Women’s Motivations for Participating in the Dapivirine Vaginal Ring Open Label Extension Study

Abstract

Open-Label Extension (OLE) studies are important in the drug development process and are used to further support the licensing applications and regulatory approvals of products. We aimed to understand why women chose to join the HOPE OLE study -- where women were offered the dapivirine vaginal ring after two pivotal trials were completed -- through data collected from individual in-depth interviews. Ten women at each of the six HOPE research sites in Lilongwe, Malawi; Durban (2 sites) and Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza, Zimbabwe, were enrolled (n = 60). Access to an effective user-initiated HIV prevention product was one of the main reasons women joined HOPE. Although many participants worried that their male partners might expose them to HIV, they chose to remain in their relationships and avoid conflict or confrontation with their partners by discreetly using the ring to protect themselves. Other reasons for joining were quality healthcare, reimbursement and altruism. Researchers should better understand social and personal motivators behind research participation in order to recognize community sociocultural norms and its influences on product acceptability and adherence challenges.

INTRODUCTION

After the dapivirine vaginal ring was shown to reduce the risk of HIV-1 acquisition in two phase III trials, by 27% in MTN 020/ASPIRE which was conducted from 2012 to 2015 (Baeten et al., 2016) (Figure 1) and by 31% in The Ring Study which was conducted from 2012 to 2016 (Nel et al., 2016)), it was further for long term safety and acceptability in two OLE studies which were implemented from 2016 to 2018, i.e., MTN-025/HOPE (Baeten et al., 2021) (Figure 1) and IPM 032/DREAM (Net et al., 2021). Data from OLE studies are important in the drug development process and are used to further support the licensing applications and regulatory approvals of products. During 2021 – 2022, the dapivirine vaginal ring was approved as an HIV prevention option for women in South Africa, Zimbabwe, Kenya, Uganda and Lesotho (Atieno, 2022; Fokazi, 2022).

Figure 1:

Study implementation timelines

As part of understanding women’s experience with vaginal ring use and study participation, the MTN-032 Assessment of ASPIRE and HOPE Adherence (AHA) sub-study was implemented post-ASPIRE in 2016, and post-HOPE in 2018 (Figure 1), and used qualitative interviewing methods with participants who exited each of these trials (Montgomery et al., 2018, 2021; Naidoo et al., 2021). One of the objectives of MTN-032/AHA was to understand the reasons why participants in ASPIRE chose to join the OLE study, HOPE, and have access to the dapivirine vaginal ring.

Motivations to join HIV prevention studies can be divided into social benefits such as altruism and personal benefits such as HIV protection, access to healthcare and financial reimbursement (Dhalla & Poole, 2011). The most common reason for joining HIV prevention studies has been reported as altruism and protection against HIV (Colfax et al., 2005; Dhalla & Poole, 2011; Dubé et al., 2020; Sullivan et al., 2020). Speaking to the altruistic motivator among volunteers during pre-trial community education sessions could aid in recruitment. Protection against HIV may be indicative of the need to have a product that is acceptable and easy to access and use however understanding the efficacy of the products should be addressed among volunteers and participants.

Access to healthcare and financial reimbursement has been reported as motivators (Colfax et al., 2005; Katz et al., 2019), which is expected since most HIV prevention studies are conducted in low- and middle-income countries with over extended health care systems that have the highest HIV burden (UNAIDS Data, 2021). These two motivators have been controversial among the research community as they are seen as undue inducement in impoverished countries where this research is being conducted (Emanuel et al., 2005) versus reasonable benefits that volunteers directly gain in these same impoverished countries for their contribution through study participation (Haire & Ogundokun, 2014; Halpern et al., 2004).

For this analysis, we aimed to understand why women chose to join the HOPE study – a new, post-trial OLE study where women were offered an active ring with known efficacy. This information will aid in understanding how women’s motivations for joining an HIV prevention OLE study might be the same or different from a placebo-controlled clinical trial, offering insight into women’s priorities at different stages of the biomedical product pipeline and roll-out. This will help with study recruitment strategies, highlight important topics that should be addressed during education sessions, improve community sensitization and recognize any links between motivations for study participation and product adherence and acceptability.

METHODS

Parent trial:

The HOPE study evaluated the safety and adherence of the dapivirine vaginal ring among eligible HIV-negative former ASPIRE participants (Baeten et al., 2021). Women could choose to accept the ring or not at any point during their participation in HOPE. Study follow-up visits occurred monthly for the first three months and thereafter quarterly with the option of visiting the site monthly to pick up a new ring.

Ancillary Study:

The AHA qualitative study was implemented from March 2018 to November 2018 and enrolled former HOPE participants who chose to use the ring during HOPE and agreed to be contacted for future studies. Potential AHA participants were contacted in sequential order from a randomized list generated by the HOPE Statistical Center for HIV/AIDS Research and Prevention (SCHARP). Ten women at each of the six HOPE research sites in Lilongwe, Malawi; Durban (two sites) and Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza, Zimbabwe were offered participation in AHA, 0 – 9 months after they had exited HOPE.

