Addressing unmet needs in HIV treatment with an injectable long-acting combination maintenance therapy

Prof. Chloe Orkin
Queen Mary University of London
Dr. Maggie Czarnogorski
Washington DC VA Medical Center
Washington, US
Dr. Gary Sinclair
PrismHealth North Texas
Texas, US
08 Sep 2021
While the global response against HIV in the last two decades is widely regarded as a success, the epidemic is far from over and many challenges remain in the management of people living with HIV (PLHIV). At the International AIDS Society 2021 Conference, experts shared updates on maintenance therapy for PLHIV, with particular emphasis on long-acting (LA) combination antiretroviral therapy (ART) and strategies for its implementation.

Daily oral antivirals: Physical, psychosocial and emotional challenges

Daily ART has been the mainstay of treatment for PLHIV for more than 30 years, with advances in ART leading to reduction in morbidity and mortality. Despite this, many challenges remain, notably in terms of high pill burdens, adherence, stigma, and development of resistance. [Br J Clin Pharmacol 2015;79:182-194]  

Daily oral ART, in particular, is associated with challenges such as difficulty in swallowing pills and stress from daily dosing routine. Many patients have reported disguising or hiding their HIV medicines to avoid revealing their HIV status, or having missed some doses of their medications due to lack of privacy. [AIDS Behav 2021;25:961-972] 

“A monthly or bimonthly dosing regimen of cabotegravir [CAB] and rilpivirine [RPV] – the first complete injectable LA regimen recommended by treatment guidelines for maintenance of virologic suppression in PLHIV – may address some of the challenges associated with daily oral ART,” said Professor Chloe Orkin of the Queen Mary University of London, UK. [Panel on Antiretroviral Guidelines for Adults and Adolescents, Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV; JAMA 2020;324:1651-1669]

The phase III ATLAS study previously showed that monthly LA CAB plus RPV was noninferior to daily standard oral therapy in PLHIV who had been receiving ART for at least 6 months without virologic failure. Similarly, the FLAIR study showed that over 96 weeks, monthly LA CAB plus RPV was noninferior to the daily single-tablet regimen of dolutegravir/abacavir/ lamivudine (DTG/ABC/3TC) for maintenance of viral suppression in ART-naïve PLHIV who had received 20 weeks of induction therapy with the single-tablet regimen of DTG/ABC/3TC. [Lancet HIV 2021;8:e185-e196]

“At week 124, monthly LA CAB plus RPV continued to maintain high levels of virologic suppression [HIV-1 RNA<50 copies/mL] in 80.2 percent of patients, with only an additional 1.8 percent of patients having HIV-1 RNA ≥50 copies/mL since the week 96 analysis,” noted Orkin. (Figure 1) “The safety and tolerability profile at week 124 was consistent with that at weeks 48 and 96, and injection site reactions [ISRs] were mostly mild or moderate in severity and decreased over time. These results demonstrate the durability of monthly LA CAB plus RPV as a well-tolerated and effective maintenance therapy for PLHIV.” [Orkin C, et al, IAS 2021, abstract OAB0302]


Few patient-reported barriers to implementation of monthly LA CAB plus RPV
“To achieve optimal health outcomes with the novel combination of monthly LA CAB plus RPV, it is necessary to understand how the implementation of the regimen can be best supported in routine clinical care,” said Dr Maggie Czarnogorski of Washington DC VA Medical Center, US.

The phase IIIb, hybrid III implementation-effectiveness CUSTOMIZE study examined the barriers to, facilitators of, and effective strategies for successful implementation of the LA CAB plus RPV injectable regimen in US clinical practice settings.

