Use of Injectable CAB/RPV LA as Replacement ART in Virally Suppressed Adults

Date of current publication: May 15, 2023
Lead author: Joseph P. McGowan, MD
Writing group: Steven M. Fine, MD, PhD; Rona M. Vail, MD; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD; Charles J. Gonzalez, MD; Christopher J. Hoffmann, MD, MPH
Committee: Medical Care Criteria Committee
Date of original publication: April 7, 2022

Purpose: This guideline was developed by the New York State Department of Health (NYSDOH) AIDS Institute (AI) to provide clinicians with evidence-based recommendations and information on the use of injectable long-acting cabotegravir/rilpivirine (CAB/RPV LA) as replacement antiretroviral therapy (ART) for adults (≥18 years old) with HIV who are virally suppressed (HIV RNA level <50 copies/mL) FDA 2021. The goal is to provide clinicians with the information necessary to:

• Weigh the risks and benefits of switching from an oral to an injectable ART regimen
• Engage patients in informed, shared decision-making regarding a switch to injectable ART
• Choose, initiate, and maintain a monthly (every 4 weeks) or bimonthly (every 8 weeks) dosing schedule, respond to missed doses, and manage discontinuation of injectable ART when indicated
• Develop medical practice protocols and procedures for implementing injectable ART

Rationale for injectable ART: Daily adherence to oral ART is challenging for some patients for a wide variety of complex and intersecting reasons, including pill counts and sizes, disclosure and privacy concerns, HIV-related stigma, neurocognitive disorders and mental health conditions, active substance use, psychological trauma, personal belief systems, travel requirements, occupation, and health literacy. Interventions to improve medication adherence include the use of pillbox organizers, motivational interviewing, peer-based education and counseling, directly administered ART, text messaging, and alarms Babudieri, et al. 2011; Hardy, et al. 2011; Lester, et al. 2010; Altice, et al. 2007; Johnson, et al. 2007; Petersen, et al. 2007; Purcell, et al. 2007; Golin, et al. 2006; Mannheimer, et al. 2006; Remien, et al. 2005. The availability of simplified, single-tablet oral regimens has improved medication adherence significantly Sutton, et al. 2016; Hanna, et al. 2014; Nachega, et al. 2014. However, real-world clinician and patient experiences have demonstrated that barriers to ART adherence remain Cohen, et al. 2020.

Phase 3 clinical trial results suggest that the injectable long-acting combination of the integrase strand transfer inhibitor cabotegravir and the nonnucleoside reverse transcriptase inhibitor rilpivirine (CAB/RPV LA) may be a suitable option for patients engaged in care who would prefer an alternative to daily oral therapy Overton, et al. 2021; Orkin, et al. 2020; Swindells, et al. 2020. In the FLAIR and ATLAS trials, participants whose virus was suppressed with oral ART regimens were randomly assigned to receive monthly injectable CAB/RPV LA therapy or standard of care oral therapy. Injectable therapy was determined to be noninferior to oral therapy after 48 weeks of treatment Orkin, et al. 2020; Swindells, et al. 2020.

Note on “experienced” and “expert” HIV care providers: Throughout this guideline, when reference is made to “experienced HIV care provider” or “expert HIV care provider,” those terms are referring to the following 2017 NYSDOH AI definitions:

• Experienced HIV care provider: Practitioners who have been accorded HIV Experienced Provider status by the American Academy of HIV Medicine or have met the HIV Medicine Association’s definition of an experienced provider are eligible for designation as an HIV Experienced Provider in New York State. Nurse practitioners and licensed midwives who provide clinical care to individuals with HIV in collaboration with a physician may be considered HIV Experienced Providers as long as all other practice agreements are met (8 NYCRR 79-5:1; 10 NYCRR 85.36; 8 NYCRR 139-6900). Physician assistants who provide clinical care to individuals with HIV under the supervision of an HIV Specialist physician may also be considered HIV Experienced Providers (10 NYCRR 94.2)
• Expert HIV care provider: A provider with extensive experience in the management of complex patients with HIV.

Based on safety and efficacy data from randomized clinical trials, the U.S. Food and Drug Administration (FDA) has approved injectable long-acting cabotegravir/rilpivirine (CAB/RPV LA), administered as a monthly (every 4 weeks) or bimonthly (every 8 weeks) intramuscular injection, as replacement antiretroviral therapy (ART) for adults (≥18 years old) with HIV who are virally suppressed (HIV RNA level <50 copies/mL) ViiV Healthcare 2022; FDA 2021.

FLAIR trial: In the randomized, open-label FLAIR trial, 566 participants who initiated ART with 20 weeks of fixed-dose dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) were subsequently randomly assigned to either 4 weeks of oral lead-in therapy with CAB 30 mg and RPV 25 mg daily followed by monthly injections of CAB/RPV LA (n = 283) or to continue oral therapy with DTG/ABC/3TC (n = 283). Participants were ≥18 years old, ART-naive, and had a plasma HIV RNA level ≥1,000 copies/mL at screening. Key exclusion criteria included pregnancy, breastfeeding, coinfection with hepatitis B virus (HBV), severe liver disease, and known resistance to integrase strand transfer inhibitors (INSTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), excluding the K103N mutation in isolation. The primary endpoint was the percentage of participants with an HIV RNA level ≥50 copies/mL at week 48 of the maintenance phase; a secondary endpoint was the percentage of participants with an HIV RNA level <50 copies/mL at week 48. At week 48, 6 of 283 (2.1%) participants in the injectable therapy arm had an HIV RNA level ≥50 copies/mL compared with 7 of 283 participants (2.5%) in the oral therapy arm, meeting criteria for noninferiority, and 93.6% of those in the injectable therapy arm achieved an HIV RNA level <50 copies/mL at week 48, compared with 93.3% of those in the oral therapy arm (see Table 1, below) Orkin, et al. 2020.

