Lauren L. Katzen

Acceptability in microbicide and PrEP trials: Current status and a reconceptualization:

Purpose of reviewAssessment of acceptability is a central component of most oral PrEP and microbicide trials. In this paper we review current definitions and frameworks employed in acceptability research, discuss findings from recent studies of product acceptability and summarize trends in acceptability research. We conclude by offering a new framework for investigating product acceptability within clinical trials, one which considers product acceptability to be conceptually distinct from adherence. Recent findingsAlthough numerous studies have investigated product acceptability, a consensus is lacking regarding the definition and operationalization of the concept. In addition fewer than half of the studies reviewed investigated actual candidate products. To the extent that an overall measure of acceptability is considered, the consensus is that most participants find the products acceptable. However, it is the rare study that investigates whether product adherence is associated with acceptability. SummaryGiven that adherence is critical to the success of clinical trials, it is important to identify the extent to which acceptability is a factor in product usage and to ascertain which dimensions of acceptability – product attributes, dosing regimen, delivery mechanism, use attributes, partners attitudes, effect of product on the sexual encounter, product-related norms – if any, affect adherence.

Validation of a dye stain assay for vaginally inserted hydroxyethylcellulose-filled microbicide applicators.

Background: The reliability and validity of self-reports of vaginal microbicide use are questionable given the explicit understanding that participants are expected to comply with study protocols. Our objective was to optimize the use of Population Councils previously validated dye stain assay (DSA) and related procedures, and to establish predictive values for the DSAs ability to identify vaginally inserted single-use, low-density polyethylene microbicide applicators filled with hydroxyethylcellulose gel. Methods: Applicators, inserted by 252 female sex workers enrolled in a microbicide feasibility study in Southern India, served as positive controls for optimization and validation experiments. Before validation, optimal dye concentration and staining time were ascertained. Three validation experiments were conducted to determine sensitivity, specificity, and negative and positive predictive values. Results: The dye concentration of 0.05% (wt/vol) FD&C Blue No. 1 Granular Food Dye (Prime Ingredients, Inc, Saddlebrook, NJ) and staining time of 5 seconds were determined to be optimal and were used for the 3 validation experiments. There were a total of 1848 possible applicator readings across validation experiments; 1703 (92.2%) applicator readings were correct. On average, the DSA performed with 90.6% sensitivity, 93.9% specificity, and had a negative predictive value of 93.8% and a positive predictive value of 91.0%. No statistically significant differences between experiments were noted. Conclusions: The DSA was optimized and successfully validated for use with single use, low-density polyethylene applicators filled with hydroxyethylcellulose gel. We recommend including the DSA in future microbicide trials involving vaginal gels so as to identify participants who have low adherence to dosing regimens. In doing so, we can develop strategies to improve adherence as well as investigate the association between product use and efficacy.

Evaluation of 3 approaches for assessing adherence to vaginal gel application in clinical trials

Background Accurate measurement of adherence to product use is an ongoing challenge in microbicide trials. Methods We compared adherence estimates using 2 applicator tests (a dye stain assay [DSA] and an ultraviolet light assay [UVA]), the Wisebag (an applicator container that electronically tracks container openings), and self-reported adherence (ability, frequency, and percent missed doses). Healthy, HIV-negative, nonpregnant US women aged 23 to 45 years received a Wisebag and 32 applicators filled with placebo gel were instructed to insert 1 applicator daily for 30 days, returned the Wisebag and all applicators, and completed an exit interview. Emptied applicators were tested by UVA and then DSA, and scored by 2 blinded readers. Positive and negative controls were randomly included in applicator batches. Results Among 42 women enrolled, 39 completed the study. Both DSA and UVA yielded similar sensitivity (97% and 95%) and specificity (79% and 79%). Two participants had fully inoperable Wisebags, and 9 had partially inoperable Wisebags. The proportion of participants considered to have high adherence (≥80%) varied: 43% (Wisebag), 46% (UVA), 49% (DSA), and 62% to 82% (self-reports). For estimating high adherence, Wisebag had a sensitivity of 76% (95% confidence interval, 50%–93%) and a specificity of 85% (95% confidence interval, 62%–97%) compared with DSA. Although 28% of participants reported forgetting to open the Wisebag daily, 59% said that it helped them remember gel use. Conclusions Dye stain assay and UVA performed similarly. Compared with these tests, self-reports overestimated and Wisebag underestimated adherence. Although Wisebag may encourage gel use, the applicator tests currently seem more useful for measuring use in clinical trials.

A First-in-Human Trial of MIV-150 and Zinc Acetate Co-Formulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence and Pharmacodynamics.

Objective:To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. Design:A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. Methods:Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose–response inhibition analysis. Results:Participants (n = 20) ranged from 19–44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti–herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. Conclusions:PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti–human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted infection prevention.

