The Big Picture

Staying Current on HCV: A Summary of Recent Updates to the Guidelines

The rapid evolution of highly effective, curative therapies for hepatitis C virus infection, establishment of new HCV screening practice guidelines, and rising rates of HCV-related complications have prompted the need for updated, evidence-based and expert-developed recommendations for practitioners managing HCV.

Sujit Janardhan

Sujit V. Janardhan

Nancy S Reau

Nancy S. Reau

As a result, the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and the International Antiviral Society–USA (IAS-USA) have developed a comprehensive set of recommendations regarding HCV management (the guidance).

The Web-based format of the guidance allows rapid formulation and dissemination of information and recommendations. Reflecting the rapidly changing HCV landscape, guidance recommendations are continually updated to reflect current best practice. Significant updates to sections involving initial treatment, re-treatment, monitoring and management of unique HCV populations were made in late 2014 to reflect newly available therapies, changes in management philosophies and treatment-related data. The purpose of this article is to highlight several of these updates, focusing on the most recent changes occurring in late 2014. This article is not intended to summarize any given section of the guidance and the reader is directed to the Web-based guidance (available at www.hcvguidelines.org) for details regarding any particular recommendation.

The first iteration of the guidance (published online Jan. 29, 2014) included sections that discussed: “Screening and Linkage to Care,” “Initial Treatment of HCV Infection,” “Retreatment of Persons in Whom Prior Therapy Has Failed” and management of “Unique Patient Populations.” Since initial publication, the original sections have been revised and new sections have been added including: “When and in Whom to Initiate Therapy,” “Monitoring Patients Who Are Starting HCV Treatment, Are on Treatment, or Have Completed Therapy” and “Management of Acute HCV Infection.”

A Living Document

Given the constant evolution of HCV therapies in various stages of development and the growing body of literature describing the use of these agents in “real-world settings” and/or special populations, the guidance is, by necessity, a “living document” that is expected to change as knowledge matures. Therefore, although the guidance also is available as a printable document, practitioners must be aware that “static” forms may not reflect the current version. For this reason, practitioners are encouraged to frequently access the Web-based version for the most up-to-date recommendations and commentary.

When and in Whom to Treat

When the guidance was initially released, the recommended treatment regimens for most HCV genotypes (other than genotypes 2 and 3) still required interferon use, including those containing newly FDA-approved direct-acting antiviral agents (DAAs), simeprevir (Olysio, Janssen Therapeutics) and sofosbuvir (Sovaldi, Gilead Sciences). An all-oral, interferon-free regimen using both of these DAAs in combination had promising results for HCV genotype 1, but was only supported by a small phase 2 trial (at the time) and was, therefore, only listed as an alternative treatment regimen for genotype 1.

Because of known interferon-related adverse effects, the “When and in Whom to Initiate Therapy” section of the guidance prioritized interferon-based therapies to only those patients who were at high risk of disease-related complications and, therefore, could not wait for approval of expected all-oral regimens. When multiple all-oral regimens were approved by the FDA for genotype 1 in late 2014 (with impressive clinical results for other genotypes as well), this section was altered to reflect that these new therapies could benefit almost all chronically HCV-infected individuals, and that urgent therapy was required in certain populations. Specifically, the guidance states that, “Successful hepatitis C treatment results in sustained virologic response (SVR), which is tantamount to virologic cure, and as such, is expected to benefit nearly all chronically infected persons. Evidence clearly supports treatment in all HCV-infected persons, except those with limited life expectancy (less than 12 months) due to non–liver-related comorbid conditions. … Urgent initiation of treatment is recommended for some patients.”