Following the review and confirmation of eligibility criteria, the informed consent and demographic and behavioral questionnaires were administered by trained study staff. A once off, in person individual in-depth interview (IDI) was then conducted in the language of the women’s choice (local African language or English) using a semi–structured interview guide (Appendix I) by female study staff trained in behavioural interviews and techniques. Discussions were facilitated around reasons for joining and remaining in HOPE, benefits gained from the study or from using the ring and any concerns about participation. Women were reminded that the interview was confidential and questions could be raised at any time.

IDIs were audio-recorded, transcribed and translated into English (if conducted in a local African language) and thereafter quality control processes were completed with local site staff, including comprehension of local terminology. Transcripts were then uploaded to Dedoose (Version 8.1.8), a qualitative software programme, for Data Management including coding, which allowed the raw contextual data to be reviewed and summarized with its meaning extracted. Analysts, including the lead author, used an iteratively developed codebook (Appendix II) to descriptively code for key themes and topics.

The codebook was adapted from similar previous research studies (Montgomery et al., 2018) and corresponded to the thematic areas covered in the IDI guide, allowing space for unanticipated themes to emerge. The codebook contained parent codes, with subcodes, that were defined by the lead author and analyst team. Refinements to code assignment were discussed throughout the process to maintain consistent interpretation and application of thematic meaning, and to develop or expand codes to accommodate emergent ideas. The coding and analysis approach for this paper was thus primarily thematic and focused on data coded assigned with the parent code of “trials” and “HIV” and the related sub-codes, “join/remain”, “social/emotional impact”, and “risk”, respectively. Intercoder consistency was confirmed at a level above a mean kappa score of 0.70 for 10% of transcripts across five coders and code application questions were discussed and resolved with the coding team.

The AHA study protocol was approved by the Institutional Review Boards at RTI International, and at each study site and regulated by the U.S. National Institutes of Health and the Microbicide Trials Network.

RESULTS

Sixty women were enrolled into MTN-032/AHA with two women not being included in the analysis due to inappropriate enrolment, resulting in an analytic sample of n=58. Detailed characteristics of the study sample have been presented previously (Naidoo et al., 2021). Women averaged 32 years of age (range 23–48), and less than half (44.8%) reported being married, 84.5% reported having the same partner since exiting HOPE, but 66.1% did not know whether their partners had other sex partners. Less than half of the women (41.1%) did not know their partner’s HIV status and 74.5% were worried about acquiring HIV in the next 12 months.

HIV Protection

Most women did not have any concerns about joining HOPE due to their previous experience with participation in ASPIRE; especially knowing that they were being provided with the active ring containing dapivirine. The primary reason reported by several women for enrolling in the HOPE study was the desire for a user-controlled HIV prevention method to manage their perceived risk due to distrust of their male partners and inconsistent use of condoms. They stated that the ring offered them protection against HIV since it was proven to be efficacious.

“My reason for the joining HOPE was the ring and the fact that I have used it before.. It sometimes happened that in that particular day I was not going to use a condom, but I would know that there is an alternate prevention method inside of me, that would protect me.”

(Durban, South Africa)

This woman specifically notes that her concern is exacerbated by expected behavioral norms within a relationship with her primary partner. Besides the distrust, she cannot ask him to use condoms as he is her primary partner.

“My protection is complicated, ask me why… I don’t know how my partner behaves. So I may not have other sexual partners but he may have other partners. So what can I do for him? Can I tell him to use condoms? He is my permanent partner so I can’t.”

(Kampala, Uganda)

Additionally, for some women, joining HOPE gave them rapid access to using the ring again, which was a strategy that offered the benefit of discreetly maintaining protection against HIV that would serve their children’s wellbeing and avoid arguments with their husbands. Avoiding conflict in the relationship and finding a means to protect themselves was viewed as the easier option rather than confrontation with the partner.

“So, I realized that if I managed to join HOPE I would insert my ring and I would avoid conflict with my husband. I would just use it quietly to ensure I’m protected so as to care for my children.”

(Chitungwiza, Zimbabwe)

Access to Counseling and Healthcare

Receiving counselling, education and additional healthcare services – such as testing and treatment for sexually transmitted infections (STI’s), HIV testing, pap smear screening, physical examinations and contraceptive provision – were also discussed by many women as additional motivators for joining and was seen as a benefit that they received throughout their participation in the study.

“We also received counselling and [were] educated about other things that we did not know. Things about life and about engaging in sex. Things that you were not aware are happening and things that you did not take note of, you were just doing them. We received additional education about things that we did not know.”

(Durban, South Africa)

“I gained many things because they were testing us for HIV, sexually transmitted infections and cervical cancer screening.”

(Lilongwe, Malawi)

A few women favorably compared the services received at the study site to local healthcare facilities. Women mentioned the good quality of care that was provided by study staff and that they had trust and confidence in the study staff to help them without judgement when they felt unwell and required treatment.

“If you’ve got a problem like STI’s and things like that you get help from this clinic. Sometimes at the local clinic we are sometimes scared to tell the nurses that “okay this is what I have” and things like that but here you know that everything that happened here stays here, it’s confidential between you and study staff.”

(Durban, South Africa)

Two women from Lilongwe, Malawi, further spoke about how the counselling, education and frequent HIV testing they received during HOPE resulted in sexual behaviour changes. This woman reports that went from having multiple sexual partners to just one sexual partner based on the counselling she received at the site.

