Hepatitis C - Response to Interferon-α/Ribavirin Does Not Decrease on Retreatment

Response to Interferon-α/Ribavirin Does Not Decrease on Retreatment of Hepatitis C

Among study participants with the same end-of-study response status, HCV RNA declines at 4 weeks were similar between treatment-naive patients and treatment-experienced ones.

Participants in treatment studies of hepatitis C virus (HCV) infection are generally categorized as treatment naive or treatment experienced, based on previous receipt of an interferon-based regimen such as pegylated interferon-α plus ribavirin (P/R). Treatment-experienced individuals with P/R treatment failure can be further subdivided into relapsers, partial responders, and null responders, based on plasma HCV RNA concentrations during and after therapy.

To date, no data have emerged to indicate resistance to interferon-α–based therapy, suggesting that the response rate to P/R should not be lower with retreatment than with initial therapy. To examine this issue, investigators at the FDA examined data for participants in eight earlier trials (2996 treatment-naive and 754 treatment-experienced patients with genotype-1 HCV infection who had completed P/R treatment and had week-4 viral load data available).

In both treatment-naive and treatment-experienced patients, the HCV RNA change from baseline at 4 weeks was strongly correlated with the likelihood of achieving a sustained viral response (i.e., an undetectable viral load 24 weeks after the end of treatment). When therapy response was compared between treatment-experienced patients (stratified according to previous treatment outcomes) and treatment-naive patients (stratified based on end-of-treatment outcomes), the 4-week decline in HCV RNA was similar between the corresponding groups.

Comment: Despite its retrospective nature, this study suggests that responsiveness to Interferon-α/Ribavirin  (P/R) does not decrease with retreatment. As the authors point out, this finding has implications for trials of interferon-based triple therapy — P/R plus one of the newer direct-acting antivirals emerging for HCV.

— Neil M. Ampel, MD

Published in Journal Watch Infectious Diseases September 19, 2012

Citation(s):

Liu J et al. Interferon responsiveness does not change in treatment-experienced hepatitis C subjects: Implications for drug development and clinical decisions. Clin Infect Dis 2012 Sep 1; 55:639.

• Original article (Subscription may be required)
• Medline abstract (Free)

Protease Inhibitors - Maximizing Treatment Benefit in HCV

Alimentary Pharmacology & Therapeutics

Despite Poor Interferon Response in Advanced Hepatitis C Virus Infection, Models of Protease Inhibitor Treatment Predict Maximum Treatment Benefit

I. A. Rowe; D. D. Houlihan; D. J. Mutimer

 

Posted: 09/28/2012; Aliment Pharmacol Ther. 2012;36(7):670-679. © 2012 Blackwell Publishing

Source-Medscape

Abstract

Background Protease inhibitors have improved sustained virological response (SVR) rates for subjects with genotype 1 hepatitis C virus infection (HCV). There is however uncertainty regarding how, and in whom, these agents should be used. In previously treated subjects, prior response to interferon has a major effect on SVR rates with protease inhibitor therapy.
Aim To assess the benefits of treatment and to understand the utility of a stopping rule for subjects with a poor interferon response following a 4-week lead-in with pegylated interferon and ribavirin.
Methods Treatment responses and long-term outcomes were modelled using hypothetical 1000 subject cohorts with 5 years of follow-up. Treatment strategies were compared with number needed to treat (NNT) and comparative effectiveness approaches.
Results Over 5 years of follow-up the NNT to prevent liver-related mortality for subjects with advanced fibrosis was substantially lower than that for subjects with all fibrosis stages (18 vs. 60) indicating particular benefit in this high-risk population. The use of a stopping rule for subjects with advanced fibrosis and a poor interferon response after a 4-week lead-in reduces the number of subjects exposed to a protease inhibitor by 55%. However, 33% fewer liver-related deaths are prevented using this strategy, indicating that there is unacceptable harm associated with this approach over a 5-year follow-up period.
Conclusions Subjects with advanced fibrosis should be prioritised for triple therapy on the basis of need. Treatment should be continued regardless of initial interferon response to maximise the early prevention of hepatitis C virus-related mortality.

Introduction
Hepatitis C virus (HCV) infection affects up to 200 million individuals worldwide and is an important cause of both morbidity and mortality.^[1] Indeed up to 30% will develop cirrhosis with the attendant risks of liver failure and the development of hepatocellular cancer (HCC).^{[2, 3]} Antiviral treatment has improved during the last two decades, but sustained virological response (SVR) rates remained below 50% for individuals infected with genotype 1 HCV who were treated with pegylated interferon and ribavirin. Since these were until recently the only available treatments many patients have been treated and not cured. Many of these individuals have cirrhosis, are at significant risk from liver related mortality and are prime candidates for more efficacious treatments that will reduce this mortality risk. To estimate this risk reduction it is crucial to understand the impact of the surrogate outcome of SVR on liver-related morbidity and mortality. This understanding permits well-informed discussion with patients who are considering retreatment.^[4]

In the last year, the first generation of directly acting antiviral (DAA) agents has been licensed for treatment of patients with genotype 1 HCV infection. These are NS3 serine protease inhibitors that, when used with pegylated interferon and ribavirin, substantially improve response rates and have the potential to cure many individuals who would not have been cured with the previous standard of care.^{[5, 6]} This increased cure rate comes at the expense of increased adverse events and an increased pill burden. Furthermore, DAAs have the potential to cause drug resistance, analogous to that seen with antiviral treatment for human immunodeficiency virus and hepatitis B virus (reviewed in).^[7]

Resistant species are associated with antiviral treatment failure, but the long-term ramifications of resistance are not known. It is possible that resistance to these agents will compromise the chance of treatment success with regimens that contain similar agents in the future. To limit the development of resistance, all of the phase II and III studies employed strict stopping rules to prevent futile drug exposure. Despite this up to 50% of those treated and who were not cured still developed drug resistant variants although these were frequently short-lived in the plasma.^[8]

In the boceprevir development programme and in the phase III study of previously treated subjects with telaprevir, a 4-week lead-in phase with pegylated interferon and ribavirin was employed.^[8–10] This strategy confirmed that interferon responsiveness was a key determinant of successful treatment. It has been suggested that the lead-in could be used to identify individuals with poor interferon response where treatment with first-generation protease inhibitors should be avoided, thus eliminating the risk of drug resistance and reducing the frequency and severity of treatment-associated adverse events.^[11–13] Indeed, some experts would use the 4-week lead-in with both telaprevir and boceprevir where poor interferon response might be expected to aid decision making.^[14] This approach is the subject of intense debate as some patients with poor response during the lead-in phase are subsequently cured with DAA containing treatment.

The aims of this study were therefore twofold: first to quantify the benefit associated with protease inhibitor treatment in previously treated subjects to aid patient selection for treatment, and second to evaluate the benefits and risks of using a lead-in phase with interferon and ribavirin dual therapy to identify patients who will benefit from addition of a protease inhibitor. The comparative effectiveness of treatment strategies was assessed using hypothetical patient cohorts over a clinically relevant 5-year follow-up period.

Maximizing Treatment Benefit in HCV: Methods

Methods
Treatment Strategy
All patients who had previously failed treatment with interferon and ribavirin were considered suitable for treatment. The proportions of subjects with previous null response (<2log₁₀ decline in plasma HCV RNA during 12 weeks of dual therapy), partial response (>2log₁₀ decline in plasma HCV RNA but without achieving plasma HCV RNA PCR negativity) and relapse (PCR negativity at end of antiviral treatment, but subsequent relapse) were estimated at 45%, 20%, 35% respectively.^[15–17] There is no head-to-head comparison of boceprevir and telaprevir, and treatment responses appear comparable.^{[8–10, 18]} As patients with prior null response to dual therapy were not included in the registration studies of boceprevir we planned treatment using a prototypic protease inhibitor modelled on telaprevir. Sustained virological response rates were estimated from studies in previously treated subjects and their subgroup analyses (Table 1, and supplementary information).^{[9, 19]} The utility of treating subjects with advanced fibrosis (defined as METAVIR F3/F4) was first determined using these SVR estimates and by comparison with treatment of subjects with all stages of fibrosis.

Treatment regimens with and without a stopping rule after the 4-week pegylated interferon and ribavirin lead-in phase (<1log₁₀ reduction in HCV RNA) in subjects with advanced fibrosis were then assessed. The variables included in this analysis are shown in Table 2 (and are summarised in Supplementary Figure S1). Standard stopping rules to avoid futile treatment were left in place (i.e. HCV RNA greater than 1000 IU/mL at either 4 weeks or 12 weeks after the start of triple therapy^[20]) but were not explicitly modelled. In each case, analyses were done containing only those showing previous partial or null response since it was considered likely that previous relapsers would receive full treatment regardless of response to lead-in pegylated interferon and ribavirin (SVR rates in this population are very high regardless of baseline fibrosis stage).^[9] Frequency of poor interferon response was extracted from a subgroup analysis of the REALIZE trial.^{[9, 19]}

Table 1. Calculation of estimated rates of sustained virological response (SVR) for previously treated subjects

Prior treatment response	Treat all		Advanced fibrosis only
	Measured SVR (%)	Number of subjects with SVR per 100 subjects	Measured SVR (%)	Number of subjects with SVR per 100 subjects
Relapse	85.7	30.0	84.8	29.7
Partial responder	56.7	11.3	42	8.4
Null responder	31.3	14.1	25	11.3
Total (%)		55.4		49.4

Pooled measured SVR rates of protease inhibitor treated subjects⁹ were used to estimate SVR rates from an unselected, previously treated, HCV-infected population. Frequency of prior responses was determined as above: relapse 35%, partial response 20% and null response 45%.

