Attitudes and perceptions towards novel objective measures of ARV-based vaginal ring use: Results from a global stakeholder survey

Results of recent microbicide and pre-exposure prophylaxis clinical trials have shown adherence to be a significant challenge with new HIV prevention technologies. As the vaginal ring containing dapivirine moves into two open label follow-on studies (HOPE/MTN-025 and DREAM) and other antiretroviral-based and multi-purpose prevention technology ring products advance through the development pipeline, there is a need for more accurate and reliable measures of adherence to microbicide ring products. We previously conducted a comprehensive landscape analysis to identify new technologies that could be applied to adherence measurement of vaginal rings containing antiretrovirals. To explore attitudes and perceptions towards the approaches that we identified, we conducted a survey of stakeholders with experience and expertise in microbicide and HIV prevention clinical trials. From May to July 2015 an electronic survey was distributed via email to 894 stakeholders; a total of 206 eligible individuals responded to at least one question and were included in the data analysis. Survey respondents were presented with various objective measures and asked about their perceived acceptability to trial participants, feasibility of implementation by study staff, usefulness for measuring adherence and ethical concerns. Methods that require no additional input from the participant and require no modifications to the existing ring product (i.e., measurement of residual drug or excipient, or a vaginal analyte that enters the ring) were viewed as being more acceptable to trial participants and more feasible to implement in the field. Respondents saw value in using objective measures to provide real-time feedback on adherence. However, approaches that involve unannounced home visits for sample collection or spot checks of ring use, which could provide significant value to adherence feedback efforts, were met with skepticism. Additional research on the acceptability of these methods to potential trial participants and trial staff is recommended.

Q2.2 Do you have fluency in written English?  Yes (1)  No (2) Q2.3 In the previous 24 months, have you been actively involved in any of the following roles or activities related to an ARV-based HIV prevention trial, or ancillary research directly related to such a trial, that enrolled women as participants? Please select all that apply.  Protocol team member (1)  Trial implementation (e.g., investigator, manager, coordinator) (2)  Program officer at a funding organization (3)  Adherence and product use counselor (4)  Trial participant recruiter (5)  Trial monitor (6)  Community liaison officer, outreach worker, or educator (7)  Ethics review committee member or administrator (8)  Ethics consultant (9)  None of the above (10) [If Q2.1=1, Q2.2=2 OR Q2.3=10] Q3.1 We're sorry, but you do not meet the eligibility requirements for this survey. We thank you for your interest and appreciate your time.
[If Q2.1=2,3,4 AND Q2.2=1 AND Q2.3=1,2,3,4,5,6,7,8,9] Q4.1 Thank you for answering these questions. You meet the eligibility criteria for this study. Do you consent to participate in this survey?  Yes, I consent to participate in this survey. (1)  No, I do not consent to participate in this survey. (2) Answer If Q4.1=1 Q4.2 Some of the questions in the survey will be about vaginal rings. Here is a picture of a vaginal ring made of silicone that includes an antiretroviral called dapivirine. It is currently being tested in phase III clinical trials in Africa by the International Partnership for Microbicides (IPM) and the Microbicide Trials Network (MTN). Other ARV-based rings, including some with a contraceptive drug, are in development.

Q4.3
Answer If Q4.1=1 Q4.4 Please note that while taking this survey, you can stop at any time and return to continue the survey later --your responses are automatically saved as you go along. By using the arrow buttons at the bottom of the page, you may scroll back and forth within most sections, but you will not be able to page backwards between different sections.
Q16.1 Biometric Technologies & Approaches to Detect Adherence In this set of questions we will describe several biometric technologies or methods that could be used to objectively measure vaginal ring adherence in clinical trials. Based on your experiences and local knowledge, we would like to know if you think these biometric technologies and methods would be acceptable to research teams and women who might participate in HIV prevention trials in the settings where you work.