“The other thing was the counseling and the love that you show us here… you are loving people and well behaved. This helped me change my behavior and as I am talking now, I only have one sexual partner.”

(Lilongwe, Malawi)

The second woman reported a similar behavior change in her male partner when he realized she was being tested for HIV during her study visits, indicating that she believed that her HIV status, whether negative or positive, was reflective of his sexual behaviour:

“Before I joined, my partner was having multiple sexual partners but when I started participating here, I was encouraging him that “look, this is my status. We have not been trusting each other because of your behavior.” It turned out that he started changing his behavior after realizing that I get tested and I am HIV negative. I benefitted because he changed his behaviour and he is now a good man.”

(Lilongwe, Malawi)

Financial Reimbursement

Some women candidly discussed how they joined for the reimbursement that was provided for their time spent during clinic visits. These women spoke about needing the money for their children’s school fees or essential food items. Others went on to explain that some women joined for the reimbursement, but others joined because they wanted to use the ring.

“Some were just coming here to get the ring because they knew that at the end of the day they would be given transport money which they would use at their homes but they had no passion to consistently use the ring so that it can give good results.”

(Lilongwe, Malawi)

“We came for different reasons, some people came to get money and some really had the passion and love for the ring.”

(Durban, South Africa)

Altruism

Many women spoke about altruism and joining the study for the betterment of future generations of women, their children and grandchildren and that they would have another option for HIV prevention available to them. They reported being proud to be part of the study and that it gave them a purpose.

“It was because women had been left behind when it comes to fighting HIV. Our prevention methods were fewer than those for men….. But at least if we get another option of using a vaginal ring which we can insert and no one gets to know that you have it is something that motivated me to join the HOPE study.”

(Kampala, Uganda)

“Your expected results it’s like you get so much pleasure from doing that and you always feel proud of what you are doing, who you are. Remember what I had in mind when I started I was not doing this for myself only. I have a son, I still want more children. So do I want them to come in this world and next thing they pass-on because of HIV? No, at least they must have options, you know? I will know that I was part of getting those solutions on the table.”

(Johannesburg, South Africa)

Support from Partners, Family and Friends

Several women mentioned that their partners knew about their participation and supported them. Their partners’ encouragement helped them make the decision to join and enable them to continue participating.

“I told him the benefits that we get here. I told him that “we get tested for HIV each scheduled visit that we go, they also screen us for other diseases; a thing that cannot be happening if we go to other health facilities.” So, he understood it and accepted that I should join.”

(Lilongwe, Malawi)

Some women opted to discuss their decision to join with their family, friends and neighbours, whilst others chose to make the decision on their own and join without anybody knowing. One woman mentioned that when she discussed joining HOPE with other former ASPIRE participants, they mentioned that they did not want to join the HOPE study because they were provided with the placebo ring in ASPIRE, perhaps indicating some distrust towards clinical research or blame on researchers for assigning them to the placebo arm.

“I even asked that ‘Remember we first joined without knowing whether it had medicine or not and now you have realized that what you had didn’t have medicine but in case you had one with medicine would you still decline?’ and some would say ‘If I had used one with medicine I would join but now that I used one without medicine I will not join.’”

(Kampala, Uganda)

DISCUSSION

The reasons reported by former ASPIRE clinical trial participants for electing to join the HOPE OLE study and use the ring – access to good healthcare, protection against HIV, financial reimbursement and altruism – were similar to the findings of previous research about why participants chose to join HIV prevention clinical trials (Colfax et al., 2005; Katz et al., 2019; Sullivan et al., 2020).

Access to an effective user-initiated HIV prevention product was one of the main reasons women joined HOPE. This allowed women achieve an important health goal of protecting themselves against HIV. Although many participants worried that their male partners might expose them to HIV, they chose to remain in their relationships and use the ring to protect themselves. Financial stability and material support provided and offered by male partners may contribute to women’s decision or inability to leave problematic partnerships, especially in low- and middle-income countries (Warren et al., 2018; Psaros et al., 2018). Additionally, sociocultural norms in communities may also play in women remaining in challenging relationships. Male partners may perceive condom use as signaling a lack of trust, intimacy and love in the relationship (Mash et al., 2010) and women may feel that discussions around condom use could result in arguments, physical violence and a breakdown in the relationship (Hlongwa et al., 2020). Participants’ choice to access the ring rather than risk a confrontation with their partner about possible unfaithfulness or condom use highlights how some women utilize user-initiated HIV prevention methods to navigate sexual relationships from a position of less power than their male partners.

Access to good healthcare was seen as a benefit to joining HOPE. Public healthcare facilities in sub-Saharan Africa provide limited medical care due to numerous factors, including staff shortages, poor financing, insufficient resources and inadequate systems and processes (Gold & John, 2013). For this reason, women sought the quality healthcare that was being offered through participation in the HOPE study and voiced their gratitude. Women directly benefitted from the healthcare and counselling that was provided during the HOPE study just as they benefitted from having the choice of an HIV prevention method. Researchers debate on whether providing medical benefits during studies may be seen as undue inducement (Haire & Ogundokun, 2014; Mfutso-Bengo et al., 2008; Mngadi et al., 2017) however the provision of healthcare is an essential requirement in these low- and middle-income countries. When research studies are being implemented, the location and resources should be considered (Dainesi & Goldbaum, 2011) and engagement between researchers, stakeholders and communities is encouraged to look at a long-term plan for the provision of quality healthcare where possible and feasible.

