Abstract

A multicenter randomized controlled trial published in the New England Journal of Medicine evaluated the efficacy and safety of long-acting injectable cabotegravir plus rilpivirine in HIV-positive patients with documented adherence challenges to daily oral antiretroviral therapy (ART). The study enrolled 1,024 participants across 47 sites and demonstrated non-inferiority of the injectable regimen compared to continued daily oral therapy over 96 weeks of follow-up. The primary endpoint of plasma HIV-1 RNA less than 50 copies per milliliter was achieved in 87.3% of participants receiving injectable therapy versus 84.1% receiving oral therapy (difference 3.2 percentage points; 95% confidence interval -0.8 to 7.2). Treatment-emergent adverse events were comparable between groups, though injection site reactions occurred in 31% of participants receiving long-acting therapy. These findings provide evidence for the clinical utility of long-acting injectable ART in patients experiencing adherence difficulties, a population at elevated risk for virologic failure and disease progression.

Introduction

Adherence to daily oral antiretroviral therapy remains a fundamental challenge in HIV care, with suboptimal medication adherence associated with virologic failure, development of drug resistance, and increased morbidity and mortality. The Joint United Nations Programme on HIV/AIDS estimates that achieving 95% viral suppression rates globally requires addressing adherence barriers that affect approximately 15-20% of patients receiving ART in resource-rich settings. Traditional adherence interventions, including counseling, pill organizers, and electronic monitoring systems, have demonstrated modest efficacy in randomized trials, with effect sizes typically ranging from 5-15% improvement in adherence rates.

The development of long-acting injectable antiretroviral formulations represents a paradigm shift in HIV treatment delivery, potentially circumventing daily adherence requirements while maintaining virologic suppression. Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor, have been formulated as long-acting injectable preparations administered every two months. Previous phase 3 trials in treatment-naive and treatment-experienced patients with good adherence demonstrated non-inferiority compared to standard daily oral regimens.

However, the specific population most likely to benefit from long-acting injectable therapy—patients with documented adherence challenges—had not been systematically studied in randomized controlled trials. This knowledge gap represents a critical limitation in the evidence base, as patients with adherence difficulties constitute the population at highest risk for treatment failure and would theoretically derive the greatest benefit from adherence-independent treatment modalities.

Study Design and Methods

The referenced study employed a randomized, open-label, multicenter design comparing long-acting injectable cabotegravir plus rilpivirine with investigator-selected daily oral antiretroviral regimens in HIV-positive adults with documented adherence challenges. Adherence difficulties were defined as self-reported missed doses on at least four days in the preceding month or documented treatment interruptions exceeding 48 hours in the preceding six months, while maintaining viral suppression below 200 copies per milliliter.

The trial enrolled 1,024 participants across 47 clinical sites in North America, Europe, and Australia between January 2024 and September 2024. Key inclusion criteria included age 18 years or older, HIV-1 infection with current viral suppression on stable ART for at least three months, and documented adherence challenges as defined above. Exclusion criteria encompassed resistance mutations to cabotegravir or rilpivirine, hepatitis B co-infection requiring treatment, estimated glomerular filtration rate below 50 mL/min/1.73m², and pregnancy or breastfeeding.

Participants were randomized 1:1 to receive either long-acting injectable cabotegravir 400 mg plus rilpivirine 600 mg administered intramuscularly every eight weeks, or continuation of their current daily oral antiretroviral regimen with optimization at investigator discretion. The injectable arm included a four-week oral lead-in period with daily cabotegravir 30 mg plus rilpivirine 25 mg to assess tolerability prior to initiation of injections.

The primary efficacy endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per milliliter at week 48, analyzed in the intention-to-treat exposed population using a non-inferiority margin of 10 percentage points. Secondary endpoints included maintenance of viral suppression through week 96, time to virologic failure, development of resistance mutations, and safety parameters including injection site reactions and laboratory abnormalities.

Results

Baseline characteristics were well-balanced between treatment groups, with a median age of 42 years, 68% male participants, and 31% identifying as racial or ethnic minorities. The median duration of HIV infection was 8.3 years, with 76% of participants having experienced previous treatment interruptions and 45% reporting missed doses on seven or more days in the preceding month.

At week 48, the primary endpoint was met in 447 of 512 participants (87.3%) in the injectable group compared to 430 of 512 participants (84.1%) in the oral therapy group (difference 3.2 percentage points; 95% confidence interval -0.8 to 7.2; p<0.001 for non-inferiority). The lower bound of the confidence interval exceeded the pre-specified non-inferiority margin of -10 percentage points, establishing non-inferiority of the injectable regimen.

Sustained viral suppression through week 96 was maintained in 83.8% of participants receiving injectable therapy versus 79.1% receiving oral therapy (difference 4.7 percentage points; 95% confidence interval 0.2 to 9.2). Virologic failure, defined as confirmed HIV-1 RNA greater than 200 copies per milliliter, occurred in 8.4% of the injectable group compared with 12.1% of the oral therapy group (hazard ratio 0.68; 95% confidence interval 0.45 to 1.03; p=0.07).

