Dual Long-Acting Cabotegravir/Rilpivirine Plus Lenacapavir in Integrase Strand Transfer Inhibitor Resistance: A Case Report and Review of the Literature

Abstract

Long-acting injectable (LAI) antiretroviral therapy (ART) is a promising option for people with HIV who face persistent adherence challenges, though literature to support its use in cases of integrase strand transfer inhibitor (INSTI) resistance remains limited. We describe a 36-year-old man with advanced HIV-1, long-standing nonadherence to oral medications, and virologic failure who harbored both an INSTI major mutation (E92Q) and accessory mutation (E157Q). Given persistent nonadherence and viremia, he was started on dual LAI lenacapavir plus cabotegravir/rilpivirine. His viral load declined to 143 copies/mL within 6 weeks after initiation of injectable ART and has remained undetectable thereafter. This case suggests that dual LAI ART may be effective in certain cases of underlying INSTI resistance and highlights the need for further study of this novel regimen in treatment-experienced individuals.

The introduction of long-acting injectable (LAI) antiretroviral therapy (ART) is a promising advancement in HIV care with the potential to help more people living with HIV (PLWH) achieves viral suppression, particularly those experiencing difficulties adhering to oral regimens [1–5]. Injectable cabotegravir (CAB)/rilpivirine (RPV) comprised of an integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI), respectively, is currently the only FDA-approved complete LAI regimen for HIV. Injectable lenacapavir (LEN) is a capsid inhibitor approved for HIV prevention and as part of combination ART regimens [6]. The combination of LEN plus CAB +/− RPV has been successfully applied in a limited number of case reports of individuals with drug-resistant HIV, with particular focus on background NNRTI resistance [7–10]. This case report describes a patient with 2 INSTI resistance associated mutations (RAMs) who achieved durable virologic suppression with LEN plus CAB/RPV, adding to the limited literature evaluating dual LAI ART in INSTI resistance.

CASE REPORT

A 36-year-old male was diagnosed with advanced HIV during a hospitalization in 2016 after presenting with fever and cough secondary to bacterial pneumonia. The patient was initially from Cabo Verde and arrived in the United States 1 week prior to hospital presentation. He had an initial HIV-1 viral load of 407 000 copies/mL and a CD4 count of 102 cells/μL. Baseline genotype testing revealed no significant RAMs. After his hospitalization, he was subsequently connected to outpatient HIV care and started on oral ART.

Following initiation of ART in May 2016, the patient experienced persistent viremia due to medication nonadherence. In addition to HIV, the patient had a history of alcohol use disorder and housing instability which contributed to his nonadherence. Multidisciplinary efforts were made to provide comprehensive psychosocial, substance use, and logistical support to optimize the patient's adherence to his oral ART regimen with limited impact. His viral load reached a peak of 2 370 000 copies/mL in 2023 and a CD4 count nadir of 10 cells/μL. In 2024, he asked his HIV provider if he could be transitioned to LAI ART given his difficulty taking pills. By that time, he had been prescribed the following ART regimens:

• May 2016—January 2017: Tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat

• January 2017—April 2019: Tenofovir alafenamide/emtricitabine plus darunavir/cobicistat

• April 2019—August 2024: Tenofovir alafenamide/emtricitabine/bictegravir plus darunavir/cobicistat

Genotype resistance testing over the years revealed the following resistance patterns:

• May 2016: Wild-type

• February 2017: M184V (NRTI), E92Q (INSTI)

• July 2019: Wild-type

• October 2022: Wild-type

• July 2024: E157Q (INSTI)

According to the Stanford HIV drug resistance database, E92Q is considered to be a major INSTI RAM and E157Q an accessory INSTI RAM [11]. The combination of E92Q and E157Q mutations is predicted to result in low-level reduced susceptibility to CAB, with the use of CAB/RPV considered to be relatively contraindicated.

In spite of this resistance profile and given the patient's continued adherence challenges with virologic failure, the patient was initiated on combination LAI LEN plus CAB/RPV in August 2024. At that time of initiation, the patient had a viral load of 23 200 copies/mL and a CD4 count of 11 cells/μL. The patient's regimen followed a clinic viremic protocol based on examples from literature demonstrating successful use of CAB/RPV in nonsuppressed patients [1–3, 12, 13]. LEN 927 mg was administered subcutaneously every 6 months after loading with 600 mg orally for 2 days upon the start of injections. CAB/RPV 400–600 mg was administered intramuscularly every 4 weeks following a loading dose of CAB/RPV 600–900 mg.

Six weeks after initiation of the regimen, the patient's viral load decreased to 143 copies/mL. From 18 weeks following initiation to the most recent testing at 68 weeks, the patient has maintained a viral load of <20 copies/mL. In addition, his CD4 count increased to 340 cells/μL. However, the patient's care is not without challenges. Alcohol use disorder and homelessness continue to impact his ability to consistently follow-up. Over the course of 68 weeks, he missed 7 injection appointments with the most recent interruption resulting in a 25-week interval between CAB/RPV doses and a 42-week interval between LEN doses. He did not take oral ART during the period of missed injections. Despite the treatment interruptions, his viral load remained undetectable upon reconnecting to care in December 2025. At that time, he was reloaded with LEN and CAB/RPV and he currently remains on dual LAI ART.

DISCUSSION

The advent of LAI medications marks the beginning of a promising era in HIV treatment with the potential to achieve optimal therapy adherence and viral suppression in individuals who face multifaceted challenges with traditional oral regimens [1–5]. Although there has been an early uptake of injectable ART for some patients, drug resistance in treatment-experienced individuals remains a concern for clinicians when considering the use of LAI regimens.

