Early Prediction of Sustained Virological Response at Day 3 of Treatment with Albinterferon-α-2b in Patients with Genotype 2/3 Chronic Hepatitis C
Avidan U. Neumann; Vincent G. Bain; Eric M. Yoshida; Keyur Patel; Erik Pulkstenis; G. Mani Subramanian
Posted Oct 5
Published Sept 23
Abstract and Introduction
Abstract
Abstract
Background Albinterferon-α-2b (albIFN) is a long-acting fusion polypeptide composed of albumin and IFN-α-2b. In a phase 2 study of albIFN 1500 μg q2wk or q4wk in patients with genotype 2/3 chronic hepatitis C, albIFN demonstrated sustained virological response (SVR) rates of 62–77% (intent-to-treat population).
Aims To assess the association of initial viral kinetics during albIFN therapy with baseline factors and SVR prediction.Methods In all, 43 patients were treated with albIFN 1500 μg (q2wk/q4wk) plus ribavirin (RBV) 800 mg/day for 24 weeks. Hepatitis C virus (HCV)-RNA levels were measured by real-time polymerase chain reaction, insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR) and serum albIFN levels by enyzme-linked immunosorbent assay.
Prediction analysis was performed in a per protocol 28-patient subset who were ≥80% adherent to albIFN/RBV and had HCV-RNA levels measured at treatment day 3.Results Day-3 HCV-RNA level and first-phase viral decline as well as second-phase slope of viral decline were significantly associated with SVR. In adherent patients, 82.1% had a day-3 viral load <> 1.25 log10 IU/ml, which was predictive of SVR, both positively (95.7%; sensitivity: 100%) and negatively (100%; specificity: 83.3%). As low first-phase decline was associated with a high pretreatment HOMA-IR index (P=0.004) and a low day-3 serum albIFN level (P=0.01).
Conclusions First-phase viral decline with albIFN/RBV was predictive of SVR in this study and may be modulated in part by IR.
Introduction
With a global prevalence of 3%, chronic hepatitis C (CHC) is now the leading cause of liver transplantation in developed nations. Although infection with genotype (Gt) 1, hepatitis C virus (HCV) is predominant in the US and Europe, Gts 2 and 3 represent 20–30% of all patients with CHC. A 24-week therapy regimen with pegylated interferon (PEG-IFN) in combination with ribavirin (RBV) represents the current standard of care for patients with Gt 2/3 CHC, with sustained virological response (SVR) rates ranging from 70 to 80%.[1–4] Reducing therapy duration to 16 weeks for patients with Gt 2/3 CHC has not been shown to be as effective as 24 weeks of therapy.[4,5]
With a global prevalence of 3%, chronic hepatitis C (CHC) is now the leading cause of liver transplantation in developed nations. Although infection with genotype (Gt) 1, hepatitis C virus (HCV) is predominant in the US and Europe, Gts 2 and 3 represent 20–30% of all patients with CHC. A 24-week therapy regimen with pegylated interferon (PEG-IFN) in combination with ribavirin (RBV) represents the current standard of care for patients with Gt 2/3 CHC, with sustained virological response (SVR) rates ranging from 70 to 80%.[1–4] Reducing therapy duration to 16 weeks for patients with Gt 2/3 CHC has not been shown to be as effective as 24 weeks of therapy.[4,5]
Another selective approach to optimizing treatment management has been to develop early predictors of virological response, which are mostly based on early viral kinetic responses to IFN-based therapy.[6] Rapid virological response (RVR; HCV-RNA level less than the limit of quantification at week 4) has been shown to be associated with a high likelihood of achieving an SVR in patients with Gt 2/3 CHC.[4,5,7,8] However, a negative predictive rule for patients with Gt 2/3 CHC that could effectively predict who will not achieve an SVR [with a negative predictive value (NPV)> 95%] has not been well determined.
The antiviral mechanism that leads to RVR has been best described by the biphasic pattern of HCV-RNA decline, which is characterized by the major IFN effect of blocking virion production or release (first-phase viral decline), followed by loss of infected cells (second-phase slope of viral decline).[6,9] Following the initiation of treatment, the magnitude and the slope of the initial HCV-RNA reduction in patients with Gt 2/3 CHC is greater than that observed in patients with Gt 1.[10] In patients with Gt 1 CHC, first-phase decline has been shown to be predictive of a rapid second-phase slope and, thus, RVR and, subsequently, SVR.[9,11,12] First-phase decline, therefore, may also be an important predictor of RVR and, subsequently, SVR in patients with Gt 2/3 CHC.