Outcomes After Treatment
Estimations of the rates of liver-related mortality, hepatic decompensation, and for the development of HCC were reported in a meta-analysis of previously treated patients,^[21] and more recently in a prospective study of patients entered into clinical trials in a single centre.^[22] These data allow the calculation of the absolute risk reduction (ARR) for each of these clinical events with successful treatment. For instance in the meta-analysis,^[21] in previously treated subjects with advanced fibrosis and who do not achieve SVR the annual risk of liver-related mortality is estimated at 2.7%. For individuals with SVR the annual risk reduction is estimated at 0.19, or an annual mortality risk of 0.5% thus giving an ARR of liver-related mortality of 2.2% in those with SVR. The ARR for each outcome is given in Table 2. Adverse outcomes were calculated considering a follow-up duration of 5 years as it is unlikely that additional classes of DAAs will be licensed in that timeframe, and since it is interferon failure in this group that governs poor treatment response this is likely the minimum time until interferon-free regimens are licensed.

Table 2. Variables included in the analysis of a stopping rule after a 4-week lead-in with pegylated interferon and ribavirin

Variable	Base case (%)	Sensitivity (%)	Reference
Previous treatment response			[15–17]
Partial response	29	20–40
Null response	71	60–80
Interferon sensitivity: <1log10 After 4-week P/R lead-ina			[9, 19]
Previous partial response	37	30–40
Previous null response	62	60–75
SVR with protease inhibitor			[9, 19]
Previous partial response
<1log10 After 4-week P/R lead-in	56	50–60
>1log10 After 4-week P/R lead-in	59	50–65
Previous null response
<1log10 After 4-week P/R lead-in	15	10–20
>1log10 After 4-week P/R lead-in	54	50–60
Annual ARR following SVR			[21, 39]
Liver related mortality	2.2	2–4
Decompensation	2.5	2–5
Hepatocellular carcinoma	2.2	2–5
Risk of treatment emergent adverse events			[27–29]
Decompensation	2	1–3
Death	1	0.5–2

ARR, absolute risk reduction; P/R, pegylated interferon and ribavirin; SVR sustained virological response.

*Estimate includes all subjects receiving pegylated interferon and ribavirin for 4 weeks, i.e. control group and lead-in arm.

Comparison of Treatment Regimens
Calculations were based on hypothetical cohorts of 1000 subjects, and were compared using a decision analysis and comparative effectiveness approach.^[23–25] These cohorts were assigned to receive treatment according to the regimens defined above. Treatment benefit was estimated using a number needed to treat (NNT) approach.^[26] The NNT was calculated using the formula below accounting both for the ARR associated with successful treatment (i.e. the SVR) and also the relative probability of that success.



Since the ARR is expressed per annum, to account for 5-year follow-up, the NNT was divided by 5 to give a 5-year NNT for each outcome.
The rate of clinical events in each cohort was then calculated using the NNT and compared by treatment regimen. The rate of the treatment related serious adverse events of hepatic decompensation (2%) and death (1%)^[27–29] were also compared using this approach.

Sensitivity Analyses
Selected parameters in the base case analysis were varied within plausible limits (Table 2). For instance, rates of ARR for liver-related mortality and HCC varied from 2% to 4%, and 2% to 5%, respectively, in line with recently published data.^{[21, 22]} As relatively few subjects with advanced fibrosis were included in the phase III studies, and those that were had well-preserved liver function, SVR rates varied from 10% to 20% in previous null responders and from 40% to 60% in partial responders. The proportion of subjects not achieving a 1log₁₀ reduction at 4 weeks also varied from 32% to 45% in partial responders and from 55% to 70% in null responders. The relative proportion of null and partial responders included varied from 80/20 to 60/40 splits. Finally, the rate of treatment emergent adverse events varied between 1% and 3% for hepatic decompensation and 0.5% and 2% for treatment-related death.

Maximizing Treatment Benefit in HCV: Results

Results
Mortality Reduction After Treatment
The effect of antiviral treatment on mortality has been assessed in relatively few studies due to the slowly progressive nature of HCV infection and the consequent use of SVR as a surrogate endpoint. To assess the treatment benefit of protease inhibitor containing triple therapy in previously treated subjects, we calculated the 5-year NNT for two groups: those with any stage of liver disease, and those with advanced fibrosis.^[30] For those treated with a protease inhibitor, the 5-year NNT for those with any stage of liver disease is 60 to prevent one liver-related death whereas it is 18 when considering those with advanced fibrosis, despite a reduced SVR (Table 3). The impact of the NNT is highlighted when the number of deaths prevented in each treatment strategy is calculated in hypothetical patient cohorts: more than threefold more deaths are prevented when treating only subjects with advanced disease. These data highlight the importance of considering treatment in this high-risk group and indicate that this group should be prioritised for treatment on the basis of need.

Table 3. Comparison of liver-related mortality benefit in treatment of previously treated subjects with HCV infection stratified by fibrosis stage

Treatment group	Annual ARR in liver-related mortality (%)21	SVR (%)a9	5-year NNT to prevent 1 death	HCV deaths prevented per 1000 patient cohort over 5 years
Treat all	0.6	55.4	60	17
Advanced fibrosis only	2.2	49.4	18	54

ARR, annual risk reduction; NNT, number needed to treat; SVR, sustained virological response.
*Calculated SVR based on estimated proportion of prior null and partial responders as described.

Comparative Effectiveness of Including a Stopping Rule After the 4-week Lead-in
The outcomes of subjects treated with protease inhibitor containing triple therapy are shown in Figure 1. The strategy of treating all patients regardless of response after the 4-week lead-in with pegylated interferon and ribavirin results in the maximal prevention of death (Figure 1a). Employing the virological response to a 4-week lead-in with dual therapy as a stopping rule (Figure 1b) allows treatment to be stopped in the majority of this difficult-to-treat population thus reducing protease inhibitor exposure, and reducing the total number of treatment emergent adverse events. However, there is a notable increase in the efficacy of protease inhibitor containing therapy if treatment is stopped in subjects not achieving a >1log₁₀ reduction in HCV RNA. As those with unfavourable responses are excluded from protease inhibitor containing treatment SVR rates for subjects treated with triple therapy are increased from 37.9% in the treat all strategy to 56.1% when the 4-week stopping rule is applied (Figure 1a,b).

Figure 1.
Flow diagram of the hypothetical 1000 subject cohort based on two strategies. (a) All 1000 subjects were treated with protease inhibitor containing triple therapy regardless of initial interferon response, and (b) after a 4-week lead-in treatment was stopped in subjects not achieving >1log₁₀ reduction in HCV RNA. The number needed to treat for each scenario of completed treatment was calculated. After 5-year follow-up the number of deaths prevented was also assessed. F/U, follow-up; NNT, number needed to treat; P/R, pegylated interferon and ribavirin; SVR, sustained virological response.

There is however a significant reduction in overall clinical effectiveness associated with using the 4-week stopping rule. The number of patients achieving SVR is reduced by 37% as a result of excluding those subjects who would otherwise have been cured by continued treatment (SVR 'missed', Figure 1b). As this is a high-risk group and subjects who are not cured remain at significant risk of liver related morbidity and mortality we calculated the effects of the 4-week stopping rule on these parameters (Table 4). For subjects treated with triple therapy but without a stopping rule at week 4, 42 deaths are prevented over 5-year follow-up. However, only 28 deaths are prevented when the 4-week stopping rule is applied, a reduction of 33%. This indicates that by using the 4-week stopping rule 14 premature deaths occur that would have otherwise have been prevented by treating in the absence of the stopping rule.

Table 4. Effect of treatment emergent adverse events on clinical outcomes after antiviral treatment in previously treated HCV infected subjects with advanced fibrosis

Clinical event	Treatment strategy		Events incurred by using 4-week stopping rule*
	Treat all	Stop if <1log10 reduction after 4 weeks
Prevented HCV death	42	28	14
On treatment death	10	5	-5
Net	32	23	9
Prevented HCV decompensation	47	32	15
On treatment decompensation	20	9	-11
Net	27	23	4
Prevented HCC	42	28	14
On treatment HCC	0	0	0
Net	42	28	14

HCC, hepatocellular carcinoma; HCV, hepatitis C virus.
Calculations are based on a hypothetical 1000 subject cohort with 5-year follow-up after antiviral treatment.
*Negative values indicate events that are reduced when the stopping rule is applied.

The Impact of Treatment Emergent Adverse Effects on Outcome
This difficult to treat population is at risk of treatment emergent adverse effects that can negatively impact on the outcome of treatment. In similar studies of dual therapy hepatic decompensation occurs in approximately 2% of those treated and death occurs in approximately 1%.^{[28, 29]} These data are supported by the initial safety data reported in the early expanded access to protease inhibitor programmes in France.^[27] The impact on these episodes is summarised in Table 4. For instance, treatment emergent hepatic decompensation (i.e. decompensation precipitated by treatment) decreases overall treatment effectiveness. In effect there is an approximately 40% reduction in the net number of decopmensation episodes prevented by treatment in the treat-all strategy. When the 4-week stopping rule is employed there is a reduction in treatment-related decompensation episodes, but the advantage of treating all subjects regardless of response at week 4 of treatment remains. The impact on death is similar and these data indicate that the development of treatment emergent adverse effects does not significantly reduce the comparative benefit that is achieved by treating subjects regardless of virological response at treatment week 4.

Sensitivity Analyses
In sensitivity analyses, the overall benefit of continued treatment despite poor virological response at treatment week 4 was maintained despite variation in the proportion of null and partial responders, low SVR rates to protease inhibitor containing treatment, and also in cohorts containing an increased frequency of subjects not achieving >1log₁₀ reductions at treatment week 4. However, in scenarios where there was greater mortality associated with treatment, and particularly where this was associated with low treatment efficacy, there was no difference in overall mortality between those treated regardless of virological response and those treated according to the 4-week stopping rule (Table 5). These analyses support not using the 4-week lead-in as a universal stopping rule but rather individualising treatment where subjects at high risk of on-treatment mortality due to the presence of advanced cirrhosis and portal hypertension^{[28, 29]} should have interferon sensitivity considered in treatment planning.

Table 5. Outcomes of sensitivity analyses

Sensitivity parameter	Net deaths prevented by treatment strategy		Deaths incurred by using 4-week stopping rule
	Treat all	Stop if <1log10 reduction after 4 weeks
Base case	32	23	9
High ARR death	76	51	25
Low ARR death	28	21	7
Low SVR rates	26	20	6
Increased prior null response	29	22	7
Increased poor interferon response	28	18	10
High on-treatment mortality	22	19	3
Low SVR AND high on-treatment mortality	16	16	0

SVR, sustained virological response.
Calculations are based on a hypothetical 1000 subject cohort with 5-year follow-up after antiviral treatment. Outcomes presented here are based on the extremes of the sensitivity parameters provided in Table 2.

