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HIV RNA and DNA in GALT Similar With Raltegravir and Dolutegravir
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17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
Mark Mascolini
Although raltegravir produced significantly higher concentrations than dolutegravir in gut-associated lymphoid tissue (GALT) of adults with HIV infection, HIV RNA and HIV DNA levels in GALT did not differ significantly between the two integrase inhibitors [1]. Most immunologic markers in GALT were also similar with raltegravir and dolutegravir.
Previous work by University of North Carolina (UNC) researchers found more than 100-fold higher raltegravir concentrations in GALT than blood but more than 5-fold lower dolutegravir concentrations in GALT [2,3]. Antiretroviral levels in GALT could be important because HIV can replicate in tissue reservoirs during antiretroviral therapy. To determine the impact of raltegravir and dolutegravir concentrations on viral load and immunologic markers in GALT, the UNC team conducted this phase 4 open-label trial.
The study involved 20 adults with plasma HIV RNA below 50 copies while taking raltegravir or dolutegravir with tenofovir/emtricitabine for more than 90 days. The researchers collected blood plasma 2 hours after dosing and GALT specimens from the terminal ileum, splenic flexure, and rectum 2 to 6 hours after dosing. They used combined tissues to measure HIV RNA and DNA by Droplet Digital PCR, and they used ileum and splenic flexure specimens to measure immunologic markers by flow cytometry.
Ten participants took raltegravir and 10 dolutegravir. Five were women and 15 African American. Median age stood at 54.5 years (range 48 to 64) in the raltegravir group and 49.5 (range 32 to 56) in the dolutegravir group. Time since HIV diagnosis was nonsignificantly longer in the dolutegravir group (median 17 versus 9.5 years), but time on raltegravir was significantly longer than time on dolutegravir (median 5.3 versus 1.0 year, P
Median dolutegravir concentration in rectal tissue stood at 810 ng/g (interquartile range [IQR] 510 to 1408), compared with 5308 ng/g (IQR 3958 to 19,600) with raltegravir. Tissue-to-plasma ratios were 0.44 (IQR 0.29 to 0.65) for dolutegravir and 11.3 (IQR 7.7 to 25.2) for raltegravir. Yet HIV RNA and DNA in combined GALT samples did not differ significantly between the two groups: median RNA with dolutegravir versus raltegravir 0.05 versus 0.16 copies per 1000 cells (P = 0.47); median DNA 0.05 versus 0.13 copies per 1000 cells (P = 0.14). But higher proportions of people taking dolutegravir than raltegravir had undetectable RNA in GALT (40% versus 20%) and undetectable DNA in GALT (40% versus 10%).
CD4 and CD8 percentages did not differ between the dolutegravir and raltegravir groups. People taking raltegravir had significantly lower CCR5 expression on CD8 cells than did those taking dolutegravir (median 0.15% versus 0.63%, P = 0.03).
"Even though raltegravir produced higher tissue exposures than dolutegravir consistent with previous studies," the researchers concluded, "no significant differences in tissue HIV RNA, DNA, or most immunologic markers were observed." And they noted that higher tissue concentrations of raltegravir than dolutegravir did not translate into better virologic or immunologic control. The researchers are conducting tissue imaging to get a fix on raltegravir and dolutegravir concentrations and viral expression in cell subtypes.
References
1. Weber MD, Andrews E, Prince HA, et al. Virologic and immunologic responses to raltegravir and dolutegravir in GALT of HIV+ men and women. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC. Abstract O12.
2. Greener BN, Patterson KB, Prince HM, et al. Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing. J Acquir Immune Defic Syndr. 2013;64:39-44. http://www.natap.org/2013/HIV/Dolutegravir_Pharmacokinetics_in_the_Genital_Tract.7.pdf
3. Patterson KB, Prince HA, Stevens T, et al. Differential penetration of raltegravir throughout gastrointestinal tissue: implications for eradication and cure. AIDS. 2013;27:1413-1419. http://www.natap.org/2013/HIV/Differential_Penetration_of_Raltegravir_throughout.98670.pdf
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