Nancy S. Reau, MD

Prior to 2013, the backbone of hepatitis C virus (HCV) therapy was pegylated interferon (PEG) in combination with ribavirin (RBV). This year-long therapy was associated with significant side effects and abysmal cure rates. Although efficacy improved with the addition of first-generation protease inhibitors, cure rates remained suboptimal and treatment side effects continued to be significant.

Clinicians and patients needed better options and looked to the drug pipeline with hope. However, even among the most optimistic, the idea that HCV therapy could evolve into an all-oral option seemed a relative pipe dream.

The Sofosbuvir Revolution Begins

The Liver Meeting held in 2013 changed everything.

Several presentations featured compelling data with sofosbuvir, a new polymerase inhibitor that, when combined with RBV, offered an all-oral option to patients with genotypes 2 and 3, as well as improved efficacy for patients with genotypes 1, 4, 5, and 6 when it was combined with 12 weeks of PEG/RBV.

However, the glass ceiling of HCV care was truly shattered with the randomized COSMOS trial, a late-breaker abstract that revealed 12-week functional cure rates in patients receiving sofosbuvir in combination with the protease inhibitor simeprevir.

This phase 2a trial in treatment-naive and -experienced genotype 1 patients with and without cirrhosis showed that an all-oral option was not only viable for the most common strain of HCV but was also safe and efficacious, even in difficult-to-treat populations.

On December 6, 2013, the US Food and Drug Administration (FDA) approved sofosbuvir for the treatment of HCV, ushering in a new era of therapy.

Guidelines quickly changed to advocate for both expansive HCV screening and generous treatment. Yet, as this more permissive approach was being recommended, the high price tag and large anticipated volume of those seeking prescriptions were setting off alarms. The drug cost triggered extensive restrictions based on degree of fibrosis, sobriety, and provider type in an effort to prevent immediate healthcare expenditures.

Given its high cost, rules restricting a patient to only one course of sofosbuvir-based therapy also surfaced. Although treatment with first-generation protease inhibitors carried a hefty price of $161,813.49 per sustained virologic response (SVR), compared with $66,000-$100,000 for 12 weeks of all-oral therapy, its uptake was low and limited by side effects and comorbid conditions. All-oral treatment appeared to have few medical barriers, leading payers to find ways to slow utilization. These restrictions are now gradually being eliminated.

Because of high SVR rates and few contraindications to therapy, most patients who gained access to treatment achieved cure. This included patients who had previously not responded to treatment and prioritized those with more advanced disease.

This quickly led to a significant shift in the population in need of treatment. Prior to 2013, many patients with HCV had advanced disease and did not respond to prior treatment options. After uptake of all-oral therapy, individuals in need were typically treatment naive without advanced disease.

This shift also added new psychosocial dimensions, as many of the newly infected individuals were struggling with active substance abuse. HCV treatment providers needed to change, with increasing recruitment of advanced practice providers, primary care physicians, and addiction medication specialists.

Progress, but Far From Reaching Targets

Fast-forward to 2023.

Ten years after FDA approval, 13.2 million individuals infected with HCV have been treated globally, 82% with sofosbuvir-based regimens and most in lower-middle-income countries. This is absolutely cause for celebration, but not complacency.

In 2016, the World Health Assembly adopted a resolution of elimination of viral hepatitis by 2030. The World Health Organization (WHO) defined elimination of HCV as 90% reduction in new cases of infection, 90% diagnosis of those infected, 80% of eligible individuals treated, and 65% reduction of deaths by 2030.

Despite all the success thus far, the CDA Foundation estimates that the WHO elimination targets will not be achieved until after the year 2050. They also note that in 2020, over 50 million individuals were infected with HCV, of which only 20% were diagnosed and 1% annually treated.

The HCV care cascade, by which the patient journeys from screening to cure, is complicated, and a one-size-fits-all solution is not possible. Reflex testing (an automatic transition to HCV polymerase chain reaction [PCR] testing in the lab for those who are HCV antibody positive) has significantly improved diagnosis. However, communicating these results and linking a patient to curative therapy remain significant obstacles.

Models and real-life experience show that multiple strategies can be successful. They include leveraging the electronic medical record, simplified treatment algorithms, test-and-treat strategies (screening high-risk populations with a point-of-care test that allows treatment initiation at the same visit), and co-localizing HCV screening and treatment with addiction services and relinkage programs (finding those who are already diagnosed and linking them to treatment).

In addition, focusing on populations at high risk for HCV infection — such as people who inject drugs, men who have sex with men, and incarcerated individuals — allows for better resource utilization.

Though daunting, HCV elimination is not impossible. There are several examples of success, including in the countries of Georgia and Iceland. Although, comparatively, the United States remains behind the curve, the White House has asked Congress for $11 billion to fund HCV elimination domestically.

As we await action at the national level, clinicians are reminded that there are several things we can do in caring for patients with HCV:

• A one-time HCV screening is recommended in all individuals aged 18 or older, including pregnant people with each pregnancy.
• HCV antibody testing with reflex to PCR should be used as the screening test.
• Pan-genotypic all-oral therapy is recommended for patients with HCV. Cure rates are greater than 95%, and there are few contraindications to treatment.
• Most people are eligible for simplified treatment algorithms that allow minimal on-treatment monitoring.

Without increased screening and linkage to curative therapy, we will not meet the WHO goals for HCV elimination.

Dr. Reau is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to this news organization. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair of the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels. She disclosed ties with AbbVie, Gilead, Arbutus, Intercept, and Salix.

A version of this article appeared on Medscape.com.

Prior to 2013, the backbone of hepatitis C virus (HCV) therapy was pegylated interferon (PEG) in combination with ribavirin (RBV). This year-long therapy was associated with significant side effects and abysmal cure rates. Although efficacy improved with the addition of first-generation protease inhibitors, cure rates remained suboptimal and treatment side effects continued to be significant.