Albinterferon α-2b (albIFN) is an 85.7-kDa protein consisting of recombinant human IFNα-2b genetically fused to recombinant human albumin.[13] In a recently completed phase 2 study of albIFN administered every 2 weeks (q2wk) or 4 weeks (q4wk) in combination with RBV, albIFN was shown to be safe and well tolerated in addition to demonstrating significant antiviral activity in a treatment-adherent population (SVR rates of 85.7 and 78.9% in the q2wk and q4wk treatment arms respectively) of patients with Gt 2/3 CHC.[14] This study also confirmed the positive predictive value (PPV) of RVR for SVR, with a PPV of 96% in adherent patients. Furthermore, pretreatment insulin resistance (IR) – indicated by a homeostasis model assessment of insulin resistance (HOMA-IR) index > 2 – was shown to be an independent predictor of both RVR and SVR.
The aim of the present analysis was to define the association of viral kinetics – in particular, first-phase viral decline (day 3 following treatment initiation) – with SVR in patients with Gt 2/3 CHC receiving albIFN and RBV. An integrated prediction approach was utilized based on patients who were ≥80% adherent to both albIFN and RBV, absolute HCV-RNA levels and magnitude of first-phase decline. Further, the correlations of drug levels and pretreatment IR with early viral kinetics were explored.
Patients and Methods
Patient Selection
Patient Selection
In all, 43 patients were enrolled in this open-label study in two dose cohorts to receive subcutaneous albIFN 1500 μg q4wk or q2wk in combination with oral RBV 800 mg/day, as described in a previous publication.[14] Treatment duration was 24 weeks, with 24-week follow-up to document SVR. The present subanalysis included the per protocol population of 28 patients who had a day-3 HCV-RNA level recorded, were ≥80% adherent to both albIFN and RBV. Adherence to albIFN and RBV was calculated as the ratio of the total dose received to the total dose planned (based on the 24-week treatment duration).
Assessment of Hepatitis C Virus-RNA and Albinterferon α-2b Serum Levels
Hepatitis C virus-RNA assessments were carried out at days 0, 3, 7, 14, 17, 21 and 28 and then at weeks 6, 8, 12, 16, 20 and 24. HCV RNA levels were quantified by real-time polymerase chain reaction (CE-marked COBAS® Ampliprep/COBAS® Taqman® HCV test; Roche Diagnostics, Basel, Switzerland). The dynamic range of this assay was 43 IU/ml–69 million IU/ml. The limit of quantification was 43 IU/ml and the lower limit of detection was 10 IU/ml. Serum albIFN concentrations were measured using a qualified IFN-capture, IFN-detection sandwich enyzme-linked immunosorbent assay.[15]
Statistical Analysis
Prediction analysis was performed in the per protocol population. Predictive thresholds of HCV-RNA level and first-phase viral decline were selected based on optimal PPV/sensitivity or NPV/specificity to detect SVR. First-phase decline (and viral load) was calculated using log HCV-RNA at days 0 (before first dosing) and 3. Second-phase slope of viral decline was calculated by log-linear regression over the HCV-RNA levels available from days 3 to 28 or until the first time the viral load was below the limit of quantification.
Fisher's exact nonparametric test was used to test statistical significance of differences in the fraction of response between the different patient subgroups. The nonparametric Mann–Whitney U test was used to test the significance of differences in distribution of continuous pharmacokinetic and viral kinetic variables between patient subgroups. The nonparametric Spearman test was used to test the significance of correlations between continuous variables. All statistical tests were two-sided and significance was assumed atP<>
The HOMA-IR index was available in 19 of the 28 patients using the following formula: fasting plasma glucose (mmol/L) × fasting serum insulin (μIU/L)÷22.5. Serum albIFN concentrations were available in 27 patients
Results
Patient Baseline Factors and Sustained Virological Response Rates
Baseline patient demographics for the 28 patients included in this analysis are shown in Table 1. There were no baseline differences in either demographical variables or disease characteristics between the two treatment arms. Patients with Gt 2 vs 3 CHC had similar baseline characteristics and SVR rates [75 vs 81%; P=not significant (NS)]. The SVR rates were similar for the q2wk and q4wk arms [83.3% (10 of 12 patients) and 75.0% (12 of 16) respectively; P=NS]. Achievement of an SVR was associated with both lower age (P=0.003) and lower HOMA-IR index (P=0.009) at baseline (Table 1). Other baseline factors, including HCV-RNA level (Fig. 1C), were not associated with SVR.
