Therapeutic response to peg-IFN-alpha-2b and ribavirin in HIV/HCV co-infected African-American and Caucasian patients as a function of HCV viral kinetics and interferon pharmacodynamics

Abstract

Method: In this study we sought to characterize the relationship between several pharmacokinetic and pharmacodynamic parameters and virologic responses among HIV/hepatitis C virus genotype-1 co-infected patients receiving pegylated interferon-alpha-2b (peg-IFN2b) and ribavirin. We also tried to establish the underlying mechanisms that lead to poor sustained virologic responder rates observed with African-Americans against Caucasians and compared their results with those observed in a cohort of hepatitis C virus mono-infected patients.

Results: Among our studied population, a viral decline of more than 1.0 log at day 3 combined with viral load of less than 5.0 log IU/ml at day 28 predicted sustained virologic responders with negative predictive value 100% and positive predictive value 100%. African-Americans had significantly (P < 0.01) slower hepatitis C virus viral kinetics as compared to Caucasians. However, peg-IFN2b concentrations and pharmacokinetic parameters, peg-IFN2b(max) and peg-IFN2b half-life, were similar in both groups and did not predict sustained virologic responders. Nevertheless, the pharmacodynamic parameter EC(50), estimated from nonlinear fitting of the viral kinetics together with peg-IFN2b concentration data, showed that HIV/ hepatitis C virus co-infected African-Americans have lower sensitivity to interferon-alpha thus giving rise to slower viral decline. The combined pharmacokinetic/pharmacodynamic parameter IFN(max)/EC(90) was an excellent predictor of sustained virologic responders, thus showing the importance of maintaining peg-IFN2b levels above EC(90) to achieve successful treatment.

Conclusion: Further studies are needed to evaluate whether these pharmacodynamic predictions are a result of differential host response to peg-IFN2b or other viral factors conferring relative resistance to peg-IFN2b.

Conflict of interest statement

Conflict of Interest Statement

None of the other authors have any conflicts of interest to report.

Figures

Figure 1

A–D: HCV Viral Kinetics (A and C) and pharmacokinetics (B and D) in HIV/HCV genotype 1 co-infected patients treated with peg-interferon alfa-2b (1.5 µg/kg/wk) and ribavirin (1–1.2 g/d). Median HCV RNA concentrations are plotted (A) as function of race (black circles for African Americans and red squares for Caucasians), and (C) according to the treatment outcome (green circles for SVR, blue triangles for REL, red squares for VB and black diamonds for NR) for the first 84 days of treatment. Note the different time scale in x-axis at days 0–7 versus days 7–84, in order to clarify the transient viral rebound at day 3–7. Interferon-alpha serum concentrations are plotted (B) as function of race (black circles for African Americans and red squares Caucasians), and (D) according to the treatment outcome (green circles for SVR, blue triangles for REL, red squares for VB and black diamonds for NR) for the first 14 days of treatment. Statistical significant differences in viral decline between the groups are marked with * (P<0.05) or ** (P<0.03). Dashed horizontal lines mark the level of HCV RNA and peg-IFN detection. E–H: Correlation between early viral kinetic parameters and therapeutic response in African-American (A and C) and Caucasian (B and D) HIV/HCV co-infected patients. Sustained viral response (SVR, green circles) can be predicted in our study with NPV=100% and PPV=100% by the combination of HCV-RNA decline larger than 1.0 log IU/ml at day 3 (x-axis in A and B) and HCV-RNA load below 5.0 log IU/ml at day 28 (y-axis in A and B). Non-responders (NR, black diamonds) have lower decline in viral load than patients with viral breakthrough (VB, red squares) and patients with relapse (REL, blue triangles). Also, a second phase viral decline slope (y-axis in C and D) slower than 0.3 log/week is predictive of lack of SVR, but the transient rebound at days 3–7 (x-axis in C and D) is not correlated with therapeutic response). In addition, it is possible to observe the faster decline in Caucasians (B and D) as compared to African-Americans (A and C), in both first phase decline at day 3 and second phase decline, as well as viral load at day 28.

Figure 1

A–D: HCV Viral Kinetics (A and C) and pharmacokinetics (B and D) in HIV/HCV genotype 1 co-infected patients treated with peg-interferon alfa-2b (1.5 µg/kg/wk) and ribavirin (1–1.2 g/d). Median HCV RNA concentrations are plotted (A) as function of race (black circles for African Americans and red squares for Caucasians), and (C) according to the treatment outcome (green circles for SVR, blue triangles for REL, red squares for VB and black diamonds for NR) for the first 84 days of treatment. Note the different time scale in x-axis at days 0–7 versus days 7–84, in order to clarify the transient viral rebound at day 3–7. Interferon-alpha serum concentrations are plotted (B) as function of race (black circles for African Americans and red squares Caucasians), and (D) according to the treatment outcome (green circles for SVR, blue triangles for REL, red squares for VB and black diamonds for NR) for the first 14 days of treatment. Statistical significant differences in viral decline between the groups are marked with * (P<0.05) or ** (P<0.03). Dashed horizontal lines mark the level of HCV RNA and peg-IFN detection. E–H: Correlation between early viral kinetic parameters and therapeutic response in African-American (A and C) and Caucasian (B and D) HIV/HCV co-infected patients. Sustained viral response (SVR, green circles) can be predicted in our study with NPV=100% and PPV=100% by the combination of HCV-RNA decline larger than 1.0 log IU/ml at day 3 (x-axis in A and B) and HCV-RNA load below 5.0 log IU/ml at day 28 (y-axis in A and B). Non-responders (NR, black diamonds) have lower decline in viral load than patients with viral breakthrough (VB, red squares) and patients with relapse (REL, blue triangles). Also, a second phase viral decline slope (y-axis in C and D) slower than 0.3 log/week is predictive of lack of SVR, but the transient rebound at days 3–7 (x-axis in C and D) is not correlated with therapeutic response). In addition, it is possible to observe the faster decline in Caucasians (B and D) as compared to African-Americans (A and C), in both first phase decline at day 3 and second phase decline, as well as viral load at day 28.

Figure 2

Non-linear fitting of the viral load data (red circles) and the IFN concentration data (white triangles) by a pharmacodynamical model (solid lines, Eqs 1–6) for each individual patient (given here for 4 representative cases each for a different therapeutic response group). Note that the transient rebound in viremia at days 3–7 (and 10–14) are due to the decline in the IFN levels below the Ec90 threshold (dashed horizontal line). This non-linear fitting allowed us to obtain individual estimates for the pharmacodynamical parameters Ec90 (or Ec50) and Nhill.

Figure 3

Pharmacokinetic (PK) and pharmacodynamic (PD) parameters for individual patients given as function of race and therapeutic response. No difference in the IFN max concentration (Cmax, A) or in the IFN half-life (B) is observed between any of the groups. Ec50 (B) is significantly (P