Generic placeholder image

Current HIV Research

Editor-in-Chief

ISSN (Print): 1570-162X
ISSN (Online): 1873-4251

Review Article

Low-level Viremia in Treated HIV-1 Infected Patients: Advances and Challenges

Author(s): Ruojing Bai, Shiyun Lv, Hao Wu* and Lili Dai*

Volume 20, Issue 2, 2022

Published on: 30 March, 2022

Page: [111 - 119] Pages: 9

DOI: 10.2174/1570162X20666220216102943

Price: $65

Abstract

Antiretroviral therapy (ART) can effectively suppress HIV-1 replication, improving quality of life and restoring the lifespan of persons living with HIV (PLWH) to near-normal levels. However, after standardized ART, a low level of HIV-1 RNA, i.e., low-level viremia (LLV), may still be identified in 3% to 10% of the patients. LLV is capable of impacting the immunological and clinical outcomes of patients and serves as a risk factor for transmission. The underlying mechanism of LLV is not yet certain, and the effects of LLV on patient outcomes remain under evaluation. Understanding LLV will allow effective prevention and control strategies to be designed for the benefit of PLWH.

Keywords: Antiretroviral therapy, HIV-1 infection, low-level viremia, virological failure, HIV-1 reservoir, clinical management.

[1]
Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the international antiviral society-USA panel. JAMA 2020; 324(16): 1651-69.
[http://dx.doi.org/10.1001/jama.2020.17025] [PMID: 33052386]
[2]
Santoro MM, Fabeni L, Armenia D, et al. Reliability and clinical relevance of the HIV-1 drug resistance test in patients with low viremia levels. Clin Infect Dis 2014; 58(8): 1156-64.
[http://dx.doi.org/10.1093/cid/ciu020] [PMID: 24429430]
[3]
Havlir DV, Bassett R, Levitan D, et al. Prevalence and predictive value of intermittent viremia with combination hiv therapy. JAMA 2001; 286(2): 171-9.
[http://dx.doi.org/10.1001/jama.286.2.171] [PMID: 11448280]
[4]
Young J, Rickenbach M, Calmy A, et al. Transient detectable viremia and the risk of viral rebound in patients from the Swiss HIV Cohort Study. BMC Infect Dis 2015; 15(1): 382.
[http://dx.doi.org/10.1186/s12879-015-1120-8] [PMID: 26392270]
[5]
Hofstra LM, Mudrikova T, Stam AJ, et al. Residual viremia is preceding viral blips and persistent low-level viremia in treated HIV-1 patients. PLoS One 2014; 9(10): e110749.
[http://dx.doi.org/10.1371/journal.pone.0110749] [PMID: 25354368]
[6]
Cohen C. Low-level viremia in HIV-1 infection: Consequences and implications for switching to a new regimen. HIV Clin Trials 2009; 10(2): 116-24.
[http://dx.doi.org/10.1310/hct1002-116] [PMID: 19487182]
[7]
Fleming J, Mathews WC, Rutstein RM, et al. Low-level viremia and virologic failure in persons with HIV infection treated with antiretroviral therapy. AIDS 2019; 33(13): 2005-12.
[http://dx.doi.org/10.1097/QAD.0000000000002306] [PMID: 31306175]
[8]
Bernal E, Gómez JM, Jarrín I, et al. Low-level viremia is associated with clinical progression in HIV-infected patients receiving antiretroviral treatment. J Acquir Immune Defic Syndr 2018; 78(3): 329-37.
[http://dx.doi.org/10.1097/QAI.0000000000001678] [PMID: 29543636]
[9]
Elvstam O, Medstrand P, Yilmaz A, Isberg PE, Gisslén M, Björkman P. Virological failure and all-cause mortality in HIV-positive adults with low-level viremia during antiretroviral treatment. PLoS One 2017; 12(7): e0180761.
[http://dx.doi.org/10.1371/journal.pone.0180761] [PMID: 28683128]
[10]
Esber A, Polyak C, Kiweewa F, et al. Persistent low-level viremia predicts subsequent virologic failure: Is it time to change the third 90? Clin Infect Dis 2019; 69(5): 805-12.
[http://dx.doi.org/10.1093/cid/ciy989] [PMID: 30462188]
[11]
Joya C, Won SH, Schofield C, et al. Persistent low-level viremia while on antiretroviral therapy is an independent risk factor for virologic failure. Clin Infect Dis 2019; 69(12): 2145-52.
