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Twice-weekly pegylated interferon-α-2a and ribavirin results in superior viral kinetics in HIV/hepatitis C virus co-infected patients compared to standard therapy
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"Our study suggests that twice-weekly peg-IFN-α-2a for 4 weeks followed by weekly dosing and ribavirin has a superior early virologic response compared with the standard therapy of weekly peg-IFN-α-2a and ribavirin among HIV/HCV co-infected genotype 1 individuals, particularly among African-Americans."
AIDS: 1 June 2011
"twice-weekly peginterferon-α-2a 180 μg/week (for 4 weeks, followed by weekly dosing)........Twice-weekly peginterferon-α-2a was associated with more frequent early virological responses with similar safety profiles when compared with standard therapy.....investigational therapy was most beneficial in African-Americans who represent the most difficult-to-treat subgroup in the HIV/HCV co-infected patients.....Our study suggests that twice-weekly peg-IFN-α-2a for 4 weeks followed by weekly dosing and ribavirin has a superior early virologic response compared with the standard therapy of weekly peg-IFN-α-2a and ribavirin among HIV/HCV co-infected genotype 1 individuals, particularly among African-Americans."
Murphy, Alison Aa,*; Herrmann, Evab,*; Osinusi, Anu Oa,d; Wu, Lynnc; Sachau, Williama; Lempicki, Richard Ad; Yang, Jund; Chung, Tei Lb; Wood, Brad Je; Haagmans, Bart Lf; Kottilil, Shyama; Polis, Michael Aa
aLIR, NIAID, NIH, DHHS, Bethesda, Maryland, USA
bDepartment of Medicine, Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany
cDivision of Pulmonary, Allergy and Rheumatology Products, The Food and Drug Administration, Silver Spring, USA
dSAIC-Frederick Inc., NCI, Frederick, USA
eDivision of Radiology, Radiology and Imaging Sciences, NIH, Bethesda, Maryland, USA
fErasmus Medical Center, Rotterdam, The Netherlands.
*Alison A. Murphy and Eva Herrmann contributed equally to the writing of the article.
Correspondence to Dr Michael A. Polis, Collaborative Clinical Research Branch, NIAID, NIH, 6700B Rockledge Drive, 1118 Bethesda, MD, USA. Tel: +1 301 496 8027; fax: +1 301 435 6739; e-mail: mpolis@niaid.nih.gov
Abstract
Background: Hepatitis C virus (HCV)/HIV co-infected patients have more rapid progression of liver fibrosis and only modest cure rates (sustained virologic responses, SVRs) when compared to HCV monoinfected patients.
Method: We compared the virologic responses of either twice-weekly peginterferon-α-2a 180 μg/week (for 4 weeks, followed by weekly dosing) or weekly peginterferon-α-2a 180 μg/week, and weight-based ribavirin (1-1.2 g/day), among HIV/HCV co-infected genotype-1 individuals.
Results: Patients receiving the investigational dosing had lower levels of HCV RNA at all time points after initiation of therapy. More patients on this arm achieved clinically relevant early virological responses at weeks 1, 2, 4, 12, and 24. The enhanced early virologic response observed with the investigational arm was associated with a higher induction of interferon-stimulated genes. This early double dose regimen also resulted in a rapid normalization of liver enzymes. Twice-weekly peginterferon-α-2a was associated with more frequent early virological responses with similar safety profiles when compared with standard therapy.
Conclusion: Our results, when confirmed in larger randomized clinical trials, may provide a novel therapeutic approach to improve SVR among HIV/HCV co-infected patients, especially African-American patients.
Introduction
Hepatitis C virus (HCV) co-infection occurs approximately in one-third of all patients infected with HIV in the United States [1]. Although the successful implementation of antiretroviral therapy (ART) has dramatically decreased the number of AIDS-related opportunistic infections, morbidity and mortality rates related to HCV-related liver disease have increased in this group [2-4]. In comparison to HCV monoinfected patients, HIV/HCV co-infected patients have an accelerated progression of liver disease [5] and only attain modest cure rates with treatment of pegylated interferon (peg-IFN) and ribavirin [6-11]. Along with significant associated toxicities, the standard treatment of peg-IFN and ribavirin yields only low rates of sustained virological response (SVR) among HIV/HCV co-infected genotype 1 patients. Furthermore, African-Americans have poor viral kinetics, pharmacodynamics, and SVR rates in comparison to whites, but constitute a significant proportion of all HIV/HCV co-infected individuals [9,12,13]. This warrants the development of novel therapeutic regimens to improve SVR in this difficult-to-treat population [7,10,11].
