Emory University School of Medicine Department of Medicine HIV-1 RNA persists in rectal tissue despite rapid virologic suppression in blood plasma with dolutegravir-based combination antiretroviral therapy in treatment naïve patients Cecile D. Lahiri, MD, MS Emory University School of Medicine Department of Medicine Division of Infectious Diseases Nakita Brown, MS; Hsin Chien, PhD; Aswani Vunnava, MS; Kevin J. Ryan, MS; Edward P. Acosta, PharmD; Anandi S. Sheth, MD, MS; Jessica Ingersoll, MS; Igho Ofotokun, MD, MS

Conflict of Interest No conflicts of interest to declare.

Background and Methods Despite plasma virologic suppression with cART, HIV persists in gut Tissue HIV viral dynamics and relationships with ART drug concentrations remain poorly understood Methods Study population: Treatment-naïve HIV+ adults in Atlanta, Georgia USA Statistical analyses: Participants grouped: Undetectable rectal HIV RNA (<40 cop/g) vs Detectable RNA Median DTG concentrations in blood and rectal tissue between groups compared by Mann-Whitney non-parametric tests We conducted a LONGITUDINAL COHORT STUDY enrolling treatment naïve HIV infected adults within Atlanta, Georgia in the United States. Participants were enrolled into an 84 day (or 12 week) study where they initiated a dolutegravir-based regiment that included an NRTI backbone. Blood plasma and rectal tissue biopsies were obtained at Days 0 (which was pre-initiation of ART) as well as 3 other time points up to Day 84. Half the samples were obtained in the early part of the Dolutegravir dosing interval and half were obtained at the end of the dosing interval. Both blood plasma and rectal tissue were analyzed for HIV RNA quantitation using the Abbott Real-Time PCR as well as DTG quantitation using HPLC tandem mass spectroscopy, with assays validated for each anatomic site. Participants were grouped into those who had UNDETECTABLE RECTAL HIV RNA AT ANY TIMEPOINT vs those with PERSISTENT DETECTABLE RECTAL HIV. Median DTG concentrations were compared between these two groups using Mann-Whitney non-parametric tests

Results: HIV Viral Dynamics 8 participants enrolled 30 paired plasma and rectal tissue samples available for HIV RNA analysis Blood plasma Rectal tissue 8 participants were enrolled Half were female, 75% BLACK, median age 39 years, median CD4 208, and median baseline HIV viral load ranged from 2-6 log. The graph to the left shows viral dynamics in BLOOD PLASMA. As expected, ALL PARTICIPANTS had rapid decline in their viral load, and all were undetectable in plasma by Day 42. In contrast, the graph to the right shows viral dynamics in RECTAL TISSUE for the same participants. The majority had PERSISTENT DETECTABLE HIV RNA IN THE RECTUM up to Day 84. 3 participants did have undetectable rectal HIV RNA at a single timepoint. It is important to note however, that one of these 3 participants did have rebound detectable HIV RNA at Day 84 despite maintaining plasma virologic suppression.

Results and Discussion 22 paired plasma and rectal tissue samples for steady state DTG analysis 7 samples from participants attaining undetectable rectal HIV RNA 15 samples from participants with persistent detectable rectal HIV RNA Rectal DTG concentrations HIV RNA persisted in rectal tissue Those with undetectable rectal HIV RNA had higher median tissue DTG concentrations Implications: ART pharmacometrics plays a role in tissue HIV viral dynamics 22 paired plasma and rectal tissue samples were available for steady state DTG analysis where participants had been receiving daily DTG for at least 7 consecutive days. In the group with undetectable rectal HIV RNA, they had median rectal DTG concentrations that were TWO TIMES HIGHER than the group with persistent detectable HIV and THIS DIFFERENCE WAS STATISTICALLY SIGNIFICANT. There was a trend toward higher blood DTG concentrations in the undetectable vs detectable group, but this did not reach statistical significance. There were no significant differences between the undetectable and detectable groups with regard to demographic or clinical characteristics, including baseline CD4 or viral load, time since HIV diagnosis, or type of NRTI backbone. In summary, HIV RNA persisted in rectal tissue for the majority of participants in the first 84 days of DTG-based ART. Those that did have undetectable rectal HIV RNA had higher median tissue DTG concentration ART pharmacometrics likely DOES PLAY A ROLE in tissue HIV viral dynamics. Further studies are NEEDED to determine the implications with regard to rectal transmission as well as barriers to HIV tissue reservoir eradication. *median 1340 ng/g (IQR 683-2100) vs 626 ng/g (371-1022), p <0.05.

Acknowledgements Emory ID Division Igho Ofotokun, MD, MS Nakita Brown, MS Hsin Chien, PhD Aswani Vunnava, MS Anandi Sheth, MD, MS Emory CFAR Virology Core Lab Colleen Kraft, MD, MS Jessica Ingersoll, MS UAB Division of Clinical Pharmacology Edward P. Acosta, PharmD Kevin Ryan, MS Atlanta WIHS Team Grady Infectious Disease Program Funding sources K23AI124913 KL2TR000455 and UL1TR000454 Atlanta WIHS: U-01 AI103408 Emory CFAR: P30 AI050409 Emory Medical Care Foundation