As injectable long-acting (LA) antiretroviral therapy (ART) becomes more accessible to people living with HIV (PLHIV), its impacts on HIV management practices should be anticipated to ensure that patient outcomes are not compromised. At an industry-sponsored symposium during the 2022 HIV Glasgow Congress in Glasgow, Scotland, UK, European pioneers in HIV research and treatment shared their experiences in the use of LA ART and discussed its potential implications in the future management of PLHIV.
Patient eligibility for LA ART
“The 2022 European AIDS Clinical Society [EACS] guidelines recommend bimonthly intramuscular [IM] injections of the LA ART regimen containing the integrase strand transfer inhibitor [INSTI], cabotegravir [CAB], and the non-nucleoside reverse-transcriptase inhibitor [NNRTI], rilpivirine [RPV], as replacement ART for adults [≥18 years of age] with HIV who are virologically suppressed [ie, HIV-1 RNA level <50 copies/mL for ≥6 months],” noted Professor Celia Jonsson-Oldenbüttel of MVZ München am Goetheplatz in Munich, Germany. “Known contraindications to this regimen include prior INSTI or NNRTI resistance and chronic hepatitis B virus [HBV] infection or no HBV immunity.” [EACS Guidelines version 11.1, October 2022; Cabenuva US Prescribing Information]
Post hoc multivariate analysis of phase III clinical studies investigated risk factors associated with confirmed virologic failure (CVF: two consecutive plasma HIV-1 RNA measurements ≥200 copies/mL) in 1,039 adults naïve to LA CAB + RPV. CVF was rare and occurred in 1.25 percent of participants (13/1,039). Baseline factors associated with CVF included proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, and body mass index (BMI) ≥30 kg/m2. The study also showed that 96.7 percent of patients had at most only one risk factor, and only 0.4 percent experienced CVF. Meanwhile, a combination of at least two baseline risk factors was seen in 3.4 percent of patients and was associated with increased CVF risk (25.7 percent). [AIDS 2021;35:1333-1342]
“Thus, you need at least two risk factors for significant increase in CVF risk,” Jonsson-Oldenbüttel noted. “The presence of only one risk factor [eg, BMI >30 kg/m2] does not preclude the use of LA CAB + RPV.”
Advantages of LA CAB + RPV
According to a PLHIV who spoke at the symposium in pseudonymity, a bimonthly LA ART regimen has advantages beyond convenience vs daily oral ART. For example, bimonthly LA ART allows patients to be more discreet about their condition with family members and friends, since they no longer need to hide their oral ART medications at home or when travelling.
This sentiment was also one of the findings in the CARLOS cohort, a noninterventional, multicentre, prospective real-world study in Germany that described the reasons why PLHIV switched to LA CAB + RPV and their clinical characteristics. The CARLOS study also documented other common challenges experienced by PLHIV who used daily oral ART before switching to LA ART, which are summarized in Figure 1. [Wyen C, et al, AIDS 2022, abstract EPB179]
Expanding patient eligibility for LA CAB + RPV
An observational study in a large HIV clinic in the US showed that among 39 patients who received at least two follow-up LA ART injections by database closure, all patients (n=24) who were virolocially suppressed at treatment initiation maintained viral suppression. Importantly, among the 15 patients with detectable viraemia at treatment initiation, 12 achieved viral suppression, while three patients had a 2-log viral load decline after a median of 22 days. [Clin Infect Dis 2022;doi:10.1016/j.antiviral.2022.105427]
Similarly, results from the OPERA cohort study in the US (n=145,398 PLHIV) demonstrated that 91 percent (19 of 21) of patients with initial HIV-1 RNA ≥200 copies/mL achieved HIV-1 RNA <200 copies/mL after receiving their first injection of LA CAB + RPV. [Sension MG, IDWeek 2022, abstract 1582]
“These promising early treatment outcomes show that more diverse patient groups may actually be eligible for LA ART, including those with detectable viraemia due to adherence challenges,” said Jonsson-Oldenbüttel.
