What are guideline recommendations and literature surrounding Apretude (cabotegravir)?

Please summarize any guideline recommendations and literature surrounding Apretude (cabotegravir)

Comment by InpharmD Researcher

Given that the use of long-acting cabotegravir (Apretude®), a long-acting injectable suspension, in pre-exposure prophylaxis (PrEP) is still under investigation, CDC guidelines do not currently recommend one PrEP regimen over another. However, the long half-life of cabotegravir compared to daily oral PrEP may lead to better adherence rates. Data from the HPTN083 trial (Table 1) and preliminary results from the HPTN084 trial have demonstrated the superiority of cabotegravir compared with tenofovir disoproxil fumarate/emtricitabine (Truvada®) in reducing the risk of acquiring incident HIV-1 infection. A recent 2022 pharmacoeconomic analysis concluded that the effectiveness of oral PrEP might potentially limit the additional price society is willing to pay for long-acting cabotegravir.

Background

According to 2021 Centers for Disease Control and Prevention (CDC) pre-exposure prophylaxis (PrEP) guidelines, PrEP with intramuscular cabotegravir injections is recommended for HIV prevention in adults reporting sexual behaviors that place them at substantial ongoing risk of HIV exposure and acquisition. Its use may be particularly beneficial in patients with significant renal disease, those who have had difficulty with adherent use of oral PrEP, and those who prefer injections every two months to an oral PrEP dosing schedule. However, guidelines do not currently recommend one PrEP regimen over another. [1]

A recent review evaluated the use of long-acting (LA) cabotegravir, a newly approved integrase strand transfer inhibitor (INSTI), in HIV/AIDS PrEP. Compared to dolutegravir, another second-generation INSTI, cabotegravir was bound by human serum proteins about 5-fold more effectively than dolutegratvir, leading to its formulation as an injectable 200 mg/mL nanosuspension with an average particle size of 0.2 μm. Its unique physicochemical property also makes it compatible with LA non-nucleoside RT inhibitor rilpivirine for injection coformulation and storage. Commonly used PrEP regimen, emtricitabine and tenofovir disoproxil fumarate, requires strict once-daily oral dosing to maintain adequate drug plasma levels, posing an inevitable adherence issue at the population level. As such, cabotegravir’s long half-life (3 to 7 weeks) for intramuscular administration is more advantageous than traditional oral agents. Data from the recent HPTN 083 trial (Table 1) demonstrated that LA cabotegravir was associated with a more favorable outcome in HIV infection reduction compared to emtricitabine and tenofovir disoproxil fumarate (13 infected vs. 39 infected), leading to a 66% reduction of infection hazard in the participants receiving cabotegravir. [2]

It was noted, however, that the likelihood of virological failure could not be completely ruled out when cabotegravir levels dip below the required plasma concentrations to effectively inhibit HIV-1 replication, even though the risk of virological failure might be relatively low compared to other second-generation INSTIs. The overall preliminary evidence appeared to be promising, especially in vulnerable and marginalized populations. At this point, the effects of the potential emergence of cabotegravir-resistant mutant viruses from infected participants remained unknown. [2]

A recent 2022 pharmacoeconomic analysis evaluated the cost-effectiveness of long-acting injectable cabotegravir (CAB-LA) HIV PrEP compared to tenofovir-based PrEP among men who have sex with men and transgender women (MSM/TGW) in the United States over a 10-year horizon. Among those at very high risk for HIV (VHR), compared with generic emtricitabine/tenofovir disoproxil fumarate (F/TDF) and branded emtricitabine/tenofovir alafenamide (F/TAF), CAB-LA increased life expectancy by 28,000 quality-adjusted life-years (QALYs) and 26,000 QALYs, respectively. At 10 years, CAB-LA could achieve an incremental cost-effectiveness ratio (ICER) of at most $100,000 per QALY compared with generic F/TDF at a maximum premium price of $3,700 per year over generic F/TDF (CAB-LA price <$4,100 per year). In a PrEP-eligible population at high risk for HIV, rather than at VHR, CAB-LA could achieve an ICER of at most $100,000 per QALY versus generic F/TDF at a maximum price premium of $1,100 per year over generic F/TDF (CAB-LA price <$1,500 per year). It was concluded that the superiority of CAB-LA to generic F/TDF, notwithstanding the presence of highly effective oral PrEP alternatives, limits the additional price that payers should be willing to pay for CAB-LA. [3]

