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Expanding HIV PrEP with long-acting injectables: What can we learn about acceptability from a clinical trial?

An ounce of prevention is worth a pound of cure. Questions remain though in the field of HIV prevention on how best to deliver that ounce. The use of HIV pre-exposure prophylaxis (PrEP) is a way for people to prevent HIV infection. A daily oral PrEP pill is effective at reducing the risk of HIV infection among men who have sex with men (Grant et al., 2010) and among couples where only one partner is HIV-positive (Baeten et al., 2012). However, PrEP administered by pill, vaginal gel or ring products among women, many in sub-Saharan Africa, shows no (Marrazzo et al., 2015) or more modest (Baeten et al., 2016) effectiveness. The difference? It comes down to adherence, meaning it only works if people consistently take PrEP according to the prescribed schedule.

One way to eliminate the need for daily PrEP adherence is to make a drug that stays in the system and works over a longer period. These “long acting” drugs are often delivered through an injection. The safety and acceptability of a long-acting injectable drug was tested in the HPTN 077 phase 2a clinical trial. As part of the trial, my colleagues and I conducted a study to explore if participants would actually find a long-acting injectable PrEP product desirable and acceptable (Tolley et al., 2020). Our findings are important for researchers and program implementers planning to introduce or design such injectable products, and I describe several key takeaways here.

About HPTN 077 and our study

The HPTN 077 trial evaluated the safety, tolerability and acceptability of a long-acting injectable HIV prevention drug called cabotegravir. By acceptability we mean, “Are people willing to use the product if they desire protection from HIV?” and “Would they use this product if other options were also available?”

The trial enrolled a total of 199 men and women from Brazil, Malawi, South Africa and the United States (U.S.) who were randomized to receive either cabotegravir or placebo injections administered through two shots every 12 weeks (cohort one) or through one larger shot given every eight weeks (cohort two). Because the trial included both men and women, was located at sites in the U.S., South America and Africa, and evaluated two different dosing regimens, it provided a unique opportunity to understand how acceptability and future demand for a long-acting injectable PrEP product might vary by gender, geography and/or dosing strategy.

It is true that people who participate in clinical trials may differ from those who might use a future product. Still, there is much we can learn about product acceptability in the context of a trial.
It is true that people who participate in clinical trials may differ from those who might use a future product. Still, there is much we can learn about product acceptability in the context of a trial (Tolley and Severy, 2006). This includes how people experience using the product, their preferences for and/or dislike of product features, and whether they or others might consider using this product if it were offered through routine health services.

In our study, we conducted a baseline questionnaire to examine participants’ motivations for joining the trial, their past experiences with contraceptive or other injections, and their perceived HIV-related risks and product preferences. We conducted follow-up acceptability surveys one week after the first, second and third injection in both cohorts, as well as after the fourth and fifth injection for cohort two. We asked participants in follow-up surveys how acceptable they found a range of product attributes, experiences of pain and other side effects. In the last follow-up survey in each cohort, we asked participants to indicate their level of interest in using an injectable PrEP product if available post-trial.

An interesting aside is that we originally developed our acceptability questionnaires for a separate phase 2 trial of a different injectable PrEP product (rilpivirine) which was evaluated in African women, HPTN 076 (Tolley et al., 2019). When we use similar questionnaires in different studies, it makes it possible to compare findings across different products and populations.

Takeaways for researchers and implementers

Acceptability is high overall

Our study showed high levels of acceptability for long-acting injectable PrEP overall – with the highest levels in settings outside the U.S.
First, our study showed high levels of acceptability for long-acting injectable PrEP overall – with the highest levels in settings outside the U.S. (These findings are similar to results in the sister HPTN 076 study.) While more than half of participants in the U.S. and almost 75% of participants outside the U.S. preferred an injectable over other PrEP products at baseline, this preference increased to almost two-thirds for participants in the U.S. and more than 90% for participants outside the U.S. after receiving three or more rounds of injection. Most participants, regardless of gender, region, dosing regimen or study cohort, liked “somewhat” to “a lot” the number, size, location frequency and privacy of injections. However, assessments of pain were more variable, especially among participants in the cabotegravir product cohort. In fact, although few participants discontinued the trial early (n=27), those who did rated the level of pain they experienced as “less acceptable” than participants who completed the trial. From a service delivery perspective, providing information and proactive use of topical or systemic pain medications could support uptake and continued use of an injectable PrEP product.

Interest equals acceptability

The “fit of the product” in terms of its frequency, number, size and location of injections was a more important indicator of future demand than participants’ experience with pain or side effects.
Second, participants with the strongest interest in using a long-acting injectable outside of a trial setting also had the highest acceptability ratings for product attributes, were more likely to be from settings outside the U.S. and reported both personal and altruistic reasons for trial participation. Interestingly, the “fit of the product” in terms of its frequency, number, size and location of injections was a more important indicator of future demand than participants’ experience with pain or side effects. With a growing arsenal of HIV prevention products becoming available, policymakers and providers should ensure that an array of prevention options are available and that clients are presented with sufficient information about the attributes and potential trade-offs of different product options so they can make informed choices that best align with their life circumstances.

Experience with injectable contraception influences interest

…women who had previously used injectable contraception were more interested in using injectable PrEP…
Finally, women who had previously used injectable contraception were more interested in using injectable PrEP than women who had never used an injectable contraceptive method! African women were especially interested in using an injectable PrEP product; relatedly, three-fourths of women outside the U.S. compared to just 14% of women in the U.S. had ever used injectable contraception. If proven effective in women (HPTN 084 will decide this) we should look for ways to co-locate contraceptive and injectable PrEP services for women, while at the same time continuing to explore the potential to develop multipurpose injectable prevention options.

Final thoughts

There is still much we must learn after the HPTN 077 trial. Some of it is clinical. For example, does this injectable PrEP product work for women as it has been shown to work for men? But there is also much we can learn that is more sociocultural or behavioral. For example, will women continue to use an injectable product over a period of years and what aspects of the product will they find most or least acceptable? What aspects of the product, the user and his/her context will generate the willingness – or even desire to use the product beyond a clinical trial setting? Ultimately, we need to develop and deliver products that are not just effective but also desirable if we are going to replace a pound of cure (antiretroviral treatment) with an ounce of prevention (PrEP).


Photo credit: Daniel Chetroni/EyeEm (Getty Images)

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