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 Development of This Guideline

Lead author: Elliot DeHaan, MD
Writing group: Joseph P. McGowan, MD; Steven M. Fine, MD, PhD; Rona M. Vail, MD; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD
Committee: Medical Care Criteria Committee
Date published: 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 for adults (≥18 years old) with HIV who are virally suppressed (HIV RNA level <50 copies/mL) [FDA 2021]. The goal is to ensure that clinicians understand:

  • The risks and benefits of switching to injectable antiretroviral therapy (ART)
  • How to engage patients in shared decision-making regarding treatment
  • How to develop protocols within their institution or medical practice to deliver injectable ART based on currently available evidence from published clinical trial data

Development: This guideline was developed by the NYSDOH AI Clinical Guidelines Program, which is a collaborative effort between the NYSDOH AI Office of the Medical Director and the Johns Hopkins University School of Medicine, Division of Infectious Diseases.

Established in 1986, the goal of the Clinical Guidelines Program is to develop and disseminate evidence-based, state-of-the-art clinical practice guidelines to improve the quality of care throughout NYS for people who have HIV, hepatitis C virus, or sexually transmitted infections; people with substance use issues; and members of the LGBTQ community. NYSDOH AI guidelines are developed by committees of clinical experts through a consensus-driven process.

The NYSDOH AI charged the Medical Care Criteria Committee with developing evidence-based clinical recommendations for primary care clinicians in NYS who provide medical services to individuals with HIV. The resulting recommendations are based on an extensive review of the medical literature and reflect consensus among this panel of experts. Each recommendation is rated for the strength and quality of the evidence (see below). If recommendations are based on expert opinion, the rationale for the opinion is included.

AIDS Institute Clinical Guidelines Program: Recommendations Ratings
(updated June 2019 [a])
Strength of Recommendation Ratings
A Strong recommendation
B Moderate recommendation
C Optional
Quality of Supporting Evidence Ratings
1 Evidence is derived from published results of at least one randomized trial with clinical outcomes or validated laboratory endpoints.
* Evidence is strong because it is based on a self-evident conclusion(s); conclusive, published, in vitro data; or well-established practice that cannot be tested because ethics would preclude a clinical trial.
2 Evidence is derived from published results of at least one well-designed, nonrandomized clinical trial or observational cohort study with long-term clinical outcomes.
2† Evidence has been extrapolated from published results of well-designed studies (including non-randomized 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 Recommendation is based on the expert opinion of the committee members, with rationale provided in the guideline text.
  1. With the June 2019 update, the ratings for quality of supporting evidence were expanded to add the * rating and the 2† rating.
Reference

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 8]

Rationale for and Efficacy of Injectable ART

Lead author: Elliot DeHaan, MD, with the Medical Care Criteria Committee; July 2021

Daily adherence to oral antiretroviral therapy (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 [Remien, et al. 2005; Golin, et al. 2006; Mannheimer, et al. 2006; Altice, et al. 2007; Johnson, et al. 2007; Petersen, et al. 2007; Purcell, et al. 2007; Lester, et al. 2010; Babudieri, et al. 2011; Hardy, et al. 2011]. The availability of simplified, single-tablet regimens has improved medication adherence significantly [Hanna, et al. 2014; Nachega, et al. 2014; Sutton, et al. 2016]. However, real-world clinician and patient experiences have demonstrated that barriers to ART adherence remain [Cohen, et al. 2020].

Recent phase 3 clinical trial results suggest that the injectable long-acting combination of the integrase strand transfer inhibitor (INSTI) cabotegravir and the nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (CAB/RPV LA) may be a suitable option for patients engaged in care who want an alternative to daily oral therapy [Orkin, et al. 2020; Swindells, et al. 2020; Overton, et al. 2021]. In the FLAIR and ATLAS trials, participants whose virus was suppressed with oral ART regimens were randomly assigned to receive monthly CAB/RPV LA injectable 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].

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 INSTIs or 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 (RAMs), 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 CAV/RPV LA as ART > Adverse Effects for more details).

Patient satisfaction: Participants expressed high levels of satisfaction with injectable therapy in phase II and III 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].

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].

