TreatmentUpdate
229

December 2018 

Dual drug therapy—impact on the HIV reservoir

As explained earlier in this issue of TreatmentUpdate, clinical trials with dual drug regimens based on the powerful integrase inhibitor dolutegravir are underway. One dual drug combination, Juluca (dolutegravir + rilpivirine), has already been approved for use in Canada and other high-income countries. Juluca is meant for use as simplification in place of more complex regimens among patients whose viral loads are less than 50 copies/mL and have been that way for some time. Another combination, dolutegravir + 3TC, is expected to be approved in 2019 in Canada and other high-income countries.

About the reservoir

After HIV infection has occurred, the virus becomes established in cells of the immune system—T-cells and a group of relatively long-lived cells called monocytes (in their mature form these are called macrophages). Monocytes/macrophages travel throughout the body, spending time in major organ-systems. As a result, HIV-infected cells are found in many parts of the body, including the following:

  • brain and spinal cord
  • the immune system: lymph nodes and lymphoid tissues as well as organs such as the spleen, bone marrow and thymus gland
  • lungs
  • kidneys
  • fatty tissues

Although potent combination anti-HIV therapy (ART) greatly suppresses the production of HIV in the blood, some studies suggest that small amounts of HIV are still produced in lymph nodes.

Researchers refer to the burden of HIV-infected cells in the body as the reservoir. Studies are underway to try to reduce and possibly eliminate this burden.

An important question about dual drug therapy is its impact on the reservoir.

The Verona study

Researchers at the University of Verona in Italy conducted a pilot study to assess the impact of induction-maintenance therapy. All participants who were new to ART were initially treated with standard triple-drug therapy, in this case Triumeq (dolutegravir + 3TC + abacavir). After participants had achieved and maintained viral suppression for 12 consecutive months, their regimens were simplified to dolutegravir + 3TC.

In 14 participants who were able to undergo dual therapy for between one and eight months, researchers found no significant differences in the burden of infected cells in their blood samples compared to the level of these cells after 12 months of taking triple therapy.

Thus, data from this pilot study strongly suggest that induction-maintenance therapy does not increase the size of the HIV reservoir, at least over the short term. Longer and larger studies should be done to confirm this finding.

—Sean R. Hosein

REFERENCES:

  1. Lanzafame M, Nicole S, Rizzardo S, et al. Immunovirological outcome and HIV-1 DNA decay in a small cohort of HIV-1-infected patients deintensificated from abacavir/lamivudine/dolutegravir to lamivudine plus dolutegravir. New Microbiologica. 2018; in press.
  2. Damouche A, Pourcher G, Pourcher V, et al. High proportion of PD-1-expressing CD4+ T cells in adipose tissue constitutes an immunomodulatory microenvironment that may support HIV persistence. European Journal of Immunology. 2017 Dec;47(12):2113-2123.
  3. Al-Harti L, Joseph J, Nath A. Astrocytes as an HIV CNS reservoir: highlights and reflections of an NIMH-sponsored symposium. Journal of Neurovirology. 2018; in press.
  4. Cenker JJ, Stultz RD, McDonald D. Brain microglial cells are highly susceptible to HIV-1 infection and spread. AIDS Research and Human Retroviruses. 2017 Nov;33(11):1155-1165.
  5. Lamers SL, Rose R, Maidji E, et al. HIV DNA is frequently present within pathologic tissues evaluated at autopsy from combined antiretroviral therapy-treated patients with undetectable viral loads. Journal of Virology. 2016 Sep 29;90(20):8968-83.
  6. Rose R, Lamers SL, Nolan DJ, et al. HIV maintains an evolving and dispersed population in multiple tissues during suppressive combined antiretroviral therapy in individuals with cancer. Journal of Virology. 2016 Sep 29;90(20):8984-93.
  7. Nolan DJ, Rose R, Rodriguez PH, et al. The spleen is an HIV-1 sanctuary during combined antiretroviral therapy. AIDS Research and Human Retroviruses. 2018 Jan;34(1):123-125.
  8. Clayton KL, Collins DR, Lengieza J, et al. Resistance of HIV-infected macrophages to CD8+ T lymphocyte-mediated killing drives activation of the immune system. Nature Immunology. 2018 May;19(5):475-486.
  9. Castellano P, Prevedel L, Eugenin EA. HIV-infected macrophages and microglia that survive acute infection become viral reservoirs by a mechanism involving Bim. Scientific Reports. 2017 Oct 9;7(1):12866.
  10. Bandera A, Ferrario G, Saresella M, et al. CD4+ T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals. PLoS One. 2010 May 24;5(5):e10788.
  11. Costiniuk CT, Salahuddin S, Farnos O, et al. HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy. AIDS. 2018 Oct 23;32(16):2279-2289.
  12. Blasi M, Balakumaran B, Chen P, et al. Renal epithelial cells produce and spread HIV-1 via T-cell contact. AIDS. 2014 Oct 23;28(16):2345-53.
  13. Noto A, Procopio FA, Banga R, et al. CD32+ and PD-1+ lymph node CD4 T cells support persistent HIV-1 transcription in treated aviremic individuals. Journal of Virology. 2018 Sep 26;92(20).
  14. Huot N, Bosinger SE, Paiardini M, et al. Lymph node cellular and viral dynamics in natural hosts and impact for HIV cure strategies. Frontiers in Immunology. 2018 Apr 19;9:780.
  15. Dahl V, Peterson J, Fuchs D, et al. Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS. 2014 Sep 24;28(15):2251-8.
  16. Reeves DB, Duke ER, Wagner TA, et al. A majority of HIV persistence during antiretroviral therapy is due to infected cell proliferation. Nature Communications. 2018 Nov 16;9(1):4811