ATLAS trial: The randomized, open-label ATLAS trial compared injectable CAB/RPV LA with standard of care oral therapy in participants who were virally suppressed for a minimum of 6 months before enrollment. The trial included 616 adults ≥18 years old on uninterrupted ART without medication changes in the last 6 months and without virologic failure for 6 months before screening who had an HIV RNA level of <50 copies/mL at screening and within 6 and 12 months before screening. A single regimen switch was allowed ≥6 months before screening for reasons of tolerability, simplification, or access to medications but not for virologic failure. Participants taking DTG/ABC/3TC were excluded because prior treatment with that regimen was adequately represented in the FLAIR trial. Other exclusion criteria were active HBV infection, pregnancy, and the presence of INSTI or NNRTI resistance-associated mutations, except the K103N mutation in isolation. Participants were randomly assigned to either continue oral therapy (n = 308) or switch to monthly injections of CAB/RPV LA (n = 308). The primary endpoint was the percentage of participants with an HIV RNA level ≥50 copies/mL at week 48 of the maintenance phase, and a secondary endpoint was the percentage of participants with an HIV RNA level <50 copies/mL at week 48. At week 48, 5 (1.6%) participants in the injectable therapy arm and 3 (1%) in the oral therapy arm had an HIV RNA level ≥50 copies/mL, meeting criteria for noninferiority, and 92.5% of those in the injectable therapy arm achieved an HIV RNA level <50 copies/mL at week 48, compared with 95.5% of those in the oral therapy arm (see Table 1, below) Swindells, et al. 2020.

Adverse effects: Pooled adverse effects of CAB/RPV LA in both the FLAIR and ATLAS trials included injection site reactions that rarely led to medication discontinuation, musculoskeletal pain, nausea, sleep disorders, dizziness, depression, and rash FDA 2021. Laboratory abnormalities in aspartate aminotransferase, alanine aminotransferase, total bilirubin, creatine phosphokinase, and lipase were also noted FDA 2021 (for more details, see guideline section Benefits, Limitations, and Risks of CAB/RPV LA as ART > Adverse effects).

Noninferiority of bimonthly dosing—the ATLAS-2M trial: The randomized, open-label, phase 3b ATLAS-2M trial demonstrated similar efficacy between 4-week (n = 523) and 8-week (n = 522) maintenance dosing schemes of CAB/RPV LA. This study included 391 prior ATLAS study participants from both arms (injectable therapy and oral therapy). Newly recruited participants had received a first or second oral ART regimen for at least 6 months, had no history of virologic failure, had an HIV RNA level <50 copies/mL twice in the prior year, and no known INSTI or NNRTI resistance, excluding K103N mutation in isolation. Participants were randomly assigned to receive injectable CAB 400 mg/RPV 600 mg LA every 4 weeks or CAB 600 mg/RPV 900 mg LA every 8 weeks (those new to injectable therapy received the standard 4-week oral lead-in with CAB and RPV, similar to FLAIR and ATLAS). The primary endpoint was the percentage of participants with an HIV RNA level ≥50 copies/mL at week 48; a secondary endpoint was the percentage of participants with an HIV RNA level <50 copies/mL at week 48. Of participants in the 8-week treatment arm, 9 (2%) had an HIV RNA level ≥50 copies/mL at week 48, compared with 5 (1%) in the 4-week treatment arm, meeting criteria for noninferiority, and 94% of participants in the 8-week arm achieved an HIV RNA level <50 copies/mL at week 48, compared with 93% of those in the 4-week arm Overton, et al. 2021.

At 96 weeks, 11 (2.1%) of participants in the 8-week treatment arm and 6 (1.1%) in the 4-week treatment arm had an HIV RNA level ≥50 copies/mL, and 91% of those in the 8-week arm versus 90% in the 4-week arm achieved an HIV RNA level <50 copies/mL (see Table 1, below) Jaeger, et al. 2021. CAB/RPV LA was initially FDA-approved for monthly (every 4 weeks) maintenance dosing. Based on demonstrated safety and efficacy at 96 weeks, the FDA subsequently approved CAB/RPV LA for bimonthly (every 8 weeks) dosing and made the oral medication lead-in optional.

Follow-up data from week 152 show that dosing every 8 weeks remains noninferior to dosing every 4 weeks, with 87% and 86% of participants, respectively, maintaining an HIV RNA level <50 copies/mL Overton, et al. 2023.

Benefits: Study participants have expressed high levels of satisfaction with injectable therapy in phase 2 and 3 trials. In the FLAIR trial, 257 of 283 (91%) participants who received injectable CAB/RPV LA preferred it over their previous oral therapy Orkin, et al. 2020. In the ATLAS trial, 266 of 308 (86%) participants in the intention-to-treat exposed population preferred injectable therapy to daily oral therapy Swindells, et al. 2020. These data are consistent with participant preferences in the earlier LATTE-2 trial Kerrigan, et al. 2018. In the ATLAS-2M trial, 92% of participants preferred bimonthly injections of CAB/RPV LA over the oral regimen and the monthly dosing schedule Chounta, et al. 2021. Injectable therapy also eliminates the need to take daily oral medications, may reduce any stigma associated with daily dosing, and may help patients maintain privacy regarding their HIV status.

