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

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

Purpose and Goals of This Guideline

Reviewed and updated: Joseph P. McGowan, MD; August 15, 2022
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
Original lead author: Elliot DeHaan, MD
Date of original publication: July 2021

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].

References

Altice FL, Maru DS, Bruce RD, et al. Superiority of directly administered antiretroviral therapy over self-administered therapy among HIV-infected drug users: a prospective, randomized, controlled trial. Clin Infect Dis 2007;45(6):770-778. [PMID: 17712763

Babudieri S, Dorrucci M, Boschini A, et al. Targeting candidates for directly administered highly active antiretroviral therapy: benefits observed in HIV-infected injecting drug users in residential drug-rehabilitation facilities. AIDS Patient Care STDS 2011;25(6):359-364. [PMID: 21612546

Cohen J, Beaubrun A, Bashyal R, et al. Real-world adherence and persistence for newly-prescribed HIV treatment: single versus multiple tablet regimen comparison among US medicaid beneficiaries. AIDS Res Ther 2020;17(1):12. [PMID: 32238169

FDA. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use. 2021 Jan. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf [accessed 2021 Mar 08]

Golin CE, Earp J, Tien HC, et al. A 2-arm, randomized, controlled trial of a motivational interviewing-based intervention to improve adherence to antiretroviral therapy (ART) among patients failing or initiating ART. J Acquir Immune Defic Syndr 2006;42(1):42-51. [PMID: 16763491

Hanna DB, Hessol NA, Golub ET, et al. Increase in single-tablet regimen use and associated improvements in adherence-related outcomes in HIV-infected women. J Acquir Immune Defic Syndr 2014;65(5):587-596. [PMID: 24326606

Hardy H, Kumar V, Doros G, et al. Randomized controlled trial of a personalized cellular phone reminder system to enhance adherence to antiretroviral therapy. AIDS Patient Care STDS 2011;25(3):153-161. [PMID: 21323532

Johnson MO, Charlebois E, Morin SF, et al. Effects of a behavioral intervention on antiretroviral medication adherence among people living with HIV: the Healthy Living Project randomized controlled study. J Acquir Immune Defic Syndr 2007;46(5):574-580. [PMID: 18193499

Lester RT, Ritvo P, Mills EJ, et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 2010;376(9755):1838-1845. [PMID: 21071074

Mannheimer SB, Morse E, Matts JP, et al. Sustained benefit from a long-term antiretroviral adherence intervention. Results of a large randomized clinical trial. J Acquir Immune Defic Syndr 2006;43 Suppl 1:S41-47. [PMID: 17091022

Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. Clin Infect Dis 2014;58(9):1297-1307. [PMID: 24457345

Orkin C, Arasteh K, Gorgolas Hernandez-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med 2020;382(12):1124-1135. [PMID: 32130806

Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet 2021;396(10267):1994-2005. [PMID: 33308425

Petersen ML, Wang Y, van der Laan MJ, et al. Pillbox organizers are associated with improved adherence to HIV antiretroviral therapy and viral suppression: a marginal structural model analysis. Clin Infect Dis 2007;45(7):908-915. [PMID: 17806060

Purcell DW, Latka MH, Metsch LR, et al. Results from a randomized controlled trial of a peer-mentoring intervention to reduce HIV transmission and increase access to care and adherence to HIV medications among HIV-seropositive injection drug users. J Acquir Immune Defic Syndr 2007;46 Suppl 2:S35-47. [PMID: 18089983]

Remien RH, Stirratt MJ, Dolezal C, et al. Couple-focused support to improve HIV medication adherence: a randomized controlled trial. AIDS 2005;19(8):807-814. [PMID: 15867495]

Sutton SS, Hardin JW, Bramley TJ, et al. Single- versus multiple-tablet HIV regimens: adherence and hospitalization risks. Am J Manag Care 2016;22(4):242-248. [PMID: 27143289

Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med 2020;382(12):1112-1123. [PMID: 32130809

Efficacy of CAB/RPV LA

Lead author: Joseph P. McGowan, MD, with the Medical Care Criteria Committee; updated August 15, 2022

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] (see Benefits, Limitations, and Risks of CAB/RPV LA as ART > Adverse Effects for more details).

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. 2022].

