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Patient-Reported Outcomes Through 1 Year of an HIV-1 Clinical Trial Evaluating Long-Acting Cabotegravir and Rilpivirine Administered Every 4 or 8 Weeks (ATLAS-2M)
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Preference
Among those participants in the Q8W arm with prior CAB + RPV exposure responding to the preference question at Week 48, 94% (n = 179/191) preferred CAB + RPV LA Q8W dosing versus Q4W (3%, n = 6/191) or daily oral dosing (2%, n = 4/191) (Fig. 5a). Participants without prior CAB + RPV exposure who received CAB + RPV LA Q8W dosing with recorded responses to the preference question at Week 48 also preferred this regimen over daily oral dosing (98%, n = 300/306) (Fig. 5a). Participants in the Q4W group (no experience of Q8W dosing) responding to the preference question at Week 48 preferred CAB + RPV LA Q4W dosing over daily oral dosing (94%, n = 468/497) (Fig. 5b). The most commonly cited reasons for long-acting preference were administration frequency and convenience, whereas the most common reasons supporting preference for daily oral dosing were the impact of side effects and convenience (electronic supplementary material Figure S4a, S4b, and S4c).
Abstract
Background
Advances in HIV-1 therapeutics have led to the development of a range of daily oral treatment regimens, which share similar high efficacy rates. Consequently, more emphasis is being placed upon the individual's experience of treatment and impact on quality of life. The first long-acting injectable antiretroviral therapy for HIV-1 (long-acting cabotegravir + rilpivirine [CAB + RPV LA]) may address challenges associated with oral treatment for HIV-1, such as stigma, pill burden/fatigue, drug–food interactions, and adherence. Patient-reported outcomes (PROs) collected in an HIV-1 clinical trial (ATLAS-2M; NCT03299049) comparing participants' experience with two dosing regimens (every 4 weeks [Q4W] vs. every 8 weeks [Q8W]) of CAB + RPV LA are presented herein.
Methods
PRO endpoints evaluated through 48 weeks of therapy included treatment satisfaction (HIV Treatment Satisfaction Questionnaire [HIVTSQ]), treatment acceptance ("General Acceptance" domain of the Chronic Treatment Acceptance [ACCEPT®] questionnaire), acceptability of injections (Perception of Injection [PIN] questionnaire), treatment preference (questionnaire), and reasons for switching to/continuing long-acting therapy (exploratory endpoint; questionnaire). Participants were randomized 1:1 to receive CAB + RPV LA Q8W or Q4W. Results were stratified by prior CAB + RPV exposure in either preplanned or post hoc analyses.
Results
Overall, 1045 participants were randomized to the Q8W (n = 522) and Q4W (n = 523) regimens; 37% (n = 391/1045) had previously received CAB + RPV in ATLAS. For participants without prior CAB + RPV exposure, large increases from baseline were reported in treatment satisfaction in both long-acting arms (HIVTSQ status version), with Q8W dosing statistically significantly favored at Weeks 24 (p = 0.036) and 48 (p = 0.004). Additionally, improvements from baseline were also observed in the "General Acceptance" domain of the ACCEPT questionnaire in both long-acting arms for participants without prior CAB + RPV exposure; however, no statistically significant difference was observed between arms at either timepoint (Week 24, p = 0.379; Week 48, p = 0.525). Significant improvements (p < 0.001) in the "Acceptance of Injection Site Reactions" domain of the PIN questionnaire were observed from Week 8 to Weeks 24 and 48 in both arms for participants without prior CAB + RPV exposure. Participants with prior CAB + RPV exposure reported high treatment satisfaction (mean [HIVTSQ status version]: Q8W 62.2/66.0; Q4W 62.0/66.0), treatment acceptance (mean: Q8W 89.3/100; Q4W 91.2/100), and acceptance of injection site reactions (mean [5 = not at all acceptable; 1 = totally acceptable]: Q8W 1.72; Q4W 1.59) at baseline/Week 8 that were maintained over time. Participants without prior CAB + RPV exposure who received Q8W dosing preferred this regimen over oral CAB + RPV (98%, n = 300/306). Among those with prior Q4W exposure, 94% (n = 179/191) preferred Q8W dosing versus Q4W dosing (3%, n = 6/191) or oral CAB + RPV (2%, n = 4/191).