Maximizing Treatment Benefit in HCV: Discussion

Discussion
The development of novel DAA agents targeting HCV has the potential to significantly improve outcomes for subjects with HCV infection.^{[5, 6]} There are however a number of questions regarding how, and in whom, these agents should be used.^{[13, 14, 31]} This analysis provides a clear rationale for prioritising subjects with advanced fibrosis who are at significant risk of liver-related morbidity and mortality for treatment. This group represents at least 25% of infected subjects at current estimates^[32] and targeted treatment offers the potential to reduce liver-related mortality in a relevant timeframe. Our modelling cautions against the use of the 4-week lead-in phase as a universal decision point in subjects with advanced fibrosis as this strategy will disadvantage as many as 37% of subjects who would otherwise ultimately have derived benefit from continued treatment.

Recent licensing of DAA agents has brought further complexity to the management of genotype 1 HCV infection. In addition, the rapid development of new agents has led to uncertainty regarding which subjects to treat now, and which patients might be deferred from treatment.^[33] Using the analyses presented here we have illuminated this difficult topic, particularly highlighting the benefits of treating subjects with advanced fibrosis. This population is in need of effective treatment and the benefit of this analysis is that it clarifies the clinical outcome that results as a consequence of treatment vs. no treatment in a clinically relevant timeframe. There is clinical heterogeneity in a group containing all subjects with advanced fibrosis (METAVIR F3/F4), however, the data included in the model are supported by clinical data drawn directly from this population. For instance, treatment responses are from randomised controlled data, and long-term follow-up data are from a meta-analysis of more than 1400 subjects.^{[9, 21]} Using these analyses to support clinical decision making and the prioritisation of subjects for treatment should allow clinicians to maximise treatment benefit through mortality reduction in the next 5 years despite relatively low SVR rates and whilst further developments in therapy occur. Furthermore, the analyses provide critical information in the explanation of the potential benefits (and risks) of treatment for clinicians to share with subjects with advanced fibrosis who are considering treatment.

The rationale for using the 4-week lead-in phase for decision making has been based on concerns regarding increased toxicity in subjects with advanced disease, and also concerns about the evolution and persistence of drug resistant variants.^[11–13] The registration studies for both boceprevir and telaprevir included patients with advanced fibrosis, albeit at a relatively low frequency, and these patients had well compensated liver disease. In subjects treated with pegylated interferon and ribavirin dual therapy there is evidence that the treatment emergent adverse effects of hepatic decompensation and death are more common in those with advanced cirrhosis and portal hypertension.^{[28, 29]} Our analysis indicates that allowing for treatment-associated decompensation at a rate of 1 in 50 treated patients and mortality at 1 in 100 (in keeping with reports from early access programs),^[27] there remains a benefit in continuing treatment regardless of treatment response at treatment week 4. The development of resistant variants is more difficult to model since the consequences of these frequently short-lived variants are uncertain. Whilst there is the potential for these variants to persist and to impact on future protease inhibitor containing treatment^[7] and candidacy for future clinical trials of perhaps more effective therapies, the likelihood is that for many of the subjects included in this analysis this would be the last opportunity for treatment (prior to liver transplantation or death). This is especially apparent as it is interferon sensitivity that governs the poor responses to treatment in this group and that pegylated interferon is likely to remain a component of standard of care therapy for the next 5 years at least.

This analysis is limited by several factors. The data are extracted from several studies, none of which were intended to address this particular question. Furthermore, none of the studies contained large numbers of patients with advanced fibrosis and indeed the boceprevir development programme did not address treatment responses in prior null responders. The treatment responses for boceprevir and telaprevir appear broadly similar and we therefore considered a prototypic protease inhibitor based on the published data that were available. In sensitivity analyses, we varied the proportions of prior null and partial responders, the SVR rates and the rates of treatment emergent adverse effects to address the areas where there were uncertainty in the primary reports. These analyses indicated that there was benefit of continued treatment regardless of virological response at treatment week 4. There were however important exceptions to this, and that is in scenarios where there are high rates of treatment emergent mortality. In these situation there was no benefit to continued treatment following a <1log₁₀ reduction in HCV RNA when considering 5-year follow-up. These scenarios might be represented by subjects with advanced cirrhosis and significant portal hypertension where treatment is already risky and where a failure to respond to the 4-week lead-in could be considered an indication to stop treatment. The analyses presented here therefore provide important evidence to support individualised treatment decision making in this difficult population. Further studies addressing this population should be carefully designed to ensure that stopping rules are implemented both for virological failure and to protect those included from excessive treatment related morbidity and mortality.

This analysis contains a relatively crude assessment of benefit and harm. Whilst this is based on important clinical outcomes of death, hepatic decompensation and the development of HCC rather than the surrogate measure of SVR it is likely that the lasting benefits of SVR are underestimated. Whilst several investigators have studied the effects of SVR on more relevant outcomes, such as serum biochemistry^[34] and fibrosis stage,^{[35, 36]} the overall clinical outcomes of SVR are seldom reported. We therefore utilised a meta-analysis of clinical outcomes after SVR.^[21] A more recent prospective report suggests that both the annual risk of liver-related mortality, and the ARR in mortality might be greater than we considered^[22] suggesting that the mortality reductions in the base case analysis might underestimate the true effect of treatment. Furthermore considering follow-up of only 5 years duration will underestimate the overall benefit of treatment. This parameter was however set at 5 years to permit decisions to be made in this clinically relevant timeframe. Additional data indicating that productivity is decreased and absenteeism is increased in HCV infected subjects suggests significant additional benefit from successful treatment.^{[37, 38]} Although these outcomes are difficult to model the benefit we have highlighted in continuing treatment regardless of response at treatment week 4 is likely increased when all factors are considered. Of course, additional treatment emergent adverse events will also be incurred through continued treatment of this population regardless of virological response at week 4, and some of these will be severe. In those subjects with advanced disease these are likely to be more frequent, and to contribute to treatment emergent decompensation and death. These events, however, do not negate the benefit of treatment. A decision to wait for further treatment developments in this high-risk group therefore has the potential to cause the greatest harm when compared with any of the treatment strategies presented here and the mortality reduction noted with treatment strongly cautions against that approach.

These analyses describe previously treated subjects with prior null and partial responses. As the absolute risk reduction in mortality associated with successful treatment in the untreated population is likely to be similar^[39] these findings are generalisable to all subjects with advanced fibrosis undergoing treatment with protease inhibitor containing treatment. The findings are however not applicable to subjects with early fibrosis where the harms of treatment manifest through treatment emergent adverse effects, or the development of resistant variants, may outweigh the benefits of continued treatment in poor interferon responders. Whilst information on the significance of resistance is emerging there are concerns that the harms relating to resistant variants may be significant and individualised decision making is appropriate until such data are available.

In summary, this analysis indicates that subjects with advanced disease should be prioritised on the basis of need. Furthermore, when considering protease inhibitor treatment of previously treated subjects with advanced fibrosis, this should be done without consideration of interferon responsiveness following the 4-week lead-in. This analysis provides critical information regarding both selection and on-treatment decision making for previously treated subjects that should be included in guidance for physicians using protease inhibitors to treat subjects with HCV infection.

References

1. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5: 558–67.
2. Seeff LB. Natural history of hepatitis C. Am J Med 1999; 107: 10S–5S.
3. Kanwal F, Hoang T, Kramer JR, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology 2011; 140: 1182–8.
4. Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ 2011; 343: d7995.
5. Rowe IA, Mutimer DJ. Protease inhibitors for treatment of genotype 1 hepatitis C virus infection. BMJ 2011; 343: d6972.
6. Lange CM, Sarrazin C, Zeuzem S. Review article: specifically targeted antiviral therapy for hepatitis C – a new era in therapy. Aliment Pharmacol Ther 2010; 32: 14–28.
7. Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology 2011; 53: 1742–51.
8. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1207–17.
9. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417–28.
10. Poordad F, McCone JJ, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195–206.
11. Sarrazin C, Hezode C, Zeuzem S, Pawlotsky JM. Antiviral strategies in hepatitis C virus infection. J Hepatol 2012; 56(Suppl.): S88–100.
12. Bacon BR, Khalid O. Triple therapy with boceprevir for HCV genotype 1 infection: phase III results in relapsers and nonresponders. Liver Int 2012; 32(Suppl. 1): 51–3.
13. Ramachandran P, Fraser A, Agarwal K, et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther 2012; 35: 647–62.
14. Jacobson IM, Pawlotsky JM, Afdhal NH, et al. A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C. J Viral Hepat 2012; 19(Suppl. 2): 1–26.
15. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa- 2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958–65.
16. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38: 645–52.
17. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa- 2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580–93.
18. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–16.
19. Foster GR, Zeuzem S, Andreone P, et al. Subanalyses of the trlaprevir leadin arm in the REALIZE study: response at week 4 is not a substitute for prior null response categorisation. J Hepatol 2011; 54: S3.
20. Telaprevir (Incivo) Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/25038/spc. Accessed June 2, 2012.
21. Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010; 8: 280–8.
22. Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol 2010; 52: 652–7.
23. Pauker SG, Kassirer JP. Decision analysis. N Engl J Med 1987; 316: 250–8.
24. Plevritis SK. Decision analysis and simulation modeling for evaluating diagnostic tests on the basis of patient outcomes. AJR Am J Roentgenol 2005; 185: 581–90.
25. El-Serag HB, Talwalkar J, Kim WR. Efficacy, effectiveness, and comparative effectiveness in liver disease. Hepatology 2010; 52: 403–7.
26. Moore A, McQuay H. Numbers needed to treat derived from meta analysis. NNT is a tool, to be used appropriately. BMJ 1999; 319: 1200.
27. Hezode C, Dorival C, Zoulim F, et al. Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotic non-responders. First results of the French early access program (ANRS CO20-CUPIC) in reallife setting. GAJ 2011; 7: 54.
28. Massoumi H, Elsiesy H, Khaitova V, et al. An escalating dose regimen of pegylated interferon and ribavirin in HCV cirrhotic patients referred for liver transplant. Transplantation 2009; 88: 729–35.
29. Everson GT, Trotter J, Forman L, et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 2005; 42: 255–62.
30. Rowe IA, Armstrong M, Houlihan D. Prioritising treatment experienced patients with hepatitis C infection for treatment with telaprevir. A number needed to treat approach. Hepatology 2012; 55: 1644–5.
31. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 1433–44.
32. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138: 513–21.
33. AASLD. AASLD: Response to Comments on An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection. Available at: http://www.aasldorg/practiceguidelines/Pages/hepccomments. Accessed June 20, 2012.
34. Everson GT, Shiffman ML, Hoefs JC, et al. Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C trial. Aliment Pharmacol Ther 2009; 29: 589–601.
35. Everson GT, Balart L, Lee SS, et al. Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis. Aliment Pharmacol Ther 2008; 27: 542–51.
36. Hezode C, Castera L, Roudot-Thoraval F, et al. Liver stiffness diminishes with antiviral response in chronic hepatitis C. Aliment Pharmacol Ther 2011; 34: 656–63.
37. DiBonaventura M, Wagner JS, Yuan Y, L'Italien G, Langley P, Ray Kim W. The impact of hepatitis C on labor force participation, absenteeism, presenteeism and non-work activities. J Med Econ 2011; 14: 253–61.
38. Su J, Brook RA, Kleinman NL, Corey-Lisle P. The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs. Hepatology 2010; 52: 436–42.
39. Alazawi W, Cunningham M, Dearden J, Foster GR. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther 2010; 32: 344–55.