Table 1: Viral Load at Weeks 48 and 96 of Maintenance Phase in the ATLAS, FLAIR, and ATLAS-2M Trials
HIV Viral Load ATLAS
(n = 308/308) [a]
FLAIR
(n = 283/283) [b]
ATLAS-2M
(n = 523/522) [c]
CAB/RPV LA Oral
ART 
[d]
CAB/RPV LA Oral
ART 
[e]
CAB/RPV
LA monthly
CAB/RPV
LA bimonthly
Week 48 HIV RNA <50 copies/mL 92.5% 95.5% 93.6% 93.3% 93.0% 94.0%
Week 48 HIV RNA ≥50 copies/mL 1.6% 1.0% 2.1% 2.5% 1.0% 2.0%
Week 96 HIV RNA <50 copies/mL 100% [f] 97.0% [f] 87.0% 89.0% 90.0% 91.0%
Week 96 HIV RNA ≥50 copies/mL 0% [g] 3.0% 3.0% [g] 3.0% [g] 1.0% 2.0%

Abbreviations: ART, antiretroviral therapy; CAB/RPV LA, injectable long-acting cabotegravir/rilpivirine; INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

Notes:

  1. Participants in ATLAS were ≥18 years old, had received uninterrupted and unchanged ART with no virologic failure for 6 months prior to screening, and had an HIV RNA level of <50 copies/mL at screening and within 6 and 12 months before screening [Orkin, et al. 2020].
  2. Participants in FLAIR were ≥18 years old, ART-naive, and had a plasma HIV RNA level of ≥1,000 copies/mL at screening [Swindells, et al. 2020].
  3. [Jaeger, et al. 2021]
  4. Participants continued their current daily PI-, NNRTI-, or INSTI-based oral regimen.
  5. Daily oral dolutegravir/abacavir/lamivudine.
  6. Extension phase of ATLAS study (n = 52) after discontinuations or roll-over to ATLAS-2M [Swindells, et al. 2022].
  7. [Orkin, et al. 2021]
References

FDA. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use. 2021 Jan. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf [accessed 2021 Mar 08]

Jaeger H, Overton ET, Richmond G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet 2021;8(11):e679-e689. [PMID: 34648734]

Orkin C, Arasteh K, Gorgolas Hernandez-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med 2020;382(12):1124-1135. [PMID: 32130806

Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study. Lancet HIV 2021;8(4):e185-e196. [PMID: 33794181

Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet 2021;396(10267):1994-2005. [PMID: 33308425]

Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir + rilpivirine every 2 months: ATLAS-2M week 152 results. CROI; 2022 Feb 12-16; Virtual. https://www.croiconference.org/abstract/long-acting-cabotegravir-rilpivirine-every-2-months-atlas-2m-week-152-results/

Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med 2020;382(12):1112-1123. [PMID: 32130809]

Swindells S, Lutz T, Van Zyl L, et al. Week 96 extension results of a Phase 3 study evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment. AIDS 2022;36(2):185-194. [PMID: 34261093

ViiV Healthcare. ViiV Healthcare announces US FDA approval of cabenuva (cabotegravir, rilpivirine) for use every two months, expanding the label of the first and only complete long-acting HIV treatment. 2022 https://viivhealthcare.com/hiv-news-and-media/news/press-releases/2022/january/viiv-healthcare-announces-fda-approval-of-cabenuva-for-use-every-two-months/ [accessed 2022 Feb 9]

Benefits, Potential Risks, and Limitations of CAB/RPV LA

Lead author: Joseph P. McGowan, MD, with the Medical Care Criteria Committee; updated August 15, 2022

RECOMMENDATIONS
Patients for Whom CAB/RPV LA Is Not Recommended
  • Before recommending a switch to CAB/RPV LA, clinicians should determine patients’ hepatitis B status (hepatitis B surface antigen, core antibody, surface antibody, and HBV DNA if indicated); CAB/RPV LA should not be recommended for patients with active HBV coinfection [a] without concurrent oral therapy for HBV. (A*)
  • Before recommending CAB/RPV LA for patients who have been treated previously with INSTIs or NNRTIs, clinicians should review results of prior resistance testing and ART treatment history or consider baseline genotypic resistance testing if no prior results are available; genotypic resistance testing should include both the reverse transcriptase and integrase genes. (A3)
  • Clinicians should not recommend CAB/RPV LA in patients with known or suspected INSTI or NNRTI RAMs, excluding the K103N mutation in isolation, at baseline. (A1)
  • Because there are no currently available data on the safety and efficacy of this regimen in children or adolescents or during pregnancy or breastfeeding, clinicians should not recommend treatment with CAB/RPV LA for these patients. (A*)
  • Preexisting CAB and RPV RAMs have been associated with virologic failure; therefore, clinicians should obtain proviral DNA genotypic resistance testing before switching to CAB/RPV LA in any patient for whom historical resistance test results are not available. (B2)

———
Abbreviations: ART, antiretroviral therapy; CAB, cabotegravir; CAB/RPV LA, injectable long-acting cabotegravir/rilpivirine; HBV, hepatitis B virus; INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; RAM, resistance-associated mutation; RPV, rilpivirine.