Baseline patient demographics for the 28 patients included in this analysis are shown in Table 1. There were no baseline differences in either demographical variables or disease characteristics between the two treatment arms. Patients with Gt 2 vs 3 CHC had similar baseline characteristics and SVR rates [75 vs 81%; P=not significant (NS)]. The SVR rates were similar for the q2wk and q4wk arms [83.3% (10 of 12 patients) and 75.0% (12 of 16) respectively; P=NS]. Achievement of an SVR was associated with both lower age (P=0.003) and lower HOMA-IR index (P=0.009) at baseline (Table 1). Other baseline factors, including HCV-RNA level (Fig. 1C), were not associated with SVR.
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Figure 1
Figure 1
Figure 1.
The relationship between sustained virological response (SVR) and early viral kinetics in patients receiving albinterferon-α-2b every 2 weeks (q2wk) or 4 weeks (q4wk) is depicted: (A) mean hepatitis C virus (HCV)-RNA reductions during the first 12 weeks of treatment; (B) relationship of first-phase viral decline with HCV-RNA level at day 3; relationships of second-phase slope of viral decline with HCV-RNA level at baseline (C) and day 3 (D).
Figure 1.
The relationship between sustained virological response (SVR) and early viral kinetics in patients receiving albinterferon-α-2b every 2 weeks (q2wk) or 4 weeks (q4wk) is depicted: (A) mean hepatitis C virus (HCV)-RNA reductions during the first 12 weeks of treatment; (B) relationship of first-phase viral decline with HCV-RNA level at day 3; relationships of second-phase slope of viral decline with HCV-RNA level at baseline (C) and day 3 (D).
Biphasic Viral Kinetics in Patients with Genotype 2/3 Chronic Hepatitis C
Viral decline during treatment with albIFN in patients with Gt 2/3 CHC showed a biphasic viral kinetic pattern (Fig. 1A). The first-phase viral decline (mean drop: 2.2 log10 IU/ml) was similar in the two treatment arms (Table 1; Fig. 1A and B) as well as in patients with Gt 2 vs 3 CHC (mean drop: 2.4 vs 2.0 log10 IU/ml; P=NS). The first-phase decline was followed by a second-phase decline, with a mean drop of 0.75 log10 IU/ml/week that was comparable in the two treatment arms (Table 1; Fig. 1A and C) and in patients with Gt 2 vs 3 CHC (mean drop: 0.8 vs 0.7 log10 IU/ml/week; P=NS). The second-phase slope did not correlate with baseline viral load (Fig. 1C) or any other baseline factor in this study. The second-phase slope was inversely correlated with viral load at day 3 (R=0.65; P < r="0.43;" p="0.03)." p="0.02;" href="javascript:newshowcontent(">Table 1; Fig. 1A and B). A first-phase decline > 1.25 log10 IU/ml was observed in 78.6% of the patients (n=22), which was significantly predictive of SVR (P < ppv="95.5%;" npv="83.3% Table 2). An HCV-RNA level < n=" p="0.007;" ppv="94.7%;" npv="55.6%;" href="javascript:newshowcontent(">Table 2). One patient failed to achieve a first-phase decline > 1.25 log10 IU/ml, but went on to achieve an SVR.
Achievement of an SVR was also significantly associated with a more rapid second-phase slope of viral decline (P=0.007; Table 1; Fig. 1A and C). A second-phase slope > 0.3 log10 IU/ml/week was observed in 77.8% of the patients and accurately predicted SVR with a PPV of 95.2%; the NPV of 83.2% was similar to that seen with a first-phase viral decline > 1.25 log10 IU/ml (Table 2). As expected, RVR was a positive predictor of SVR (PPV=95.0%), but the NPV was lower (71.4%).
The optimal algorithm for SVR prediction determined in this study was obtained with the combination of day-3 HCV-RNA level <> 1.25 log10 IU/ml (P < n="23)." href="javascript:newshowcontent(">Table 2). By intent-to-treat analysis, this algorithm provided a NPV of 97.5%, with 38/39 patients not achieving SVR.
Albinterferon α-2b Level and First-phase Viral Decline
Prior pharmacokinetic studies have indicated a dose-proportional increase in maximal serum albIFN concentration, a time to maximal albIFN concentration of 65–87 h and an elimination half-life of 6 days.[15] In the present analysis, serum albIFN concentrations at day 3 were available in 27 patients and were similar between the q2wk and the q4wk treatment arms (110 and 109 ng/ml respectively; P=NS; Table 1). Serum albIFN concentration at day 3 was not associated with SVR (mean concentrations: 111 and 104 ng/ml in patients with and without an SVR respectively; P=NS; Table 1 and Fig. 2A). All four patients who failed to achieve an SVR due to a low first-phase viral decline (< p="0.01)."> 125 ng/ml (P=NS).
Figure 2.