Dr.MLShiffman;Complexities of Treating Chronic Hepatitis C (HCV)

The Complexities of Treating Chronic Hepatitis C (HCV)

“Dear Dr.,
I am a 57 year old female diagnosed with HCV 1B. In 2004, I got pneumonia for no reason. I have always lead a very active lifestyle: married to a chiropractor, I started as a teen lifting weights etc. At the time of I was also diagnosed with gallstones and had my gallbladder removed. I had high liver enzymes, the surgeon (on her game) did a liver biopsy while she was in there and found the HCV. I was then referred to a gastro and started peg/ribovarin. In the beginning of 2005, I had very high iron levels so testing was performed for hemochromatosis (negative). Treatment was started–no blood letting. I was very precise in every aspect of treatment down to the time of day medication was taken, but I did not reach the expected load decrease at twelve weeks. It was slight. I was kept on treatment for a total of 46 weeks. I had a very ill reaction to medication.

During this time, I had educated myself, fear was gone, I knew something was wrong. I went to see Dr. Gene Lesage, at the Texas Liver Center. He took me off treatment almost immediately and I have since learned I never should have been put on treatment. Biopsy had slight bridging fibrosis. I was labeled a slow responder. There is no available treatment for 1B. I have been sick for 6 years: severe fatigue, nausea, headaches, and severe, severe pain in lower extremities. I am just sick all the time. I was not before starting treatment except for getting the pneumonia…” — Karyn of Marble Falls, Texas

August 15, 2011 by Dr.MLShiffman
Karyn’s story is not unlike many with chronic HCV. Chronic HCV is known to cause scarring or fibrosis in the liver and lead to cirrhosis. Advnaced fibrosis is associated with severe fatigue. HCV is know to interact with the immune system and cause diffuse muscle and joint pains. It does so by forming complexes in the blood called cryoglobulins, which is the hepatitis C virus covered by numerous antibodies. These complexes are deposited in small capillaries and damage nerves, joints and skin causing skin rashes, and pain.

Karyn is also like many other persons who tried peginterferon and ribavirin in the past but failed to respond and be cured of HCV with of this treatment. We now know the reason why some patients with chronic HCV respond to treatment and others do not is based upon genetics. We all have a gene, called IL28B, which modulates our response to interferon. If the gene is “turned on” and makes us sensitive to interferon the cure rate for patients with HCV is about 70% when treated with peginterferon and riabvirin. If the gene is “turned off” the cure rates are only about 20-25%. I suspect Karyn is genetically not sensitive to interferon and that is why she did not respond well. She can be tested for this gene, the test is commercially available and this will help Karyn know her chances of being cured of HCV with the new treatments.

Fortunately, the FDA has now approved 2 new potent anti-viral agents for HCV; telaprevir and boceprevir. These drugs directly inhibit HCV and make the virus much more sensitive to interferon and ribavirin treatment. When combined with peginterferon and ribavirin either one of these anti-viral agents significantly increase the number of patients who are cured of HCV. The likelihood that a patient will be cured is related to the interferon sensitive gene, IL28B. If the gene is in the “on position” the cure rate approaches 90%. If the gene is in the off position the cure rate is about 50%. IF the gene is in the middle position the cure rate is about 66%.

Karyn’s previous non-response to peginterferon and ribavirin also gives us information about her chance of being cured on re-treatment. It is hard to tell from her story if she was a “Null responder” and had mess than a 100-fold (2 log) decline in the virus during her previous treatment. She may have been a “Partial responder” and had a significant drop in the virus but just did not become negative. Patients with prior null response have a 33% of cure when retreated with either of the anti-viral agents peginterferon and ribavirin. In contrast, patients with prior partial response are more sensitive to interferon and therefore have a 66% chance of being cured on re-treatment.

At the Liver Institute of Virginia my staff and I take the time to explain all of these issues to our patients with chronic HCV. Many anti-viral agents for HCV are currently being developed and studied and there is great hope and promise that all patients with chronic HCV like Karyn will one day be cured of HCV. It just may take a bit more time to develop all the tools we need for all patients.

+ Learn more about the Liver Institute of Virginia.+ Find out about clinical research trials offered at the Liver Institute of Virginia.+ Read another article on Liver Health

Realize the advance in Hepatitis C treatment, but remain cautious.

J Hepatol. 2011 Aug 8. [Epub ahead of print]

Realize the advance in HCV treatment, but remain cautious.

Asselah T.
Source
Service d'hépatologie, Hôpital Beaujon, Clichy, France and INSERM, U773, Centre de Recherche Bichat-Beaujon CRB3, and University Paris Diderot.

Abstract
BACKGROUND:
Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin.

METHODS:
In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response.

A total of 663 patients were assigned to one of three groups:
the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug.

RESULTS:
Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%).

CONCLUSIONS:
Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase.

(Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

More From CCO
*Free Registration Required

From Podium to Practice: Clinical Impact of New Data From EASL 2011
Source: CCO Independent Conference Coverage of the 2011 Annual Meeting of the European Association for the Study of the Liver*
By: Graham R. Foster, FRCP, PhD, Paul Y. Kwo, MD, Stefan Zeuzem, MD

BL is a patient infected with genotype 1 hepatitis C virus (HCV) who previously relapsed following peginterferon/ribavirin therapy. You are planning to begin a course of telaprevir-based therapy in this patient.

Would you counsel this patient that a peginterferon/ribavirin lead-in phase would be a useful tool in guiding the course of her therapy? To maximize the value of your assessment, this response is required.

REALIZE: Telaprevir Plus Peginterferon alfa-2a/Ribavirin in Patients With Genotype 1 HCV Who Failed Previous Peginterferon/Ribavirin

Expert Analysis

Stefan Zeuzem, MD: At the 2011 Annual Meeting of the European Association for the Study of the Liver (EASL), investigators presented extensive new data from studies evaluating the efficacy and safety of direct-acting antiviral (DAA) agents for the treatment of HCV infection. Two key discussion points that emerged from these studies included how can these agents be combined to optimize patient outcomes and what are the most important predictors of response? In addition, several notable reports focused on emerging data related to the treatment of hepatitis B virus (HBV) infection, hepatocellular carcinoma, and nonalcoholic steatohepatitis. We will begin this Expert Analysis with an in-depth review of the HCV highlights from the meeting.

The randomized, placebo-controlled phase III REALIZE trial evaluated telaprevir plus peginterferon alfa-2a/ribavirin in patients infected with genotype 1 HCV who previously failed peginterferon/ribavirin therapy (Capsule Summary).[1] In total, 662 patients were randomized to the following treatment arms: telaprevir plus peginterferon alfa-2a/ribavirin for 12 weeks followed by peginterferon alfa-2a/ribavirin alone for 36 weeks (n = 266); peginterferon alfa-2a/ribavirin lead-in for 4 weeks then telaprevir plus peginterferon alfa-2a/ribavirin for 12 weeks followed by peginterferon alfa-2a/ribavirin alone for 32 weeks (n = 264); or peginterferon alfa-2a/ribavirin alone for 48 weeks (n = 132). The study included patients with previous null response, partial response, or relapse following at least 1 previous course of peginterferon/ribavirin therapy; patients with previous viral breakthrough were excluded.
The sustained virologic response (SVR) rates were significantly higher in the telaprevir-containing arms relative to the peginterferon/ribavirin control arm in each previous treatment failure subgroup (P < .001 for each comparison); however, SVR rates to telaprevir-based treatment were notably higher among previous relapsers vs previous partial or null responders (83% to 88% vs 29% to 59%, respectively), with previous null responders exhibiting the lowest SVR rates of 29% to 33%.

Among previous relapsers, SVR rates to telaprevir-based therapy were similar regardless of fibrosis stage. These data suggest that the lower response rates among previous partial and null responders are not related to fibrosis stage but rather to their poor responsiveness to peginterferon/ribavirin. In addition, SVR rates to telaprevir-based therapy were higher with subtype 1b HCV compared with subtype 1a HCV (in particular for previous partial and null responders).

Graham R. Foster, FRCP, PhD: To investigate the predictors of response to telaprevir-based therapy among treatment-experienced patients, my colleagues and I[2] conducted a retrospective subanalysis of the REALIZE study comparing the use of previous response categories (null, partial, or relapse) vs HCV RNA response to a 4-week peginterferon/ribavirin lead-in phase as predictors of SVR (Capsule Summary).