The guidance supports these statements by citing literature that highlights the durable nature of SVR and the numerous health benefits derived from virologic cure, including improved health-related quality of life, reduced progression and (in some cases) regression of liver fibrosis or cirrhosis, reduced risk for liver malignancy, reduced clinical manifestations of liver disease (eg, portal hypertension), reduced/resolved extrahepatic manifestation of HCV (eg, cryoglobulinemic vasculitis and lymphoma), reduced need for liver transplantation and reduced liver-related and all-cause mortality. Given these benefits, treatment of all chronically infected individuals is a class I, level A recommendation (See the guidance for explanation of levels of evidence and strength of recommendations).

The ability to treat HCV-infected individuals is limited by resources available to the health care system. This includes not only financial resources for high-cost HCV medications, but also workforce resources provided by a relatively small pool of clinical and administrative staff with experience in selecting, procuring and administering these medications to specific HCV-infected populations. Given this, the guidance recognizes the need to prioritize therapy to those individuals expected to derive the most immediate benefit. As such, HCV-infected populations are grouped into those with the “Highest Priority for Treatment Owing to Highest Risk for Severe Complications” and those with “High Priority for Treatment Owing to High Risk for Complications.”

The guidance recommends immediate therapy for patients with highest priority (class I, level A) and as resources are available, immediate therapy to patients with high priority (varying levels of evidence and strength of recommendation). A recent re-analysis of data from the Chronic Hepatitis Cohort Study (CHeCS) suggests that these two patient populations account for approximately 60% of the total HCV-infected population.

The guidance also notes that prioritization of therapy should be considered for a special population of “Persons at Elevated Risk of HCV Transmission and in Whom HCV Treatment May Yield Transmission Reduction Benefits” (class IIa, level C). Treatment of this population is advocated due to the public health benefit that can be achieved by preventing the ongoing spread of viral infection. This recommendation is supported by modeling data demonstrating that even a modest increase in the rate at which injection drug users are successfully treated can decrease overall HCV prevalence and incidence, and that this effect is amplified as more of the population is cured.

Populations identified to be at elevated risk for transmission in previous versions of the guidance included men who have high-risk sexual practices with other men, active injection drug users, incarcerated persons and those on long-term hemodialysis. The recent update added “HCV-infected women of childbearing potential wishing to get pregnant” to this group. This is based on the ability to prevent vertical transmission of HCV to the fetus if the mother is cured and the lack of safety and efficacy data of available therapies in pregnant women.

Recommended Treatment Regimens

Treatment recommendations are based on HCV genotype, clinical context (initial treatment vs. re-treatment, no cirrhosis vs. compensated cirrhosis vs. decompensated cirrhosis, postliver transplant, HIV coinfection, renal insufficiency). To maximize therapeutic flexibility, treatment algorithms are listed as “Recommended” or “Alternative” and several regimens with similar efficacy may be listed (in alphabetical order) under each section.

In late 2014, the FDA approved the combined use of two previously approved DAAs: simeprevir and sofosbuvir, as well as a new two-drug combination of ledipasvir and sofosbuvir (Harvoni, Gilead Sciences) and a new three-drug combination of paritaprevir/ritonavir, ombitasvir and dasabuvir (Viekira Pak, AbbVie), to be used with or without ribavirin for treating HCV. These approvals provided three all-oral treatment options for the majority of patients infected with HCV. This obviously resulted in extensive changes to recommended and alternative HCV treatment regimens. The recommendation for an all-oral treatment regimen was extended to all HCV genotypes other than genotype 5 (a new recommendation for genotypes 1, 4, and 6, with sofosbuvir and ribavirin having been approved previously for genotypes 2 and 3) regardless of previous treatment, presence of cirrhosis (compensated or decompensated), HIV coinfection, or recurrent infection after liver transplant.

With all-oral therapies taking the main stage, interferon use was marginalized in the updated guidance. It remains part of the recommended regimen for genotype 5 (due to insufficient data to support the use of an all-oral regimen) and part of alternative regimens to shorten treatment duration or provide alternative treatment regimens for other genotypes (3-6). Importantly, the combination of simeprevir and interferon, as well as previously approved protease inhibitors telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck), were no longer part of any recommended or alternative treatment recommendation.

