Raltegravir Activity In Lymphoid Tissues

Overview

The reduction with antiretroviral therapy (ART) of HIV RNA in blood, and HIV RNA in infected cells and in viruses associated with the follicular dendritic cell (FDC) network in lymphatic tissues, typically follows a two-phase pattern of decline. The half-life of the first-phase is about 1 day and that of the second phase is about 14 days, with comparable estimates for first-phase decay in SIV-infected rhesus macaques. While substantial evidence supports the current view that first-phase decay reflects the death of activated CD4+ T cells infected before ART was begun, the sources of viral RNA in the second phase have not as yet been conclusively established. Possible sources of viral RNA that have been invoked in mathematical models, or for which there is experimental evidence, include longer-lived infected cells such as macrophages and resting CD4+ T cells, dissociation of virus from the FDC network, and productively infected CD4+ T cells that are not subject to clearance by host immune responses because of waning levels of HIV antigen. Raltegravir (MK-0518) belongs to a new class of integrase inhibitors that potently suppress HIV and SIV replication, and reportedly markedly alters the second phase HIV decline in a way that challenges the current view that longer-lived infected cells are the source of virus in this phase. While mathematical modeling of decay of HIV RNA in blood was most consistent with 1) cells newly infected by long-lived cells, or 2) from activation of latently infected cells with full-length unintegrated HIV DNA as a source of second phase virus, we think the data are also quite consistent with the greater efficacy of integrase inhibitors in a particular cell type and/or anatomic site such as the gut. In this protocol we will test the hypothesis that the rapid decrease in HIV replication associated with raltegravir is due to a more complete suppression of viral replication in lymphatic compartments such as lymph nodes and gastrointestinal lymphatic tissue. We will also investigate compartment-specific intracellular levels of raltegravir to potentially explain differences in changes in these compartments.

The study will evaluate rates of HIV elimination in peripheral blood in comparison to secondary lymphatic tissues, including inguinal lymph nodes (LN) and gastrointestinal lymphatic tissues (GALT). HIV-infected patients who are antiretroviral therapy (ART) naive and fit criteria to initiate ART will be randomized to either Truvada (tenofovir/emtricitabine) + Sustiva (efavirenz - 600mg qDAY orally - standard of care) or Truvada + Isentress (raltegravir - 400mg BID orally). Patients will have a blood draw, a colonoscopy with biopsies, and inguinal lymph node excision at days 0, 2, 7, 14, and week 52. Plasma HIV RNA and CD4+ T cell quantitation will be performed conventionally. HIV mRNA will be quantitated in LN and GALT using in-situ hybridization (ISH). Immunohistochemistry (IHC) will be performed to quantitate changes in CD4+ cell numbers over time in tissues from each respective ART regimen.