The Big Picture

Impact of Sustained Virologic Response in Hepatitis C Therapy

As chronic infection with hepatitis C virus remains a major cause of liver-related morbidity, hepatocellular carcinoma and mortality worldwide, efforts to achieve eradication of the virus are of critical importance. The availability of direct-acting antiviral therapy has transformed the management of chronic HCV, as the vast majority of patients can now undergo a course of treatment that is highly effective with minimal side effects. In light of this evolving landscape, a renewed emphasis has been placed on the screening and diagnosis of HCV infection, as a large proportion of the estimated 3 to 4 million patients with chronic hepatitis C remain undiagnosed and are at risk for disease progression, including a projected increase in the prevalence of advanced liver disease and incidence of HCC over the next two decades.

Achievement of viral eradication through antiviral therapy, defined by a sustained virologic response, can alter the natural history of chronic liver disease associated with HCV infection, including the potential for fibrosis regression, decreased risk for clinical decompensation or need for liver transplantation, decreased risk for HCC, and increased survival. Although these long-term benefits have been most clearly demonstrated in those with advanced liver disease, achievement of SVR can also have a major impact in those without cirrhosis, including a survival benefit and improvement in health-related quality of life.

Stevan A. Gonzalez

Efficacy of Current Therapy

Nine direct-acting antiviral (DAA) agents are now available in the U.S., either as single-drug formulations or in combination, with the anticipated release of additional agents in the near future. Although many regimens are ribavirin-free, the addition of ribavirin may be required to optimize virologic response and shorten duration of therapy, particularly in patients with advanced disease. Treatment options are now available for all HCV genotypes. Based on an ever-expanding body of evidence from prospective randomized controlled trials, SVR can be achieved in well over 90% of treatment candidates, including many populations that are historically difficult to treat. In addition, reports from large-scale, real-world databases such as HCV Target and the TRIO network have described similar efficacy to clinical trials. However, patients who are prior treatment failures and those with cirrhosis or advanced disease may still experience lower response rates and may require the addition of ribavirin or longer duration of therapy. In particular, challenges remain in those with decompensated cirrhosis, in which recent data suggest a decline in efficacy compared with clinically compensated cirrhosis and the safety of DAA therapy in this population has yet to be fully established.

 

Defining Eradication, Durability

As the HCV life cycle does not involve an intranuclear component and the virus does not integrate itself into the host genome, HCV can be eradicated with antiviral therapy. Achievement of eradication is heralded by the achievement of SVR, initially defined by undetectable serum HCV RNA 24 weeks after completion of therapy (SVR24). However, SVR has been redefined in the era of DAA therapy, in which undetectable serum HCV RNA at 12 weeks following completion of therapy (SVR12) was found to have a very high concordance with SVR24, allowing for its use as a clinical endpoint in registration trials of emerging DAA regimens. Large-scale analyses involving patients enrolled in clinical trials of interferon-based, and more recently DAA-based therapy, have reported concordance of SVR12 with SVR24 of greater than 99%. Consequently, SVR12 is now considered a reliable endpoint of DAA therapy in clinical practice.

The durability of SVR is well established. Several large-scale long-term follow up studies involving cohorts treated with interferon-based therapy have reported durability of SVR in over 99% of patients. Reports describing follow-up of patients who achieved SVR in the earliest trials of interferon-based therapy have documented durability of SVR up to 18 years following completion of therapy. In light of these data, clinicians can have confidence that eradication of HCV is possible with antiviral therapy and that achievement of SVR is equivalent to a long-term cure.

Potential for Fibrosis Regression

The regenerative capacity of the liver is well known, including the observation that regression of fibrosis can occur following resolution of chronic liver disease states such as HCV infection. In patients with chronic HCV who achieve viral eradication, fibrosis regression can occur, even in those with cirrhosis. Several long-term follow-up studies with paired liver biopsy data primarily from the era of interferon-based therapy have demonstrated decreases in fibrosis stage in a significant proportion of patients who experience SVR. These studies have reported regression from liver biopsy METAVIR fibrosis stage F4 to at least stage F3 in over one-half of patients in some cohorts (Figure 1). Although the histologic fibrosis stage did not decrease in all patients involved in these studies, a significant reduction in hepatic collagen content may occur in the majority of patients. As more accurate noninvasive methods to estimate liver fibrosis have become available, such as transient elastography, improvements in degree of fibrosis following SVR can be more easily assessed. Although recent reports utilizing elastography are limited and appear to vary substantially, we anticipate that more data demonstrating regression of fibrosis following SVR will emerge in the DAA era.

