Short-course Raltegravir Intensification Does Not Reduce Persistent Low-level Viremia in Patients with HIV-1 Suppression During Receipt of Combination Antiretroviral Therapy

Overview

Journal Clin Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2010 Feb 17

PMID 20156060

Citations 132

Authors

D McMahon

J Jones

A Wiegand

S J Gange

M Kearney

S Palmer

S McNulty

J A Metcalf

E Acosta

C Rehm

J M Coffin

J W Mellors

F Maldarelli

Affiliations

Soon will be listed here.

Abstract

Background: Combination antiretroviral therapy suppresses but does not eradicate human immunodeficiency virus type 1 (HIV-1) in infected persons, and low-level viremia can be detected despite years of suppressive antiretroviral therapy. Short-course (28-day) intensification of standard antiretroviral combination therapy is a useful approach to determine whether complete rounds of HIV-1 replication in rapidly cycling cells contribute to persistent viremia. We investigated whether intensification with the integrase inhibitor raltegravir decreases plasma HIV-1 RNA levels in patients receiving suppressive antiretroviral therapy.

Methods: Subjects (n = 10) with long-term HIV-1 suppression receiving combination antiretroviral regimens had their regimens intensified for 4 weeks with raltegravir. Plasma HIV-1 RNA level was determined before, during, and after the 4-week intensification period, using a sensitive assay (limit of detection, 0.2 copies of HIV-1 RNA/mL of plasma). A 4-week intensification course was chosen to investigate potential HIV-1 replication in cells with relatively short (approximately 1-14-day) half-lives.

Results: There was no evidence in any subject of a decline in HIV-1 RNA level during the period of raltegravir intensification or of rebound after discontinuation. Median levels of HIV-1 RNA before (0.17 log10 copies/mL), during (0.04 log10 copies/mL), and after (0.04 log10 copies/mL) raltegravir intensification were not significantly different (P > .1 for all comparisons in parametric analyses). High-performance liquid chromatography and mass spectroscopy experiments confirmed that therapeutic levels of raltegravir were achieved in plasma during intensification.

Conclusions: Intensification of antiretroviral therapy with a potent HIV-1 integrase inhibitor did not decrease persistent viremia in subjects receiving suppressive regimens, indicating that rapidly cycling cells infected with HIV-1 were not present. Eradication of HIV-1 from infected persons will require new therapeutic approaches.

Trial Registration: ClinicalTrials.gov identifier: NCT00618371.

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References

Varatharajan L, Thomas S . The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antiviral Res. 2009; 82(2):A99-109. PMC: 2678986. DOI: 10.1016/j.antiviral.2008.12.013. View

Wong J, Hezareh M, Gunthard H, Havlir D, Ignacio C, Spina C . Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997; 278(5341):1291-5. DOI: 10.1126/science.278.5341.1291. View

Chun T, Stuyver L, Mizell S, Ehler L, Mican J, Baseler M . Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997; 94(24):13193-7. PMC: 24285. DOI: 10.1073/pnas.94.24.13193. View

Lewin S, Vesanen M, Kostrikis L, Hurley A, Duran M, Zhang L . Use of real-time PCR and molecular beacons to detect virus replication in human immunodeficiency virus type 1-infected individuals on prolonged effective antiretroviral therapy. J Virol. 1999; 73(7):6099-103. PMC: 112674. DOI: 10.1128/JVI.73.7.6099-6103.1999. View

Havlir D, Strain M, Clerici M, Ignacio C, Trabattoni D, Ferrante P . Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol. 2003; 77(20):11212-9. PMC: 224988. DOI: 10.1128/jvi.77.20.11212-11219.2003. View

Wilkin T, McKinnon J, DiRienzo A, Mollan K, Fletcher C, Margolis D . Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy: final 48-week clinical and virologic outcomes. J Infect Dis. 2009; 199(6):866-71. PMC: 2680942. DOI: 10.1086/597119. View

Koelsch K, Liu L, Haubrich R, May S, Havlir D, Gunthard H . Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J Infect Dis. 2008; 197(3):411-9. DOI: 10.1086/525283. View

Palmer S, Wiegand A, Maldarelli F, Bazmi H, Mican J, Polis M . New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol. 2003; 41(10):4531-6. PMC: 254331. DOI: 10.1128/JCM.41.10.4531-4536.2003. View

Long M, Bennetto-Hood C, Acosta E . A sensitive HPLC-MS-MS method for the determination of raltegravir in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2008; 867(2):165-71. DOI: 10.1016/j.jchromb.2008.03.022. View

10.

Ramratnam B, Ribeiro R, He T, Chung C, Simon V, Vanderhoeven J . Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases, but does not eliminate, ongoing virus replication. J Acquir Immune Defic Syndr. 2004; 35(1):33-7. DOI: 10.1097/00126334-200401010-00004. View

11.

Storch C, Theile D, Lindenmaier H, Haefeli W, Weiss J . Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol. 2007; 73(10):1573-81. DOI: 10.1016/j.bcp.2007.01.027. View

12.

Finzi D, Blankson J, Siliciano J, Margolick J, Chadwick K, Pierson T . Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999; 5(5):512-7. DOI: 10.1038/8394. View

13.

Shiu C, Cunningham C, Greenough T, Muresan P, Sanchez-Merino V, Carey V . Identification of ongoing human immunodeficiency virus type 1 (HIV-1) replication in residual viremia during recombinant HIV-1 poxvirus immunizations in patients with clinically undetectable viral loads on durable suppressive highly active.... J Virol. 2009; 83(19):9731-42. PMC: 2748010. DOI: 10.1128/JVI.00570-09. View

14.

Clements J, Li M, Gama L, Bullock B, Carruth L, Mankowski J . The central nervous system is a viral reservoir in simian immunodeficiency virus--infected macaques on combined antiretroviral therapy: a model for human immunodeficiency virus patients on highly active antiretroviral therapy. J Neurovirol. 2005; 11(2):180-9. DOI: 10.1080/13550280590922748-1. View

15.

Murray J, Emery S, Kelleher A, Law M, Chen J, Hazuda D . Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS. 2007; 21(17):2315-21. DOI: 10.1097/QAD.0b013e3282f12377. View

16.

Ho D, Neumann A, Perelson A, Chen W, Leonard J, Markowitz M . Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995; 373(6510):123-6. DOI: 10.1038/373123a0. View

17.

Tobin N, Learn G, Holte S, Wang Y, Melvin A, McKernan J . Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus. J Virol. 2005; 79(15):9625-34. PMC: 1181593. DOI: 10.1128/JVI.79.15.9625-9634.2005. View

18.

Markowitz M, Morales-Ramirez J, Nguyen B, Kovacs C, Steigbigel R, Cooper D . Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006; 43(5):509-15. DOI: 10.1097/QAI.0b013e31802b4956. View

19.

Peeters M, Colebunders R, Van Den Abbeele K, Nys P, Goeman J, Colans P . Comparison of human immunodeficiency virus biological phenotypes isolated from cerebrospinal fluid and peripheral blood. J Med Virol. 1995; 47(1):92-6. DOI: 10.1002/jmv.1890470117. View

20.

Schito M, Kennedy P, Kowal R, BERGER E, Sher A . A human immunodeficiency virus-transgenic mouse model for assessing interventions that block microbial-induced proviral expression. J Infect Dis. 2001; 183(11):1592-600. DOI: 10.1086/320716. View