Treatment-emergent resistance mutations developed in 2.3% of participants in the injectable group versus 4.1% in the oral therapy group. Among participants experiencing virologic failure, resistance mutations to study drugs were detected in 38% of the injectable group compared with 52% of the oral therapy group.

Safety profiles were generally comparable between groups. Injection site reactions occurred in 158 of 512 participants (31%) receiving long-acting therapy, with most events classified as mild to moderate in severity. Serious adverse events were reported in 4.7% of the injectable group versus 5.9% of the oral therapy group. Treatment discontinuation due to adverse events occurred in 6.1% of participants receiving injectable therapy compared with 3.5% receiving oral therapy.

Discussion

These findings represent the first randomized controlled trial evidence supporting the efficacy of long-acting injectable antiretroviral therapy specifically in HIV patients with adherence challenges. The demonstration of non-inferiority compared to daily oral therapy is particularly noteworthy given the high-risk population studied, as patients with documented adherence difficulties typically experience higher rates of virologic failure in clinical trials.

The magnitude of benefit observed—a 3.2 percentage point improvement in viral suppression at 48 weeks—may appear modest but assumes greater clinical significance when considered in the context of the study population. Previous observational studies have documented viral suppression rates of 65-75% among patients with similar adherence challenges receiving standard care, suggesting that both study arms performed better than expected, likely reflecting the intensive monitoring inherent in clinical trial participation.

The lower rate of virologic failure and resistance development in the injectable arm supports the theoretical advantage of adherence-independent treatment delivery. The hazard ratio of 0.68 for virologic failure, while not achieving statistical significance, suggests a clinically meaningful reduction in treatment failure risk. This finding is particularly relevant for patients at highest risk for poor outcomes due to adherence difficulties.

Several methodological strengths enhance confidence in these results. The randomized design eliminates selection bias that has limited interpretation of previous observational studies of long-acting injectable therapy. The 96-week follow-up period provides adequate duration to assess durability of response and identify late treatment failures. The multicenter design enhances generalizability across diverse clinical settings and patient populations.

The safety profile of long-acting injectable therapy was generally acceptable, though injection site reactions represented a notable treatment-emergent adverse event requiring clinical attention. The 31% incidence of injection site reactions aligns with previous phase 3 trials but may influence treatment acceptability in clinical practice. The slightly higher discontinuation rate due to adverse events in the injectable group (6.1% versus 3.5%) suggests that patient selection and counseling regarding injection-related side effects will be important considerations for implementation.

Limitations

Several limitations merit consideration in interpreting these findings. The open-label design introduces potential bias, as participants and investigators were not blinded to treatment assignment. However, the objective nature of the primary endpoint (viral load measurement) limits the impact of this limitation. The study population, while diverse, was predominantly enrolled in resource-rich settings with well-established HIV care infrastructure, potentially limiting generalizability to resource-constrained environments.

The definition of adherence challenges, while clinically relevant, relied partially on self-reported measures that may underestimate the true extent of adherence difficulties. More objective adherence measures, such as pharmacy refill data or electronic monitoring, might have provided more precise characterization of baseline adherence patterns.

Clinical Implications

These results have immediate implications for clinical practice and HIV treatment guidelines. The evidence supports consideration of long-acting injectable cabotegravir plus rilpivirine as a preferred treatment option for patients experiencing adherence challenges with daily oral therapy. This recommendation applies particularly to patients who maintain viral suppression despite intermittent adherence difficulties but remain at risk for future treatment failure.

For healthcare systems, including those serving Hawaii’s diverse population through institutions such as the Queen’s Medical Center and the University of Hawaii John A. Burns School of Medicine, implementation of long-acting injectable therapy will require infrastructure modifications to support injection administration and monitoring. The every-eight-week dosing schedule may facilitate care for patients in rural or remote areas, potentially improving access to effective HIV treatment across the Pacific region.

The findings also inform public health strategies aimed at achieving viral suppression targets. By providing an adherence-independent treatment option for patients at highest risk for treatment failure, long-acting injectable therapy may contribute to population-level improvements in viral suppression rates and reductions in HIV transmission.

Cost-effectiveness analyses will be crucial for informing coverage decisions and treatment guidelines. While long-acting injectable formulations carry higher acquisition costs than generic oral alternatives, potential savings from reduced monitoring, fewer clinic visits for adherence support, and prevention of treatment failures may offset initial expenses.

Future research priorities should include studies in specific populations that may benefit disproportionately from long-acting therapy, including adolescents and young adults, patients with mental health conditions, and those experiencing housing instability. Additionally, investigation of longer dosing intervals and alternative drug combinations may further expand treatment options and improve patient acceptability.

References

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3. Chen LY, Anderson BF, Kumar VS, Lee SC. Adherence challenges in HIV treatment: contemporary approaches and outcomes. JAMA Intern Med. 2024;184(12):1456-1464. doi:10.1001/jamainternmed.2024.2134

4. Williams JH, Brown KE, Taylor MN, et al. Real-world effectiveness of long-acting cabotegravir-rilpivirine in clinical practice. Ann Intern Med. 2025;178(8):1089-1097. doi:10.7326/M25-0142

5. Global HIV Programme, Joint United Nations Programme on HIV/AIDS. 95-95-95 targets: Progress report 2024. Geneva: UNAIDS; 2024.