Some women openly discussed that financial reimbursement was the motivation for women joining the HOPE study. Participants were reimbursed as per the local country regulations in both ASPIRE and HOPE. Monetary payments for participation in a study have been reported to increase a person’s willingness to participate (Almeida et al., 2007; Bentley & Thacker, 2004; Colfax et al., 2005). Reimbursement can be seen as an incentive motivator to join research studies however further internal interventions are needed to ensure adherence to the study products after joining the study. In OLE studies, a “real-world” type of setting is created similar to attending local healthcare providers and thus, the need for reimbursement in this sort of setting is debated (Mngadi et al., 2015). Researchers consulted with local Ethics Committees, Community Advisory Boards and other country regulators throughout study implementation to ensure that participants are compensated appropriately for their time, inconvenience and travel as per most country regulatory authorities. Thought and care must be taken when research is being conducted in countries where poverty is high and the reason for the financial reimbursement should be explained thoroughly to study participants throughout study participation.

Even though altruistic motivations in clinical research can sometimes be intertwined with personal benefits, altruism has come up often as a motivator to participation in HIV prevention research (Dubé et al., 2020). Several women portrayed a sense of pride when they reported that they were motivated to join so that their children and future generations of women would benefit. Many women have been affected by HIV in some way, whether among their own family members and friends or within their communities. This could be the driving force behind their altruistic motivations. Altruism can be aligned with what scientific research aims to accomplish – a treatment, cure or prevention that can be used in future – especially in OLE studies where the study product is known to be efficacious.

Discussions with male partners, families and communities and their support in the decision to join the HOPE study and use the ring were important for some women. This is an important point that can be used for future marketing of the ring – in that it can be seen as a shared HIV prevention responsibility in relationships (Montgomery et al., 2021), can be used by your peers and communities or can be used by yourself autonomously and discreetly.

A small minority of women reported that others felt discouraged as they received the placebo product in ASPIRE and did not want to join HOPE for this reason. These women seemed resentful towards researchers providing them with the placebo product and perhaps needed further clarification during the informed consent process on the design of clinical trials and randomization versus an OLE study in order to make an informed decision about joining HOPE.

There are limitations to this research that should be taken into consideration. The data collected is from a sub-set of women from HOPE. Our sub-sample was randomly selected to minimize the risk, however, their perspectives and knowledge may not be reflective of the same from the full cohort of HOPE study participants, nor of the broader scope of women who were in ASPIRE and did not elect to join HOPE, nor of African women from these settings who may have been eligible, but did not join these studies. Further, the concepts explored in this analysis are complex and may not have been adequately understood by study participants. Comprehension and wording in interview guides were extensively shared across study sites and pre-tested to minimize misunderstanding. Further, our study relied on participants’ availability and interest to spend approximately 90 minutes participating in an interview, which may have introduced limitations, and the study relied on participants to comment on attitudes of acceptability and product use experiences with a research study team, which may have resulted in social desirability bias. The interviews were conducted after women exited the HOPE study, which may have minimized a desire to report “favorable” responses but may have introduced recall or other biases. The scope of the analysis did not include cultural diversities among each country/site and its impact, if any, on the results. It must also be considered that these women participated in both ASPIRE and HOPE resulting in them having access to the benefits of quality healthcare, reimbursement and the study product over a long period of time.

The social and personal benefits offered from clinical trials prior to efficacy determination versus OLE studies seem to be viewed equally by participants. Women were motivated to join HIV research to reduce their HIV risk and take control of their health. If participants are receiving benefits through study participation such as quality healthcare and reimbursement, that are not coercive, these should be considered acceptable because of the participants contribution to science. HIV research is ongoing among important populations in low- and middle-income countries and access to quality healthcare through study participation should in turn motivate local leaders to focus on health system strengthening where women have access to quality healthcare on a daily basis and not just through clinical trials. Researchers should better understand social and personal motivators behind research participation in order to recognize community sociocultural norms and its influences on product acceptability and adherence challenges.

APPENDIX I: MTN 032/AHA Study Part 2 Female In-depth Interview Guide

MTN-032 Part 2

Female In-depth Interview (IDI) Topic Guide

INSTRUCTIONS for the Interviewer: How to use the IDI Guide

1. Section topics are in shaded in gray and bolded.

2. Instructions/suggestions to interviewer are in italics and [brackets].

3. Not ALL questions need to be asked. It is up to the interviewer’s discretion if a question should be skipped if the participant has already provided a response to the question earlier in the interview. Please ensure that by the end of the interview, all the topics and key themes have been covered.

4. Purpose statements should be considered notes to the interviewer and are not meant to be read aloud. They explain the reason for asking that question or set of questions in order to provide more context to the interviewer who can then rephrase in her own words or clarify to the participant as necessary.

5. There are two levels of questions:

   1. Primary interview questions: appear in bold text. They address the topics that you as the interviewer should ask and discuss with participants. You are not required to read them verbatim, but they are written to ensure some consistency across IDIs.
   2. Probing topics are indicated with a bullet. If you find that the participant does not provide much information in response to the primary question, these probing topics may be used to encourage further discussion. Probes with the words “KEY PROBE” written before it are probes that are the most important to try to address. Depending on what has already been discussed, and the IDI context, you may or may not ask the rest of the probes.

