Virological and immunological responses to raltegravir and dolutegravir in the gut-associated lymphoid tissue of HIV-infected men and women.

Michael D Weber, Elizabeth Andrews, Heather A Prince, Craig Sykes, Elias P Rosen, Camden Bay, Nicholas J Shaheen, Ryan D Madanick, Evan S Dellon, Kristina De Paris, Julie Ae Nelson, Cynthia L Gay, Angela Dm Kashuba

Journal: Antiviral therapy 2019;23(6):495-504

PMID: 29714167

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Abstract

BACKGROUND

Raltegravir (RTG) and dolutegravir (DTG) have different pharmacokinetic patterns in the gastrointestinal tract. To determine if this results in pharmacodynamic differences, we compared HIV RNA, HIV DNA and immunological markers in gut-associated lymphoid tissue (GALT) of HIV-infected participants receiving RTG or DTG with tenofovir+emtricitabine (TDF/FTC).

METHODS

GALT specimens from the terminal ileum, splenic flexure and rectum were obtained by colonoscopy at a single time point in 20 adults treated with RTG (n=10) or DTG (n=10) with HIV RNA <50 copies/ml. Flow cytometry, drug concentrations, and HIV RNA and DNA were analysed in tissue. CD4/8 T-cells were tested for γδ TCR, and markers of T-cell activation and exhaustion. Data are reported as median (Q1-Q3).

RESULTS

A total of 15 men and 5 women were enrolled. There was no difference in time since HIV diagnosis for those on RTG (9.5 [4-22] years) and DTG (17 [1-24] years; P=0.6), although time on RTG (5.4 [2.3-6.7] years) was greater than DTG (1.0 [0.1-1.5] years; P<0.001). Concentrations of RTG and DTG in rectal tissue were similar to previous reports: median tissue:plasma ratio was 11.25 for RTG and 0.44 for DTG. RNA:DNA ratios were 1.14 (0.18-5.10) for the RTG group and 0.90 (0.30-18.87) for the DTG group (P=0.95). No differences (P≥0.1) between CD4 and CD8 T-cell markers were found.

CONCLUSIONS

RTG produced higher tissue exposures than DTG, but no significant differences in GALT HIV RNA, DNA or most immunological markers were observed. ClinicalTrials.gov NCT02218320.

Address: University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, USA.; Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.

DOI: 10.3851/IMP3236

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MeSH Terms: Adult, Anti-HIV Agents, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Colon, Transverse, DNA, Viral, Emtricitabine, Female, Gene Expression, HIV Infections, HIV-1, Heterocyclic Compounds, 3-Ring, Humans, Ileum, Immunity, Innate, Lymphoid Tissue, Male, Middle Aged, Oxazines, Piperazines, Pyridones, RNA, Viral, Raltegravir Potassium, Receptors, Antigen, T-Cell, gamma-delta, Rectum, Tenofovir, Treatment Outcome