Data presented at the 2021 Conference on Retroviruses and Opportunistic Infections further support the noninferiority of bimonthly dosing. Among participants in the ATLAS-2M trial, at week 96, 11 (2.1%) participants in the 8-week treatment arm and 6 (1.1%) of those in the 4-week treatment arm had an HIV RNA level ≥50 copies/mL, and 91% of those in the 8-week arm versus 90.2 % in the 4-week arm achieved an HIV RNA level <50 copies/mL [Jaeger, et al. 2021]. Because of the excellent efficacy and safety data on bimonthly dosing in phase 3 clinical trials up to 96 weeks, it is expected that injectable CAB/RPV LA will be approved for this dosing protocol in the near future. However, at this time, only monthly dosing has been approved by the U.S. Food and Drug Administration (FDA) and is covered in these recommendations. Approval is being sought to make the oral lead-in component optional. Future guidelines will reconsider these data and any new FDA approvals when available.

Table 1: Viral Load at Week 48 of Maintenance Phase in the ATLAS and FLAIR Trials
Data compiled from [Orkin, et al. 2020] and [Swindells, et al. 2020]
HIV Viral Load at Week 48 ATLAS [a] FLAIR [b]
CAB/RPV LA
(n = 308)
Oral ART [c]
(n = 308)
CAB/RPV LA
(n = 283)
Oral ART [d]
(n = 283)
HIV RNA ≥50 copies/mL 1.6% 1.0% 2.1% 2.5%
HIV RNA <50 copies/mL 92.5% 95.5% 93.6% 93.3%

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.
  2. Participants in FLAIR were ≥18 years old, ART-naive, and had a plasma HIV RNA level of ≥1,000 copies/mL at screening.
  3. Participants continued their current daily PI-, NNRTI-, or INSTI-based oral regimen.
  4. Daily oral dolutegravir/abacavir/lamivudine.
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 8]

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

Jaeger H, Overton ET, Richmond G, et al. Week 96 efficacy and safety of cabotegravir + rilpivirine every 2 months: ATLAS-2M. CROI; 2021 Mar 6-10; (Virtual). https://www.croiconference.org/wp-content/uploads/sites/2/resources/2021/vCROI-2021-Abstract-eBook.pdf

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

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

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

Benefits, Limitations, and Risks of CAB/RPV LA as ART

Lead author: Elliot DeHaan, MD, with the Medical Care Criteria Committee; July 2021

RECOMMENDATIONS
Limitations of Use
  • Clinicians should not prescribe injectable long-acting cabotegravir/rilpivirine (CAB/RPV LA) for patients with active hepatitis B virus (HBV) coinfection without concurrent oral therapy for HBV. (A*)
  • Clinicians should not initiate CAB/RPV LA in patients with known or suspected integrase strand transfer inhibitor (INSTI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs), excluding the K103N mutation in isolation, at baseline. (A1)
  • Clinicians should discontinue CAB/RPV LA in patients with confirmed virologic failure (defined as 2 consecutive plasma HIV-1 RNA measurements ≥200 copies/mL) and 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)
  • 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*)
  • Before initiating CAB/RPV LA in patients who have been treated previously with INSTIs or NNRTIs, clinicians should review results of prior resistance testing and antiretroviral therapy (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)
  • CAB/RPV LA should be administered by a licensed and trained healthcare professional. (A*)

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 [Margolis, et al. 2015; Margolis, et al. 2017; Orkin, et al. 2020; Swindells, et al. 2020]:

  • If dosing is interrupted, there is potential for development of resistance due to the long half-life of CAB/RPV LA
  • Required 4-week lead-in treatment with oral CAB/RPV
  • 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, though this is rare

Limitations of current evidence: 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 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 [Margolis, et al. 2015; Margolis, et al. 2017; Orkin, et al. 2020; Swindells, et al. 2020].

