Lenacapavir Plus Cabotegravir as Combination Treatment: Real-world Use Cases From the National Clinician Consultation Center

Abstract

Background

The use of long-acting injectable (LAI) lenacapavir (LEN) plus cabotegravir (CAB) +/− rilpivirine (RPV) may increase viral suppression in people with HIV (PWH) with a history of oral antiretroviral therapy (ART) adherence challenges or drug-resistant virus. Data on the LEN+ CAB+/−RPV effectiveness and tolerability are limited.

Methods

We report observations on real-world LEN+ CAB+/−RPV use from the National Clinician Consultation Center (NCCC), a federally funded teleconsultation resource for US-based clinicians. Providers contacting NCCC from 1 December 2022 to 30 August 2024 for cases related to ART modification to LEN+ CAB+/−RPV were surveyed. Data from NCCC's secure database and survey responses were summarized using descriptive statistics.

Results

Among 76 potential cases, 50 (66%) surveys were completed. Of these, 14 (28%) modified ART to LEN+ CAB+/−RPV, including 9 (64%) who changed to LEN+ CAB/RPV and 1 (7%) to LEN+ CAB, and 4 (29%) with no regimen details. ART modification was not made in 35 cases, and in one, the provider was unsure of changes. Nonexclusive reasons for LAI-ART modifications included viremia on oral ART (n = 6, 43%), inability/refusal to take oral ART (3, 21%), non-nucleoside reverse transcriptase inhibitor mutation(s) (3, 21%), integrase strand transferase inhibitor mutation(s) (2, 14%), or persistent viremia on CAB/RPV alone (2, 14%). LEN+ CAB+/−RPV was effective and well-tolerated: among 10 cases with follow-up information, viral load decreased by a mean of 3.88log₁₀ copies/mL within a median of 56 days (range = 29–166 days), and 5 experienced injection-site reactions rated as “not at all” to “slightly” problematic.

Conclusions

These data support further investigations into LEN+ CAB+/−RPV use among PWH with oral ART challenges and/or drug resistance.

Introduction

National surveillance estimates indicate 67% of people with HIV-1 (PWH) in the United States (US) achieved viral suppression in 2023 [1], underscoring the need for additional engagement and treatment interventions to support individual health, quality of life, and decrease transmissions. Despite the availability of once-daily, well-tolerated antiretroviral therapy (ART) regimens, some PWH continue to experience challenges adhering to oral ART. Barriers include stigma, unmet housing or subsistence needs, mental health and substance use challenges, or other factors impacting a person's ability to take oral ART. Long-acting injectable ART (LAI-ART) can help overcome some of these challenges [2]. Currently, Food and Drug Administration (FDA)-approved LAI-ART options include cabotegravir (CAB, an integrase strand transfer inhibitor [INSTI]) and rilpivirine (RPV, a non-nucleoside reverse transcriptase inhibitor [NNRTI]), both administered as intramuscular injections every 1 or 2 months, and subcutaneous injections of lenacapavir (LEN, a capsid inhibitor) administered every 6 months.

CAB/RPV was initially FDA-approved in January 2021 for PWH who are virally suppressed on oral ART. However, this combination has successfully been used off-label for PWH with adherence challenges and those unable to take oral ART [3–5]. An AIDS Clinical Trials Group study demonstrated superior rates of viral suppression with CAB/RPV compared to oral ART among participants with adherence challenges but without viremia [6]. Clinic demonstration projects have shown that CAB/RPV can be successfully used among PWH with adherence challenges and ongoing viremia [3–5]. Accordingly, the International Antiviral Society–USA and the Department of Health and Human Services (DHHS) guidelines now endorse using CAB/RPV for PWH with viremia and adherence challenges [7, 8].