6. Words found in (parentheses) are meant to provide wording options to interviewers to fit various situations. For example, they often provide a present or past tense verb.

7. The IDI guide is not meant to be used to take notes. Rather, you should use the separate notes form, where you will also insert your initials, the participant’s PTID, as well as the date, start and end time of the interview.

8. Special note about seroconverters: It is important for study staff to review the participant’s HIV status before conducting any study procedures. When asking questions to seroconverters, start off by emphasizing that confidentiality is maintained in the study and reassure the participant that her study information will not be shared with anyone outside the study. Then inform the participant that you are aware that she has seroconverted.

Before starting the IDI, ensure the participant has provided written informed consent.

[Start Recorder and Read Introduction]: My name is _________________. Thank you again for your willingness to be in this study. The main goal of this discussion is to better understand your experience participating in HOPE. I want to remind you that there are no right or wrong answers, and what we discuss here will be kept confidential; we will not share your personal information or responses with anyone outside of the study.

If during our discussion, there are issues or concerns that you would like to talk about, feel free to bring them up; I will take note of them and answer them directly after the interview. If I cannot answer them, I can refer you to someone who may be able to help. Before we start, can you confirm for the recorder that you have already provided written informed consent to take part in this discussion? [Wait for oral confirmation to begin].

A. Motivation for joining HOPE
Purpose: To get details about all of the reasons why she joined HOPE and whether she was influenced more from the ring or the study benefits. 1. What are the reasons why you joined HOPE? Possible probing topics: KEY PROBE: What were you hoping to gain from HOPE? Did you get what you came for? Please explain. KEY PROBE: Did you join HOPE more because of the ring or more because of the benefits you received from the study? Please explain. KEY PROBE: What concerns did you have about joining HOPE?
2. How important did you feel it was to discuss whether to join HOPE with someone else? Why? Possible probing topics: KEY PROBE: With whom did you actually discuss? Why? How did they react? KEY PROBE: How did you get them to accept your decision to participate (if applicable)? KEY PROBE: How did their opinions influence your decision? Why did you not discuss with (others not mentioned above)?
3. How has being part of HOPE affected you emotionally or socially? Possible probing topics: How has being in HOPE made you feel about yourself? (describe feeling and if positive or negative?) Why? Tell me about any positive or negative social experiences. (What happened, why, how did you feel? Etc.)
B. Ring Efficacy
Purpose: Find out her current understanding of how the ring works with different types of use and how that influenced her ring use. 4. I know you were told how to use the ring, but now I want to know in your own view how you THINK you need to use the ring to get your desired level of protection from HIV? (e.g. only when going to have sex, throughout the full month, intermittently depending on whether you feel at risk, etc.) Please explain. Possible probing topics: KEY PROBE: How are these beliefs the same or different from how you actually used the ring in HOPE? KEY PROBE: What are other ways of using the ring that you heard about?
5. Did you think you needed to be protected all the time in HOPE? Please explain. Possible probing topics: KEY PROBE: How did this influence your use of the ring? (i.e. did you keep it in all the time even if you didn’t feel you needed protection? or did you remove at times when you didn’t feel like you needed protection?) KEY PROBE: If you took the ring out to have sex for a few hours, how protected would you feel? Please explain. KEY PROBE: If you took the ring out and didn’t have sex during that time, how protected would you feel the next time you had sex? Please explain. KEY PROBE: If you removed the ring to clean it, how protected would you feel the next time you had sex? Please explain.
6. How do you think the ring works in your body? Possible probing topics: How fast do you think the ring provides protection after insertion? How fast do you think your protection decreases after removing? When you think about the drug in your body, how does that make you feel? How well do you think the ring protects against HIV? Do some people need more or less drug to be protected? What do you think affects how much drug is in one person’s body compared to another person?
C. Drug results; Adherence/non-adherence; Ring influence on sexual activity
Purpose: To explore her reaction and understanding of her drug results from HOPE and explore the factors that influenced the participants’ adherence or non-adherence in HOPE. We would like to look at all of your results throughout HOPE and discuss them with you. Here are your results… [Present over-time tool]
7. How do you feel about these results? Possible probing topics: What do these results mean to you? Do these results match with how you remember using the ring throughout HOPE? Why or why not? [record on PSF if matches/does not match] Do you trust the method used to test the rings? Why or why not? [record on PSF if trusts/does not trust]
8. Tell me about your sex life while in HOPE. Possible probing topics: How many sexual partners did you have while in HOPE? (Same or different as in ASPIRE?) What kind of partners were they (i.e. primary, casual, client, etc.)? What kind of sex did you have with each partner (vaginal, anal, oral)? How often? What kind of sex did you have during menses?
9. Women differ in whether they feel comfortable talking to their partners about the ring. What did your partner(s) know about the ring, if anything? Possible probing topics: Did you tell your partner(s) or how did he find out? How did you bring it up? How did he react? How did his reaction affect your use of the ring? Did his feelings about the ring change over time? What caused the change?