Known interactions between HCV therapies and commonly used medications (provided in table form on the guidelines website), as well as pretreatment, on-treatment and post-treatment monitoring guidelines, also were updated to reflect the new regimens.

Another important change to the treatment recommendations was that all patients who had previously failed interferon-based therapy were treated with the same regimen, regardless of whether the previous treatment failure was due to nonresponse, partial response or relapse. The rationale behind this change was the difficulty in accurately characterizing previous treatment failures and that the studies supporting these new therapies did not distinguish between different types of “treatment-experienced” individuals.

The updated guidance also provides support for the management of patients whose genotyping assays reveal a mixed infection with multiple genotypes. The guidance notes sparse data regarding therapeutic efficacy in this rare population, but suggests that the choice and duration of therapy be tailored to “maximize efficacy against each genotype represented in the assay,” and that expert consultation be sought when the correct combination or duration is not clear.

Several changes also were made to address treatment of unique HCV-infected populations with newly approved therapies. The guidance notes that that “HIV/HCV coinfected persons should be treated and re-treated the same as persons without HIV infection, after recognizing and managing interactions with antiretroviral medications.” To facilitate management of these interactions, the guidance provides a detailed explanation of which antiretroviral agents can be used safely with various anti-HCV agents, which should be avoided, and which should be used with caution.

Recommendations for patients with decompensated cirrhosis also were updated to note that treatment of this population should be done by practitioners with expertise in managing decompensated liver disease and, ideally, should occur at a transplant center. Nonetheless, updated treatment data and recommendations were provided for all patients with decompensated cirrhosis who were infected with genotypes 1 to 4, including those who were treatment-naive or -experienced, and those with infection in the native or transplanted liver.

Guidance also was provided for administering new therapies to patients with renal dysfunction. For patients with mild to moderate renal impairment (creatinine clearance [CrCl] > 30 mL/min), no dose adjustment was recommended for sofosbuvir, simeprevir, ledipasvir/sofosbuvir or paritaprevir/ritonavir/ombitasvir plus dasabuvir. However, expert consultation was recommended for patients with CrCl less than 30 mL/min, as safety and efficacy data are not available for this population. It should be noted, however, that the package insert for paritaprevir/ritonavir/ombitasvir plus dasabuvir reports that this medication can be provided to patients with CrCl as low as 15 mL/min, but not to patients on dialysis.

Conclusion

The availability of highly effective new therapies against hepatitis C represents an exciting time for patients infected with hepatitis C and the practitioners that manage their care. However, practitioners must have an efficient avenue by which they can remain “up to date” on therapeutic practices that are evidence-based and expert-generated. The online availability of the joint AASLD/IDSA/IAS-USA HCV guidance statements plays an invaluable role in disseminating such recommendations in a timely way. However, to be most effective, practitioners will need to be cognizant of rapid changes to these recommendations and will need to continually update their knowledge base with the information provided therein.

References:
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. Available at: www.hcvguidelines.org. Accessed Feb. 6, 2015.
Xu, F, et al. Abstract LB-29. Presented at: American Association for the Study of Liver Diseases (AASLD) Liver Meeting; Nov. 7-12, 2014; Boston.
For more information:
Nancy S. Reau, MD, is an associate professor of medicine at The University of Chicago Medical Center. She can be reached at 5841 S. Maryland Ave., MC 7120, Chicago, IL 60637. Email: NReau@medicine.bsd.uchicago.edu.
Sujit V. Janardhan, MD, PhD, is a clinical instructor of medicine at the University of Chicago Medical Center and can be reached at 5841 S. Maryland Ave., MC 4076, Chicago, IL 60637. Email: Sujit.Janardhan@uchospitals.edu.

Disclosures: Janardhan reports no relevant financial disclosures. Reau reports financial relationships with Abbott Laboratories, AbbVie, Accordant, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Hyperion Therapeutics and Merck.