The current subanalysis was restricted to patients treated in the control arm (n = 121) and in the telaprevir arm that included a 4-week peginterferon/ribavirin lead-in phase: peginterferon/ribavirin for 4 weeks followed by telaprevir plus peginterferon/ribavirin for 12 weeks followed by peginterferon/ribavirin for 32 weeks (n = 240). The importance of the REALIZE study was that it included true null responders whose HCV RNA decreased by < 2 log10 at Week 12 of peginterferon/ribavirin, as well as patients who experienced some degree of viral suppression (partial responders whose HCV RNA decreased by ≥ 2 log10 at Week 12 but remained detectable during treatment) and relapse patients (HCV RNA undetectable at the end of treatment but detectable after stopping treatment). Enormous efforts were taken to establish a previous treatment history before patients were enrolled. The question posed by the retrospective analysis was, “Is it better to examine the patients’ previous treatment response or to give the patients a quick 4-week lead-in of peginterferon and ribavirin to characterize them as responders vs nonresponders?”

This analysis concluded that if there is a very clear history showing how the patient previously responded to peginterferon/ribavirin, one can obtain a good prediction of how the patient will respond to retreatment with telaprevir-based therapy. Specifically, previous relapsers experienced a 90% SVR rate with telaprevir-based therapy. By contrast, the SVR rate was 58% among previous partial responders and 30% among previous null responders.

When assessing SVR rates based on response to the 4-week peginterferon/ribavirin lead-in, it is interesting that some patients who ultimately did very well with telaprevir-based retreatment initially responded rather poorly through 4 weeks of treatment. For example, 10% of previous relapsers experienced a < 1 log10 reduction in HCV RNA after the 4-week lead-in phase; however, 62% of these patients achieved SVR with subsequent telaprevir-based therapy. Likewise, previous partial responders who experienced a < 1 log10 HCV RNA reduction during the 4-week lead-in phase achieved a 56% SVR rate with telaprevir-based retreatment. That finding raises concern that if treatment response predictions were based on the 4-week lead-in response in this population, clinicians may discontinue therapy in a significant minority of patients who would otherwise have achieved SVR. Thus, I would counsel our case patient (a previous relapser) that a 4-week lead-in phase would add very little value and would not be helpful in determining her optimal course of therapy.

By contrast, response to the 4-week lead-in phase had much stronger predictive value among previous null responders. The SVR rate following telaprevir-based therapy among previous null responders who experienced a < 1 log10 HCV RNA decrease during the 4-week lead-in phase was 15% vs 54% in the subgroup who achieved ≥ 1 log10 HCV RNA reduction with the lead-in.
Therefore, in my practice, I plan to treat all patients for whom I have identified a well-characterized previous null response with a 4-week lead-in of peginterferon/ribavirin prior to adding telaprevir; if they do not exhibit an adequate response to the lead-in, I will discuss with them the limited value of continuing treatment. However, if they do respond, I will encourage them to initiate a telaprevir-based regimen. On the other hand, I will not assess the HCV RNA response at Week 4 in previous relapsers and previous partial responders because I do not think the information will alter my management plan. There are also patients for whom I do not have sufficient information to accurately characterize their previous treatment response; in those patients, the 4-week lead-in might provide some additional information, although this approach should be used with caution, bearing in mind that if their previous response was partial or relapse, a poor response to the 4-week lead-in may not portend a low likelihood of SVR.

Paul Y. Kwo, MD: I agree completely that the 4-week lead-in will be very useful in patients who do not have an accurate viral kinetics profile from their previous treatment course, with the important caveat noted by Dr. Foster that if the unknown previous response was relapse or partial response, basing the retreatment decision on the 4-week lead-in response may discourage therapy in a considerable proportion of patients who would have benefited. For example, in the REALIZE study, previous relapsers with a less than 1 log10 IU/mL reduction in HCV RNA after the 4-week lead in went on to a high SVR rates (62%). If one had relied on just the lead-in period to decide whether or not to add telaprevir because you did not have accurate pretreatment viral kinetics—that is, if one chose to stop treatment and not add telaprevir—one might potentially deny a relapse patient a very good opportunity to achieve SVR. In well-characterized null responders, I concur with Dr. Foster’s approach of using a lead-in in this setting as well.

Stefan Zeuzem, MD: In considering the poorer SVR rates among previous null responders, there are 4 key factors that potentially impact their retreatment response: liver histology, HCV subtype, IL28B genotype, and response to a 4-week peginterferon/ribavirin lead-in phase. It is important to distinguish between the relative contributions of each of these factors in order to determine the best individualized treatment approach for previous null responders. A careful dissection of an individual patient’s likelihood of response to retreatment with a protease inhibitor–containing regimen can allow clinicians to better counsel patients on the relative benefit of initiating retreatment at the current time vs waiting until newer, more effective therapies such as quadruple regimens are available.

As noted earlier, fibrosis stage did not appear to be a significant factor in previous relapsers; however, in previous partial and null responders, SVR rates were impaired in patients with cirrhosis. The significance of IL28B genotype is also likely to be limited in this setting because the majority of patients with a null response to previous peginterferon/ribavirin will have the unfavorable CT or TT genotype. However, this analysis of the REALIZE trial showed convincingly that among previous null responders, response to the 4-week lead-in phase of peginterferon/ribavirin alone identified subgroups with a notable difference in SVR rates with telaprevir-based therapy. Based on these data, I agree that previous null responders may represent a population in which response to 4-week peginterferon/ribavirin lead-in could be an important determinant of whether to proceed with treatment using protease inhibitor–based triple therapy or to wait longer for more effective options.

Paul Y. Kwo, MD: For previous null responders, the risks of offering therapy to those who have a poor response to a 4-week lead-in include the adverse effects of peginterferon/ribavirin and the generation of resistance associated variants. Also, preliminary data suggest that more effective regimens with combinations of DAA agents may be available in the future for this group of patients. The most challenging patients continue to be previous null responders with advanced fibrosis. This group exhibits poor response to peginterferon/ribavirin and they often have many negative predictive factors, yet these patients are most at risk for decompensated cirrhosis, hepatocellular cancer, and the need for liver transplantation. In the absence of other available protocols or for this group it may be reasonable to consider retreatment despite the lower likelihood of success.

Graham R. Foster, FRCP, PhD: I agree entirely, particularly when considering that in the United Kingdom 20% of patients are dying on the wait list for liver transplantation. In that context, a 15% chance of response may well be worth taking even among this group with a poor initial response to a peginterferon/ribavirin lead-in phase. Therefore, it is important to counsel the patient on their options, provide them with all of the data, and help them to make the most informed decision possible.

http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Berlin%202011/Tracks/From%20Podium%20to%20Practice/EASL_EA/Pages/Page%201.aspx

EASL;CTS-1027 Plus Pegasys/Riba geno 1 null-responder 24-week interim results in hepatitis C patients

Conatus Pharmaceuticals Presents Results From a Phase 2 Clinical Trial of CTS-1027 in HCV Genotype 1 Null-Responders

By Conatus Pharmaceuticals Inc.

Published: Thursday, Mar. 31, 2011 - 12:08 pm

SAN DIEGO, March 31, 2011 -- /PRNewswire/ -- Conatus Pharmaceuticals Inc. announced today 24-week interim results from a clinical trial with CTS-1027 in combination with Peginterferon Alpha-2a (Pegasys®) and ribavirin (Copegus®) in a treatment experienced, hepatitis C virus (HCV) null-responder patient population. Null-responder patients are the most difficult to treat patient population and are clinically defined as those patients failing to achieve an early virologic response (EVR) when undergoing treatment with the current standard of care (SOC; pegylated interferon and ribavirin). EVR is defined as at least a 2 log decline in HCV-RNA by week 12 of SOC treatment. The CTS-1027-04 clinical trial enrolled 67 HCV genotype 1 null-responder patients. The clinical trial is a single arm and open label design with sustained viral response (SVR; no detectable virus 24 weeks after the end of treatment) as its primary end point. At week 12, 51% (31/61) of patients receiving 15 mg twice a day of CTS-1027 in addition to standard doses of Pegasys® and Copegus® achieved an EVR on a per protocol (PP) basis. HCV-RNA was below quantifiable limit (BQL) in 5 patients (8.2%, PP) at week 12 and increased to 17 patients (34%, 17/50, PP) at week 24. This clinical trial is ongoing and final SVR results are expected in 2011.

Data from the CTS-1027-04 clinical trial were presented at the 46th annual meeting of the European Association for the Study of the Liver (EASL) held in Berlin, Germany, as Abstract 468. The full abstract is available at http://www.conatuspharma.com/ .

Consistent with expectations, the majority of patients tested for genetic analysis of IL-28B (95%, 58/61) carried the CT or TT allelic variant. Patients possessing these genetic variants are predicted to be less responsive to the antiviral actions of interferon.

"Most other approaches to treat HCV infection are direct-acting anti-viral drugs whose activity is directed against virus proteins or enzymes with the objective of reducing the production of virus in infected cells. CTS-1027, by comparison, is distinctly different in that its activity is hypothesized to facilitate the immune clearance of virus-infected cells and decrease the frequency of new infections, both of which are of key importance in curing HCV infections," said Alfred P. Spada, Ph.D., Senior Vice President of R & D of Conatus.

"Clearance of infected cells is a slow but essential process to achieving a sustained viral response. It is intriguing to observe this significant improvement in viral load reduction at such a low dose of CTS-1027. A recently initiated Phase 2b clinical trial (CTS-1027-05) will test CTS-1027 at higher doses in combination with Pegasys® and Copegus® in the null-responder patient population," said Steven J. Mento, Ph.D., President and CEO of Conatus.

Conatus Pharmaceuticals Inc. is a privately-held biopharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease and oncology. Conatus' lead drug candidate, CTS-1027 is in multiple Phase 2 clinical trials for the treatment of hepatitis C virus (HCV). Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the sale of Idun to Pfizer. For additional information, please visit www.conatuspharma.com.

Pegasys® and Copegus® are registered trademarks of F. Hoffman-La Roche, Inc.

SOURCE Conatus Pharmaceuticals Inc.

