CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

Conclusion: MK-8591 would be expected to lead to HIV suppression after multiple daily doses as low as 0.25 mg.

participants at baseline (n=347), TFV-DP was lower in Blacks (1428 [1251,1630]) vs. Whites (1793 [1678,1916], P=0.002), and vs. Hispanics (1752 [1557,1972], P=0.02); in non-boosted (1614 [1508,1727]) vs. boosted (1884 [1745,2033], P=0.003) regimens, and; in NNRTI-based (1563 [1432,1707]) vs. PI-based (1890 [1704,2095], P=0.006), and vs. multiclass-based (1927 [1650,2252], P=0.02) regimens. The aOR of virologic suppression, after adjusting for age, gender, race, body mas index, serum creatinine, CD4+ T cell count, antiretroviral drug class, duration of therapy and dosing category was 76.5 (95% CI; 26.6-220.5) for a TFV-DP concentration ≥1850 fmol/punch (75 th percentile of daily dosing) compared to <350 fmol/punch (<2 doses/wk), as shown in the Figure. The median HIV viral load decreased with higher TFV-DP concentrations; most HIV viral loads were <200 copies/mL in the highest TFV-DP categories. Conclusion: TFV-DP in DBS is a powerful predictor of virologic suppression in HIV-infected individuals on TDF-based therapy, after controlling for clinically- relevant covariates, and a promising adherence tool in this population. TFV-DP showed slight differences across subgroups. Additional research is required to assess the contributions of antiretroviral adherence versus biology/ pharmacology on TFV-DP concentrations among these subgroups.

Oral Abstracts

27 COMPARATIVE LYMPHOID TISSUE PHARMACOKINETICS (PK) OF INTEGRASE INHIBITORS (INSTI)

Courtney V. Fletcher 1 , Ann Thorkelson 2 , Lee Winchester 3 , Timothy Mykris 3 , Jon Weinhold 3 , Kayla Campbell 3 , Jodi Anderson 2 , Jacob Zulk 2 , Puleng Moshele 2 , Timothy Schacker 2 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 University of Minnesota, Minneapolis, MN, USA, 3 University of Nebraska, Omaha, NE, USA Background: The secondary lymphoid tissues (LT), lymph nodes (LN) and gut-associated lymphoid tissue (GALT), are the primary sites of HIV replication and where the latent pool of virus is maintained. In HIV-infected persons with undetectable plasma HIV-RNA, an association has been reported between low concentrations of antiretroviral drugs (ARVs) in LT and measures of persistent viral production. None of those individuals, however, were receiving an INSTI- based regimen. The objective of this work was to compare the LT PK of the INSTIs, dolutegravir (DTG), elvitegravir EVG) and raltegravir (RAL). Methods: Study participants were HIV-infected persons receiving DTG, EVG (with cobicistat), or RAL, with other ARVs. PBMCs and mononuclear cells (MNCs) from LN, ileum and rectal tissues were obtained, and intracellular concentrations of INSTIs were quantified by LC-MS/MS. Inhibitory quotients (IQ) as the ratio of intracellular concentrations to the protein-binding corrected 90 or 95% inhibitory concentration (IC90-95) of the respective INSTIs were determined. Summary statistics were calculated. Results: PK data were obtained from a total of 27 persons: DTG, n=10; EVG, n=11; RAL, n=6. NRTIs were: TDF/FTC, n=20; ABC/3TC, n=4; ABC/3TC/TDF, n=1; TDF/3TC, n=1; and TAF/FTC, n=1. Median (and interquartile range) IQ values for the INSTIs in PBMCs, LN, ileum and rectum are given in the Table. Conclusion: In PBMCs, the median IQ values for DTG, EVG and RAL were 5-fold or more above the IC90-95. This is consistent with clinical trial results showing these INSTIs produce rapid and potent decreases in plasma HIV RNA. In LT, however, all median IQ values were lower than those in PMBCs, except for EVG in the ileum and rectum, which were greater or equivalent, respectively. Only EVG had a median IQ value in the LN (1.85) above the IC90-95. As shown for other ARVs, these INSTIs achieved lower concentrations particularly in the LN, than in peripheral blood. Plasma concentrations of DTG, EVG and RAL have been linked with virologic response; the standard doses of these INSTIs achieve plasma IQ values of 8 or greater. Pharmacodynamic evaluations are needed to determine whether the low concentrations observed in LT create conditions in LT that allow persistent viral production.

26 MULTIPLE DAILY DOSES OF MK-8591 AS LOW AS 0.25 MG ARE EXPECTED TO SUPPRESS HIV Randolph P. Matthews 1 , Deanne J. Rudd 1 , Vanessa Levine 1 , Sandra Zhang 1 , Laura Sterling 2 , Jay Grobler 1 , Ryan Vargo 1 , S. Aubrey Stoch 1 , Marian Iwamoto 1 1 Merck & Co, Inc, Kenilworth, NJ, USA, 2 Celerion, Lincoln, NE, USA Background: MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development for the treatment of HIV-1 infection. MK-8591-triphosphate (MK-8591-TP), the active phosphorylated anabolite of MK-8591, exhibits a half-life of ~78-128 hours in human peripheral blood mononuclear cell (PBMCs). MK-8591 has been assessed in a monotherapy pharmacodynamic (PD) trial in treatment-naïve HIV-1-infected subjects, where single oral doses of MK-8591 from 0.5 mg – 30 mg demonstrated robust viral load lowering after 7-10 days. Here we present pharmacokinetic (PK) data from a clinical trial examining daily administration of MK-8591 in healthy subjects, and the relationship of these data with data from the antiviral efficacy trial in HIV-1 infected subjects. Methods: In a double-blind, placebo-controlled, three-panel trial, healthy subjects were administered daily placebo or MK-8591 at 5 mg for six weeks, 0.25 mg for four weeks, or 0.75 mg for four weeks (12 active and 4 placebo in each panel). Blood samples were collected for MK-8591 and PBMC MK-8591-TP PK at prespecified times. Vaginal (5 mg, 0.75 mg) or rectal (all three dose levels) biopsies were performed in a subset of subjects to obtain tissue for PK analysis. Results: All doses were generally well tolerated, with a limited number of mild/moderate adverse experiences reported. Intracellular concentrations of MK-8591-TP that exceeded the EC 50 were noted following the first dose of 0.25 mg MK-8591. After 2-3 weeks of dosing, steady-state levels of intracellular MK-8591-TP exceeded 1.0 pmol/million cells on average, comparable to levels seen after dosing 10 mg weekly. In the limited assessment of tissue PK, steady- state levels of active MK-8591-TP at all examined dose levels were comparable to reported levels of tenofovir diphosphate observed in rectal tissue following single doses of emtricitabine/tenofovir.

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CROI 2018