Despite this common clinical question, there are limited examples in the literature of CAB/RPV plus LEN for patients with underlying drug resistance. A case series by Gandhi et al. reporting on 34 patients treated with combination LEN and CAB +/− RPV provides an important call for additional investigation into the efficacy of dual LAI ART among patients with NNRTI resistance [7]. Evidence is even more limited to support the efficacy of dual LAI ART in the setting of INSTI resistance. To date, there are 3 case reports or series, which describe a total of 10 patients with INSTI resistance successfully treated with combination CAB/RPV plus LEN (Figure 1) [7–10]. Among these 10 patients, 5 had a CAB mutation score >0, suggesting some potential effect of the INSTI mutation on CAB efficacy [11]. There was 1 patient who harbored both a major INSTI mutation in addition to an accessory mutation, similar to our patient's resistance profile [8]. The other 9 patients had either a single major or accessory INSTI mutation with predicted low-level resistance or full susceptibility to CAB.

Figure 1.

Summary of cases reports/series of LEN plus CAB/PRV in individuals with INSTI resistance [7–10]. Mutation interpretation and CAB mutation scores are reported according to the Stanford HIV drug resistance database [11].

Although there are limited reported cases of dual LAI ART used in individuals with INSTI resistance, it is fair to assume there are many more people with similar resistance profiles who may be good candidates for such regimens. INSTIs have become a cornerstone of recommended first-line ART regimens used globally for both treatment-naive and treatment-experienced PLWH [14]. A meta-analysis of 81 international studies found that the prevalence of INSTI resistance shows a recent increasing then decreasing trend, thought to reflect the shift away from first-generation INSTIs with lower barrier to resistance and toward second-generation INSTIs [14–17]. Despite a more recent decrease in overall INSTI resistance, data show the highest resistance rates among INSTI-experienced patients in part due to variable degrees of cross-resistance between generations [15]. Furthermore, data show that CAB has the highest resistance rates among second-generation INSTIs in the treatment-experienced population. In vitro data also support a lower genetic barrier to resistance of CAB compared with bictegravir and dolutegravir [18]. The genetic mechanisms contributing to CAB resistance are currently being studied. Phenotypic testing has identified INSTI RAMs that, in isolation, reduce CAB susceptibility by at least 2.0-fold [19, 20]. There are also double- and triple-mutation patterns that confer more significant impact on CAB IC50 [19–21]. There is less data on our patient's 2 INSTI mutations, E92Q and E157Q, as they pertain to CAB susceptibility. E92Q alone in macaque SIV isolates is associated with a 2.5-fold reduced CAB susceptibility, but data from human isolates are limited [19]. Further investigation into the genotypic mechanisms of CAB resistance is needed to determine which individuals with background INSTI resistance may be successfully treated with a CAB-containing LAI regimen.

It is also important to note that INSTI resistance is pharmacologically and clinically distinct from NNRTI resistance in the discussion of dual LAI regimens, owed to the high barrier to resistance of second-generation INSTIs and their ability to overcome first-generation resistance mechanisms [18, 22, 23]. Data from the VIKING trials demonstrate the efficacy of twice daily dolutegravir in cases of first-generation INSTI resistance, although evidence is lacking to support similar applications of its second-generation counterparts, bictegravir and CAB [23]. Our patient and the 10 other reported cases with INSTI resistance suggest some degree of preserved CAB activity despite 1–2 RAMs resulting in first-generation resistance, therefore deriving benefit from maintaining CAB in their LAI regimens. This is in contrast to the 11 out of 34 patients in Gandhi et al's case series who had NNRTI resistance and thus had RPV omitted entirely from their regimens [7]. Still, the extent to which CAB may retain activity despite first-generation resistance is poorly defined compared with the durable applications elucidated for dolutegravir. The upper bounds of a CAB-containing LAI regimen will be important to clarify for the numerous patients with background INSTI resistance who may benefit from long-acting ART.

Our case adds to the limited literature illustrating the potential utility of dual LAI ART in individuals with INSTI resistance and underscores the importance of additional investigation. The case also highlights the multitude of social barriers to care that often persist after patients are initiated on injectable ART. Identifying and working to address these challenges remain essential when electing to initiate and continue an injectable regimen. Our patient's course remains challenged by the same barriers that contributed to his nonadherence on oral medications, which his multidisciplinary team continually strives to mitigate. The patient fortunately remains virally suppressed despite extended treatment interruptions, and he continues to receive LAI ART as it remains the most realistic option for him to maintain viral suppression. While this approach is unconventional with limited evidence to support it, it bears emphasizing that the patient's course on LAI ART represents the longest duration of viral suppression since his diagnosis, allowing for meaningful immune reconstitution (Figure 2). For an individual without feasible treatment alternatives, dual LAI ART represents an invaluable opportunity to turn the course of his HIV prognosis and overall health.

Figure 2.

Viral load and CD4 count since time of diagnosis through most recent follow-up after initiation of LEN plus CAB/RPV in August 2024.

As the field of HIV medicine makes innovative advancements in diagnostic, preventative, and treatment modalities, efforts to ensure expansive access to these interventions become increasingly important. This includes thoughtful consideration of which patients may be at risk of exclusion from next-generation intervention rollouts due to various limitations including lack of clinical data to assure clinicians of safety and efficacy in particular patient groups. Elucidating the broadest potential scope for a dual LAI ART regimen will allow for more opportunities to treat individuals with HIV who are otherwise at the highest risk for poor outcomes. Our patient's successful viral suppression on dual LAI ART supports that this novel regimen can be carefully considered for individuals with both long-standing adherence barriers and background INSTI resistance.