Box 1: Benefits, Limitations, and Risks of Injectable Long-Acting Cabotegravir and Rilpivirine
Benefits:
  • Improved patient satisfaction
  • Monthly 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
Limitations:
  • Cannot be used if a patient has prior resistance to INSTIs or NNRTIs, 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 HBV coinfection
  • Lack of data on use in patients with prior virologic failure
  • Treatment with 4 weeks of oral CAB and RPV (oral lead-in) required before the first injection to assess for unexpected reactions or allergies to RPV or CAB
  • Requires oral medications as bridging therapy when injections are missed
  • Medication storage requirements (2° C to 8° C [36° F to 46° F])
  • Requires ≥12 in-person visits with a healthcare provider per year
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

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 (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 ≥30 kg/m2, and HIV-1 subtype A6/A1 were significantly associated with confirmed virologic failure; the presence of 2 of these factors concurrently was rare but was found in 9 of the 13 participants with confirmed virologic failure, and 1 participant had all 3. The L74I integrase polymorphism was commonly found among participants with confirmed virologic failure: 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 confirmed virologic failure 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 confirmed virologic failure had the HIV-1 B subtype alone, without the L74I integrase polymorphism [Cutrell, et al. 2021].

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. 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 females [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 females [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 to ensure monthly injection administration
  • Use of bridging oral therapy if injections are missed
  • Small risk of developing resistance even if adherence is optimal

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 injections.

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].

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 and UCSF HIV InSite Database of Antiretroviral Drug Interactions.

References

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 8]

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/

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]

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

Considerations for Implementation of CAB/RPV LA as ART

Lead author: Elliot DeHaan, MD, with the Medical Care Criteria Committee; July 2021

Box 2: Institutional, Clinician, and Patient Preparations for Implementation of Injectable Antiretroviral Therapy (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.

Initiation of injectable ART requires institutional, clinician, and patient preparation, as detailed in Box 2, above. Key considerations are noted above, but each institution 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 shuts down, 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.

Initiation and Maintenance of CAB/RPV LA as ART

Lead author: Elliot DeHaan, MD, with the Medical Care Criteria Committee; July 2021

RECOMMENDATIONS
Initiation and Maintenance
  • Clinicians should initiate injectable long-acting cabotegravir/rilpivirine (CAB/RPV LA) only after a patient has completed 4 weeks of therapy with daily oral CAB 30 mg and RPV 25 mg. (A1)
  • To prepare and administer CAB/RPV LA, clinicians should follow the protocols detailed below and in the medication package inserts. (A1)

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

Participants in the ATLAS and FLAIR trials received oral CAB 30 mg and RPV 25 mg daily for a 4-week lead-in period, followed by a loading dose of CAB LA 600 mg and RPV LA 900 mg given as 2 separate 3 mL IM injections [Orkin, et al. 2020; Swindells, et al. 2020]. Subsequent injections were given at a maintenance dose of CAB LA 400 mg and RPV LA 600 mg in 2 separate 2 mL IM injections at week 4 and then every 4 weeks through week 52 of the maintenance phase, within appropriate window periods (see discussion below).

Clinicians should initiate 4 weeks of oral lead-in therapy after an appropriate discussion with patients about the need for daily adherence, potential adverse effects, and the plan to initiate the loading injections at week 4 (see Table 2, below). This discussion should also address the potential need for bridging with oral CAB and RPV should patients be outside the window for subsequent injections, which the manufacturer has defined as 7 days before or after the next scheduled monthly dose. Should maintenance dosing be delayed beyond 2 months, a loading dose will be required for CAB/RPV LA if injectable therapy is resumed (see below for further details) [FDA 2021].

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 3, below. For specific dose amounts, see Table 2, below.

Box 3: 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.

For more detail, see instructions for use in the CAB/RPV LA package insert [FDA 2021].

Table 2: Recommended Dosing Strategy for Cabotegravir/Rilpivirine [a]
Drug Oral Medication Lead-In (≥4 weeks) Intramuscular Initiation Dose Intramuscular Maintenance Doses (once monthly, within 7 days before or after scheduled date)
Cabotegravir 30 mg once daily by mouth with a meal 600 mg (3 mL) 400 mg (2 mL)
Rilpivirine 25 mg once daily by mouth with a meal 900 mg (3 mL) 600 mg (2 mL)

Note:

  1. Adapted from [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.

Monthly maintenance 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.

Delayed doses: If a monthly maintenance injection must be delayed by >7 days, the patient should take daily oral therapy at the same dose administered for the oral lead-in. Oral bridging therapy may be used to replace up to 2 months of maintenance injections, and maintenance injections should be resumed as soon as possible [FDA 2021].

