The presence of resistance-associated mutations in reverse transcriptase gene is associated with cerebrospinal fluid HIV-1 escape: A multicentric retrospective analysis.
Humans
HIV-1
/ genetics
Retrospective Studies
Antiretroviral Therapy, Highly Active
RNA-Directed DNA Polymerase
/ genetics
HIV Infections
/ complications
Anti-Retroviral Agents
/ therapeutic use
HIV Seropositivity
/ drug therapy
Mutation
Peptide Hydrolases
/ genetics
Viral Load
Anti-HIV Agents
/ therapeutic use
Drug Resistance, Viral
/ genetics
HIV Reverse Transcriptase
/ genetics
central nervous system penetration effectiveness score
cerebrospinal fluid viral escape
dual therapy
genotype resistance testing
resistance-associated mutations
reverse transcriptase
Journal
Journal of medical virology
ISSN: 1096-9071
Titre abrégé: J Med Virol
Pays: United States
ID NLM: 7705876
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
revised:
07
02
2023
received:
28
12
2022
accepted:
23
03
2023
medline:
17
5
2023
pubmed:
28
3
2023
entrez:
27
3
2023
Statut:
ppublish
Résumé
Higher risk of cerebrospinal fluid escape (CVE) has been associated with the use of specific antiretroviral (ARV) classes, such as protease inhibitors. We assessed whether archived resistance-associated mutations (RAMs) can mediate this relationship by identifying patients treated with incompletely active antiretroviral regimens. A retrospective multicentric study on 282 adult people with HIV on antiretroviral therapy (ART) and available historical plasma genotype resistance testing (HGRT) for reverse transcriptase (RT) and protease genes between 2001 and 2021. The odds ratio for demographic, clinic-, and ART-related variables and CVE was estimated by multivariable modeling. HGRT-adjusted central nervous system effectiveness penetration (CPE) score was computed in modeling the risk. Median age, plasma VL, and CD4 count were 49 years, <50 copies/mL, and 310 cells/μL. CVE was detected in 51 participants (17.0%). No difference in CVE prevalence was observed according to ART type, number of ARVs or ARV classes. Participants with CVE had more frequently plasma (52.9% vs. 32.1%, p = 0.005) and CSF RAMs in RT (n = 63, 57.1% vs. 28.6%, p = 0.029), but not in protease gene. The presence of plasma RAMs in RT associated with increased odds of CVE in adjusted analyses (aOR 3.9, p < 0.001) and in models restricted to plasma viral load ≤50 copies/mL (n = 202; aOR 4.3, p = 0.003). CVE risk decreased by 40% per each point increase in HGRT-adjusted CPE score in multivariable models (p < 0.001). Rather than the type of ARV classes or of ART regimens, functional mono or dual regimens caused by the presence of RAMs affecting ART components may explain the majority of cases of CVE.
Substances chimiques
RNA-Directed DNA Polymerase
EC 2.7.7.49
Anti-Retroviral Agents
0
Peptide Hydrolases
EC 3.4.-
Anti-HIV Agents
0
HIV Reverse Transcriptase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e28704Informations de copyright
© 2023 Wiley Periodicals LLC.
Références
Barton K, Winckelmann A, Palmer S. HIV-1 reservoirs during suppressive therapy. TIM. 2016;24(5):345-355. doi:10.1016/j.tim.2016.01.006
Collier D, Haddow L, Brijkumar J, Moosa MY, Benjamin L, Gupta R. HIV cerebrospinal fluid escape and neurocognitive pathology in the era of combined antiretroviral therapy: what lies beneath the tip of the iceberg in Sub-Saharan Africa? Brain Sci. 2018;8(10):190. doi:10.3390/brainsci8100190
Di Carlofelice M, Everitt A, Muir D, Winston A. Cerebrospinal fluid HIV RNA in persons living with HIV. HIV Med. 2018;19(5):365-368. doi:10.1111/hiv.12594
Edén A, Fuchs D, Hagberg L, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis. 2010;202(12):1819-1825. doi:10.1086/657342
Pérez-Valero I, Ellis R, Heaton R, et al. Cerebrospinal fluid viral escape in aviremic HIV-infected patients receiving antiretroviral therapy: prevalence, risk factors and neurocognitive effects. AIDS. 2019;33(3):475-481. doi:10.1097/QAD.0000000000002074
Joseph J, Cinque P, Colosi D, et al. Highlights of the global HIV-1 CSF escape consortium meeting, 9 June 2016, Bethesda, MD, USA. J Virus Erad. 2016;2(4):243-250.