Although LAI-ART holds significant promises, broader use of CAB/RPV may be limited by prevalent HIV drug resistance, particularly among treatment-experienced PWH, specifically, those with pre-existing RPV-associated mutations or INSTI resistance or those with persistent viremia on CAB/RPV. These situations prompt consideration of additional antiretroviral agent(s). For PWH on LAI-ART due to challenges with oral ART, one such option is the addition of LEN, which was FDA-approved in December 2022 for highly treatment-experienced PWH in combination with other ART agents. Thus far, 3 case series have reported clinical experience and outcomes when using LEN+ CAB with or without RPV. These reports were from US academic medical centers and described high rates of virologic suppression on the LAI ART combination [9–11]. In this new era of LAI-ART, additional real-world experiences are needed to advance the understanding regarding optimal use of these combinations and inform adoption in clinical practice.

The National Clinician Consultation Center (NCCC, nccc.ucsf.edu) is a long-standing clinical resource offering provider-to-provider teleconsultation education and capacity-building. It is part of the Health Resources and Services Administration (HRSA) Ryan White HIV/AIDS Program AIDS Education and Training Centers network, housed within the University of California, San Francisco's Department of Family and Community Medicine. NCCC operates multiple teleconsultation services for US-based clinicians, including the national HIV Warmline, Perinatal HIV Hotline, Pre-exposure Prophylaxis Hotline (“PrEPline”), Post-exposure Prophylaxis Hotline (“PEPline”), Substance Use Warmline, and Hepatitis C Warmline. The service is staffed by clinical subject matter experts, including HIV and viral hepatitis-experienced physicians, advanced practice nurses, and clinical pharmacists who provide individualized, free-of-charge, case-based consultations and education. This report describes a case series reflecting the consideration and use of LAI combinations that involved LEN+ CAB+/−RPV based on calls received by the NCCC.

METHODS

We identified HIV Warmline calls received between December 1, 2022 (LEN was approved in Dec 2022) and August 30, 2024, where managing providers were considering potential HIV treatment modification to injectable ART combinations that have not been studied in clinical trials, including LEN+ CAB, LEN+ CAB/RPV, or LEN+ RPV. NCCC consultants do not directly interface with patients or their health records; the managing clinician provides all clinical and laboratory testing information to consultants based on the managing provider's review of available records during the initial call/electronic case submission. After reviewing case details and providing guidance, consultants document individual notes in a customized, Health Insurance Portability and Accountability Act (HIPAA)-compliant Salesforce database, including structured and unstructured data entry fields. As such, one author ran a keyword search in NCCC's Salesforce database for the keywords “cabotegravir,” “lenacapavir,” “Cabenuva,” “Sunlenca,” “CAB/RPV,” “CAB/RIL,” “CAB-RPV,” or “LEN” to generate a list of HIV Warmline calls where at least one of these terms was entered by NCCC consultants in the case notes. Next, one author reviewed the list to identify cases that included any mention of LEN. For this subgroup, 2 authors then reviewed detailed consultation notes to confirm case eligibility for inclusion in this analysis (ie, use of LEN+ CAB/RPV, LEN+ CAB, or LEN+ RPV) and extracted additional clinical information.

Callers for these eligible cases were then emailed an 18-question Qualtrics survey. Survey questions inquired about the specific regimen to which the patient's ART was changed (ie, LEN+ CAB/RPV, LEN+ CAB, or LEN+ RPV); main reason(s) for this therapy change, including documented or suspected NNRTI and/or INSTI mutations, detectable HIV viral load (VL) on oral ART, persistent viremia on CAB/RPV alone, or other reason; and HIV VL before and after the ART change. Additionally, providers were asked if the patient had experienced injection site reactions, which medication(s) they may have reacted to, how problematic the reaction had been, if there had been any delayed/missed injections, and if the patient was considering LAI-ART continuation. Providers were not offered an incentive for completing the survey. Using Microsoft Excel, we used descriptive statistics to summarize case details and survey results.

