Taking a stab at HIV

Since the late 1990s, standard antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection has consisted of three active agents in order to maintain viral suppression, reduce morbidity and mortality, improve quality of life and minimize transmission.1 Injectable therapies, such as intravenous zidovudine2 and subcutaneous enfuvirtide,3 are occasionally used in specific settings; however, these drugs have largely fallen out of favour due to inconvenience and poor tolerability.2,3 The recent advent of new long-acting injectable antiretrovirals offers the possibility to simplify or eliminate oral pill burden and decrease dosing frequency, which can improve adherence and reduce stigma. Currently, three long-acting antiretrovirals (ARVs) are approved in Canada: cabotegravir,4 rilpivirine4 and lenacapavir.5 This article reviews the approved and potential roles of these agents in HIV treatment and prevention, with a focus on considerations for community pharmacists.Cabotegravir/rilpivirine (Cabenuva)This regimen consists of the new integrase strand transfer inhibitor (INSTI), cabotegravir, and the previously approved non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine. It is a complete regimen for treatment of HIV-1 in individuals 12 years of age or older who are currently virologically suppressed on oral therapy with no resistance mutations to either component. The drugs are available as separate extended-release injectable suspensions for intramuscular (IM) administration, and as individual oral tablets for an optional lead-in period and/or for oral bridging of missed/late injections.4 A summary of drug characteristics is provided in Table 1.4,5What is the evidence? Landmark trials examining the use of cabotegravir/rilpivirine as maintenance therapy in virally suppressed patients are summarized in Table 2.6-8 Cabotegravir/rilpivirine was found to be non-inferior to continuing oral ART, with over 93% of participants in either arm maintaining viral suppression at 48 weeks. The presence of at least two of the following baseline characteristics was associated with a higher risk of virologic failure: HIV-1 subtype A6/A1 (common in eastern Europe, particularly Russia), rilpivirine-associated mutations, or body mass index (BMI) ≥ 30.9ln a recent update from the IAS-USA guidelines panel,10 cabotegravir/rilpivirine can be used, in certain circumstances, in patients with a detectable viral load.11 This can be particularly beneficial if patients have difficulty accessing or being adherent to oral ART. Only limited data are available in pregnancy. If a person becomes pregnant while on cabotegravir/rilpivirine, a shared decision should be made regarding continuing the regimen with more frequent viral load monitoring, or switching to a preferred/alternate three-drug oral ART regimen for the duration of pregnancy.12Dosing Oral cabotegravir 30 mg and rilpivirine 25 mg daily may be used as an optional, one-month lead-in period to assess tolerability prior to starting injections, or to bridge therapy if an injection appointment is late or missed. Since cabotegravir and rilpivirine are usually well tolerated, most practitioners now skip the oral lead-in phase.The injection schedule includes an initiation phase with cabotegravir 600 mg/rilpivirine 900 mg given monthly for two months, followed by maintenance dosing of cabotegravir 400 mg/rilpivirine 600 mg monthly or 600 mg/900 mg every two months; the latter is most commonly used due to improved convenience. At each injection visit, two ventrogluteal (or dorsogluteal) IM injections of 2 mL or 3 mL are administered at separate injection sites.6 For individuals with a BMI ≥ 30, a longer (2-inch) needle should be used. No dosage adjustment is required for mild/moderate renal or hepatic insufficiency; no data are available in severe renal or hepatic impairment.4Missed/late doses The date of the first initiation injection becomes the target date moving forward, with future scheduled injections administered +/- 7 days from the target date. For instance, if the first injection was on the 15th of the month, all subsequent injection visits should fall between the 8th and 22nd of the month. If a patient cannot receive or misses a scheduled injection, they should receive oral bridging ART and then reinitiate injections upon discussion with their healthcare provider.4 Oral bridging can consist of oral cabotegravir and rilpivirine tablets taken daily, or the patient’s previous oral ART regimen.13Side effects Injection site reactions are common and include pain/discomfort, nodules and induration; they usually last three days after each injection and may decrease in severity with subsequent doses.6 Approaches to minimizing injection site reactions include bringing the vials to room temperature before injection, relaxing the gluteal muscle prior to injection, injecting the contents slowly and distracting the patient.14 Over-the-counter analgesics may be used. QT prolongation can occur with rilpivirine exposures at three times the dose of oral or injected rilpivirine; therefore, it should be used with caution in combination with drugs that have a known risk of torsade de pointes.15Drug interactions Cabotegravir is a substrate of UGT1A1 and UGT1A9, and rilpivirine is a substrate of CYP3A4. Oral and IM cabotegravir and rilpivirine are contraindicated with potent inducers of CYP3A4 and UGT1A1 or UGT1A9. Oral rilpivirine is contraindicated with proton pump inhibitors and oral cabotegravir should be spaced apart from oral cations, such as antacids or mineral supplements, to avoid chelation; these interactions are not a concern when these antiretrovirals