Clinicians and patients needed better options and looked to the drug pipeline with hope. However, even among the most optimistic, the idea that HCV therapy could evolve into an all-oral option seemed a relative pipe dream.

The Sofosbuvir Revolution Begins

The Liver Meeting held in 2013 changed everything.

Several presentations featured compelling data with sofosbuvir, a new polymerase inhibitor that, when combined with RBV, offered an all-oral option to patients with genotypes 2 and 3, as well as improved efficacy for patients with genotypes 1, 4, 5, and 6 when it was combined with 12 weeks of PEG/RBV.

However, the glass ceiling of HCV care was truly shattered with the randomized COSMOS trial, a late-breaker abstract that revealed 12-week functional cure rates in patients receiving sofosbuvir in combination with the protease inhibitor simeprevir.

This phase 2a trial in treatment-naive and -experienced genotype 1 patients with and without cirrhosis showed that an all-oral option was not only viable for the most common strain of HCV but was also safe and efficacious, even in difficult-to-treat populations.

On December 6, 2013, the US Food and Drug Administration (FDA) approved sofosbuvir for the treatment of HCV, ushering in a new era of therapy.

Guidelines quickly changed to advocate for both expansive HCV screening and generous treatment. Yet, as this more permissive approach was being recommended, the high price tag and large anticipated volume of those seeking prescriptions were setting off alarms. The drug cost triggered extensive restrictions based on degree of fibrosis, sobriety, and provider type in an effort to prevent immediate healthcare expenditures.

Given its high cost, rules restricting a patient to only one course of sofosbuvir-based therapy also surfaced. Although treatment with first-generation protease inhibitors carried a hefty price of $161,813.49 per sustained virologic response (SVR), compared with $66,000-$100,000 for 12 weeks of all-oral therapy, its uptake was low and limited by side effects and comorbid conditions. All-oral treatment appeared to have few medical barriers, leading payers to find ways to slow utilization. These restrictions are now gradually being eliminated.

Because of high SVR rates and few contraindications to therapy, most patients who gained access to treatment achieved cure. This included patients who had previously not responded to treatment and prioritized those with more advanced disease.

This quickly led to a significant shift in the population in need of treatment. Prior to 2013, many patients with HCV had advanced disease and did not respond to prior treatment options. After uptake of all-oral therapy, individuals in need were typically treatment naive without advanced disease.

This shift also added new psychosocial dimensions, as many of the newly infected individuals were struggling with active substance abuse. HCV treatment providers needed to change, with increasing recruitment of advanced practice providers, primary care physicians, and addiction medication specialists.

Progress, but Far From Reaching Targets

Fast-forward to 2023.

Ten years after FDA approval, 13.2 million individuals infected with HCV have been treated globally, 82% with sofosbuvir-based regimens and most in lower-middle-income countries. This is absolutely cause for celebration, but not complacency.

In 2016, the World Health Assembly adopted a resolution of elimination of viral hepatitis by 2030. The World Health Organization (WHO) defined elimination of HCV as 90% reduction in new cases of infection, 90% diagnosis of those infected, 80% of eligible individuals treated, and 65% reduction of deaths by 2030.

Despite all the success thus far, the CDA Foundation estimates that the WHO elimination targets will not be achieved until after the year 2050. They also note that in 2020, over 50 million individuals were infected with HCV, of which only 20% were diagnosed and 1% annually treated.

The HCV care cascade, by which the patient journeys from screening to cure, is complicated, and a one-size-fits-all solution is not possible. Reflex testing (an automatic transition to HCV polymerase chain reaction [PCR] testing in the lab for those who are HCV antibody positive) has significantly improved diagnosis. However, communicating these results and linking a patient to curative therapy remain significant obstacles.

Models and real-life experience show that multiple strategies can be successful. They include leveraging the electronic medical record, simplified treatment algorithms, test-and-treat strategies (screening high-risk populations with a point-of-care test that allows treatment initiation at the same visit), and co-localizing HCV screening and treatment with addiction services and relinkage programs (finding those who are already diagnosed and linking them to treatment).

In addition, focusing on populations at high risk for HCV infection — such as people who inject drugs, men who have sex with men, and incarcerated individuals — allows for better resource utilization.

Though daunting, HCV elimination is not impossible. There are several examples of success, including in the countries of Georgia and Iceland. Although, comparatively, the United States remains behind the curve, the White House has asked Congress for $11 billion to fund HCV elimination domestically.

As we await action at the national level, clinicians are reminded that there are several things we can do in caring for patients with HCV:

• A one-time HCV screening is recommended in all individuals aged 18 or older, including pregnant people with each pregnancy.
• HCV antibody testing with reflex to PCR should be used as the screening test.
• Pan-genotypic all-oral therapy is recommended for patients with HCV. Cure rates are greater than 95%, and there are few contraindications to treatment.
• Most people are eligible for simplified treatment algorithms that allow minimal on-treatment monitoring.

Without increased screening and linkage to curative therapy, we will not meet the WHO goals for HCV elimination.

Dr. Reau is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to this news organization. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair of the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels. She disclosed ties with AbbVie, Gilead, Arbutus, Intercept, and Salix.

A version of this article appeared on Medscape.com.

Prior to 2013, the backbone of hepatitis C virus (HCV) therapy was pegylated interferon (PEG) in combination with ribavirin (RBV). This year-long therapy was associated with significant side effects and abysmal cure rates. Although efficacy improved with the addition of first-generation protease inhibitors, cure rates remained suboptimal and treatment side effects continued to be significant.

Clinicians and patients needed better options and looked to the drug pipeline with hope. However, even among the most optimistic, the idea that HCV therapy could evolve into an all-oral option seemed a relative pipe dream.

The Sofosbuvir Revolution Begins

The Liver Meeting held in 2013 changed everything.