Potential risks and limitations: Initiating injectable instead of oral antiretroviral medications requires shared decision-making and discussion of the benefits, limitations, and risks of injectable therapy (see Box 1, below). Concerns include the following Orkin, et al. 2020; Swindells, et al. 2020; Margolis, et al. 2017; Margolis, et al. 2015:

• Potential for development of resistance with interrupted dosing, due to the long half-life of CAB/RPV LA
• Required return to oral CAB/RPV if injections are interrupted
• Potential adverse effects, which are mainly injection site reactions
• Low rates of virologic failure; however, resistance can develop despite optimal adherence, although this is rare
• No safety or efficacy data are available about the use of injectable ART during pregnancy and while breastfeeding or in children and adolescents
• Patients with prior virologic failure or active HBV coinfection and prior virologic failure were excluded from clinical trials
• No data are available on the efficacy of injectable therapy in people with gluteal implants or soft tissue fillers

Drug resistance: Existing NNRTI- and INSTI-associated drug resistance mutations may limit a patient’s eligibility for CAB/RPV LA treatment. INSTI- and NNRTI-associated RAMs, except the K103N mutation in isolation, were exclusionary criteria in the ATLAS, FLAIR, and ATLAS-2M trials. In the FLAIR and ATLAS trials, 5 of the 7 participants who experienced virologic failure had HIV-1 subtype A1 and the integrase substitution L74I detected at baseline and upon failure Orkin, et al. 2020; Swindells, et al. 2020. The L74I mutation in other subtypes, such as B, which is commonly seen in the United States, was not associated with virologic failure Orkin, et al. 2020; Swindells, et al. 2020. See the CAB/RPV LA package insert for other mutations commonly associated with CAB and RPV resistance FDA 2021.

In a post-hoc multivariable analysis, baseline factors associated with confirmed virologic failure (CVF)—defined as 2 consecutive plasma HIV-1 RNA measurements ≥200 copies/mL—were investigated using pooled data from the ATLAS, FLAIR, and ATLAS-2M trials from 1,039 participants naive to CAB/RPV LA treatment Cutrell, et al. 2021. Virologic failure was confirmed in 13 participants. Proviral RPV RAMs, body mass index (BMI) ≥30 kg/m², and HIV-1 subtype A6/A1 were significantly associated with CVF; the presence of 2 of these factors concurrently was rare but was found in 9 of the 13 participants with CVF, and 1 participant had all 3. The L74I integrase polymorphism was commonly found among participants with CVF: 7 of these cases were associated with the A6/A1 HIV-1 subtype, and 1 was associated with the HIV-1 C subtype. There were no cases of CVF among participants with both the L74I integrase polymorphism and HIV-1 B subtype, which was the most common subtype among participants, and 4 of the 13 participants with CVF had the HIV-1 B subtype alone, without the L74I integrase polymorphism Cutrell, et al. 2021. Further multivariable analysis through week 152, and including predicted CAB and RPV troughs, confirmed that the strongest predictor of treatment failure for CAB/RPV LA was the presence of baseline RPV RAMs (adjusted incidence rate ratio [IRR], 25.7), followed by having HIV subtype A6/A1 (IRR, 15.5). The analysis also found that having 2 or more factors (including BMI ≥30 kg/m²) enhanced predictive sensitivity and specificity for risk of failure Orkin, et al. 2023.

These findings were also reflected in data from week 152 of the ATLAS-2M trial by itself Overton, et al. 2023:

• In all, 13 participants had CVF: 11 from the 8-week dosing arm and 2 from the 4-week dosing arm.
• Of the 13, 10 had CVF by week 48; 6 of them had at least 2 baseline factors (proviral RPV RAMs, HIV-1 subtype A6/A1, BMI ≥30 kg/m²) that were associated with increased risk of virologic failure.
• Between weeks 96 and 152, CVF occurred in 2 participants.
• In participants with CVF, there were no injection delays longer than 7 days.
• CAB and/or RPV RAMs were identified in 11 of the 13 participants with CVF.
• Viral suppression was restored with oral ART in 12 of the 13 participants with CVF; nonadherence to a protease inhibitor–based regimen was reported in the remaining 1 participant.

In the SOLAR study, in which 447 participants were randomized to switch from bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) to CAB/RPV LA or continue BIC/TAF/FTC, 1 of 3 participants experiencing virologic failure had an INSTI RAM identified at baseline via proviral DNA sequencing Rampgopal, et al. 2023.

If a patient does not take oral bridging therapy when an injection of CAB/RPV LA is missed, the differing half-lives of these 2 drugs may result in the equivalent of HIV monotherapy, which can lead to the development of resistance. Ensuring that patients understand the risk and potential consequences is an important component of patient education before initiating this ART regimen. After discontinuation of injectable therapy among participants in the LATTE-2 and ATLAS trials, the median half-lives of CAB and RPV were 6.4 weeks and 29.6 weeks, respectively, and measurable plasma levels of CAB or RPV were detected in participants for ≥1 year after final injections Ford, et al. 2020. Other prevention studies reported similar results. RPV persisted in plasma for up to 112 days in male and female participants in phase 1 trials and was detectable at 168 days after a 1,200 or 600 mg initial dose in female participants McGowan, et al. 2016. In a secondary analysis of CAB pharmacokinetic data from the HPTN 077 trial, 23% of male participants had detectable plasma CAB concentrations at 52 to 60 weeks after the final injection, and 13% had detectable CAB concentrations at week 76, compared with 63% and 42% of female participants, respectively. Median time from the last injection to CAB concentrations below the lower limit of quantification was 43.7 weeks for male participants and 67.3 weeks for female participants Landovitz, et al. 2020.

