Impact of Raltegravir on HIV-1 cDNA Slope Following Antiretroviral Therapy (ART) Initiation

Overview

Recent clinical trials of combination antiretroviral therapy (cART) containing the first approved integrase inhibitor (i.e. raltegravir) have demonstrated a more rapid decay of HIV-1 RNA in plasma, compared to conventional potent antiretroviral combinations. This was observed especially during the early phase (up to week 12) following initiation of cART. To explain this, two mechanistic hypotheses have been developed: 1. \- Macrophage reservoir death hypothesis. A major source of virus production during the second phase decay are believed to be long-lived infected cells with continuous virus production - e.g. macrophages. An accumulation of unintegrated, episomal HIV-1 cDNAs can promote apoptosis (Li et al. Embo J. 2001;20: 3272). In case of HIV superinfection of such a productively infected cell, an INI-based cART may induce apoptosis and thus contribute to a decrease in HIV RNA load during second phase decay. However, no study has thus far addressed the consequences of INI treatment on HIV-1 cDNA species on any cell population in vivo. 2. \- Resting CD4 T-cell reservoir integration block hypothesis. Resting CD4 T-cells may represent a substantial reservoir for HIV replication during the second phase decay as well. A special characteristic of these cells is that HIV-1 cDNA is typically localized to the nucleus in a not-integrated form (Chun et al., PNAS 1997;94:13193). These resting cells likely integrate HIV-DNA upon activation and then contribute to HIV viremia and viral spread. Conceptually, integration could be prevented by RGV, but not by RTI or PI. An accumulation of circular episomal HIV-1 cDNA species may also be a consequence of RGV treatment in this cell type. Patient disposition: To explore raltegravir-induced shifts in HIV-1 cDNA species in vivo, this non-interventional clinical observation investigates the dynamics of the three major HIV-1 cDNA species (total HIV-1 cDNA, HIV-1 integrants in the host cell genome, episomal HIV-1 2-LTR circles) over a period of 4 months in two groups of patients starting off cART from a single study center. Patients who begin cART in regular clinical routine with 2N(t)RTI plus either (n=10 patients) raltegravir or (n=10 patients) a boosted protease inhibitor/ alternatively an NNRTI will be offered to participate in this observation. Only patients are offered to participate in this trial if no other antiretroviral drugs than the above mentioned and no concomitant drugs with relevant impact on antiretroviral's pharmacokinetics are administered. At time of study inclusion, patients should be characterised by a HIV-1 RNA load of \>5,000 copies/mL and CD4-cell count of \>200/µL within 12 weeks before cART initiation. Preliminary analyses of PBMCs from HIV-infected patients indicate that all three major HIV-1 cDNA species can be quantified by real-time PCR under these baseline conditions.