Several presentations featured compelling data with sofosbuvir, a new polymerase inhibitor that, when combined with RBV, offered an all-oral option to patients with genotypes 2 and 3, as well as improved efficacy for patients with genotypes 1, 4, 5, and 6 when it was combined with 12 weeks of PEG/RBV.

However, the glass ceiling of HCV care was truly shattered with the randomized COSMOS trial, a late-breaker abstract that revealed 12-week functional cure rates in patients receiving sofosbuvir in combination with the protease inhibitor simeprevir.

This phase 2a trial in treatment-naive and -experienced genotype 1 patients with and without cirrhosis showed that an all-oral option was not only viable for the most common strain of HCV but was also safe and efficacious, even in difficult-to-treat populations.

On December 6, 2013, the US Food and Drug Administration (FDA) approved sofosbuvir for the treatment of HCV, ushering in a new era of therapy.

Guidelines quickly changed to advocate for both expansive HCV screening and generous treatment. Yet, as this more permissive approach was being recommended, the high price tag and large anticipated volume of those seeking prescriptions were setting off alarms. The drug cost triggered extensive restrictions based on degree of fibrosis, sobriety, and provider type in an effort to prevent immediate healthcare expenditures.

Given its high cost, rules restricting a patient to only one course of sofosbuvir-based therapy also surfaced. Although treatment with first-generation protease inhibitors carried a hefty price of $161,813.49 per sustained virologic response (SVR), compared with $66,000-$100,000 for 12 weeks of all-oral therapy, its uptake was low and limited by side effects and comorbid conditions. All-oral treatment appeared to have few medical barriers, leading payers to find ways to slow utilization. These restrictions are now gradually being eliminated.

Because of high SVR rates and few contraindications to therapy, most patients who gained access to treatment achieved cure. This included patients who had previously not responded to treatment and prioritized those with more advanced disease.

This quickly led to a significant shift in the population in need of treatment. Prior to 2013, many patients with HCV had advanced disease and did not respond to prior treatment options. After uptake of all-oral therapy, individuals in need were typically treatment naive without advanced disease.

This shift also added new psychosocial dimensions, as many of the newly infected individuals were struggling with active substance abuse. HCV treatment providers needed to change, with increasing recruitment of advanced practice providers, primary care physicians, and addiction medication specialists.

Progress, but Far From Reaching Targets

Fast-forward to 2023.

Ten years after FDA approval, 13.2 million individuals infected with HCV have been treated globally, 82% with sofosbuvir-based regimens and most in lower-middle-income countries. This is absolutely cause for celebration, but not complacency.

In 2016, the World Health Assembly adopted a resolution of elimination of viral hepatitis by 2030. The World Health Organization (WHO) defined elimination of HCV as 90% reduction in new cases of infection, 90% diagnosis of those infected, 80% of eligible individuals treated, and 65% reduction of deaths by 2030.

Despite all the success thus far, the CDA Foundation estimates that the WHO elimination targets will not be achieved until after the year 2050. They also note that in 2020, over 50 million individuals were infected with HCV, of which only 20% were diagnosed and 1% annually treated.

The HCV care cascade, by which the patient journeys from screening to cure, is complicated, and a one-size-fits-all solution is not possible. Reflex testing (an automatic transition to HCV polymerase chain reaction [PCR] testing in the lab for those who are HCV antibody positive) has significantly improved diagnosis. However, communicating these results and linking a patient to curative therapy remain significant obstacles.

Models and real-life experience show that multiple strategies can be successful. They include leveraging the electronic medical record, simplified treatment algorithms, test-and-treat strategies (screening high-risk populations with a point-of-care test that allows treatment initiation at the same visit), and co-localizing HCV screening and treatment with addiction services and relinkage programs (finding those who are already diagnosed and linking them to treatment).

In addition, focusing on populations at high risk for HCV infection — such as people who inject drugs, men who have sex with men, and incarcerated individuals — allows for better resource utilization.

Though daunting, HCV elimination is not impossible. There are several examples of success, including in the countries of Georgia and Iceland. Although, comparatively, the United States remains behind the curve, the White House has asked Congress for $11 billion to fund HCV elimination domestically.

As we await action at the national level, clinicians are reminded that there are several things we can do in caring for patients with HCV:

• A one-time HCV screening is recommended in all individuals aged 18 or older, including pregnant people with each pregnancy.
• HCV antibody testing with reflex to PCR should be used as the screening test.
• Pan-genotypic all-oral therapy is recommended for patients with HCV. Cure rates are greater than 95%, and there are few contraindications to treatment.
• Most people are eligible for simplified treatment algorithms that allow minimal on-treatment monitoring.

Without increased screening and linkage to curative therapy, we will not meet the WHO goals for HCV elimination.

Dr. Reau is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to this news organization. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair of the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels. She disclosed ties with AbbVie, Gilead, Arbutus, Intercept, and Salix.

A version of this article appeared on Medscape.com.

In June 2023, a multisociety group agreed to change the name of the disease formerly known as nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction–associated steatotic liver disease (MASLD).

In the week leading up to this, Intercept Pharmaceuticals announced that their program to develop obeticholic acid (OCA) as a first-to-market, long-awaited potential drug therapy for metabolic dysfunction–associated steatohepatitis (MASH), the more pathogenic form of this disease, was being abandoned after the Food and Drug Administration Gastrointestinal Drugs Advisory Committee voted against accelerated approval of the drug. This decision was made in large part owing to data showing modest efficacy coupled with multiple drug-related side effects, including worsening metabolic dysfunction.

The juxtaposition of these two events highlights what could be a fundamental change in perspective when it comes to the management of patients with MASLD and the development of therapies for this disease.
 

A more precise nomenclature for a broad-spectrum disease

The updating of the NAFLD nomenclature to MASLD represents an important change in the way that the medical community is being asked to view and approach the disease of “fatty liver.”

