Reduced immune activation during tenofovir-emtricitabine therapy in HIV-negative individuals

Abstract

Background: Elevated immune activation is associated with an increased risk of HIV acquisition. Tenofovir (TFV) has immunomodulatory properties in vitro, but how this extends in vivo remains unknown.

Methods: HIV-negative adults received daily coformulated TFV disoproxil fumarate 300 mg/emtricitabine (FTC) 200 mg for 30 days followed by a 30-day washout. Markers of T-cell activation, inflammation, and cytokines were measured before drug and on days 30 (on drug) and 60 (30-day washout). Data were analyzed using one-way analysis of variance/pairwise comparisons. Intracellular disposition of TFV-diphosphate and FTC-triphosphate in CD4 and CD8 T-cells and monocytes was characterized, and the relationship with immune activation was evaluated using Pearson's correlation coefficient.

Results: T-cell activation was available in 19 participants. CD38/HLA-DR coexpression on CD8 T-cells decreased from baseline to day 30 (3.97% vs. 2.71%; P = 0.03) and day 60 (3.97% vs. 2.41%; P = 0.008). Soluble CD27 decreased from baseline to day 60 (184.1 vs. 168.4 pg/mL; P = 0.001). Cytokines and inflammation markers were not significantly different. TFV-diphosphate and FTC-triphosphate were approximately 4-fold higher in monocytes vs. CD4 and CD8 T-cells but neither correlated with activation markers.

Conclusions: TFV disoproxil fumarate/FTC therapy was associated with decreased T-cell activation in HIV-negative adults, which could contribute to the antiviral effect of pre-exposure prophylaxis (NCT01040091; www.clinicaltrials.gov).

Conflict of interest statement

Potential Conflicts of Interest (see separate forms):

Dr. Anderson reports donation of study drug from Gilead Sciences during the conduct of the study and Contract work with Gilead Sciences. All others authors: no conflict of interest.

Figures

Figure 1

CD8+ T-cell (Panel A) and CD4+ T-cell (Panel B) immune activation (CD38/HLA-DR co-expression) at baseline (before drug), day 30 (after 30 days of TDF/FTC) and day 60 (30 days of washout). CD8+ T-cell ANOVA P=0.02. CD4+ T-cell ANOVA P=0.25. Bars and error bars represent geometric means and 95% confidence intervals, respectively. Statistical tests were conducted on loge transformed data. Abbreviations: TDF/FTC, tenofovir-disoproxil-fumarate/emtricitabine.

Figure 2

Plasma sCD27 (Panel A) and plasma sCD14 (Panel B) concentrations at baseline (before drug), day 30 (after 30 days of TDF/FTC) and day 60 (30 days of drug washout. sCD27 ANOVA P=0.001. sCD14 ANOVA P=0.06. Bars and error bars represent geometric means and 95% confidence intervals, respectively. Statistical tests were conducted on loge transformed data. Abbreviations: TDF/FTC, tenofovir-disoproxil-fumarate/emtricitabine; sCD27 plasma soluble CD27; sCD14, plasma soluble CD14.