Mastrangelo A, Turrini F, de Zan V, Caccia R, Gerevini S, Cinque P. Symptomatic cerebrospinal fluid escape. AIDS. 2019;33(suppl 2):S159-S169. doi:10.1097/QAD.0000000000002266
Chan TYH, De Zan V, Gregg A, et al. The symptomatology of cerebrospinal fluid HIV RNA escape: a large case-series. AIDS. 2021;35(14):2341-2346. doi:10.1097/QAD.0000000000002992
Trunfio M, Joseph SB, Ghisetti V, et al. Symptomatic cerebrospinal fluid HIV-1 escape with no resistance-associated mutations following low-level plasma viremia. J Neurovirol. 2018;24(1):132-136. doi:10.1007/s13365-017-0605-1
Trunfio M, Pinnetti C, Focà E, et al. Cerebrospinal fluid HIV-1 escape according to different thresholds and underlying comorbidities: is it time to assess the definitions? AIDS. 2019;33(4):759-762. doi:10.1097/QAD.0000000000002091
Edén A, Nilsson S, Hagberg L, et al. Asymptomatic cerebrospinal fluid HIV-1 viral blips and viral escape during antiretroviral therapy: a longitudinal study. J Infect Dis. 2016;214(12):1822-1825. doi:10.1093/infdis/jiw454
Mukerji SS, Misra V, Lorenz DR, et al. Impact of antiretroviral regimens on cerebrospinal fluid viral escape in a prospective multicohort study of antiretroviral therapy-experienced human immunodeficiency virus-1-infected adults in the United States. Clin Infect Dis. 2018;67(8):1182-1190. doi:10.1093/cid/ciy267
Nightingale S, Geretti AM, Beloukas A, et al. Discordant CSF/plasma HIV-1 RNA in patients with unexplained low-level viraemia. J Neurovirol. 2016;22(6):852-860. doi:10.1007/s13365-016-0448-1
Patel AK, Patel KK, Gohel S, Kumar A, Letendre S. Incidence of symptomatic CSF viral escape in HIV infected patients receiving atazanavir/ritonavir (ATV/r)-containing ART: a tertiary care cohort in western India. J Neurovirol. 2018;24(4):498-505. doi:10.1007/s13365-018-0642-4
Dravid AN, Natrajan K, Kulkarni MM, et al. Discordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India. Medicine. 2018;97(8):e9969. doi:10.1097/MD.0000000000009969
Ssebambulidde K, Segawa I, Laker E, et al. Symptomatic cerebrospinal fluid HIV-1 escape in two patients on second-line antiretroviral therapy in Uganda. Oxf Med Case Rep. 2019;2019(2):omy132. doi:10.1093/omcr/omy132
Calcagno A, Simiele M, Alberione MC, et al. Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral control. Clin Infect Dis. 2015;60(2):311-317. doi:10.1093/cid/ciu773
Tiraboschi JM, Knobel H, Imaz A, et al. Cerebrospinal fluid and plasma lopinavir concentrations and viral response in virologically suppressed patients switching to lopinavir/ritonavir monotherapy once daily. Antivir Ther. 2016;21(4):359-363. doi:10.3851/IMP3015
Di Yacovo S, Molto J, Ferrer E, et al. DRV concentrations and viral load in CSF in patients on DRV/r 600/100 or 800/100mg once daily plus two NRTI. J Int AIDS Soc. 2014;17(4 suppl 3):19821. doi:10.7448/IAS.17.4.19821
Antinori A, Perno CF, Giancola ML, et al. Efficacy of cerebrospinal fluid (CSF)-penetrating antiretroviral drugs against HIV in the neurological compartment: different patterns of phenotypic resistance in CSF and plasma. Clin Infect Dis. 2005;41(12):1787-1793. doi:10.1086/498310
Best BM, Letendre SL, Brigid E, et al. Low atazanavir concentrations in cerebrospinal fluid. AIDS. 2009;23(1):83-87. doi:10.1097/QAD.0b013e328317a702