The previous nomenclature clarified that pathogenic liver steatosis can exist in the absence of alcohol. However, it failed to define the primary drivers of the most common form of NAFLD: that is, metabolic syndrome diseases. The new nomenclature not only better defines the broad spectrum of steatotic liver diseases (alcohol, metabolic, drug/genetic, cryptogenic) but also refocuses the attention of providers on the fundamental basis of MASLD as a critical member of the metabolic syndrome spectrum of diseases.

This is in line with the recently updated American Association for the Study of Liver Disease Practice Guidelines for NAFLD (now MASLD), which focus on active screening to identify patients at risk for advanced MASLD, in particular those with medically complicated obesity or high-risk metabolic characteristics such as diabetes. This is a change from previous versions of the guidelines that were cautious to recommend broad screening guidelines in part owing to the lack of “available therapies.”

The increasing clinical burden of MASH has led to the recognition that patients do not have the luxury of waiting for “anticipated therapies” that have frequently shown only marginal or insignificant efficacy. As a result, some providers have refocused their efforts on the development of care pathways that can efficiently provide comprehensive lifestyle interventions to treat MASH and related metabolic comorbidities within hepatology or other subspecialty clinics.
 

Learning from OCA’s limitations

The approach to drug development for MASH seems to be shifting in a similar, metabolic syndrome–focused way.

The risk-benefit analysis from the FDA advisory committee evaluating OCA noted that the drug provided only modest (albeit statistically significant) benefits over placebo in achieving one of two primary clinical endpoints (improvement in fibrosis by one stage without worsening of NASH), but was associated with toxicity as well as significant drug-related side effects, including new or worsening dyslipidemia, accelerated progression to prediabetes or diabetes, and worsening glycemic control in patients with diabetes.

Worsening clinical markers of metabolic health were an important factor in the advisory committee’s decision to not provide accelerated approval of OCA. This informs the criteria upon which future MASH therapies will be evaluated for approval: that an ideal agent for MASH not only will have a significant impact on MASH pathophysiology but will also provide benefit for (or at least not worsen) the metabolic comorbidities associated with MASH.
 

New treatments on the horizon

Fortunately, several new MASH therapeutics in development seem to have promising metabolic profiles.

In the phase 3 MAESTRO-NASH biopsy trial, treatment with resmetirom, a thyroid hormone receptor–beta selective agonist versus placebo resulted in a clinically significant improvement in liver fibrosis by one stage or more (26% vs. 14%) and NASH resolution (30% vs. 10%). Unlike OCA, resmetirom was associated with a clinically significant reduction in LDL cholesterol (–16% compared with placebo).

Resmetirom has received a breakthrough therapy designation, and Madrigal Pharmaceuticals recently completed submission of a new drug application for accelerated approval of this agent to the FDA.

Semaglutide is a glucagonlike peptide–1 receptor agonist that is already FDA approved for treatment of diabetes and obesity and is being studied in a phase 3 analysis for NASH.

In a phase 2 trial, daily dosing of semaglutide vs placebo led to clinically significant improvement in NASH resolution (59% vs. 17%) but not significant improvement in fibrosis (43% vs 33%). Although it is impossible to make a meaningful comparison in outcomes between clinical trials, it should be noted that the absolute rate of response in this trial was higher than is routinely seen in other NASH trials and that the placebo rate for improvement in fibrosis was higher than expected, a common problem with NASH trials.

As expected, treatment with semaglutide was associated with dose-dependent reduction in body weight and hemoglobin A1c, highlighting the global metabolic benefit of this agent.

Another major class of agents being studied for NASH treatment are the fibroblast growth factor (FGF) 21 analogs.

In the recently published phase 2b ENLIVEN trial, treatment with the FGF21 analog pegozafermin versus placebo led to a statistically significant improvement in liver fibrosis by one stage (27% vs. 7%) and a numerical improvement in NASH resolution (26% vs. 2%).

In addition to its effects directly in the liver, FGF21 has been associated with promoting positive global metabolic effects, including improved peripheral insulin sensitivity and amelioration of dyslipidemia. Consistent with this, treatment with pegozafermin resulted in a decrease in serum triglycerides and an increase in serum HDL cholesterol and adiponectin levels.

Ultimately, the best therapeutic strategy for MASH may be one that uses combination therapy to maximize liver-directed effects and also ameliorate concomitant or contributing metabolic dysfunction. This approach is already being investigated. What seems clear, however, is that MASH therapy without concurrent treatment of metabolic comorbidities is probably destined to be ineffective, if not counterproductive.

So, what’s in a name? When it comes to MASLD, it seems quite a bit.
 

Dr. Janardhan is an assistant professor, department of internal medicine, at Rush University Medical Center, Chicago. Dr. Reau is a professor, department of internal medicine, Rush University. Dr. Janardhan reported conflicts of interest with Target RWE, Novo Nordisk, Intercept, and Enanta. Dr. Reau reported conflicts of interest with AbbVie, Gilead, and AASLD.

A version of this article appeared on Medscape.com.

In June 2023, a multisociety group agreed to change the name of the disease formerly known as nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction–associated steatotic liver disease (MASLD).

In the week leading up to this, Intercept Pharmaceuticals announced that their program to develop obeticholic acid (OCA) as a first-to-market, long-awaited potential drug therapy for metabolic dysfunction–associated steatohepatitis (MASH), the more pathogenic form of this disease, was being abandoned after the Food and Drug Administration Gastrointestinal Drugs Advisory Committee voted against accelerated approval of the drug. This decision was made in large part owing to data showing modest efficacy coupled with multiple drug-related side effects, including worsening metabolic dysfunction.

The juxtaposition of these two events highlights what could be a fundamental change in perspective when it comes to the management of patients with MASLD and the development of therapies for this disease.
 

A more precise nomenclature for a broad-spectrum disease

The updating of the NAFLD nomenclature to MASLD represents an important change in the way that the medical community is being asked to view and approach the disease of “fatty liver.”

