Purpose of This Guideline

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.

Efficacy of CAB/RPV LA

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]. See the NYSDOH AI guideline Second-Line ART After Treatment Failure or for Regimen Simplification for use of CAB/RPV LA in patients who are not virally suppressed.

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, Potential Risks, and Limitations of CAB/RPV LA

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

Initiation, Maintenance, and Discontinuation of CAB/RPV LA as ART

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.

Laboratory Testing and Patient Follow-Up

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].

Implementing CAB/RPV LA in Clinical Practice

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.

All Recommendations

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Supplementary Material

Supplement: Guideline Development and Recommendation Ratings