Impact of Raltegravir on HIV-1 RNA and DNA Forms Following Initiation of Antiretroviral Therapy in Treatment-Naive Patients

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / virology*
  • HIV Integrase Inhibitors / pharmacology*
  • HIV Integrase Inhibitors / therapeutic use*
  • HIV Long Terminal Repeat
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Leukocytes, Mononuclear / virology
  • Male
  • Middle Aged
  • Pilot Projects
  • Proviruses
  • Pyrrolidinones / pharmacology*
  • Pyrrolidinones / therapeutic use*
  • RNA, Viral
  • Raltegravir Potassium
  • Viral Load
  • Virus Integration
  • Young Adult

Substances

  • HIV Integrase Inhibitors
  • Pyrrolidinones
  • RNA, Viral
  • Raltegravir Potassium