[http://dx.doi.org/10.1093/cid/ciz129] [PMID: 30785191]
[12]
Taiwo B, Gallien S, Aga E, et al. Antiretroviral drug resistance in HIV-1-infected patients experiencing persistent low-level viremia during first-line therapy. J Infect Dis 2011; 204(4): 515-20.
[http://dx.doi.org/10.1093/infdis/jir353] [PMID: 21791652]
[13]
Vandenhende MA, Ingle S, May M, et al. Impact of low-level viremia on clinical and virological outcomes in treated HIV-1-infected patients. AIDS 2015; 29(3): 373-83.
[http://dx.doi.org/10.1097/QAD.0000000000000544] [PMID: 25686685]
[14]
Laprise C, de Pokomandy A, Baril J-G, Dufresne S, Trottier H. Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: Results from 12 years of observation. Clin Infect Dis 2013; 57(10): 1489-96.
[http://dx.doi.org/10.1093/cid/cit529] [PMID: 23946221]
[15]
Qin S, Lai J, Zhang H, et al. Predictive factors of viral load high-risk events for virological failure in HIV/AIDS patients receiving long-term antiviral therapy. BMC Infect Dis 2021; 21(1): 448.
[http://dx.doi.org/10.1186/s12879-021-06162-z] [PMID: 34006230]
[16]
Zhang T, Ding H, An M, et al. Factors associated with high-risk low-level viremia leading to virologic failure: 16-year retrospective study of a Chinese antiretroviral therapy cohort. BMC Infect Dis 2020; 20(1): 147.
[http://dx.doi.org/10.1186/s12879-020-4837-y] [PMID: 32066392]
[17]
Hermans LE, Moorhouse M, Carmona S, et al. Effect of HIV-1 low-level viraemia during antiretroviral therapy on treatment outcomes in WHO-guided South African treatment programmes: A multicentre cohort study. Lancet Infect Dis 2018; 18(2): 188-97.
[http://dx.doi.org/10.1016/S1473-3099(17)30681-3] [PMID: 29158101]
[18]
Leierer G, Grabmeier-Pfistershammer K, Steuer A, et al. Factors associated with low-level viraemia and virological failure: Results from the Austrian HIV Cohort Study. PLoS One 2015; 10(11): e0142923.
[http://dx.doi.org/10.1371/journal.pone.0142923] [PMID: 26566025]
[19]
Navarro J, Caballero E, Curran A, et al. Impact of low-level viraemia on virological failure in HIV-1-infected patients with stable antiretroviral treatment. Antivir Ther 2016; 21(4): 345-52.
[http://dx.doi.org/10.3851/IMP3023] [PMID: 26756461]
[20]
Swenson LC, Cobb B, Geretti AM, et al. Comparative performances of HIV-1 RNA load assays at low viral load levels: Results of an international collaboration. J Clin Microbiol 2014; 52(2): 517-23.
[http://dx.doi.org/10.1128/JCM.02461-13] [PMID: 24478482]
[21]
Lima V, Harrigan R, Montaner JS. Increased reporting of detectable plasma HIV-1 RNA levels at the critical threshold of 50 copies per milliliter with the Taqman assay in comparison to the Amplicor assay. J Acquir Immune Defic Syndr 2009; 51(1): 3-6.
[http://dx.doi.org/10.1097/QAI.0b013e31819e721b] [PMID: 19247185]
[22]
Smit E, Bhattacharya S, Osman H, Taylor S. Increased frequency of HIV-1 viral load blip rate observed after switching from Roche Cobas Amplicor to Cobas Taqman assay. J Acquir Immune Defic Syndr 2009; 51(3): 364-5.
[http://dx.doi.org/10.1097/QAI.0b013e3181aa13b3] [PMID: 19553776]
[23]
Nettles RE, Kieffer TL, Kwon P, et al. Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA 2005; 293(7): 817-29.
[http://dx.doi.org/10.1001/jama.293.7.817] [PMID: 15713771]
[24]
Lee PK, Kieffer TL, Siliciano RF, Nettles RE. HIV-1 viral load blips are of limited clinical significance. J Antimicrob Chemother 2006; 57(5): 803-5.
[http://dx.doi.org/10.1093/jac/dkl092] [PMID: 16533823]
[25]
Stosor V, Palella FJ Jr, Berzins B, et al. Transient viremia in HIV-infected patients and use of plasma preparation tubes. Clin Infect Dis 2005; 41(11): 1671-4.
[http://dx.doi.org/10.1086/498025] [PMID: 16267742]
[26]
Jones LE, Perelson AS. Opportunistic infection as a cause of transient viremia in chronically infected HIV patients under treatment with HAART. Bull Math Biol 2005; 67(6): 1227-51.