The previous nomenclature clarified that pathogenic liver steatosis can exist in the absence of alcohol. However, it failed to define the primary drivers of the most common form of NAFLD: that is, metabolic syndrome diseases. The new nomenclature not only better defines the broad spectrum of steatotic liver diseases (alcohol, metabolic, drug/genetic, cryptogenic) but also refocuses the attention of providers on the fundamental basis of MASLD as a critical member of the metabolic syndrome spectrum of diseases.

This is in line with the recently updated American Association for the Study of Liver Disease Practice Guidelines for NAFLD (now MASLD), which focus on active screening to identify patients at risk for advanced MASLD, in particular those with medically complicated obesity or high-risk metabolic characteristics such as diabetes. This is a change from previous versions of the guidelines that were cautious to recommend broad screening guidelines in part owing to the lack of “available therapies.”

The increasing clinical burden of MASH has led to the recognition that patients do not have the luxury of waiting for “anticipated therapies” that have frequently shown only marginal or insignificant efficacy. As a result, some providers have refocused their efforts on the development of care pathways that can efficiently provide comprehensive lifestyle interventions to treat MASH and related metabolic comorbidities within hepatology or other subspecialty clinics.
 

Learning from OCA’s limitations

The approach to drug development for MASH seems to be shifting in a similar, metabolic syndrome–focused way.

The risk-benefit analysis from the FDA advisory committee evaluating OCA noted that the drug provided only modest (albeit statistically significant) benefits over placebo in achieving one of two primary clinical endpoints (improvement in fibrosis by one stage without worsening of NASH), but was associated with toxicity as well as significant drug-related side effects, including new or worsening dyslipidemia, accelerated progression to prediabetes or diabetes, and worsening glycemic control in patients with diabetes.

Worsening clinical markers of metabolic health were an important factor in the advisory committee’s decision to not provide accelerated approval of OCA. This informs the criteria upon which future MASH therapies will be evaluated for approval: that an ideal agent for MASH not only will have a significant impact on MASH pathophysiology but will also provide benefit for (or at least not worsen) the metabolic comorbidities associated with MASH.
 

New treatments on the horizon

Fortunately, several new MASH therapeutics in development seem to have promising metabolic profiles.

In the phase 3 MAESTRO-NASH biopsy trial, treatment with resmetirom, a thyroid hormone receptor–beta selective agonist versus placebo resulted in a clinically significant improvement in liver fibrosis by one stage or more (26% vs. 14%) and NASH resolution (30% vs. 10%). Unlike OCA, resmetirom was associated with a clinically significant reduction in LDL cholesterol (–16% compared with placebo).

Resmetirom has received a breakthrough therapy designation, and Madrigal Pharmaceuticals recently completed submission of a new drug application for accelerated approval of this agent to the FDA.

Semaglutide is a glucagonlike peptide–1 receptor agonist that is already FDA approved for treatment of diabetes and obesity and is being studied in a phase 3 analysis for NASH.

In a phase 2 trial, daily dosing of semaglutide vs placebo led to clinically significant improvement in NASH resolution (59% vs. 17%) but not significant improvement in fibrosis (43% vs 33%). Although it is impossible to make a meaningful comparison in outcomes between clinical trials, it should be noted that the absolute rate of response in this trial was higher than is routinely seen in other NASH trials and that the placebo rate for improvement in fibrosis was higher than expected, a common problem with NASH trials.

As expected, treatment with semaglutide was associated with dose-dependent reduction in body weight and hemoglobin A1c, highlighting the global metabolic benefit of this agent.

Another major class of agents being studied for NASH treatment are the fibroblast growth factor (FGF) 21 analogs.

In the recently published phase 2b ENLIVEN trial, treatment with the FGF21 analog pegozafermin versus placebo led to a statistically significant improvement in liver fibrosis by one stage (27% vs. 7%) and a numerical improvement in NASH resolution (26% vs. 2%).

In addition to its effects directly in the liver, FGF21 has been associated with promoting positive global metabolic effects, including improved peripheral insulin sensitivity and amelioration of dyslipidemia. Consistent with this, treatment with pegozafermin resulted in a decrease in serum triglycerides and an increase in serum HDL cholesterol and adiponectin levels.

Ultimately, the best therapeutic strategy for MASH may be one that uses combination therapy to maximize liver-directed effects and also ameliorate concomitant or contributing metabolic dysfunction. This approach is already being investigated. What seems clear, however, is that MASH therapy without concurrent treatment of metabolic comorbidities is probably destined to be ineffective, if not counterproductive.

So, what’s in a name? When it comes to MASLD, it seems quite a bit.
 

Dr. Janardhan is an assistant professor, department of internal medicine, at Rush University Medical Center, Chicago. Dr. Reau is a professor, department of internal medicine, Rush University. Dr. Janardhan reported conflicts of interest with Target RWE, Novo Nordisk, Intercept, and Enanta. Dr. Reau reported conflicts of interest with AbbVie, Gilead, and AASLD.

A version of this article appeared on Medscape.com.

In June 2023, a multisociety group agreed to change the name of the disease formerly known as nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction–associated steatotic liver disease (MASLD).

In the week leading up to this, Intercept Pharmaceuticals announced that their program to develop obeticholic acid (OCA) as a first-to-market, long-awaited potential drug therapy for metabolic dysfunction–associated steatohepatitis (MASH), the more pathogenic form of this disease, was being abandoned after the Food and Drug Administration Gastrointestinal Drugs Advisory Committee voted against accelerated approval of the drug. This decision was made in large part owing to data showing modest efficacy coupled with multiple drug-related side effects, including worsening metabolic dysfunction.

The juxtaposition of these two events highlights what could be a fundamental change in perspective when it comes to the management of patients with MASLD and the development of therapies for this disease.
 