RESULTS

The initial keyword search yielded 559 cases, 163 (29%) of which mentioned LEN. Of those, 76 (47%) cases had a mention of LEN+ CAB/RPV, LEN+ CAB, or LEN+ RPV. The remaining 87 cases (53%) discussed general information about LEN (eg, drug–drug interactions), use of LEN with other oral ART, or use of LEN plus fostemsavir or ibalizumab. Providers of eligible cases were emailed up to 3 times with a survey link from November 2024 through April 2025. Among the 76 eligible cases, 50 (66%) follow-up surveys were completed.

Of these 50 cases, 14 (28%) providers had modified ART after initial NCCC consultation to any combination of LEN+ CAB+/−RPV, and 35 (70%) had not yet made an ART modification to any of these combinations. One caller (2%) was unsure what change had been made. Of the 14 cases where ART was modified to LEN+ CAB+/−RPV, 9 (64%) involved a modification to LEN+ CAB/RPV, 1 (7%) to LEN+ CAB, and 4 (29%) did not indicate the specific LAI-ART regimen in the survey response.

Among the 10 cases with available follow-up information, the mean patient age was 51 years (SD = 14), 6 were cisgender men, 3 were cisgender women, and one was a transgender woman. Three were Black/African American, 3 were white, 2 were Latine, one was Asian, and 2 did not have race/ethnicity documented. Provider/patient location spanned 7 US states, including a community-based health center, a private practice, a large academic institution, and a Veterans Affairs medical center. Six patients received monthly CAB or CAB/RPV, and 4 were on bimonthly dosing. LEN initiation was rated as “not at all” to “slightly” difficult in 9 cases and “moderately difficult” in 1. Regarding the motivations for therapy modification, 0 to 4 reasons were provided per case for changing to LEN+ CAB+/−RPV, including detectable VL on oral ART (n = 6, 43%), documented/suspected NNRTI mutation(s) (3, 21%), inability/refusal to take oral ART (3, 21%), documented/suspected INSTI mutation(s) (2, 14%), or persistent viremia on CAB/RPV alone (2, 14%). Five out of 10 individuals experienced injection-site reactions to either CAB/RPV, LEN, or all 3, and the managing provider rated reactions to be “not at all” to “slightly” problematic.

Among 10 cases with available follow-up information, VL decreased by a mean of 3.88 log₁₀ copies/mL within a median of 56 days (range = 29–166 days; Table 1). In 8 individuals, VL decreased to <200 copies/mL; among 2 individuals, VL decreased from a baseline of >6.2 log₁₀ copies/mL to 210 and 313 copies/mL. One PWH experienced a delayed/missed CAB/RPV injection, with no delayed/missed LEN injections. In all but 1 case (due to patient death for an unstated reason), the managing provider noted a desire for the patient to continue the new LAI-ART combination.

Table 1.

Details on NNRTI and INSTI Mutations, Viral Load Before and After ART Modification, and the Number of Days to Viral Load Follow-up

