Hep C Treatment Failure Can Still Mean Less Liver Inflammation
HCV Viral Load Reduction Improved
Inflammation, Fibrosis, Clinical
Outcomes with PegIFn Lead-In Maintenance therapy in HALT-C
Download the PDF @ NATAP
DISCUSSION ONLY
Our previous intention-to-treat analysis of the HALT-C Trial demonstrated no effect of long-term half-dose maintenance peginterferon
treatment on the occurrence of clinical outcomes and fibrosis progression in
1,050 previous interferon nonresponders with advanced hepatic fibrosis (7). The current post-hoc analysis of a subset of HALT-C Trial patients expands and extends early observations on the impact of interferon-induced reduction of hepatic inflammation on fibrosis progression (6) owing to our focus on
patients with advanced hepatic fibrosis, the measurement of clinical outcomes, the long duration of the follow-up period (up to 8.5 years), and the large sample size.
We report that improved hepatic inflammation was associated with marked reductions in serum HCV RNA during the preceding 24-week lead-in phase of full-dose peginterferon/ribavirin treatment. Thus, improved hepatic inflammation
in subsets of both the maintenance peginterferon and control groups could be explained by the fact that all of these patients were pretreated with full-dose peginterferon/ribavirin. Patients with profound virological suppression during the lead-in phase who were also able to maintain substantially suppressed viral levels during the randomized half-dose maintenance phase were most likely to experience improvement in hepatic inflammation. Most importantly, improved inflammation was associated with fewer clinical outcomes and less fibrosis progression compared to patients without such improvement.
We previously showed that maximal suppression of HCV RNA levels (≥4 log10) during lead-in therapy was the most important variable associated with a reduced frequency of subsequent clinical decompensation outcomes, although no direct relationship was found between HCV RNA suppression and histological fibrosis progression (8).
Here we report that HCV RNA suppression during lead-in therapy was associated with reduction of hepatic inflammation and, separately, reduced hepatic inflammation was associated with less fibrosis progression. Overall, these data confirm the close association between HCV RNA levels and hepatic inflammation and suggest that amelioration of these factors is crucial to limiting liver disease progression (6,16).
The effect of virological suppression during lead-in therapy on reduction of hepatic inflammation appeared to be surprisingly
durable even in patients with subsequent viral recrudescence, as reduced hepatic inflammation was found in a subset of patients randomized to the untreated-control group as long as 3.5 years after the cessation of peginterferon/ribavirin treatment. This observation confirms the notion that peginterferon therapy has two distinct effects that may be separable: (1)
reduction of viremia and (2) long-term reduction of hepatic inflammation. This clinical observation is consistent with the many reports of the direct effects of interferon-alfa on viral replication (17), distinct from effects on proinflammatory lymphocyte function (18) and on inhibition of collagen production by hepatic stellate cells (19).
What could be the biological basis for the durability of the reduced hepatic inflammation induced by peginterferon/ribavirin treatment?
The reduction in the hepatic inflammatory cell infiltrate and of hepatocyte death as documented in the year-1.5 and year-3.5 HAI scores, even with viral recurrence to near baseline levels, suggests the possibility that peginterferon/ribavirin may have had durable epigenetic molecular effect(s) on cells within the liver that have a role in liver inflammation. Whatever these effects might have been, peginterferon/ribavirin clearly had direct or indirect (downstream) effects on lymphocyte recruitment and activity in the liver, as indicated by reductions in portal and periportal inflammation and parenchymal injury in the HAI scores. Future detailed studies of liver samples from patients who experience maximal HCV RNA suppression will be necessary to determine what durable molecular events could account for the post-treatment effects we describe.