Hepatitis C-Phase 2 Trial CTS-1027 For Null Responder

Thursday, February 17, 2011

Look! Up In The Sky! It's Financings of the Fortnight!

Excerpt From IN VIVO

Conatus Pharmaceuticals:
Liver disease specialist Conatus announced a $20 million Series B round that remains open to additional investors. First-time backer AgeChem Venture Fund of Montreal joined Conatus’ existing investors, Aberdare Ventures, Advent Venture Fund, Bay City Capital, Gilde Healthcare Partners and Roche Venture Fund. The round builds upon the startup’s $27.5 million Series A from 2007. Formed by former executives at Idun Pharmaceuticals after Pfizer acquired that startup in 2005, Conatus’ funding needs increased last summer, when it bought at fire-sale prices Idun’s assets, which the Big Pharma left idle as a result of its reorganization. Nonetheless, Conatus says most of the new money is intended to support ongoing trials on CTS-1027, a Phase II hepatitis C therapy it licensed from Roche in late 2006. The former Idun pipeline includes emricasan, a Phase II candidate that was also investigated for hepatitis C, and other drugs designed to inhibit caspases, proteins that induce apoptosis. In conjunction with the new preferred stock round, Conatus also converted promissory bridge notes issued in the interim between rounds into Series B stock. AgeChem, which typically invests in therapeutics targeting disorders related to aging, took a Conatus board seat. -- Paul Bonano...Continue Reading...

Press Release........

Conatus Pharmaceuticals Initiates Confirmatory Phase 2 Clinical Trial of CTS-1027 for the Treatment of Hepatitis C Virus (HCV)
function translationdrop(b1)

SAN DIEGO, Feb. 17, 2011 /PRNewswire/ -- Conatus Pharmaceuticals Inc. announced today the treatment of the first patient in a multi-center Phase 2b clinical trial evaluating CTS-1027 in combination with Peginterferon Alfa-2a (Pegasys®) and ribavirin (Copegus®) in a treatment experienced, hepatitis C (HCV) null responder patient population. Safety, tolerability, and antiviral activity of the triple combination will be assessed after up to 48 weeks of therapy.
CTS-1027 is an oral, small molecule compound that inhibits the activity of key members of a class of protease enzymes, the matrix metalloproteinases or MMPs.

CTS-1027 has been shown to reduce and/or block HCV infection in in vitro preclinical models and more recently, has displayed the potential to amplify the effectiveness of existing therapies in difficult to treat HCV-infected patients. This is in addition to CTS-1027's anti-inflammatory and anti-fibrotic effects which have been well established in models of acute hepatitis and liver fibrosis.

"Our previous clinical trials indicate that CTS-1027 used in combination with existing standard-of-care HCV drugs has the potential to impact the second phase of HCV virus inhibitory kinetics in patients. This phase is associated with the gradual reduction and replacement of HCV infected cells by new uninfected liver cells. While reducing HCV virus production in infected cells is extremely important, eliminating HCV-infected cells is crucial to curing HCV," said Dr. Steven J. Mento, President and CEO of Conatus. "We believe that CTS-1027 represents a novel approach to treating HCV disease and look forward to developing this drug candidate in combination with the existing standard-of-care drugs as well as the new antiviral drugs under development."
"We have established a collaborative relationship with key opinion leaders and clinical investigators in the hepatitis community," said Ms. MiRa Huyghe, Vice President of Clinical Development of Conatus. "We are encouraged by our investigators' interest in CTS-1027 and together with our investigators look forward to offering a new treatment option for HCV null responders."

"We are excited to participate in this Phase 2b trial of CTS-1027," said Dr. Paul J. Pockros, Head, Division of Gastroenterology/Hepatology at The Scripps Clinic and Director of the SC Liver Research Consortium in La Jolla, CA. "Current treatment options for HCV null responders are very limited. We believe CTS-1027 may enhance the effectiveness of pegylated interferon and ribavirin in this difficult to treat patient population."

This clinical trial is a placebo-controlled, multicenter, double-blind, randomized trial of Peginterferon Alfa-2a (Pegasys®) and ribavirin (Copegus®) with or without CTS-1027 in HCV null responders. Dosing will last for up to 48 weeks. The trial will also examine whether higher dose levels of CTS-1027 will improve on previously observed results. The Company expects approximately 260 patients to be enrolled. The clinical trial will be conducted at up to fifty medical centers in the U.S.

Additional information about the trial can be found at: http://www.clinicaltrials.gov/ (Identifier NCT01051921) or http://www.clinicaltrials.gov/ct2/results?term=cts-1027.
Conatus Pharmaceuticals Inc. is a privately-held biopharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease and oncology. Conatus' lead drug candidate, CTS-1027, is in multiple Phase 2 clinical trials for the treatment of hepatitis C virus (HCV). Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the sale of Idun to Pfizer. For additional information, please visit http://www.conatuspharma.com/.

Pegasys® and Copegus® are registered trademarks of F. Hoffman-La Roche, Inc.
SOURCE Conatus Pharmaceuticals

RELATED LINKShttp://www.conatuspharma.com/

Treating Hepatitis C With Telaprevir/SVR Stats 2011

My friends are back discussing SVR treating with Telaprevir in combination with Pegylated interferon and Ribavirin.

.

From more information see:

http://hepatitiscnewdrugresearch.com/telaprevirboceprevir-genotype-123.html

hepatitis C:New direct-acting antivirals' combination/2011

.Youtube Channel

IMO-2125 induces strong Th1-type (T helper type 1 cells) immune responses in null-responder Hepatitis C patients

Activation of the Innate Immune System: A Novel Immune Modulator for the Treatment of Hepatitis C

Ekambar Kandimalla, PhD, VP of Discovery; Nicola La Monica, PhD, VP of Biology;

Idera Pharmaceuticals, Cambridge, Mass.Drug Discovery & Development -

December 01, 2010

Hepatitis C (HCV) is caused by a single-stranded RNA virus; about 170 million people worldwide are chronically infected with the virus. Chronic infection can lead to liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. HCV is the leading cause for liver transplantation. Importantly, not all acutely-infected patients become chronically infected. It is estimated that 20 to 30% of HCV-infected patients may clear the virus on their own, demonstrating that chronic infection may be due to an inability of the host immune system clear the virus.1

Current standard of care for HCV infections is a 48-week regimen of interferon-α (IFN-α) or PEGylated IFN-α (the long-acting form of IFN-α) injections in combination with ribavirin, an oral generic antiviral. Only around 50% of patients infected with the HCV virus strain genotype 1—the most common form in the U.S. and Europe—respond to IFN-α based therapy. Response in HCV means a sustained virologic response (SVR) in which HCV RNA is undetectable in blood for six months after cessation of treatment. Phase 3 clinical trials have shown that adding a direct-acting antiviral, such as the protease inhibitors telaprevir or boceprevir, to standard of care may generate SVR rates of 70 to 75% among treatment-naïve genotype 1 subgroups, including patients treated for only 24 weeks.2,3

A major cause for discontinuing HCV treatment is patient intolerance to IFN-α therapy. The frequency and diversity of the side effects attributed to IFN-α are relatively significant and include flu-like symptoms, hematological side effects, and depression. Although adding a new agent to the current standard of care may improve efficacy, it doesn’t address the tolerability issue associated with the IFN-α. New options, including more tolerable and effective immune modulatory agents for non-responders (all patients who initiate therapy but do not reach an SVR) and null-responders (patients who failed to achieve a 2 log10 reduction in viral load with standard of care treatment of at least 12 weeks duration) are needed. The immune modulatory component will most likely continue to be part of standard of care even with the changing treatment landscape as direct antiviral agents are potentially introduced to the market. To date, nearly everyone cured of HCV infection has been treated with IFN-α.

IMO-2125 is a synthetic agonist of the Toll-like receptor 9 (TLR9).4 TLR9 recognizes DNA patterns, which are not shared with the host but are specific to viral or bacterial pathogens, as foreign and activates an innate immune response. Preclinical studies have shown that IMO-2125 induced IFN-α and other cytokines in a dose-dependent manner in human immune cell cultures in vitro and in non-human primates in vivo. Furthermore, IMO-2125 demonstrated marked antiviral activity in a test, which measures the potency of antiviral compounds against HCV replication.5

Click To Enlarge

Stimulation of PBMCs with IMO-2125 induces higher levels of multiple cytokines including IFN-a, compared to stimulation with exogenous human INF-a. (Source: Idera Pharmaceuticals)

An ongoing Phase 1 study has revealed that IMO-2125 induces strong Th1-type (T helper type 1 cells) immune responses in null-responder HCV patients with dose-dependent increases in serum IFN-α, IP-10, 2’,5’-OAS, expression of CD69 activation marker on CD4+ and CD8+ T cells, and in the frequency of NK cells. Importantly, the induced serum IFN-α concentrations are inversely correlated with dose-dependent decreases in HCV viral load.6 IMO-2125 is well-tolerated and has not shown any serious adverse events for the doses investigated.

Enhancing the natural immune response of treatment-naïve patients may have a significant therapeutic effect for this patient population as well. A Phase 1 trial in treatment-naïve HCV patients for IMO-2125 in combination with ribavirin is ongoing.

IMO-2125 is being developed as a more effective and tolerable alternative to PEGylated IFN-α for administration in combination with ribavirin and direct-acting antiviral agents.

References
1. Horner SM, Gale M. Intracellular innate immune cascades and interferon defenses that control hepatitis C virus. Journal of Interferon & Cytokine Research. 2009;29(9):489.
2. Sherman KE, et al. Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naïve Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response: Final Results of Phase 3 ILLUMINATE Study. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD);2010.
3. Poordad F, et al. Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results. 61st Annual Meeting of the American Association for the Study of Liver Diseases; 2010.
4. Agrawal S, Kandimalla ER. Synthetic agonists of Toll-like receptors 7, 8 and 9. Biochem Soc Trans; 2007.

5. Sullivan T, et al. Presentation at 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago, 2007.

6. Rodriguez-Torres M, et al. IMO-2125, a TLR9 Agonist,

Induces Immune Responses which Correlate with Reductions in Viral Load in Null Responder HCV Patients. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD);2010.