Early HCV viral kinetics have shown a strong predictive ability for SVR in HIV/HCV co-infected patients [14], and improvements in early viral kinetics could potentially translate into higher rates of SVR. Recent studies on early HCV kinetics in HIV/HCV co-infected patients show that almost 90% of patients treated with peg-IFN α-2b and ribavirin experienced an end of the week rebound consistent with a decline in serum IFN levels [14-17]. A large, randomized controlled trial of 896 patients attempted to overcome the end of the week rebound with high-induction dosing of peg-IFN and ribavirin at the beginning of each week [18]. Although this high-dose peg-IFN enhanced early virologic response rates, SVR rates were not significantly improved [18-20]. A better alternative approach to induction dosing is twice-weekly dosing of peg-IFN. The additional dose of peg-IFN is given as serum IFN levels begin to decline, which may prevent an end of the week rebound [12]. Studies of HCV viral kinetics in HCV monoinfected patients have suggested the use of twice-weekly peg-IFN to improve early HCV kinetics and subsequently enhance SVR rates [21]. These studies suggest that a twice-weekly dosing of peg-IFN could prevent an end of the week rebound, improve the early virological response (EVR), and potentially increase SVR among HIV/HCV co-infected individuals.
In this study, we treated HIV/HCV genotype 1 co-infected patients with weekly or twice-weekly peg-IFN for 4 weeks, followed by once weekly peg-IFN and standard doses of ribavirin for a total of 48 weeks. We evaluated viral kinetics, biochemical responses, and adverse events in order to compare safety, tolerability, and early virological efficacy.
Results
Investigational therapy yields better early virologic response
The baseline demographics of the 19 patients participating in this study are shown in Supplemental Table 1, http://links.lww.com/QAD/A135. The patient population was predominantly men (84%) and African-American (58%) with a median CD4+ T-cell count of 483 cells/μl. All patients were co-infected with HIV and HCV genotype 1. Four patients (two receiving investigational therapy and two receiving standard therapy) stopped treatment early at weeks 3, 4, 10, and 32 due to adverse events.
All 19 patients met the primary end point, which was the change in HCV RNA levels on day 7 between the two groups. Patients who received investigational therapy had a significantly lower HCV viral load on day 7 [median log10 HCV RNA 3.61 (range <2.79-6.11)] compared to those who were randomized to receive standard therapy [median log10 HCV RNA 5.59 (range 4.65-6.40); P = 0.032]. Furthermore, patients who received investigational therapy showed a significantly larger decline in HCV viral load than the standard therapy during the first week (median log10 HCV RNA decline 1.28 vs. 0.17; P = 0.018; Fig. 1a).
Patients on the investigational arm experienced a steeper first phase decline than patients on the standard arm (Fig. 1a). Other early virological end points (Fig. 1b) also showed that more patients receiving investigational therapy achieved relevant on-treatment virological response defined as at least 2-log drop in HCV viral load from baseline by week 2 (44 vs. 0%), week 4 (63 vs. 40%), and week 12 (71 vs. 50%). Clinical end points were week 4 RVR (63 vs. 30%), EVR (63 vs. 44%), week 48 ETR (57 vs. 63%), and week 72 SVR (57 vs. 50%; Fig. 1c). Although all early virologic response parameters were superior in patients receiving investigational therapy, these differences did not reach statistical significance given the small sample size.
HIV/hepatitis C virus co-infected African-Americans have improved viral kinetics on investigational therapy
A subset analysis of African-Americans, who represent the major group of patients who poorly respond to standard therapy, was performed. In HIV/HCV genotype-1 co-infected African-American patients, a significantly faster viral load decline at day 7 was observed in patients receiving investigational in comparison to those receiving standard therapy (median log10 HCV RNA 1.67 vs. 0.04, P = 0.009; Fig. 1d). Most early virologic parameters were more favorable in African-Americans receiving investigational therapy compared to those receiving standard therapy, such as at least 2-log drop in HCV viral load from baseline by week 2 (60 vs. 0%) and RVR (75 vs. 0%; P < 0.05). Thus, investigational therapy was most beneficial in African-Americans who represent the most difficult-to-treat subgroup in the HIV/HCV co-infected patients.