Case #	Demographics (Age, Sex, Race/ethnicity)	ART Prior to Modification and ARV History	LAI-ART Combination	NNRTI and INSTI Treatment Resistance History	Viral Load Before Initiation (copies/mL)	Viral Load at Follow-up	Number of Days to Follow-up
1	60 yo, male, Black	DTG+ FTC/TAF. Detailed ARV history not available.	LEN+ CAB/RPV	NNRTI and INSTI experienced. NNRTI: K103N, E138 K, I178 M, V179 V/I, P225H, K238 V.	65 800	Undetectable	166
2	38 yo, male, White	Not taking oral ART. ARV history: FTC/TDF, RPV, EFV.	LEN+ CAB/RPV	NNRTI experienced (off ART at the time of genotype). NRTI: M184 V.	2 640 000	313	48
3	60 yo, male, unknown race	EVG/c/FTC/TAF. ARVs history: d4T, ddI, AZT, 3TC, EFV, NFV, IND, ATV, RTV.	LEN+ CAB/RPV	NNRTI and INSTI experienced. INSTI: N155H, D232N.	581	Undetectable	94
4	48 yo, male, unknown race	ZDV/3TC+ DRV/RTV+ DTG. ARVs history: FTC/TDF, EFV, NVP, MVC, RAL.	LEN+ CAB/RPV	NNRTI and INSTI experienced NNRTI: V179I INSTI: K14R, V72I, P90S, L101I, T112 V, V113I, S119R, T124N, G163E, S195T, V201I, V234L.	4 280 000	210	153
5	50 yo multiracial female	Not taking oral ART. ARV history: FTC/TXF, ABC/3TC, RPV, ETR, DOR, LPV/r, ATV/r, DRV/r, RAL, DTG, BIC.	LEN+ CAB/RPV	NNRTI and INSTI experienced. NNRTI: K103N, Y181C, G190A.	138	42	33
6	23 yo Black female	BIC/FTC/TAF. ARV history: AZT/3TC, FTC/TAF, NVP, EVG/c, DTG.	LEN+ CAB/RPV	NNRTI and INSTI experienced NNRTI: E138K INSTI: R263 K.	510	100	29
7	59 yo White male	DRV/c/FTC/TAF. Detailed ARV history not available.	LEN+ CAB/RPV	NNRTI and INSTI experienced. NNRTI: V106A, F227L/F, Y318Y/F. INSTI: T97A, G140S, Q148H.	68 800	97	57
8	43 yo Black male	Off ART. Detailed ARV history not available.	LEN+ CAB/RPV	NNRTI and INSTI experienced. RT: K103N, V106I, V179 V/I, T200A, I202 V. IN: E10D, E11E/D, G52G/R, T112R, V113I, S119S/G, T122I, T124T/A, T125A, K156N, D167D/E, V201I, V234I, D256E, A265A/V, D286D/N.	8655	Undetectable	55
9	54 yo, female, Hispanic/Latine	ABC+ 3TC+ DTG. ARV history: FTC/TXF, DRV/r (also DRV/c), DTG.	LEN+ CAB/RPV	INSTI experienced. INSTI: G163E.	335	61	135
10	71 yo, female, Hispanic/Latine	DRV/c/FTC/TAF + DTG. ARV history: FTC/TAF, RPV.	LEN+ CAB	NNRTI and INSTI experienced NNRTI: V90I, K101P, 103S, V179I/V.	81 000	114	31

3TC, lamivudine; ABC, abacavir; AZT, zidovudine; ART, antiretroviral therapy; ARV, antiretroviral; ATV/r, atazanavir boosted with ritonavir; BIC, bictegravir; CAB, cabotegravir; d4T, stavudine; ddI, didanosine; DOR, doravirine; DRV/c, darunavir boosted with cabotegravir; DRV/r, darunavir boosted with ritonavir; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; EVG/c, elvitegravir boosted with cabotegravir; IND, indinavir; INSTI, integrase strand transfer inhibitor; LAI, long-acting injectable; LEN, lenacapavir; MVC, maraviroc; NFV, nelfinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide; TXF, tenofovir alafenamide or tenofovir disoproxil fumarate.

Bolded mutations indicate major cabotegravir or rilpivirine mutations.

DISCUSSION

This real-world case series, reflecting data collected from a unique provider-facing capacity-building resource, describes the use of the novel combination of LAI LEN+ CAB+/−RPV among 10 treatment-experienced PWH receiving care in various clinical settings across the US. The most common reason for considering a transition to these combinations was detectable viremia on oral ART, most often in the setting of confirmed or suspected resistance to NNRTIs and/or INSTIs. Patients experienced a significant reduction in VL in about 2 months following the initiation of these combinations. Managing providers reported minimal difficulties initiating the new combinations and no serious adverse reactions. Early follow-up indicated that all patients intended to continue the new LAI-ART regimen.