are administered by injection.4Role in HIV PrEP (pre-exposure prophylaxis) Long-acting cabotegravir 600 mg given IM bimonthly is approved in the United States for HIV prevention,16 and received Health Canada priority review status in January 2024.17 Studies have found cabotegravir to be superior to daily tenofovir disoproxil fumarate–emtricitabine for PrEP in men who have sex with men, and in transgender women and cisgender women (Table 2).18,19 If an individual acquires HIV while on injectable cabotegravir, detection of a new infection may be delayed, potentially leading to INSTI resistance. Therefore, a viral load should be completed prior to each cabotegravir injection. Since cabotegravir can remain in the body for up to a year or more,16 patients who discontinue cabotegravir are advised to initiate oral PrEP within two months of the last injection if they may continue to benefit from HIV prevention methods, and should be followed quarterly for 12 months or longer.16Lenacapavir (Sunlenca)Lenacapavir is a capsid inhibitor that prevents the formation of the HIV capsid, virus assembly/release and HIV capsid uptake. It is a treatment option for adults with treatment-resistant HIV, with resistance to two or more ART classes, and must be used with other antiretrovirals to form an effective regimen. Following a short mandatory oral lead-in period, lenacapavir is administered every six months via subcutaneous injection (Table 1).5What is the evidence? The CAPELLA trial found that in patients with multidrug-resistant HIV, those who received lenacapavir plus an optimized background regimen had a greater reduction in viral load versus those who received placebo plus an optimized background regimen.20 At 26 weeks, more than 80% of patients receiving lenacapavir plus an optimized background regimen achieved viral suppression. Oral and injectable lenacapavir-containing regimens are also being studied in treatment-naive individuals (Table 2).21Dosing Oral lead-in dosing is mandatory in order to quickly achieve therapeutic concentrations. After the oral lead-in, lenacapavir is administered every six months (26 weeks) as two 1.5 mL subcutaneous injections into the abdomen (Table 1). No dosage adjustment is required for mild/moderate renal or hepatic insufficiency; no data are available in severe renal or hepatic impairment.5Missed/late doses The scheduled injections should be administered every 26 weeks +/- 2 weeks from the last injection. If more than 28 weeks have elapsed since the last injection, initiation with the oral lead-in needs to be repeated.5Side effects The most common adverse reactions include nausea (4%) and injection site reactions (65%). Most are mild-moderate in severity and resolve in an average of five days; nodules and indurations at the injection site may take longer to resolve (148 and 70 days, respectively).5,22Drug interactions Lenacapavir is a CYP3A4 substrate and is contraindicated with potent CYP3A4 inducers. It is also a moderate CYP3A4 inhibitor; caution is advised when co-administering with sensitive CYP3A4 substrates with a narrow therapeutic index (e.g., phosphodiesterase-5 inhibitors, direct-acting anticoagulants, ergot agents, certain statins). The inhibiting effects of lenacapavir may persist for up to nine months after the last injection.5Role in HIV PrEP Lenacapavir is being investigated for PrEP in various populations at risk of acquiring HIV, including adolescents and young girls, cisgender women, gay/bisexual/gender diverse men who have sex with men, and people who inject drugs (Table 2).23-26Appropriate candidates for injectable antiretroviral therapyPatients may desire long-acting therapy for a variety of reasons, including reduced/elimination of daily pill burden, increased discretion, reduced stigma or reminder of disease, enhanced regimen potency, management of swallowing/absorption difficulties and avoidance of drug interactions. People who may be appropriate candidates for injectable ART are those who are able to attend regular appointments for injections and follow-up tests; with cabotegravir/rilpivirine, these visits may be more frequent than what patients on stable oral ART may be used to.Patients who may not be ideal candidates for long-acting ART include those who fear needles, are unable to regularly attend appointments or who have challenges adhering to oral therapy (i.e., an optimized background regimen with lenacapavir), are on a contraindicated co-medication, or have other risk factors for virologic failure. Patients with hepatitis B will need additional anti-hepatitis B virus therapy. When discontinuing injections, appropriate oral ART should be started by what would have been the next scheduled injection date.Pharmacist’s role with injectable ARTThe pharmacist plays a crucial role in injectable ART access, administration and adherence.4,5Pharmacists can be instrumental in advocacy and ensuring access to these drugs, often referring patients and prescribers to patient support programs if private or provincial programs do not cover the medications.Adherence support is important in order to minimize the risk of resistance. In particular, lenacapavir is not a complete regimen and adherence to the oral backbone therapy is critical. Ensure patients attend injection appointments and manage missed or late injection doses appropriately.Long-acting antiretrovirals could potentially be administered by community pharmacists; additional training for IM gluteal injection of cabotegravir/rilpivirine may be required. Ensure the injection space provides adequate privacy and patient comfort; an exam room table is recommended for gluteal injections.Drug interactions