Risk Reduction

The greatest impact associated with SVR can be seen in the diminished risk for events over time, including clinical decompensation, incidence of HCC, need for liver transplantation and mortality. Based on large prospective cohort studies, it is now well established that chronic infection with HCV is associated with an increase in liver-related, as well as non–liver-related, mortality compared with noninfected individuals, which can be seen across all stages of HCV-associated liver disease. In patients who successfully undergo antiviral therapy and achieve SVR, a significant reduction in all-cause mortality can be seen. A recent comprehensive review and meta-analysis of 31 studies involving greater than 30,000 patients evaluated the 5-year all-cause mortality risk in a general population with chronic HCV infection, patients with cirrhosis and those with HIV/HCV co-infection. Individuals who achieved SVR benefited from a significant reduction in mortality with a protective effect observed in all groups after adjustment for potential covariates (see Table). Additional reports from large-scale cohorts and meta-analyses have described a decline in all-cause mortality following SVR in all stages of hepatic fibrosis, independent of comorbidities and other risk factors including HCV genotype. Achievement of SVR may also have a positive impact on non–liver-related mortality, as well as events related to cardiovascular disease, kidney disease, diabetes, malignancy and health-related quality of life. Successful treatment of recurrent HCV infection following liver transplantation also improves patient and allograft survival.

 

The impact of SVR appears to be greatest in those with advanced liver disease. Individuals with cirrhosis or advanced fibrosis who achieve long-term viral clearance after completion of therapy demonstrate a much greater absolute risk reduction and decline in incidence of various endpoints, including clinical decompensation, HCC and liver-related mortality. Several retrospective and prospective studies over the last decade involving cohorts with compensated cirrhosis have consistently demonstrated a reduction in liver-related morbidity and mortality associated with SVR in this population. One of the largest long-term cohort follow-up studies to evaluate all-cause mortality as a clinical endpoint in this population included 530 patients with advanced fibrosis. In this cohort, the mortality risk was fourfold lower in those with SVR vs. patients in which therapy was unsuccessful, in addition to decreases in risk for liver-related mortality or need for liver transplantation, HCC and clinical decompensation (Figure 2). A follow-up analysis to this study revealed that once SVR was achieved in these patients with advanced fibrosis, no difference in survival was seen in comparison with non-HCV age- and sex-matched controls. Although these studies have reported a decline in risk for HCC in cirrhotics who achieve SVR, this risk is not entirely eliminated. Consequently, all patients with cirrhosis should be maintained on a long-term surveillance program after SVR.

Treatment Strategies in Advanced Disease

It is clear that all individuals with chronic HCV infection can benefit from achievement of SVR and eradication of the virus; however, it is apparent that patients with cirrhosis may have the most to gain. Despite this, the development of the optimal treatment strategy in those with decompensated cirrhosis or those who are liver transplant candidates remains elusive. Several randomized controlled trials of DAA regimens have included patients with decompensated cirrhosis, all of which have consistently demonstrated achievement of SVR in the majority of patients treated; however, virologic response is comparatively lower in this population.