A more precise nomenclature for a broad-spectrum disease

The updating of the NAFLD nomenclature to MASLD represents an important change in the way that the medical community is being asked to view and approach the disease of “fatty liver.”

The previous nomenclature clarified that pathogenic liver steatosis can exist in the absence of alcohol. However, it failed to define the primary drivers of the most common form of NAFLD: that is, metabolic syndrome diseases. The new nomenclature not only better defines the broad spectrum of steatotic liver diseases (alcohol, metabolic, drug/genetic, cryptogenic) but also refocuses the attention of providers on the fundamental basis of MASLD as a critical member of the metabolic syndrome spectrum of diseases.

This is in line with the recently updated American Association for the Study of Liver Disease Practice Guidelines for NAFLD (now MASLD), which focus on active screening to identify patients at risk for advanced MASLD, in particular those with medically complicated obesity or high-risk metabolic characteristics such as diabetes. This is a change from previous versions of the guidelines that were cautious to recommend broad screening guidelines in part owing to the lack of “available therapies.”

The increasing clinical burden of MASH has led to the recognition that patients do not have the luxury of waiting for “anticipated therapies” that have frequently shown only marginal or insignificant efficacy. As a result, some providers have refocused their efforts on the development of care pathways that can efficiently provide comprehensive lifestyle interventions to treat MASH and related metabolic comorbidities within hepatology or other subspecialty clinics.
 

Learning from OCA’s limitations

The approach to drug development for MASH seems to be shifting in a similar, metabolic syndrome–focused way.

The risk-benefit analysis from the FDA advisory committee evaluating OCA noted that the drug provided only modest (albeit statistically significant) benefits over placebo in achieving one of two primary clinical endpoints (improvement in fibrosis by one stage without worsening of NASH), but was associated with toxicity as well as significant drug-related side effects, including new or worsening dyslipidemia, accelerated progression to prediabetes or diabetes, and worsening glycemic control in patients with diabetes.

Worsening clinical markers of metabolic health were an important factor in the advisory committee’s decision to not provide accelerated approval of OCA. This informs the criteria upon which future MASH therapies will be evaluated for approval: that an ideal agent for MASH not only will have a significant impact on MASH pathophysiology but will also provide benefit for (or at least not worsen) the metabolic comorbidities associated with MASH.
 

New treatments on the horizon

Fortunately, several new MASH therapeutics in development seem to have promising metabolic profiles.

In the phase 3 MAESTRO-NASH biopsy trial, treatment with resmetirom, a thyroid hormone receptor–beta selective agonist versus placebo resulted in a clinically significant improvement in liver fibrosis by one stage or more (26% vs. 14%) and NASH resolution (30% vs. 10%). Unlike OCA, resmetirom was associated with a clinically significant reduction in LDL cholesterol (–16% compared with placebo).

Resmetirom has received a breakthrough therapy designation, and Madrigal Pharmaceuticals recently completed submission of a new drug application for accelerated approval of this agent to the FDA.

Semaglutide is a glucagonlike peptide–1 receptor agonist that is already FDA approved for treatment of diabetes and obesity and is being studied in a phase 3 analysis for NASH.

In a phase 2 trial, daily dosing of semaglutide vs placebo led to clinically significant improvement in NASH resolution (59% vs. 17%) but not significant improvement in fibrosis (43% vs 33%). Although it is impossible to make a meaningful comparison in outcomes between clinical trials, it should be noted that the absolute rate of response in this trial was higher than is routinely seen in other NASH trials and that the placebo rate for improvement in fibrosis was higher than expected, a common problem with NASH trials.

As expected, treatment with semaglutide was associated with dose-dependent reduction in body weight and hemoglobin A1c, highlighting the global metabolic benefit of this agent.

Another major class of agents being studied for NASH treatment are the fibroblast growth factor (FGF) 21 analogs.

In the recently published phase 2b ENLIVEN trial, treatment with the FGF21 analog pegozafermin versus placebo led to a statistically significant improvement in liver fibrosis by one stage (27% vs. 7%) and a numerical improvement in NASH resolution (26% vs. 2%).

In addition to its effects directly in the liver, FGF21 has been associated with promoting positive global metabolic effects, including improved peripheral insulin sensitivity and amelioration of dyslipidemia. Consistent with this, treatment with pegozafermin resulted in a decrease in serum triglycerides and an increase in serum HDL cholesterol and adiponectin levels.

Ultimately, the best therapeutic strategy for MASH may be one that uses combination therapy to maximize liver-directed effects and also ameliorate concomitant or contributing metabolic dysfunction. This approach is already being investigated. What seems clear, however, is that MASH therapy without concurrent treatment of metabolic comorbidities is probably destined to be ineffective, if not counterproductive.

So, what’s in a name? When it comes to MASLD, it seems quite a bit.
 

Dr. Janardhan is an assistant professor, department of internal medicine, at Rush University Medical Center, Chicago. Dr. Reau is a professor, department of internal medicine, Rush University. Dr. Janardhan reported conflicts of interest with Target RWE, Novo Nordisk, Intercept, and Enanta. Dr. Reau reported conflicts of interest with AbbVie, Gilead, and AASLD.

A version of this article appeared on Medscape.com.

Because hepatitis C virus (HCV) infection is typically asymptomatic, its presence can easily be overlooked without appropriate screening efforts. For those screening efforts to be effective, they must keep pace with the changing demographic face of this increasingly prevalent but treatable disease.

Perhaps the most dramatic shift in HCV demographics in recent years has been the increase of infections among those born after 1965, a trend primarily driven by the opioid epidemic. In addition, data from the National Notifiable Diseases Surveillance System show that cases of diagnosed HCV doubled among women of childbearing age from 2006 to 2014, with new infections in younger women surpassing those in older age groups.

With such trends in mind, the Centers for Disease Control and Prevention broadened their recommendations regarding HCV in 2020 to include one-time testing in all adults aged 18 years and older and screening of all pregnant women during each pregnancy, except where the prevalence of infection is less than 0.1%, a threshold that no state has yet achieved.