Conclusions
Both long-acting regimens provided high treatment satisfaction and acceptance, irrespective of prior CAB + RPV exposure, with most participants preferring Q8W dosing over both the Q4W regimen and their previous daily oral regimen. The PRO data collected at Week 48 support the therapeutic potential of CAB + RPV LA.
Funding
ViiV Healthcare and Janssen.
Discussion
The PRO data collected at Week 48 of the ATLAS-2M study demonstrate that both dosing regimens of CAB + RPV LA can improve and maintain treatment satisfaction and acceptance, supporting the therapeutic potential of the injectable regimen and highlighting participants' preference for long-acting therapy over daily oral dosing. These results complement the high overall rates of virologic suppression and favorable safety and tolerability profiles observed for CAB + RPV LA Q8W and Q4W in ATLAS-2M [18]. The PRO analysis was stratified by prior CAB + RPV exposure to accommodate the difference in treatments assessed at baseline. As such, participants without prior CAB + RPV exposure were reporting their experience with daily oral therapy at baseline, whereas participants with prior CAB + RPV exposure were reporting their experience with the Q4W long-acting regimen they received during the ATLAS study.
Although ISRs were frequent during ATLAS-2M [18], particularly pain events, they seldom led to withdrawal and nearly all participants preferred the long-acting regimen to their previous oral therapy. The majority of participants reported high acceptability of pain and local reactions at early timepoints in the study, with acceptability increasing with subsequent injections. These improvements are mirrored by the reduction in frequency of ISRs over time observed in the safety analysis of ATLAS-2M [18], providing evidence that ISRs associated with CAB + RPV LA become perceived as less burdensome over time by participants. Despite ISRs being more prevalent per visit with the Q8W regimen versus the Q4W regimen, although offset over time by less frequent dosing, similar improvements in acceptability of pain and local reactions were observed regardless of dosing regimen (Q8W vs. Q4W). Therefore, it could be argued that the increased volume of liquid delivered with the Q8W regimen does not impact the tolerability or acceptability of injections (Q8W 2 x 3 mL; Q4W 2 x 2 mL).
With respect to treatment satisfaction and acceptance, participants entering ATLAS-2M with only prior experience of daily oral therapy reported large improvements at Weeks 24 and 48 across both long-acting groups. The magnitude of the improvements were consistent with the improvements in satisfaction and acceptance observed in participants in the ATLAS and FLAIR phase 3 clinical studies, which for ATLAS was proven to meet the minimal clinically important difference threshold [16, 17, 22]. For participants entering ATLAS-2M having received CAB + RPV LA Q4W in ATLAS, treatment satisfaction and acceptance was high at baseline and maintained through Week 48 in both long-acting groups. Further, most participants transitioning from ATLAS switched from the Q4W regimen and had therefore accumulated ≥ 96 weeks of CAB + RPV LA exposure by Week 48 of ATLAS-2M (65%, n = 253/391). These longer-term findings are consistent with the high participant satisfaction reported at Week 96 in FLAIR, and when taken together suggest that the benefits of long-acting therapy can be sustained over ∼ 2 years [38]. Over time, minor fluctuations are to be expected in treatment satisfaction and acceptance scores, both of which remained at high levels throughout the study. For participants with prior CAB + RPV exposure, the negative trend in treatment acceptance score was more pronounced for the Q4W arm. This could be attributable to some participants' disappointment with receiving the same regimen they had received in ATLAS, missing the opportunity to initiate the less frequent, potentially more desirable, Q8W dosing regimen. For treatment satisfaction scores, small decreases were observed between Weeks 24 and 48, irrespective of participants' prior CAB + RPV exposure. For participants without prior CAB + RPV exposure and participants randomized to the Q8W regimen, this may be a consequence of inflated satisfaction scores recorded at Week 24 due to the initial excitement associated with receiving a novel therapeutic or being randomized to the less frequent dosing regimen.
For participants with prior CAB + RPV exposure, high values for both treatment acceptance and satisfaction (HIVTSQs) were maintained across treatment regimens; however, no significant differences were observed between Q8W and Q4W dosing. A significant difference favoring the Q8W regimen was only observed in treatment satisfaction (HIVTSQs) for participants without prior CAB + RPV exposure. This can be partially attributed to the ceiling effects observed with the use of the ACCEPT and HIVTSQs instruments, which mean the high baseline values for participants with prior CAB + RPV exposure do not permit the full magnitude of treatment effects to become apparent. With the use of HIVTSQc, developed to account for ceiling effects, the change in satisfaction relative to prior treatment scores significantly favored Q8W over Q4W at Week 48, irrespective of prior exposure.
