What is the role of Apretude (cabotegravir) in HIV prevention for a high-risk adult?

Apretude (Cabotegravir) for HIV Prevention in High-Risk Adults

Apretude (long-acting injectable cabotegravir) is a highly effective, FDA-approved option for HIV pre-exposure prophylaxis (PrEP) in high-risk adults, administered as 600 mg intramuscular injections every 8 weeks after an initial loading phase, and has demonstrated superior efficacy compared to daily oral tenofovir/emtricitabine in preventing HIV acquisition. 1, 2

Approved Indications and Patient Selection

• Apretude is indicated for PrEP in adults and adolescents weighing ≥35 kg who are HIV-negative but at risk of sexually acquired HIV-1 infection 2, 3
• The drug showed superior efficacy to daily oral emtricitabine/tenofovir disoproxil fumarate in preventing HIV acquisition in cisgender men who have sex with men (MSM), transgender women, and cisgender women at high risk 3, 4
• In the HPTN 083 trial, cabotegravir reduced HIV incidence by 69% compared to daily oral PrEP (HR 0.31,95% CI 0.17-0.58, p=0.0003) during the blinded phase 4

Dosing Schedule and Administration

The standard dosing regimen consists of two initial 600 mg intramuscular injections given 4 weeks apart, followed by maintenance injections every 8 weeks thereafter. 1, 5

• All injections are administered intramuscularly in the gluteal region at 600 mg (3 mL) 5
• An oral lead-in with cabotegravir tablets (30 mg daily for approximately 4 weeks) may be used to assess tolerability before initiating injections, though this is optional 5, 2
• If injections are delayed by 8 or more weeks, "reloading" with two injections 4 weeks apart is required before returning to every-8-week dosing 5

Critical Pre-Initiation Requirements

Comprehensive HIV testing is absolutely mandatory before the first injection and must include BOTH a fourth- or fifth-generation antigen/antibody test AND an HIV RNA test with a lower limit of quantification ≤50 copies/mL. 1, 5

• Do not initiate cabotegravir if HIV status cannot be confirmed as negative—this is a critical safety measure to prevent integrase inhibitor resistance 5, 2
• If clinical suspicion exists for acute HIV infection (flu-like symptoms, recent high-risk exposure), cabotegravir must not be started until HIV RNA results confirm negative status 5, 2
• Baseline testing must also include: serum creatinine and estimated creatinine clearance, hepatitis B surface antigen, hepatitis C antibody, pregnancy test (if applicable), and comprehensive STI screening at all exposed sites 5, 6

Ongoing Monitoring Protocol

Before every subsequent injection (every 8 weeks), perform both a rapid point-of-care HIV antibody test AND send a laboratory-based combination antigen/antibody test. 1, 7

• HIV RNA testing is NOT routinely recommended at follow-up visits because it has low positive predictive value and false-positives cause significant harm 1, 7
• The exception: HIV RNA testing should be performed at the 1-month follow-up visit after the first injection to detect any breakthrough infections during the loading phase 5
• Perform three-site STI screening (rectal, pharyngeal, urogenital) every 3 months for MSM and at-risk individuals 6
• Monitor renal function (serum creatinine and eGFR) every 6-12 months, or more frequently (every 3-6 months) in patients >50 years, with baseline eGFR <90 mL/min, or taking medications affecting renal function 6

Critical Safety Considerations and Contraindications

Absolute contraindications include: confirmed or suspected HIV-positive status, unknown HIV status, and allergy to cabotegravir. 2

• Do not use cabotegravir with potent UGT1A1 inducers (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine) as they reduce cabotegravir concentrations 5, 2
• Rifabutin requires dose adjustment when coadministered with cabotegravir 5
• Use caution in individuals with gluteal implants or fillers as the intramuscular injection site may be compromised 5

Management of PrEP Breakthrough Infections

If HIV seroconversion occurs while on cabotegravir PrEP, immediately obtain genotypic resistance testing including integrase mutations and switch to a protease inhibitor or NNRTI-based antiretroviral regimen—NEVER continue an integrase inhibitor-based regimen. 7

• Cabotegravir can delay HIV seroconversion and mask early infection, a phenomenon termed LEVI (long-acting early viral inhibition) 1
• Two sequential testing results showing detectable HIV RNA at any level (even below the limit of quantification) is highly predictive of true HIV infection 1
• All breakthrough infections with cabotegravir resistance showed cross-resistance to elvitegravir and raltegravir but retained susceptibility to dolutegravir and bictegravir 2
• Discordant or difficult-to-interpret HIV test results should be discussed with experts at the PrEP Warmline (1-855-HIVPrEP in the US) 1

Common Adverse Effects

• Injection-site reactions occurred in up to 81% of trial participants but typically diminish in severity over time 5, 8
• Incident hypertension in the cabotegravir group requires further investigation and monitoring 4
• The drug was generally well tolerated in clinical trials, though long-term safety data continue to accumulate 3

Important Clinical Pitfalls to Avoid

• Never skip pre-injection HIV testing, even if the patient seems low-risk or was recently tested—missing this step could result in undetected HIV infection and multi-drug resistance 7
• Never use standard antibody tests alone at initiation—they may miss acute HIV infection, particularly given cabotegravir's long half-life and resistance risk 7
• Never continue cabotegravir or switch to another integrase inhibitor if seroconversion is detected—this will select for multi-drug resistant virus 7
• Ensure patients have a 1-month supply of oral tenofovir-based PrEP available for bridging if injection delays of 7 days or more occur 5

Patient Counseling Points

• Cabotegravir does not prevent other sexually transmitted infections—patients should continue safer sex practices including condom use 2
• Missing doses or delayed injections increases the risk of HIV acquisition 2
• Patients must return for HIV testing before every injection—this is non-negotiable for safety 7
• The time from initiation to maximal protection is unknown, so additional prevention measures should be maintained 2