Q17.1 Magnets embedded in vaginal rings One technology being considered to detect and measure vaginal ring usage is the inclusion of a very small magnet (magnetic tag) embedded in a vaginal ring. Magnetic tags emit a magnetic field that could be detected up to several feet, depending on the strength of the magnet.
A magnetic tag could be as small as a pinhead and potentially invisible when placed in the ring. Portable handheld meters can detect and measure magnets, are readily available, and could be used by trial staff with minimal training to detect and measure the presence or absence of a ring in a woman's vagina. Use of a handheld meter would not require a physical exam, or physically touching the woman in order to determine if the ring was inserted in the vagina. For example, the meter would be able to tell the difference between a ring placed in a skirt pocket and one inserted in the vagina.
Q17.2 In your opinion, how acceptable to women participating in clinical trials would it be to use a ring embedded with a magnetic tag for detecting and measuring vaginal ring adherence in clinical trials?  Very acceptable (1)  Somewhat acceptable (2)  Not acceptable (3)  Don't know (4) Q17.3 Do you think women would be skeptical or worried about having a very small magnet in their bodies?  Yes, they would be very skeptical or worried (1)  Yes, they would be somewhat skeptical or worried (2)  No, they would not be skeptical or worried (3)  Don't know (4) Q17.4 In general, do you think women would prefer a physical (vaginal) exam or use of a handheld meter to detect the presence of a ring embedded with a magnetic tag within the vagina?  Women would prefer use of a meter and ring with magnetic tag to check for ring insertion (1)  Women would prefer a physical (vaginal) exam to check for ring insertion (2)  Women would have no preference for either using a meter and ring with magnetic tag or a physical (vaginal) exam (3)  Don't know (4) Q17.5 One potential advantage of using magnetic tags is that trial staff could potentially check for ring adherence at home visits without having to do a physical (vaginal) exam. In your opinion, how acceptable do you think it would be to trial staff themselves to use a meter at home visits to measure real-time adherence of vaginal rings embedded with magnetic tags?  Very acceptable (1)  Somewhat acceptable (2)  Not acceptable (3)  Don't know (4) Q17.6 In your opinion, how feasible or practical do you think it would be for trial staff to carry out real-time adherence checks of trial participants with a meter at home visits to measure real-time adherence of vaginal rings embedded with magnetic tags?  Very feasible (1)  Somewhat feasible (2)  Not feasible (3)  Don't know (4) Q17.7 Spot checks of vaginal rings with magnetic tags could be carried out at random, unannounced home visits. At the beginning of the trial, in the informed consent process, women would be asked to consent, or agree, to having random, unannounced home visits that might include checking for ring adherence with a hand-held meter, and they would be informed about whether and how often these unannounced home visits might occur during the trial. In your opinion, how acceptable to participants do you think it would be to use random, unannounced, home visits for the purpose of performing spot checks on ring insertion via use of a hand-held meter?  Very acceptable (1)  Somewhat acceptable (2)  Not acceptable (3)  Don't know (4) Q18.1 Breath test -volatile tagents Another possible biometric technology centers on the use of a breath test to detect the presence of a non-toxic chemical added to the vaginal ring. The chemical would be absorbed by the body in a way that would allow it to be detected using the breath test. Trial participants would be asked to blow into a plastic syringe or bag using a mouthpiece. The air would then be tested to see if the chemical from the ring is present. If the chemical is not present, it means that the ring was removed from the vagina. This method has been piloted with microbicidal gels, but the technology has not yet been developed for vaginal rings. In general, how acceptable to women participating in clinical trials would it be to take a breath test to detect the presence of a vaginal ring? (4) Q18.2 The chemical used in the microbicidal gel pilot resulted in an unacceptable taste for some, but not all, participants. If women knew they may experience an unfavorable taste from a chemical used in a vaginal ring, how likely do you think it is that women would refuse to use the ring?  Very likely (1)  Somewhat likely (2)  Not likely (3)  Don't know (4) Q19.1 Collection of hair, blood, and vaginal fluid samples Another type of approach to assessing adherence would be to collect blood, vaginal fluid, or hair samples from study participants. Participants would be told how, when, and where such samples would be collected during the informed consent process.