Worth emphasizing is the observation that the HALT-C Trial was dominated by patients who were null (virological) responders-who experienced <2 log10 HCV RNA reduction with full-dose peginterferon/ribavirin lead-in treatment (Figure 2, N=360 of 657). By contrast, most patients in this analysis with improved hepatic inflammation derived from the subset with profound virological suppression (≥4 log10) by week 20 of lead-in therapy who experienced subsequent virological breakthrough during or relapse after up to 24 more weeks of full-dose peginterferon/ribavirin treatment compared with the true nonresponders. Whether such profound and mostly sustained virological suppression (≥4 log10) by peginterferon/ribavirin treatment in this small subset was related to common host or viral characteristics among these patients is not known. Our findings are consistent with the possibilities that virological suppression can result in reduction of hepatic inflammation, that virological suppression serves as a marker of persons more likely to reduce hepatic inflammation as a consequence of treatment, or both. Moreover, our data are consistent with the notion that patients who can achieve profound virological suppression and reduction of hepatic inflammation may have the potential to benefit from longer-term pharmacological suppression of HCV replication. On the other hand, we also identified a potential cost of maintenance peginterferon therapy: almost 50% of patients who experienced worsening of hepatic inflammation with therapy had clinical outcomes (Figure 6a). Although the increased inflammation may have been a marker for those destined to have a poor outcome rather than a result of maintenance interferon therapy, these latter findings support our previous conclusion that the use of long-term interferon maintenance therapy in HCV-infected nonresponder patients with advanced liver disease cannot be recommended at this time. Our findings may help to explain why we were unable to demonstrate clinical benefit of maintenance peginterferon among the 1,050 patients enrolled in the overall HALT-C Trial. The majority of patients were true null virological responders with a <2 log10 decrease of HCV RNA during full-dose peginterferon/ribavirin therapy. Among these patients, few demonstrated improvement of hepatic inflammation, most demonstrated no change, and some demonstrated worsening inflammation during therapy. During subsequent randomized-phase treatment with half-dose peginterferon, the vast majority of patients exhibited <2 log10 virological suppression and relatively few patients experienced substantial virological suppression (7). Thus, based upon the data presented here and elsewhere (8), if virological suppression is required for clinical benefit to occur, then we speculate that the degree of virological suppression with half-dose peginterferon therapy during the maintenance phase was insufficient to reduce hepatic inflammation and clinical and fibrosis outcomes in the entire treated group. Alternatively, the durable histological impact of short-term virological suppression during lead-in therapy might have had an overwhelming, confounding effect that might have obscured a difference in fibrosis progression and clinical outcomes between the randomized control and maintenance-peginterferon groups in the HALT-C Trial. In conclusion, analysis of laboratory data and paired serial liver biopsies from a subset of well-pedigreed patients with advanced hepatic fibrosis enrolled in the HALT-C Trial demonstrates the associations between peginterferon/ribavirin-induced virological suppression, hepatic inflammation, serum ALT levels, hepatic fibrosis progression, and liver disease outcomes (of hepatic decompensation, liver cancer, and death). Although maximal virological suppression during the lead-in phase of the Trial was shown to have no direct impact on fibrosis progression (8), profound suppression of HCV RNA, achieved in a small minority of patients, was found to be associated with decreased hepatic inflammation. Decreased hepatic inflammation, in turn, appeared to be a critical factor that was associated with reduced fibrosis progression and, to a lesser extent, fewer clinical outcomes. The surprisingly durable beneficial effect of peginterferon/ribavirin (3.5 years later) on hepatic inflammation was also associated with a sustained improvement of ALT, despite viral recrudescence at the time of repeat biopsy and serum laboratory measurements. Of note, these results also suggest potential benefit for patients with advanced liver disease currently being treated with direct-acting antiviral agents in combination with peginterferon/ribavirin, regardless of whether they achieve SVR. We conclude that reduction of hepatic inflammation appears to be an important target for future therapeutic interventions to retard the progression of hepatitis C-related liver disease.
http://www.natap.org/2012/HCV/071012_02.htm
Download the PDF @ NATAP
Inflammation, Fibrosis, Clinical
Outcomes with PegIFn Lead-In Maintenance therapy in HALT-C
Download the PDF @ NATAP
DISCUSSION ONLY
Our previous intention-to-treat analysis of the HALT-C Trial demonstrated no effect of long-term half-dose maintenance peginterferon
treatment on the occurrence of clinical outcomes and fibrosis progression in
1,050 previous interferon nonresponders with advanced hepatic fibrosis (7). The current post-hoc analysis of a subset of HALT-C Trial patients expands and extends early observations on the impact of interferon-induced reduction of hepatic inflammation on fibrosis progression (6) owing to our focus on
patients with advanced hepatic fibrosis, the measurement of clinical outcomes, the long duration of the follow-up period (up to 8.5 years), and the large sample size.