[http://dx.doi.org/10.1016/j.bulm.2005.01.006] [PMID: 16023709]
[27]
Kolber MA, Gabr AH, De La Rosa A, et al. Genotypic analysis of plasma HIV-1 RNA after influenza vaccination of patients with previously undetectable viral loads. AIDS 2002; 16(4): 537-42.
[http://dx.doi.org/10.1097/00002030-200203080-00004] [PMID: 11872996]
[28]
Wojewoda CM, Spahlinger T, Harmon ML, et al. Comparison of roche cobas ampliprep/cobas TaqMan HIV-1 test version 2.0 (CAP/CTM v2.0) with other real-time PCR assays in HIV-1 monitoring and follow-up of low-level viral loads. J Virol Methods 2013; 187(1): 1-5.
[http://dx.doi.org/10.1016/j.jviromet.2012.10.004] [PMID: 23098667]
[29]
Farmer A, Wang X, Ganesan A, et al. Factors associated with HIV viral load “blips” and the relationship between self-reported adherence and efavirenz blood levels on blip occurrence: A case-control study. AIDS Res Ther 2016; 13(1): 16.
[http://dx.doi.org/10.1186/s12981-016-0100-4] [PMID: 27006682]
[30]
Elvstam O, Marrone G, Medstrand P, et al. All-cause mortality and serious non-AIDS events in adults with low-level human immunodeficiency virus viremia during combination antiretroviral therapy: Results from a swedish nationwide observational study. Clin Infect Dis 2021; 72(12): 2079-86.
[http://dx.doi.org/10.1093/cid/ciaa413] [PMID: 32271361]
[31]
WHO. Update of recommendations on first- and second-line antiretroviral regimens: HIV treatment. 2020. Available from: https://apps.who.int/iris/bitstream/handle/10665/325892/WHO-CDS-HIV-19.15-eng.pdf [cited Nov 10, 2021].
[32]
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV 2021. Available from: https://clinicalinfo. hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf [cited Nov 10, 2021].
[33]
Churchill MJ, Deeks SG, Margolis DM, Siliciano RF, Swanstrom R. HIV reservoirs: What, where and how to target them. Nat Rev Microbiol 2016; 14(1): 55-60.
[http://dx.doi.org/10.1038/nrmicro.2015.5] [PMID: 26616417]
[34]
Sahu GK, Sarria JC, Cloyd MW. Recovery of replication-competent residual HIV-1 from plasma of a patient receiving prolonged, suppressive highly active antiretroviral therapy. J Virol 2010; 84(16): 8348-52.
[http://dx.doi.org/10.1128/JVI.00362-10] [PMID: 20519388]
[35]
Simonetti FR, Sobolewski MD, Fyne E, et al. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc Natl Acad Sci USA 2016; 113(7): 1883-8.
[http://dx.doi.org/10.1073/pnas.1522675113] [PMID: 26858442]
[36]
Zhang X, Sharaf R, Etemad B, et al. Persistent HIV low-level viremia can arise from an active proviral clone. In: HIV reservoir cells seattle: Proviral landscape, and rebound virus. 2019. Available from: https://www.croiconference.org/abstract/persistent-hiv-low-level-viremia-can-arise-active-proviral-clone/
[37]
Lorenzo-Redondo R, Fryer HR, Bedford T, et al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 2016; 530(7588): 51-6.
[http://dx.doi.org/10.1038/nature16933] [PMID: 26814962]
[38]
Kearney MF, Wiegand A, Shao W, et al. Ongoing HIV replication during ART reconsidered. Open Future Infect Dis 2017; 4(3): ofx173.
[http://dx.doi.org/10.1093/ofid/ofx173]
[39]
Kearney MF, Spindler J, Shao W, et al. Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy. PLoS Pathog 2014; 10(3): e1004010.
[http://dx.doi.org/10.1371/journal.ppat.1004010] [PMID: 24651464]
[40]
Van Zyl GU, Katusiime MG, Wiegand A, et al. No evidence of HIV replication in children on antiretroviral therapy. J Clin Invest 2017; 127(10): 3827-34.
[http://dx.doi.org/10.1172/JCI94582] [PMID: 28891813]
[41]
Yukl SA, Gianella S, Sinclair E, et al. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis 2010; 202(10): 1553-61.
[http://dx.doi.org/10.1086/656722] [PMID: 20939732]
[42]
Lafeuillade A, Cheret A, Hittinger G, et al. Rectal cell-associated HIV-1 RNA: A new marker ready for the clinic. HIV Clin Trials 2009; 10(5): 324-7.
