Characterizing long-acting injectable antiretroviral therapy eligibility and initiation at a safety net academic medical center in the southeastern United States

Abstract

Background: Long-acting injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) extends dosing intervals from daily to every 8 weeks. Equitable implementation requires anticipating and addressing barriers to use. We described LAI-CAB/RPV eligibility and initiation among persons with HIV (PWH) receiving care at a Southeastern US academic medical center. Methods: We included PWH ≥18 years, in care 01/01/2020-12/31/2021, and participating in the UNC CFAR HIV Clinical Cohort. We characterized LAI-CAB/RPV eligibility, compared those with and without recent detectable viral load (VL), and described clinical outcomes on LAI-CAB/RPV. Results: Among 1672 PWH, 425 (25.4%) had LAI-CAB/RPV drug-resistance. Among 1238 LAI-eligible PWH, 8.9% had detectable VL. Median age was 53 (interquartile range 40, 61), 54.6% were non-Hispanic Black, and 73.6% male. Over one-third lived >50 miles from clinic, one-fifth were uninsured, and 7.4% reported hazardous alcohol use. Gaps in care (prior 12-month) were more common among PWH with detectable VL versus suppressed (23.1% vs 13.9%, p = 0.03). 6/47 initiated LAI-CAB/RPV had detectable VL prior to injection; >95% sustained suppression and those with detectable VL had a rapid decline in viremia. Conclusions: Three-quarters of PWH were eligible for LAI-CAB/RPV, but equitable implementation may require addressing challenges such as distance to care, inconsistent care engagement, and other comorbid conditions, particularly for PWH with viremia.

Keywords

Long-acting injectable rurality implementation HIV

Introduction

Effective antiretroviral therapy (ART) suppresses HIV replication, which interrupts forward transmission and improves health outcomes and life expectancy for persons with HIV (PWH).^1–3 Viral suppression is therefore a pillar in the effort to end the HIV epidemic.^4,5 Unfortunately, only two-thirds of PWH in the United States (US) were virally suppressed in 2019.⁶ Differences in suppression rates according to race, sex, age, and region of residence expose disparities in healthcare access and engagement.^7–9 Obstacles to viral suppression are complex, but nonadherence to a daily pill is often the most proximal behavior related to viremia.¹⁰

Recent advances in ART include approval of the first-ever long-acting injectable (LAI) regimen in January 2021. Delivered via two injections every 8 weeks, a combination of long-acting cabotegravir (CAB) and rilpivirine (RPV) was non-inferior to oral ART for maintaining viral suppression in clinical trials,^11–13 and effective for achieving viral suppression in some observational clinic-based studies.^14,15 LAI regimens offer a compelling alternative to oral ART, particularly for persons who struggle with daily pill adherence.

Despite substantial interest among PWH and HIV providers,^16–18 the scale-up of LAI-CAB/RPV faces many logistic challenges and may exacerbate health inequities among PWH.¹⁹ The need for in-clinic injections may be an impediment for PWH residing in peri-urban or rural districts, particularly in the Southern US where limited HIV providers contributes to worse clinical outcomes.^6,20 Furthermore, the initial Food and Drug Administration (FDA) approval specified that LAI-CAB/RPV is indicated only for virally suppressed (HIV RNA <50 copies/mL) PWH without a history of treatment failure, excluding PWH with barriers to consistent care engagement or adherence to daily oral pills. Characterizing patient needs and potential challenges to LAI-CAB/RPV provision, such as insurance, transportation, care engagement, and contraindications,^21,22 is critical to develop successful LAI-CAB/RPV implementation strategies.

Our objective is to inform LAI-CAB/RPV scale-up strategies that account for the complex patient characteristics and potential challenges among a population of PWH receiving at a large academic medical center and safety-net clinic in the Southeastern US. We characterized LAI-CAB/RPV eligibility and distribution of potential barriers to LAI-CAB/RPV use, and patient characteristics and clinical outcomes among PWH who initiated LAI-CAB/RPV. We further describe the process for clinical referral, evaluation, and LAI-CAB/RPV initiation in place at the time of study.

Methods

Study setting and population

This study used data from the University of North Carolina (UNC) Center for AIDS Research (CFAR) HIV Clinical Cohort (UCHCC). The UCHCC prospectively collects demographic, clinical, and behavioral data on adult PWH ≥18 years receiving care at the UNC Infectious Disease (ID) clinic, which is affiliated with the UNC. Data are collected from electronic health records (EHR), manual EHR reviews, and patient-reported outcome (PRO) surveys. Death data come from EHRs and state and national death registries. UCHCC design and participants have been previously described.²³ The UNC ID clinic is a Ryan White funded clinic that serves ∼2000 adult PWH each year from all 100 counties across the state and is the state safety net HIV clinic for PWH living in NC. The majority of PWH receiving care at UNC ID (>95%) participate in the UCHCC.

We included PWH in the UCHCC who had at least one HIV viral load (VL) between January 1, 2020, and December 31, 2021, and were alive on January 1, 2022. We examined LAI-CAB/RPV eligibility, a combination of an integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI). PWH with a contraindication for CAB/RPV, namely HIV drug class resistance, or the use of a contraindicated medication (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone, and St John’s wort), were considered ineligible. We did not exclude persons with known previous virologic failure (i.e. viremia) unless resistance criteria were met. We examined HBV infection as a potential challenge to LAI-CAB/RPV uptake but not a contraindication. HBV status was classified according to available serology (antibody and antigen) and DNA test results as: susceptible, immune (natural infection or vaccinated), infected (acute or chronic), likely resolved infection, and uncategorizable (incomplete testing).

We used historical genotypes to classify cumulative ART resistance. Resistance to INSTI and NNRTI was evaluated according to the Stanford Mutation Database’s drug resistance mutation (DRM) penalty scores and resistance interpretation. We excluded PWH with a score ≥10 for any INSTI or NNRTI. Persons with no genotyping available were considered susceptible to both classes.

We compared key clinical and demographic characteristics between persons with recent viremia versus those with sustained viral suppression.

We evaluated all PWH who received ≥1 injection LAI-CAB/RPV between January 1, 2022, and December 31, 2022. Persons initiating LAI-CAB/RPV reflected clinical practice, including some who were viremic and/or harbored resistance. We examined differences in characteristics between persons initiating LAI-CAB/RPV and those who would typically be considered (namely persons without NNRTI or INSTI class resistance).

Patient consent statement

All UCHCC participants provide written, informed consent. This study conforms to ethical research standards as established in the USA and was approved by the UNC Biomedical Institutional Review Board.

Study measures

We examined demographic, clinical, and geographic characteristics (e.g., driving distance to clinic and rurality). HIV VL was classified as suppressed if the most recent measurement was <50 copies/mL. Driving distance was the distance between persons’ residential addresses and the UNC HIV Clinic. Rurality was defined according to the National Center for Health Statistics 2013 Classification Scheme for Counties.²⁴

We characterized engagement based on missing scheduled visits (in-person or telehealth) in prior 24 months, or documented gaps in care using the Health Resources and Services Administration (HRSA) definition for “gap in HIV medical visit”.²⁵ This HRSA measure is defined as the proportion of PWH with a clinic (in-person or telehealth) visit in the first 6 months of a calendar year who do not have a visit in the last 6 months of that year.

PRO surveys, administered routinely at HIV clinic visits up to every 6 months, captured depression (PHQ-8,²⁶), housing stability, alcohol use (AUDIT-C²⁷), self-reported ART adherence,^28,29 and Likert-scale responses to questions related to perceived stigma associated with HIV.³⁰

LAI outcomes

We described injection prescription (i.e. 4 vs 8 weeks), HIV and HBV VL at initiation, and clinical outcomes on LAI treatment. Outcomes were assessed via direct chart review through February 15, 2023, and included HIV and HBV VL, documented on-time receipt of injections (+/− 7 days of appointment date), being lost from care, or choosing to transition back to oral ART.

Statistical analyses

Primary analyses describe characteristics of LAI-eligible PWH. Among the total LAI-eligible population, we compared suppressed and non-suppressed PWH. All variables were measured at the last HIV VL measured in the study period. We explore differences based on duration of viral suppression relative to each person’s most recent VL measure within the 2-year eligibility period. Comparisons were evaluated using Pearson Chi square or Fisher’s Exact for categorical and wilcoxon rank-sum for continuous variables.