LEN has not been studied with CAB or RPV in clinical trials. Information from our analysis adds to data describing favorable clinical and virologic outcomes after CAB+ LEN+/−RPV initiation from other case series. It is notably the first to include patients receiving HIV care at sites outside of academic medical centers. Given ongoing disparities in access to newer HIV therapies, including LAI agents, it is essential to highlight early experiences with LAI-ART outside of large-volume, specialty-driven HIV programs. Indeed, LAI-ART implementation in many community settings is expected to be more challenging, particularly when it includes “off-label” combinations and/or indications. Such challenges may be due to factors such as limited provider experience and/or comfort with newer ART; limited provider or pharmacy capacity to navigate insurance-related barriers; limited staffing to operationalize injection scheduling, administer doses, and engage in appointment reminders; and/or logistical issues related to procurement and/or on-site storage.

Consistent with previously published reports, our data support the overall feasibility and potential utility of these novel LAI-ART combinations and further illustrate the need for ongoing research on specific considerations for eligibility, monitoring, durability, and implementation across various practice settings. Only 67% of PWH in the US achieved viral suppression in 2023 [1]; however, individual and population health outcomes may worsen if current health systems are underfunded or other policies restricting medication access introduce new challenges for procuring LAI ART. For example, coverage of CAB/RPV and LEN varies widely across state AIDS Drug Assistance Programs (ADAP) and Medicaid programs, which can make these LAI-ART regimens unattainable for some and challenging to access for others. As of 2024, 8 states did not cover CAB/RPV through their ADAP programs, and 7 required prior authorization (PA) [12]. Fifteen states did not cover LEN through their ADAP program, and 3 required a PA. Especially for community sites that may have fewer resources, ensuring broad access to novel regimens and treatment strategies remains paramount in reaching the National HIV/AIDS Strategy goal of 95% viral suppression by 2030 [13].

In September 2024, the US DHHS expanded considerations for LAI ART when they updated their guidelines on Adult and Adolescent Antiretroviral Therapy to recommend using CAB/RPV in select cases with persistent virologic failure on oral ART despite intensive adherence support [8]. This recommendation reflects the growing literature showing rates of virologic suppression of >90% for people with viremia and poor oral adherence started on LA-CAB/RPV [2–4, 14–16]. LAI-ART may be a preferable option for a range of reasons, including pill aversion, psychological trauma, privacy concerns, impaired gastric absorption, and recall concerns. Injectable regimens also allow providers to confirm timely medication adherence when administered in clinical settings. However, there is limited evidence for LAI-ART outside of CAB/RPV, which is only an option for individuals without baseline RPV or CAB resistance. Those with barriers to oral ART are at particular risk for such resistance, as they may have had inadequate virologic control on prior regimens. This is of particular concern for RPV, as NNRTIs have a low barrier to resistance, were first-line therapy for 2 decades, and their associated drug resistance mutations have little impact on viral fitness compared to the other drug classes, making them the most transmitted HIV drug resistance mutations. NNRTIs were part of first-line regimens until 2015 in the US and continue to be used globally. Many individuals with barriers to oral ART have NNRTI resistance due to past adherence challenges on NNRTI-based regimens, while others may have transmitted drug resistance. Even though INSTI resistance is uncommon, it may increase over time with the use of injectable CAB for pre-exposure prophylaxis. Therefore, additional injectable regimens beyond CAB/RPV alone are needed for individuals with RPV or CAB resistance mutations.

We note several limitations with our study, including its small sample size and limited follow-up and clinical detail (eg, some cases had missing ART history, and we did not systematically collect information on BMI or needle length used for CAB/RPV doses). Additionally, all cases were from providers who initiated requests for NCCC consultation and agreed to provide follow-up via survey; thus, callers may not represent the broader population of US HIV providers nor overall LAI-ART prescribing practices. Furthermore, information collected by the study itself was limited in scope to avoid undue administrative burden on providers because no compensation was offered for survey completion. Therefore, our results may not be generalizable.

Nonetheless, this case series supports other recent reports describing the addition of LEN within an all-injectable 2- or 3-drug ART regimen for PWH experiencing challenges with oral ART, providing further proof of concept for using these novel combinations. Future research should examine the uptake and long-term follow-up of these LAI-ART combinations in larger, prospective series and trials.