Data presented from the SOLAR-1 and SOLAR-2 trials evaluating sofosbuvir and ledipasvir (Harvoni, Gilead Sciences) plus ribavirin for 12 weeks in patients with genotype 1 and 4 noted SVR rates of 87% and up to 86% in patients with Child-Turcotte-Pugh (CTP) classification of B and C, respectively, in which extension of therapy to 24 weeks did not improve efficacy. The ALLY-1 trial evaluated sofosbuvir (Sovaldi, Gilead Sciences) daclatasvir (Daklinza, Bristol-Myers Squibb) and ribavirin for 12 weeks in patients with genotypes 1 to 4 with decompensated cirrhosis and reported an SVR of 94% in patients with CTP class B; however, SVR declined to 56% in those with CTP class C. Similar efficacy was reported in a real world setting through the NHS England early access program in which an SVR of greater than 80% was observed in genotype 1 patients with clinical decompensation utilizing regimens of sofosbuvir/ledipasvir or sofosbuvir and daclatasvir with ribavirin. However, SVR was reported in only 70% with genotype 3 infection. A question is whether combinations of multiple DAA agents may improve efficacy in this challenging population, as suggested by results from the IMPACT study involving the ribavirin-free combination of simeprevir (Olysio, Janssen), sofosbuvir and daclatasvir for 12 weeks, in which SVR was reported in 100% of patients who received this regimen.

Despite promising reports of efficacy, safety concerns exist in the setting of decompensated cirrhosis, particularly in regimens requiring ribavirin, as tolerability may be diminished substantially and patients frequently require dose reductions, blood transfusions and even discontinuation of ribavirin. In addition, deaths have been reported while on therapy. Although the small number of deaths that have occurred in the setting of clinical trials involving decompensated cirrhosis could not be attributed directly to therapy, it is clear that caution should be taken in this population. The regimen of ombitasvir, parataprevir/ritonavir, and dasabuvir (Viekira Pak, AbbVie) is now contraindicated in the setting of decompensated cirrhosis, and simeprevir-based regimens are not recommended according to the AASLD/IDSA guidelines for HCV therapy.

 

In patients with decompensated HCV cirrhosis who are awaiting liver transplantation, a successful course of antiviral therapy can significantly improve laboratory parameters including bilirubin and albumin as well as the MELD score, which may decline in up to 70% of patients. It remains to be seen whether this incremental benefit associated with SVR will translate into a significant recovery of liver function in some individuals or rather compromise a person’s likelihood of undergoing liver transplantation due to the reduction in MELD score. As a result, some liver transplant candidates may be left untreated, particularly those with high MELD scores; however, a debate exists regarding this strategy. The decision on whether or not to withhold therapy in this setting and at what threshold of MELD score is individualized and may vary greatly based on local practices, organ availability in the region relative to an individual’s MELD score and the use of HCV-positive organs.

It is encouraging that recent data have emerged suggesting that a reduction in portal hypertension can occur following SVR based on decreases in measured hepatic venous pressure gradient, improved platelet counts and decreased spleen size. Ultimately, patients who undergo liver transplantation can benefit greatly from antiviral therapy, in which maintaining viral clearance for at least 4 weeks prior to transplantation can prevent post-transplant recurrence in over 95% of patients. Alternatively, antiviral therapy is also effective after liver transplantation, including cases of severe recurrence and fibrosing cholestatic HCV.

Challenges Ahead

Our ability to achieve eradication of HCV on an individual basis and on a large scale continues to improve as more effective DAA therapy becomes available; however, challenges remain. Despite a renewed emphasis on screening and diagnosis of individuals at risk for HCV infection, we are confronted with a majority of infected individuals who remain undiagnosed. As this population is projected to progress towards advanced liver disease in the years ahead, treating even a modest proportion of patients now could reduce the burden of liver failure and liver-related death substantially. Although initiating treatment with the goal of achieving SVR is cost effective, challenges exist in providing access to care and treatment in many patients who have been diagnosed with chronic HCV infection.

Although questions remain regarding the appropriate treatment strategy for patients with decompensated liver disease and those awaiting liver transplantation, it is clear that achievement of SVR is beneficial to virtually all patients. As more patients achieve this endpoint, we must also be attentive to which individuals will require ongoing surveillance after SVR, including surveillance for HCC in those with cirrhosis and managing comorbidities that could influence fibrosis progression such as fatty liver disease and obesity. Ultimately a greater understanding of these potential cofactors will be important in optimizing long-term outcomes and preserving the benefits of viral eradication.

Disclosure: Gonzalez reports consulting for AbbVie. He also reports being on the speaker’s bureau for AbbVie, Gilead Sciences and Merck.