Note:

  1. Active HBV infection is defined as having a positive hepatitis B surface antigen or HBV DNA test result.

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 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
Box 1: Summary of Benefits, Limitations, and Risks of Injectable Long-Acting Cabotegravir and Rilpivirine
Benefits:
  • Improved patient satisfaction
  • Monthly (every 4 weeks) or bimonthly (every 8 weeks) administration
  • Directly observed
  • Noninferior to oral ART
  • Potential option for patients who have ongoing substance use, mental health concerns, neurocognitive disorders, disclosure concerns, or other challenges associated with adherence to oral ART, including difficulty swallowing pills
  • Removes the daily reminder of HIV status that is associated with taking pills
Potential Risks:
  • Potential injection site reactions and other adverse effects, including pyrexia
  • Potential for resistance to develop if doses are missed outside the 7-day window period, given the long half-life (“tail”) of CAB and RPV
Limitations:
  • Cannot be used if a patient has prior resistance to integrase strand transfer inhibitors or nonnucleoside reverse transcriptase inhibitors, excluding the K103N mutation in isolation (see Drug Resistance, below)
  • Lack of data on use during pregnancy or breastfeeding and in children and adolescents
  • Does not treat hepatitis B virus coinfection
  • Lack of data on use in patients with prior virologic failure
  • Treatment with 4 weeks of oral CAB and RPV (oral lead-in) may be used before the first injection to assess for unexpected reactions or allergies to CAB or RPV
  • Requires oral medications as bridging therapy when injections are missed
  • Medication storage requirements (2° C to 8° C [36° F to 46° F])
  • Requires 6 to 12 in-person visits with a healthcare provider per year
Abbreviations: ART, antiretroviral therapy; CAB, cabotegravir; RPV, rilpivirine.

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].

These findings were also reflected in data from week 152 of the ATLAS-2M trial by itself [Overton, et al. 2022]:

  • 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.

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. 2022]. 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].

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:

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.

References

Chounta V, Overton ET, Mills A, et al. Patient-reported outcomes through 1 year of an HIV-1 clinical trial evaluating long-acting cabotegravir and rilpivirine administered every 4 or 8 weeks (ATLAS-2M). Patient 2021;14(6):849-862. [PMID: 34056699

Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS 2021;35(9):1333-1342. [PMID: 33730748]

FDA. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use. 2021 Jan. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf [accessed 2021 Mar 08]

Ford S, Crauwels H, Han K, et al. Cabotegravir and rilpivirine PK following long-acting HIV treatment discontinuation. CROI; 2020 Mar 8-11; Boston, MA. https://www.croiconference.org/abstract/cabotegravir-and-rilpivirine-pk-following-long-acting-hiv-treatment-discontinuation/

Kerrigan D, Mantsios A, Gorgolas M, et al. Experiences with long acting injectable ART: A qualitative study among PLHIV participating in a phase II study of cabotegravir + rilpivirine (LATTE-2) in the United States and Spain. PLoS One 2018;13(1):e0190487. [PMID: 29304154

Landovitz RJ, Li S, Eron JJ, Jr., et al. Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial. Lancet HIV 2020;7(7):e472-e481. [PMID: 32497491

Margolis DA, Brinson CC, Smith GH, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis 2015;15(10):1145-1155. [PMID: 26201299

Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet 2017;390(10101):1499-1510. [PMID: 28750935

McGowan I, Dezzutti CS, Siegel A, et al. Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment. Lancet HIV 2016;3(12):e569-e578. [PMID: 27658864

Orkin C, Arasteh K, Gorgolas Hernandez-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med 2020;382(12):1124-1135. [PMID: 32130806

Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir + rilpivirine every 2 months: ATLAS-2M week 152 results. CROI; 2022 Feb 12-16; Virtual. https://www.croiconference.org/abstract/long-acting-cabotegravir-rilpivirine-every-2-months-atlas-2m-week-152-results/

Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med 2020;382(12):1112-1123. [PMID: 32130809

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

Lead author: Joseph P. McGowan, MD, with the Medical Care Criteria Committee; updated August 15, 2022

