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  HIV Glasgow 2020, 5-8 October
Virtual Meeting
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Multidrug Resistance Still Boosts
Death Risk in 31,000-Person Italian Study

  HIV Drug Therapy/Glasgow 2020, October 5-8, 2020
Mark Mascolini
Despite availability of more and stronger antiretrovirals in classes without overlapping resistance, recent multidrug resistance (MDR) still raised the risk of death in a multicohort study of 31,455 people in Italy [1]. Cohort members with MDR also had a higher risk of a combined endpoint of AIDS or death.
Definitions of MDR changed as more antiretroviral classes including drugs with higher barriers to resistance emerged. Although MDR often ushers in virologic failure and worsening disease, its relation to death risk in the current antiretroviral era remains uncertain. Researchers across Italy conducted this study to see whether MDR increased mortality in recent years compared with earlier days in the HIV epidemic.
The analysis included HIV-positive adults from three sources, the Icona Foundation cohort, the ARCA database, and anonymous databases in Italian clinical centers. Everyone had at least one follow-up during 1996-2020 and at least one resistance genotype.
To define MDR the investigators used both the Stanford GSS (genotypic sensitivity score) v8.9 and each person's history of virologic failure while taking specific antiretrovirals (VFscore). For every month of follow-up they considered the nucleoside/nucleotide class active if the GSS and/or VFscore were at or above 2; they considered nonnucleoside and protease inhibitor classes plus maraviroc and enfuvirtide (T-20) active at a GSS and/or VFscore at or above 1; and they considered the integrase inhibitor class active at a GSS and/or VFscore at or above 1.5. MDR at each month meant currently having 2 or fewer active drug classes. The research team used Poisson analysis to determine crude and adjusted relative rates for deaths and a combined endpoint of AIDS or death.
Among 31,445 people studied, 5954 (19%) had MDR. The study group had a median age of 38 years (interquartile range [IQR] 32 to 46), median year of cohort enrollment 2008 (IQR 2003 to 2013), and median year of MDR 1998 (IQR 1997 to 2001). Women made up 26% of this study group. Injection drug users accounted for a higher proportion of the MDR group than the non-MDR group (34.6% vs 10.3%), whereas the opposite proved true for men who have sex with men (18.4% vs 26.8%) (P < 0.001). Hepatitis B surface antigen positivity proved more frequent in the MDR group than the non-MDR group (4.7% vs 2.7%, P < 0.001), as did HCV antibody positivity (19.1% vs 5.4%, P < 0.001).
The researchers counted 1332 deaths from any cause over 217,886 person-years of follow-up for an incidence of 0.60 deaths per 100 person-years. The 134 deaths (10%) that occurred in people with MDR yielded an incidence rate of 0.88 (95% confidence interval [CI] 0.74 to 1.04) per 100 person-years. The 1198 deaths (90%) in people without MDR yielded an incidence of 0.59 (95% CI 0.56 to 0.63) per 100 person-years. After statistical adjustment for potential confounders, people with MDR had an overall two thirds higher risk of death (adjusted relative rate [aRR] 1.67, 95% CI 1.31 to 2.13, P < 0.001).
Compared with 1996-2007, during 2008-2019 the overall adjusted relative rate for death was lower (aRR 0.57, 95% CI 0.48 to 0.68, P < 0.001). In 1996-2007 the adjusted relative rate of death with versus without MDR was 1.62 (95% CI 1.24 to 2.12, P < 0.001). In 2008-2019 the adjusted relative rate of death moved even higher with versus without MDR (2.43), but that higher rate lacked statistical significance (95% CI 0.60 to 9.80, P = 0.213).
Among 25,084 people evaluated for the combined endpoint of AIDS or death, 5257 (21%) had MDR. Poisson regression indicated that MDR boosted the AIDS/death rate almost 25% (aRR 1.24, 95% CI 0.93 to 1.67), but this association was not statistically significant (P = 0.142). The increase in AIDS/death rate was nearly significant in an analysis limited 1996-2007 (aRR 1.39, 95% CI 1.00 to 1.92, P = 0.051) and significant in 2008-2019 (aRR 3.24, 95% CI 1.03 to 10.17, P = 0.044).
The researchers concluded that, although the death rate dropped significantly in this HIV group over time, people with versus without MDR still have a heightened death risk in recent years.
1. Gagliardini R, Cozzi-Lepri A, Zazzi M, et al. Impact of multi-drug resistance on mortality: a multi-cohort Italian study. HIV Drug Therapy/Glasgow 2020, October 5-8, 2020. Abstract O323.