Real-World Patterns of Discontinuation and Virologic Failure with Long-Acting Cabotegravir–Rilpivirine

Long-acting injectable cabotegravir–rilpivirine (LA CAB/RPV) is the first complete long-acting antiretroviral therapy (ART) regimen approved for HIV treatment in the United States. It offers an alternative to daily oral therapy for individuals who are virologically suppressed, have no history of treatment failure, and have no known or suspected resistance to either agent, although emerging data suggest benefit for select viremic patients with adherence challenges.^1,2 Clinical trials have demonstrated that LA CAB/RPV is noninferior to standard oral regiments, achieving high rates of virologic suppression, low rates of virologic failure, and favorable tolerability.^3–5 Beyond efficacy, LA CAB/RPV provides advantages in convenience and adherence, reducing pill burden, mitigating stigma associated with daily oral medications, and is associated with improved quality of life and high patient satisfaction. ⁶

However, translating clinical trial success into real-world practice poses challenges. Patients may initiate LA CAB/RPV with incomplete treatment histories or uncertain resistance profiles, and insurance, access, and logistic barriers may affect both initiation and continuation of therapy. ⁷ These factors are important, as virologic failure on LA CAB/RPV, while uncommon, can result in the emergence of resistance-associated mutations in both the integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) classes, limiting future therapeutic options. ⁸ Risk factors for virologic failure include higher baseline body mass index (BMI), pre-existing NNRTI mutations, incomplete adherence, and certain HIV subtypes. ³ Understanding how these risks translate to clinical practice remains critical as use of LA CAB/RPV expands.

To address this issue, we describe real-world experience with LA CAB/RPV among adults with HIV receiving care at a large academic infectious diseases clinic in an urban Midwest Medicaid expansion state. Our objectives were to characterize reasons for LA CAB/RPV discontinuation and to describe cases of virologic failure.

We retrospectively reviewed adults who received LA CAB/RPV for HIV treatment at our clinic between January 1, 2022, and April 17, 2025. The clinic provides access to LA-ART through the state AIDS Drug Assistance Program, and all patients underwent coverage assessment prior to initiation of LA CAB/RPV. Participants were identified through the electronic medical record based on receipt of at least one injection during the study period. Data abstracted included age, sex, BMI, HIV viral load, prior ART regimen, resistance history, and reason for discontinuation as applicable.

Primary outcomes were duration of LA CAB/RPV therapy and reason for discontinuation, categorized as insurance barriers, adherence issues, intolerance, patient preference, virologic failure, or death, based on provider documentation. Secondary outcomes were virologic failure, defined as two or more consecutive HIV RNA levels ≥200 copies/mL after initiation of LA CAB/RPV prompting a change in therapy. Genotypic and phenotypic resistance testing results were reviewed when available.

Descriptive statistics were used to summarize patient characteristics and outcomes. Group comparisons were performed using Wilcoxon rank-sum test for continuous variables. p-values <.05 were considered statistically significant. Statistical analyses were conducted using R version 4.4.2.

This project was conducted as part of a quality improvement (QI) initiative and was reviewed by our institution’s QI oversight body, which determined it to be nonhuman subjects research and exempt from institutional review board review.

During the study period, 201 adults with HIV received LA CAB/RPV for HIV treatment with a median duration of 380 days (IQR, 206–729 days). The cohort was predominantly male (n = 172, 85.6%) with a mean age of 47 ± 12 years (SD). At the end of follow-up, 160 (80%) patients remained on therapy, 30 (15%) had discontinued LA CAB/RPV, and 11 (5%) transferred care with continuation status unknown.

Among those who discontinued, the most common reasons were insurance barriers (n = 8, 27%), adherence issues (n = 7, 23%), patient preference (n = 7, 23%), virologic failure (n = 4, 13%), intolerance (n = 3, 10%), and death (n = 1, 3%). Among patients who discontinued for reasons other than virologic failure (n = 26/30, 87%) and had follow-up data available (n = 20/26, 77%), all resumed oral ART, and the majority (n = 17/20, 85%) were virologically suppressed at the next evaluation. Residual viremia appeared to be related to adherence challenges, although testing was not uniformly performed.

Virologic failure occurred in four patients (2%) (Table 1). There was no significant difference in BMI between patients with and without virologic failure (mean 32.0 vs. 28.9 kg/m², p = .12).

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Table 1.

