Impact of Integrase Inhibition Compared with Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues

Meghan Rothenberger; Krystelle Nganou-Makamdop; Cissy Kityo; Francis Ssali; Jeffrey G. Chipman; Gregory J. Beilman; Torfi Hoskuldsson; Jodi Anderson; Jake Jasurda; Thomas E. Schmidt; Samuel P. Calisto; Hope Pearson; Thomas Reimann; Caitlin David; Katherine Perkey; Peter Southern; Steve Wietgrefe; Erika Helgeson; Cavan Reilly; Ashley T. Haase; Daniel C. Douek; Courtney V. Fletcher; Timothy W. Schacker

doi:10.1097/QAI.0000000000002026

Impact of Integrase Inhibition Compared with Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues

Meghan Rothenberger, Krystelle Nganou-Makamdop, Cissy Kityo, Francis Ssali, Jeffrey G. Chipman, Gregory J. Beilman, Torfi Hoskuldsson, Jodi Anderson, Jake Jasurda, Thomas E. Schmidt, Samuel P. Calisto, Hope Pearson, Thomas Reimann, Caitlin David, Katherine Perkey, Peter Southern, Steve Wietgrefe, Erika Helgeson, Cavan Reilly, Ashley T. HaaseDaniel C. Douek, Courtney V. Fletcher, Timothy W. Schacker

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Abstract

Background:HIV is produced in lymphoid tissues (LT) and stored on the follicular dendritic cell network in LT. When antiretroviral therapy is started, plasma viremia decays in 2 phases; the first within days of starting therapy and the second over weeks. Raltegravir (RAL), an integrase inhibitor, has been associated with only a single rapid phase of decay, and we speculated this may be due to higher intracellular concentration (IC) of RAL in LT. We have previously measured suboptimal ICs of antiretroviral therapy agents in LT, which were associated with slower decay of both vRNA+ cells and the follicular dendritic cell network pool.Setting:Outpatient clinic at the Joint Clinical Research Center in Kampala, Uganda.Methods:We compared the rate of decay in LT in people starting RAL with those starting efavirenz (EFV).Results:There was no difference in the rate of virus decay in LT. The ratio of the ICs of RAL and EFV in lymph node to the concentration of drug that inhibits 95% of virus in blood was 1 log lower in lymph node for EFV and >3 logs lower for RAL.Conclusion:These data further highlight the challenges of drug delivery to LT in HIV infection and demonstrate that RAL is not superior to EFV as judged by direct measurements of the source of virus in LT.

Original language	English (US)
Pages (from-to)	355-360
Number of pages	6
Journal	Journal of Acquired Immune Deficiency Syndromes
Volume	81
Issue number	3
DOIs	https://doi.org/10.1097/QAI.0000000000002026
State	Published - Jul 1 2019

Bibliographical note

Funding Information:
From the aDepartment of Medicine, University of Minnesota, Minneapolis, MN; bVaccine Research Center, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD; cJoint Clinical Research Center, Kampala, Uganda; Departments of dSurgery; eMicrobiology and Immu-nology; and fBiostatistics, University of Minnesota, Minneapolis, MN; and gCollege of Pharmacy, University of Nebraska Medical Center, Omaha, NE Supported by an unrestricted grant from Merck, R01-AI124965, and UL1TR000114. No sponsor or funder played a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc.

Keywords

HIV
antiviral effect
drug levels
pharmacology
virus decay

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1097/QAI.0000000000002026

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582649

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Rothenberger, M., Nganou-Makamdop, K., Kityo, C., Ssali, F., Chipman, J. G., Beilman, G. J., Hoskuldsson, T., Anderson, J., Jasurda, J., Schmidt, T. E., Calisto, S. P., Pearson, H., Reimann, T., David, C., Perkey, K., Southern, P., Wietgrefe, S., Helgeson, E., Reilly, C., ... Schacker, T. W. (2019). Impact of Integrase Inhibition Compared with Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues. Journal of Acquired Immune Deficiency Syndromes, 81(3), 355-360. https://doi.org/10.1097/QAI.0000000000002026

Rothenberger, M, Nganou-Makamdop, K, Kityo, C, Ssali, F, Chipman, JG , Beilman, GJ, Hoskuldsson, T, Anderson, J, Jasurda, J, Schmidt, TE, Calisto, SP, Pearson, H, Reimann, T, David, C, Perkey, K, Southern, P, Wietgrefe, S, Helgeson, E , Reilly, C , Haase, AT, Douek, DC, Fletcher, CV & Schacker, TW 2019, 'Impact of Integrase Inhibition Compared with Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues', Journal of Acquired Immune Deficiency Syndromes, vol. 81, no. 3, pp. 355-360. https://doi.org/10.1097/QAI.0000000000002026

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title = "Impact of Integrase Inhibition Compared with Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues",

abstract = "Background:HIV is produced in lymphoid tissues (LT) and stored on the follicular dendritic cell network in LT. When antiretroviral therapy is started, plasma viremia decays in 2 phases; the first within days of starting therapy and the second over weeks. Raltegravir (RAL), an integrase inhibitor, has been associated with only a single rapid phase of decay, and we speculated this may be due to higher intracellular concentration (IC) of RAL in LT. We have previously measured suboptimal ICs of antiretroviral therapy agents in LT, which were associated with slower decay of both vRNA+ cells and the follicular dendritic cell network pool.Setting:Outpatient clinic at the Joint Clinical Research Center in Kampala, Uganda.Methods:We compared the rate of decay in LT in people starting RAL with those starting efavirenz (EFV).Results:There was no difference in the rate of virus decay in LT. The ratio of the ICs of RAL and EFV in lymph node to the concentration of drug that inhibits 95% of virus in blood was 1 log lower in lymph node for EFV and >3 logs lower for RAL.Conclusion:These data further highlight the challenges of drug delivery to LT in HIV infection and demonstrate that RAL is not superior to EFV as judged by direct measurements of the source of virus in LT.",