As chronic infection with hepatitis C virus remains a major cause of liver-related morbidity, hepatocellular carcinoma and mortality worldwide, efforts to achieve eradication of the virus are of critical importance. The availability of direct-acting antiviral therapy has transformed the management of chronic HCV, as the vast majority of patients can now undergo a course of treatment that is highly effective with minimal side effects. In light of this evolving landscape, a renewed emphasis has been placed on the screening and diagnosis of HCV infection, as a large proportion of the estimated 3 to 4 million patients with chronic hepatitis C remain undiagnosed and are at risk for disease progression, including a projected increase in the prevalence of advanced liver disease and incidence of HCC over the next two decades.

Achievement of viral eradication through antiviral therapy, defined by a sustained virologic response, can alter the natural history of chronic liver disease associated with HCV infection, including the potential for fibrosis regression, decreased risk for clinical decompensation or need for liver transplantation, decreased risk for HCC, and increased survival. Although these long-term benefits have been most clearly demonstrated in those with advanced liver disease, achievement of SVR can also have a major impact in those without cirrhosis, including a survival benefit and improvement in health-related quality of life.

Stevan A. Gonzalez

Efficacy of Current Therapy

Nine direct-acting antiviral (DAA) agents are now available in the U.S., either as single-drug formulations or in combination, with the anticipated release of additional agents in the near future. Although many regimens are ribavirin-free, the addition of ribavirin may be required to optimize virologic response and shorten duration of therapy, particularly in patients with advanced disease. Treatment options are now available for all HCV genotypes. Based on an ever-expanding body of evidence from prospective randomized controlled trials, SVR can be achieved in well over 90% of treatment candidates, including many populations that are historically difficult to treat. In addition, reports from large-scale, real-world databases such as HCV Target and the TRIO network have described similar efficacy to clinical trials. However, patients who are prior treatment failures and those with cirrhosis or advanced disease may still experience lower response rates and may require the addition of ribavirin or longer duration of therapy. In particular, challenges remain in those with decompensated cirrhosis, in which recent data suggest a decline in efficacy compared with clinically compensated cirrhosis and the safety of DAA therapy in this population has yet to be fully established.

 

Defining Eradication, Durability

As the HCV life cycle does not involve an intranuclear component and the virus does not integrate itself into the host genome, HCV can be eradicated with antiviral therapy. Achievement of eradication is heralded by the achievement of SVR, initially defined by undetectable serum HCV RNA 24 weeks after completion of therapy (SVR24). However, SVR has been redefined in the era of DAA therapy, in which undetectable serum HCV RNA at 12 weeks following completion of therapy (SVR12) was found to have a very high concordance with SVR24, allowing for its use as a clinical endpoint in registration trials of emerging DAA regimens. Large-scale analyses involving patients enrolled in clinical trials of interferon-based, and more recently DAA-based therapy, have reported concordance of SVR12 with SVR24 of greater than 99%. Consequently, SVR12 is now considered a reliable endpoint of DAA therapy in clinical practice.

The durability of SVR is well established. Several large-scale long-term follow up studies involving cohorts treated with interferon-based therapy have reported durability of SVR in over 99% of patients. Reports describing follow-up of patients who achieved SVR in the earliest trials of interferon-based therapy have documented durability of SVR up to 18 years following completion of therapy. In light of these data, clinicians can have confidence that eradication of HCV is possible with antiviral therapy and that achievement of SVR is equivalent to a long-term cure.

PAGE BREAK

Potential for Fibrosis Regression

The regenerative capacity of the liver is well known, including the observation that regression of fibrosis can occur following resolution of chronic liver disease states such as HCV infection. In patients with chronic HCV who achieve viral eradication, fibrosis regression can occur, even in those with cirrhosis. Several long-term follow-up studies with paired liver biopsy data primarily from the era of interferon-based therapy have demonstrated decreases in fibrosis stage in a significant proportion of patients who experience SVR. These studies have reported regression from liver biopsy METAVIR fibrosis stage F4 to at least stage F3 in over one-half of patients in some cohorts (Figure 1). Although the histologic fibrosis stage did not decrease in all patients involved in these studies, a significant reduction in hepatic collagen content may occur in the majority of patients. As more accurate noninvasive methods to estimate liver fibrosis have become available, such as transient elastography, improvements in degree of fibrosis following SVR can be more easily assessed. Although recent reports utilizing elastography are limited and appear to vary substantially, we anticipate that more data demonstrating regression of fibrosis following SVR will emerge in the DAA era.