The rapid evolution of highly effective, curative therapies for hepatitis C virus infection, establishment of new HCV screening practice guidelines, and rising rates of HCV-related complications have prompted the need for updated, evidence-based and expert-developed recommendations for practitioners managing HCV.

Sujit Janardhan

Sujit V. Janardhan

Nancy S Reau

Nancy S. Reau

As a result, the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and the International Antiviral Society–USA (IAS-USA) have developed a comprehensive set of recommendations regarding HCV management (the guidance).

The Web-based format of the guidance allows rapid formulation and dissemination of information and recommendations. Reflecting the rapidly changing HCV landscape, guidance recommendations are continually updated to reflect current best practice. Significant updates to sections involving initial treatment, re-treatment, monitoring and management of unique HCV populations were made in late 2014 to reflect newly available therapies, changes in management philosophies and treatment-related data. The purpose of this article is to highlight several of these updates, focusing on the most recent changes occurring in late 2014. This article is not intended to summarize any given section of the guidance and the reader is directed to the Web-based guidance (available at www.hcvguidelines.org) for details regarding any particular recommendation.

The first iteration of the guidance (published online Jan. 29, 2014) included sections that discussed: “Screening and Linkage to Care,” “Initial Treatment of HCV Infection,” “Retreatment of Persons in Whom Prior Therapy Has Failed” and management of “Unique Patient Populations.” Since initial publication, the original sections have been revised and new sections have been added including: “When and in Whom to Initiate Therapy,” “Monitoring Patients Who Are Starting HCV Treatment, Are on Treatment, or Have Completed Therapy” and “Management of Acute HCV Infection.”

A Living Document

Given the constant evolution of HCV therapies in various stages of development and the growing body of literature describing the use of these agents in “real-world settings” and/or special populations, the guidance is, by necessity, a “living document” that is expected to change as knowledge matures. Therefore, although the guidance also is available as a printable document, practitioners must be aware that “static” forms may not reflect the current version. For this reason, practitioners are encouraged to frequently access the Web-based version for the most up-to-date recommendations and commentary.

When and in Whom to Treat

When the guidance was initially released, the recommended treatment regimens for most HCV genotypes (other than genotypes 2 and 3) still required interferon use, including those containing newly FDA-approved direct-acting antiviral agents (DAAs), simeprevir (Olysio, Janssen Therapeutics) and sofosbuvir (Sovaldi, Gilead Sciences). An all-oral, interferon-free regimen using both of these DAAs in combination had promising results for HCV genotype 1, but was only supported by a small phase 2 trial (at the time) and was, therefore, only listed as an alternative treatment regimen for genotype 1.

Because of known interferon-related adverse effects, the “When and in Whom to Initiate Therapy” section of the guidance prioritized interferon-based therapies to only those patients who were at high risk of disease-related complications and, therefore, could not wait for approval of expected all-oral regimens. When multiple all-oral regimens were approved by the FDA for genotype 1 in late 2014 (with impressive clinical results for other genotypes as well), this section was altered to reflect that these new therapies could benefit almost all chronically HCV-infected individuals, and that urgent therapy was required in certain populations. Specifically, the guidance states that, “Successful hepatitis C treatment results in sustained virologic response (SVR), which is tantamount to virologic cure, and as such, is expected to benefit nearly all chronically infected persons. Evidence clearly supports treatment in all HCV-infected persons, except those with limited life expectancy (less than 12 months) due to non–liver-related comorbid conditions. … Urgent initiation of treatment is recommended for some patients.”

PAGE BREAK

The guidance supports these statements by citing literature that highlights the durable nature of SVR and the numerous health benefits derived from virologic cure, including improved health-related quality of life, reduced progression and (in some cases) regression of liver fibrosis or cirrhosis, reduced risk for liver malignancy, reduced clinical manifestations of liver disease (eg, portal hypertension), reduced/resolved extrahepatic manifestation of HCV (eg, cryoglobulinemic vasculitis and lymphoma), reduced need for liver transplantation and reduced liver-related and all-cause mortality. Given these benefits, treatment of all chronically infected individuals is a class I, level A recommendation (See the guidance for explanation of levels of evidence and strength of recommendations).