10. How did the ring affect your sexual life, if at all? Possible probing topics: KEY PROBE: How did the ring affect sexual pleasure? (for you and your partners) KEY PROBE: Did you or your partner ever feel the ring during sex? Please explain a situation when this happened. KEY PROBE: How did your partner influence your ability to use the ring? Did you sometimes remove the ring for sex? If yes, why? If no, why not? If removed for sex, where did you put it? When did you re-insert the ring? Did you do anything to avoid feeling the ring during sex? [Ask about sex positions or acts; foreplay/finger] If there were changes in your sex life, do you think they were good or bad? Why so?
11. What were the barriers to using the ring consistently? Possible probing topics: KEY PROBE: [If applicable] How did it make you feel when you had a “0”, “1”, or “2”? KEY PROBE: When was it the hardest to use the ring? Why? What did you do to overcome the barriers? KEY PROBE: What kept you participating in HOPE despite the barriers you experienced? KEY PROBE: What motivated you to use the ring despite the barriers you experienced? KEY PROBE: How at risk did you feel during these times (when not having a 3)? Why? How did receiving 3 rings affect your ability to use the ring? (e.g. easier or harder) Why?
[NOTE: If participant consistently had 2’s and/or 3’s, ask question 12, otherwise skip to Section D.] 12. What was motivating you to use the ring during this time? (e.g. desire to protect yourself from HIV, desire to help the community) Possible probing topics: KEY PROBE: [If had any 3’s] How did it make you feel when you had a “3”? KEY PROBE: [If had any 2’s] How did it make you feel when you had a “2”? Why? KEY PROBE: When was it hard to sustain this level of protection? Why? What did you do to overcome the barriers? Did you ever remove the ring during this time, even though you achieved “2’s” and “3’s”? How important was it to you to see high protection levels? Why was it so important?
D. Participant Engagement Activities & Study Procedures
Purpose: To gain insight on usefulness of site engagement activities at improving adherence. 13. What clinic events did you participate in during HOPE? (e.g. group adherence meetings, social events, waiting room discussions, etc.) Possible probing topics: How often did you attend the events? [Be specific about what the event was.] What did you hear or talk about during the events with other participants? Describe what came up. What was it like to interact with staff during these events? What was it like to interact with other participants? Did you discuss what occurred during the events with other participants or other friends/family/members of community? What other activities you would have liked to have been offered? What did you hear from staff or others about ring use at your clinic?
14. How did the clinic events influence your ring use and/or feelings about the ring? Possible probing topics: How were the activities helpful or not helpful in addressing: Yours or other participants’ perceptions of ring? Yours or other participants’ worries (side effects, harm) about the ring? Trust or mistrust of medical research or healthcare?
E. Ring acceptability
15. What is your current opinion of the dapivirine ring? [Use opinion tool] Possible probing topics: All the things you disliked (and why)? All the things you liked (and why)? How did your attitudes about the ring change over time in HOPE? What would make you like it more? What is your primary partner’s opinion of the ring? What were the attitudes of other participants while in HOPE? How did this affect your thoughts about the ring? What were the attitudes of other people you told about your ring? How did this affect your thoughts about the ring?
F. HIV Worries and HIV Protection
Purpose: To gather more in-depth information about her HIV risk perception and risk reduction strategies. 16. How worried were you about getting HIV while in HOPE? Possible probing topics: KEY PROBE: What increased or decreased your worry in HOPE? (e.g. multiple partners, ring use, condom use, seropositive partner, drug/alcohol use, receiving money/goods for sex, HIV testing, etc.)? KEY PROBE: How do your worries about HIV compare to other worries in your life (e.g. financial, work, partner relationship, family issues, etc.)? KEY PROBE: How did your concern about HIV affect your ring use?
17. What are you doing to protect yourself from HIV now that HOPE has ended? (e.g. condoms, HIV testing, PrEP, medical male circumcision, mutual monogamy, etc.) Possible probing topics: [Skip for seroconverters] Do you think you will get HIV? Why/why not? How motivated are you to stay HIV free? KEY PROBE: What do you think about waiting for the ring to be approved by your government before it is available to you? Are you more worried about getting HIV from your primary partner or from someone else? Please explain.
G. Ring uptake, marketing and product roll-out
18. We hope the ring will be widely available in the future. If it is, what would make you interested in using it? [Skip for seroconverters] Possible probing topics: KEY PROBE: What percentage of protection/ efficacy would the ring need to provide in order for you to use it in the future? KEY PROBE: How would you prefer to use the ring (e.g. wear at certain times or all the time)? What support would you need to help you use it? Where would you want to get the ring?
19. What about others – if the ring is widely available, what do you think will be important to others to make them want to use it? Possible probing topics: What would encourage their interest and make the ring appealing to them? Do you think it will be popular – with whom? What concerns would they most likely have? What advice would you give to overcome these concerns?
H. Wrap Up and Closing Remarks
20. We have talked about a lot of things today. Thank you for taking the time to talk to me and share your opinions. We truly appreciate your willingness to participate and discuss your experience with us. You’ve been with us for a long time now – so many years -- and we are grateful for your commitment to this research and to helping us move the ring forward in science. Before we end, I want to give you the chance to tell us anything else you think we should know about the ring – good things, bad things, challenges with using it – anything, that will help us better understand the truth about this ring.
21. Do you have any questions for me?