Wensing AMJ, van Maarseveen NM, Nijhuis M. Fifteen years of HIV protease inhibitors: raising the barrier to resistance. Antiviral Res. 2010;85(1):59-74. doi:10.1016/j.antiviral.2009.10.003
Kelentse N, Moyo S, Molebatsi K, et al. Reversal of CSF HIV-1 escape during treatment of HIV-associated cryptococcal meningitis in Botswana. Biomedicines. 2022;10(6):1399. doi:10.3390/biomedicines10061399
Hagberg L, Price RW, Zetterberg H, Fuchs D, Gisslén M. Herpes zoster in HIV-1 infection: the role of CSF pleocytosis in secondary CSF escape and discordance. PLoS One. 2020;15(7):e0236162. doi:10.1371/journal.pone.0236162
de Almeida SM, Rotta I, de Pereira AP, et al. Cerebrospinal fluid pleocytosis as a predictive factor for CSF and plasma HIV RNA discordance and escape. J Neurovirol. 2020;26(2):241-251. doi:10.1007/s13365-020-00828-1
Ulfhammer G, Edén A, Antinori A, et al. Cerebrospinal fluid viral load across the spectrum of untreated human immunodeficiency virus type 1 (HIV-1) infection: a cross-sectional multicenter study. Clin Infect Dis. 2022;75(3):493-502. doi:10.1093/cid/ciab943
Milia MG, Allice T, Gregori G, et al. Magnetic-silica based nucleic acid extraction for human immunodeficiency virus Type-1 drug-resistance testing in low viremic patients. J Clin Virol. 2010;47(1):8-12. doi:10.1016/j.jcv.2009.10.012
Santos GMA, Locatelli I, Métral M, et al. Cross-sectional and cumulative longitudinal central nervous system penetration effectiveness scores are not associated with neurocognitive impairment in a well treated aging human immunodeficiency virus-positive population in Switzerland. Open Forum Infect Dis. 2019;6(7):277. doi:10.1093/ofid/ofz277
Mukerji SS, Misra V, Lorenz D, et al. Temporal patterns and drug resistance in CSF viral escape among ART-experienced HIV-1 infected adults. J Acquir Immune Defic Syndr. 2017;75(2):246-255. doi:10.1097/QAI.0000000000001362
Wijting I, Rokx C, Boucher C, et al. Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial. Lancet HIV. 2017;4(12):e547-e554. doi:10.1016/S2352-3018(17)30152-2
Arenas-Pinto A, Stöhr W, Clarke A, et al. Evaluation of cerebrospinal fluid virological escape in patients on long-term protease inhibitor monotherapy. Antivir Ther. 2017;22(6):535-538. doi:10.3851/IMP3146
Arribas J, Girard PM, Paton N, et al. Efficacy of PI monotherapy versus triple therapy for 1964 patients in 10 randomised trials. J Int AIDS Soc. 2014;17(4 suppl 3):19788. doi:10.7448/IAS.17.4.19788
Ferretti F, Bigoloni A, Passeri L, et al. Cerebrospinal fluid analysis for HIV replication and biomarkers of immune activation and neurodegeneration in long-term atazanavir/ritonavir monotherapy treated patients. Medicine. 2016;95(28):e4144. doi:10.1097/MD.0000000000004144
Donath M, Wolf T, Stürmer M, et al. HIV-1 replication in central nervous system increases over time on only protease inhibitor therapy. Med Microbiol Immunol. 2016;205(6):575-583. doi:10.1007/s00430-016-0469-7
Trunfio M, Rugge W, Mighetto L, et al. Dual antiretroviral therapies are effective and safe regimens in the central nervous system of neurologically symptomatic people living with HIV. AIDS. 2020;34(13):1899-1906. doi:10.1097/QAD.0000000000002601
Joseph SB, Trunfio M, Kincer LP, Calcagno A, Price RW. What can characterization of cerebrospinal fluid escape populations teach us about viral reservoirs in the central nervous system? AIDS. 2019;33(suppl 2):S171-S179. doi:10.1097/QAD.0000000000002253