Research ArticleHIV

An open-label phase 1 clinical trial of the anti-α4β7 monoclonal antibody vedolizumab in HIV-infected individuals

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Science Translational Medicine  11 Sep 2019:
Vol. 11, Issue 509, eaax3447
DOI: 10.1126/scitranslmed.aax3447
  • Fig. 1 Clinical trial design.

    Nineteen study participants received intravenous infusions of vedolizumab (300 mg) for 30 min at weeks 0, 2, 6, 10, 14, 18, 22, 26, and 30. Antiretroviral therapy (ART) was discontinued after the infusion at week 22. During the analytical treatment interruption phase (ATI), CD4+ T cell counts and plasma viremia were monitored every 2 weeks. The green arrows indicate time of vedolizumab administration in weeks.

  • Fig. 2 Effect of vedolizumab administration on plasma viremia after discontinuation of antiretroviral therapy.

    (A) Longitudinal plasma viremia of study participants during the ATI phase is shown. The gray dotted horizontal line indicates the limit of detection of the assay (40 HIV RNA copies/ml). The white triangles indicate undetectable plasma viremia. The gray shaded areas indicate duration of ATI. The blue asterisks indicate the time point at which ART was reinitiated. (B) Kaplan-Meier analysis of the percentage of study participants (n = 18) remaining off ART during the treatment interruption phase of the study compared to historical participants (n = 15) in the placebo arm of a therapeutic vaccine trial (18). The x axis indicates the time in weeks since stopping ART. P value was calculated by log-rank test. (C) Kaplan-Meier analysis of suppression of plasma viremia after cessation of ART. Duration of plasma viremia under 400 HIV RNA copies/ml after discontinuation of ART was compared between the vedolizumab study participants (n = 18) and historical controls from the placebo arm of a therapeutic vaccine trial (n = 15) (18). The graph depicts the percentage of participants in both groups with plasma viremia of <400 HIV RNA copies/ml (y axis) as a function of time after discontinuation of ART (x axis). P value was calculated by log-rank test.

  • Fig. 3 Effect of vedolizumab administration on CD4+ T cell counts and β7 expression.

    (A) Shown are CD4+ T cell counts of study participants who received vedolizumab infusions over a 22-week period. (B) Shown is β7 expression on peripheral blood CD4+ T cells from study participants. Blood samples taken at baseline and at weeks 10 and 22 of vedolizumab infusions were obtained, while the study participants were receiving ART. Blood samples taken at follow-up time points were obtained after the study participants reinitiated ART at the end of the analytical treatment interruption phase. P values were computed using the Wilcoxon signed-rank test.

  • Fig. 4 Pharmacokinetics of vedolizumab in study participants.

    Blood samples from HIV-infected patients on ART were obtained at baseline and at the indicated time points during vedolizumab treatment. Serum concentrations of vedolizumab were determined using a validated sandwich enzyme-linked immunosorbent assay. Thick gray line represents the median value for vedolizumab serum concentrations for the group of study participants.

  • Fig. 5 Effect of vedolizumab on the HIV reservoir during antiretroviral drug treatment.

    (A) HIV DNA in peripheral blood CD4+ T cells from study participants was measured before discontinuation of ART. The frequency of CD4+ T cells carrying HIV DNA was determined by droplet digital PCR. (B) Cell-associated HIV RNA in peripheral blood CD4+ T cells from study participants was measured before discontinuation of ART. Cell-associated HIV RNA copy number was determined by droplet digital PCR and was normalized per 1 × 106 TATA-box binding protein (TBP) RNA. P values were computed using the Wilcoxon signed-rank test.

  • Table 1 Baseline characteristics of study participants.

    NNRTI, non-nucleotide reverse transcriptase inhibitor; PI, protease inhibitor; INSTI, integrase strand transfer inhibitor.

    CharacteristicsVedolizumab (n = 19)Historical controls*
    (n = 16)
    P value**
    Sex, number (%)0.49
      Male17 (89)16 (100)
      Female2 (11)
    Age, years0.55
      Median (interquartile range)42 (32, 52)42 (32, 48)
      Range29–5924–65
    Race or ethnic group, number (%)0.51
      African-American4 (21)2 (12.5)
      Caucasian12 (63)10 (62.5)
      Hispanic3 (16)2 (12.5)
      Asian02 (12.5)
    Antiretroviral regimen, number (%)0.45
      NNRTI4 (21)7 (44)
      PI2 (11)2 (12)
      PI/INSTI1 (5)0
      INSTI12 (63)7 (44)
    Duration of HIV suppression on ART at
    study entry
    0.15
      Years, median (interquartile range)8 (5, 12)4.8 (2.7, 10.3)
      Range2.1–211.1–13
    CD4+ T cell count0.24
      Cells/mm3 at study entry, median
    (interquartile range)
    870 (741, 945)758 (596, 1165)
      Range597–1197501–2162

    *Historical participants in the placebo arm of a therapeutic vaccine trial (18).

    **Wilcoxon rank sum test (age, ART duration, and CD4+ T cell count) and Fisher’s exact test (sex, race/ethnic group, and antiretroviral drug regimen).

    Supplementary Materials

    • stm.sciencemag.org/cgi/content/full/scitranslmed.aax3447/DC1

      Fig. S1. Effect of vedolizumab administration on immunological and virological parameters.

      Table S1. List of adverse events.

      Table S2. Comparison of baseline CD4+ T cell counts and percentages of CD38+HLA-DR+CD8+ T cell between participants who met ART restart criteria before or after week 26 of analytical treatment interruption.

      Study protocol

    • This PDF file includes:

      • Fig. S1. Effect of vedolizumab administration on immunological and virological parameters.
      • Table S1. List of adverse events.
      • Table S2. Comparison of baseline CD4+ T cell counts and percentages of CD38+HLA-DR+CD8+ T cell between participants who met ART restart criteria before or after week 26 of analytical treatment interruption.
      • Study protocol

      [Download PDF]

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