Results

Study sample and demographics

We assessed LAI-CAB/RPV eligibility among 1672 PWH in clinical care 2020-2021. One-quarter (25.4%) were deemed ineligible for LAI-CAB/RPV due to documented resistance to INSTI (N = 72) and/or NNRTI (N = 410) (Table 1). Overall, 63% with available genotype had no documented INSTI or NNRTI resistance (N = 733), and PWH without available genotype were presumptively classified as INSTI and NNRTI susceptible (n = 514). Nine PWH (0.7%; N = 9/1247 without resistance) were considered ineligible due to receipt of contraindicated medications.

Table 1.

ART resistance among persons with HIV, UCHCC, 2020-2021.

ART resistance^a	N (%)
All patients	1672 (100)
Any INSTI resistance	72 (4.3)
Any cabotegravir resistance	66 (3.9)
Potential low-level	34 (2.0)
Low-level	21 (1.3)
Intermediate	11 (0.7)
High-level	0
Any NNRTI resistance	410 (24.5)
Any rilpivirine resistance	270 (16.1)
Potential low-level	80 (4.8)
Low-level	63 (3.8)
Intermediate	65 (3.9)
High-level	62 (3.7)
Any INSTI or NNRTI resistance	425 (25.4)

Antiretroviral therapy (ART), integrase strand transfer inhibitors (INSTI), non-nucleoside reverse transcriptase inhibitors (NNRTI).

^aResistance is characterized as cumulative resistance based on all available genotypes. Scores are defined by the Stanford HIV Database; Integrase resistance is defined as a resistance score of 10 or above to BIC, CAB, DTG, EVG, and RAL; NNRTI resistance is defined as a resistance score of 10 or above to DOR, EFV, ETR, NVP, and RPV. The qualitative breakdown of specific ART resistance was defined by the Stanford Database scoring system; potential low-level (10–14), low-level (15–29), intermediate (30–59), high-level (>=60); a susceptible score (0–9) was not defined as having resistance to ART and was excluded from the qualitative breakdown.

1238 (74%) were eligible for LAI-CAB/RPV. The median age was 53 years (interquartile range [IQR] 40, 61), most were male (73.6%), and just over half were non-Hispanic Black (Table 2). Over one-third lived greater than 50 miles from the clinic one way, with a median distance to clinic of 37 miles (IQR: 22, 70), and one-fifth resided in rural counties. At the most recently available measure, 1128 PWH (91.1%) had HIV RNA <50 copies/mL, and most (76.4%) were suppressed >12 months.

Table 2.

Characteristics of LAI-eligible and LAI-initiating persons with HIV in clinical care, UCHCC 2020-2021.

