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Multiclass Resistance to Antiretrovirals Waning in Europe
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18th European AIDS Conference, EACS 2021, October 27-30, 2021, London
Mark Mascolini
Rates of resistance to 3 or 4 antiretroviral classes peaked around the year 2005 and fell through 2019, according to analysis of the EuResist database in Italy, Germany, Sweden, Luxembourg, Spain, Portugal, and Belgium [1]. But the authors warned that certain drivers of multidrug resistance-like highest pretreatment viral load and lowest CD4 count-remain in people taking antiretrovirals.
Definitions of multidrug resistance have evolved with the changing availability of antiretroviral classes. In the current integrase inhibitor era, multidrug resistance usually means resistance to at least one antiretroviral in three or four of the main antiretroviral classes (sometimes plus enfuvirtide or maraviroc).
According to a previous EuResist analysis, prevalence of 4-class resistance in antiretroviral-experienced people in Europe fell from about 7% in 2008 to about 2.5% in 2019 [2]. That study defined 4-class resistance as at least intermediate resistance to at least one nucleos(t)ide (NRTI), nonnucleoside, protease inhibitor, or integrase inhibitor.
The new EuResist analysis aimed to update findings on 3-class resistance in 1996-2019 and 4-class resistance in 2008-2019 in Italy, Germany, Sweden, Luxembourg, Spain, Portugal, and Belgium. The researchers defined class resistance as at least one drug in the class with intermediate or high-level resistance according to the Stanford HIV database 8.9-1. They based resistance to NRTIs, nonnucleosides, and protease inhibitors on genotype, while they defined resistance to integrase inhibitors by genotype or integrase inhibitor therapy based on circumstances assumed to indicate emergent resistance to an integrase inhibitor.
Among 39,956 people in the 3-class analysis, 3-class resistance developed in 2768 (6.9%). Prevalence of 3-class resistance peaked at 10% in 2005, while incidence reached its zenith of 2.7% in the same year. Among 16,019 people in the 4-class resistance analysis, 4-class resistance arose in 291 (1.8%). At the end of the study period, prevalence and incidence of 4-class resistance lay well below 1%.
Multivariable analysis identified six variables independently associated with 3-class resistance at the following adjusted odds ratios (aOR) and 95% confidence intervals (CI):
- Subtype B HIV-1: aOR 1.38, 95% CI 1.04 to 1.85, P = 0.030
- Male gender: aOR 1.52, 95% CI 1.27 to 1.83, P < 0.001
- Highest viral load: aOR 1.08, 95% CI 1.04 to 1.11, P < 0.001
- Number of virologic failures: aOR 1.24, 95% CI 1.18 to 1.32, P < 0.001
- Number of therapeutic regimens: aOR 1.02, 95% CI 1.02 to 1.02, P < 0.001
- Year of first treatment: aOR 0.97, 95% CI 0.95 to 1.00, P = 0.037
Seven factors independently predicted 4-class resistance:
- Subtype B HIV-1: aOR 2.18, 95% CI 1.06 to 4.74, P = 0.041
- Highest viral load: aOR 1.12, 95% CI 1.03 to 1.23, P = 0.012
- Lowest CD4 count: aOR 1.00, 95% CI 1.00 to 1.00, P = 0.033
- Number of virologic failures: aOR 1.23, 95% CI 1.11 to 1.36, P < 0.001
- Number of therapeutic regimens: aOR 1.01, 95% CI 1.01 to 1.01, P < 0.001
- Year of first treatment: aOR 1.06, 95% CI 1.00 to 1.13, P = 0.042
- Years since HIV diagnosis: aOR 1.05, 95% CI 1.02 to 1.09, P = 0.005
The researchers suggested that the association of subtype B with higher odds of multidrug resistance probably indicates more antiretroviral exposure and a greater chance of treatment with suboptimal regimens among people infected with subtype B HIV-1.
The EuResist team proposed that multidrug resistance resulted mainly from treatment shortcomings that have been "progressively fixed" with improvements in antiretroviral agents and strategies. Such shortcomings include use of suboptimal or add-on treatments, antiretrovirals with low genetic barriers to resistance, and regimens that challenged steady adherence. They cautioned, though, that some people come to treatment with factors favoring multidrug resistance, such as high zenith viral load and low nadir CD4 count.
References
1. Dewandre J, Vercauteren J, Vandamme AM, et al. Declining incidence of HIV multidrug resistance in Europe. 18th European AIDS Conference, EACS 2021, October 27-30, 2021, London. Abstract BPD1/1.
2. Vercauteren J, Vandamme AM, Rossetti B, et al. 4-class resista,nce is rare in treatment-experienced patients across Europe. Conference on Retroviruses and Opportunistic Infections (CROI). March 8-11, 2020. Boston. Abstract 523.
https://www.croiconference.org/abstract/incidence-of-hiv-infection-with-daily-or-on-demand-oral-prep-with-tdf-ftc-in-france/
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