Antiviral therapy · 2018
Virological and immunological responses to raltegravir and dolutegravir in the gut-associated lymphoid tissue of HIV-infected men and women.
Клиническое исследование IV фазыСтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Weber Michael D, Andrews Elizabeth, Prince Heather A, Sykes Craig, Rosen Elias P, Bay Camden, Shaheen Nicholas J, Madanick Ryan D, Dellon Evan S, De Paris Kristina, Nelson Julie Ae, Gay Cynthia L, Kashuba Angela Dm
Аннотация
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.
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.
Предметные рубрики MeSH
AdultAnti-HIV AgentsCD4 Lymphocyte CountCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesColon, TransverseDNA, ViralEmtricitabineFemaleGene ExpressionHIV InfectionsHIV-1Heterocyclic Compounds, 3-RingHumansIleumImmunity, InnateLymphoid TissueMaleMiddle AgedOxazinesPiperazinesPyridonesRNA, ViralRaltegravir PotassiumReceptors, Antigen, T-Cell, gamma-deltaRectumTenofovirTreatment OutcomeDolutegravir