Strategy for missed doses: If a patient does not take oral bridging therapy when injections are missed, an assessment is required to determine whether they should continue injectable CAB/RPV LA [FDA 2021]. If a patient resumes injectable therapy >2 months after the last injection, the dose administered should be the same as the first loading dose: CAB LA 600 mg/RPV LA 900 mg. Up to 2 months after the last injection, standard maintenance dosing may resume.

KEY POINTS
  • In providing initial and maintenance treatment with CAB/RPV LA, clinicians should follow the protocols detailed in the text for storage, preparation, dosing, and administration.
  • If maintenance dosing is delayed beyond 2 months, a loading dose will be required for CAB/RPV LA if injectable therapy is resumed.
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 8]

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

Laboratory Testing and Patient Follow-up

Lead author: Elliot DeHaan, MD, with the Medical Care Criteria Committee; July 2021

RECOMMENDATION
Laboratory Testing and Monitoring

Genotypic testing: Clinicians should obtain a baseline HIV-1 genotype test that includes the reverse transcriptase and integrase genes before initiating ART with long-acting cabotegravir/rilpivirine (CAB/RPV LA) to rule out underlying resistance-associated mutations (RAMs) if they have a history of virologic failure or if there is clinical suspicion for integrase strand transfer inhibitor (INSTI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance. 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.

KEY POINTS
  • Hepatitis B status should be determined before initiation of CAB/RPV (hepatitis B surface antigen, core antibody, surface antibody, and DNA if indicated).
  • CAB/RPV LA should not be continued in a patient who has confirmed resistance to CAB or RPV.
  • CAB/RPV LA should not be continued in a patient with virologic failure (HIV RNA ≥200 copies/mL on 2 consecutive viral load tests).

Abnormal laboratory test results were reported in phase 3trials 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 [Markowitz, et al. 2017; Orkin, et al. 2020; Swindells, et al. 2020]. 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 and within 2 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

All Recommendations

Lead author: Elliot DeHaan, MD, with the Medical Care Criteria Committee; July 2021

ALL RECOMMENDATIONS: USE OF INJECTABLE CAB/RPV LA AS REPLACEMENT ART IN VIRALLY SUPPRESSED ADULTS
Initiation and Maintenance
  • Clinicians should initiate injectable long-acting cabotegravir/rilpivirine (CAB/RPV LA) only after a patient has completed 4 weeks of therapy with daily oral CAB 30 mg and RPV 25 mg. (A1)
  • To prepare and administer CAB/RPV LA, clinicians should follow the protocols detailed below and in the medication package inserts. (A1)
Limitations of Use
  • Clinicians should not prescribe injectable long-acting cabotegravir/rilpivirine (CAB/RPV LA) for patients with active hepatitis B virus (HBV) coinfection without concurrent oral therapy for HBV. (A*)
  • Clinicians should not initiate CAB/RPV LA in patients with known or suspected integrase strand transfer inhibitor (INSTI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs), excluding the K103N mutation in isolation, at baseline. (A1)
  • Clinicians should discontinue CAB/RPV LA in patients with confirmed virologic failure (defined as 2 consecutive plasma HIV-1 RNA measurements ≥200 copies/mL) and 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)
  • 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*)
  • Before initiating CAB/RPV LA in patients who have been treated previously with INSTIs or NNRTIs, clinicians should review results of prior resistance testing and antiretroviral therapy (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)
  • CAB/RPV LA should be administered by a licensed and trained healthcare professional. (A*)
Laboratory Testing and Monitoring

How This Guideline Was Developed

July 2021

This guideline was developed by the New York State (NYS) Department of Health (DOH) AIDS Institute (AI) Clinical Guidelines Program, which is a collaborative effort between the NYSDOH AI Office of the Medical Director and the Johns Hopkins University School of Medicine, Division of Infectious Diseases.

Established in 1986, the goal of the Clinical Guidelines Program is to develop and disseminate evidence-based, state-of-the-art clinical practice guidelines to improve the quality of care provided to people with HIV, hepatitis C virus, or sexually transmitted infections; people with substance use issues; and members of the LGBTQ community. NYSDOH AI guidelines are developed by committees of clinical experts through a consensus-driven process.