RECOMMENDATIONS
Administration
  • CAB/RPV LA should be administered by a licensed and trained healthcare professional. (A*)
  • To prepare and administer CAB/RPV LA, clinicians should follow the protocols detailed in Box 2, below, and in the medication package inserts. (A1)
Dosing Strategy
Managing Missed Injections
  • If a patient plans to miss or delay a monthly CAB/RPV LA injection by >7 days, the clinician should arrange for oral medication (CAB 30 mg and RPV 25 mg daily) to be available in advance in an adequate supply (up to 2 months/8 weeks) to cover the gap in injections.
  • Clinicians should resume CAB/RPV LA in patients who miss injections as detailed in Managing Missed or Delayed Injections. (A3)
Discontinuing CAB/RPV LA
  • Clinicians should discontinue CAB/RPV LA in patients with confirmed virologic failure (defined as 2 consecutive plasma HIV-1 RNA measurements ≥200 copies/mL) or evidence of INSTI or NNRTI RAMs, excluding the K103N mutation in isolation, on subsequent genotype testing. (A1)
  • Clinicians should discontinue CAB/RPV LA in patients with evidence of INSTI or NNRTI RAMs (excluding the K103N mutation in isolation) on subsequent proviral DNA-based genotype testing (which may be performed for another clinical indication or following a viral blip), regardless of viral load suppression status, including an undetectable viral load (defined as plasma HIV-1 RNA measurement <50 copies/mL). (B3)
  • When extended or frequent gaps occur between injections, resulting in prolonged periods of subtherapeutic drug concentrations, the risk of drug resistance increases; to avoid this risk, clinicians should encourage patients to adhere to the injection schedule and should switch to oral therapy for patients who cannot maintain the injection schedule. (A3)
  • If CAB/RPV LA is discontinued, the clinician should initiate a fully suppressive oral ART regimen no later than 1 month (4 weeks) following the final CAB/RPV LA monthly injection or 2 months (8 weeks) following final CAB/RPV LA bimonthly injection. (A2)

———
Abbreviations: ART, antiretroviral therapy; CAB, cabotegravir; CAB/RPV LA, injectable long-acting cabotegravir/rilpivirine; INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; RAM, resistance-associated mutation; RPV, rilpivirine.

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.

Dosing Strategies

Tables 2, 3, and 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.

Table 2: Optional Lead-in, Initiation, and Maintenance for MONTHLY (every 4 weeks) CAB/RPV LA Dosing [a]
Download PDF

Timing Dosing and Administration Comments
Optional oral lead-in:
Therapy initiation:
Week 0 (aka month 0)
CAB 30 mg/RPV 25 mg once daily by mouth with a meal x 4 weeks Oral medication lead-in
Week 4 (aka month 1) CAB 600 mg (3 mL)/RPV 900 mg (3 mL) IM injection Initiation dose: Administer on last day of oral lead-in or prior suppressive ART regimen
Week 8 (aka month 2) and
every 4 weeks (aka every 1 month) thereafter
CAB 400 mg (2 mL)/RPV 600 mg (2 mL) IM injection Maintenance dose: Administer within 7 days before or after scheduled date (see Managing Missed or Delayed Injections)

Abbreviations: aka, also known as; ART, antiretroviral therapy; CAB, cabotegravir (brand name Vocabria); CAB/RPV LA, injectable long-acting cabotegravir/rilpivirine (brand name Cabenuva); IM, intramuscular; RPV, rilpivirine (brand name Edurant).

Note:

  1. [FDA 2021]

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.

Table 3: Optional Lead-in, Initiation, and Maintenance for BIMONTHLY (every 8 weeks) CAB/RPV LA Dosing [a,b]
Download PDF
Timing Dosing and Administration Comments
Optional oral
lead-in:
Therapy initiation:
Week 0 (aka month 0)
CAB 30 mg/RPV 25 mg once daily by mouth with a meal x 4 weeks Oral medication lead-in
Week 4 (aka month 1) CAB 600 mg (3 mL)/RPV 900 mg (3 mL) IM injection Initiation dose: Administer on last day of oral lead-in or prior suppressive ART regimen
Week 8 (aka month 2) CAB 600 mg (3 mL)/RPV 900 mg (3 mL) IM injection Maintenance dose: Administer within 7 days before or after scheduled date (see Managing Missed or Delayed Injections)
Week 16 (aka month 4) and every 8 weeks (aka every 2 months) thereafter CAB 600 mg (3 mL)/RPV 900 mg (3 mL) IM injection Maintenance dose: Administer within 7 days before or after scheduled date (see Managing Missed or Delayed Injections)

Abbreviations: aka, also known as; ART, antiretroviral therapy; CAB, cabotegravir (brand name Vocabria); CAB/RPV LA, injectable long-acting cabotegravir/rilpivirine (brand name Cabenuva); IM, intramuscular; RPV, rilpivirine (brand name Edurant).