Hepatitis C: Why Do Nonresponders Not Respond

Ongoing Challenges in Hepatitis C: Why Do Nonresponders Not Respond

Anne S. Henkel, MD; Steven L. Flamm, MD
Authors and Disclosures
CME Released: 10/27/2010;

Valid for credit through 10/27/2011


Hepatitis C virus (HCV) infection is a common cause of chronic liver disease worldwide and is currently the leading indication for liver transplantation in the United States.[1] The current standard of care for the initial treatment of chronic HCV infection is combination therapy with pegylated interferon alfa-2a or -2b and ribavirin. Unfortunately, less than half of treatment-naive patients with HCV genotype 1 infection successfully eradicate the virus with this regimen.[2-4]

Patients infected with HCV genotype 2 or 3 have a much greater chance of attaining a sustained virologic response (SVR; defined as undetectable HCV RNA [less then 50 IU/mL] 24 weeks after completion of treatment),[5] but there remains a significant number of patients who do not respond to standard-of-care therapy.

This column addresses factors associated with nonresponse to the current standard-of-care therapy and discusses the efficacy of strategies for the management of these patients. Definitions of Virologic Response and Nonresponse to HCV Therapy The efficacy of treatment with combination pegylated interferon alfa-2a or -2b and ribavirin is most commonly assessed by monitoring the serum hepatitis C viral load (HCV RNA level).

The ultimate goal of therapy is to achieve an SVR. HCV genotype 1 patients who achieve an SVR have a 99% chance of maintaining HCV RNA negativity over the long-term.[6] Additional virologic goals include an early virologic response (EVR) and a rapid virologic response (RVR), which are highly predictive of the likelihood of achieving an SVR. Partial EVR (pEVR) is defined as a 2-log or greater decline in viral load from the pretreatment level at 12 weeks of therapy. If EVR is not achieved, it is highly unlikely that an SVR will be achieved.[7] Complete EVR (cEVR) is defined as undetectable HCV RNA at week 12 of therapy. This is highly associated with achieving an SVR. RVR is defined as undetectable HCV RNA at week 4 of treatment.[5]

Patients with HCV genotype 1 demonstrating an RVR are predicted to have a 90% chance of ultimately achieving an SVR.[8] There are data to indicate that patients with HCV genotype 2 or 3 disease who achieve an RVR may require only 14 weeks of therapy instead of 24 weeks, but this remains controversial.[9] Additionally, there are data to support reducing the length of treatment from 48 weeks to 24 weeks in patients with HCV genotype 1 infection who achieve an RVR.[10] Patients who do not achieve an EVR are considered nonresponders, and therapy should be discontinued.[7,11]

If an EVR is achieved, treatment should be continued and serum HCV RNA should be reassessed at week 24 of therapy. If the serum HCV RNA remains detectable (ie, more then 600 IU/mL) at week 24 of therapy, the likelihood of achieving an SVR is exceedingly low.[7] Such patients are also considered nonresponders, and therefore therapy should be discontinued.[5]

For patients with HCV genotype 1 infection who are HCV RNA undetectable at week 24 of therapy, treatment should be maintained for 48 weeks if the patient is tolerating the treatment well.[7,11] Nonresponders can be subcategorized into partial responders and null responders. Null responders are patients who fail to achieve at least a 2-log decline in HCV RNA after 24 weeks of therapy. Partial responders demonstrate a more then 2-log decline in HCV RNA at treatment week 12 (EVR) but fail to achieve an undetectable level at week 24. The term "slow responder" has been applied to patients who have detectable HCV RNA at week 12 but successfully eradicate the virus by week 24. There are data to indicate that this subgroup of patients may benefit from 72 weeks of therapy rather than 48, although this is controversial.[5,12]

Viral breakthrough and relapse are also types of nonresponse. Viral breakthrough is uncommon and is characterized by detectable HCV RNA in a patient maintained on therapy who previously had undetectable HCV RNA. Relapse is defined as a detectable HCV RNA level in a patient who had undetectable HCV RNA at the completion of a full course of therapy. Unlike breakthrough, relapse is common with standard therapy.[5]

Factors Associated With Nonresponse to Hepatitis C Therapy
Numerous factors influence the likelihood of achieving an SVR with the standard-of-care therapy, combination pegylated interferon and ribavirin. Some factors are innate to the host or the virus and therefore are not modifiable. Other predictors of nonresponse are potentially modifiable, such as patient adherence and appropriate medication dosing by the physician.

Viral Factors
The strongest predictor of response to treatment is HCV genotype. HCV genotype 1 is present in approximately 75% of HCV-infected individuals in the United States, making it the most prevalent genotype in this country.[13] Unfortunately, HCV genotype 1 is also less responsive to standard-of-care treatment than is genotype 2 or 3. Large trials demonstrating the efficacy of combination pegylated interferon and ribavirin therapy found that patients with HCV genotype 1 infection have about a 40% chance of achieving an SVR.[2,3] This is in contrast to a greater than 80% rate of achieving SVR in patients with genotypes 2 and 3.[2,3]

Baseline viral load has been identified as an independent predictor of response to pegylated interferon and ribavirin therapy.[2,3,14] Patients with high pretreatment viral loads, defined as more then 600,000 IU/mL, have lower SVR rates than those with lower pretreatment viral loads (42% vs 78%, respectively).[2,5]

Host Factors
Race has also been shown to have a significant impact on the response to HCV therapy. Less than one third of black patients with HCV genotype 1 will achieve an SVR with pegylated interferon and ribavirin-based therapy, compared with over 50% of white patients.[15] Black patients with HCV genotype 1, in particular, benefit from weight-based dosing of ribavirin; however, even with optimal ribavirin dosing, the disparity in SVR rates is not eliminated.[16] Latino patients are also less responsive to conventional HCV therapy compared with whites.[17]

Metabolic factors such as insulin resistance, obesity, and the presence of hepatic steatosis may also affect response to HCV therapy. A study conducted in HCV genotype 1 patients found that only 32.8% of persons with insulin resistance achieved an SVR, compared with 60.5% of those without insulin resistance.[18] A subsequent study examined whether enhancing insulin sensitivity with metformin* in conjunction with pegylated interferon and ribavirin would translate to improved rates of SVR in HCV genotype 1 patients.[19] The triple-therapy regimen (compared with standard-of-care therapy) resulted in statistically significant improvement in SVR rates in women only (58% vs 29%, respectively).

Obesity may be associated with therapeutic nonresponse in HCV-infected patients as well, but data are conflicting. The suboptimal response of some obese patients to conventional therapy may be related in part to inadequate dosing of ribavirin.[20-22] Hepatic steatosis is often present in patients with HCV infection and is associated with a more aggressive disease course. Furthermore, there are data to indicate that the presence of hepatic steatosis reduces the virologic response to standard-of-care therapy with pegylated interferon and ribavirin.[23]

Therapy should be strongly considered in patients with advanced fibrosis or cirrhosis secondary to HCV infection given the high likelihood for disease progression and hepatic decompensation. Advanced fibrosis is associated with a lower virologic response rate compared with less advanced disease.[2,3,14,24] Data from the HALT-C (Hepatitis C Antiviral Long-term Treatment Against Cirrhosis) study showed that SVR rates in response to pegylated interferon and ribavirin ranged from 23% in HCV genotype 1 patients with bridging fibrosis and platelet counts > 125,000cells/mm3 to only 9% in patients with cirrhosis and platelet counts less then 125,000 cells/mm3.[24]

Active alcohol use is associated with a more aggressive disease course in patients with chronic HCV infection and also diminishes the likelihood of responding to antiviral therapy.[25] Although the mechanism mediating this effect is not well established, it has been suggested that alcohol may potentiate HCV replication.[25] Patients should be counseled to discontinue alcohol use prior to beginning antiviral therapy for HCV infection.

Coinfection with HCV is common among patients with HIV as a result of similar risk factors for transmission. HIV coinfection has been associated with more rapid progression of liver disease in patients with chronic hepatitis C and is associated with poor response to HCV therapy. A meta-analysis of 6 randomized controlled trials found that patients with HCV/HIV coinfection had only a 37% chance of achieving an SVR with standard-of-care therapy.[26]

There has been recent interest in identifying molecular markers that can help identify patients who are unlikely to respond to treatment. Three genome-wide association studies identified single nucleotide polymorphisms in the gene that encodes interleukin 28B (IL28B) on chromosome 19 as strongly predictive of response to HCV therapy in HCV genotype 1 patients.[27-29]

A recent study found that among white HCV genotype 1 patients, the rate of SVR was 69% in those with IL28B genotype CC compared with 33% and 27% in patients with genotypes CT and TT, respectively.[30] It was concluded that the IL28B genotype is the strongest predictor of SVR among HCV genotype 1 patients. The variation in IL28B genotype among racial/ethnic groups may partially explain the discrepancy in response rates to standard HCV therapy. IL28B genotyping is not yet standard practice. Its role is unclear, but this test has recently become commercially available in the United States and may become a routine component of the evaluation of potential treatment candidates in the near future.

Medication Dosing and Adherence
Suboptimal dosing of ribavirin is a significant factor that contributes to therapeutic nonresponse. Initially, the approved combination regimen for the treatment of HCV infection included a flat dose of ribavirin at 800 mg/day. However, numerous subsequent trials have demonstrated better SVR rates with higher doses as well as with weight-based dosing of ribavirin.[14,16] Weight-based ribavirin dosing is now approved for use with both pegylated interferon alfa-2a and -2b.