Participants in the phase 3 ATLAS and FLAIR trials were required to take oral bridging therapy when ART injections occurred outside the recommended window period Orkin, et al. 2020; Swindells, et al. 2020. However, resistance to CAB/RPV has developed even in patients with optimal adherence (no missed injections). Among ATLAS participants who received CAB/RPV LA, virologic failure was confirmed in 3, the E138A RAM was found in 1, the E138K and V108I RAMs were found in 1, and the E138E/K and N155H RAMs were found in 1. None of these participants missed an injection or received injections outside the permitted window Swindells, et al. 2020. In light of these data, informed decision-making regarding initiation of injectable CAB/RPV LA requires discussion of the following:

• Adherence requirements for monthly (every 4 weeks) or bimonthly (every 8 weeks) injections
• Use of bridging oral therapy if injections are missed
• Small risk of developing resistance even if adherence is optimal

Adverse effects: Of participants receiving CAB/RPV LA in the ATLAS trial, 83% experienced injection site reactions Swindells, et al. 2020; however, 99% of these reactions were of mild or moderate severity. The most common reaction was pain, followed by nodules, induration, and swelling, generally beginning 1 day after injection and lasting 3 to 4 days. These declined in incidence with subsequent injections. Similarly, in the FLAIR trial, the incidence of injection site reactions declined from 71% to 20% during the trial, and 4 of 238 participants receiving CAB/RPV LA withdrew because of injection site reactions Orkin, et al. 2020. The dose of CAB/RPV is higher for bimonthly (every 8 weeks) than for monthly (every 4 weeks) dosing. Through week 152 in the ATLAS-2M trial, 16% of participants in the 8-week dosing arm reported injection site reactions, with 2% discontinuing treatment as a result, compared with 11% in the 4-week arm, with 3% discontinuing treatment as a result Overton, et al. 2023. The number of injection site reactions declined through week 48 and remained stable thereafter.

Clinicians should counsel patients about possible discomfort from CAB/RPV LA injections, particularly with the initial doses, and discuss strategies to ameliorate adverse effects if they occur. The risk of other possible adverse effects, such as pyrexia and elevations in liver functions tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin), creatine phosphokinase (8%, ≥10 × upper limit of normal [ULN]), and lipase (5%, ≥3 × ULN), should also be discussed before initiation of therapy, so the patient can make an informed decision. Additional adverse effects (all grades) reported in ≥2% of patients included musculoskeletal pain and discomfort, nausea, sleep disorders, dizziness, and rash FDA 2021.

Weight gain has been associated with the use of INSTIs to treat HIV infection Kanters, et al. 2022. The SOLAR trial assessed weight gain at 12 months among participants on a suppressive oral regimen of BIC/TAF/FTC for at least 6 months who were randomized 2:1 to switch to CAB/RPV LA received every 2 months, with or without an oral lead-in, or to continue on BIC/FTC/TAF Tan, et al. 2023. There was no difference in weight gain, proportion of patients changing BMI categories, change in waist or hip circumference, or incidence of metabolic syndrome or insulin resistance. Of note, all participants were being switched from an INSTI-based regimen and any weight changes associated with use of agents in this drug class may have already occurred.

Drug-drug interactions: Drugs that are contraindicated with CAB/RPV LA include the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the rifamycins rifabutin, rifampin, and rifapentine; dexamethasone (more than a single treatment); and St. John’s Wort (Hypericum perforatum). These medications lower CAB and/or RPV drug levels and can be used after CAB/RPV LA has been discontinued. Macrolides other than azithromycin should not be coadministered. Clinicians should refer to prescribing information for oral CAB and oral RPV for other drug interactions FDA 2021. Special attention should also be paid to over-the-counter medications and other supplements that patients may be taking.

For more information on CAB and RPV drug-drug interactions, see the following tables in the NYSDOH AI Resource: ART Drug-Drug Interactions:

• Table 1: Mechanisms of Antiretroviral Drug-Drug Interactions
• Table 6: Cabotegravir Interactions
• Table 11: Rilpivirine Interactions

Free online resources available to check specific drug-drug interactions include the University of Liverpool HIV Drug Interaction Checker.

Storage and administration: Injectable CAB/RPV LA must be refrigerated at 2° C to 8° C (36° F to 46° F) until ready to use. Before injection, the medication must be brought to room temperature for a minimum of 15 minutes and no longer than 6 hours. Once the 2 separate syringes have been prepared, CAB/RPV LA must be administered within 2 hours FDA 2021. Injectable CAB/RPV LA has to be administered in an office, hospital, or pharmacy setting by a licensed healthcare professional, given the volume of the injections (intragluteal 2 × 3 mL loading dose and 2 × 2 mL maintenance dose), the refrigeration requirements, and the necessity of administration within 2 hours of syringe preparation. Monitoring is required for 10 minutes after a patient receives the CAB/RPV LA injection. Medical institutions and clinicians will have to develop internal protocols for appropriate patient scheduling, staff availability and training, storage of injectable ART medications, and dispensing of oral CAB and RPV for lead-in and, if required, bridging periods. Significant preparation is necessary, including revising hospital and clinic formularies to include injectable CAB and RPV; designating hospital and clinic personnel, such as nurses and medical providers, to administer the medication; and establishing appropriate billing protocols for monthly or bimonthly injections.

CAB/RPV LA given as an intramuscular (IM) injection in the gluteal muscle is currently the only regimen for injectable ART.

Clinicians may consider a lead-in of oral CAB and RPV for up to 4 weeks before initiation of CAB/RPV LA injections after discussing the need for adherence to daily oral medications, potential adverse effects, and the plan to initiate the injections at week 4, on the last day of the oral lead-in (see Tables 2 and 3, below). In the extension phase of the FLAIR study, no difference in adverse events was identified between participants who completed an oral lead-in before initiating CAB/RPV LA and those who did not, and 99% of participants who did not receive an oral lead-in maintained viral suppression, compared with 93% who did receive an oral lead-in Orkin, et al. 2021. Omitting the oral lead-in simplifies treatment initiation, allows earlier access to injectable treatment, and removes the barrier of maintaining adherence to an oral dosing regimen.

