CROI 2024: Promising results from first study of long-acting treatment in Africa
10 March 2024. Related: Conference reports, Antiretrovirals, Treatment access, CROI 2024 Denver.
Polly Clayden, HIV i-Base
HIV treatment with long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) was non-inferior to standard oral ART at week 48, using a public health approach with sparse viral load monitoring in settings where pre-existing RPV resistance, subtype A1 virus and obesity are common.
These findings from the CARES study, conducted in three African countries, were presented at CROI 2024.
LA injectable treatment with CAB + RPV is approved for monthly and two-monthly dosing and is recommended in treatment guidelines for high-income countries as maintenance for people with virologic suppression.
Additional evidence (and much access and programmatic work) is needed before this regimen can be used in treatment programmes in Africa, where:
- The majority of people with HIV are Black African women
- HIV-1 subtypes are different
- High levels of NNRTI exposure and pre-treatment resistance
- Care and treatment strategies are simpler with less frequent viral load and safety monitoring
The aim of the study was to assess non-inferiority of switching virologically suppressed adults to LA CAB + RPV every 8 weeks vs continuing with oral standard of care (SOC) in an African population, managed using a public health approach.
CARES (Cabotegravir and Rilpivirine Long-Acting in Africa study ) is an ongoing 96-week phase 3b randomised, multicentre, open-label trial evaluating efficacy, safety, and tolerability of switching from oral ART to LA CAB + RPV.
Adults with HIV, stable on first-line oral ART with viral load <50 copies/mL at screening were enrolled at eight African sites. Exclusion criteria were past virologic failure, pregnancy and HBV infection.
Participants were randomised (1:1) to continue oral ART or switch to CAB (600 mg) and RPV (900 mg) intramuscular injections every 8 weeks. Viral load was monitored at week 4, week 24 and then every 24 weeks . Laboratory monitoring was at weeks 4, 8 (LA) or 12 (SOC), 24 weeks and then every 24 weeks. Resistance testing was done retrospectively on archived DNA at baseline in all participants, and at confirmed virologic failure.
The primary outcome was the proportion of participants with viral load <50 copies/mL at week 48, (FDA snapshot algorithm; non-inferiority margin 10%). Confirmed virologic failure was defined as two consecutive viral load >200 copies/ mL.
The study enrolled 512 participants in Uganda (47.7%), Kenya (31.6%) and South Africa (20.7%). Retention was high, 99% at week 48; 82% received all their scheduled injections within the protocol-mandated seven day window.
Overall, 58% of participants were women, with a median age of 42 years, 21% had BMI >30 kg/m2, and over 99% were of Black ethnicity. The median duration of treatment was 8 years, 92% were on dolutegravir (DTG)-based ART, 74% had prior NNRTI exposure and 57% were viral subtype A1.
Archived viral DNA in PBMCs at baseline revealed that 10.1% of participants had intermediate or high-level resistance to RPV and 8.3% had intermediate or high-level resistance to CAB.
Four participants withdrew by week 48 (2 in each group). At 48 weeks, 97.3% in the LA and 98.1% in the SOC group had viral load <50 copies/mL, adjusted difference (ITT) -0.5% (95% CI -3.4 to 2.4), meeting the non-inferiority criterion.
There was one confirmed virologic failure at week 48 in the LA group. This participant was a woman with no delayed injections and no baseline INSTI or NNRTI resistance. Her viral load was 8608 copies/mL. She had high-level resistance to RPV and intermediate resistance to CAB, and no dolutegravir resistance at rebound. She resuppressed on TDF/3TC/DTG.
At the same time point, and also in the LA group, there was a second unconfirmed case of virologic failure in a man with no delayed injections and low-level RPV resistance at baseline. His viral load was 44,984 copies/mL and he had low-level resistance to RPV, high-level resistance to CAB and intermediate-level resistance to DTG. This participant died before re-test of a non-HIV-related cause.
Adverse events of grade 3 and above occurred in 24 (9%) in LA and 10 (4%) in SOC group. Only one adverse event in the LA group led to treatment discontinuation (injection-site sterile abscess).
Three participants in the LA group had grade 3 or above adverse reactions that were considered drug-related (injection-site nodule, increased LDL cholesterol and proteinuria).
In the SOC group, two participants had grade 3 or above adverse reactions that were considered drug related (eGFR and increased blood glucose).
Sixty-three per cent of participants in the LA group had a grade 1 injection site reaction and 10% grade 2 or above.
At baseline, 53.6% and 52% of participants reported satisfaction with their treatment, in the LA and SOC groups respectively. At week 48, this had increased by 28% vs 17% in the respective groups: adjusted mean difference 10.4% (p<0.001).
comment
These results are impressive and in the Q&A after the session, presenting author, Nick Paton was asked why he thought this was the case considering the high proportion of participants with AI subtype and archived RPV (which might have translated to around 20% failure with A6 subtype). He said that more work needs to be done to better understand the roles of resistance and subtypes. It was noted that it appears A6 has a poorer response to CAB not A1.
He described the CARES results as “the essential first step to discussing a role for LA in treatment programmes in sub-Saharan Africa using the public health approach” but rightly remarked that there are many things that need to be done before LA treatment could become a WHO recommendation.
There appears to be strong demand for LA treatment and many could be eligible for CAB + RPV, if it were available, with the notable exception of people with hepatitis B.
But after this essential first step, there is a very long way to go. Treatment programmes in low- and middle-income countries (LMICs) have been designed around daily oral pills which can be given multi-monthly, reducing health facility visits. LA CAB + RPV require 8-weekly IM injections, which mean more visits and health worker time. As well as this it requires a cold chain.
To date it has been difficult to get drug for treatment studies and implementation research, which currently is only available from the originator manufacturers.
But in July 2022 ViiV healthcare and the Medicines Patent Pool signed voluntary licence agreements for CAB-LA (for prevention) with three generic manufacturers. And ViiV announced a non-profit price of $30 per vial in November 2023. Prevention programmes using CAB are slowly starting. Zambia is the first African country to launch a CAB-LA programme, with PEPFAR donated vials, starting February of this year.
Whether LA CAB + RPV will end up being used widely as treatment in LMICs remains to be seen.
Would ultra long-acting (ULA) CAB with 4-monthly interval, subcutaneous injection and no cold chain requirement (currently under development) and or combining with lenacapavir (no studies yet) make LA treatment in LMICs more feasible – if they were available?
Currently there are many, many questions and data gaps but as Professor Paton said these CARES results are an important first step.
Reference
Kityo CM et al. Randomised trial of cabotegravir and rilpivirine long-acting in Africa (CARES): Week 48 results. CROI 2024. Denver, Colorado. 3–6 March 2024. Oral abstract 122.
https://www.croiconference.org/abstract/randomized-trial-of-cabotegravir-and-rilpivirine-long-acting-in-africa-cares-week-48-results (abstract)