Risk Reduction

The greatest impact associated with SVR can be seen in the diminished risk for events over time, including clinical decompensation, incidence of HCC, need for liver transplantation and mortality. Based on large prospective cohort studies, it is now well established that chronic infection with HCV is associated with an increase in liver-related, as well as non–liver-related, mortality compared with noninfected individuals, which can be seen across all stages of HCV-associated liver disease. In patients who successfully undergo antiviral therapy and achieve SVR, a significant reduction in all-cause mortality can be seen. A recent comprehensive review and meta-analysis of 31 studies involving greater than 30,000 patients evaluated the 5-year all-cause mortality risk in a general population with chronic HCV infection, patients with cirrhosis and those with HIV/HCV co-infection. Individuals who achieved SVR benefited from a significant reduction in mortality with a protective effect observed in all groups after adjustment for potential covariates (see Table). Additional reports from large-scale cohorts and meta-analyses have described a decline in all-cause mortality following SVR in all stages of hepatic fibrosis, independent of comorbidities and other risk factors including HCV genotype. Achievement of SVR may also have a positive impact on non–liver-related mortality, as well as events related to cardiovascular disease, kidney disease, diabetes, malignancy and health-related quality of life. Successful treatment of recurrent HCV infection following liver transplantation also improves patient and allograft survival.

 

The impact of SVR appears to be greatest in those with advanced liver disease. Individuals with cirrhosis or advanced fibrosis who achieve long-term viral clearance after completion of therapy demonstrate a much greater absolute risk reduction and decline in incidence of various endpoints, including clinical decompensation, HCC and liver-related mortality. Several retrospective and prospective studies over the last decade involving cohorts with compensated cirrhosis have consistently demonstrated a reduction in liver-related morbidity and mortality associated with SVR in this population. One of the largest long-term cohort follow-up studies to evaluate all-cause mortality as a clinical endpoint in this population included 530 patients with advanced fibrosis. In this cohort, the mortality risk was fourfold lower in those with SVR vs. patients in which therapy was unsuccessful, in addition to decreases in risk for liver-related mortality or need for liver transplantation, HCC and clinical decompensation (Figure 2). A follow-up analysis to this study revealed that once SVR was achieved in these patients with advanced fibrosis, no difference in survival was seen in comparison with non-HCV age- and sex-matched controls. Although these studies have reported a decline in risk for HCC in cirrhotics who achieve SVR, this risk is not entirely eliminated. Consequently, all patients with cirrhosis should be maintained on a long-term surveillance program after SVR.

PAGE BREAK

Treatment Strategies in Advanced Disease

It is clear that all individuals with chronic HCV infection can benefit from achievement of SVR and eradication of the virus; however, it is apparent that patients with cirrhosis may have the most to gain. Despite this, the development of the optimal treatment strategy in those with decompensated cirrhosis or those who are liver transplant candidates remains elusive. Several randomized controlled trials of DAA regimens have included patients with decompensated cirrhosis, all of which have consistently demonstrated achievement of SVR in the majority of patients treated; however, virologic response is comparatively lower in this population.