Characteristic^a	All LAI-eligible in clinical care (N = 1238)			LAI non-initiators	LAI initiators
	HIV RNA level
	<50 copies/mL N = 1128 (91%)	≥50 copies/mL N = 110 (8.9%)	p-value^α	N = 1208*	N = 47*	p-value^β
Age in years	53 (41, 61)	44 (33, 56)	<0.01	53 (40, 61)	44 (32, 55)	<0.01
Sex			0.12
Female	291 (25.8)	36 (32.7)		320 (26.5)	11 (23.4)	0.64
Race/ethnicity^b			0.18			0.71^δ
White, non-hispanic	365 (32.4)	28 (25.5)		384 (31.8)	14 (29.8)
Black, non-hispanic	605 (53.6)	71 (64.6)		661 (54.7)	25 (53.2)
Hispanic	115 (10.2)	8 (7.3)		119 (9.9)	5 (10.6)
Other/unknown	43 (3.8)	3 (2.7)		44 (3.6)	3 (6.4)
HIV transmission risk factor^c			0.06			0.61^δ
MSM	599 (53.1)	48 (43.6)		629 (52.1)	28 (59.6)
PWID	67 (5.9)	7 (6.4)		72 (6.0)	3 (6.4)
Heterosexual contact	382 (33.9)	40 (36.4)		415 (34.4)	12 (25.5)
Other/unknown	80 (7.1)	15 (13.6)		92 (7.6)	4 (8.5)
Years since diagnosis	15 (9, 23)	13 (7, 19)	0.02	15 (9, 23)	11 (5, 16)	<0.01
Years since ART initiation	13 (7, 20)	11 (5, 16)	<0.01	13 (7, 20)	7 (4, 13)	<0.01
Gap in care in 12-month period^d	128 (13.9)	18 (23.1)	0.03	143 (14.7)	4 (10.0)	0.41
≥2 missed visits in last 24 months	226 (20.0)	49 (44.6)	<0.01	265 (21.9)	14 (29.8)	0.20
Total care interactions (lab or provider visit) in last 24 months	5 (3, 7)	5 (2, 7)	0.08	5 (3, 7)	8 (6, 11)	<0.01
Nadir CD4 count (cells/mm³)	254 (100, 428)	181 (70, 342)	0.02	243 (89, 416)	430 (253, 551)	<0.01
Detectable VL at LAI initiation^e	NA	NA		NA	6 (12.8)	N/A
Acute/chronic hepatitis B infection	40 (3.6)	4 (3.6)	1.00^δ	44 (3.6)	1 (2.1)	1.00^δ
Current (previous^f) base ART			0.16^δ
INSTI	915 (81.1)	90 (81.8)		979 (81.0)	42 (89.4)	0.64^δ
NNRTI	160 (14.2)	12 (10.9)		169 (14.0)	4 (8.5)
PI	49 (4.3)	6 (5.5)		54 (4.5)	1 (2.1)
NRTI	3 (0.3)	2 (1.8)		5 (0.4)	0
Unknown	1 (0.1)	0		1 (0.1)	0
Insurance			<0.01			<0.01
Medicare	318 (28.2)	26 (23.6)		342 (28.3)	3 (6.4)
Medicaid	100 (8.9)	21 (19.1)		117 (9.7)	11 (23.4)
Public	79 (7.0)	2 (1.8)		78 (6.5)	3 (6.4)
Private	401 (35.6)	21 (19.1)		411 (34.0)	17 (36.2)
Uninsured	229 (20.3)	40 (36.4)		259 (21.4)	13 (27.7)
Unknown	1 (0.1)	0		1 (0.1)	0
Distance to clinic (miles)	37 (22, 69)	38 (26, 72)	0.23	37 (23, 70)	27 (13, 46)	<0.01
Distance to clinic >50 miles	396 (37.2)	41 (38.2)	0.81	431 (37.7)	10 (21.3)	0.02
Rurality index			0.27			0.12
Large metro	249 (22.6)	29 (26.9)		270 (22.9)	13 (27.7)
Large fringe metro	73 (6.6)	3 (2.8)		76 (6.5)	1 (2.1)
Medium metro	421 (38.2)	40 (37.0)		443 (37.6)	25 (53.2)
Small metro	124 (11.3)	10 (9.3)		131 (11.1)	4 (8.5)
Micropolitan	198 (18.0)	19 (17.6)		216 (18.3)	3 (6.4)
Non-core	36 (3.3)	7 (6.5)		43 (3.7)	1 (2.1)

All numbers are N (percentage) or median (interquartile range). Antiretroviral therapy (ART), human immunodeficiency virus (HIV), integrase strand transfer inhibitors (INSTI), men who have sex with men (MSM), not applicable (NA), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), persons who inject drugs (PWID).*the 47 persons who initiated LAI were not entirely captured by the “LAI eligible” population as some were noted to have drug class resistance that would has otherwise been characterized as ineligible; ^α comparing persons with suppress and non-suppressed VL; ^β comparing all LAI initiators to all LAI-eligible who did not initiate; ^δindicates comparison using Fisher’s Exact test.

^aAll characteristics measured at most recent HIV clinical visit. May not sum to 100% due to missing data.

^bOther/unknown includes Native Hawaiian/Pacific Islander, American Indian or Alaska Native, and if race/ethnicity was unvailable.

^cPersons with both MSM and PWID are included as PWID (overall [N = 19], suppressed [N = 17] and non-suppressed [N = 2]). Other/unknown includes health care or clinical laboratory worker, perinatal transmission, receipt of blood transfusion, and unknown risk.

^dDenominator is 999 persons with one visit in the first 6 months of the calendar year, based on HRSA definition.

^eVL ranged from 52 to 813,426 cp/mL; 2 PWH 40-<1000cp/mL, 3 PWH 1000-<10,0000cp/mL, 1 PWH ≥10,000cp/mL.

^fAmong LAI initiators.

PWH without viral suppression

We stratified patient characteristics by virologic suppression (Table 2). Among those not virally suppressed (N = 110, 8.9%) the median VL was 491 copies/mL (IQR: 87, 9311), and three patients were treatment naïve with their last VL corresponding to the time of HIV diagnosis. PWH who were not virally suppressed at their last visit were younger than PWH with suppressed VL (median age of 44 years compared to 53 years, p < 0.01).

