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

Meghan K 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, Stephen W Wietgrefe, Erika S Helgeson, Cavan S Reilly, Ashley T Haase & 3 others Daniel C. Douek, Courtney V. Fletcher, Timothy W Schacker

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)355-360
Number of pages6
JournalJournal of acquired immune deficiency syndromes (1999)
Volume81
Issue number3
DOIs
StatePublished - Jul 1 2019

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Integrases
efavirenz
Lymphoid Tissue
HIV
Follicular Dendritic Cells
Viruses
Lymph Nodes
Integrase Inhibitors
Anti-Retroviral Agents
Uganda
Viremia
Ambulatory Care Facilities
Pharmaceutical Preparations
HIV Infections
Raltegravir Potassium
Therapeutics

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  • Journal Article

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Impact of Integrase Inhibition Compared With Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues. / Rothenberger, Meghan K; Nganou-Makamdop, Krystelle; Kityo, Cissy; Ssali, Francis; Chipman, Jeffrey G; Beilman, Gregory J; Hoskuldsson, Torfi; Anderson, Jodi; Jasurda, Jake; Schmidt, Thomas E.; Calisto, Samuel P.; Pearson, Hope; Reimann, Thomas; David, Caitlin; Perkey, Katherine; Southern, Peter; Wietgrefe, Stephen W; Helgeson, Erika S; Reilly, Cavan S; Haase, Ashley T; Douek, Daniel C.; Fletcher, Courtney V.; Schacker, Timothy W.

In: Journal of acquired immune deficiency syndromes (1999), Vol. 81, No. 3, 01.07.2019, p. 355-360.

Research output: Contribution to journalArticle

Rothenberger, MK, 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, SW, Helgeson, ES, Reilly, CS, 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 (1999), vol. 81, no. 3, pp. 355-360. https://doi.org/10.1097/QAI.0000000000002026
Rothenberger, Meghan K ; Nganou-Makamdop, Krystelle ; Kityo, Cissy ; Ssali, Francis ; Chipman, Jeffrey G ; Beilman, Gregory J ; Hoskuldsson, Torfi ; Anderson, Jodi ; Jasurda, Jake ; Schmidt, Thomas E. ; Calisto, Samuel P. ; Pearson, Hope ; Reimann, Thomas ; David, Caitlin ; Perkey, Katherine ; Southern, Peter ; Wietgrefe, Stephen W ; Helgeson, Erika S ; Reilly, Cavan S ; Haase, Ashley T ; Douek, Daniel C. ; Fletcher, Courtney V. ; Schacker, Timothy W. / Impact of Integrase Inhibition Compared With Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues. In: Journal of acquired immune deficiency syndromes (1999). 2019 ; Vol. 81, No. 3. pp. 355-360.
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T1 - Impact of Integrase Inhibition Compared With Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues

AU - Rothenberger, Meghan K

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, Stephen W

AU - Helgeson, Erika S

AU - Reilly, Cavan S

AU - Haase, Ashley T

AU - Douek, Daniel C.

AU - Fletcher, Courtney V.

AU - Schacker, Timothy W

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.

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