Q19.2 Blood samples Drug levels in the blood could be used to objectively assess adherence to the vaginal ring, as has been done in several other microbicide and PrEP clinical trials. This would involve either a traditional blood draw with a needle stick or a finger prick for dried blood spot collection. How acceptable do you think collecting blood samples at random, unannounced home visits would be to trial participants, in order to detect and measure product adherence? (4) Q19.3 How feasible or practical would it be for trial staff to collect blood samples at random, unannounced home visits with participants? (4) Q19.4 Vaginal Fluid samples Collecting vaginal fluid samples to measure drug levels may be seen as more physically intrusive than collecting blood because of the nature of the collection procedure. One way to reduce the intrusiveness is for study participants themselves to selfswab while under a privacy gown. This approach could be used during random, unnanounced home-checks. This method, self-insertion of vaginal swabs with use of a privacy gown, has been successfully used in some studies to measure product adherence.
Very (1) Somewhat (2) Not at all (3) (4) Q19.6 Hair samples Another approach would be the collection of hair samples to detect drug levels in the hair. This would involve taking about 20 to 30 strands of hair from a participant and testing it in the lab. The collection of hair samples could take place during regular clinic followup visits.
Very (1) Somewhat (2) Not at all (3)  A sensor that measures how long a ring is exposed to air. Since the ring would have to be removed in order for it to be exposed to air, the device would indicate whether and how long a ring was removed. A temperature sensor that measures how long a ring is exposed to internal body temperatures; this would indicate whether and how long a ring was inserted in the vagina. A pressure sensor that can tell whether and how long a ring is inserted in the vagina. A pH sensor that is calibrated to the pH level of the vagina and can tell how long a ring is inserted. Q20.2 In your opinion, how acceptable to women participating in clinical trials would it be to use an electronic sensor embedded in a vaginal ring to measure adherence through things like exposure to temperature, pH, air, or vaginal pressure?  Very acceptable (1)  Somewhat acceptable (2)  Not acceptable (3)  Don't know (4) Q20.3 Do you think women would be skeptical or worried about having a vaginal ring with this kind of sensor in their bodies?  Yes, they would be very skeptical or worried (1)  Yes, they would be somewhat skeptical or worried (2)  No, they would not be skeptical or worried (3)  Don't know (4) Q20.4 It is possible that some trial participants would try to outsmart this approach by removing their rings and storing them in ways that might "fool" the sensor. How likely do you think it is that trial participants would be able to outsmart an electronic sensor that measures things like exposure to temperature, pH, air, or vaginal pressure?  Very likely (1)  Somewhat likely (2)  Not likely (3)  Don't know (4) Q21.1 Measurement of residual drug in used rings Another approach is to require that trial participants return their used rings to study staff at the end of the ring's use period so it can be evaluated to see how much drug is left in the ring. This method can determine whether drug has been released while being worn in the vagina. It cannot measure the number of days a ring was used, but if the amount of drug in the ring is similar to that in an unused ring, it means that the ring probably was not worn at all or not worn long enough to provide protection. If placebo rings are used during a trial, they could not be used in this way to measure adherence because there would be no drug to assess. Therefore, to maintain blinding, this approach could not be used to determine which participants are adherent until after a trial had ended, but it could be used to get an idea of overall levels of adherence among participants at a given site during the trial.