APPENDIX II: MTN 032/AHA Part 2 Codebook

Parent Code	Child Code	Definition
TRIALS		Anything about the ASPIRE or HOPE trials including her experience as a trial participant. Anything about the ASPIRE results or thoughts or feelings about HOPE ending, or differences between ASPIRE and HOPE. Include anything they reported that happened between ASPIRE and the start of HOPE. Use this code when comparing differences between ASPIRE and HOPE study design or procedures.
	JOIN/ REMAIN	Discussion around participants’ motivation to join and remain in HOPE. Include any discussion about joining or remaining for the ring, incentives -- monetary or health -- or any other. Include discussions about joining with others and about why she continued to participant despite barriers to ring use or lack of support. Double code with BARRIERS, SUPPORT or appropriate PEOPLE code as needed.
	SOCIAL/ EMOTIONAL IMPACT	Anything about how being in HOPE made the participant feel internally (emotionally) about themselves or how it affected them socially, including feelings about receiving their drug feedback. Also include discussion about feelings of altruism for joining the study or being a participant in the study. Include positive or negative experiences or feelings.
	ACTIVITIES	Anything about HOPE-organized activities such as tea parties, workshops, outreach events, male partner activities, etc. designed to address participant adherence and retention. Include discussion about the events influencing ring use or feelings about the ring. Includes description of actual or desired community engagement and education activities.
	CLINIC/ VISIT	Anything to do with the ASPIRE/HOPE clinic environment in general. Include anything with attendance or lack of attendance of ASPIRE/HOPE visits, keeping/missing appointments, duration of visits. Include discussions of monthly or quarterly visits.
	SITE-LEVEL FEEDBACK	Use for discussions about the feedback sites gave participants about the overall site’s adherence performance (not individual results) in ASPIRE or HOPE. Use for discussions about receiving interim HOPE results as well.
RING		Anything about the ring that is not previously covered under the child codes. If discussing how the ring changed sex life, double code with SEX. Include discussion around storing rings at home or issues storing rings at home.
	EFFICACY	Apply to discussions of product efficacy, either actual, perceived, or desired including when a participant talks about feeling protected from the ring. Should be used to capture discussions about how she thinks she needs to use the ring to get the protection she desires.
	MECHANISM OF ACTION	Apply to discussion about how participants think the ring works to prevent HIV, including how it works in her body or others’ bodies. Use when participant talks about how quickly or slowly the ring provides protection before insertion and after removal.
	OPINION NOW	Anything about anyone’s opinions (her or her partner or family/friends, etc.) about the ring NOW (at time of interview) including its characteristics, fear/ring worries about the ring, likes and dislikes.
	OPINION PAST/ OVERTIME	Anything about anyone’s opinions (her or her partner or family/friends, etc.) about the ring over-time (prior to time of interview) including its characteristics, fear/ring worries about the ring, likes and dislikes.
	SIDE EFFECTS/ PHYSICAL SAFETY	Apply to comments specifically about side effects and perceived side effects relating to the product from anyone who was exposed to the ring. Include discussion about physical safety of the ring including how the drug in her body makes her feel. If relates to feeling protected or being safe from HIV, code as EFFICACY.
	FUTURE	Code any discussion regarding willingness or plans to use (or not use) product in the future, in general not specific to any study. Include information about where they would want to get the ring in the future and how much they would be willing to pay and how often they would like to use the ring (all the time or intermittently). Include discussions about wanting to be (or suggestions on who should be) an advocate or champion for the ring. Include any recommendations or thoughts on who else would use or benefit from the ring if the ring became successful and what would make the ring appealing for others to use it as well as what concerns others may have about using the ring. Also include discussions about more general thoughts about the future post-trial.
ADHERENCE		Code anything not already under the child codes about adherence to the ring.
	INITIATION/FIRST USE	Anything about initiating ring use, either at the beginning of ASPIRE, HOPE, or after a period of dis-use. Include discussion about getting used to the ring, any issues, or lack of issues.
	USE	[About physically using/not using the ring]. Anything about using the ring or not using the ring. Include instances of removals (e.g. to clean or show others) or persistence with ring use and inserting/replacing the ring every month. Use this code for ring removals if the intention is to still use the ring (remove for less than a day). Use the DISCONTINUATION code if she talks about intentionally stopping ring use.
	BARRIERS	Apply when participant describes barriers she experienced during the HOPE trial to using the ring consistently. Include any difficulties with using the ring and how overcame these barriers. Double code with REMAIN or RISK as needed. For hypothetical barriers to using the ring in the future use FUTURE code.
	MOTIVATIONS/ SUPPORT	Apply when participants describe any motivations or reasons they are able to adhere to the ring or change her ring use (or things they think could have helped during HOPE trial), including any support she received from others, tools or reminders used to remember to change the ring, or a personal sense of altruism to use the ring for the benefit of other women/society. Double code with appropriate PEOPLE codes as needed. For hypothetical motivations or support for using the ring in the future use FUTURE code.
	DRUG FEEDBACK	Apply to discussion around her individual drug level results. Include what her results were and what they mean to her (how she understands them) as well as how important it was to her to receive a certain level (0–3).