Dose reductions of pegylated interferon and/or ribavirin are common during the course of treatment, occurring in an estimated 27% and 43% of HCV genotype 1 patients, respectively.[31] Dose reductions may occur because of patient nonadherence or due to physician management of adverse events associated with the standard-of-care therapy, such as influenza-type symptoms, emotional disturbances, or hematologic toxicity.[5] Reductions in the cumulative doses of pegylated interferon and ribavirin have been shown to adversely affect the likelihood of achieving an SVR. It has been shown that patients who receive less than 60% of the cumulative dose of ribavirin over 48 weeks of treatment have reduced SVR rates.[31] In the HALT-C trial, reductions in the dose of pegylated interferon also resulted in reduced rates of SVR.However, contrary to findings from previous studies, reductions in the total dose of ribavirin did not result in decreased SVR rates if the full dose of pegylated interferon was maintained throughout.[32]

Management of Nonresponders**
There is no standardized approach to the management of patients who have failed to respond to interferon-based therapy. However, a number of options exist. Factors to consider include the specific type of previous therapy received (ie, standard vs pegylated interferon, with or without ribavirin) and tolerability to the initial therapeutic regimen. The type of prior nonresponse is another factor to consider. For example, previous relapsers will have a higher chance of achieving an SVR than will pure nonresponders.[5,33] Other factors to consider include the presence of advanced liver disease or an unfavorable HCV genotype, either of which may warrant a more aggressive approach to re-treatment.[5]

It has been clearly established that combination therapy with pegylated interferon and ribavirin is superior to standard interferon (nonpegylated) alone or standard interferon plus ribavirin for the management of treatment-naive patients with chronic HCV infection.[2,3,20] In the HALT-C trial, 604 patients with hepatitis C and advanced fibrosis who had failed to respond to prior treatment with interferon alone or in combination with ribavirin were re-treated with pegylated interferon and ribavirin. The response rate was 28% in patients who had previously been treated with interferon alone and 12% in patients previously treated with interferon plus ribavirin.[21] Other studies have shown similarly disappointing SVR rates in nonresponders. Most experts agree that until more effective treatment options become available, it is reasonable to consider a trial of pegylated interferon plus ribavirin in nonresponders to previous treatment with standard interferon who have HCV genotype 2 or 3 infection or moderate-to-advanced liver disease and who tolerated the initial course of antiviral therapy reasonably well. For patients with HCV genotype 1 infection and minimal liver fibrosis, or poor tolerance to the initial therapeutic regimen, observation or enrollment in a clinical research trial (if eligible) with an investigational agent is preferable.[5]

There is a rapidly growing population of patients who have failed to respond to treatment with pegylated interferon and ribavirin. As noted, there is no standardized approach to the management of these challenging patients. Re-treatment with the same regimen is generally regarded as an ineffective strategy. The EPIC (Evaluation of Pegintron in Control of Hepatitis C Cirrhosis )-3 trial found that among patients who had previously failed to respond to treatment with pegylated interferon and ribavirin-based therapy, re-treating with pegylated interferon alfa-2b and weight-based ribavirin resulted in an SVR rate of only 17%.[34] If, however, there was significant dose reduction or early termination of the initial treatment course, it is reasonable to consider re-treatment with pegylated interferon and ribavirin in select patients. Regarding the possible use of longer-duration or higher-dose pegylated interferon and ribavirin in this patient population, the results of clinical trials have not demonstrated sufficient benefit to support such strategies.[12,35,36]

In addition, there is no evidence to suggest that switching pegylated interferon products is helpful. There has been considerable interest in whether long-term viral suppression with maintenance therapy may be of benefit in nonresponders by slowing the progression of liver disease in the absence of SVR. The most notable study to examine this issue was the HALT-C trial, which concluded that prolonged treatment (average, 3.5 years) with low-dose pegylated interferon alfa-2a (90 µg per week) did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis who had failed to respond to previous treatment with pegylated interferon and ribavirin.[37] The EPIC-3 and CoPilot (Colchicine Versus PEG-Intron Long Term) trials demonstrated similarly disappointing results with maintenance therapy.[34,38] There is also little evidence that high-dose, daily interferon alfacon-1 (consensus interferon) given in combination with ribavirin is helpful in most patients who have failed to respond to previous pegylated interferon and ribavirin-based therapy (the DIRECT [Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy] study).[39]

Patients who have failed to respond to treatment with pegylated interferon and ribavirin may benefit from enrolling in a clinical trial with one of the emerging therapies if they are eligible and if a trial is available. If a trial is not an option, watchful waiting may be the best option while optimizing other conditions that can affect disease progression. In patients with cirrhosis and signs of decompensation, early referral for a liver transplant evaluation is appropriate.

Emerging Therapies for HCV
Given the limitations of the currently available therapy for HCV infection, there has been a strong effort to develop novel therapies to enhance efficacy. Although a number of strategies are currently in development, the most promising class of medications closest to approval are the direct-acting antiviral agents (DAAs). Whereas the currently available treatment for chronic HCV infection works by enhancing the immune system response to the virus, these newer therapies are designed to directly target HCV by inhibiting viral-specific enzymes. These compounds target HCV-specific enzymes such as the NS3/4A serine protease and the NS5B RNA-dependent RNA-polymerase. The DAAs furthest along in development are the protease inhibitors telaprevir (VX-950)* and boceprevir (SCH 503034).* Trials using these DAAs in nonresponders have focused on HCV genotype 1 patients only. Data in nonresponders with genotypes 2 and 3 are eagerly awaited. Numerous data are available on the effectiveness of these DAAs in treatment-naive HCV-infected patients, but this topic is beyond the scope of this column.

Telaprevir is a selective inhibitor of the NS3/4A serine protease. The results of the PROVE (Protease Inhibition for Viral Evaluation) 3 trial (phase 2), which were published recently, investigated the efficacy of telaprevir in patients with HCV genotype 1 infection who had failed to respond to previous treatment with pegylated interferon and ribavirin.[40] Subjects were randomly assigned to 1 of 3 telaprevir-based regimens or to the control group (standard of care). The rate of SVR was an impressive 51% among patients who received triple therapy (pegylated interferon alfa-2a, ribavirin, and telaprevir) for 12 weeks followed by pegylated interferon alfa-2a and ribavirin for an additional 12 weeks. By comparison, the control group, which received pegylated interferon alfa-2a plus ribavirin only for 48 weeks, had an SVR rate of only 14%. SVR was highest among patients whose previous treatment failure was due to relapse rather than nonresponse (69% vs 39%, respectively). Berg and colleagues[41] recently presented data from the Study 107 trial, in which open-label access to telaprevir-based therapy was provided to HCV genotype 1 patients enrolled in the control arms of the PROVE 1, 2, and 3 trials and who did not achieve an SVR after 48 weeks of pegylated interferon and ribavirin. Seventy percent of these patients had previously received at least 2 courses of pegylated interferon and ribavirin. All patients were treated with triple therapy (telaprevir, pegylated interferon alfa-2a, and ribavirin) for the initial 12 weeks of the study. Subsequently, patients were treated with pegylated interferon alfa-2a and ribavirin for either 12 weeks or 36 weeks depending on the type of nonresponse to initial therapy. Overall, the rate of SVR among all cohorts was 59%. When analyzed by type of nonresponse, the SVR rates were 97%, 75%, 55%, and 37% in patients with prior relapse, viral breakthrough, partial response, and null response, respectively.[7] A preliminary unpublished report from REALIZE (REtreAtment of nonresponders to peginterferon/ribavirin with teLaprevir based regimen to optimIZEoutcomes), a phase 3 trial of telaprevir in previous nonresponders to pegylated interferon and ribavirin, was released recently.[42] Treatment with telaprevir in combination with the current standard of care, pegylated interferon and ribavirin, resulted in a 65% overall SVR rate in patients with HCV genotype 1 who did not achieve viral cure after at least 1 prior course of pegylated interferon and ribavirin-based therapy. When analyzed according to the type of previous nonresponse, the rates of SVR were 86%, 57%, and 31% among previous relapsers, partial responders, and null responders, respectively.

Boceprevir is another potent inhibitor of the HCV NS3 serine protease that has demonstrated promising results. A preliminary, unpublished report from RESPOND (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol)-2, a phase 3 trial examining the efficacy of boceprevir in previous HCV genotype 1 nonresponders to pegylated interferon and ribavirin-based therapy, was recently made available.[43] Patients who received boceprevir plus the standard of care, pegylated interferon alfa-2b and ribavirin, for 48 weeks had an SVR rate of 66% compared with only 21% in controls treated with pegylated interferon and ribavirin alone.

Although the use of triple therapy is expected to significantly advance the management of chronic HCV infection, complicating factors such as an increase in side effects and the emergence of viral resistance are anticipated.

Other Strategies on the Horizon
A number of other agents are in development, including new interferons, ribavirin-like molecules, protease and polymerase inhibitors, and cyclophilin inhibitors,[44-47] among others; each holds promise for the therapy of treatment-experienced patients. In addition, data are available on the use of RG7128,* an oral cytidine nucleoside analog that inhibits the HCV RNA-dependent RNA polymerase, in treatment-experienced patients with HCV genotype 2 and 3. In a recent study by Gane and colleagues,[48] 20 previous nonresponders with HCV genotype 2 or 3 were randomly assigned to receive RG7128 plus pegylated interferon alfa-2a and ribavirin for 28 days followed by pegylated interferon alfa-2a and ribavirin alone for 20-44 weeks. In the cohort that received triple therapy followed by 44 weeks of the standard of care, the SVR rate was 90%.

Conclusion
Understanding the factors associated with nonresponse to HCV therapy is critical in the management of patients seeking treatment. The current standard of care for the management of chronic hepatitis C is not effective in nearly half of treatment-naive patients with genotype 1 infection. The side effects, associated cost, and inconvenience of therapy may outweigh the potential benefits in those patients who possess numerous predictors of nonresponse. Among potential treatment candidates, optimizing the modifiable predictors of nonresponse can help increase the chance of achieving an SVR. The management of patients with chronic hepatitis C who do not respond to standard-of-care therapy remains a challenge. The most promising therapies in clinical development appear to be the DAAs. Novel agents will likely assume a key role in the future management of the increasing number of patients who do not respond to the current standard of care.

*The US Food and Drug Administration has not approved this medication for this use.
**This section includes discussion of non-US Food and Drug Administration (FDA)-approved therapies and/or administration options that deviate from FDA recommendations.

Supported by independent educational grants from Vertex Pharmaceuticals, Genentech, and Merck.

Also See : Changing the Game in Hepatitis C: Where Are We and Where Are We Going? MedscapeCME Gastroenterology, October 27, 2010

http://cme.medscape.com/viewarticle/730978