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J Antimicrob Chemother. 2014 Oct;69(10):2809-18. doi: 10.1093/jac/dku213. Epub 2014 Jun 23.

Impact of raltegravir on HIV-1 RNA and DNA forms following initiation of antiretroviral therapy in treatment-naive patients.

Author information

1
Medical Department no. 2, Infectious Diseases Unit, University Hospital Frankfurt, Frankfurt, Germany.
2
Institute of Medical Virology, National Reference Center for Retroviruses, University Hospital Frankfurt, Frankfurt, Germany Department of Infectious Diseases, Virology, University of Heidelberg, Heidelberg, Germany.
3
VIROQUANT Research Group Modeling, Bioquant BQ0026, University of Heidelberg, Heidelberg, Germany Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany.
4
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
5
Institute of Medical Virology, National Reference Center for Retroviruses, University Hospital Frankfurt, Frankfurt, Germany Department of Infectious Diseases, Virology, University of Heidelberg, Heidelberg, Germany oliver.keppler@kgu.de.

Abstract

OBJECTIVES:

The rapid early-phase decay of plasma HIV-1 RNA during integrase inhibitor-based therapy is not fully understood. The accumulation of biologically active episomal HIV-1 cDNAs, following aborted integration, could contribute to antiviral potency in vivo.

METHODS:

This prospective, controlled clinical observation study explored raltegravir's impact on the dynamics of HIV-1 RNA in plasma, and concentrations of total HIV-1 cDNA, episomal 2-long terminal repeat (LTR) circles and HIV-1 integrants in peripheral blood mononuclear cells (PBMC). Individuals starting therapy with two nucleoside reverse transcriptase inhibitors plus either raltegravir (raltegravir group; n = 10 patients) or boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitor (control group; n = 10 patients) were followed for 48 weeks.

RESULTS:

Suppression of HIV-1 RNA (<50 copies/mL) was reached earlier (5/10 versus 0/10 at week 4; 8/10 versus 4/10 at week 12) on raltegravir. Significant total HIV-1 cDNA reductions in PBMC were reached by day 99 and persisted until day 330, with median factors of decrease of 7.2 and 8.9, respectively. Broad inter-individual variations, yet no treatment-associated differences, were noted for HIV-1 cDNA concentrations. Despite reductions in HIV-1 RNA (∼3 log) and total HIV-1 cDNA (∼1 log), concentrations of integrants and 2-LTR circles remained largely unchanged.

CONCLUSIONS:

These results extend the previously reported early benefit of raltegravir on the decline of plasma viraemia to treatment-naive patients. The modest treatment-associated, yet group-independent, decline in total HIV-1 cDNA load and the lack of significant changes in integrated and episomal HIV-1 cDNA suggest that most integrated DNA is archival and targeting of HIV reservoirs other than PBMC may underlie beneficial effects of raltegravir.

KEYWORDS:

2-LTR circles; antiretroviral therapy; decay; episomal DNA; integrase inhibitor; slope; viral dynamics; virus load

PMID:
24962031
DOI:
10.1093/jac/dku213
[Indexed for MEDLINE]

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