We report that improved hepatic inflammation was associated with marked reductions in serum HCV RNA during the preceding 24-week lead-in phase of full-dose peginterferon/ribavirin treatment. Thus, improved hepatic inflammation
in subsets of both the maintenance peginterferon and control groups could be explained by the fact that all of these patients were pretreated with full-dose peginterferon/ribavirin. Patients with profound virological suppression during the lead-in phase who were also able to maintain substantially suppressed viral levels during the randomized half-dose maintenance phase were most likely to experience improvement in hepatic inflammation. Most importantly, improved inflammation was associated with fewer clinical outcomes and less fibrosis progression compared to patients without such improvement.
We previously showed that maximal suppression of HCV RNA levels (≥4 log10) during lead-in therapy was the most important variable associated with a reduced frequency of subsequent clinical decompensation outcomes, although no direct relationship was found between HCV RNA suppression and histological fibrosis progression (8).
Here we report that HCV RNA suppression during lead-in therapy was associated with reduction of hepatic inflammation and, separately, reduced hepatic inflammation was associated with less fibrosis progression. Overall, these data confirm the close association between HCV RNA levels and hepatic inflammation and suggest that amelioration of these factors is crucial to limiting liver disease progression (6,16).
The effect of virological suppression during lead-in therapy on reduction of hepatic inflammation appeared to be surprisingly
durable even in patients with subsequent viral recrudescence, as reduced hepatic inflammation was found in a subset of patients randomized to the untreated-control group as long as 3.5 years after the cessation of peginterferon/ribavirin treatment. This observation confirms the notion that peginterferon therapy has two distinct effects that may be separable: (1)
reduction of viremia and (2) long-term reduction of hepatic inflammation. This clinical observation is consistent with the many reports of the direct effects of interferon-alfa on viral replication (17), distinct from effects on proinflammatory lymphocyte function (18) and on inhibition of collagen production by hepatic stellate cells (19).
What could be the biological basis for the durability of the reduced hepatic inflammation induced by peginterferon/ribavirin treatment?
The reduction in the hepatic inflammatory cell infiltrate and of hepatocyte death as documented in the year-1.5 and year-3.5 HAI scores, even with viral recurrence to near baseline levels, suggests the possibility that peginterferon/ribavirin may have had durable epigenetic molecular effect(s) on cells within the liver that have a role in liver inflammation. Whatever these effects might have been, peginterferon/ribavirin clearly had direct or indirect (downstream) effects on lymphocyte recruitment and activity in the liver, as indicated by reductions in portal and periportal inflammation and parenchymal injury in the HAI scores. Future detailed studies of liver samples from patients who experience maximal HCV RNA suppression will be necessary to determine what durable molecular events could account for the post-treatment effects we describe.
Worth emphasizing is the observation that the HALT-C Trial was dominated by patients who were null (virological) responders-who experienced <2 log10 HCV RNA reduction with full-dose peginterferon/ribavirin lead-in treatment (Figure 2, N=360 of 657). By contrast, most patients in this analysis with improved hepatic inflammation derived from the subset with profound virological suppression (≥4 log10) by week 20 of lead-in therapy who experienced subsequent virological breakthrough during or relapse after up to 24 more weeks of full-dose peginterferon/ribavirin treatment compared with the true nonresponders. Whether such profound and mostly sustained virological suppression (≥4 log10) by peginterferon/ribavirin treatment in this small subset was related to common host or viral characteristics among these patients is not known. Our findings are consistent with the possibilities that virological suppression can result in reduction of hepatic inflammation, that virological suppression serves as a marker of persons more likely to reduce hepatic inflammation as a consequence of treatment, or both. Moreover, our data are consistent with the notion that patients who can achieve profound virological suppression and reduction of hepatic inflammation may have the potential to benefit from longer-term pharmacological suppression of HCV replication. On the other hand, we also identified a potential cost of maintenance peginterferon therapy: almost 50% of patients who experienced worsening of hepatic inflammation with therapy had clinical outcomes (Figure 6a). Although the increased inflammation may have been a marker for those destined to have a poor outcome rather than a result of maintenance interferon therapy, these latter findings support our previous