Pharmacokinetic and viral kinetic modeling
We fitted a full pharmacokinetic and viral kinetic model for the data of the first 6 weeks. Interestingly, dose-independent pharmacokinetic parameters as the elimination rate were similar between the investigational group and the standard treatment group, but trough levels of IFN from the pharmacokinetic fit were significantly larger for bi-weekly dosing (Table 1 and Fig. 2, at day 7: P = 0.011). Differences in pharmacokinetics between African-American and other patients were small (P > 0.2 for the pharmacokinetic parameters).
Viral kinetic analysis showed comparable Hill coefficients and IC50 levels between the investigational treatment group and the standard treatment group (Table 1). Nevertheless, significantly higher mean and maximum efficiency were observed in the investigational group (Table 1, P = 0.046 and 0.038, respectively). Once bi-weekly dosing ended after week 4, the advantage in treatment efficiency in the investigational group was lost, and viral kinetics became slower (Fig. 2 a and c).
Interferon-stimulated gene expression
Our previous studies have demonstrated that induction of ISGs is a major biological correlate of antiviral efficacy of IFN-based anti-HCV therapy [27]. We investigated whether the enhanced antiviral effect observed with the investigational therapy was associated with similar levels of induction of ISG. As anticipated, the additional bi-weekly dosing of peg-IFN significantly increased the expression of ISG in all patients receiving investigational therapy from baseline when compared to that observed with standard therapy (Fig. 3a). Additionally, patients who attained SVR were able to induce significantly higher levels of ISG than nonresponders whether they received standard or investigational therapy. These results suggest that induction of ISG is an important surrogate biomarker of therapeutic response to IFN-based anti-HCV treatment regimens.
Investigational therapy results in earlier normalization of liver enzymes
Normalization of serum levels of ALT and AST are indicators of HCV clearance and subsequent reduction in hepatic inflammation. At baseline, all but four patients had elevated ALT and AST levels, which were not significantly different at baseline between the treatment groups. Patients with elevated hepatic enzymes at baseline undergoing investigational dosing normalized hepatic enzymes quicker than patients on standard therapy (Fig. 3b). ALT levels at week 24 and at the end of treatment were significantly lower in the investigational group than in the standard treatment group. Thus, investigational therapy normalizes liver enzymes much earlier than standard therapy, suggesting earlier clearance of HCV from infected hepatocytes.
Investigational therapy is safe and well tolerated in HIV/hepatitis C virus co-infected individuals
In this study, the investigational therapy was equally well tolerated as standard therapy in HIV/HCV genotype-1 co-infected individuals. The overall incidence of adverse events was similar in both groups (P > 0.05), with no significant differences in quantity or grade of adverse events (Fig. 4a). The rates of adverse events such as hemoglobin level less than 12 g/dl was 30 vs. 44% (P > 0.05) or absolute neutrophil count less than 1000 cells/μl was 20 vs. 33% (P > 0.05) in standard vs. investigational arms respectively(Fig. 4b). Both groups experienced a decline in CD4+ T-cell counts (median decline of 78 vs. 51 cells/μl in the standard arm vs. investigational arm by week 6, (P > 0.20; Fig. 4c), but the CD4+ T-cell percentage remained unchanged (30 vs. 31%, P > 0.20). Although both groups experienced adverse events commonly associated with IFN-based therapy, the investigational group did not demonstrate significantly more toxicities, which suggests that the biweekly therapy is safe and as equally well tolerated as standard therapy.
Discussion
Our study suggests that twice-weekly peg-IFN-α-2a for 4 weeks followed by weekly dosing and ribavirin has a superior early virologic response compared with the standard therapy of weekly peg-IFN-α-2a and ribavirin among HIV/HCV co-infected genotype 1 individuals, particularly among African-Americans. More patients receiving investigational therapy met early virologic end points than those receiving standard therapy and did not report a significantly higher number of adverse events. Mathematical modeling suggests the improved early virologic response was associated with a successful prevention of viral rebound at the end of the week and an increased efficacy of the investigational therapy compared with standard therapy. Host genomic analysis indicates the ability to induce ISG as a major potential mechanism for the observed virologic response. Thus, the superior viral kinetics, pharmacokinetics, pharmacodynamics, and enhanced ISG induction of the investigational treatment arm illustrate the potential significance of this viral kinetics-driven therapy for eradicating HCV in this difficult-to-treat patient population.
Although previous studies have attempted to improve early viral kinetics via high-dose peg-IFN-α-2a induction therapy, our study uniquely targeted the end of the week viral rebound with twice-weekly dosing of peg-IFN-α-2a. By administering an additional dose of peg-IFN-α-2a midweek as serum IFN levels begin to decline and HCV viral load correspondingly increases, a more rapid decline in HCV viral load was observed in patients receiving investigational therapy. Furthermore, a subset analysis of African-American patients demonstrated that the investigational therapy significantly benefited this group. As previously suggested, improving early viral kinetics may be essential in developing more effective anti-HCV therapies as early viral kinetics are important predictors of long-term virologic outcomes [28].