PWH who were not virally suppressed had more frequent gaps in care (23.1% vs 13.9%, p = 0.03) in prior 12 months and a greater proportion had missed two or more visits in the past 24 months (44.6% vs 20.0%, p < 0.01). More than one-third (36.4%) of PWH who were not virally suppressed were without any insurance at their last assessment, compared to approximately one-fifth of PWH with suppressed VL (20.3%, p = 229). Immunity to HBV was similar between groups, and <5% of persons had acute or chronic hepatitis B (p = 1.00) (Tables 2 and 3).

Table 3.

Hepatitis B characteristics of persons with HIV in clinical care, UCHCC 2020-2021^a.

Characteristic	Overall	<50 copies/mL	≥50 copies/mL	LAI initiators
Characteristic	N = 1238	N = 1128	N = 110	N = 47
Susceptible^b	311 (25.1)	274 (24.9)	37 (33.6)	6 (12.8)
Immune^c	741 (59.9)	683 (60.5)	58 (52.7)	40 (85.1)
Acute/chronic infection^d	44 (3.6)	40 (3.5)	4 (3.6)	1 (2.1)
Likely resolved infection^e	29 (2.3)	25 (2.2)	4 (3.6)	0
Uncategorized^f	113 (9.1)	106 (9.4)	7 (6.4)	0

All numbers are N (percentage). Hepatitis B surface antibody (Anti-HBc), hepatitis B surface antibody (Anti-HBs), hepatitis B deoxyribonucleic acid (HBDNA), hepatitis B surface antigen (HBsAg), human immunodeficiency virus (HIV).

^a425 persons with INSTI or NNRTI resistance, and 9 persons actively taking contraindicated medications to CAB/RPV were excluded.

^bIncludes persons with negative HBsAg and unknown Anti-HBs/Anti-HBc, or unknown HBsAg and negative Anti-HBs/Anti-HBc.

^cIncludes persons with vaccination, or natural infection, or combinations of negative HBAg and HB DNA with positive Anti-HBs and unknown Anit-HBc.

^dIncludes persons with positive HBsAg or HBDNA.

^eIncludes persons with negative HBsAg and positive Anti-HBc.

^fMissing all HBV labs for 42 (3.4%), 40 (3.6%), and 2 (1.8%) persons overall, all suppressed, and non-suppressed, respectively.

582 of all PWH completed additional surveys capturing patient-reported outcomes. PWH with viremia were more likely to endorse recent moderate to severe depression (32.3% vs 12.2%, p < 0.01) (Table 4). Reports of stigma were endorsed more frequently among PWH with viremia, and they were less likely to report stable housing (p = 0.03). Hazardous drinking exceeded 10% in both groups, though no statistically significant differences were observed in alcohol use patterns between those with viremia and those without.

Table 4.

Mental health and social characteristics of LAI-eligible and LAI-initiating person with HIV in clinical care, UCHCC 2020-2021^a.

Characteristic	All LAI-eligible in clinical care (N = 582)			LAI non-initiators	LAI initiators
	HIV RNA level
	<50 copies/mL N = 549 (94.3%)	≥50 copies/mLN = 33 (5.7%)	p-value^δ	N = 569	N = 18	p-value^δ
Depression severity^b			<0.01			1.00
None to mild	467 (87.8)	21 (67.7)		478 (86.6)	14 (87.5)
Moderate to severe	65 (12.2)	10 (32.3)		74 (13.4)	2 (12.5)
HIV stigma^c
Felt like a bad person	37 (7.8)	6 (19.4)	0.04	40 (8.2)	3 (17.7)	0.17
Felt disgusting	51 (10.9)	6 (19.4)	0.15	54 (11.0)	4 (23.5)	0.12
Felt ashamed	123 (26.1)	10 (32.3)	0.53	127 (25.9)	7 (41.2)	0.17
Felt less of themselves	62 (13.1)	7 (22.6)	0.17	67 (13.7)	2 (11.8)	1.00
Missed an ARV dose in past 7 days
No	417 (79.6)	10 (37.0)	<0.01	418 (77.6)	11 (64.7)	0.24
Housing			0.03			1.00
Homeless	7 (1.5)	3 (9.7)		10 (2.0)	0
Unstable	18 (3.8)	1 (3.2)		19 (3.9)	0
Stable	443 (93.3)	26 (83.9)		457 (92.5)	16 (100.0)
Don’t know	7 (1.5)	1 (3.2)		8 (1.6)	0
Alcohol use^d			0.37			1.00
No drinking	176 (46.7)	11 (50.0)		183 (46.9)	6 (50.0)
Non-hazardous	162 (43.0)	7 (31.8)		165 (42.3)	5 (41.7)
Hazardous	39 (10.3)	4 (18.2)		42 (10.8)	1 (8.3)