keywords = "HIV, antiviral effect, drug levels, pharmacology, virus decay",

author = "Meghan Rothenberger and Krystelle Nganou-Makamdop and Cissy Kityo and Francis Ssali and Chipman, {Jeffrey G.} and Beilman, {Gregory J.} and Torfi Hoskuldsson and Jodi Anderson and Jake Jasurda and Schmidt, {Thomas E.} and Calisto, {Samuel P.} and Hope Pearson and Thomas Reimann and Caitlin David and Katherine Perkey and Peter Southern and Steve Wietgrefe and Erika Helgeson and Cavan Reilly and Haase, {Ashley T.} and Douek, {Daniel C.} and Fletcher, {Courtney V.} and Schacker, {Timothy W.}",

note = "Funding Information: From the aDepartment of Medicine, University of Minnesota, Minneapolis, MN; bVaccine Research Center, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD; cJoint Clinical Research Center, Kampala, Uganda; Departments of dSurgery; eMicrobiology and Immu-nology; and fBiostatistics, University of Minnesota, Minneapolis, MN; and gCollege of Pharmacy, University of Nebraska Medical Center, Omaha, NE Supported by an unrestricted grant from Merck, R01-AI124965, and UL1TR000114. No sponsor or funder played a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2019 The Author(s). Published by Wolters Kluwer Health, Inc.",

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T1 - Impact of Integrase Inhibition Compared with Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues

AU - Rothenberger, Meghan

AU - Nganou-Makamdop, Krystelle

AU - Kityo, Cissy

AU - Ssali, Francis

AU - Chipman, Jeffrey G.

AU - Beilman, Gregory J.

AU - Hoskuldsson, Torfi

AU - Anderson, Jodi

AU - Jasurda, Jake

AU - Schmidt, Thomas E.

AU - Calisto, Samuel P.

AU - Pearson, Hope

AU - Reimann, Thomas

AU - David, Caitlin

AU - Perkey, Katherine

AU - Southern, Peter

AU - Wietgrefe, Steve

AU - Helgeson, Erika

AU - Reilly, Cavan

AU - Haase, Ashley T.

AU - Douek, Daniel C.

AU - Fletcher, Courtney V.

AU - Schacker, Timothy W.

N1 - Funding Information: From the aDepartment of Medicine, University of Minnesota, Minneapolis, MN; bVaccine Research Center, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD; cJoint Clinical Research Center, Kampala, Uganda; Departments of dSurgery; eMicrobiology and Immu-nology; and fBiostatistics, University of Minnesota, Minneapolis, MN; and gCollege of Pharmacy, University of Nebraska Medical Center, Omaha, NE Supported by an unrestricted grant from Merck, R01-AI124965, and UL1TR000114. No sponsor or funder played a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background:HIV is produced in lymphoid tissues (LT) and stored on the follicular dendritic cell network in LT. When antiretroviral therapy is started, plasma viremia decays in 2 phases; the first within days of starting therapy and the second over weeks. Raltegravir (RAL), an integrase inhibitor, has been associated with only a single rapid phase of decay, and we speculated this may be due to higher intracellular concentration (IC) of RAL in LT. We have previously measured suboptimal ICs of antiretroviral therapy agents in LT, which were associated with slower decay of both vRNA+ cells and the follicular dendritic cell network pool.Setting:Outpatient clinic at the Joint Clinical Research Center in Kampala, Uganda.Methods:We compared the rate of decay in LT in people starting RAL with those starting efavirenz (EFV).Results:There was no difference in the rate of virus decay in LT. The ratio of the ICs of RAL and EFV in lymph node to the concentration of drug that inhibits 95% of virus in blood was 1 log lower in lymph node for EFV and >3 logs lower for RAL.Conclusion:These data further highlight the challenges of drug delivery to LT in HIV infection and demonstrate that RAL is not superior to EFV as judged by direct measurements of the source of virus in LT.

AB - Background:HIV is produced in lymphoid tissues (LT) and stored on the follicular dendritic cell network in LT. When antiretroviral therapy is started, plasma viremia decays in 2 phases; the first within days of starting therapy and the second over weeks. Raltegravir (RAL), an integrase inhibitor, has been associated with only a single rapid phase of decay, and we speculated this may be due to higher intracellular concentration (IC) of RAL in LT. We have previously measured suboptimal ICs of antiretroviral therapy agents in LT, which were associated with slower decay of both vRNA+ cells and the follicular dendritic cell network pool.Setting:Outpatient clinic at the Joint Clinical Research Center in Kampala, Uganda.Methods:We compared the rate of decay in LT in people starting RAL with those starting efavirenz (EFV).Results:There was no difference in the rate of virus decay in LT. The ratio of the ICs of RAL and EFV in lymph node to the concentration of drug that inhibits 95% of virus in blood was 1 log lower in lymph node for EFV and >3 logs lower for RAL.Conclusion:These data further highlight the challenges of drug delivery to LT in HIV infection and demonstrate that RAL is not superior to EFV as judged by direct measurements of the source of virus in LT.

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KW - antiviral effect

KW - drug levels

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Impact of Integrase Inhibition Compared with Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues

Abstract

Bibliographical note

Keywords

UN SDGs

Access

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