HCV Viral Kinetics prediction of Therapeutic Response among HIV/HCV Co-infected Patients
When we examined the predictive ability of HCV viral kinetics for therapeutic response,, within each race group there wee differences in viral kinetics as function of the result of treatment. At all time points we examined, non-responders had significantly lower HCV viral load decline when compared to those who experience viral breakthrough, relapse or sustained virologic response (). In addition, absolute HCV viral load on days 3 and 28 was statistically significant lower for patients with SVR compared to patients with relapse (p=0.05). There was no significant difference in viral kinetics between the relapsers and viral breakthrough groups.
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 (more ...)
In order to better understand the relationship between early HCV kinetics and therapeutic response rates we analyzed the role of several HCV kinetic parameters as predictors of SVR (see ). All patients who achieved SVR (both African-Americans and Caucasians), experienced a larger than 1.0 log decline in HCV-RNA at day 3 (p=0.005), as well as an absolute HCV viral load of less than 5.0 log IU/ml at day 28 (p=0.002), suggesting that a rapid decline in viral load earlier during therapy may be predictive of SVR (). The combination of a 1 log viral decline at day 3 with viral load less than 5 log IU/ml at day 28 gives NPV=100% and PPV=100% in our study.
When we examined the slope of the second phase decline (), those patients who achieved an SVR, irrespective of their race, all had a second phase slope faster than 0.3 log/week (NPV=100%, p=0.005), but the PPV for the second phase slope was not as good. The rebound in viral load between days 3 and 7 was not predictive of the therapeutic response. Notably, serum interferon-alpha concentrations at all measured time points, as well as the pharmacokinetic parameters, maximum concentration of Interferon and IFN half-life, were comparable for all therapeutic end-point groups: SVR, REL, VB or NR (, and ).
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. (more ...)
HIV/HCV co-infected patients - summary of viral kinetics, pharmacokinetics and pharmacodynamics parameters per patient.
Pharmacodynamic Parameters as Combination Predictors of Therapeutic Response
In order to better understand the relationship between HCV viral decline and interferon-alpha pharmacokinetics, we have fit the viral decline as function of the drug concentration data. This was achieved by an ODE mathematical model of pharmacokinetics combined with viral dynamics with a linking pharmacodynamical function as described in the Methods. The fit of both the viral kinetics and the pharmacokinetics was good as can be seen in for 4 representative examples from each of the non responders, relapsers, viral breakthrough and SVR groups.
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 (more ...)
Consequently, from the non-linear fits, we obtained estimates of the pharmacodynamic parameters Ec50 (or Ec90), describing the sensitivity of the virus to IFN, and the Nhill coefficient describing the second order sensitivity to changes in IFN concentration. Although, as mentioned above, the IFN pharmacokinetics were similar among all different groups of patients (), we nevertheless find that Ec50 is significantly (P<0.03) lower for Caucasians (3.2 log pg/ml) as compared to African-Americans (3.6), see and . Thus suggesting that the differences in viral kinetics between the races is not due to abnormal pharmacokinetics of interferon-alpha but due to lower sensitivity of the virus, or most probably virus related host factors, to interferon-alfa in African-Americans. There was no statistically significant difference in the Nhill coefficient between Caucasians and African-Americans (see and ), although there was a trend for lower Nhill in Caucasians (1.8) as compared to AA (2.6).
As to the effect of pharmacodynamics on therapeutic response, there were no statistical differences in relation to either the Ec50 (or Ec90) or Nhill coefficients among the different therapeutic response groups, non-responders, viral breakthroughs, relapsers. or SVR. Nevertheless, when we calculated the number of days for which the predicted concentration of interferon-alpha (see ) remained above the Ec90 level, 80% of Caucasians (4/5) and 50% of African Americans (1/2) who had maintained interferon-alpha concentration above EC90 for at least 1 day during the first week achieved SVR (). Moreover, none of the AA (10) or Caucasians (5) patients who did not achieve an IFN Cmax concentration above their own Ec90 level had achieved SVR (NPV=100%), see .