[http://dx.doi.org/10.1310/hct1005-324] [PMID: 19906625]
[43]
North TW, Higgins J, Deere JD, et al. Viral sanctuaries during highly active antiretroviral therapy in a nonhuman primate model for AIDS. J Virol 2010; 84(6): 2913-22.
[http://dx.doi.org/10.1128/JVI.02356-09] [PMID: 20032180]
[44]
Fletcher CV, Staskus K, Wietgrefe SW, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci USA 2014; 111(6): 2307-12.
[http://dx.doi.org/10.1073/pnas.1318249111] [PMID: 24469825]
[45]
Conway JM, Perelson AS. Residual viremia in treated HIV+ individuals. PLOS Comput Biol 2016; 12(1): e1004677.
[http://dx.doi.org/10.1371/journal.pcbi.1004677] [PMID: 26735135]
[46]
Cai CW, Sereti I. Residual immune dysfunction under antiretroviral therapy. Semin Immunol 2021; 51: 101471.
[http://dx.doi.org/10.1016/j.smim.2021.101471] [PMID: 33674177]
[47]
Younas M, Psomas C, Reynes C, et al. Residual viremia is linked to a specific immune activation profile in HIV-1-infected adults under efficient antiretroviral therapy. Front Immunol 2021; 12: 663843.
[http://dx.doi.org/10.3389/fimmu.2021.663843] [PMID: 33859653]
[48]
Ostrowski SR, Katzenstein TL, Thim PT, Pedersen BK, Gerstoft J, Ullum H. Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy. J Infect Dis 2005; 191(3): 348-57.
[http://dx.doi.org/10.1086/427340] [PMID: 15633093]
[49]
Karlsson AC, Younger SR, Martin JN, et al. Immunologic and virologic evolution during periods of intermittent and persistent low-level viremia. AIDS 2004; 18(7): 981-9.
[http://dx.doi.org/10.1097/00002030-200404300-00005] [PMID: 15096800]
[50]
Yang X, Su B, Zhang X, Liu Y, Wu H, Zhang T. Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders. J Leukoc Biol 2020; 107(4): 597-612.
[http://dx.doi.org/10.1002/JLB.4MR1019-189R] [PMID: 31965635]
[51]
Menkova-Garnier I, Hocini H, Foucat E, et al. P2X7 receptor inhibition improves CD34 T-cell differentiation in HIV-infected immunological nonresponders on c-ART. PLoS Pathog 2016; 12(4): e1005571.
[http://dx.doi.org/10.1371/journal.ppat.1005571] [PMID: 27082982]
[52]
Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: The new challenge in HIV-1 infection. Blood 2011; 117(21): 5582-90.
[http://dx.doi.org/10.1182/blood-2010-12-322453] [PMID: 21403129]
[53]
Mackie NE, Phillips AN, Kaye S, Booth C, Geretti AM. Antiretroviral drug resistance in HIV-1-infected patients with low-level viremia. J Infect Dis 2010; 201(9): 1303-7.
[http://dx.doi.org/10.1086/651618] [PMID: 20350161]
[54]
Delaugerre C, Gallien S, Flandre P, et al. Impact of low-level-viremia on HIV-1 drug-resistance evolution among antiretroviral treated-patients. PLoS One 2012; 7(5): e36673.
[http://dx.doi.org/10.1371/journal.pone.0036673] [PMID: 22590588]
[55]
Zhang S, van Sighem A, Kesselring A, et al. Episodes of HIV viremia and the risk of non-AIDS diseases in patients on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr 2012; 60(3): 265-72.
[http://dx.doi.org/10.1097/QAI.0b013e318258c651] [PMID: 22531756]
[56]
Hughes JP, Baeten JM, Lingappa JR, et al. Determinants of per-coital-act HIV-1 infectivity among African HIV-1-serodiscordant couples. J Infect Dis 2012; 205(3): 358-65.
[http://dx.doi.org/10.1093/infdis/jir747] [PMID: 22241800]
[57]
Mayaux MJ, Dussaix E, Isopet J, et al. Maternal virus load during pregnancy and mother-to-child transmission of human immunodeficiency virus type 1: The French perinatal cohort studies. J Infect Dis 1997; 175(1): 172-5.
[http://dx.doi.org/10.1093/infdis/175.1.172] [PMID: 8985214]
[58]
O’Donovan D, Ariyoshi K, Milligan P, et al. Maternal plasma viral RNA levels determine marked differences in mother-to-child transmission rates ofHIV-1 and HIV-2 in The Gambia. AIDS 2000; 14(4): 441-8.
[http://dx.doi.org/10.1097/00002030-200003100-00019] [PMID: 10770548]
[59]
Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml. J Infect Dis 2001; 183(4): 539-45.
[http://dx.doi.org/10.1086/318530] [PMID: 11170978]
[60]
Prevention Access Campaign. Undetectable=Untransmittable 2018. Available from: https://www.preventionaccess.org/ undetectable [cited Oct 18, 2018].
[61]
Rodger A, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in MSM couples with suppressive ART: The PARTNER2 Study extended results in gay men. J Int AIDS Soc 2018; 21(Suppl. 6): 163.
[http://dx.doi.org/10.1002/jia2.25148]
[62]
Charpentier C, Landman R, Laouénan C, et al. Persistent low-level HIV-1 RNA between 20 and 50 copies/mL in antiretroviral-treated patients: Associated factors and virological outcome. J Antimicrob Chemother 2012; 67(9): 2231-5.
[http://dx.doi.org/10.1093/jac/dks191] [PMID: 22643190]
[63]
Konstantopoulos C, Ribaudo H, Ragland K, Bangsberg DR, Li JZ. Antiretroviral regimen and suboptimal medication adherence are associated with low-level human immunodeficiency virus viremia. Open Forum Infect Dis 2015; 2(1): ofu119.
[http://dx.doi.org/10.1093/ofid/ofu119] [PMID: 25884007]
[64]
Henrich TJ, Wood BR, Kuritzkes DR. Increased risk of virologic rebound in patients on antiviral therapy with a detectable HIV load <48 copies/mL. PLoS One 2012; 7(11): e50065.
[http://dx.doi.org/10.1371/journal.pone.0050065] [PMID: 23166820]
[65]
Taiwo B, Zheng L, Gallien S, et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS 2011; 25(17): 2113-22.
[http://dx.doi.org/10.1097/QAD.0b013e32834bbaa9] [PMID: 21857490]
[66]
Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008; 358(20): 2095-106.
[http://dx.doi.org/10.1056/NEJMoa074609] [PMID: 18480202]
[67]
Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: A multicentre, double-blind randomised controlled trial. Lancet 2009; 374(9692): 796-806.
[http://dx.doi.org/10.1016/S0140-6736(09)60918-1] [PMID: 19647866]
[68]
Jacobson K, Ogbuagu O. Integrase inhibitor-based regimens result in more rapid virologic suppression rates among treatment-naïve human immunodeficiency virus-infected patients compared to non-nucleoside and protease inhibitor-based regimens in a real-world clinical setting: A retrospective cohort study. Medicine (Baltimore) 2018; 97(43): e13016.
[http://dx.doi.org/10.1097/MD.0000000000013016] [PMID: 30412140]
[69]
Miller LG, Golin CE, Liu H, et al. No evidence of an association between transient HIV viremia (“Blips”) and lower adherence to the antiretroviral medication regimen. J Infect Dis 2004; 189(8): 1487-96.
[http://dx.doi.org/10.1086/382895] [PMID: 15073687]
[70]
Maggiolo F, Di Filippo E, Comi L, et al. Reduced adherence to antiretroviral therapy is associated with residual low-level viremia. Pragmat Obs Res 2017; 8: 91-7.
[http://dx.doi.org/10.2147/POR.S127974] [PMID: 28603436]
[71]
Inzaule SC, Bertagnolio S, Kityo CM, et al. The relative contributions of HIV drug resistance, nonadherence and low-level viremia to viremic episodes on antiretroviral therapy in sub-Saharan Africa. AIDS 2020; 34(10): 1559-66.
[http://dx.doi.org/10.1097/QAD.0000000000002588] [PMID: 32675566]
[72]
Hines DM, Ding Y, Wade RL, Beaubrun A, Cohen JP. Treatment adherence and persistence among HIV-1 patients newly starting treatment. Patient Prefer Adherence 2019; 13: 1927-39.
[http://dx.doi.org/10.2147/PPA.S207908] [PMID: 31806941]
[73]
Wirden M, Todesco E, Valantin M-A, et al. Low-level HIV-1 viraemia in patients on HAART: Risk factors and management in clinical practice. J Antimicrob Chemother 2015; 70(8): 2347-53.
[http://dx.doi.org/10.1093/jac/dkv099] [PMID: 25921516]
[74]
Calvez V. 16th European AIDS Conference (EACS 2017). Milan, Italy. 2017.Oct 25-27, 2017; Brussels. 2017.
[75]
Quercia R, Orkin C, D’Amico R, et al. EACS 2019 Abstract Book. HIV Med 2019; 20(S9): 3-316.
[http://dx.doi.org/10.1111/hiv.12814]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy