After 12-15 months of follow-up, a structured questionnaire was administered to evaluate hypothetical willingness to participate in future HIV vaccine trials. Of 250 persons (80% MSM by design) enrolled in SiVET, 214 attended the final study visit and 174 (81%) of them expressed hypothetical willingness to participate in future HIV vaccine trials. These were 82% of MSM and 80% of FSW of those who attended the final study visit. Having a very good experience in the SiVET trial predicted willingness to participate in future HIV vaccine trials. Motivating factors for participation included a desire to receive education about HIV (59%) and to receive healthcare (57%). Our data demonstrate high willingness among key populations in Kenya, to participate in future HIV vaccine trials after completing participation in a SiVET. The findings suggest that these groups might be a reliable target population for consideration in future HIV vaccine trials. Assessment of willingness to participate in these populations provides important information that may help to inform future education and recruitment efforts for vaccine trials. Improving the research experience for members of key populations could impact their willingness to participate in HIV vaccine trials.

Comparison of HIV Risk Behaviors Between Clinical Trials and Observational Cohorts in Uganda

Many key populations have high-risk behaviors for HIV infection making them suitable for HIV vaccine efficacy trials. However, these behaviors may change when participants enroll into a trial. We used HIV simulated vaccine efficacy trials (SiVETs) nested within observational cohorts of fisherfolks and female sex workers in Uganda to evaluate this difference. We screened observational cohort participants for enrolment into SiVETs, until 572 were enrolled. Those not enrolled (n = 953) continued participation in the observational cohorts. We determined risk behaviors at baseline and at 1 year, assigned a numeric score to each behavior and defined composite score as the sum of reported behaviors. We compared changes in scores over 12 months. Both observational cohorts and SiVETs saw a significant decrease in score but greatest in the SiVETs. Investigators recruiting for trials from these populations should consider the likely effect of reduction in risk behaviors on incident HIV infection and trial statistical power.

Factors associated with vaccination completion and retention among HIV negative female sex workers enrolled in a simulated vaccine efficacy trial in Kampala, Uganda

BackgroundFemale sex workers (FSWs) at substantial risk of HIV are potentially a suitable group for HIV prevention trials including vaccine trials. Few HIV vaccine preparatory studies have been conducted among FSWs in Sub-Saharan Africa (SSA); data are therefore limited on acceptability of vaccine trial procedures. We determined vaccination completion and one-year retention among FSWs in Kampala, Uganda.MethodsWe conducted a prospective study that simulated a vaccine efficacy trial among HIV negative FSWs (18–49 years). Hepatitis B vaccine (Engerix B) was used to mimic an HIV vaccine product. Volunteers received 1 ml intramuscular injection at 0, 1 and 6 months, and made additional visits (3 days post-vaccination and months 3, 9 and 12). They were censored at that visit if diagnosed as HIV positive or pregnant. We collected socio-demographic, behavioral and clinical data at baseline, 6 and 12 months and fitted Poisson regression models with robust standard error to find factors associated with vaccination completion and retention.ResultsWe enrolled 290 volunteers (median age 27 years) of whom 230 reached a study end-point as follows: 7 became HIV infected, 11 became pregnant and 212 completed both the vaccination schedule and 12-month visit giving a retention of 77.9% (212/272). Vaccination completion was 82.4%.Non-retention at 1 year was more likely among those reporting symptoms of genital ulcer disease (GUD) in the past 3 months (IRR 1.90; 95% CI 1.09–3.32) and those < 35 years; (IRR 6.59; 95% CI 2.11–20.57). Non-completion of the vaccination schedule was associated with being < 35 years (IRR 13.10; 95% CI 1.89–90.92, reporting GUD symptoms (IRR 3.02; 95% CI 1.71–5.33) and reporting consistent condom use with new sexual partners (IRR 2.57; 95% CI 1.10–6.07).ConclusionsFSWs are at substantial risk of HIV infection and yet willing to participate in HIV vaccine and prevention research; young FSWs should be empowered, and those reporting GUD symptoms need close follow up to improve participation in future HIV vaccine trials.

Simulated vaccine efficacy trials to estimate HIV incidence for actual vaccine clinical trials in key populations in Uganda

BackgroundFisherfolks (FF) and female sex workers (FSW) in Uganda could be suitable key populations for HIV vaccine efficacy trials because of the high HIV incidence and good retention in observational cohorts. However, the observed HIV incidence may differ in participants who enroll into a trial. We used simulated vaccine efficacy trials (SiVET) nested within observational cohorts in these populations to evaluate this difference. MethodsSiVETs were nested in two observational cohorts (Jul 2012–Apr 2014 in FF and Aug 2014–Apr 2017 in FSW). From Jan 2012 all observational cohort participants (aged 18–49 years) presenting for quarterly visits were screened for enrolment into SiVETs, until 572 were enrolled. Those not enrolled (screened-out or not screened) in SiVET continued participation in the observational cohorts. In addition to procedures in the observational cohorts (HIV testing & risk assessment), SiVET participants were given a licensed Hepatitis B vaccine mimicking a schedule of a possible HIV vaccine, and followed-up for 12 months. FindingsIn total, 3989 participants were enrolled into observational cohorts (1575 FF prior to Jul 2012 and 2414 FSW prior to Aug 2014). Of these 3622 (90.8%) returned at least once, 672 (44.1%) were screened and 572 enrolled in the SiVETs. HIV incidence pre SIVETs was 4.5/100 person years-at-risk (pyar), 95%CI (3.8–5.5). HIV incidence in SiVET was 3.5/100 pyar, (2.2–5.6) and higher in those not enrolled in the SiVET, 5.9/100 pyar, (4.3–8.1). This difference was greatest among FF. In the 12 months post-SIVET period (FF, May 2014–Apr 2015 and FSW, May 2017–Apr 2018), the HIV incidence was 3.7/100 pyar, (2.5–5.8). InterpretationHIV incidence was lower in SiVET participants compared to non-SiVET. This difference was different for the two populations. Researchers designing HIV efficacy trials using observational cohort data need to consider the potential for lower than expected HIV incidence following screening and enrolment.