Notes:

  1. [ViiV Healthcare 2022]
  2. [FDA 2021]
Table 4: Advantages and Limitations of CAB/RPV LA Dosing Strategies
Advantage or Limitation Monthly (every 4 weeks) Dosing Bimonthly (every 8 weeks) Dosing
Required annual visits 12 6
Injection site pain [a] Less More
CVF despite on-time dosing [b] Rare Rare
Risk of CAB and/or RPV RAMs if CVF [c] Common Common
Patient satisfaction [c,d] High Preferred
Staffing, administration time, and cost More Less

Abbreviations: CAB/RPV LA, injectable long-acting cabotegravir/rilpivirine; CVF, confirmed virologic failure; RAM, resistance-associated mutation.

Notes:

  1. In the ATLAS-2M trial, 3% of participants in the monthly injection arm and 2% in the bimonthly injection arm discontinued treatment because of injection site pain [Overton, et al. 2022; Jaeger, et al. 2021].
  2. In the ATLAS-2M trial, <1% of participants in the monthly injection arm and 2% in the bimonthly injection arm had CVF [Overton, et al. 2021].
  3. [Overton, et al. 2021]
  4. [Chounta, et al. 2021]

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: Guidance on preparing and administering the initial loading dose and ongoing maintenance doses of CAB/RPV LA is provided in Box 2, below.

Box 2: Preparation and Administration of Initial and Maintenance Doses of Injectable Long-Acting Cabotegravir/Rilpivirine (CAB/RPV LA) [a]
  1. Bring the vials [a] of CAB LA and RPV LA to room temperature for at least 15 minutes and for a maximum of 6 hours.
  2. Prepare 2 syringes [a]. Once CAB/RPV LA has been drawn into the syringes, they must be used within 2 hours.
  3. For aspiration, use a vial adaptor or general-use sterile 21 gauge × 1½ inch hypodermic needle [b]. Shake the vial vigorously for at least 10 seconds before aspiration.
  4. For injection, use a general-use sterile 23 gauge × 1½ inch hypodermic needle [b]. Administer the injection within 2 hours of syringe preparation. A patient’s build or body mass index may be considered when selecting an appropriate injection needle length.
  5. Inject into the gluteus medius muscle [c] at a 90° angle, ventrogluteal (preferred) or dorsogluteal (upper-outer quadrant of the buttock), with care that the compound is not injected into a vein.

Notes:

  1. The same preparation and administration are used for both initial and maintenance doses of CAB/RPV LA. Follow sterile technique at all points while preparing syringes and injecting compounds. Use 3 mL vials/syringes for the initial dose and 2 mL vials/syringes for maintenance doses.
  2. The hypodermic needle must be long enough to inject the medication into the muscle mass without penetrating underlying nerves, blood vessels, or bone.
  3. Inject CAB LA into the gluteus medius muscle and RPV LA into the contralateral gluteus medius muscle. Injections can be given on opposite sides or on the same side, 2 cm apart.
  4. For more detail, see instructions for use in the CAB/RPV LA package insert [FDA 2021].

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.

Managing Missed or Delayed Injections

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].

Discontinuing Injectable ART

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 (t1/2) 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 t1/2 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].

References

Charpentier C, Storto A, Soulie C, et al. Prevalence of genotypic baseline risk factors for cabotegravir + rilpivirine failure among ARV-naive patients. J Antimicrob Chemother 2021;76(11):2983-2987. [PMID: 34015097

Chounta V, Overton ET, Mills A, et al. Patient-reported outcomes through 1 year of an HIV-1 clinical trial evaluating long-acting cabotegravir and rilpivirine administered every 4 or 8 weeks (ATLAS-2M). Patient 2021;14(6):849-862. [PMID: 34056699

Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS 2021;35(9):1333-1342. [PMID: 33730748

FDA. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use. 2021 Jan. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf [accessed 2021 Mar 08]

Ford S, Chiu J, Lovern M, et al. Population PK approach to predict cabotegravir (CAB, GSK1265744) long-acting injectable doses for phase 2b. Abstract H-645. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014); 2014 5-9 Sep; Washington, DC.