LA CAB + RPV administration practices
Oral lead-in vs direct-to injection approach
An oral lead-in to assess tolerability to CAB and RPV is currently the standard practice prior to initiating injectable LA CAB + RPV. [Cabenuva US Prescribing Information]
“An oral lead-in also helps us better prepare clinic resources as we schedule patients’ appointments for LA ART administration,” shared Dr Laurence Slama of the Hôtel Dieu Hospital in Paris, France. “However, a direct-to-injection pathway is emerging as an acceptable approach in eligible patients based on results of the ongoing randomized, open-label, phase III FLAIR extension study, which showed that switching to LA CAB + RPV with or without an oral lead-in phase had similar safety, tolerability and efficacy, supporting future evaluation of the simpler direct-to-injection approach.” [Lancet HIV 2021;8:e668-e678]
Testing for RAMs
CARISEL is a phase IIIb implementation study on the efficacy and safety of bimonthly dosing of LA CAB + RPV in PLHIV with virologically suppressed disease (n=430) across 18 clinics in Europe. After 12 months, 87 percent of participants (n=373) maintained HIV-1 RNA levels <50 copies/mL. Two patients who experienced virologic failure had RAMs. [Jonsson-Oldenbüttel C, et al, AIDS 2022, abstract EPLBB05]
“These findings suggest that testing for RAMs when accessible may be a practical consideration prior to starting LA ART,” said Jonsson-Oldenbüttel.
LA ART safety considerations
Of the 84 percent of patients who reported any adverse events (AEs) in CARISEL, 36 percent of patients were assessed as having drug-related AEs. Most AEs were mild, with only 9 percent of cases assessed as grade ≥3, and only 6 percent of cases leading to withdrawal. [Jonsson-Oldenbüttel C, et al, AIDS 2022, abstract EPLBB05]
“Injection-site reactions [ISRs] are perhaps the most common AEs our patients experience with LA CAB + RPV,” noted Slama. “In CARISEL, 86 percent of patients experienced ISRs, but most [98 percent] were mild-to-moderate in severity. Mean ISR duration was 3 days, and 82 percent of cases resolved within 7 days. Importantly, ISRs tend to occur less frequently over time, which should encourage continued adherence to LA CAB + RPV.” (Figure 2)
“We usually administer CAB injections first, since RPV injections tend to be more painful,” shared Jonsson-Oldenbüttel. “In some patients, applying traditional Chinese medicine patches on the injection site helps relieve some of the discomfort associated with CAB + RPV injections.”
“For patients with higher BMI, we administer the IM injections in the ventrogluteal area, since this is associated with less pain and discomfort,” shared study coordinator in HIV unit, Ms Mireia Santacreu Guerrero of Hospital Universitario 12 de Octubre, Madrid, Spain. “We also recommend using larger needles [ie, 21-guage, 2 inches] for these patients, for optimal IM administration.”
“After the injections, we generally advise patients to remain active and avoid prolonged sitting, since these may help lessen the discomfort associated with injectable LA ART,” Guerrero added. “Oral pain relievers may also be prescribed as needed.”
Healthcare implications of LA ART
“Although LA ART means less frequent dosing vs oral ART, it does require more clinic visits per year,” noted Dr Eric Florence of the Institute of Tropical Medicine in Antwerp, Belgium. “This may increase the burden on healthcare infrastructure, requiring clinics to adapt their services to facilitate the growing demand for LA ART.”
Nevertheless, delivery of LA ART administration services is expected to improve over time. For instance, in the interim analysis of CARISEL, mean appointment duration for LA CAB + RPV injections decreased by 30.4 percent (24.4 minutes) from the first to the sixth month of implementation of LA ART administration services in clinics across Europe. [Hocqueloux L, EACS 2021, abstract PE2/37]
“We are constantly trying to improve LA ART strategies for PLHIV, for example with longer dosing intervals, single-injection formulations, and more convenient routes of administration,” commented Professor Stephane De Wit of the Saint-Pierre University Hospital in Brussels, Belgium. “We hope to transfer these advances to the management of other chronic illnesses in the future.”
Summary
The bimonthly injectable LA CAB + RPV regimen helps simplify ART for PLHIV with demonstrated efficacy and acceptable tolerability in maintaining and achieving virologic suppression for a diverse group of PLHIV. While it may overcome some of the challenges encountered with daily oral ART, implementation of injectable LA ART services requires concomitant healthcare infrastructure changes to accommodate the increasing access and demand for this regimen in PLHIV.
The above editorial is for medical education purpose supported by GlaxoSmithKline Limited.