Long-acting injectable treatment with cabotegravir and rilpivirine did not result in a higher rate of viral rebound, a study in the Netherlands shows.
But looking at five cases of viral rebound in the Dutch cohort, investigators observed the development of high-level drug resistance to one or both injectable agents that could seriously limit future treatment options.
The findings were presented last week at the 19th European AIDS Conference (EACS 2023) in Warsaw.
Long-acting cabotegravir (Vocabria) and rilpivirine (Rekambys) is the first long-acting injectable treatment for HIV. It was approved in the European Union in 2020 for treatment of people with supressed viral load.
The ATHENA cohort is a national study following almost everyone in HIV care in the Netherlands. Dr Vita Jongen reported on the outcomes of 619 ATHENA participants who had switched to long-acting injectable treatment up to September 2023. People who switched were eligible for inclusion in the analysis if they had no history of treatment failure (viral load above 200 copies/ml) prior to switching.
Each person who switched was matched with two cohort members who had not switched treatment to assess the risk of treatment failure. Switchers were matched by age, gender, HIV exposure category, CD4 count, duration of antiretroviral treatment, anchor drug in their previous regimen and timing of most recent clinical visit. Fifty-three per cent of the control group were taking an integrase inhibitor, 27% a non-nucleoside reverse transcriptase inhibitor (NNRTI), 5% a protease inhibitor and 16% were taking a two-drug regimen.
Those who switched treatment had a median age of 44 years; the median age of the control group was 46 years. Ninety per cent in both groups were male, 76% were gay or bisexual men and had been taking antiretroviral treatment for a median of 8.7 years. The median CD4 count was 730 in the switch group and 770 in the control group. People who switched were more often clinically obese (BMI> 30kg/m2) than those in the control group (15% vs 11%), which is of interest as higher body mass is one factor that may reduce the effectiveness of injectable cabotegravir and rilpivirine.
Of the 619 people who switched, 588 had more than one clinic visit during a median follow-up period of 0.7 years. Fifty-eight people (9%) discontinued injectable treatment during the follow-up period.
There was no significant difference in the rate of virological failure between people who switched to injectable treatment (0.9%) and the control group (1.8%).
Two people in the injectable treatment group experienced virological failure with the development of multi-drug class resistance.
Three people experienced viral rebound above 200 copies, but their viral load was subsequently resuppressed without any change in treatment. It is unclear if these cases of viral rebound occurred due to incorrect injection technique but analysis of drug concentrations showed that they were sufficient to suppress HIV in both cases.
Dr Annemarie Wensing of University Medical Center Utrecht reported on five cases of virological failure that have occurred in the Netherlands. None had experienced previous treatment failure and they had been taking antiretroviral treatment for between three and 18 years.
The treatment failures occurred in three men and two women, one transgender. All five received their injectable treatment at the specified two-monthly intervals. Two out of five had a single pre-existing risk factor for failure of long-acting cabotegravir and rilpivirine (body mass index above 30).
Viral rebound occurred between three and 13 months after switching. The earliest rebound occurred three months after switching in a man who did not receive the one-month oral lead-in recommended when injectable cabotegravir and rilpivirine was first approved in Europe. Oral lead-in is designed to minimise the risk of liver toxicity. In this case, viral load rebounded to 830,000 copies and the man had detectable resistance to rilpivirine. He also had the 179D mutation associated with resistance to the NNRTI etravirine at the time of HIV diagnosis but no evidence of rilpivirine resistance at the time he switched.
In a second case, viral load eventually rebounded to 610,000 copies after a first detectable measure of 260 copies. This patient developed cross-class resistance to integrase inhibitors and NNRTIs.
In each case of virological rebound, levels of at least one drug were found to be suboptimal, although further investigation of the relationship between drug concentrations and treatment failure is needed.
Looking for explanations of viral rebound despite adherence to treatment, the study investigators say that some individual characteristics may have affected treatment response. In the transgender woman who experienced rebound after nine months of injectable treatment, substantial weight gain may have affected drug levels, as her body mass index increased from 29 to 33.5kg/m2 after the switch to cabotegravir/rilpivirine. This weight gain was probably a consequence of the hormonal treatment supporting gender transition, Dr Wensing said. In another patient with a very high body mass index (45.5kg/m2), a longer-than-usual needle was used in an attempt to ensure that injections reached muscle tissue.
