Long-acting ART effective in and preferred by PLHIV

Cabotegravir (CAB) plus rilpivirine (RPV) is currently the only long-acting (LA) injectable antiretroviral therapy (ART) recommended for people living with HIV (PLHIV) who have achieved viral suppression with oral medications. At the 30^th Conference on Retroviruses and Opportunistic Infections (CROI 2023) in Seattle, Washington, US, Dr Moti Ramgopal of the Midway Immunology and Research Center in Fort Pierce, Florida, US, presented 12-month results of the SOLAR (Switch Onto Long-Acting Regimen) study, which demonstrated the efficacy, safety and improved patient satisfaction of LA CAB + RPV in PLHIV vs daily oral ART.

SOLAR study: Background and study design
“CAB + RPV is the first and only complete LA injectable regimen currently recommended by international guidelines for maintenance of virologic suppression in PLHIV,” said Ramgopal. [JAMA 2020;324:1651-1669; https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-andadolescent-arv; www.eacsociety.org/media/final2021eacsguidelinesv11.0_oct2021.pdf; JAMA 2023;329:63-84]

“Compared with daily oral ART, LA CAB + RPV is administered less frequently [ie, every 2 months (Q2M)], which may help overcome some of the challenges associated with daily oral ART, including PLHIV’s psychosocial concerns such as fear of disclosure of their disease, stigma, anxiety around medication adherence, and the daily reminder of their HIV status,” he continued. [Open Forum Infect Dis 2019;6(Suppl 2):S481]

“These challenges may impact the health-related quality of life [QoL] of PLHIV,” he commented. “Beyond viral suppression, improving QoL has become an important consideration for choosing the most appropriate ART in PLHIV. The more convenient Q2M dosing of LA CAB + RPV may be uniquely suited to support the health-related QoL goals of PLHIV.” [https://www.unaids.org/sites/default/files/media_asset/90-90-90_en.pdf; BMC Med 2016;14:94; JAMA 2023;329:63-84]

The phase IIIb SOLAR study is the first large, head-to-head comparison of LA CAB + RPV injections dosed Q2M vs the daily oral regimen of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). It was a randomized, open-label, multicentre, noninferiority study that investigated the efficacy, safety and patient-reported outcomes (PROs) of switching from oral BIC/FTC/TAF QD to intramuscular (IM) injections of LA CAB (600 mg) + RPV (900 mg) Q2M vs continuing with BIC/FTC/TAF in adult patients ≥18 years of age with virologically suppressed HIV (ie, HIV-1 RNA <50 copies/mL for ≥6 months prior to and at screening; n=670). In consultation with their provider after randomization, patients who received LA CAB + RPV were given the option of an oral lead-in with CAB + RPV or to start with the IM injections upon switching. (Figure 1) [Ramgopal MN, CROI 2023, abstract OA-12]

The primary endpoint was the proportion of patients with plasma HIV-1 RNA ≥50 copies/mL (ie, virologic nonresponse). Secondary endpoints included the proportion of patients with HIV-1 RNA <50 copies/mL (ie, virologic success), incidence of confirmed virologic failure (CVF; two consecutive measures of HIV-1 RNA ≥200 copies/mL), safety, tolerability, treatment satisfaction (HIV Treatment Satisfaction Questionnaire status version scores [HIVTSQs]), and patient preference.

The primary analysis was based on the modified intention-to-treat exposed (mITT-E) population. Study endpoints were assessed at month 12 (ie, month 11 for those who received IM injections upon switching and month 12 for those who received the oral lead-in or continued with BIC/FTC/TAF).

SOLAR study: 12-month results
After screening, 447 patients were randomly switched to LA CAB + RPV Q2M, while 223 patients continued with BIC/FTC/TAF daily oral therapy (mITT-E population).

“Approximately 60 percent of patients who received LA CAB + RPV chose to start with the injections, and around 40 percent opted for an oral-lead in period,” said Ramgopal. (Figure 1)

In both treatment groups, the median age of the patients was approximately 37 years, and about 20 percent were female. Most patients had been on ART for approximately 2.5 years.