Medical Care Criteria Committee (MCCC) for adult HIV care guidelines: The NYSDOH AI charged the MCCC (adult HIV and related guidelines) with developing evidence-based recommendations for clinicians in NYS who provide care to individuals with HIV. The purpose of the Use of Injectable CAB/RPV LA as Replacement ART in Virally Suppressed Adults clinical practice guideline is provide healthcare practitioners with evidence-based recommendations on the use of injectable long-acting cabotegravir/rilpivirine (CAB/RPV LA) as replacement ART in virally suppressed adults with HIV.

Committee makeup: Members of the MCCC (see Box A1: MCCC Leaders and Members, below) were appointed by the NYSDOH AI to ensure representation of clinical practice in all major regions of the state, relevant medical disciplines and subspecialties, key NYS agencies, community stakeholders, and patient advocates. Individuals confirmed as MCCC members are required to disclose any potential conflicts of interest; disclosures are reviewed and approved by the NYSDOH AI Office of the Medical Director (see Funding and Disclosure of Potential Conflicts of Interest, below).

Committee role: Committee members actively participate in guideline development, including evidence review, drafting of recommendations and text, manuscript review, consensus approval of all recommendations, and rating of recommendations.

Committee leadership: Working with the lead author, the MCCC Writing Group reviewed and refined the manuscript, facilitated consensus approval of all recommendations, and addressed feedback from the Committee at large.

Johns Hopkins University (JHU) Editorial Role: The JHU editorial team coordinated, guided, and documented all Committee activities and edited the guideline material for clarity, flow, and style.

MCCC Writing Group (all Committee members and reviewers are listed in Box A1, below)

  • Elliot DeHaan, MD, Lead author
  • Joseph P. McGowan, MD, FACP, FIDSA, Chair
  • Steven Fine, MD, PhD, Co-Vice-Chair (effective January 2021)
  • Rona Vail, MD, Co-Vice-Chair (effective January 2021)
  • Samuel T. Merrick, MD, Chair Emeritus
  • Charles J. Gonzalez, MD, AI Medical Director
  • Asa Radix, MD, MPH, FACP, AAHIVS
  • Christopher J. Hoffmann, MD, MPH, Director, JHU-NYSDOH Guidelines Program