The ability to treat HCV-infected individuals is limited by resources available to the health care system. This includes not only financial resources for high-cost HCV medications, but also workforce resources provided by a relatively small pool of clinical and administrative staff with experience in selecting, procuring and administering these medications to specific HCV-infected populations. Given this, the guidance recognizes the need to prioritize therapy to those individuals expected to derive the most immediate benefit. As such, HCV-infected populations are grouped into those with the “Highest Priority for Treatment Owing to Highest Risk for Severe Complications” and those with “High Priority for Treatment Owing to High Risk for Complications.”

The guidance recommends immediate therapy for patients with highest priority (class I, level A) and as resources are available, immediate therapy to patients with high priority (varying levels of evidence and strength of recommendation). A recent re-analysis of data from the Chronic Hepatitis Cohort Study (CHeCS) suggests that these two patient populations account for approximately 60% of the total HCV-infected population.

The guidance also notes that prioritization of therapy should be considered for a special population of “Persons at Elevated Risk of HCV Transmission and in Whom HCV Treatment May Yield Transmission Reduction Benefits” (class IIa, level C). Treatment of this population is advocated due to the public health benefit that can be achieved by preventing the ongoing spread of viral infection. This recommendation is supported by modeling data demonstrating that even a modest increase in the rate at which injection drug users are successfully treated can decrease overall HCV prevalence and incidence, and that this effect is amplified as more of the population is cured.

Populations identified to be at elevated risk for transmission in previous versions of the guidance included men who have high-risk sexual practices with other men, active injection drug users, incarcerated persons and those on long-term hemodialysis. The recent update added “HCV-infected women of childbearing potential wishing to get pregnant” to this group. This is based on the ability to prevent vertical transmission of HCV to the fetus if the mother is cured and the lack of safety and efficacy data of available therapies in pregnant women.

Recommended Treatment Regimens

Treatment recommendations are based on HCV genotype, clinical context (initial treatment vs. re-treatment, no cirrhosis vs. compensated cirrhosis vs. decompensated cirrhosis, postliver transplant, HIV coinfection, renal insufficiency). To maximize therapeutic flexibility, treatment algorithms are listed as “Recommended” or “Alternative” and several regimens with similar efficacy may be listed (in alphabetical order) under each section.

In late 2014, the FDA approved the combined use of two previously approved DAAs: simeprevir and sofosbuvir, as well as a new two-drug combination of ledipasvir and sofosbuvir (Harvoni, Gilead Sciences) and a new three-drug combination of paritaprevir/ritonavir, ombitasvir and dasabuvir (Viekira Pak, AbbVie), to be used with or without ribavirin for treating HCV. These approvals provided three all-oral treatment options for the majority of patients infected with HCV. This obviously resulted in extensive changes to recommended and alternative HCV treatment regimens. The recommendation for an all-oral treatment regimen was extended to all HCV genotypes other than genotype 5 (a new recommendation for genotypes 1, 4, and 6, with sofosbuvir and ribavirin having been approved previously for genotypes 2 and 3) regardless of previous treatment, presence of cirrhosis (compensated or decompensated), HIV coinfection, or recurrent infection after liver transplant.

PAGE BREAK

With all-oral therapies taking the main stage, interferon use was marginalized in the updated guidance. It remains part of the recommended regimen for genotype 5 (due to insufficient data to support the use of an all-oral regimen) and part of alternative regimens to shorten treatment duration or provide alternative treatment regimens for other genotypes (3-6). Importantly, the combination of simeprevir and interferon, as well as previously approved protease inhibitors telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck), were no longer part of any recommended or alternative treatment recommendation.