In order to understand the antiviral effect of peg-IFN-α-2a in weekly and bi-weekly dosing, we modeled viral kinetic, pharmacokinetic, and pharmacodynamic parameters based upon treatment as well as race. Pharmacokinetic modeling not only confirmed that trough serum IFN levels were increased by bi-weekly dosing during the first 4 weeks, but maximum serum IFN levels remain equal or are only moderately increased. After stopping bi-weekly dosing, subsequently, the pharmacokinetic profile normalized. Though patients on the investigational arm only received increased IFN for the first 4 weeks of therapy, the viral kinetics were significantly improved in the investigational therapy and HCV viral levels were already below the level of detection in most patients. Again by improving early viral kinetics, the investigational therapy attained more early virologic responses that prior studies have shown to be predictive of achieving SVR. This improved antiviral response in the investigational arm can also be confirmed by pharmacodynamic modeling. The mean estimated efficiency of blocking viral production is significantly higher in the investigational arm during the bi-weekly dosing phase. In a subset analysis, these effects were improved among African-Americans. Hence, this viral kinetics-driven clinical strategy would appear to benefit the patient population who are least responsive to the current standard of care.
While data from this pilot study showed an increased antiviral efficacy of the investigational regimen, this study also showed the safety and tolerability of twice-weekly dosing. Combination therapy for HCV with peg-IFN-α-2a and ribavirin is associated with many serious dose-limiting adverse events, ranging from fatigue, headache, nausea, insomnia, pyrexia, anemia, myalgia, neutropenia, and depression to severe hematological disorders [29]. Conceivably, increasing the frequency of peg-IFN-α-2a in the first 4 weeks could result in increased rates of adverse events and study discontinuation rates; however, statistical analysis showed no significant differences between patients in both groups. Although many patients experienced adverse events, these were easily manageable. Patients receiving investigational therapy also had a faster normalization of hepatic enzymes, indicating an earlier more rapid clearance of HCV from infected hepatocytes and reversal of ongoing hepatic parenchymal damage. These results suggest that twice-weekly peg-IFN-α-2a with ribavirin was well tolerated, safe, and resulted in improved virologic and biochemical response when compared to the standard therapy among HIV/HCV co-infected individuals.
Previous DNA microarray studies examining the baseline expression of ISG have demonstrated that nonresponders exhibit significantly higher levels of baseline ISG expression than responders [27,30,31]. Moreover, patients with high baseline levels of ISG do not induce higher levels of ISG expression during IFN therapy, whereas those who achieve SVR do induce ISG after IFN therapy [27,30,31]. These studies suggest that elevated endogenous IFN expression potentially accounts for the refractoriness of immune cells to exogenous IFN therapy in nonresponders, and these patients have an increased threshold for antiviral effect with IFN-based therapy for HCV. Our results are consistent with earlier findings that nonresponders to combination therapy have slower viral kinetics and pharmacodynamic parameters that suggest a greater refractoriness to IFN therapy. Therefore, increasing the frequency of IFN dosing may overcome this mechanism of treatment failure by inducing higher levels of ISG expression. Patients in this study who attained SVR induced significantly higher levels of ISG expression in comparison to nonresponders. In addition, our study demonstrates the effectiveness of twice-weekly peg-IFN-α-2a dosing in IFN induction, as all patients receiving investigational therapy induced significantly higher levels of ISG in comparison to patients receiving standard therapy. These combined results of enhanced ISG induction and superior early virologic responses of the bi-weekly dosing of peg-IFN-α-2a therapy further suggest the induction of ISG as an important biological correlate of antiviral efficacy of IFN-based anti-HCV treatment, especially with twice-weekly peg-IFN-α-2a and ribavirin.
In conclusion, twice-weekly dosing of peg-IFN-α-2a in combination with ribavirin resulted in superior early virologic response rates, superior viral kinetics, pharmacokinetics, pharmacodynamics, and superior ISG induction, although this study was not powered to analyze SVR. The results of this pilot study show promise for a more effective therapy, particularly for HIV/HCV genotype-1 co-infected African-Americans. Future studies are warranted to validate the clinical utility of using twice-weekly peg-IFN treatment to improve SVR among HCV and HIV co-infected patients.
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