As shown in Table 1, a total of 199 participants enrolled across the two cohorts, with 110 participants in C1 (82 on CAB LA and 28 on placebo) and 89 participants in C2 (69 on CAB LA and 20 on placebo). Overall, 66% of participants were born female (n = 132) and 47% of all participants were from non-U.S. sites (n = 93). Regional differences at baseline included employment, prior injection experience, HIV risk perception and HIV testing as an HIV prevention behavior. Seventy-four percent of U.S. participants versus 37% of non-U.S. participants were employed either full- or part-time. Among females, only 14% of U.S. versus 76% of non-U.S. females had ever used an injectable contraceptive method. About twice as many non-U.S. participants as those from the U.S. were somewhat or very worried about their risk of HIV. Some differences in employment status and HIV risk perception also exist by sex-at-birth and cohort (Table 1).
Aim 1: Acceptability of Injectable PrEP Characteristics, Attributes and Physical Experiences
Baseline Attitudes Towards Injectable PrEP Characteristics
At baseline, participants most liked the idea that a PrEP injectable would be easier to use than other methods, might protect against HIV and could provide a longer duration of protection than other methods. However, about a third of participants expressed concerns about potential side effects and pain (Table 2).
Acceptability of Product Attributes
Participants’ acceptability of injectable attributes was high. After receiving a first injection at week 6, at least 50% of participants in C1 and approximately 75% or more of participants in C2 rated the number, frequency, location and duration of injection as highly acceptable (Figs. 1 and 2). Similar patterns of product attribute-related acceptability were reported at 1 week after last full injection (week 30 for C1 and 34 for C2) (Figs. S1 and S2 in Supplemental Materials). Overall, no significant difference was observed by region and visit. However, more non-U.S. participants reported pain to be unacceptable (a little, somewhat or a lot) than did U.S. participants at both timepoints. Participants receiving CAB LA injections were more likely to find the location of the injectable—in the buttocks—acceptable than those receiving saline injections (Figs. S3 and S4).
On the other hand, participants’ acceptability of physical experiences and their reported number of ISRs differed by cohort and arm. After their first injection, approximately 40% of C1 participants in the CAB LA arm and 75% of C1 placebo participants reported either experiencing no pain or pain that was highly acceptable (Fig. S3). This was similar for C2 participants (Fig. S4). After each injection visit, participants in the placebo arm reported significantly higher acceptability of physical experiences than those in the CAB LA arm. In addition, C2 versus C1 participants and those randomized to the placebo versus CAB LA arm reported significantly fewer ISRs across each timepoint (Table 3).
Product attribute acceptability scores remained high across study follow-up and were significantly higher in C2 than C1 participants, but did not differ by region, sex at birth, or arm. While composite scores for acceptability of physical experiences (i.e., injection site pain, rash and any side effects) were also generally high over time, participants’ scores were significantly higher after the first injection in C2 versus C1 and among those on placebo versus CAB LA over time.
Over the injection phase of the trial, 27 participants permanently discontinued injectable product use. Stated reasons for discontinuation included product-related side effects, inability or unwillingness to follow study procedures, abnormal lab values, reactive HIV tests, and desire for pregnancy or to terminate the study . In a supplemental analysis, we found a significant inverse association between participants’ perceived acceptability of pain and discontinuation; participants with higher acceptability of pain had a lower risk for discontinuation. The risk of product discontinuation during the injection phase was associated with a 23% (hazard ratio 0.77, p = 0.02) reduction per one unit increase in participant’s acceptability of pain score.
Aim 2: Future Interest in Using Injectable PrEP
Preferences for Prevention
At baseline, approximately half of U.S. participants, but almost three-fourths of non-U.S. participants (51% vs 71%) preferred an injectable HIV prevention method to other methods. In the U.S., preferences for a LAI-PrEP were higher among males than females. In non-U.S. sites, females were more likely to prefer an injectable PrEP compared to their male counterparts at baseline. At 1 week after last injection, (i.e., week 30 for C1 and week 34 for C2), 64% U.S. participants and 93% of non-U.S. participants preferred injectable PrEP to other methods (Table 4).
Determinants of Future Interest in Injectable PrEP (FIIP)
In univariate models (Table 5), FIIP was positively associated with non-U.S. versus U.S. region (OR 2.9, p = 0.0002), with higher levels of acceptability for product attributes (OR 4.77, p < 0.0001) and for physical experiences (OR 1.6, p = 0.0002), having higher levels of altruism (OR 1.96, p < 0.0001) and fewer total injection site reactions (OR 0.9, p = 0.004). In addition, C2 participants, who received one injection every 2 months, tended toward higher levels of FIIP than those in C1, who received two injections every three months (OR 1.64, p = 0.07). Females tended to have higher FIIP than males (OR 1.48, p = 0.16), as well as those with higher perceived HIV risk (OR 1.34, p = 0.13) and those with higher levels of baseline condom use (OR 1.12, p = 0.10), although these associations were not statistically significant. Among participants born female, having ever used a contraceptive injectable was associated with a significant increase in FIIP (OR 3.4, p = 0.001).
In the multivariable model, FIIP was most strongly associated with the composite acceptability score for product attributes (OR 4.84, p < 0.0001) (Table 5). Non-U.S. participants (OR 2.9, p = 0.0003) and those with higher levels of altruism at baseline (OR 1.52, p = 0.005) had higher FIIP. FIIP tended to be higher among participants in C2 than in C1. However, acceptability of physical experiences and number of reported ISRs were no longer significantly associated with FIIP in the multivariable model. In the sensitivity analysis, redefining the regional variable (Africa versus Americas) to more closely reflect differences in the epidemics, the multivariable model results were similar (Table SI). In this second model, African participants and those with higher product attribute acceptability reported higher FIIP as well as those with altruistic reasons for trial participation.