Tables 2 to 4, below, present the approved dosing strategies for CAB/RPV LA, each of which may be preceded by the same 4-week oral medication lead-in, and the advantages and limitations of each dosing strategy. Both injection dosing schedules are initiated with a first IM injection administered on the last day of the oral medication lead-in, if used, or the last dose of a prior suppressive ART regimen. For the monthly (every 4 weeks) schedule, the initial IM dose is higher than the maintenance dose that begins at month 3 (week 12) and is administered every month (every 4 weeks) thereafter.

For a bimonthly dosing schedule, the first 2 IM injections are administered 4 weeks apart, and then bimonthly maintenance injections begin 3 months (12 weeks) after the initial IM dose, at the same dose as the initial injection.

Adherence requirement: Once the injection frequency is determined and a dosing schedule is planned, the clinician should ensure that the patient understands that adherence entails ensuring receipt of injections within 7 days of the scheduled date for each injection. The clinician should also address the potential need to take oral CAB/RPV for up to 2 months (8 weeks), as “bridging” therapy, if an injection is missed. It is reasonable to use the patient’s previous suppressive oral ART regimen as a bridge if supplies are readily available and if it was well tolerated. Note that if any of a patient’s coadministered medications have been changed, there is the potential for drug-drug interactions.

Injection preparation and administration: Box 2, below, provides, guidance on preparing and administering the initial loading dose and ongoing maintenance doses of CAB/RPV LA.

Post-injection observation: Observe patients on-site for at least 10 minutes after administering their initial loading dose in case of adverse reactions.

Maintenance injection administration: Maintenance dosing of CAB/RPV LA should be administered within the recommended 7-day window period and requires the same preparations outlined for the initial loading doses. Administer maintenance injections at the same time, at 2 different sites (i.e., gluteal injections on opposite sides or, if on the same side, 2 cm apart). Clinicians may choose to maintain laterality of medications throughout a patient’s course of treatment by injecting CAB LA in the same gluteus medius muscle and RPV LA in the same contralateral gluteus medius muscle each time.

Planned: If a patient plans to miss or delay a scheduled injection by >7 days, oral therapy (CAB 30 mg/RPV 25 mg, once daily with a meal) can be taken for up to 2 consecutive months (8 weeks). Alternatively, a patient’s previous suppressive oral ART regimen may be considered as a bridge if it was well tolerated, with care to assess for potential drug interactions with coadministered medications. Oral therapy should be started approximately 1 month (4 weeks) after the last injection of monthly CAB/RPV LA or 2 months (8 weeks)  after the last bimonthly CAB/RPV LA injection and continued until the day on which injections are resumed FDA 2021.

Unplanned, monthly (every 4 weeks) injection schedule: If a patient who is not taking oral bridging CAB/RPV misses a monthly injection by >7 days and will resume injectable therapy, restart injections as follows FDA 2021:

• If the patient’s last injection was ≤2 months (≤8 weeks) prior, resume as soon as possible with a maintenance dose injection of CAB 400 mg (2 mL)/RPV 600 mg (2 mL) IM.
• If the patient’s last injection was >2 months (>8 weeks) prior, resume as soon as possible with a high-dose injection of CAB 600 mg (3 mL)/RPV 900 mg (3 mL) IM once followed by monthly (every 4 weeks) maintenance dosing 400 mg (2 mL)/RPV 600 mg (2 mL) IM.

Unplanned, bimonthly (every 8 weeks) injection schedule: If a patient who is not taking oral bridging CAB/RPV misses an injection and will resume injectable therapy, restart injections as soon as possible: within 2 months (8 weeks) if the second initial injection was missed or within 3 months (12 weeks) if any other bimonthly maintenance injection was missed.

If outside of those windows, a second dose should be administered 1 month (4 weeks) after reinitiation of injections, with subsequent return to bimonthly (every 8 weeks) dosing ViiV Healthcare 2022; FDA 2021.

Clinicians should recommend discontinuation of CAB/RPV LA when virologic failure (defined as confirmed plasma HIV viral load >200 copies/mL) occurs or if CAB- or RPV-associated RAMs are identified through current or historical genotypic or phenotypic resistance testing or proviral DNA genotypic resistance testing. Pooled data from the ATLAS, FLAIR, and ATLAS-2M trials identified that having at least 2 of the following factors was associated with virologic failure: HIV subtype A6/A1, a body mass index (BMI) ≥30 kg/m², low RPV trough levels at week 8, and the presence of RPV proviral genotypic RAMs Cutrell, et al. 2021. All but one of the participants with HIV subtype A6/A1 were from Russia; this subtype more commonly contains the L74I integrase gene polymorphism, which may facilitate treatment failure. The L74I polymorphism was not found in participants with HIV subtype B, which is the vastly predominant subtype in the United States. A separate analysis of baseline genotypic resistance testing of HIV-1 from 4,212 treatment-naive individuals from university clinics in Paris, France, found that 3.2% had virus with at least 1 CAB RAM (a rate that jumped to 16.2% if the L74I polymorphism was included) and 14.3% had RPV RAMs Charpentier, et al. 2021. Knowledge of these preexisting mutations may not be readily available when switching to CAB/RPV LA from a suppressive oral regimen.

Decreased drug exposure due to slower absorption rates of CAB LA and RPV LA has been associated with female sex and increased BMI Ford, et al. 2014; Jackson, et al. 2014; strict adherence to dosing schedules should be emphasized in these populations to prevent subtherapeutic drug levels.