The HTPN084 trial is a phase 3, double-blind, randomized-controlled clinical trial which evaluates the safety and efficacy of long-acting injectable cabotegravir compared to daily oral tenofovir disoproxil fumarate/emtricitabine for PrEP in HIV-uninfected women. Results of this trial are not currently published; however, preliminary results can be found within the prescribing information for cabotegravir (see Prescribing Information). The estimated study completion date is May 31, 2022. [4]

Relevant Prescribing Information

CLINICAL STUDIES [5]

In HPTN 084, a superiority study, 3,224 cisgender women were randomized 1:1 and received either cabotegravir (n = 1,614) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC; n = 1,610) as blinded study medication up to Week 153. Participants randomized to receive cabotegravir initiated oral lead-in dosing with 1 oral cabotegravir 30-mg tablet and a placebo daily for up to 5 weeks, followed by cabotegravir 600 mg (3-mL) intramuscular injection at months 1 and 2 and every 2 months thereafter and a daily placebo tablet. Participants randomized to receive TDF/FTC initiated oral TDF 300 mg/FTC 200 mg and placebo daily for up to 5 weeks, followed by oral TDF/FTC daily and placebo intramuscular injection at months 1 and 2 and every 2 months thereafter.

At baseline, the median age of participants was 25 years, >99% were non-White, >99% were cisgender women, and 49% were <25 years of age.The primary endpoint was the rate of incident HIV-1 infections among participants randomized to oral cabotegravir and injections of cabotegravir compared with oral TDF/FCT (corrected for early stopping). The primary analysis demonstrated the superiority of cabotegravir compared with TDF/FTC with an 88% reduction in the risk of acquiring incident HIV-1 infection, hazard ratio (95% CI) 0.12 (0.05, 0.31); further testing revealed 1 of the infections on cabotegravir to be prevalent then yielding a 90% reduction in the risk of HIV-1 incident infection relative to TDF/FTC.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Please summarize any guideline recommendations and literature surrounding Apretude (cabotegravir)

Level of evidence

A - Multiple high-quality studies with consistent results Read more→

Please see Table 1 for your response.

Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women
Design	Randomized, double-blind, double-dummy, noninferiority trial N= 4,566
Objective	To compare long-acting injectable cabotegravir at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of human immunodeficiency virus (HIV) infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men
Study Groups	Cabotegravir (n= 2,282) TDF-FTC (n= 2,284)
Inclusion Criteria	Cisgender MSM and transgender women who have sex with men; age ≥ 18 years; negative HIV serologic test; undetectable blood HIV RNA viral load within 14 days before trial entry; creatinine clearance ≥ 60 mL/min; at high risk for HIV infection
Exclusion Criteria	Use of illicit intravenous drugs within 90 days before enrollment; previous participation in the active treatment group of an HIV vaccine trial; coagulopathy; buttock implants or fillers; seizure disorder; corrected QT interval > 500 msec; positive hepatitis B virus surface antigen test or hepatitis C virus antibody test
Methods	Patients were randomized (1:1) to receive either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Following an oral-tablet lead-in phase in which patients received two oral tablets (one active and one placebo) daily for 5 weeks (cabotegravir given as a 30 mg tablet and active TDF-FTC given as a fixed-dose combination of 300 mg TDF plus 200 mg TDF-FCT), patients with at least 50% adherence to the oral tablets were permitted to progress to injections. During the injection phase, patients received a supply of daily oral tablets and a 3 mL intramuscular injection at the beginning of the phase, 4 weeks after beginning, and every 8 weeks thereafter. Cabotegravir was administered as a single 3 mL injection (600 mg cabotegravir), while placebo for the cabotegravir group was an injectable fat emulsion (20% intralipid solution). Active TDF-FTC was given in the same manner as was given during the oral lead-in phase. Masked tablets were dispensed and injections were administered at weeks 5, 9, and 17 and every 8 weeks thereafter through week 153 (3 years of exposure). Patients who discontinued injections received open-label TDF-FTC for 48 weeks.
Duration	Enrollment: December 6, 2016 to March 16, 2020 Intervention: 153 weeks
Outcome Measures	Primary: incident HIV infection Safety: occurrence of an adverse event of grade 2 or higher
Baseline Characteristics		Cabotegravir (n= 2,282)	TDF-FTC (n= 2,284)
	Median age (interquartile range [IQR]), years	26 (22 to 32)	26 (22 to 32)
	Cohort MSM Transgender women who have sex with men	2,013 (88.2%) 266 (11.7%)	1,979 (86.6%) 304 (13.3%)
	Latino or Hispanic according to geographic region United States Latin America	149/849 (17.6%) 894/980 (91.2%)	154/849 (18.1%) 912/984 (92.7%)
	SexPro score according to geographic region† United States ≤ 16 > 16 Latin America ≤ 16 > 16	- 729/849 (85.9%) 120/849 (14.1%) - 825/980 (84.2%) 155/980 (15.8%)	- 718/849 (84.6%) 131/849 (15.4%) - 850/984 (86.4%) 134/984 (13.6%)
	Race in United States Black Non-Black	411/849 (48.4%) 437/849 (51.5%)	434/849 (51.1%) 414/849 (48.8%)
	†SexPro is a Web-based tool that provides a sexual health promotion score. It is validated to predict the 6-month risk of HIV acquisition on the basis of sexual behaviors, sexual networks, substance use, history of sexually transmitted infections, race or ethnic group (United States only), and age. Scores range from 1 to 20, with higher scores indicating a lower risk of acquiring HIV infection.
Results	Endpoint	Cabotegravir (n= 2,282)	TDF-FTC (n= 2,284)	Hazard ratio (95% confidence interval); p-value
	HIV infection Incidence per 100 person-years	13 0.41	39 1.22	0.34 (0.18 to 0.62); <0.001
	Any adverse event of grade 2 or higher	2,106/2,280 (92.4%)	2,116/2,282 (92.7%)	-
	The median adherence during the oral-tablet lead-in phase, as determined by pill count, was 96.6% (IQR 89.7 to 100) across the trial groups. Integrase strand inhibitor (INSTI) resistance mutations were detected in 1 of the 4 cases identified as a baseline infection and in 4 of 9 incident cases that had a resistance test result. In the TDF–FTC group, 2 of the 39 incident HIV infections occurred in cases in which the drug concentrations that were measured were consistent with good PrEP adherence.
Adverse Events	Common Adverse Events (grade 2 or higher): decreased creatinine clearance (69.6% vs. 73.1%), increased creatine kinase (21.2% vs. 20.6%), nasopharyngitis (19.6% vs. 17.4%), increased serum creatinine (16.8% vs. 18.8%) Injection site reactions: 81.4% vs. 31.3%; Of 10,666 injection-site reactions in the cabotegravir group, 6,486 (60.8%) were pain and 2,530 (23.7%) were tenderness; the events began a median of 1 day (IQR 0 to 2) after injection and lasted a median of 3 days (IQR 2 to 6).
	Serious Adverse Events: total (5.3% vs. 5.3%), grade 3 or higher: increased creatine kinase (14.2% vs. 13.5%), decreased creatinine clearance (7% vs. 8.3%) Adverse events of special interest: seizure (0.1% vs. 0.2%), liver-related adverse event resulting in discontinuation of oral tablets or both oral tablets and injections (2.1% vs. 2.1%)
	Percentage that Discontinued due to Adverse Events: Permanent discontinuation of the oral tablets or both oral tablets and injections owing to adverse events other than injection-site reactions occurred in 172 participants (3.8%) overall, with a similar overall frequency in the two groups. The incidence of discontinuation in either group was not reported. Of the 2,117 participants who received at least one active cabotegravir injection, 50 (2.4%) permanently discontinued the injections owing to an injection-related adverse event.
Study Author Conclusions	Cabotegravir was superior to daily oral TDF–FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of cabotegravir PrEP failure.
InpharmD Researcher Critique	Inadequate TDF–FTC adherence among some participants appeared to drive the overall finding of HIV incidence that was three times the incidence in the cabotegravir group; adherence may have confounded the results.

References:
[1] Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med. 2021;385(7):595-608. doi:10.1056/NEJMoa2101016