Clinical Consequences of Delaying Implementation of Long-Acting Antiretroviral Therapy for People With HIV and Persistent Viremia in the United States

Abstract

Background: People with HIV (PWH) with persistent viremia and adherence challenges to oral antiretroviral therapy (ART) can achieve viral suppression (VS) with long-acting cabotegravir/rilpivirine (LA-CAB/RPV). The US guidelines, however, recommend CAB/RPV only in limited situations. We projected the impact of delaying LA-CAB/RPV implementation while awaiting trial data.

Methods: Using a microsimulation model, we considered 2 approaches for PWH with persistent viremia and intermittent care engagement: daily first-line oral ART or LA-CAB/RPV, both with intensive-support-services (ISS) to maximize adherence. We evaluated 4 CAB/RPV implementation scenarios: (1) Current practice (1% on CAB/RPV); (2) hypothetical Immediate/Delayed complete implementation (100% CAB/RPV after 0-4 year); (3) 2 Post-trial implementation scenarios: Post-one-arm-trial implementation (1-year trial, 5% uptake/year thereafter), Post-randomized-trial implementation (3-year trial, 15% uptake/year thereafter; and (4) Immediate incomplete implementation (1%-20% uptake/year). Outcomes were virologically suppressed person-years (VSPY) and 5-yearmortality. Inputs included cohort size 33,600, initial CD4 count of 150/µL, 6-month-VS from observational data: 23% (oral ART), 65% (LA-CAB/RPV).

Results: Current practice projects 35 810 VSPY and 17 640 deaths at 5 years. Immediate complete implementation increases VSPY by 26 830 and averts 3980 deaths; Delayed complete implementation produces 5370 fewer VSPY and 800 more deaths/delayed year. Post-one-arm-trial implementation yields 1700 more VSPY and 330 fewer deaths than Current practice; Post-randomized-trial implementation yields 1280 more VSPY and 270 fewer deaths. Immediate incomplete implementation at 3% and 2% uptake/year is similar to Post-one-arm-trial implementation and Post-randomized-trial implementation.

Conclusions: LA-CAB/RPV for US PWH with persistent viremia and intermittent care engagement would increase VS and decrease mortality. Increased LA-CAB/RPV implementation with ISS should be undertaken while awaiting trial results.

Keywords: HIV; clinical trials; implementation; long-acting antiretrovirals; resistance.

Figure 1.. CAB/RPV Implementation levels of four implementation scenarios.

The x-axis represents the year(s) from the status quo, and the y-axis represents the implementation level (% of the population receiving CAB/RPV) at a given time. 1) The grey line represents Current practice (1% of the modeled population receives CAB/RPV over the next 5 years), 2) Green green lines represent Immediate and Delayed complete implementation scenarios (100% of the modeled population receives CAB/RPV) with 1–4 years delayed, 3) Orange lines represent 2 Post-trial implementation scenarios: 3a), Post-one-arm trial implementation (1-year trial, 5% uptake/yr thereafter), 3b) Post-randomized-trial implementation (3-year trial, 15% uptake/yr thereafter), 4) Blue lines represent Immediate incomplete implementation scenarios with 1–20% uptake/year. Abbreviations: CAR/RPV, cabotegravir/rilpivirine. ^a Current practice indicates 1% of the modeled population receives CAB/RPV over the next 5 years. ^b Immediate complete implementation indicates 100% of the modeled population receives CAB/RPV over the next 5 years. ^c Post-one-arm-trial implementation indicates implementation after a 1-year one-arm trial with 5% uptake/year thereafter. ^d Post-randomized-trial implementation indicates implementation after 3-year randomized trial with 15% uptake/year thereafter.

Figure 2.. One-way sensitivity analysis of implementation scenarios for the outcomes of virologically suppressed person-years (Panels A and B) and deaths at five years (Panels C and D).

Each tornado diagram displays the impact of varying individual parameters on the outcome for that scenario. Each horizontal bar displays the range of outcomes that result from varying a single parameter. The base case value is in parentheses, followed by the varied range. The vertical line through the bars represents the outcomes from the base case estimates. (A) represents the percent of virologically suppressed person-years in Current practice (CAB/RPV for 1% of the modeled population over the next 5 years), (B) percent of virologically suppressed person-years in Immediate complete implementation (CAB/RPV for 100% of the modeled population over the next 5 years), (C) percent of deaths in Current practice, and (D) percent of deaths in Immediate complete implementation. Abbreviations: CAB/RPV, cabotegravir/rilpivirine; CD4, cluster of differentiation 4; PI, protease inhibitor-based antiretroviral therapy; RMR, relative mortality ratio compared to the general population; RTC, return to care. ^a Current practice indicates 1% of the modeled population receives CAB/RPV over the next 5 years. ^b Immediate complete implementation indicates 100% of the modeled population receives CAB/RPV over the next 5 years. * The bar is not visible because the range of outcomes associated with varying the corresponding parameter is very small. ^† The disengagement from care at 12 months (22%), 32–2%, represents those who are on CAB/RPV. The disengagement from care at 12 months for those who are on oral INSTI is (82%), 84–77%, and on PI is (97%), 97–98%.

Figure 3.. Virologically suppressed person-years gained over 5 years, compared to Current practice, as a function of years of delay to trial end (trial length) and post-trial uptake/year.

This heatmap shows the tradeoff between the delay and post-trial uptake of CAB/RPV. Light green represents fewer virologically suppressed person-years gained, compared to Current practice (CAB/RPV for 1% of the modeled population over the next 5 years), and dark green represents more virologically suppressed person-years gained. The x-axis is the years delayed (length of the trial) varied between 1–4 years, and the y-axis is the % uptake/year post-trial. The leftmost column (0-year delay) represents Immediate incomplete implementation scenarios (immediate CAB/RPV uptake at 1–20% uptake/year). ^a Number indicates virologically suppressed person-years gained in Post-one-arm-trial implementation scenario (a 1-year trial with 5% uptake/year thereafter). ^b Number indicates virologically suppressed person-years gained in Post-randomized-trial implementation scenario (a 3-year trial with 15% uptake/year thereafter.