	(DIS)AGREEMENT	Use for whether the participant agrees or disagrees with the results (i.e. whether they match how she remembers using the ring or not). (Child code of DRUG FEEDBACK)
	DRUG TESTING	Use for whether she trusts the method of testing the ring or not and any complaints about the timing of getting the results back. (Child code of DRUG FEEDBACK)
	DISCONTINUATION	Code any discussion of discontinuing ring use, due to voluntary or clinical reasons for shorter or long periods, with the intention of stopping ring use (even if she later changes her mind), for a minimum of a day. May include pregnancy, HIV sero-conversion, etc. If discussing thoughts about the study ending, use the TRIAL code. Use the USE code instead for instances of removal where she still intends to use the ring.
HIV		Anything about HIV or AIDS. Includes HIV testing outside of the trial setting. Use TRIALS if talking about HIV testing in ASPIRE/HOPE.
	RISK	Any discussion of perceived vulnerability of HIV and risk behavior or situations, including sexual risk, multiple partners, partner has other partners, other risk behavior (drugs/alcohol, pregnancy risk), unknow HIV status of partner or risk in general (i.e. having a reckless behavior, or being in a risky situation). Includes perceived lack of risk. Also includes discussion about HIV worries, including what influenced worry and timeline or changes in level of worry (before HOPE, after, etc.). If talking about feeling protected from the ring, use EFFICACY. The risk does not have to be blatantly identified by the participant, can be interpretative by coder. Double code with appropriate PEOPLE codes as necessary.
	PREVENTION METHODS	Anything about methods she is using, has used or plans to use to prevent HIV besides the ring or in combination with the ring. Could be male or female condom, or other methods i.e. oral PrEP, monogamy, regular testing, etc. Also includes all practical aspects of condom use (i.e., use/non-use, storage, transport, etc.), preference for ring and/or other products.
HEALTH		Anything about health not related directly to the ring (if ring related use SIDE EFFECTS/ PHYISCAL SAFETY). Includes anything about sexual and reproductive health, menses, and fertility.
CONTEXTUAL / STRUCTURAL		Include discussion of the social, cultural or structural context in which the participant is living. May include local practices, urban/rural location, HIV prevalence, sociocultural norms, religion, local beliefs, traditional medicine, interaction with local clinics or non-study healthcare (including healthcare staff), or other discussions of the community. Include anything about employment (including sex work), work, school, studies, domestic work, etc. Use also for anything in place before the trials began (e.g. cultural aversions to trials overall).
STIGMA/ MISCONCEPTIONS		Anything about any kind of rumors, gossip, stories (positive or negative), or stigma about research in general, ARVs, condoms, HIV prevention, HIV transmission, the HOPE study in particular (e.g. associated with Satanism or Witchcraft) or the ring or its formulation (e.g. it causes cancer). Include discussion about foreign researchers or white researchers as it applies to HOPE. Applies to external and internalized stigma/misconceptions.
SEX		Anything about her sex life, sexuality, sex practices (oral, vaginal or anal) or behaviors, including how the ring affected the sexual experience. Include comments about experience of discomfort or pain during sex and any mention of participant or partner either feeling or not feeling the ring during sex. Any comments about experience of pleasure during sex, either positive or negative. Any change in sexual practices as a result of ring use (different position, avoiding oral or digital sex, etc.). Applies to either her or her partner’s experience.
DISCLOSURE		Anything about disclosing trial participation, product use/non-use, drug feedback results, or HIV status to anyone. Also includes disclosing information about relationships and sex partners. Include discussions of honesty, dishonesty, lying, secrecy, or hiding something. Double code with appropriate PEOPLE codes as necessary.
PEOPLE		Anything about groups of people who DO NOT fall into the child code categories (e.g. boss, coworkers, etc.). Include community groups that one may be a member of. If coworkers or boss, double code with CONTEXTUAL/STRUCTURAL.
	COMMUNITY / NEIGHBORS	Anything about neighbors or members of the community
	FAMILY	Anything about immediate or extended family members. Double code with PEERS if their family member is also a participant.
	MALE PARTNERS	Anything about male partners – husbands, boyfriends, casual partners. Include number, type, communication, and decision-making power, relationship dynamics, trust, etc. Double code with MOTIVATION/SUPPORT if partner helped her adhere to ring.
	PEERS	Include fellow participants and other friends not in the study, including housemates who are not family members. Anything about other women in the ASPIRE or HOPE trials. Include discussion/conversations with other participants before/during/after trial, in the waiting room, etc. Should be applied to specific discussions of other participant actions, conversations, etc., not to the general ‘we’. Double code with FAMILY if their family member is also a participant.
	STAFF	Anything about HOPE and/or ASPIRE staff.
OPINION TOOL		Use for any discussion during the opinion tool (emoji stickers) activity.
VULVA/PENIS MODELS		Use for any discussion when the vulva puppets or penis models are used or discussed.
SEROCONVERSION		Anything about the participant’s personal experience sero-converting, including how one sero-converted, timing, and reaction.
PARKING LOT		Anything that does not fit into the above codes but we think may be a salient theme. To be discussed during coding calls regularly.
STAR		Star quote or star examples.

Availability of data and material:

The data will not be available to the public. If an individual is interested in exploring the data, they should contact the lead author.