are a source of concern; CYP3A4 and UGT1A1/1A9 inducers are contraindicated. HIV-specific databases with practical management strategies are available through HIV Drug Interactions (Liverpool)27 and the Canadian-specific HIV/HCV Drug Therapy Guide.28Some community pharmacists offer HIV testing or comprehensive oral PrEP programs, which may be adapted for injectable PrEP modalities.SummaryCabotegravir/rilpivirine and lenacapavir are new long-acting injectable therapies that represent revolutionary advances in the HIV landscape. They have different roles in treatment: cabotegravir/rilpivirine allows people to be completely free of oral antiretroviral pills, while lenacapavir is a novel therapeutic agent for people with limited treatment options and must be used with other oral antiretrovirals. Cabotegravir and lenacapavir injections also represent exciting alternatives to oral HIV PrEP strategies. Development of additional long-acting agents and delivery modalities continues to be a priority for HIV medicine, with the hope of offering patients more choices throughout the prevention and treatment spectrum.Julian Hopwood-Raja (Julian.hopwood-raja@uhn.ca) is an HIV Advanced Year 2 Pharmacy Resident at the University Health Network in Toronto, ON, and McGill University Health Centre (Glen Site) in Montreal, QC.Alice Tseng is an HIV Pharmacotherapy Specialist at the Immunodeficiency Clinic in the University Health Network and an Associate Professor, Leslie Dan Faculty of Pharmacy and Pharmaceutical Sciences, in Toronto, ON.References:Tseng A, Seet J, Phillips EJ. The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. Br J Clin Pharmacol 2015;79(2):182-94.ViiV Healthcare ULC. Retrovir (zidovudine) product monograph. Montreal QC; June 16, 2023. (accessed November 18, 2023).Hoffmann-La Roche. Fuzeon (enfuvirtide) product monograph. Mississauga, ON; March 25 2020. (accessed November 5, 2023).ViiV Healthcare ULC. Cabenuva (cabotegravir and rilpivirine injectable) product monograph. Montreal, QC; July 5, 2023. (accessed November 6, 2023).Gilead Sciences Canada. Sunlenca (lenacapavir) product monograph. Mississauga, ON; November 1, 2022. (accessed November 6, 2023).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):1112-23.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 randomized, open-label, phase 3 FLAIR study. Lancet HIV 2021;8(4):e185-e196.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 randomized, multicentre, open-label, phase 3b, non-inferiority study. Lancet 2020;396:1994-2005.Jeffrey JL, St. Clair M, Wang P, et al. Impact of integrase sequences from HIV-1 subtypes A6/A1 on the in vitro potency of cabotegravir or rilpivirine. Antimicrob Agents Chemother 2022; 66(3):e01702-21.Sax PE, Thompson MA, Saag MS, IAS-USA Treatment Guidelines Panel. Updated treatment recommendation on use of cabotegravir and rilpivirine for people with HIV From the IAS-USA Guidelines Panel. JAMA 2024 Mar 1. doi: 10.1001/jama.2024.2985Gandhi M, Hickey M, Imbert E, et al. Demonstration project of long-acting antiretroviral therapy in a diverse population of people with HIV. Ann Intern Med. 2023;176(7):969-74.National Institutes of Health. Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. Updated January 31, 2023. (accessed December 1, 2023).Orkin C, Morell EB, Tan DHS, et al. Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study. Lancet HIV 2021;8(11):e668-e678.Teichner P, Elliot E, Pascual-Bernáldez M, et al. ViiV Healthcare. “Give it a shot”: best practices from HCPs for administering long-acting cabotegravir + rilpivirine. Updated 2022. (accessed December 9, 2023).Credible Meds. QTDrugs lists. Tucson, AZ. (accessed November 29, 2023.ViiV Healthcare ULC. Apretude (cabotegravir long-acting injectable) product monograph. Research Triangle Park, NC; December, 2021. (accessed November 18, 2023).ViiV Healthcare. Health Canada grants priority review status of ViiV Healthcare’s new drug submission for cabotegravir long-acting injectable and tablets for prevention of HIV. Montreal, QC: Newswire; January 10, 2024. (accessed January 11, 2024).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.Delany-Moretlwe S, Hughes JP, Bock P, et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomized clinical trial. Lancet 2022;399:1779-89.Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 Infection. N Engl J Med 2022;386:1793-803.Gupta SK, Berhe M, Crofoot G, et al. Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomized, open-label, active-controlled, phase 2 trial. Lancet HIV 2023;10(1):e15-e23.Gilead Sciences. Sunlenca (lenacapavir injection) product monograph. Foster City, CA; December, 2022. (accessed December 20, 2023).Gilead Sciences. Pre-exposure prophylaxis study of lenacapavir and emtricitabine/tenofovir alafenamide in adolescent girls and young women at risk of HIV infection. Updated October 10, 2023. (accessed November 19, 2023).Gilead Sciences. Study of lenacapavir for HIV pre-exposure prophylaxis in people who are at risk for HIV infection. Updated November 24, 2023. (accessed November 19, 2023).Gilead Sciences. Study of lenacapavir and emtricitabine/tenofovir disoproxil fumarate (F/TDF) in prevention of HIV in cisgender women in the United States (HPTN-102). Updated December 8, 2023. (accessed November 19, 2023).Gilead Sciences. Study of lenacapavir and emtricitabine/tenofovir disoproxil fumarate (F/TDF) for prevention of HIV in people who inject drugs (HPTN-103). Updated November 7, 2023. (accessed November 19, 2023).University of Liverpool. HIV drug interactions. 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Taking a stab at HIV

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