conclusion that the use of long-term interferon maintenance therapy in HCV-infected nonresponder patients with advanced liver disease cannot be recommended at this time. Our findings may help to explain why we were unable to demonstrate clinical benefit of maintenance peginterferon among the 1,050 patients enrolled in the overall HALT-C Trial. The majority of patients were true null virological responders with a <2 log10 decrease of HCV RNA during full-dose peginterferon/ribavirin therapy. Among these patients, few demonstrated improvement of hepatic inflammation, most demonstrated no change, and some demonstrated worsening inflammation during therapy. During subsequent randomized-phase treatment with half-dose peginterferon, the vast majority of patients exhibited <2 log10 virological suppression and relatively few patients experienced substantial virological suppression (7). Thus, based upon the data presented here and elsewhere (8), if virological suppression is required for clinical benefit to occur, then we speculate that the degree of virological suppression with half-dose peginterferon therapy during the maintenance phase was insufficient to reduce hepatic inflammation and clinical and fibrosis outcomes in the entire treated group. Alternatively, the durable histological impact of short-term virological suppression during lead-in therapy might have had an overwhelming, confounding effect that might have obscured a difference in fibrosis progression and clinical outcomes between the randomized control and maintenance-peginterferon groups in the HALT-C Trial. In conclusion, analysis of laboratory data and paired serial liver biopsies from a subset of well-pedigreed patients with advanced hepatic fibrosis enrolled in the HALT-C Trial demonstrates the associations between peginterferon/ribavirin-induced virological suppression, hepatic inflammation, serum ALT levels, hepatic fibrosis progression, and liver disease outcomes (of hepatic decompensation, liver cancer, and death). Although maximal virological suppression during the lead-in phase of the Trial was shown to have no direct impact on fibrosis progression (8), profound suppression of HCV RNA, achieved in a small minority of patients, was found to be associated with decreased hepatic inflammation. Decreased hepatic inflammation, in turn, appeared to be a critical factor that was associated with reduced fibrosis progression and, to a lesser extent, fewer clinical outcomes. The surprisingly durable beneficial effect of peginterferon/ribavirin (3.5 years later) on hepatic inflammation was also associated with a sustained improvement of ALT, despite viral recrudescence at the time of repeat biopsy and serum laboratory measurements. Of note, these results also suggest potential benefit for patients with advanced liver disease currently being treated with direct-acting antiviral agents in combination with peginterferon/ribavirin, regardless of whether they achieve SVR. We conclude that reduction of hepatic inflammation appears to be an important target for future therapeutic interventions to retard the progression of hepatitis C-related liver disease.
http://www.natap.org/2012/HCV/071012_02.htm
Download the PDF @ NATAP
July 6, 2012
Hep C Treatment Failure Can Still Mean Less Liver Inflammation
Hepatitis C treatment is typically seen as an all-or-nothing approach—nothing short of a sustained virologic response (SVR), or cure, will benefit people living with the virus. New data, however, suggest that even among those who don’t achieve an SVR, but who do see a substantial drop in hep C viral loads during treatment, there may be a reduction in inflammation associated with liver disease. This encouraging finding, published ahead of print by the American Journal of Gastroenterology, is based on data from an older 1.050-patient clinical trial dubbed the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) study.
The primary goal of HALT-C was to determine whether 3.5 years of ongoing treatment with pegylated interferon (peg-IFN) monotherapy could slow liver disease progression—notably the development of liver cancer, liver failure or death—in people living with hepatitis C virus (HCV) who weren’t able to achieve an SVR using peg-IFN plus ribavirin.
According to the original results from the study, published in the journal Gastroenterology in January 2009, those who
continued on long-term maintenance therapy with peg-IFN were no less likely to experience serious liver disease or death than those who did not receive additional treatment. What remained unclear, however, is whether failed treatment—either during the peg-IFN/ribavirin “lead-in” period or during the long peg-IFN monotherapy maintenance period—was a complete wash for people who remained uncured of their infection.
In turn, study investigator Chihiro Morishima, MD, of the University of Washington in Seattle and her colleagues
turned their attention to 834 participants from HALT-C who had liver biopsy results before starting peg-IFN/ribavirin treatment and then 1.5 years after being randomized to either peg-IFN maintenance therapy or no therapy with observation.
