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. 2024 Feb;25(2):212-222.
doi: 10.1111/hiv.13556. Epub 2023 Sep 29.

Rate of response to initial antiretroviral therapy according to level of pre-existing HIV-1 drug resistance detected by next-generation sequencing in the strategic timing of antiretroviral treatment (START) study

Alessandro Cozzi-Lepri  1 , David Dunn  1 , Anna Tostevin  1 , Rasmus L Marvig  2 , Marc Bennedbaek  3 , Shweta Sharma  4 , Michael J Kozal  5 , Mark Gompels  6 , Angie N Pinto  7 , Jens Lundgren  8 , John D Baxter  9 ; INSIGHT START Study Group
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Rate of response to initial antiretroviral therapy according to level of pre-existing HIV-1 drug resistance detected by next-generation sequencing in the strategic timing of antiretroviral treatment (START) study

Alessandro Cozzi-Lepri et al. HIV Med. 2024 Feb.

Abstract

Objectives: The main objective of this analysis was to evaluate the impact of pre-existing drug resistance by next-generation sequencing (NGS) on the risk of treatment failure (TF) of first-line regimens in participants enrolled in the START study.

Methods: Stored plasma from participants with entry HIV RNA >1000 copies/mL were analysed using NGS (llumina MiSeq). Pre-existing drug resistance was defined using the mutations considered by the Stanford HIV Drug Resistance Database (HIVDB v8.6) to calculate the genotypic susceptibility score (GSS, estimating the number of active drugs) for the first-line regimen at the detection threshold windows of >20%, >5%, and >2% of the viral population. Survival analysis was conducted to evaluate the association between the GSS and risk of TF (viral load >200 copies/mL plus treatment change).

Results: Baseline NGS data were available for 1380 antiretroviral therapy (ART)-naïve participants enrolled over 2009-2013. First-line ART included a non-nucleoside reverse transcriptase inhibitor (NNRTI) in 976 (71%), a boosted protease inhibitor in 297 (22%), or an integrase strand transfer inhibitor in 107 (8%). The proportions of participants with GSS <3 were 7% for >20%, 10% for >5%, and 17% for the >2% thresholds, respectively. The adjusted hazard ratio of TF associated with a GSS of 0-2.75 versus 3 in the subset of participants with mutations detected at the >2% threshold was 1.66 (95% confidence interval 1.01-2.74; p = 0.05) and 2.32 (95% confidence interval 1.32-4.09; p = 0.003) after restricting the analysis to participants who started an NNRTI-based regimen.

Conclusions: Up to 17% of participants initiated ART with a GSS <3 on the basis of NGS data. Minority variants were predictive of TF, especially for participants starting NNRTI-based regimens.

Keywords: HIV drug resistance; antiretroviral therapy; human immunodeficiency virus (HIV); next generation sequencing.

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Conflict of interest statement

ACL declares no conflicts of interest.

Figures

Figure 1.
Figure 1.. HIVDB interpreted drug activity <1 according to drug started in first line regimen by threshold windows
Anchor drugs EVG=Elvitegravir; DTG=dolutegravir; RAL=raltegravir;; ATV=atazanavir LPV=lopinavir;; RPV=rilpivirine; EFV=efavirenz NRTIs TDF=tenofovir; 3TC=lamivudine; ZDV=zidovudine; FTC=emtricitabine; ABC=abacavir NB only interpretations for the drugs included in first line regimen are shown in the graphs
Figure 1.
Figure 1.. HIVDB interpreted drug activity <1 according to drug started in first line regimen by threshold windows
Anchor drugs EVG=Elvitegravir; DTG=dolutegravir; RAL=raltegravir;; ATV=atazanavir LPV=lopinavir;; RPV=rilpivirine; EFV=efavirenz NRTIs TDF=tenofovir; 3TC=lamivudine; ZDV=zidovudine; FTC=emtricitabine; ABC=abacavir NB only interpretations for the drugs included in first line regimen are shown in the graphs
Figure 2.
Figure 2.. Kaplan-Meier estimates of the time to treatment failure according to HIVDB GSS categories and threshold window
Figure 2.
Figure 2.. Kaplan-Meier estimates of the time to treatment failure according to HIVDB GSS categories and threshold window
Figure 2.
Figure 2.. Kaplan-Meier estimates of the time to treatment failure according to HIVDB GSS categories and threshold window
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References

    1. Stella-Ascariz N, Arribas JR, Paredes R, Li JZ. The Role of HIV-1 Drug-Resistant Minority Variants in Treatment Failure. J Infect Dis. 2017. Dec 1;216(suppl_9):S847–S850. doi: 10.1093/infdis/jix430. - DOI - PMC - PubMed
    1. Johnson JA, Li JF, Wei X, Lipscomb J, Irlbeck D, Craig C, Smith A, Bennett DE, Monsour M, Sandstrom P, Lanier ER, Heneine W. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naïve populations and associate with reduced treatment efficacy. PLoS Med. 2008. Jul 29;5(7):e158. doi: 10.1371/journal.pmed.0050158. - DOI - PMC - PubMed
    1. Li JZ, Kuritzkes DR. Clinical implications of HIV-1 minority variants. Clin Infect Dis. 2013. Jun;56(11):1667–74. doi: 10.1093/cid/cit125. Epub 2013 Feb 27. - DOI - PMC - PubMed
    1. Paredes R, Marconi VC, Campbell TB, Kuritzkes DR. Systematic evaluation of allele-specific real-time PCR for the detection of minor HIV-1 variants with pol and env resistance mutations. J Virol Methods 2007; 146:136–46. - PMC - PubMed
    1. Ellis GM, Vlaskin TA, Koth A, et al. Simultaneous and sensitive detection of human immunodeficiency virus type 1 (HIV) drug resistant genotypes by multiplex oligonucleotide ligation assay. J Virol Methods 2013; 192:39–43. - PMC - PubMed

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