Injectable treatment just as effective as standard HIV combination in Africa

Injectable treatment with cabotegravir and rilpivirine proved just as effective in maintaining viral suppression as standard oral antiretroviral treatment in a large trial in Africa, despite less intensive viral load monitoring than previous studies, Professor Nicholas Paton of the London School of Hygiene and Tropical Medicine reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2024) in Denver on Monday.

The study is the first test of injectable treatment in people with HIV in Africa. The first injectable regimen, consisting of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine, is already approved for use in Europe and North America. Treatment is given by intramuscular injection at a health facility every two months.

Before cabotegravir and rilpivirine injectable treatment can be provided through treatment programmes in Africa, several questions about its delivery and effectiveness need to be answered. People with HIV in Africa are much more likely to have previous treatment experience with an NNRTI or to have pre-treatment resistance, either of which may compromise the activity of rilpivirine. Also, at least one HIV subtype (A6) is less susceptible to the injectable combination. How effective will cabotegravir and rilpivirine prove to be against the wide range of HIV subtypes and recombinants present in African populations, especially A1?

Another factor that affects response to injectable treatment is body composition. Higher levels of body fat can affect absorption of the drugs when injected into the buttock muscle. Will differences in body fat distribution, especially in women who form the majority of people with HIV receiving treatment in Africa, affect responses to cabotegravir and rilpivirine?

And will an injectable treatment that requires two-monthly clinic visits prove to be feasible and effective in settings where viral load monitoring is less frequent?

The study

The Cabotegravir and Rilpivirine Long-Acting in Africa study (CARES) was designed to test whether the injectable treatment maintained viral suppression as effectively as standard antiretroviral treatment in people with HIV in Africa receiving treatment through a public antiretroviral programme.

The study recruited 512 adults with HIV and suppressed viral load for at least four months on antiretroviral treatment. The study recruited participants in Kenya (162), South Africa (106) and Uganda (244).

Participants were randomised to receive injectable treatment with cabotegravir and rilpivirine every eight weeks (with an optional one-month lead-in of oral treatment) or the standard oral treatment offered in the participating countries (tenofovir disoproxil, lamivudine and either dolutegravir, efavirenz or nevirapine).

The study lasted 96 weeks. Participants underwent viral load testing at week 4, week 24 and every 24 weeks thereafter, and safety laboratory monitoring at weeks 4, 8 (long-acting treatment) or 12 (standard of care), 24 weeks and every 24 weeks thereafter.

The study population was 57% female with a median age of 42 years. Approximately one in five participants (21%) had a body mass index of 30 or above, indicating a potential risk of suboptimal drug absorption. Participants had been taking antiretroviral treatment for a median of eight years, 74% had taken an NNRTI in the past and 92% were taking an integrase inhibitor at the time they volunteered to join the study.

Although participants had no history of treatment failure, analysis of archived viral DNA in peripheral blood mononuclear cells (PBMCs) at baseline showed that 10% had intermediate or high-level resistance to rilpivirine and 8% had intermediate or high-level resistance to cabotegravir.

Ninety-nine per cent of participants were retained in the study and 82% received all their scheduled injections within seven days of the target injection date.

The primary outcome of the study was the proportion of participants who had viral load below 50 copies at week 48. The proportions in each arm with viral load below 50 copies at week 48 were almost identical: 96.9% in the injectable arm and 97.3% in the standard-of-care arm.

One case of confirmed virologic failure was observed at week 48, in a woman with no delayed injections and no baseline resistance mutations. Viral load rose to approximately 8000 copies/ml before resuppression on tenofovir disoproxil / lamivudine / dolutegravir. Resistance testing showed high-level resistance to rilpivirine and intermediate-level resistance to cabotegravir, but no dolutegravir resistance, at the time of viral rebound.

A second unconfirmed case of viral rebound was observed at week 48, in a man with no delayed injections and low-level rilpivirine resistance at baseline. He experienced viral load rebound to 44,000 copies/ml and had low-level resistance to rilpivirine, high-level resistance to cabotegravir and intermediate-level resistance to dolutegravir at the time of rebound. Unfortunately, this participant died of a non-HIV-related cause before resistance investigations were completed.

Three people in the cabotegravir / rilpivirine study arm experienced grade 3 or above adverse reactions that were classified as drug related: an injection-site nodule, increased LDL cholesterol, and proteinuria. Two people in the standard-of-care arm experienced grade 3 or above adverse reactions that were classified as drug related: decreased kidney function (eGFR) and increased blood glucose.

Seventy-three per cent of participants in the injectable treatment arm developed an injection site reaction (10% grade 2 or above).

Just over half of participants expressed satisfaction with their existing treatment at study entry. By week 48, treatment satisfaction had increased by 28% in the injectable arm compared to 17% in the standard-of-care arm, a significant treatment difference of 10% (p<0.001).

Asked why the viral suppression rate was so high, given the archived rilpivirine resistance and high proportion of participants with subtype A1 virus, Professor Paton said that more work is needed to understand the relationship between archived resistance and treatment response to cabotegravir and rilpivirine. He said that although they had been concerned that subtype A1 might prove less susceptible to cabotegravir in the same way as subtype A6, the results of the study show that subtype A1 is sufficiently different from A6 to be susceptible to cabotegravir.

“This is a great study to show that it is [subtype] A6, not A1” that has a reduced response to cabotegravir, commented Professor Jonathan Schapiro of the National Hemophilia Center, Israel.

The findings of CARES are an “essential first step in discussing the role of injectable cabotegravir and rilpivirine,” said Paton, “but there are so many things we need to do before this would translate into a World Health Organization public health recommendation.”

As for who injectable treatment might be suitable for in African treatment programmes, “you have a public health approach to treatment that people really want”. Apart from people with hepatitis B, “it is hard to see who wouldn’t be eligible,” Professor Paton told a question-and-answer session after his presentation.