The slow clearance and prolonged exposure of both CAB LA and RPV LA, which are the key features that underlie the success of the combination for intermittent dosing, become an Achilles heel when doses are missed or irregularly administered. The clearance half-life (t_1/2) of CAB LA is estimated to be as long as 40 days, and detectable levels in some individuals can be measured for 1 year after final dosing Spreen, et al. 2014; the t_1/2 of RPV LA is as long as 90 days Wensing, et al. 2019; Verloes, et al. 2015. Therefore, during prolonged lapses in administration, not only would plasma levels of both drugs be expected to slowly drop below the inhibitory threshold but would also remain there for prolonged periods and would do so differentially, with RPV persisting longer and further enhancing the risk for selection of RAMs. CAB LA and RPV LA have relatively low barriers to resistance, in that selection of 1 or a few mutations would be adequate to reduce antiviral activity Oliveira, et al. 2018. It is therefore important for clinicians to support patient adherence to the selected dosing interval within a 7-day window and to manage delays with either oral bridging therapy or resumption of injections as quickly as possible. As data are lacking on the forgiveness of CAB/RPV LA in the face of delayed or irregular dosing before resistance selection becomes more likely, seeking guidance from an experienced HIV care provider may assist in decision-making regarding when discontinuation of the injectable regimen would be advisable.

A fully suppressive oral ART regimen that addresses the reason for discontinuation and any identified RAMs should be initiated as soon as possible but no later than 1 month (4 weeks) after the final injection for a monthly (every 4 weeks) CAB/RPV LA dosing schedule or 2 months (8 weeks) for a bimonthly CAB/RPV LA dosing schedule FDA 2021.

Genotypic testing: Before initiating ART with long-acting cabotegravir/rilpivirine (CAB/RPV LA) in patients with a history of virologic failure or if there is clinical suspicion for integrase strand transfer inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance, clinicians should obtain or review a baseline HIV-1 genotype test that includes the reverse transcriptase and integrase genes to rule out underlying resistance-associated mutations (RAMs). Because CAB/RPV LA is recommended only for patients already taking a fully suppressive oral ART regimen, proviral DNA genotype testing is preferred at baseline. Of note, K103 mutations alone (i.e., without additional NNRTI RAMs) are not considered exclusionary for the use of injectable RPV. Virologic failure is defined as 2 HIV-1 RNA measurements >200 copies/mL after an initial undetectable viral load or HIV RNA >200 copies/mL after 24 weeks of adherent ART. All genotypic testing (baseline and while on treatment) should include the reverse transcriptase and integrase genes. Confirmed resistance to CAB or RPV at any time is grounds for discontinuing injectable ART and switching to an oral regimen that is compatible with the patient’s resistance profile.

Abnormal laboratory test results were reported in phase 3 trials of injectable CAB/RPV LA. Five participants in the long-acting therapy group of the ATLAS trial had elevations of alanine aminotransferase to a minimum of 3 times the upper limit of normal; however, hepatitis A virus infection was diagnosed in 3 of the 5 participants, hepatitis B virus infection in 1, and hepatitis C virus infection in 1 Swindells, et al. 2020. An elevated lipase level (grade 4) was reported in 1 participant in the FLAIR trial (for additional laboratory abnormalities, see guideline section Benefits, Limitations, and Risks of CAB/RPV LA as ART > Adverse effects) Orkin, et al. 2020.

Monitoring for adverse effects: Of patients receiving CAB/RPV LA, 80% to 86% have reported injection site reactions involving pain, nodules, induration, swelling, or pruritus Orkin, et al. 2020; Swindells, et al. 2020; Markowitz, et al. 2017. Before initiation of CAB/RPV LA, education and counseling can prepare patients for adverse effects, which typically occur early in treatment, and reassure them that any ongoing adverse reactions are likely to diminish in frequency and intensity. Management of injection site reactions will depend on the severity but may include application of cold or warm packs, massage of the affected area, and application of a topical corticosteroid for pruritus. A severe adverse reaction may require clinical evaluation.

Other reported adverse effects in the ATLAS and FLAIR phase 3 trials included pyrexia (7% and 8%, respectively), fatigue (7% in ATLAS), headache (11% and 14%, respectively), nausea (6% in FLAIR), and diarrhea (7% and 11%, respectively) Orkin, et al. 2020; Swindells, et al. 2020.

Initiation of injectable antiretroviral therapy (ART) requires institutional, clinician, and patient preparation, as detailed in Box 3, below. Each institution or medical practice will have to address preparation and implementation in the context of their internal procedures and policies.

Storage requirements, including temperature regulation, security, and bookkeeping, may pose a significant obstacle for some institutions. Billing protocols for longitudinal follow-up and injections will have to be established, including appropriate current procedural terminology codes, international classification of diseases (ICD)-10 diagnoses, and electronic medical record documentation. Patient scheduling and reminder systems will have to be developed before starting patients on an indefinite course of injectable ART to maximize limited time and staff resources, which may already be strained during the current COVID-19 pandemic. In addition, wait times should be minimized and attention given to individual patient needs regarding work schedules, available time off, parking, and transportation needs.

Along the same lines, contingency plans should be in place in case a clinic becomes unable to provide injections, with attention to resources for oral therapy to bridge periods when patients may miss injections. Patients will also need traditional counseling and education about HIV and ART adherence (see NYSDOH AI guidelines Selecting an Initial ART Regimen > Specific Factors to Consider and Discuss with Patients and Rapid ART Initiation > Counseling and Education Before Initiating ART). Specific concerns regarding travel to clinic appointments and accessing oral bridging therapy in the event of an emergency should be addressed as soon as possible.

Patients should also be advised about the potential for injection site reactions and other adverse effects described in earlier sections of the guideline.

Date of current publication: August 8, 2023
Lead authors: Jessica Rodrigues, MS; Jessica M. Atrio, MD, MSc; and Johanna L. Gribble, MA
Writing group: Steven M. Fine, MD, PhD; Rona M. Vail, MD; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD
Committee: Medical Care Criteria Committee
Date of original publication: August 8, 2023

Throughout its guidelines, the New York State Department of Health (NYSDOH) AIDS Institute (AI) Clinical Guidelines Program recommends “shared decision-making,” an individualized process central to patient-centered care. With shared decision-making, clinicians and patients engage in meaningful dialogue to arrive at an informed, collaborative decision about a patient’s health, care, and treatment planning. The approach to shared decision-making described here applies to recommendations included in all program guidelines. The included elements are drawn from a comprehensive review of multiple sources and similar  attempts to define shared decision-making, including the Institute of Medicine’s original description [Institute of Medicine 2001]. For more information, a variety of informative resources and suggested readings are included at the end of the discussion.

