Intensifying Antiretroviral Therapy With Raltegravir and Maraviroc During Early Human Immunodeficiency Virus (HIV) Infection Does Not Accelerate HIV Reservoir Reduction

Persistent human immunodeficiency virus (HIV) within the CD4⁺ T-cell reservoir is an obstacle to eradication. We hypothesized that adding raltegravir and maraviroc to standard combination antiretroviral therapy (cART) during early HIV infection could substantially reduce viral reservoirs as a step towards eradication.

A prospective, randomized, double-blinded, placebo-controlled pilot trial enrolled 32 participants with documented early (<6 months) HIV infection to either standard cART (emtricitabine/tenofovir/lopinavir/ritonavir) or intensive cART (standard regimen + raltegravir/maraviroc). Human immunodeficiency virus reservoirs were assessed at baseline and at 48 weeks by (1) proviral DNA, (2) cell-associated RNA, and (3) replication-competent virus, all from purified blood CD4⁺ T cells, and (4) gut proviral DNA. A multiassay algorithm (MAA) on baseline sera estimated timing of infection.

Thirty individuals completed the study to the 48-week endpoint. The reduction in blood proviral burden was −1.03 log DNA copies/10⁶ CD4⁺ T cells versus −.84 log in the standard and intensive groups, respectively (P = .056). Overall, there was no significant difference in the rate of decline of HIV-associated RNA, replication-competent virus in blood CD4⁺ T cells, nor proviral gut HIV DNA to 48 weeks. Individuals who presented with more recent HIV infection had significantly lower virus reservoirs, and cART tended to reduce their reservoirs to a greater extent.

Intensive cART led to no additional reduction in the blood virus reservoir at 48 weeks compared with standard cART. Human immunodeficiency virus reservoir size is smaller earlier in HIV infection. Other novel treatment strategies in combination with early cART will be needed to eliminate the HIV latent reservoir.

Below:  Effect of treatments on plasma viral load and peripheral CD4/CD8 counts. Plasma virus load kinetics on treatment for 30 subjects completing primary endpoint shown in (A) and CD4 and CD8 counts at baseline and 48 weeks in (B). Medians are depicted.

Below:  Human immunodeficiency virus (HIV) viral reservoir determinations for standard and intensive therapy groups. In (A) are kinetics of proviral DNA copies/million isolated CD4+ T cells from peripheral blood mononuclear cells (PBMC) (n = 30, medians with interquartile ranges); in (B) are baseline 24- and 48-week HIV RNA/µg of RNA from isolated CD4+ T cells from PBMC (n = 30, medians with interquartile ranges); in (C) are infectious HIV units cultured/million isolated CD4+ T cells from PBMC (n = 29 evaluable), with summary graph far right (medians with interquartile ranges); and in (D) are proviral DNA copies/million isolated CD8-depleted cells from sigmoid colon mononuclear cells (n = 19 evaluable), with summary graph far right (medians with interquartile ranges). Abbreviation: VL, viral load.

Full article at: http://goo.gl/dmuX9X

By: Mario Ostrowski,1,2,4 Erika Benko,3 Feng Yun Yue,2 Connie J. Kim,2 Sanja Huibner,2 Terry Lee,7,8 Joel Singer,7,8 Jim Pankovich,7,8 Oliver Laeyendecker,5,6 Rupert Kaul,1,2 Gabor Kandel,2,4 and Colin Kovacs2,3

¹Departments of Immunology

²Medicine, University of Toronto

³Maple Leaf Clinic

⁴Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada

⁵Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda

⁶Johns Hopkins University, Baltimore, Maryland

⁷University of British Columbia

⁸CIHR Canadian HIV Trials Network, Vancouver, British Columbia, Canada

Correspondence: Mario Ostrowski, MD, Room 6271, Medical Sciences Building, 1 King's College Circle, Toronto, ON M5S1A8, Canada (Email:moc.liamg@ikswortso.oiram).

   

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