All numbers are N (percentage). Antiretroviral (ARV), alcohol use disorders identification test (AUDIT-C), human immunodeficiency virus (HIV), patient health questionnaire-8 (PHQ-8). ^δ all comparisons evaluated using Fisher’s Exact test.

^aCharacteristics are collected from the most recent self-reported patient recorded outcomes. May not sum to 100% due to missing data.

^bDepression severity is defined as the person’s PHQ-8 score with a binary (>=10) cut-off.

^cSigma is defined as answered “agree” or “strongly agree” to stigma-related questions.

^dNon-hazardous: AUDIT-C score <5 for men, <4 for women; Hazardous: AUDIT-C score ≥5 for men, ≥4 for women; 199 (33.3%), 187 (33.2%), 12 (35.3%) scores are incomplete and omitted for overall, suppressed and non-suppressed, respectively; Complete is defined as all three AUDIT-C questions answered.

LAI-CAB/RPV initiators and initiation process

Forty-seven PWH initiated LAI-CAB/RPV in 2022 (Table 2). Most (41/47; 87.2%) started on every 8-week regimen and >90% (43/47) declined oral lead in. Compared to eligible PWH who did not initiate LAI-CAB/RPV, PWH initiated on LAI-CAB/RPV were younger (median age 44 [IQR 32, 55] vs 53. [IQR 40, 61], p < 0.01), more recently diagnosed with HIV (median year since diagnosis 11 [IQR 5, 16] vs 15 [IQR 9, 23], p < 0.01), and with fewer years on oral ART (median years 7 [IQR 4, 13] vs 13 [IQR 7, 20], p < 0.01). LAI-CAB/RPV initiators also had a higher nadir CD4 count (430 cells/mm³ [IQR 253, 551] vs 243 [IQR 89, 416], p < 0.01).

LAI-CAB/RPV initiators generally lived closer to clinic (median distance 27 miles [IQR 13, 46] vs 37 miles [IQR 23, 70], p < 0.01), but no significant differences in rurality index distribution of counties of residence. Initiators had a higher median number of care interactions in prior 24 months (8 [IQR 6, 11] vs 5 [IQR 5, 7], p < 0.01). The groups were similar in terms of other demographic and clinical characteristics, without notable differences in terms of gaps in care or missed visits.

The process for referral for LAI during the period under study was developed with a multidisciplinary team of physicians, social workers, nurses, and pharmacists. The process relied on a provider-initiated request sent to a clinical pharmacist (AP) who was tasked with record review and submitting test claims with insurance, determining medical versus pharmacy benefits if insured. Providers were asked to complete an electronic-medical record-based fillable form (or “dotphrase”) through which they could assess clinical eligibility including genotypes (if available), NNRTI exposure, HBV status, preference for oral lead-in, and patient-stated willingness to return to the clinic at the designated frequency (every 4 or 8 weeks). Completion of this form was not required for referral but was used to assist with streamlining clinical eligibility review. Once reviewed by the pharmacist, with support from additional physicians on the LAI CAB/RPV team, a lead nurse (BT) would onboard patients and coordinate scheduling and providing reminders for all follow-up visits.

LAI-CAB/RPV clinical outcomes

The 47 LAI-CAB/RPV initiators included six patients with detectable viremia at their most recent HIV VL measurement preceding first injection. Among the 41 suppressed prior to first injection, nine did not have subsequent VL measurements available at the time of chart review and one had new low-level viremia (98 copies/ml) approximately 5 months after LAI-CAB/RPV initiation. The remaining 31 (75.6%) remained suppressed at follow-up. The 47 LAI-CAB/RPV initiators were followed for a median of 20.0 weeks (IQR 14.7, 26.9; range 9.7, 49.9), through data abstraction. Two patients stopped LAI-CAB/RPV due to injection site reactions, opting to return to prior oral regimen after a single injection and were suppressed at follow-up visits. During the period of observation, three patients were >7 days late for an injection – all three were undetectable at subsequent re-check and two restarted injectable therapy.