Known interactions between HCV therapies and commonly used medications (provided in table form on the guidelines website), as well as pretreatment, on-treatment and post-treatment monitoring guidelines, also were updated to reflect the new regimens.

Another important change to the treatment recommendations was that all patients who had previously failed interferon-based therapy were treated with the same regimen, regardless of whether the previous treatment failure was due to nonresponse, partial response or relapse. The rationale behind this change was the difficulty in accurately characterizing previous treatment failures and that the studies supporting these new therapies did not distinguish between different types of “treatment-experienced” individuals.

The updated guidance also provides support for the management of patients whose genotyping assays reveal a mixed infection with multiple genotypes. The guidance notes sparse data regarding therapeutic efficacy in this rare population, but suggests that the choice and duration of therapy be tailored to “maximize efficacy against each genotype represented in the assay,” and that expert consultation be sought when the correct combination or duration is not clear.

Several changes also were made to address treatment of unique HCV-infected populations with newly approved therapies. The guidance notes that that “HIV/HCV coinfected persons should be treated and re-treated the same as persons without HIV infection, after recognizing and managing interactions with antiretroviral medications.” To facilitate management of these interactions, the guidance provides a detailed explanation of which antiretroviral agents can be used safely with various anti-HCV agents, which should be avoided, and which should be used with caution.

Recommendations for patients with decompensated cirrhosis also were updated to note that treatment of this population should be done by practitioners with expertise in managing decompensated liver disease and, ideally, should occur at a transplant center. Nonetheless, updated treatment data and recommendations were provided for all patients with decompensated cirrhosis who were infected with genotypes 1 to 4, including those who were treatment-naive or -experienced, and those with infection in the native or transplanted liver.

Guidance also was provided for administering new therapies to patients with renal dysfunction. For patients with mild to moderate renal impairment (creatinine clearance [CrCl] > 30 mL/min), no dose adjustment was recommended for sofosbuvir, simeprevir, ledipasvir/sofosbuvir or paritaprevir/ritonavir/ombitasvir plus dasabuvir. However, expert consultation was recommended for patients with CrCl less than 30 mL/min, as safety and efficacy data are not available for this population. It should be noted, however, that the package insert for paritaprevir/ritonavir/ombitasvir plus dasabuvir reports that this medication can be provided to patients with CrCl as low as 15 mL/min, but not to patients on dialysis.

Conclusion

The availability of highly effective new therapies against hepatitis C represents an exciting time for patients infected with hepatitis C and the practitioners that manage their care. However, practitioners must have an efficient avenue by which they can remain “up to date” on therapeutic practices that are evidence-based and expert-generated. The online availability of the joint AASLD/IDSA/IAS-USA HCV guidance statements plays an invaluable role in disseminating such recommendations in a timely way. However, to be most effective, practitioners will need to be cognizant of rapid changes to these recommendations and will need to continually update their knowledge base with the information provided therein.

References:
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. Available at: www.hcvguidelines.org. Accessed Feb. 6, 2015.
Xu, F, et al. Abstract LB-29. Presented at: American Association for the Study of Liver Diseases (AASLD) Liver Meeting; Nov. 7-12, 2014; Boston.
For more information:
Nancy S. Reau, MD, is an associate professor of medicine at The University of Chicago Medical Center. She can be reached at 5841 S. Maryland Ave., MC 7120, Chicago, IL 60637. Email: NReau@medicine.bsd.uchicago.edu.
Sujit V. Janardhan, MD, PhD, is a clinical instructor of medicine at the University of Chicago Medical Center and can be reached at 5841 S. Maryland Ave., MC 4076, Chicago, IL 60637. Email: Sujit.Janardhan@uchospitals.edu.

Disclosures: Janardhan reports no relevant financial disclosures. Reau reports financial relationships with Abbott Laboratories, AbbVie, Accordant, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Hyperion Therapeutics and Merck.