The US Preventive Services Task Force (USPSTF) subsequently followed suit in their own recommendations.

The American Association for the Study of Liver Diseases/Infectious Diseases Society of America have long advocated for extensive expansion in their screening recommendations for HCV, including pregnancy.

Although the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine did not immediately adopt these recommendations, they have since endorsed them in May 2021 and June 2021, respectively.
 

The hepatologist perspective

As a practicing hepatologist, this seems like an uncontroversial recommendation. Obstetricians already screen for hepatitis B virus in each pregnancy. It should be easy to add HCV testing to the same lab testing.

Risk-based screening has repeatedly been demonstrated to be ineffective. It should be easier to test all women than to ask prying questions about high-risk behaviors.

Given the increase of injection drug use and resultant HCV infections in women of childbearing age, this seems like a perfect opportunity to identify chronically infected women and counsel them on transmission and cure. And pregnancy is also unique in that it is a time of near-universal health coverage.

Let’s address some of the operational issues.

The diagnostic cascade for HCV can be made very easy. HCV antibody testing is our standard screening test and, when positive, can automatically reflex to HCV polymerase chain reaction (PCR), the diagnostic test. Thus, with one blood sample, you can both screen for and diagnose infection.

Current guidelines do not recommend treating HCV during pregnancy, although therapy can be considered on an individual basis. Linkage to a knowledgeable provider who can discuss transmission and treatment, as well as assess the stage of liver injury, should decrease the burden on the ob.gyn.

The impact on pregnancy is marginal. HCV should not change either the mode of delivery or the decision to breastfeed. The AASLD/IDSA guidance outlines only four recommendations for monitoring during pregnancy:

• Obtain HCV RNA to see whether the infection is active and assess liver function at initiation of prenatal care.
• Prenatal care should be tailored to the pregnancy. There is no modification recommended to decrease mother-to-child transmission (MTCT).
• Be aware that intrahepatic is more common with HCV.
• Women with have a higher rate of adverse outcomes and should be linked to a high-risk obstetrics specialist.

But of course, what seems easy to one specialist may not be true of another. With that in mind, let’s hear the ob.gyn. perspective on these updated screening recommendations.
 

The ob.gyn. perspective

Recent guidelines from the CDC, ACOG, and SMFM recommend universal screening for HCV in all pregnant women. The increased availability of highly effective antiviral regimens makes universal screening a logical strategy, especially to identify candidates for this curative treatment. What is questionable, however, is the recommended timing by which this screening should take place.

HCV screening during pregnancy, as currently recommended, provides no immediate benefit for the pregnant woman or the fetus/neonate, given that antiviral treatments have not been approved during gestation, and there are no known measures that decrease MTCT or change routine perinatal care.

We also must not forget that a significant proportion of women in the United States, particularly those with limited resources, do not receive prenatal care at all. Most of them, however, will present to a hospital for delivery. Consequently, compliance with screening might be higher if performed at the time of delivery rather than antepartum.

Deferring screening until the intrapartum or immediate postpartum period, at least until antiviral treatment during pregnancy becomes a reality, was discussed. The rationale was that this approach might obviate the need to deal with the unintended consequences and burden of testing for HCV during pregnancy. Ultimately, ACOG and SMFM fell in line with the CDC recommendations.

Despite the lack of robust evidence regarding the risk for MTCT associated with commonly performed obstetric procedures (for example, genetic amniocentesis, artificial rupture of the membranes during labor, placement of an intrauterine pressure catheter), clinicians may be reluctant to perform them in HCV-infected women, resulting in potential deviations from the obstetric standard of care.

Similarly, it is likely that patients may choose to have a cesarean delivery for the sole purpose of decreasing MTCT, despite the lack of evidence for this. Such ill-advised patient-driven decisions are increasingly likely in the current environment, where social media can rapidly disseminate misinformation.
 

Implications for pediatric patients

One cannot isolate HCV screening in pregnancy from the consequences that may potentially occur as part of the infant’s transition to the care of a pediatrician.

Even though MTCT is estimated to occur in just 5%-15% of cases, all children born to HCV viremic mothers should be screened for HCV.

Traditionally, screening for HCV antibodies occurred after 18 months of age. In those who test positive, HCV PCR testing is recommended at 3 years. However, this algorithm is being called into question because only approximately one-third of infants are successfully screened.

HCV RNA testing in the first year after birth has been suggested. However, even proponents of this approach concur that all management decisions should be deferred until after the age of 3 years, when medications are approved for pediatric use.

In addition, HCV testing would be required again before considering therapy because children have higher rates of spontaneous clearance.
 

Seeking consensus beyond the controversy

Controversy remains surrounding the most recent update to the HCV screening guidelines. The current recommendation to screen during pregnancy cannot modify the risk for MTCT, has no impact on decisions regarding mode of delivery or breastfeeding, and could potentially cause harm by making obstetricians defer necessary invasive procedures even though there are no data linking them to an increase in MTCT.

Yet after extensive debate, the CDC, USPSTF, AASLD/IDSA, ACOG, and SMFM all developed their current recommendations to initiate HCV screening during pregnancy. To make this successful, screening algorithms need to be simple and consistent across all society recommendations.

HCV antibody testing should always reflex to the diagnostic test (HCV PCR) to allow confirmation in those who test positive without requiring an additional blood test. Viremic mothers (those who are HCV positive on PCR) should be linked to a provider who can discuss prognosis, transmission, and treatment. The importance of screening the infant also must be communicated to the parents and pediatrician alike.

Dr. Reau has served as a director, officer, partner, employee, adviser, consultant, or trustee for AbbVie, Gilead, Arbutus, Intercept, and Salix; received research grants from AbbVie and Gilead; and received income from AASLD. Dr. Pacheco disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

Because hepatitis C virus (HCV) infection is typically asymptomatic, its presence can easily be overlooked without appropriate screening efforts. For those screening efforts to be effective, they must keep pace with the changing demographic face of this increasingly prevalent but treatable disease.