Jackson AG, Else LJ, Mesquita PM, et al. A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis. Clin Pharmacol Ther 2014;96(3):314-323. [PMID: 24862215

Jaeger H, Overton ET, Richmond G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet 2021;8(11):e679-e689. [PMID: 34648734]

Oliveira M, Ibanescu RI, Anstett K, et al. Selective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir. Retrovirology 2018;15(1):56. [PMID: 30119633

Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study. Lancet HIV 2021;8(4):e185-e196. [PMID: 33794181

Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet 2021;396(10267):1994-2005. [PMID: 33308425]

Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir + rilpivirine every 2 months: ATLAS-2M week 152 results. CROI; 2022 Feb 12-16; Virtual. https://www.croiconference.org/abstract/long-acting-cabotegravir-rilpivirine-every-2-months-atlas-2m-week-152-results/

Spreen W, Ford SL, Chen S, et al. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects. J Acquir Immune Defic Syndr 2014;67(5):481-486. [PMID: 25140909

Verloes R, Deleu S, Niemeijer N, et al. Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long-acting formulation in healthy volunteers. HIV Med 2015;16(8):477-484. [PMID: 25988676

ViiV Healthcare. ViiV Healthcare announces US FDA approval of cabenuva (cabotegravir, rilpivirine) for use every two months, expanding the label of the first and only complete long-acting HIV treatment. 2022 https://viivhealthcare.com/hiv-news-and-media/news/press-releases/2022/january/viiv-healthcare-announces-fda-approval-of-cabenuva-for-use-every-two-months/ [accessed 2022 Feb 9]

Wensing AM, Calvez V, Ceccherini-Silberstein F, et al. 2019 update of the drug resistance mutations in HIV-1. Top Antivir Med 2019;27(3):111-121. [PMID: 31634862

Laboratory Testing and Patient Follow-Up

Lead author: Joseph P. McGowan, MD, with the Medical Care Criteria Committee; updated August 15, 2022

RECOMMENDATION
Laboratory Testing and Monitoring

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 [Orkin, et al. 2020]. See Benefits, Limitations, and Risks of CAB/RPV LA as ART > Adverse Effects in this guideline for additional laboratory abnormalities.

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].

GOOD PRACTICE
  • Follow up by phone within 1 week after initiation of oral therapy lead-in, if used, and within 3 days after a patient receives the initial loading dose of injectable ART to assess the patient’s tolerance.
References

Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. Lancet HIV 2017;4(8):e331-e340. [PMID: 28546090

Orkin C, Arasteh K, Gorgolas Hernandez-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med 2020;382(12):1124-1135. [PMID: 32130806

Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med 2020;382(12):1112-1123. [PMID: 32130809]

Implementing CAB/RPV LA in Clinical Practice

Lead author: Joseph P. McGowan, MD, with the Medical Care Criteria Committee; updated August 15, 2022

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.

Box 3: Institutional, Clinician, and Patient Preparations for Implementation of Injectable ART
Institutional and Clinician Preparations
  • Assess pharmacy resources and on-site procedures for storage of oral and injectable medications
  • Train nurses and other medical care providers regarding proper syringe preparation and injection techniques
  • Establish billing protocols for the procurement and administration of injectable ART medications
  • Implement a system to remind patients of appointments
  • Plan for treatment continuation in the event of pandemic-related shutdowns or other catastrophic events
  • Provide education on the use of oral bridging therapy
  • Educate patients about possible adverse effects associated with injectable long-acting cabotegravir/rilpivirine and how to manage them
  • Ensure that patients know how to reach a medical care provider if needed
  • Schedule appointments for administration in advance
Patient Preparations
  • Obtain prior authorizations for insurance or third-party coverage of ART medications
  • Confirm ability to maintain required clinic visit schedule for injections, including transportation availability
  • Confirm ability to adhere to the injection regimen
  • Confirm ability to tolerate 2 large volume intramuscular injections regularly
Abbreviation: ART, antiretroviral therapy.

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 When to Initiate ART, With Protocol for Rapid 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

Lead author: Joseph P. McGowan, MD, with the Medical Care Criteria Committee; updated August 15, 2022