Very (1) Somewhat (2) Not at all ( Q22.1 Diffusion of analytes into or out of the ring It may also be possible to estimate how long a vaginal ring has been used by adding an inactive substance to the ring that would diffuse out of the ring when it is inserted in the vagina, just like the active drug in the ring can diffuse out. The inactive substance would be a material that is known to be safe when used in the body in this way. The advantage to this approach is that such a substance could be added to the placebo ring. Just as with the active drug, the amount of this substance left in the ring could be measured to determine if the ring had been worn. Very (1) Somewhat (2) Not at all ( MOST ACCEPTABLE approaches to ring trial participants (choose 3) LEAST ACCEPTABLE approaches to ring trial participants (choose 3) ______ Magnetic tag in ring and hand-held meter during unannounced home visits (1) ______ Magnetic tag in ring and hand-held meter during unannounced home visits (1) ______ Breath test for chemical in ring during unannounced home visits (4) ______ Breath test for chemical in ring during unannounced home visits (4) ______ Measurement of residual drug in returned ring (6) ______ Measurement of residual drug in returned ring (6) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (7) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (7) ______ Diffusion of vaginal substance into returned ring (9) ______ Diffusion of vaginal substance into returned ring (9) ______ Diffusion of safe, inactive substance out of returned ring (10) ______ Diffusion of safe, inactive substance out of returned ring (10) ______ Collecting hair samples during clinic visits (12) ______ Collecting hair samples during clinic visits (12) ______ Collecting blood samples at unannounced home visits (13) ______ Collecting blood samples at unannounced home visits (13) ______ Collecting vaginal fluid sample by self-swab during unannounced home visits (14) ______ Collecting vaginal fluid sample by self-swab during unannounced home visits (14) Q23.3 We would like to know which technologies and approaches you think would be most feasible and practical. Please choose three that you feel are the most feasible and drag them to the top box, and choose three that you would find least feasible, and drag them to the bottom box.
MOST PRACTICAL approaches to measure adherence ( (6) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (7) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (7) ______ Diffusion of vaginal substance into returned ring (9) ______ Diffusion of vaginal substance into returned ring (9) ______ Diffusion of safe, inactive substance out of returned ring (10) ______ Diffusion of safe, inactive substance out of returned ring (10) ______ Collecting hair samples during clinic visits (12) ______ Collecting hair samples during clinic visits (12) ______ Collecting blood samples during unannounced home visits (13) ______ Collecting blood samples during unannounced home visits (13 (4) ______ Measurement of residual drug in returned ring (6) ______ Measurement of residual drug in returned ring (6) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (7) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (7) ______ Diffusion of vaginal substance into the returned ring (9) ______ Diffusion of vaginal substance into the returned ring (9) ______ Diffusion of safe, inactive substance out of returned ring (10) ______ Diffusion of safe, inactive substance out of returned ring (10 (4) ______ Measurement of residual drug in returned ring (2) ______ Measurement of residual drug in returned ring (2) ______ Measurement of residual drug in returned ring (2) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (3) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (3) ______ Sensor to measure exposure to temperature, air, pH, or vaginal pressure in returned ring (3) ______ Diffusion of vaginal substance into the returned ring (5) ______ Diffusion of vaginal substance into the returned ring (5) ______ Diffusion of vaginal substance into the returned ring (5) ______ Diffusion of safe, inactive substance out of returned ring (6) ______ Diffusion of safe, inactive substance out of returned ring (6) ______ Diffusion of safe, inactive substance out of returned ring (6) ______ Collecting hair samples during clinic visits (7) ______ Collecting hair samples during clinic visits (7) ______ Collecting hair samples during clinic visits (7) ______ Collecting blood samples during unannounced home visits (8) ______ Collecting blood samples during unannounced home visits (8) ______ Collecting blood samples during unannounced home visits (8) ______ Collecting vaginal fluid samples through selfswabbing during unannounced home visits (9) ______ Collecting vaginal fluid samples through selfswabbing during unannounced home visits (9) ______ Collecting vaginal fluid samples through selfswabbing during unannounced home visits (9) Q23.6 Are there any other methods for assessing vaginal ring adherence that we've missed that you think should be considered? If yes, please describe.