Sexually transmitted infections and reproductive health morbidity in a cohort of female sex workers screened for a microbicide feasibility study in Nellore, India

Short Summary: Four-month placebo vaginal gel trial conducted to determine the feasibility of recruiting FSWs for future Phase 2/3 microbicide trials. RH morbidity and HIV and STI prevalence are reported. Women constitute 38% of India’s 2.4 million HIV-infected persons. Microbicides are potential HIV-prevention products currently undergoing clinical trials for efficacy. A four-month placebo vaginal gel trial was conducted in Nellore, India to determine the feasibility of recruiting a suitable cohort of female sex workers (FSWs) for a future vaginal microbicide efficacy trial. We report on the HIV and STI prevalence and reproductive health (RH) morbidity of FSWs screened for the trial. Results: 529 FSWs completed screening procedures; of those 33.6% were found ineligible. The mean age was 30.9 years; 68.6% women were married and 57.5% were home-based FSWs. Self-reported symptoms included abnormal vaginal discharge (31.6%), genital itching (3.4%), uterine mass/prolapse (3%) and painful intercourse (2.6%). Gynecological surgery was reported by 73.2% of participants; of those 10.5% had undergone a hysterectomy. Female sterilization was the most commonly reported contraceptive method. Pelvic examination showed vaginal discharge (50.7%), cervical discharge (5.3%), uterine/vaginal wall prolapse (2.6%), and cervical mass/nodule/vesicles/genital warts (4.2%). Common epithelial findings included erythema (79.1%) and vesicles/bullae (6%); 46% of participants had Papanicolaou tests graded as inflammatory and 1.1% as malignant. HSV-2 was the mostly commonly detected STI (60.7%) followed by trichomoniasis (15.5%), HIV (5.3%), syphilis (2.8%), chlamydia (2.2%) and gonorrhoea (0.7%). RTIs were more common: bacterial vaginosis (27.8%) and candidiasis (18.9%). Conclusions: The low HIV prevalence and high RH morbidity in the population makes this site unsuitable for a future phase 2 or 3 microbicide efficacy trial. HIV prevention programs targeting this population should include access to RH services.

Use of the dye stain assay and ultraviolet light test for assessing vaginal insertion of placebo-filled applicators before and after sex

Background Applicator dye staining and ultraviolet (UV) light have been used in trials to measure adherence, but not in the setting of before and after sex gel dosing (BAT-24). This study was designed to determine if semen or presex gel dosing impacts the sensitivity and specificity of a dye stain assay (DSA) for measuring vaginal insertion of placebo-filled applicators with BAT-24 dosing. Methods Healthy monogamous couples received Microlax-type applicators (Tectubes, Åstorp, Sweden) filled with hydroxyethylcelluose placebo gel. Women were instructed to vaginally insert 1 dose of gel before and a second dose after sex and to return applicators within 48 hours after sex. Applicators were stained to detect semen, followed by UV then DSA, and scored by 2 readers. Positive and negative controls were randomly included in applicator batches. Results Fifteen couples completed the study. Each woman returned at least 6 applicators over a 30-day period. The sensitivity for insertion of postsex applicators was higher for UV (97%) compared with DSA (90%), and the specificity was similar (≥96%). For presex applicators, the sensitivity and specificity were higher for DSA (100%) compared with UV testing (87% sensitivity, 96% specificity). Among returned postsex applicators, 95% tested positive by UV compared with 87% by DSA. Agreement between readers was significantly better on the presex applicators for DSA than for UV, and for postsex readings, agreement was less than half that for UV, although the results were not statistically significant. Conclusions Applicator tests are feasible for measuring adherence in trials with gel dosing before and after sex.

To tell or not to tell: male partner engagement in a Phase 3 microbicide efficacy trial in South Africa

Gender norms that privilege mens sexual power and pleasure, and distrust of condom use in intimate relationships, leave women vulnerable to HIV and other sexually transmitted infections. Vaginal microbicides allow women to exert a degree of control over their sexual health, through responsibility for product insertion as well as the possibility of covert use. In practice, however, the uptake of new HIV-prevention products is heavily influenced by partnership dynamics. This paper presents a secondary analysis of data from two qualitative sub-studies conducted during a Phase 3 microbicide efficacy trial in South Africa. Using transcripts from in-depth interviews and focus group discussions with 278 female trial participants and 27 male partners, we investigated the extent to which women disclosed microbicide use to their partners, and the level and types of male engagement with microbicide use. Most women chose to communicate with their partners about the trial, but the timing and content of associated discussions differed according to their motivation for disclosure. Men provided their partners with both moral and practical support, but reported a desire for greater involvement in decision-making surrounding microbicide uptake and use. The findings inform recommendations for constructive male participation in future trials and, ultimately, introduction of a marketed product.

Effective approaches to user-interface design with ACASI in the developing world

User Interface Design When providing a technology solution for a literate or semi-literate population, certain key steps must be taken to ensure the system is acceptable to the participants. Designing the participant or user interface is one of the main efforts that took place during the creation of our ACASI solution. One of the key principles is to keep the screen design very simple, using elements such as color-coded butcessfully in the local environment and be welcomed by the local populations; and increase efficiency and cost-effectiveness. The solution was the development of a fully customized ACASI (audio computer-assisted self-interviewing) module. ACASI is an effective technology for obtaining more honest responses to sensitive questions than those asked face-to-face [1]. With ACASI, a respondent listens to prerecorded audio questions through headphones that are connected to a computer or handheld device and records his or her responses using a touchscreen or a keypad. Literate respondents can also simultaneously read the questions on the computer screen. Using ACASI and other ICT solutions allows for standardization, confidentiality, minimized bias, and more effectively collecting Several years ago, the Information Technology (IT) group at the Population Council was presented with a situation where researchers had a need and knew that some solutions existed, but what was available did not meet their needs. These investigators asked if there was a technology solution to help obtain more accurate responses to survey questions that concerned subject matter of a delicate nature. In response, the IT group built a software/hardware combination solution that both met the needs of the researchers and was accepted by the people who used the system— an illiterate or semi-literate population that perhaps had never seen or used a computer before. There were three goals in mind: enhance the research by obtaining the best data possible; operate sucEffective Approaches to UserInterface Design with ACASI in the Developing World