Among the six LAI-CAB/RPV initiators with detectable VL prior receipt of first injection, all were initiated on every-4-week injections, and one also received concomitant every-two-week ibalizumab (fusion inhibitor) infusions in the setting of known prior NNRTI class resistance. All six had rapid decline in viremia and four had suppressed VL at the time of chart review. Among the two patients who did not suppress, one was identified with a new Y181C mutation, conferring resistance to RPV and the second was noted with low-level rebound viremia (100 copies/ml) after >4 months of viral suppression.

One patient with CD4 < 10, Kaposi’s sarcoma, and chronic HBV, initiated LAI-CAB/RPV with both HIV and HBV viremia and continued daily oral emtricitabine (FTC)/tenofovir alafenamide (TAF) for HBV treatment. HIV VL responded appropriately after receiving every-4-week injections though HBV DNA remained detectable.

Discussion

Among PWH in care at a safety-net academic medical center in the Southeast, nearly 75% were potentially appropriate for LAI-CAB/RPV. The remaining 25% were generally excluded due to documented NNRTI class resistance, though we are unable to assess prior NNRTI exposure or drug class hypersensivity, potentially over-estimating the proportion who are eligible. Among those without documented resistance, nearly one-in-ten were viremic at their last visit. Our results expose important structural considerations to scale-up of clinic-based LAI-CAB/RPV, including distance to clinic in this more rural catchment area, and highlights potential challenges of expanding LAI-CAB/RPV use in a population with often inconsistent care engagement. Other observations, such as prevalent mental health problems, hazardous alcohol use, under-insurance, unstable housing, and perceived stigma, emphasize the complexity of HIV care in this safety-net clinic – challenges that are known to interfere with adherence to daily oral ART, but for which the relevance in the context of LAI-CAB/RPV uptake and adherence are unknown.

Distance to clinic is a major concern in the mixed peri-urban and rural settings prominent across the Southeastern US, driven in part by provider shortages.³¹ Distance and unreliable transportation negatively affects care retention and viral suppression.³² Almost 40% of LAI-CAB/RPV-eligible patients lived more than 50 miles from the clinic, though we were not able to compute true ‘travel time’, which may offer additional insights into the relevance of travel distance. Generally, long travel times and more frequent clinic visits for injections also means more time away from work. Support mechanisms (i.e. transportation assistance) may not adequately address opportunity costs inherent to increased visit frequency necessitated by LAI-CAB/RPV.³³ Novel LAI-CAB/RPV distribution strategies to ease travel and visit burden are being explored, including pharmacy³⁴ and at-home injections.³⁵ Accommodating persons who live far from brick-and-mortar clinics may be important to promote equitable LAI-CAB/RPV implementation and extend reach of long-acting therapy, particularly in the rural South.

The degree to which distance to care and rurality impacts LAI-CAB/RPV uptake and adherence may be mediated by other factors, such as stigma. HIV stigma is pervasive in the Southern US, and contributes to the regional outcome disparities observed across the care continuum.³³ Over one quarter of respondents who completed PRO surveys felt ashamed of their HIV status. LAI-CAB/RPV may help to overcome important stigma-related barriers to effective HIV management by eliminating the need for daily ART (a reminder of a person’s HIV status) and reducing the risk of inadvertent disclosure through pills.^36,37 Indeed, some PWH intentionally seek HIV care outside their communities due to concerns about disclosure to community members, which could influence the proposed solution of local pharmacy-based injections.^20,38 Ultimately, the tension between a preference for more discreet HIV treatment modalities, increased frequency of required clinic visits, and long travel time due to scarcity of HIV providers or preference for providers who do not reside in the same community, uniquely complicates LAI-CAB/RPV access for many PWH residing in the rural south. These dynamics should be a focus of implementation studies that historically have explored determinants of LAI-CAB/RPV use in more concentrated, urban communities.

