Integrase inhibitor resistance after treatment failure more common in treatment-experienced people
Keith Alcorn, reporting from HIV Glasgow, 15 November 2024
A study of people who experienced failure of an antiretroviral regimen containing bictegravir, cabotegravir or dolutegravir has found that just over one in four had major resistance mutations associated with resistance to at least one integrase inhibitor. Resistance was most likely to develop in people who had taken previous antiretroviral regimens, Dr Mafalda Miranda of the University of Utrecht reported at HIV Drug Therapy Glasgow 2024 this week.
Clinical trials of the second-generation integrase inhibitors – bictegravir, cabotegravir or dolutegravir – found that resistance to the drugs after treatment failure did not develop in previously untreated people. But, although the failure rate of integrase inhibitor-based treatment is remarkably low, the incidence of drug resistance and the resistance profile of the drugs in everyday clinical use are uncertain. Four people with HIV in every five receive treatment with an integrase inhibitor (predominantly dolutegravir), Professor Anton Pozniak of London’s Chelsea and Westminster Hospital told the conference. The majority are receiving treatment in countries where resistance testing after the failure of an antiretroviral regimen is not routine and where national surveillance of drug resistance is either non-existent or limited.
The World Health Organization’s HIV Drug Resistance Report, issued earlier this year, found that just under 5% of people with detectable HIV on an integrase-containing regimen had integrase inhibitor resistance in higher- and middle-income countries. PEPFAR studies of people receiving integrase inhibitors in low- and middle-income countries have found that anywhere from 4% to 19% of people with detectable HIV on an integrase-containing regimen had integrase inhibitor resistance.
Professor Dan Kuritzkes of Harvard Medical School, reviewing what is known about global patterns of integrase inhibitor resistance, explained that current estimates of the frequency of resistance are imprecise because studies are measuring different things, with sampling at different intervals after treatment failure and inconsistent definitions of the treated population.
Dr Mafalda Miranda of the University of Utrecht presented findings from the ROSETTA study, a registry that gathers reports of virological rebound on a regimen containing a second-generation integrase inhibitor (bictegravir, cabotegravir or dolutegravir) from patients in Europe, Africa and the Americas. Resistance tests are done on samples gathered at the time of treatment failure. The study aimed to define what proportion of people experiencing failure of a regimen containing an integrase inhibitor developed resistance, the patterns of resistance, and the risk factors for developing resistance.
The first analysis from the study contains data on the first 125 samples reported to the registry since September 2023. Most of those experiencing treatment failure were male (74%) and undergoing treatment in Europe (41%) or the Americas (55%). They had been taking antiretroviral treatment for a median of 23 months and a second-generation integrase inhibitor for a median of eight months at the time treatment failure was identified. Eighty-nine percent were taking dolutegravir, 8% bictegravir and 3% cabotegravir at the time of virological failure. The median viral load at the time treatment failure was identified was 4 log10 copies/ml (interquartile range 3.10-4.94 log10 copies/ml). Major integrase resistance mutations associated with integrase inhibitor resistance in the IAS-USA database were detected in samples from 33 of the 125 individuals (26%).
Resistance was associated with a longer duration of treatment with a second-generation integrase inhibitor (13 vs 8 months, p< 0.001), previous exposure to antiretroviral therapy (39% of those exposed had resistance vs 10% of those unexposed, p<0.001) and previous exposure to the first-generation integrase inhibitors raltegravir or elvitegravir (50% of those exposed had resistance vs 21% of those unexposed, p=0.004).
Viral load was not significantly associated with the presence of resistance mutations, and resistance was detected in seven people with viral loads below 1000 copies/ml at the time of failure. However, people with higher-level resistance scores (>60) tended to have higher viral loads at the time of detection of treatment failure.
Major integrase resistance mutations were detected more often in those who developed resistance after exposure to more than one antiretroviral regimen, especially if they had been treated with a first-generation integrase inhibitor in the past. Two mutations – 118R and 263K – only appeared in those who had not been treated with a first-generation integrase inhibitor, suggesting that the resistance pathways of different integrase inhibitors are distinct. But Dr Andrew Hill of Liverpool University cautioned against jumping to conclusions about the clinical implications of resistance mutations. “We are still at an exploratory phase in knowing which mutations will lead to someone never being able to take dolutegravir or bictegravir again, and which mutations we could treat through and get people resuppressed on,” he told the conference.
Reference
Miranda MNS et al. Clinical features and resistance patterns during second-generation INSTI failure: the ROSETTA-registry. HIV Glasgow 2024, oral abstract O31.
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Reporting from HIV Glasgow 2024 by Keith Alcorn, Gus Cairns and Roger Pebody has been financially supported by the Congress. The writers are editorially independent of the Congress and the presenting speakers.
Photo credit: Alan Donaldson Photography