Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial

Abstract

Background: To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection.

Methods: Untreated HIV-1-infected volunteers without HCV infection received 180 microg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4(+) T cell counts, pharmacokinetics, pharmacodynamic measurements of 2',5'-oligoadenylate synthetase (OAS) activity, and induction levels of interferon-inducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed.

Results: Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4(+) T cell counts at week 12 were 0.61 log(10) copies/mL (90% confidence interval [CI], 0.20-1.18 log(10) copies/mL) and -44 cells/microL (90% CI, -95 to 85 cells/microL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 [90% CI, -0.93 to -0.28] and r = -0.61 [90% CI, -0.87 to -0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log(10) copies/mL [90% CI, 0.06-0.91 log(10) copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log(10) copies/mL [90% CI, -0.93 to -0.21 log(10) copies/mL]).

Conclusion: Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations.

Trial registration: ClinicalTrials.gov NCT00078442.

Figure 1

A. Plasma HIV-1 RNA, log₁₀ copies/mL, subject-specific trajectories shown in black, median values shown in blue. Vertical line shows study week at which last injection of pegylated-interferon occurred. The number of subjects with available data is shown at the top of the graph. B. Plasma HIV-1 RNA changes from baseline, log₁₀ copies/mL, trajectories of subject-specific changes in red (three subjects with reduced dosing) and black (all other subjects). Horizontal line at zero (no change from baseline); vertical line at last weekly injection of study drug. C. Median changes in CD4⁺ T-cell count (solid red lines) and percent (broken blue lines) by study week, intervals represent 90% CIs around the medians.

Figure 2

A. Median log₁₀ interferon (ng/mL; black squares, blacks solid line), median OAS change from baseline (fold-change; red diamonds, red broken line), median IFIG change from baseline (MFI; blue circles, blue dashed line) and median plasma HIV-1 RNA change from baseline (log10 copies/mL; green triangles, green broken line) plotted against study week. Intervals represent 90% CIs around medians. Y-axis truncated at 2.5. OAS fold-change CIs: week 1 (1.3 to 4.8), week 2 (1.7 to 8.0), week 3 (1.2 to 5.7), week 4 (1.2 to 5.0), week 6 (1.7 to 4.4), week 8 (1.2 to 7.7), week 10 (1.0 to 7.7), week 12 (1.2 to 4.5), week 13 (0.7 to 3.9) and week 18 (1.3 to 3.4). B. Scatterplot of subject-specific changes in viral load against concurrent changes in OAS protein at week 0 (open black circle), week 1 (filled red circle; estimated Spearman correlation r = −0.75 [− 0.93, −0.28]), week 2 (blue square; r = −0.61 [− 0.87, −0.09]), and week 12 (green diamond; r = −0.51 [CI: −0.81, 0.02]). C. Scatterplot of subject-specific changes in viral load against changes in IFIG at week 0 (open black circle), week 3 (filled red circle; r = -0.62 [90% CI -0.90, 0.02]), week 6 (blue square; r = -0.64 [-0.90, -0.02]), week 12 (green diamond; r = -0.74 [-0.93, -0.21]) and week 18 (open gray diamond; r = 0.07 [−0.64, 0.71]).

Figure 3

A. Week 12 plasma HIV-1 RNA changes from baseline (average of pre-entry and entry, log₁₀ copies/mL) plotted against week 12 plasma concentrations for pegylated interferon alpha-2a. Red triangles, 3 subjects with reduced dosing; black circles, remaining subjects; estimated Spearman correlation r = −0.11 (90% CI −0.60 to 0.44). B. Week 12 plasma HIV-1 RNA changes from baseline (average of pre-entry and entry, log10 copies/mL) plotted against area under the concentration-time curve (weeks 0-12) for interferon. Red triangles, 3 subjects with reduced dosing; black circles, remaining subjects; r = 0.16 (90% CI, −0.39 to 0.63)

Figure 4

A. Week 12 serum OAS change from baseline plotted against absolute CD4⁺ T-cell count at baseline; estimated Spearman correlation r = 0.63 (90% CI, 0.15, 0.87). B. Week 12 plasma HIV-1 RNA log₁₀ copies/mL changes from baseline plotted against absolute CD4⁺ T-cell count at baseline; r=-0.40 (90% CI, −0.76, 0.16) C. IFIG levels at baseline, MFI, plotted against baseline CD4⁺ T-cell count; estimated Spearman correlation −0.81 (90% CI, −0.95, −0.38). D. IFIG change from baseline at week 12, MFI, plotted against baseline CD4⁺ T-cell count; r = 0.76 (90% CI, 0.26, 0.94).