This study is among the first explorations of early implementation of LAI in the Southeastern US.²¹ The demographics of LAI initiators in our study closely aligned with those of the clinic population - most were male and over half were non-Hispanic Black. Compared to the full clinic population, PWH starting LAI-CAB/RPV tended to live marginally closer to the clinic and more were privately insured. Thirteen percent of LAI-CAB/RPV initiators were likely susceptible to HBV based on prior serologies, emphasizing the importance of HBV vaccination for PWH switching to ART regimens without anti-HBV activity such as CAB/RPV, to prevent HBV infection or reactivation.³⁹ Among the 47 initiated on LAI-CAB/RPV in the 12-month period studied, all had previously been on oral therapy and six (13%) initiated in the setting of at least low level viremia (>50 copies/ml), including one person who was initiated on LAI-CAB/RPV as well as long-acting lenacapavir⁴⁰ and another with concomitant ibalizumab. These data highlight the opportunity to deploy novel combination therapy as salvage for persons who have complex resistance and difficulty with oral ART. This may be particularly relevant given the frequent RPV resistance observed (16%) in the full cohort, suggesting an important research gap regarding efficacy of combination of multiple longer-acting agents.

Increasing empirical and modelling evidence supports use of LAI-CAB/RPV as a cost-effective strategy to increase viral suppression, improve health outcomes, and interrupt HIV transmission, as realized when given to PWH who have struggled to maintain suppression on daily oral therapy.^41,42 Our findings provide additional observational evidence, albeit in a small group, on the effectiveness of CAB/RPV in PWH with viremia who were not suppressed on oral therapy; consistent with recent trials⁴³ and prior observational studies,^14,44 all six patients had a rapid decline in HIV VL. One person with a high HIV VL prior to LAI-CAB/RPV initiation had emergent NNRTI resistance, highlighting the importance of understanding risk factors for LAI-CAB/RPV failure.

Achieving the individual and public health benefits of LAI-CAB/RPV hinges on developing strategies that cater to the barriers to oral ART use experienced by PWH with viremia. In our cohort of PWH accessing care, PWH who were not suppressed were younger, frequently experienced stigma, were more likely to report moderate to severe depression symptoms and hazardous alcohol use, had less stable housing, were more likely to be uninsured, and were more likely to have recent gaps in care. Importantly, our analysis includes assessment of care engagement between 2020-2021, a time in which many clinical services were impacted by COVID-19 disruptions and may reflect abnormally high rates of gaps in care that may not reflect true levels of engagement and may not persist in more recent years. Furthermore, our analysis only includes persons with clinical care contact. Whether or how LAI-CAB/RPV could be used for persons who have fallen out of care – a group fundamentally not included in this retrospective analysis – is a crucial area of future research, particularly given HIV transmissions attributable to diagnosed PWH who are inconsistently engaged in HIV care.⁴⁵

Conclusions

LAI-CAB/RPV is an exciting and novel advance in HIV treatment that could change the course of the HIV epidemic in the US. In the Southeastern US, where complex interactions of poverty, rurality, HIV-related stigma, and a paucity of HIV providers contribute to lower rates of viral suppression, more new infections, and more frequent HIV-associated deaths, there exist unique challenges to LAI-CAB/RPV uptake and sustained use.³³ These challenges may be particularly pertinent to PWH with viremia and those with intermittent HIV care engagement – groups that are critical to maximize the impact of highly-effective but resource-intensive LAI-CAB/RPV. Developing and testing context-specific strategies tailored to local and regional circumstances to facilitate uptake and effective use is essential to achieve the potential of LAI-CAB/RPV.

Footnotes

Acknowledgements

The authors are grateful for the support of the UNC Infectious Disease Clinic and for the generosity of clients’ willing to engage in research through the UCHCC.

Author contributions

SER, JJE, VG, CEF, and SN conceptualized study design. CL, TDM, and KPL facilitated data access and analysis. All authors contributed to and reviewed final manuscript prior to submission.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JJE is a consultant to Merck, ViiV Healthcare and Gilead Science, the University of North Carolina at Chapel Hill receives research funding for studies on which JJE is an investigator.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by pilot funds provided by North Carolina Translational and Clinical Sciences Institute (UM1TR004406) and the University of North Carolina at Chapel Hill Center for AIDS Research (P30AI050410). SER received additional support from Doris Duke Charitable Foundation grant #2020143.

ORCID iDs

Sarah E Rutstein

Thibaut Davy-Mendez

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