AIDS Institute and JHU Editorial and Program Management Team

  • Laura Duggan Russell, MPH, AI Guidelines Program Manager
  • Mary Beth Hansen, MA, JHU Guidelines Project Director
  • Johanna Gribble, MA, JHU Medical Editor
  • Jen Ham, MPH, JHU Medical Editor
  • Rachel Lastra, JHU Medical Editor
  • Jesse Ciekot, JHU Program Coordinator
Box A1: MCCC Leaders and Members (when this guideline was developed)
Unless noted otherwise, Committee members had no disclosures of financial relationships with commercial entities
Leadership
  • Chair (effective March 2018)Joseph P. McGowan, MD, FACP, FIDSA, North Shore University Hospital, Manhasset, NY
  • Co-Vice-Chair (Vice-Chair effective March 2018; Co-Vice-Chair effective January 2021)Steven M. Fine, MD, PhD, University of Rochester Medical Center, Rochester, NY
  • Co-Vice-Chair (effective January 2021): Rona M. Vail, MD, Callen-Lorde Community Health Center, New York, NY
  • Chair Emeritus (effective March 2018)Samuel T. Merrick, MD, New York-Presbyterian-Weill Cornell, New York, NY
  • Medical Director: Charles J. Gonzalez, MD, New York State Department of Health AIDS Institute, New York, NY (May 2018)
  • Clinical Advisor to the AIDS Institute (effective June 2021)Lyn Stevens, MS, NP, ACRN, New York State Department of Health AIDS Institute, Albany, NY
  • Director, JHU-NYSDOH AI Guidelines Program: Christopher J. Hoffmann, MD, MPH, Johns Hopkins University School of Medicine, Baltimore, MD
Contributing Members
  • Jessica M. Atrio, MD, MSc, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
  • Oni J. Blackstock, MD, MHS, Health Justice, New York, NY
  • James C. M. Brust, MD, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
  • Ethan A. Cowan, MD, MS, Icahn School of Medicine at Mount Sinai, New York, NY
  • Elliot DeHaan, MD, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY
  • Mary E. Dyer, MD, Hudson River Healthcare, Monticello, NY
  • John J. Faragon, PHARMD, BCPS, AAHIVP, Albany Medical Center, Albany, New York
  • Shauna H. Gunaratne, MD, MPH, Columbia University Medical Center, New York, NY
  • Bruce E. Hirsch, MD, FACP, FIDSA, AAHIVS, North Shore University Hospital, Manhasset, NY
  • Christine A. Kerr, MD, Galileo Health
  • Jeremy D. Kidd, MD, MPH, New York-Presbyterian Hospital, Columbia University, New York, NY
  • Hector I. Ojeda-Martinez, MD, Nuvance Health/Health Quest Medical Practice, Poughkeepsie, NY
  • Asa E. Radix, MD, MPH, FACP, AAHIVS, Callen-Lorde Community Health Center, New York, NY
  • Sanjiv S. Shah, MD, MPH, AAHIVM, AAHIVS, NYC Health + Hospitals/Gotham Health, Gouverneur, New York, NY
  • Noga Shalev, MD, Columbia University Medical Center, New York, NY
  • Eugenia L. Siegler, MD, Weill Cornell Medical College, New York, NY
  • Maria Teresa (Tess) Timoney, MS, RN, CNM, Bronx Prevention Center, ICAP at Columbia, Bronx, NY
  • Benjamin W. Tsoi, MD, MPH, Bureau of HIV/AIDS Prevention and Control, New York City Department of Health and Mental Hygiene, New York, NY
  • Marguerite A. Urban, MD, University of Rochester School of Medicine and Dentistry, Rochester, NY
  • Antonio E. Urbina, MD, The Mount Sinai Hospital, Comprehensive Health Program–Downtown, New York, NY
    • Scientific Advisor: Gilead, ViiV, Merck
  • Geoffrey A. Weinberg, MD, University of Rochester School of Medicine and Dentistry, Rochester, NY
Peer Reviewers
  • Elizabeth Asiago-Reddy, MD, MS, SUNY Upstate Medical University, Syracuse, NY
  • Robert Murayama, MD, MPH, FACP, The Institute for Family Health, New York, NY

Funding and disclosure of potential conflicts of interest (COIs): NYS funds supported the development of this guideline through a grant awarded to the JHU School of Medicine, Division of Infectious Diseases, from the NYSDOH AI.

All active MCCC members, invited consultants and coauthors, peer reviewers, and program staff are required to disclose financial relationships with commercial entities, including gifts that may be actual conflicts of interest or may be perceived as conflicts. These individuals must disclose financial relationships annually, for themselves, their partners/spouses, and their organization/institution. On their annual disclosures, MCCC members are asked to report for the previous 12 months and the upcoming 12 months. 

All reported financial relationships with commercial entities are reviewed by the NYSDOH AI guidelines program to assess the potential for undue influence on guideline recommendations made by the Committee.

All guideline recommendations received consensus approval of the full MCCC, and the final review and approval of the recommendations were performed by the Committee Chair and the NYSDOH AI Medical Director and Deputy Medical Director, none of whom reported conflicts of interest.

Evidence collection and review: The NYSDOH AI guideline development process is based on a strategic search and analysis of the published evidence. Box A2 illustrates the evidence review and selection process.