Preference questionnaires revealed that almost all participants with experience of both the Q8W and Q4W regimens preferred Q8W dosing, the reasons for which highlight the perceived value of reduced dosing frequencies and greater convenience for participants. In addition to the participant-reported reasons for preference, the Q8W regimen has been observed to have comparable efficacy and tolerability to the Q4W regimen [18]. Further, the Q8W regimen offers fewer opportunities for missed injections and requires half the number of clinical visits per year. Whilst previous studies have reported strong preferences for the long-acting regimen over daily oral antiretroviral therapy [16, 17, 20, 22], ATLAS-2M represents the first phase 3 clinical study to report participant preference for Q8W dosing over Q4W dosing, consistent with the greater increases in satisfaction reported in Q8W arm participants compared with those in the Q4W arm. The Q8W regimen has several potential real-world advantages over Q4W dosing, as it facilitates fewer clinical interventions as well as reducing the total number of treatments/visits to six per year (excluding first loading dose).
Overall, the findings of these analyses provide robust evidence supporting the benefits of long-acting therapy outside of the clinically focused parameters of efficacy and safety, prioritizing an evaluation of the patient's experience and preferences. This sentiment is in keeping with the general trend towards a more patient-centered focus in the care of people living with HIV-1. Patient satisfaction may contribute to individual improvements in adherence, which in turn translates to better management of HIV [23]. Increasing patient satisfaction is also vital to improving overall quality of life for people living with HIV-1, a metric of ever-increasing importance as the efficacy, tolerability, and accessibility of HIV therapeutics continue to improve [1]. The results collected at Week 48 of the ATLAS-2M study are illustrative of the therapeutic potential of CAB + RPV LA, not only as an efficacious and well-tolerated maintenance regimen, but also as a regimen with the potential to facilitate improvements in adherence and a person's overall quality of life. The translation of long-acting therapies into everyday widespread clinical practice warrants comprehensive investigation and is undergoing evaluation [39].
Limitations
The present study has several limitations. Although ATLAS-2M met its enrollment target of 25% female participants (sex at birth) and also included > 25% of participants aged ≥ 50 years, the enrolled population did not include large proportions of other under-represented groups, including people from racial and ethnic minority groups, transgender individuals, and individuals with historic suboptimal adherence [18]. In addition, the enrolled population may reflect a select population of people living with HIV-1 interested in long-acting therapies. Further research, including real-world evidence, is ongoing or planned to evaluate CAB + RPV LA in different patient demographics and describe use in broader populations of people living with HIV-1. For example, the ongoing LATITUDE study (NCT03635788) is investigating CAB + RPV LA in a population with historic suboptimal adherence [40]. In addition, studies that directly compare CAB + RPV LA Q8W with contemporary standard of care antiretroviral regimens are warranted and have been planned, such as the upcoming SOLAR (NCT04542070) study, which will evaluate CAB + RPV LA dosed every 2 months compared with a bictegravir/emtricitabine/tenofovir alafenamide–based oral daily regimen [41]. A small proportion of study participants (14%; n = 147/1020 [respondents]) answered "cost of alternative options/current HIV drug or to continue receiving free study drug" as their reason for switching to/continuing long-acting therapy. This result could have inadvertently revealed a source of unconscious bias, which may have augmented some PRO item scores. The absence of a therapeutic alternative for participants due to economic constraints may also qualify as undue influence. However, participants provided written informed consent, which was approved by national, regional, or investigational center ethics committees or institutional review board, in accordance with The International Conference on Harmonisation Good Clinical Practice Guideline and applicable country-specific requirements.
Conclusions
Irrespective of dosing regimen, CAB + RPV LA was associated with large increases in treatment satisfaction and high acceptance of ISRs for those naive to CAB + RPV. For those with prior experience of the intramuscular regimen, CAB + RPV LA maintained high levels of satisfaction and acceptance. Most participants preferred Q8W and Q4W dosing over daily oral dosing, with Q8W also preferred over Q4W dosing. The PRO data presented here, along with the high rates of virologic suppression, low rates of virologic failure, and favorable safety and tolerability profiles presented in the primary analysis, support the therapeutic potential of monthly or every 2 months CAB + RPV LA and highlight participants' preference for long-acting therapy over daily oral dosing.
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