ALL RECOMMENDATIONS: USE OF INJECTABLE CAB/RPV LA AS REPLACEMENT ART IN VIRALLY SUPPRESSED ADULTS
Patients for Whom CAB/RPV LA Is Not Recommended
  • Before recommending a switch to CAB/RPV LA, clinicians should determine patients’ hepatitis B status (hepatitis B surface antigen, core antibody, surface antibody, and HBV DNA if indicated); CAB/RPV LA should not be recommended for patients with active HBV coinfection [a] without concurrent oral therapy for HBV. (A*)
  • Before recommending CAB/RPV LA for patients who have been treated previously with INSTIs or NNRTIs, clinicians should review results of prior resistance testing and ART treatment history or consider baseline genotypic resistance testing if no prior results are available; genotypic resistance testing should include both the reverse transcriptase and integrase genes. (A3)
  • Clinicians should not recommend CAB/RPV LA in patients with known or suspected INSTI or NNRTI RAMs, excluding the K103N mutation in isolation, at baseline. (A1)
  • Because there are no currently available data on the safety and efficacy of this regimen in children or adolescents or during pregnancy or breastfeeding, clinicians should not recommend treatment with CAB/RPV LA for these patients. (A*)
  • Preexisting CAB and RPV RAMs have been associated with virologic failure; therefore, clinicians should obtain proviral DNA genotypic resistance testing before switching to CAB/RPV LA in any patient for whom historical resistance test results are not available. (B2)
Administration
  • CAB/RPV LA should be administered by a licensed and trained healthcare professional. (A*)
  • To prepare and administer CAB/RPV LA, clinicians should follow the protocols detailed in Box 2, below, and in the medication package inserts. (A1)
Dosing Strategy
Managing Missed Injections
  • If a patient plans to miss or delay a monthly CAB/RPV LA injection by >7 days, the clinician should arrange for oral medication (CAB 30 mg and RPV 25 mg daily) to be available in advance in an adequate supply (up to 2 months/8 weeks) to cover the gap in injections.
  • Clinicians should resume CAB/RPV LA in patients who miss injections as detailed in Managing Missed or Delayed Injections. (A3)
Discontinuing CAB/RPV LA
  • Clinicians should discontinue CAB/RPV LA in patients with confirmed virologic failure (defined as 2 consecutive plasma HIV-1 RNA measurements ≥200 copies/mL) or evidence of INSTI or NNRTI RAMs, excluding the K103N mutation in isolation, on subsequent genotype testing. (A1)
  • Clinicians should discontinue CAB/RPV LA in patients with evidence of INSTI or NNRTI RAMs (excluding the K103N mutation in isolation) on subsequent proviral DNA-based genotype testing (which may be performed for another clinical indication or following a viral blip), regardless of viral load suppression status, including an undetectable viral load (defined as plasma HIV-1 RNA measurement <50 copies/mL). (B3)
  • When extended or frequent gaps occur between injections, resulting in prolonged periods of subtherapeutic drug concentrations, the risk of drug resistance increases; to avoid this risk, clinicians should encourage patients to adhere to the injection schedule and should switch to oral therapy for patients who cannot maintain the injection schedule. (A3)
  • If CAB/RPV LA is discontinued, the clinician should initiate a fully suppressive oral ART regimen no later than 1 month (4 weeks) following the final CAB/RPV LA monthly injection or 2 months (8 weeks) following final CAB/RPV LA bimonthly injection. (A2)
Laboratory Testing and Monitoring

———
Abbreviations: ART, antiretroviral therapy; CAB, cabotegravir; CAB/RPV LA, injectable long-acting cabotegravir/rilpivirine; HBV, hepatitis B virus; INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; RAM, resistance-associated mutation; RPV, rilpivirine.

Note:

  1. Active HBV infection is defined as having a positive hepatitis B surface antigen or HBV DNA test result.

Guideline Information and Updates

Guideline Information
Intended users

Clinicians in New York State who treat patients with HIV

Last reviewed and updated

Joseph P. McGowan, MD; August 15, 2022

Original lead author

Elliot DeHaan, MD

Original publication

July 2021

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

Developer and funding

New York State Department of Health AIDS Institute (NYSDOH AI)

Development

See Guideline Development and Recommendation Ratings Scheme, below.

Peer Reviewers
  • Elizabeth Asiago-Reddy, MD, MS, SUNY Upstate Medical University;
  • Robert Murayama, MD, MPH, FACP, The Institute for Family Health
Update

August 15, 2022
April 7, 2022

Joseph P. McGowan, MD, with the MCCC: Maintenance dosing schedule updated to reflect the U.S. Food and Drug Administration approval of bimonthly (every 8 weeks) dosing of injectable long-acting cabotegravir and rilpivirine for HIV treatment.
Guideline Development: New York State Department of Health AIDS Institute Clinical Guidelines Program
Developer New York State Department of Health AIDS Institute (NYSDOH AI) Clinical Guidelines Program
Funding Source NYSDOH AI
Program Manager

Clinical Guidelines Program, Johns Hopkins University School of Medicine, Division of Infectious Diseases. See Program Leadership and Staff.

