A Randomized, Controlled Trial of Raltegravir Intensification in Antiretroviral-treated, HIV-infected Patients with a Suboptimal CD4+ T Cell Response

Hatano, Hiroyu; Hayes, Timothy L.; Dahl, Viktor; Sinclair, Elizabeth; Lee, Tzong‐Hae; Hoh, Rebecca; Lampiris, Harry; Hunt, Peter W.; Palmer, Sarah; McCune, Joseph M.; Martin, Jeffrey N.; Busch, Michael P.; Shacklett, Barbara L.; Deeks, Steven G.

doi:10.1093/infdis/jiq138

Cited by 177 publications

(141 citation statements)

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“…[36][37][38][39] However, none of these studies was placebo-controlled, and subjects often improve their ART adherence when entering clinical trials, which may have explained the reduction in low-level viremia experienced by placebo-treated subjects in our own trial and in another recently reported intensification study. 40 The apparent reduction in T-cell activation during maraviroc intensification reported in the uncontrolled AIDS clinical trials group study (A5256) was also primarily driven by declines in CD38 expression, whereas HLA-DR expression actually increased significantly (which is largely consistent with our results), and neither of those changes were confirmed when retesting cryopreserved PBMCs from that trial. 36 The only other placebo-controlled trial of maraviroc intensification did not find any evidence for a difference in T-cell activation between placebo-and maraviroc-treated subjects, although final results have not yet been published.…”

Section: Discussionsupporting

confidence: 87%

The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

Hunt

Shulman

Hayes

et al. 2013

Blood

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129

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Key Points• Maraviroc intensification unexpectedly increases T-cell activation in peripheral blood and rectal mucosa during treated HIV infection.• Maraviroc appears to redistribute CD81 T cells from the gut to peripheral blood during treated HIV infection.The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIVinfected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm 3 and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART)to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD381HLA-DR1 peripheral blood CD81 T cells at week 24 (12.2% vs 20.7%, P 5 .014), and less of a decline in activated CD41 T cells (P < .001). The % CD381HLA-DR1 CD41 and CD81 T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1b) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligandmediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072. (Blood. 2013;121(23):4635-4646)

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Section: Discussionsupporting

confidence: 87%

The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

Hunt

Shulman

Hayes

et al. 2013

Blood

Self Cite

129

123

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“…This suggests that treatment intensification adding more drugs to current treatment regimens may not help to reduce the size of the latent reservoir or eradicate the virus. This is consistent with a number of clinical trials in which addition of new drugs such as the integrase inhibitor raltegravir did not reduce persistent low-level viremia in patients with HIV suppression during combination antiretroviral therapy [5,18,22,23,28,53]. It also agrees with our recent results of using a multi-stage model to study the dynamics of 2-LTR (long terminal repeat) circles, a marker of recent viral infection [52].…”

Section: Discussionsupporting

confidence: 92%

An HIV model with age-structured latently infected cells

Alshorman

Samarasinghe

et al. 2016

Journal of Biological Dynamics

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HIV latency remains a major obstacle to viral elimination. The activation rate of latently infected cells may depend on the age of latent infection. In this paper, we develop a model of HIV infection including age-structured latently infected cells. We mathematically analyse the model and use numerical simulations with different activation functions to show that the model can explain the persistence of lowlevel viremia and the latent reservoir stability in patients on therapy. Sensitivity tests suggest that the model is robust to the changes of most parameters but is sensitive to the relative magnitude of the net generation rate and the long-term activation rate of latently infected cells. To reduce the sensitivity, we extend the model to include homeostatic proliferation of latently infected cells. The new model is robust in reproducing the long-term dynamics of the virus and latently infected cells observed in patients receiving prolonged combination therapy. ARTICLE HISTORY

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“…usRNA can be easily detected with a seminested or nested quantitative reverse transcription PCR (qRT-PCR) (36-39) or by ddPCR, using a set of primers and probe against Pol or Gag (17, 30, 33, 39). Alternatively, some investigators have adapted commercial quantitative tests for HIV-1 plasma viremia, such as Amplicor (Roche Diagnostics) (40,41) or APTIMA HIV-1 Qualitative assay (Hologic) (42,43) for the quantitation of caRNA. msRNA primers are designed to amplify a region containing the Tat/Rev (or Tat/Nef) exon-exon junction and can be quantified by nested qRT-PCR (36, 38, 39) or ddPCR (17,39,44).…”

Section: Pcr-based Assays To Measure the Latent Reservoirmentioning

confidence: 99%