Clinical Characteristics, Resistance Profiles, and Outcomes of Patients with Virologic Failure on LA CAB/RPV

Case	Patient	BMI (kg/m²)	Baseline testing (timing)	Presentation	Relevant mutations	Phenotype	Outcome
1	42 M	38.37	Genotype negative for relevant mutations (4 years prior)	Viral blips for 20 m, then ↑ to 2350 at 21 m	K101P	High-level RPV resistance	Resumed prior regimen of FTC/TAF, DOR, and DTG and resuppressed
2	60 M	30.13	None on file	First VL at 5 m 192, then ↑ to 13,100 at 9 m	Y181C	Intermediate RPV resistance	Resumed prior regimen of ATV/r and ABC/3TC and resuppressed
3	43 M	29.28	Phenotype with resistance to DTG, EVG, RAL (1 year prior)	First VL at 3 m 17,700	Not assessed	Resistance to DTG, EVG, RAL, BIC	Resumed prior regimen of DRV/COBI/FTC/TAF and resuppressed
4	47 M	30.38	None on file	First VL at 6 m 386,000	E138A M230L	High-level RPV resistance; partial sensitivity to CAB	Resumed prior regimen of DRV/COBI/FTC/TAF and resuppressed

ABC/3TC; abacavir/lamivudine; ATV/r, atazanavir/ritonavir; BIC, bictegravir; DRV/COBI, darunavir/cobicistat; DOR, doravirine; DTG, dolutegravir; EVG, elvitegravir; FTC/TAF, emtricitabine/tenofovir alafenamide; M, months; RAL, raltegravir; VL, viral load.

Resistance patterns varied. One patient with prior negative genotype testing developed a K101P mutation, conferring high-level RPV resistance. A second patient without baseline resistance testing developed a Y181C mutation associated with intermediate RPV resistance. A third patient had preexisting INSTI resistance to dolutegravir, elvitegravir, and raltegravir, which expanded to include all INSTIs on repeat testing. The fourth patient, also without baseline resistance testing, was found to have dual E138A and M230L mutations, conferring high-level RPV and partial CAB resistance. All four patients discontinued LA CAB/RPV and achieved virologic resuppression after resuming oral ART.

One additional patient experienced transient viremia (1,230 copies/mL) that did not meet criteria for virologic failure. Testing at the time of viremia revealed no relevant mutations. LA CAB/RPV was continued, and viral suppression was reestablished within 2 months.

In this observational cohort, most patients remained on LA CAB/RPV over approximately 1 year of follow-up. Discontinuation was uncommon and primarily driven by system-level factors, including insurance and adherence challenges, rather than adverse events or intolerance. Structural barriers alone accounted for approximately half of discontinuations, highlighting the importance of health system support for long-acting ART implementation, consistent with other real-world cohorts. ⁹

Virologic failure was rare, occurring in four patients (2%), consistent with rates observed in clinical trials^3–5 and observational studies.^9,10 Failures occurred in individuals with heterogeneous baseline resistance profiles, including pre-existing mutations and incomplete or potentially outdated resistance data. This underscores the importance of reviewing prior genotypic and phenotypic data, which can be challenging for patients with multiple prior sites of care. Although all patients achieved viral resuppression after switching therapy, resistance that emerges during LA CAB/RPV may have broader implications. Meta-analyses have demonstrated that INSTI resistance develops in 40–70% of failures, often with cross-resistance to dolutegravir, raising concern for loss of the INSTI class. ⁸

BMI was not significantly associated with virologic failure, although a trend toward higher BMI was observed among those with failure. Consistent with prior studies, these findings suggest that elevated BMI alone does not increase the risk of virologic failure with LA CAB/RPV. ³ Instead, failure appears more likely when elevated BMI is accompanied by additional risk factors, such as baseline RPV mutations or HIV-1 subtype A6/A1. ³

Strengths of our study include a large, well-characterized real-world cohort with longitudinal follow-up. Limitations include the retrospective, single-center design and incomplete baseline genotypic testing. In addition, needle length used at individual injection visits was not systematically documented, and 2-inch needles were not consistently available during the study period, raising the possibility of suboptimal intramuscular delivery in patients with elevated BMI. Future research should focus on reducing system-level barriers, improving access and care transitions, and supporting adherence.

In conclusion, LA CAB/RPV is effective and well-tolerated in routine clinical practice. Discontinuations were primarily driven by system-level barriers, while virologic failures are rare and associated with resistance rather than BMI. Optimizing access, adherence, and resistance-informed patient selection are key to maximizing the benefits of this long-acting therapy in real-world settings.

Authors’ Contributions

All authors meet the criteria for authorship, reviewed and approved the final article, and agree to be accountable for the work. S.G.: Conceptualization, methodology, and writing—review and editing. D.M.: Investigation and data curation. J.B.: Investigation and data curation. S.H.: Formal analysis, interpretation, and writing—original draft. A.P.: Writing—review and editing.