Efficacy endpoint results
The study met its primary endpoint at month 12, when LA CAB + RPV Q2M demonstrated noninferior efficacy vs daily oral BIC/FTC/TAF based on the proportion of patients with HIV-1 RNA ≥50 copies/mL using the US FDA Snapshot algorithm and a 4 percent noninferiority margin (mITT-E; LA CAB + RPV, 5/447 [1 percent]; BIC/FTC/TAF, 1/223 [<1 percent]; adjusted difference, 0.7 percent; 95 percent confidence interval [CI], -0.7 to 2.0). Rates of virologic suppression were also similar between the treatment arms (LA CAB + RPV, 403/447 [90 percent]; BIC/FTC/TAF, 207/223 [93 percent]; adjusted difference: -2.7 percent; 95 percent CI, -7.0 to 1.7). (Figure 2) Noninferior virologic outcomes were also confirmed in the ITT-E and per protocol analyses.

“CVF was infrequent, but did occur in three patients in the LA CAB + RPV group and none in the BIC/FTC/TAF group,” Ramgopal explained. “Importantly, two of these patients had on-treatment RPV and/or integrase inhibitor resistance–associated mutations. All three patients subsequently achieved virologic suppression on an alternative ART regimen.”

Safety results
Both treatment regimens were generally well tolerated. The most commonly reported drug-related adverse events (AEs) in the LA CAB + RPV arm were pyrexia (3 percent), headache (2 percent), fatigue (2 percent) and diarrhoea (2 percent). In the BIC/FTC/TAF arm, the two drug-related AEs were weight gain (<1 percent) and abnormal hepatic function (<1 percent).

“More patients who received LA CAB + RPV vs BIC/FTC/TAF experienced AEs that led to study withdrawal [4 percent vs <1 percent],” noted Ramgopal.

“Since LA CAB + RPV are administered via an IM route, injection-site reactions [ISRs] were expected,” he continued. “However, most ISRs [eg, pain, discomfort and nodules] were mild [grade 1/2, 98 percent] and of short duration [median, 3 days], and few patients discontinued treatment due to injection-related reasons [n=11/445; 2 percent].”

Beyond viral suppression: Patient satisfaction and preferences
At baseline, 47 percent (n=315/670) of patients who were virologically suppressed while receiving BIC/FTC/TAF “always/often” reported at least one of these psychosocial challenges: Worries about people unintentionally discovering their HIV status; worries about forgetting their HIV medication; feeling that taking their HIV medication was an uncomfortable reminder of their HIV status.

Compared with patients who continued with BIC/FTC/TAF, mean HIVTSQ of those who switched to the LA regimen significantly improved from baseline (BIC/FTC/TAF, 58.38; LA CAB + RPV, 57.88) at month 6 (BIC/FTC/TAF, -0.40; LA CAB + RPV, +3.86; adjusted mean difference, 4.26; 95 percent CI, 3.02–5.49; p<0.001) and month 12 (BIC/FTC/TAF, -1.59; LA CAB + RPV, +3.36; adjusted mean difference, 4.95; 95 percent CI, 3.59–6.31; p<0.001). These results demonstrate greater and continued improvements from baseline in HIV treatment satisfaction for patients who switched to LA CAB + RPV from BIC/FTC/TAF.

“Importantly, among patients who switched to LA CAB + RPV and completed the survey [n=425], up to 90 percent preferred the LA therapy vs daily oral pills [n=382/425],” noted Ramgopal. The most common reasons for preferring the LA regimen vs daily oral ART are enumerated in Figure 3.

Conclusions
Results of the SOLAR study demonstrate that LA CAB + RPV administered Q2M is well tolerated and as effective as daily oral BIC/FTC/TAF in maintaining virologic suppression in adult PLHIV. Importantly, switching from BIC/FTC/TAF to LA CAB + RPV significantly improved patient satisfaction and was preferred by a majority of patients who switched to this regimen, addressing some of the important issues associated with daily oral HIV treatment.

“These findings demonstrate that beyond standard efficacy and safety data, patient preferences should also be considered, especially since important psychosocial issues associated with daily oral ART have been reported by PLHIV,” stressed Ramgopal. “LA CAB + RPV Q2M may offer an important alternative for PLHIV who want to overcome some of the challenges associated with daily oral pill intake.”