The relationships among early hepatitis C virus (HCV) kinetics (first-phase viral decline and HCV-RNA level at day 3), homeostasis model assessment of insulin resistance (HOMA-IR) and albinterferon-α-2b (albIFN) levels in patients receiving albIFN every 2 weeks (q2wk) or 4 weeks (q4wk) with and without a sustained virological response (SVR) are depicted: (A) a lower albIFN level at day 3 is associated with a less robust first-phase viral decline and no SVR; (B) an elevated HOMA-IR index is associated with increasing age; (C) an elevated HOMA-IR index is associated with a higher day-3 HCV-RNA level and no SVR.
Figure 2.
The relationships among early hepatitis C virus (HCV) kinetics (first-phase viral decline and HCV-RNA level at day 3), homeostasis model assessment of insulin resistance (HOMA-IR) and albinterferon-α-2b (albIFN) levels in patients receiving albIFN every 2 weeks (q2wk) or 4 weeks (q4wk) with and without a sustained virological response (SVR) are depicted: (A) a lower albIFN level at day 3 is associated with a less robust first-phase viral decline and no SVR; (B) an elevated HOMA-IR index is associated with increasing age; (C) an elevated HOMA-IR index is associated with a higher day-3 HCV-RNA level and no SVR.
Insulin Resistance, Age and First-phase Viral Decline
Baseline HOMA-IR index was available in 19 patients in this analysis and was similar in both treatment arms and in patients with Gt 2 or 3 CHC (Table 1).
Discussion
This exploratory study provides initial data indicating that first-phase viral decline in patients with Gt 2/3 CHC treated with albIFN is highly predictive, both positively and negatively, of SVR. RVR has been shown to predict SVR both in the present patient cohort and in several other larger studies with PEG-IFN.[4,5,7] A recent study showed that a large viral decline by treatment day 7 was a positive predictor of SVR in patients with Gt 2/3 CHC treated with PEG-IFN-α-2a.[7] In the present study, a first-phase decline > 1.25 log10 IU/ml or HCV-RNA level <> 95% for SVR in patients receiving albIFN 1500 μg q2wk or q4wk, which also resulted in an NPV of 100% (specificity: 83.3%), which was not found with previously suggested algorithms.
Similar to patients with Gt 1 CHC,[12] a correlation was observed between viral load at the end of the first-phase viral decline and the subsequent second-phase slope of viral decline. Thus, a large first-phase decline led to a more robust second-phase slope and hence a better chance of achieving an RVR and SVR. Furthermore, patients who failed to achieve an SVR due to a low first-phase viral decline had a lower albIFN concentration at day 3. These findings support further exploration of a dose–response relationship for albIFN administered q4wk in a patient population with Gt 2/3 CHC. The present study was limited by a small sample size and thus the results need to be corroborated by a larger prospective study. In addition, only patients who were ≥80% adherent to dose and duration of combination therapy were included in the study to reduce the effect of noncompliance on SVR.
Prior studies have noted that SVR rates are lower in patients with IR irrespective of Gt.[16–18] In accordance with prior observations, the present study noted that the effect of IR on SVR was independent of body mass index, but correlated with older age. The influence of steatosis on virological response was not evaluated in this study because only a small proportion of patients had a recent biopsy. The results showed a strong association between higher IR and a subdued first-phase viral decline with albIFN treatment. A recent study with PEG-IFNα-2b and RBV also noted a blunted HCV-RNA level decay at 24 h in patients with a high IR index.[19] These results indicate that IR may directly inhibit the antiviral effect of IFN and thus reduce the first-phase decline that appears important for favourable outcomes to IFN-based therapy. A complex interplay of several pathogenic mechanisms is likely to influence IFN responses in patients with CHC and IR,[20] including upregulation of suppressor of cytokine signalling-3, which inhibits signal transduction and transcription pathways important for IFN-mediated antiviral and antiproliferative responses. IR may also result in an imbalance of pro-inflammatory cytokines such as tumour necrosis factor-α and interleukin-6, which could also influence early virological response. These results have an important clinical implication indicating that amelioration of IR through prior adjunct therapeutic approaches may improve virological response to IFN-based therapy and thus increase SVR rates.
In summary, first-phase viral decline was highly predictive of SVR in patients with Gt 2/3 CHC treated with albIFN administered q2wk or q4wk. The magnitude of first-phase decline was the summation of various biological effects that included albIFN pharmacodynamics and IR. These findings indicate that a greater first-phase decline leads to a faster second-phase slope of viral decline and, ultimately, an SVR. Validation of these observations in larger cohorts is required because early predictive patterns of response outcomes may help tailor therapy for patients with Gt 2/3 CHC at an early time point, allowing for shorter or longer treatment durations in well-defined subpopulations.
http://www.medscape.com/viewarticle/708941
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