Simulated Vaccine Efficacy Trials to Estimate HIV Incidence for Actual Vaccine Clinical Trials in Key Populations in Uganda

Simulated Vaccine Efficacy Trials to Estimate HIV Incidence for Actual Vaccine Clinical Trials in Key Populations in Uganda

Comparison of HIV incidence estimated in clinical trial and observational cohort settings in a high risk fishing population in Uganda: Implications for sample size estimates

BackgroundClinical trial participants may differ from the source population due to the demands of trial participation and self-selection, inadvertent selection of a lower-risk group, or both. We investigated the HIV risk status of volunteers in a Simulated Vaccine Efficacy Trial (SiVET) nested within a prospective observational cohort of fisher folks in South Western Uganda. MethodsVolunteers aged 18–49 years, at high risk for HIV from fishing communities in Masaka district were recruited into an observational cohort and followed quarterly. High risk was defined as a self-report, of at least one of the following in the past three months; sexually transmitted infections, unprotected sex with >1 partner or a new sexual partner, use of recreational drugs, weekly alcohol use, and/or frequent travel. Volunteers who had at least three months of follow-up in the observational cohort were consecutively enrolled in SiVET, administered Hepatitis B vaccine at months (0, 1, 6) and followed-up three days post vaccinations to mimic a vaccine trial schedule. HIV incidence over the next 12 months was compared between SiVET and the observational cohort studies. ResultsBetween January 2012 and February 2013, 575 individuals were enrolled in the observational cohort, of whom 282 were enrolled in SiVET between July 2012 and February 2013. Despite similar pattern of reported risk behaviour in both studies, HIV incidence was higher in observational cohort, 11.4 cases/100 PYO [95% CI: 7.4–17.7] compared to 3.8 [95% CI: 2.0–7.0] in SiVET (p<0.01). SiVET volunteers tended to be men, having some education and longer-term residents, all factors that are also associated with lower HIV risk. ConclusionWe observed a lower HIV incidence in SiVET than in the observational cohort. The two populations differed significantly in demographics but not in reported risk. HIV incidence estimates from observational cohorts must be used with caution to estimate the trial study size.

Participation of Individuals from Fishing Communities in a Simulated Vaccine Efficacy Trial in Preparation for Future HIV Prevention Work

AIDS Research and Human RetrovirusesVol. 30, No. S1 Product Acceptability and AdherenceParticipation of Individuals from Fishing Communities in a Simulated Vaccine Efficacy Trial in Preparation for Future HIV Prevention WorkGershim Asiki, Andrew Abaasa, Ubaldo Bahemuka, Jerry Mulondo, Freddie Kibengo, Eugene Ruzagira, Anatoli Kamali, and Pat FastGershim AsikiMedical Research Council/Uganda Virus Research Institute, Entebbe, UgandaSearch for more papers by this author, Andrew AbaasaMedical Research Council/Uganda Virus Research Institute, Entebbe, UgandaSearch for more papers by this author, Ubaldo BahemukaMedical Research Council/Uganda Virus Research Institute, Entebbe, UgandaSearch for more papers by this author, Jerry MulondoMedical Research Council/Uganda Virus Research Institute, Entebbe, UgandaSearch for more papers by this author, Freddie KibengoMedical Research Council/Uganda Virus Research Institute, Entebbe, UgandaSearch for more papers by this author, Eugene RuzagiraMedical Research Council/Uganda Virus Research Institute, Entebbe, UgandaSearch for more papers by this author, Anatoli KamaliMedical Research Council/Uganda Virus Research Institute, Entebbe, UgandaSearch for more papers by this author, and Pat FastInternational AIDS Vaccine Initiative, New York, NY, United StatesSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5338.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Participation of Individuals from Fishing Communities in a Simulated Vaccine Efficacy Trial in Preparation for Future HIV Prevention Work." AIDS Research and Human Retroviruses, 30(S1), p. A163FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Gershim Asiki, Andrew Abaasa, Ubaldo Bahemuka, Jerry Mulondo, Freddie Kibengo, Eugene Ruzagira, Anatoli Kamali, and Pat Fast.Participation of Individuals from Fishing Communities in a Simulated Vaccine Efficacy Trial in Preparation for Future HIV Prevention Work.AIDS Research and Human Retroviruses.Oct 2014.A163-A163.http://doi.org/10.1089/aid.2014.5338.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Functional inference in semiparametric models using the piggyback bootstrap

This paper introduces the “piggyback bootstrap.” Like the weighted bootstrap, this bootstrap procedure can be used to generate random draws that approximate the joint sampling distribution of the parametric and nonparametric maximum likelihood estimators in various semiparametric models, but the dimension of the maximization problem for each bootstrapped likelihood is smaller. This reduction results in significant computational savings in comparison to the weighted bootstrap. The procedure can be stated quite simply. First obtain a valid random draw for the parametric component of the model. Then take the draw for the nonparametric component to be the maximizer of the weighted bootstrap likelihood with the parametric component fixed at the parametric draw. We prove the procedure is valid for a class of semiparametric models that includes frailty regression models airsing in survival analysis and biased sampling models that have application to vaccine efficacy trials. Bootstrap confidence sets from the piggyback, and weighted bootstraps are compared for biased sampling data from simulated vaccine efficacy trials.