Yukl, SA, Shergill, AK, McQuaid, K, Gianella, S, Lampiris, H, Hare, CB 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. AIDS 24: 2451-2460

San Francisco VA Medical Center (SFVAMC) and University of California, San Francisco (UCSF), San Francisco, California, USA.
AIDS (London, England) (Impact Factor: 5.55). 10/2010; 24(16):2451-60. DOI: 10.1097/QAD.0b013e32833ef7bb
Source: PubMed


To determine whether raltegravir-containing antiretroviral therapy (ART) intensification reduces HIV levels in the gut.
Open-label study in HIV-positive adults on ART with plasma HIV RNA below 40 copies/ml.
Seven HIV-positive adults received 12 weeks of ART intensification with raltegravir alone or in combination with efavirenz or darunavir. Gut cells were obtained by upper and lower endoscopy with biopsies from duodenum, ileum, colon, and rectum at baseline and 12 weeks. Study outcomes included plasma HIV RNA, HIV DNA and RNA from peripheral blood mononuclear cells (PBMC) and four gut sites, T-cell subsets, and activation markers.
Intensification produced no consistent decrease in HIV RNA in the plasma, PBMC, duodenum, colon, or rectum. However, five of seven participants had a decrease in unspliced HIV RNA per 10 CD4(+) T cells in the ileum. There was a trend towards decreased T-cell activation in all sites, which was greatest for CD8(+) T cells in the ileum and PBMC, and a trend towards increased CD4(+) T cells in the ileum.
Most HIV RNA and DNA in the blood and gut is not the result of ongoing replication that can be impacted by short-term intensification with raltegravir. However, the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible.

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Available from: Huldrych F Günthard
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    • "However, the source of this residual viremia remains controversial, with competing arguments supporting its origin from incompletely suppressed viral replication (especially in tissues), vs. suggestions that it arises from stochastic reactivation of latently infected cells, or from persistently infected cells not susceptible to inhibition by cART, and/or resistant to immune clearance. Numerous cART intensification studies have attempted to address this question, with most showing no impact, although a couple of studies have demonstrated apparent effects of treatment intensification, particularly when adding integrase inhibitors to base regimens including protease inhibitors [28], [29] [30]. "
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    • "Because HIV-1 might replicate in tissue reservoirs where drug concentrations are suboptimal (Fletcher et al., 2014), such as lymph nodes, gut associated lymphoid tissues, bone marrow and the central nervous system, some RAL intensification studies assessed the immunologic and virologic responses in tissues. Yukl et al., showed reduction in unspliced HIV RNA, T cell activation and a trend towards CD4 þ T cell increases in ileum, suggesting that this tissue may be an important site for ongoing replication in some patients on cART (Yukl et al., 2010). In contrast, therapy intensification with RAL did not impact cerebrospinal viral loads (Dahl et al., 2011) or isolated HIV semen shedding (Osborne et al., 2013). "
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    • "In support of full suppression of viral replication with cART, patients with good adherence to treatment do not show evidence of viral evolution and treatment failure; also no further decrease of residual viremia is seen with intensification of cART regimens [5-7]. However, recent treatment intensification studies with the Integrase Inhibitor (INI) Raltegravir have noted an increase in episomal DNA and a reduction in the size of the latent reservoir [2-4]. These studies suggest that there is ongoing residual viral replication, which may be suppressed by addition of INIs to existing treatment regimens. "
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