“In the CUSTOMIZE study, patients treated with monthly LA CAB plus RPV and healthcare staff [including physicians, nurses and administrators] from eight clinics across the US were invited for surveys and interviews,” noted Czarnogorski. “Patients and healthcare staff felt that LA CAB plus RPV was acceptable, appropriate and feasible to implement across different clinic types, including federally qualified health centres [FQHCs], private practices, AIDS Healthcare Foundation [AHF] clinics, university practices and health maintenance organizations [HMOs]. [Czarnogorski M, et al, IAS 2021, abstract OAD0705]

Most (78.3 percent) healthcare staff reported that optimal implementation of the LA CAB plus RPV regimen was achieved within 1–3 months, with no differences in time to optimal implementation across all types of healthcare staff. Good communication about dosing window, effective appointment reminder systems, and designated staff for appointment tracking were reported by healthcare staff as key implementation strategies for treatment adherence among patients. “Key strategies for successful clinic implementation were good staff communication, teamwork, and use of a web-based treatment planner,” said Czarnogorski. [Czarnogorski M, et al, IAS 2021, abstract OAD0705]  

At baseline, patients’ ability to keep monthly appointments, obtain transportation and flag missed visits were the most common concerns reported by healthcare staff. “All barriers to implementation, as perceived by healthcare staff, substantially decreased by month 12 except for patients' injection pain or soreness,” noted Czarnogorski. “In fact, injection pain or soreness was the most frequently reported [15 percent] factor that interfered with patients’ ability to receive injections. Seventy-four percent of patients reported no barrier against receiving LA CAB plus RPV injections and overall, patients reported fewer concerns with receiving LA CAB plus RPV injections compared with healthcare staff at month 12.” (Figure 2) [Czarnogorski M, et al, IAS 2021, abstract OAD0705]


LA CAB plus RPV preferred by patients during COVID-19 pandemic
“Because CUSTOMIZE commenced in July 2019 and continued during and after March 2020 when much of the US began coronavirus disease 2019 [COVID-19] pandemic–related closures, a separate analysis was carried out to evaluate the impact of the pandemic on LA CAB plus RPV implementation outcomes,” said Czarnogorski.

The analysis reported that at 12 months, 87 percent of all participants and 95 percent of participants with COVID-19–impacted visits found monthly clinic visits “very or extremely acceptable”. In addition, 92 percent of all participants and 95 percent of those with COVID-19–impacted visits preferred LA CAB plus RPV injection over daily oral therapy. [Czarnogorski M, et al, IAS 2021, abstract PED463]  

“Despite the healthcare disruptions caused by the pandemic, results of the CUSTOMIZE study suggest that LA CAB plus RPV continued to be an appealing treatment option from the perspective of both healthcare providers and PLHIV,” noted Czarnogorski.

Monthly LA CAB plus RPV maintains virologic suppression through month 12
“In CUSTOMIZE, CAB plus RPV therapy was initiated with a 1-month oral lead-in with CAB 30 mg plus RPV 25 mg to assess individual tolerability before transitioning to monthly LA CAB 400 mg plus RPV 600 mg intramuscular injections,” said Dr Gary Sinclair of PrismHealth North Texas, US. “At month 12, virologic suppression [HIV-1 RNA <50 copies/mL] was maintained in 88 percent of patients, and none had HIV-1 RNA ≥50 copies/mL. No confirmed virologic failures occurred through month 12.” (Figure 3) [Czarnogorski M, et al, IAS 2021, abstract OAD0705]


Through month 12, 94 percent of expected injection visits occurred within the allowable 7-day dosing window, while <1 percent of missed visits were due to the COVID-19 pandemic, all of which were covered with oral CAB plus RPV therapy without treatment disruption.  

While ISRs were frequent, most (96 percent) were mild or moderate in severity and decreased after the first injection. “Other commonly reported adverse events included arthralgia [14 percent], diarrhoea [14 percent], fatigue [12 percent] and headache [11 percent],” said Sinclair. “In conclusion, 12-month clinical outcomes from the CUSTOMIZE implementation-effectiveness study provide support for the use of monthly LA CAB plus RPV as an effective and well-tolerated treatment option preferred by PLHIV.” [Sinclair G, et al, IAS 2021, abstract PED416]
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