No Effect of Raltegravir Intensification on Viral Replication Markers in the Blood of HIV-1–Infected Patients Receiving Antiretroviral Therapy

Background: Controversy continues regarding the extent of ongoing viral replication in HIV-1–infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication. Methods: We previously reported the outcome of a randomized placebo-controlled study of raltegravir intensification in patients on ART with HIV-1 RNA <50 copies per milliliter that showed no effect on residual viremia measured by single copy assay. We now report the effects of raltegravir intensification in that trial on other potential measures of ongoing HIV-1 replication as follows: 2-LTR HIV-1 circles, total cellular HIV-1 DNA, and T-cell activation. Results: Of 50 patients tested, 12 (24%) had 2-LTR circles detected at baseline. Patients who were 2-LTR–positive had higher plasma HIV-1 RNA and HIV-1 DNA levels than 2-LTR–negative individuals. At week 12 of raltegravir intensification, there was no change from baseline in 2-LTR circles, in total HIV-1 DNA or in the ratio of 2-LTR circles to total HIV-1 DNA. There was also no change in markers of T-cell activation. Conclusions: In HIV-1–infected individuals on effective ART, we find no evidence of ongoing viral replication in the blood that is suppressible by raltegravir intensification. The results imply that raltegravir intensification alone will not eradicate HIV-1 infection.

[1]  J Witek,et al.  Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. , 1999, JAMA.

[2]  Joseph A Kovacs,et al.  ART Suppresses Plasma HIV-1 RNA to a Stable Set Point Predicted by Pretherapy Viremia , 2007, PLoS pathogens.

[3]  J. Mellors,et al.  Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy , 2008, Proceedings of the National Academy of Sciences.

[4]  Ron Milo,et al.  Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy , 2011, Nature.

[5]  Sarah Palmer,et al.  HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects , 2010, Nature Medicine.

[6]  Tara L. Kieffer,et al.  Genotypic analysis of HIV-1 drug resistance at the limit of detection: virus production without evolution in treated adults with undetectable HIV loads. , 2004, The Journal of infectious diseases.

[7]  S. Lewin,et al.  HIV cure and eradication: how will we get from the laboratory to effective clinical trials? , 2011, AIDS.

[8]  S J Gange,et al.  Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  Jeffrey N. Martin,et al.  T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. , 2003, The Journal of infectious diseases.

[10]  Meei-Li W Huang,et al.  Coamplified positive control detects inhibition of polymerase chain reactions , 1992, Journal of clinical microbiology.

[11]  C. B. Hare,et al.  Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. , 2010, The Journal of infectious diseases.

[12]  M. Lederman,et al.  The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial , 2010, PLoS medicine.

[13]  T. Calvez,et al.  Longitudinal monitoring of 2-long terminal repeat circles in peripheral blood mononuclear cells from patients with chronic HIV-1 infection , 2003, AIDS.

[14]  D. Hazuda,et al.  The Challenge of Finding a Cure for HIV Infection , 2009, Science.

[15]  John L. Sullivan,et al.  Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy , 2000, Nature Medicine.

[16]  C. B. Hare,et al.  Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy , 2010, AIDS.

[17]  Jeffrey N. Martin,et al.  A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. , 2011, The Journal of infectious diseases.

[18]  Tara L. Kieffer,et al.  Intrinsic Stability of Episomal Circles Formed during Human Immunodeficiency Virus Type 1 Replication , 2002, Journal of Virology.

[19]  Connie Celum,et al.  Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. , 2007, The Journal of infectious diseases.