But in all cases, treatment failure led to extensive cross-resistance and loss of future treatment options, as well as considerable shock for the people taking treatment and their healthcare team.
Dr Catia Marzolini, a clinical pharmacologist at the University of Basel, noted that viral rebound occurred fastest in the patients with high body mass index, suggesting the need for drug concentration testing for some patients during the early months of treatment.
In patients failing injectable treatment “we see huge inter-individual variability and we really need to understand what are the factors that could potentially lead to low levels and what is the clinical relevance [of low levels]," said Dr Marzolini. "I think it’s useful for those that can measure, to measure, so that we have enough data to understand what is going on. We are talking about treatment, but we also need to think about cabotegravir in PrEP.”
Jessy Duran Ramirez of the University of Zurich reported on the outcomes of 264 people who switched to injectable treatment in the Swiss HIV Cohort.
Less than 3% of participants in the Swiss HIV Cohort study have switched and the rate of switching has declined substantially over the past year. Only a small proportion of those who switched had a history of adherence difficulties (17%).
A questionnaire study of attitudes to long-acting injectable treatment in 228 consecutive patients seen at three Swiss HIV clinics found high satisfaction with oral antiretroviral treatment and concern that the two-monthly injection interval would lead to a loss of freedom. More people would be interested in switching to injectable treatment if a six-monthly injection interval was available, the study found.
Those who chose to switch to injectable treatment had a median age of 48 years, 82% were male, 64% were gay or bisexual men, 71% were White and 51% had a university degree or higher education. They had been taking antiretroviral treatment for a median of ten years.
Eight of the 264 people who switched to injectable treatment discontinued it for a variety of reasons. Two experienced adverse drug reactions, one had low rilpivirine blood concentrations, four discontinued for non-treatment-related reasons and one discontinued due to virological failure (two viral load measurements above 50 copies/ml).
A single-clinic UK study also found that not all people eligible for long-acting injectable treatment wanted to switch from oral treatment once they had discussed the implications of doing so with a doctor. British HIV Association guidelines recommend that people with HIV should be evaluated for long-acting injectable treatment if they have suppressed viral load and experience difficulties with pill taking. In Brighton, 160 people were reviewed for eligibility, 52 were ineligible (mainly due to resistance, viraemia or drug interactions), 57 (36%) declined a switch in treatment and 51 started long-acting injectable treatment, all of whom remain virally suppressed. Among those who declined, the main reasons were a lack of readiness to switch (20), satisfaction with their current regimen (7), concerns about the injection schedule (14) and concerns about the failure rate of injectable treatment (8).
Update: This article was amended on 1 November 2023 to correct the number of people who started long-acting injectable treatment (51 instead of 33).
Jongen V et al. Effectiveness of injectable long-acting cabotegravir and rilpivirine for the treatment of HIV-1: results from the Dutch ATHENA national observational cohort. 19th European AIDS Conference, Warsaw, abstract PS8.03, 2023.
Wensing A et al. Failure following switch from long-term suppressive oral ART to long-acting cabotegravir/rilpivirine injections. 19th European AIDS Conference, Warsaw, abstract PS8.01, 2023.
Duran Ramirez J et al. Uptake and discontinuation of the long-acting duo in the Swiss HIV Cohort Study: preliminary analysis on cabotegravir plus rilpivirine. 19th European AIDS Conference, Warsaw, abstract PS8.02, 2023.
Martin Y et al. Who wants to switch to injectables? Patients’ preferences, perceptions and knowledge in the Swiss HIV Cohort Study. 19th European AIDS Conference, Warsaw, abstract eP.A.045, 2023.
Roberts J et al. A shot in the dark: a review one year on after initiation of injectable HIV treatment in a UK HIV outpatient clinic. 19th European AIDS Conference, Warsaw, abstract eP.A.012, 2023.