Data presented from the SOLAR-1 and SOLAR-2 trials evaluating sofosbuvir and ledipasvir (Harvoni, Gilead Sciences) plus ribavirin for 12 weeks in patients with genotype 1 and 4 noted SVR rates of 87% and up to 86% in patients with Child-Turcotte-Pugh (CTP) classification of B and C, respectively, in which extension of therapy to 24 weeks did not improve efficacy. The ALLY-1 trial evaluated sofosbuvir (Sovaldi, Gilead Sciences) daclatasvir (Daklinza, Bristol-Myers Squibb) and ribavirin for 12 weeks in patients with genotypes 1 to 4 with decompensated cirrhosis and reported an SVR of 94% in patients with CTP class B; however, SVR declined to 56% in those with CTP class C. Similar efficacy was reported in a real world setting through the NHS England early access program in which an SVR of greater than 80% was observed in genotype 1 patients with clinical decompensation utilizing regimens of sofosbuvir/ledipasvir or sofosbuvir and daclatasvir with ribavirin. However, SVR was reported in only 70% with genotype 3 infection. A question is whether combinations of multiple DAA agents may improve efficacy in this challenging population, as suggested by results from the IMPACT study involving the ribavirin-free combination of simeprevir (Olysio, Janssen), sofosbuvir and daclatasvir for 12 weeks, in which SVR was reported in 100% of patients who received this regimen.

Despite promising reports of efficacy, safety concerns exist in the setting of decompensated cirrhosis, particularly in regimens requiring ribavirin, as tolerability may be diminished substantially and patients frequently require dose reductions, blood transfusions and even discontinuation of ribavirin. In addition, deaths have been reported while on therapy. Although the small number of deaths that have occurred in the setting of clinical trials involving decompensated cirrhosis could not be attributed directly to therapy, it is clear that caution should be taken in this population. The regimen of ombitasvir, parataprevir/ritonavir, and dasabuvir (Viekira Pak, AbbVie) is now contraindicated in the setting of decompensated cirrhosis, and simeprevir-based regimens are not recommended according to the AASLD/IDSA guidelines for HCV therapy.

 

In patients with decompensated HCV cirrhosis who are awaiting liver transplantation, a successful course of antiviral therapy can significantly improve laboratory parameters including bilirubin and albumin as well as the MELD score, which may decline in up to 70% of patients. It remains to be seen whether this incremental benefit associated with SVR will translate into a significant recovery of liver function in some individuals or rather compromise a person’s likelihood of undergoing liver transplantation due to the reduction in MELD score. As a result, some liver transplant candidates may be left untreated, particularly those with high MELD scores; however, a debate exists regarding this strategy. The decision on whether or not to withhold therapy in this setting and at what threshold of MELD score is individualized and may vary greatly based on local practices, organ availability in the region relative to an individual’s MELD score and the use of HCV-positive organs.

It is encouraging that recent data have emerged suggesting that a reduction in portal hypertension can occur following SVR based on decreases in measured hepatic venous pressure gradient, improved platelet counts and decreased spleen size. Ultimately, patients who undergo liver transplantation can benefit greatly from antiviral therapy, in which maintaining viral clearance for at least 4 weeks prior to transplantation can prevent post-transplant recurrence in over 95% of patients. Alternatively, antiviral therapy is also effective after liver transplantation, including cases of severe recurrence and fibrosing cholestatic HCV.

PAGE BREAK

Challenges Ahead

Our ability to achieve eradication of HCV on an individual basis and on a large scale continues to improve as more effective DAA therapy becomes available; however, challenges remain. Despite a renewed emphasis on screening and diagnosis of individuals at risk for HCV infection, we are confronted with a majority of infected individuals who remain undiagnosed. As this population is projected to progress towards advanced liver disease in the years ahead, treating even a modest proportion of patients now could reduce the burden of liver failure and liver-related death substantially. Although initiating treatment with the goal of achieving SVR is cost effective, challenges exist in providing access to care and treatment in many patients who have been diagnosed with chronic HCV infection.

Although questions remain regarding the appropriate treatment strategy for patients with decompensated liver disease and those awaiting liver transplantation, it is clear that achievement of SVR is beneficial to virtually all patients. As more patients achieve this endpoint, we must also be attentive to which individuals will require ongoing surveillance after SVR, including surveillance for HCC in those with cirrhosis and managing comorbidities that could influence fibrosis progression such as fatty liver disease and obesity. Ultimately a greater understanding of these potential cofactors will be important in optimizing long-term outcomes and preserving the benefits of viral eradication.

Disclosure: Gonzalez reports consulting for AbbVie. He also reports being on the speaker’s bureau for AbbVie, Gilead Sciences and Merck.