Box A2: Evidence Collection and Review Processes
  • NYSDOH AI and MCCC defined the goal of the guideline: To provide healthcare practitioners with information on the use of injectable CAB/RPV LA.
  • MCCC appointed a lead author who conducted a systematic literature search in PubMed using MeSH terms; all searches were limited to studies that 1) were published within the previous 5 years; 2) involved only human subjects; and 3) were published in English.
  • Lead authors reviewed studies identified through searches and excluded based on the following criteria: Publication type, study design, participants, and clinical relevance to the guideline.
  • Author and editorial staff conducted additional searches using PubMed and online databases to identify:
    • Studies published prior to the 5-year search limit.
    • Studies published during the guideline development process.
    • Recent conference abstracts.
    • Older studies known to provide strong evidence in support of specific recommendations or to undergird expert opinion.
  • Lead authors developed and the Writing Group and then all MCCC members reviewed and approved evidence-based guideline recommendations:
    • Writing Group reviewed, deliberated, refined, and approved draft recommendations.
    • MCCC members reviewed, provided written comment on, deliberated, and reached consensus on recommendations.
    • Members of the Writing Group reviewed the cited evidence and assigned a 2-part rating to each recommendation to indicate the strength of the recommendation and the quality of the supporting evidence; consensus reached on ratings.
    • Additional evidence identified and cited during the rating process (see below).
  • Ongoing update process:
    • JHU editorial staff will surveil published literature on an ongoing basis to identify new evidence that may prompt changes to existing recommendations or development of new recommendations.
    • JHU editorial staff will ensure that the MCCC reviews new studies at least 4 times per year, and more often if newly published studies, new drug approval, or drug-related warning indicate the need for an immediate change to the published guideline.
    • JHU editorial staff will track, summarize, and publish ongoing changes to the guideline.
    • MCCC will review and approve substantive changes to, additions to, or deletions of recommendations.
    • MCCC will initiate a full review of the guideline 4 years after the original publication date.
    • NYSDOH AI will publish a comprehensive update 5 years after the original publication date.

Recommendation development and rating process: This guideline was developed using the standard development process. Clinical recommendations were developed by consensus based on a synthesis of the current evidence collected through the systematic search described above. If no data were available, the recommendations are based on expert opinion, and this status is indicated in the rating and the text. Once consensus among the Writing Group members was reached, the guideline was reviewed by the full MCCC, and consensus was reached on all recommendations. Writing Group review discussions were recorded, and recordings were reviewed carefully to ensure that all decisions and changes were captured and integrated into the manuscript. Members of the Writing Group then individually reviewed the evidence for each recommendation and assigned a 2-part rating (see below). The individual ratings were compiled into a report distributed to all raters, and conference call discussions were held to deliberate ratings for which consensus was needed. Once all raters agreed on the interpretation of evidence and ratings for all recommendations, the guideline was sent to the NYSDOH AI for review and approval.

AIDS Institute Clinical Guidelines Program: Recommendations Ratings
(updated June 2019 [a])
Strength of Recommendation Ratings
A Strong recommendation
B Moderate recommendation
C Optional
Quality of Supporting Evidence Ratings
1 Evidence is derived from published results of at least one randomized trial with clinical outcomes or validated laboratory endpoints.
* Evidence is strong because it is based on a self-evident conclusion(s); conclusive, published, in vitro data; or well-established practice that cannot be tested because ethics would preclude a clinical trial.
2 Evidence is derived from published results of at least one well-designed, nonrandomized clinical trial or observational cohort study with long-term clinical outcomes.
2† Evidence has been extrapolated from published results of well-designed studies (including non-randomized 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 Recommendation is based on the expert opinion of the committee members, with rationale provided in the guideline text.
  1. With the June 2019 update, the ratings for quality of supporting evidence were expanded to add the * rating and the 2† rating.

Guideline updates: Members of the MCCC or an invited lead author who is not an MCCC member will monitor developments in an ongoing structured manner to maintain guideline currency. Once the guidelines are published on the program website, www.hivguidelines.org, and indexed in the National Library of Medicine, any updates will be made to the HTML document and all collateral materials as needed as new, peer-reviewed literature is published if evidence is made available that changes best practices.

Notification of newly published studies will be automated, and the Writing Group will review new data as available. Newly published data that provide support for existing recommendations will be cited in the text, and the studies will be added to the reference list(s).

If newly published data prompt a revision to recommendations or rationale, the lead author and the Writing Group will propose appropriate edits and determine whether the changes warrant review and approval by the entire MCCC. If MCCC review is required, JHU will distribute updates via email, and a conference call will be convened if required. Deletion of existing recommendations, addition of any new recommendations, or substantive changes to existing recommendations will prompt MCCC review and consensus.

The full guideline will be reviewed and updated on the third and the fifth anniversary of original publication and more often if an evidence-based change in recommendations is required.