Mission To produce and disseminate evidence-based, state-of-the-art clinical practice guidelines that establish uniform standards of care for practitioners who provide prevention or treatment of HIV, viral hepatitis, other sexually transmitted infections, and substance use disorders for adults throughout New York State in the wide array of settings in which those services are delivered.
Expert Committees

The NYSDOH AI Medical Director invites and appoints committees of clinical and public health experts from throughout NYS to ensure that the guidelines are practical, immediately applicable, and meet the needs of care providers and stakeholders in all major regions of NYS, all relevant clinical practice settings, key NYS agencies, and community service organizations.

Committee Structure
  • Leadership: AI-appointed chair, vice chair(s), chair emeritus, clinical specialist(s), JHU Guidelines Program Director, AI Medical Director, AI Clinical Consultant, AVAC community advisor
  • Contributing members
  • Guideline writing groups: Lead author, coauthors if applicable, and all committee leaders
Conflicts of Interest Disclosure and Management
  • Annual disclosure of financial relationships with commercial entities for the 12 months prior and upcoming is required of all individuals who work with the guidelines program, and includes disclosure for partners or spouses and primary professional affiliation.
  • The NYSDOH AI assesses all reported financial relationships to determine the potential for undue influence on guideline recommendations and, when indicated, denies participation in the program or formulates a plan to manage potential conflicts.
  • Disclosures are listed for each committee member.
Evidence Collection and Review
  • Literature search and review strategy is defined by the guideline lead author based on the defined scope of a new guideline or update.
  • A comprehensive literature search and review is conducted for a new guideline or an extensive update using PubMed, other pertinent databases of peer-reviewed literature, and relevant conference abstracts to establish the evidence base for guideline recommendations.
  • A targeted search and review to identify recently published evidence is conducted for guidelines published within the previous 3 years.
  • Title, abstract, and article reviews are performed by the lead author. The JHU editorial team collates evidence and creates and maintains an evidence table for each guideline.
Recommendation Development
  • The lead author drafts recommendations to address the defined scope of the guideline based on available published data.
  • Writing group members review the draft recommendations and evidence and deliberate to revise, refine, and reach consensus on all recommendations.
  • When published data are not available, support for a recommendation may be based on the committee’s expert opinion.
  • The writing group assigns a 2-part rating to each recommendation to indicate the strength of the recommendation and quality of the supporting evidence. The group reviews the evidence, deliberates, and may revise recommendations when required to reach consensus. 
Review and Approval Process
  • Following writing group approval, draft guidelines are reviewed by all contributors, program liaisons, and a volunteer reviewer from the AI Community Advisory Committee.
  • Recommendations must be approved by two-thirds of the full committee. If necessary to achieve consensus, the full committee is invited to deliberate, review the evidence, and revise recommendations when required.
  • Final approval by the committee chair and the NYSDOH AI Medical Director is required for publication.
External Reviewers
  • External peer reviewers recognized for their experience and expertise review guidelines for accuracy, balance, clarity, and practicality and provide feedback.
  • Peer reviewers may include nationally known experts from outside of New York State.
Update Process
  • JHU editorial staff ensure that each guideline is reviewed and determined to be current upon the 3-year anniversary of publication; guidelines that provide clinical recommendations in rapidly changing areas of practice may be reviewed annually. Published literature is surveilled to identify new evidence that may prompt changes to existing recommendations or development of new recommendations.
  • If changes in the standard of care, newly published studies, new drug approval, new drug-related warning, or a public health emergency indicate the need for immediate change to published guidelines, committee leadership will make recommendations and immediate updates.
  • All contributing committee members review and approve substantive changes to, additions to, or deletions of recommendations; JHU editorial staff track, summarize, and publish ongoing guideline changes.
Recommendation Ratings Scheme
Strength Quality of Evidence
Rating Definition Rating Definition
A Strong 1 Based on published results of at least 1 randomized clinical trial with clinical outcomes or validated laboratory endpoints.
B Moderate * Based on either a self-evident conclusion; conclusive, published, in vitro data; or well-established practice that cannot be tested because ethics would preclude a clinical trial.
C Optional 2 Based on published results of at least 1 well-designed, nonrandomized clinical trial or observational cohort study with long-term clinical outcomes.
  2† Extrapolated from published results of well-designed studies (including nonrandomized clinical trials) conducted in populations other than those specifically addressed by a recommendation. The source(s) of the extrapolated evidence and the rationale for the extrapolation are provided in the guideline text. One example would be results of studies conducted predominantly in a subpopulation (e.g., one gender) that the committee determines to be generalizable to the population under consideration in the guideline.
3 Based on committee expert opinion, with rationale provided in the guideline text.