The benefits to patients that have been associated with a shared decision-making approach include:

• Decreased anxiety [Niburski, et al. 2020; Stalnikowicz and Brezis 2020]
• Increased trust in clinicians [Acree, et al. 2020; Groot, et al. 2020; Stalnikowicz and Brezis 2020]
• Improved engagement in preventive care [McNulty, et al. 2022; Scalia, et al. 2022; Bertakis and Azari 2011]
• Improved treatment adherence, clinical outcomes, and satisfaction with care [Crawford, et al. 2021; Bertakis and Azari 2011; Robinson, et al. 2008]
• Increased knowledge, confidence, empowerment, and self-efficacy [Chen, et al. 2021; Coronado-Vázquez, et al. 2020; Niburski, et al. 2020]

Collaborative care: Shared decision-making is an approach to healthcare delivery that respects a patient’s autonomy in responding to a clinician’s recommendations and facilitates dynamic, personalized, and collaborative care. Through this process, a clinician engages a patient in an open and respectful dialogue to elicit the patient’s knowledge, experience, healthcare goals, daily routine, lifestyle, support system, cultural and personal identity, and attitudes toward behavior, treatment, and risk. With this information and the clinician’s clinical expertise, the patient and clinician can collaborate to identify, evaluate, and choose from among available healthcare options [Coulter and Collins 2011]. This process emphasizes the importance of a patient’s values, preferences, needs, social context, and lived experience in evaluating the known benefits, risks, and limitations of a clinician’s recommendations for screening, prevention, treatment, and follow-up. As a result, shared decision-making also respects a patient’s autonomy, agency, and capacity in defining and managing their healthcare goals. Building a clinician-patient relationship rooted in shared decision-making can help clinicians engage in productive discussions with patients whose decisions may not align with optimal health outcomes. Fostering open and honest dialogue to understand a patient’s motivations while suspending judgment to reduce harm and explore alternatives is particularly vital when a patient chooses to engage in practices that may exacerbate or complicate health conditions [Halperin, et al. 2007].

Options: Implicit in the shared decision-making process is the recognition that the “right” healthcare decisions are those made by informed patients and clinicians working toward patient-centered and defined healthcare goals. When multiple options are available, shared decision-making encourages thoughtful discussion of the potential benefits and potential harms of all options, which may include doing nothing or waiting. This approach also acknowledges that efficacy may not be the most important factor in a patient’s preferences and choices [Sewell, et al. 2021].

Clinician awareness: The collaborative process of shared decision-making is enhanced by a clinician’s ability to demonstrate empathic interest in the patient, avoid stigmatizing language, employ cultural humility, recognize systemic barriers to equitable outcomes, and practice strategies of self-awareness and mitigation against implicit personal biases [Parish, et al. 2019].

Caveats: It is important for clinicians to recognize and be sensitive to the inherent power and influence they maintain throughout their interactions with patients. A clinician’s identity and community affiliations may influence their ability to navigate the shared decision-making process and develop a therapeutic alliance with the patient and may affect the treatment plan [KFF 2023; Greenwood, et al. 2020]. Furthermore, institutional policy and regional legislation, such as requirements for parental consent for gender-affirming care for transgender people or insurance coverage for sexual health care, may infringe upon a patient’s ability to access preventive- or treatment-related care [Sewell, et al. 2021].

Health equity: Adapting a shared decision-making approach that supports diverse populations is necessary to achieve more equitable and inclusive health outcomes [Castaneda-Guarderas, et al. 2016]. For instance, clinicians may need to incorporate cultural- and community-specific considerations into discussions with women, gender-diverse individuals, and young people concerning their sexual behaviors, fertility intentions, and pregnancy or lactation status. Shared decision-making offers an opportunity to build trust among marginalized and disenfranchised communities by validating their symptoms, values, and lived experience. Furthermore, it can allow for improved consistency in patient screening and assessment of prevention options and treatment plans, which can reduce the influence of social constructs and implicit bias [Castaneda-Guarderas, et al. 2016].

Clinician bias has been associated with health disparities and can have profoundly negative effects [FitzGerald and Hurst 2017; Hall, et al. 2015]. It is often challenging for clinicians to recognize and set aside personal biases and to address biases with peers and colleagues. Consciously or unconsciously, negative or stigmatizing assumptions are often made about patient characteristics, such as race, ethnicity, gender, sexual orientation, mental health, and substance use [Avery, et al. 2019; van Boekel, et al. 2013; Livingston, et al. 2012]. With its emphasis on eliciting patient information, a shared decision-making approach encourages clinicians to inquire about patients’ lived experiences rather than making assumptions and to recognize the influence of that experience in healthcare decision-making.

Stigma: Stigma may prevent individuals from seeking or receiving treatment and harm reduction services [Tsai, et al. 2019]. Among people with HIV, stigma and medical mistrust remain significant barriers to healthcare utilization, HIV diagnosis, and medication adherence and can affect disease outcomes [Turan, et al. 2017; Chambers, et al. 2015], and stigma among clinicians against people who use substances has been well-documented [Stone, et al. 2021; Tsai, et al. 2019; van Boekel, et al. 2013]. Sexual and reproductive health, including strategies to prevent HIV transmission, acquisition, and progression, may be subject to stigma, bias, social influence, and violence.

In addition to the references cited below, the following resources and suggested reading may be useful to clinicians.

