Hide and Seek… Can We Eradicate HIV by Treatment Intensification?

Abstract

Although the introduction of combination antiretroviral therapy (ART) in the mid-1990s led to a remarkable reduction of human immunodeficiency virus (HIV)–associated morbidity and mortality, eradication of the virus is still regarded as the holy grail by the HIV community. However, complete elimination of HIV has remained an elusive goal. Even patients who are successfully treated with ART for several years often do not achieve full recovery of their CD4 cell count (.500 cells/lL) and exhibit increased levels of immune activation along with its detrimental effects [1]. In addition, low levels of viremia can be readily detected by sensitive single copy assays [2]. The underlying reasons for the persistent immune activation detected in these patients are not entirely understood. Although the role of microbial translocation stemming from a ‘‘leaky gut’’ in the HIV-infected patient has become more evident [3], immune activation may at least partially be caused by ongoing low-level viral replication. Residual viremia may stem from ongoing cycles of viral replication and infection of new cells, for which additional intensification of ART might be useful. Alternatively, viremia might stem from the release of virions from stable reservoirs of latently infected cells. Because no full cycle of viral replication would be needed for HIV release, intensification would be potentially fruitless in this situation [4, 5]. Thus far, all approved antiretroviral drugs have worked through interference with active viral replication but have not targeted latent infection. The advent and approval of new drug classes with new modes of action, namely integrase inhibitors and CCR5 antagonists, have revived treatment strategies aimed at eradication of HIV infection. In the absence of a cure, these strategies may at least further reduce persistent viral load and/or decrease immune activation. In this issue of the Journal, Hatano et al [6] present the latest of a series of clinical studies published over the past year (Table 1) that have examined the consequence of treatment intensification with raltegravir, a new and potent antiretroviral HIV integrase inhibitor approved by the US Food and Drug Administration in 2007. Initial kinetic calculations predicted that treatment intensification could, indeed, have an effect on re-infection of latently infected cells and impact residual low-level viremia [11]. In an earlier treatment intensification trial, Buzon et al [7] randomized 69 patients to receive treatment intensification with raltegravir in addition to conventional highly active antiretroviral therapy (HAART; 45 patients in the raltegravir treatment intensification arm, and 24 patients in the control group). The authors used a novel approach to assess the presence of low-level persistent replication, namely quantification of long terminal repeat (LTR) circles. During HIV replication, a small proportion of the linear HIV complementary DNA (cDNA) is circularized by host DNA repair enzymes and circular episomes, with 1 or 2 copies of the LTRs (1-LTRs or 2-LTRs) produced. Because raltegravir blocks integration of viral linear cDNA into genomic host cell DNA, any residual viral replication should lead to an increase of the number of LTR circles [12, 13]. The authors of this study, indeed, measured a significant, albeit transient, increase of the 2-LTRs circles in up to 30% of patients in the raltegravir group, but in only 5% of the control group [7]. Of note, however, 2-LTR circles were detectable at baseline in 5 patients in the intensification group, but not in the control group. A post hoc analysis of the subgroup of patients in whom 2-LTR circles were detected revealed that 61% of these Received and accepted 23 November 2010. Potential conflicts of interest: J.v.L. and J.S.z.W. have received speaker honoraria from Essex Pharma. J.v.L. was a clinical trials investigator, received speaker honoraria, and was a member of an advisory board for Merck. Reprints or correspondence: Jan van Lunzen, PhD, MD, Dept of Medicine, Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20246 Hamburg, Germany (v.lunzen@uke.uni-hamburg.de). The Journal of Infectious Diseases 2011;203:894–7 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com 1537-6613/2011/2037-0001$15.00 DOI: 10.1093/infdis/jiq150