Morishima’s team used the biopsy specimens to look for changes in fibrosis scores and in histology activity index (HAI) scores—a measure of inflammation, which can lead to scarring of the liver.
Looking specifically at 657 patients who received full-dose peg-IFN and ribavirin lead-in therapy, HAI improvements were noted in the biopsy samples collected 1.5 years after being randomized in the study.
The improvements were highly statistically significant in one particular group of patients, dubbed responder relapsers, who saw their HCV viral loads reduced substantially during treatment but were unable to maintain an undetectable viral
load after stopping therapy. These statistically significant improvements in HAI scores were just as likely to be seen in those who didn’t receive peg-IFN maintenance therapy compared with those who did.
Among all 834 patients followed for an average of six years, Morishima and her colleagues reported that those who achieved HAI improvements as a result of treatment were more likely to see other improvements as well. For example, among those with moderate-to-severe fibrosis at baseline, those with improved HAI scores at the 1.5-year mark had less liver fibrosis progression than those who didn’t experience HAI improvements. In conclusion, the authors explain, there may still be advantages to failed treatment, notably among responder-relapsers. “Reduced hepatic inflammation,” they write, “was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized [maintenance] treatment.”
http://www.aidsmeds.com/articles/hepatitis_treatment_inflammation_1667_22660.shtml
Hep C Treatment Failure Can Still Mean Less Liver Inflammation
Hepatitis C treatment is typically seen as an all-or-nothing approach—nothing short of a sustained virologic response (SVR), or cure, will benefit people living with the virus. New data, however, suggest that even among those who don’t achieve an SVR, but who do see a substantial drop in hep C viral loads during treatment, there may be a reduction in inflammation associated with liver disease. This encouraging finding, published ahead of print by the American Journal of Gastroenterology, is based on data from an older 1.050-patient clinical trial dubbed the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) study.
The primary goal of HALT-C was to determine whether 3.5 years of ongoing treatment with pegylated interferon (peg-IFN) monotherapy could slow liver disease progression—notably the development of liver cancer, liver failure or death—in people living with hepatitis C virus (HCV) who weren’t able to achieve an SVR using peg-IFN plus ribavirin.
According to the original results from the study, published in the journal Gastroenterology in January 2009, those who
continued on long-term maintenance therapy with peg-IFN were no less likely to experience serious liver disease or death than those who did not receive additional treatment. What remained unclear, however, is whether failed treatment—either during the peg-IFN/ribavirin “lead-in” period or during the long peg-IFN monotherapy maintenance period—was a complete wash for people who remained uncured of their infection.
In turn, study investigator Chihiro Morishima, MD, of the University of Washington in Seattle and her colleagues
turned their attention to 834 participants from HALT-C who had liver biopsy results before starting peg-IFN/ribavirin treatment and then 1.5 years after being randomized to either peg-IFN maintenance therapy or no therapy with observation.
Morishima’s team used the biopsy specimens to look for changes in fibrosis scores and in histology activity index (HAI) scores—a measure of inflammation, which can lead to scarring of the liver.
Looking specifically at 657 patients who received full-dose peg-IFN and ribavirin lead-in therapy, HAI improvements were noted in the biopsy samples collected 1.5 years after being randomized in the study.
The improvements were highly statistically significant in one particular group of patients, dubbed responder relapsers, who saw their HCV viral loads reduced substantially during treatment but were unable to maintain an undetectable viral
load after stopping therapy. These statistically significant improvements in HAI scores were just as likely to be seen in those who didn’t receive peg-IFN maintenance therapy compared with those who did.
Among all 834 patients followed for an average of six years, Morishima and her colleagues reported that those who achieved HAI improvements as a result of treatment were more likely to see other improvements as well. For example, among those with moderate-to-severe fibrosis at baseline, those with improved HAI scores at the 1.5-year mark had less liver fibrosis progression than those who didn’t experience HAI improvements. In conclusion, the authors explain, there may still be advantages to failed treatment, notably among responder-relapsers. “Reduced hepatic inflammation,” they write, “was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized [maintenance] treatment.”
http://www.aidsmeds.com/articles/hepatitis_treatment_inflammation_1667_22660.shtml