References

Acree ME, McNulty M, Blocker O, et al. Shared decision-making around anal cancer screening among black bisexual and gay men in the USA. Cult Health Sex 2020;22(2):201-16. [PMID: 30931831]

Avery JD, Taylor KE, Kast KA, et al. Attitudes toward individuals with mental illness and substance use disorders among resident physicians. Prim Care Companion CNS Disord 2019;21(1):18m02382. [PMID: 30620451]

Bertakis KD, Azari R. Patient-centered care is associated with decreased health care utilization. J Am Board Fam Med 2011;24(3):229-39. [PMID: 21551394]

Castaneda-Guarderas A, Glassberg J, Grudzen CR, et al. Shared decision making with vulnerable populations in the emergency department. Acad Emerg Med 2016;23(12):1410-16. [PMID: 27860022]

Chambers LA, Rueda S, Baker DN, et al. Stigma, HIV and health: a qualitative synthesis. BMC Public Health 2015;15:848. [PMID: 26334626]

Chen CH, Kang YN, Chiu PY, et al. Effectiveness of shared decision-making intervention in patients with lumbar degenerative diseases: a randomized controlled trial. Patient Educ Couns 2021;104(10):2498-2504. [PMID: 33741234]

Coronado-Vázquez V, Canet-Fajas C, Delgado-Marroquín MT, et al. Interventions to facilitate shared decision-making using decision aids with patients in primary health care: a systematic review. Medicine (Baltimore) 2020;99(32):e21389. [PMID: 32769870]

Coulter A, Collins A. Making shared decision-making a reality: no decision about me, without me. 2011. https://www.kingsfund.org.uk/sites/default/files/Making-shared-decision-making-a-reality-paper-Angela-Coulter-Alf-Collins-July-2011_0.pdf

Crawford J, Petrie K, Harvey SB. Shared decision-making and the implementation of treatment recommendations for depression. Patient Educ Couns 2021;104(8):2119-21. [PMID: 33563500]

FitzGerald C, Hurst S. Implicit bias in healthcare professionals: a systematic review. BMC Med Ethics 2017;18(1):19. [PMID: 28249596]

Greenwood BN, Hardeman RR, Huang L, et al. Physician-patient racial concordance and disparities in birthing mortality for newborns. Proc Natl Acad Sci U S A 2020;117(35):21194-21200. [PMID: 32817561]

Groot G, Waldron T, Barreno L, et al. Trust and world view in shared decision making with indigenous patients: a realist synthesis. J Eval Clin Pract 2020;26(2):503-14. [PMID: 31750600]

Hall WJ, Chapman MV, Lee KM, et al. Implicit racial/ethnic bias among health care professionals and its influence on health care outcomes: a systematic review. Am J Public Health 2015;105(12):e60-76. [PMID: 26469668]

Halperin B, Melnychuk R, Downie J, et al. When is it permissible to dismiss a family who refuses vaccines? Legal, ethical and public health perspectives. Paediatr Child Health 2007;12(10):843-45. [PMID: 19043497]

Institute of Medicine. Crossing the quality chasm: a new health system for the 21st century. 2001. https://www.ncbi.nlm.nih.gov/books/NBK222274/

KFF. Key data on health and health care by race and ethnicity. 2023 Mar 15. https://www.kff.org/racial-equity-and-health-policy/report/key-data-on-health-and-health-care-by-race-and-ethnicity/ [accessed 2023 May 19]

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McNulty MC, Acree ME, Kerman J, et al. Shared decision making for HIV pre-exposure prophylaxis (PrEP) with black transgender women. Cult Health Sex 2022;24(8):1033-46. [PMID: 33983866]

Niburski K, Guadagno E, Abbasgholizadeh-Rahimi S, et al. Shared decision making in surgery: a meta-analysis of existing literature. Patient 2020;13(6):667-81. [PMID: 32880820]

Parish SJ, Hahn SR, Goldstein SW, et al. The International Society for the Study of Women’s Sexual Health process of care for the identification of sexual concerns and problems in women. Mayo Clin Proc 2019;94(5):842-56. [PMID: 30954288]

Robinson JH, Callister LC, Berry JA, et al. Patient-centered care and adherence: definitions and applications to improve outcomes. J Am Acad Nurse Pract 2008;20(12):600-607. [PMID: 19120591]

Scalia P, Durand MA, Elwyn G. Shared decision-making interventions: an overview and a meta-analysis of their impact on vaccine uptake. J Intern Med 2022;291(4):408-25. [PMID: 34700363]

Sewell WC, Solleveld P, Seidman D, et al. Patient-led decision-making for HIV preexposure prophylaxis. Curr HIV/AIDS Rep 2021;18(1):48-56. [PMID: 33417201]

Stalnikowicz R, Brezis M. Meaningful shared decision-making: complex process demanding cognitive and emotional skills. J Eval Clin Pract 2020;26(2):431-38. [PMID: 31989727]

Stone EM, Kennedy-Hendricks A, Barry CL, et al. The role of stigma in U.S. primary care physicians’ treatment of opioid use disorder. Drug Alcohol Depend 2021;221:108627. [PMID: 33621805]

Tsai AC, Kiang MV, Barnett ML, et al. Stigma as a fundamental hindrance to the United States opioid overdose crisis response. PLoS Med 2019;16(11):e1002969. [PMID: 31770387]

Turan B, Budhwani H, Fazeli PL, et al. How does stigma affect people living with HIV? The mediating roles of internalized and anticipated HIV stigma in the effects of perceived community stigma on health and psychosocial outcomes. AIDS Behav 2017;21(1):283-91. [PMID: 27272742]

van Boekel LC, Brouwers EP, van Weeghel J, et al. Stigma among health professionals towards patients with substance use disorders and its consequences for healthcare delivery: systematic review. Drug Alcohol Depend 2013;131(1-2):23-35. [PMID: 23490450]