HIV/HCV Co-infected African Americans have Slower Viral Kinetics but Similar Pharmacokinetics when Compared to Caucasians
The baseline characteristics for study subjects enrolled are shown in . There were 4 patients on abacavir; of these two were non-responders, one was a relapser and the other was SVR. All patients received similar doses of Ribavirin throughout the study and no one was dose-reduced for toxicity. The average liver fibrosis score determined by Ishak scale was 2.3 for African Americans and 2.1 for Caucasians. Moreover, of the three patients who were infected with mixed genotype 1, one each achieved non-response, relapse and SVR. The study subjects were predominantly male and comprised of 10 Caucasians (43%) 12 African-Americans (AA, 52%) and one black Hispanic (5%), who was grouped with the AA for this analysis. Baseline HCV and HIV viral levels and baseline CD4+ T cell counts were similar between the groups. Most of the patients had undetectable HIV viral load. We found no correlation between HIV viral load (only 9 patients had detectable HIV VL at baseline, of which 3 were relapsers and 4 were SVR and only 2 were non-responders) and HCV therapeutic outcome. All patients had a similar HCV viral kinetic pattern although with a different behavior (see ), with a rapid first phase decline in days 0–3, followed by a transient viral rebound at days 3–7 after each injection (in conjugation with the decline in IFN serum levels at same time), as observed here in the first week as well as in the second week when mid-week samples were available. Consequently, a slower second phase viral decline slope is observed from one week to the next that is consistent as long as can be observed above the limit of detection.
Profile of Patients participated in the study
When we examined the HCV viral kinetics among African Americans and Caucasians, the mean decline in HCV viral load at 4 weeks was significantly (p=0.012) smaller (1.01 ± 0.99 log) among African-Americans compared to a the decline seen among Caucasians (1.99 ± 0.71 log) ( and ). Also, after 12 weeks of treatment, African-Americans had a mean HCV decline of 1.92 ± 1.2 log which was significantly (p=0.026) smaller than a mean HCV decline of 3.23 ± 0.78 log observed among Caucasians. This translated to a lower SVR rate in AA (1/13, 7.6%) as compared to Caucasians (4/10, 40%).
The significant difference in HCV-RNA decline between Caucasians and African-Americans starts already as early as days 1, 3 and 7 as seen in and . First phase HCV viral decline was significantly smaller among African Americans (mean 0.64 ± 0.33 log IU/ml) than Caucasians (mean 1.104 ± 0.377; p=0.015). African Americans also had slower second phase viral kinetics (mean 0.245 ± 0.267 log/week) than Caucasians (mean 0.52± 0.25; p= 0. 006) ( and ). With respect to end of week rebound (days 3–7), there was no significant difference in the magnitude of the rebound or the proportion of patients who experienced a viral rebound between the two groups (P>0.05). However, when we investigated the role of interferon-alpha to explain the differences in HCV viral kinetics, we found that the pharmacokinetics of interferon-alpha, in terms of maximal drug concentration and drug half-life, were comparable between African Americans and Caucasians (, and ). With respect to baseline CD4+ T cell counts between the two groups, African Americans had similar levels compared to that of Caucasians (538 ± 313 cells/ uL vs. 646 ± 168 cells/uL; p=0.27)
Comparison of pharmacokinetics and viral kinetics in HIV/HCV Co-infected patients versus HCV mono-infected patients
The mean reduction from baseline in HCV-RNA after 4 weeks and 12 weeks of treatment for all the HIV/HCV co-infected patients in our study was 1.38 ± 0.92 log IU/ml and 2.65 ± 1.24 log IU/ml respectively. In a similar study treating mono-infected HCV patients with the same treatment regimen [34
] the mean decline in HCV viral load at 4 weeks was 1.89 ± 0.577 and a 3 log decline after 8 weeks of treatment, significantly higher than observed with our HCV/HIV co-infected patients. However, the comparison of viral kinetics and treatment response rates between HIV/HCV co-infected patients and HCV mono-infected patients is questionable due to potential differences in the pharmacokinetics that could differ between the populations.
On the other hand, the combined pharmacodynamical parameters, e.g. Cmax/Ec90, should allow a more reliable comparison between the 2 populations, since they normalize the potential differences in pharmacokinetics. In fact, a similar pharmacodynamics analysis was performed by us on HCV mono-infected patients treated with pegylated-interfron-a2b 1.0 mg/kg qw in a study by Bruno et al [35
]. Unfortunately, the IFN Cmax concentration and Ec90 coefficient cannot be compared between the studies due to the different dose used. We have nevertheless compared the IFN half-life observed in our patients to that found for HCV mono-infected patients and found no significant difference (see ). The Nhill coefficient was higher in mono-infected Caucasian patients (3.7) as compared to the HIV/HCV Caucasian patients in our study (1.8), see . Furthermore, we found a higher proportion (80%) of HCV mono-infected Caucasian patients were able to achieve Cmax levels of interferon-alpha over their individual EC90 as compared to HIV/HCV co-infected Caucasian individuals in our study (50%) ().