Perhaps the most dramatic shift in HCV demographics in recent years has been the increase of infections among those born after 1965, a trend primarily driven by the opioid epidemic. In addition, data from the National Notifiable Diseases Surveillance System show that cases of diagnosed HCV doubled among women of childbearing age from 2006 to 2014, with new infections in younger women surpassing those in older age groups.

With such trends in mind, the Centers for Disease Control and Prevention broadened their recommendations regarding HCV in 2020 to include one-time testing in all adults aged 18 years and older and screening of all pregnant women during each pregnancy, except where the prevalence of infection is less than 0.1%, a threshold that no state has yet achieved.

The US Preventive Services Task Force (USPSTF) subsequently followed suit in their own recommendations.

The American Association for the Study of Liver Diseases/Infectious Diseases Society of America have long advocated for extensive expansion in their screening recommendations for HCV, including pregnancy.

Although the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine did not immediately adopt these recommendations, they have since endorsed them in May 2021 and June 2021, respectively.
 

The hepatologist perspective

As a practicing hepatologist, this seems like an uncontroversial recommendation. Obstetricians already screen for hepatitis B virus in each pregnancy. It should be easy to add HCV testing to the same lab testing.

Risk-based screening has repeatedly been demonstrated to be ineffective. It should be easier to test all women than to ask prying questions about high-risk behaviors.

Given the increase of injection drug use and resultant HCV infections in women of childbearing age, this seems like a perfect opportunity to identify chronically infected women and counsel them on transmission and cure. And pregnancy is also unique in that it is a time of near-universal health coverage.

Let’s address some of the operational issues.

The diagnostic cascade for HCV can be made very easy. HCV antibody testing is our standard screening test and, when positive, can automatically reflex to HCV polymerase chain reaction (PCR), the diagnostic test. Thus, with one blood sample, you can both screen for and diagnose infection.

Current guidelines do not recommend treating HCV during pregnancy, although therapy can be considered on an individual basis. Linkage to a knowledgeable provider who can discuss transmission and treatment, as well as assess the stage of liver injury, should decrease the burden on the ob.gyn.

The impact on pregnancy is marginal. HCV should not change either the mode of delivery or the decision to breastfeed. The AASLD/IDSA guidance outlines only four recommendations for monitoring during pregnancy:

• Obtain HCV RNA to see whether the infection is active and assess liver function at initiation of prenatal care.
• Prenatal care should be tailored to the pregnancy. There is no modification recommended to decrease mother-to-child transmission (MTCT).
• Be aware that intrahepatic is more common with HCV.
• Women with have a higher rate of adverse outcomes and should be linked to a high-risk obstetrics specialist.

But of course, what seems easy to one specialist may not be true of another. With that in mind, let’s hear the ob.gyn. perspective on these updated screening recommendations.
 

The ob.gyn. perspective

Recent guidelines from the CDC, ACOG, and SMFM recommend universal screening for HCV in all pregnant women. The increased availability of highly effective antiviral regimens makes universal screening a logical strategy, especially to identify candidates for this curative treatment. What is questionable, however, is the recommended timing by which this screening should take place.

HCV screening during pregnancy, as currently recommended, provides no immediate benefit for the pregnant woman or the fetus/neonate, given that antiviral treatments have not been approved during gestation, and there are no known measures that decrease MTCT or change routine perinatal care.

We also must not forget that a significant proportion of women in the United States, particularly those with limited resources, do not receive prenatal care at all. Most of them, however, will present to a hospital for delivery. Consequently, compliance with screening might be higher if performed at the time of delivery rather than antepartum.

Deferring screening until the intrapartum or immediate postpartum period, at least until antiviral treatment during pregnancy becomes a reality, was discussed. The rationale was that this approach might obviate the need to deal with the unintended consequences and burden of testing for HCV during pregnancy. Ultimately, ACOG and SMFM fell in line with the CDC recommendations.

Despite the lack of robust evidence regarding the risk for MTCT associated with commonly performed obstetric procedures (for example, genetic amniocentesis, artificial rupture of the membranes during labor, placement of an intrauterine pressure catheter), clinicians may be reluctant to perform them in HCV-infected women, resulting in potential deviations from the obstetric standard of care.

Similarly, it is likely that patients may choose to have a cesarean delivery for the sole purpose of decreasing MTCT, despite the lack of evidence for this. Such ill-advised patient-driven decisions are increasingly likely in the current environment, where social media can rapidly disseminate misinformation.
 

Implications for pediatric patients

One cannot isolate HCV screening in pregnancy from the consequences that may potentially occur as part of the infant’s transition to the care of a pediatrician.

Even though MTCT is estimated to occur in just 5%-15% of cases, all children born to HCV viremic mothers should be screened for HCV.

Traditionally, screening for HCV antibodies occurred after 18 months of age. In those who test positive, HCV PCR testing is recommended at 3 years. However, this algorithm is being called into question because only approximately one-third of infants are successfully screened.

HCV RNA testing in the first year after birth has been suggested. However, even proponents of this approach concur that all management decisions should be deferred until after the age of 3 years, when medications are approved for pediatric use.

In addition, HCV testing would be required again before considering therapy because children have higher rates of spontaneous clearance.
 

Seeking consensus beyond the controversy

Controversy remains surrounding the most recent update to the HCV screening guidelines. The current recommendation to screen during pregnancy cannot modify the risk for MTCT, has no impact on decisions regarding mode of delivery or breastfeeding, and could potentially cause harm by making obstetricians defer necessary invasive procedures even though there are no data linking them to an increase in MTCT.

Yet after extensive debate, the CDC, USPSTF, AASLD/IDSA, ACOG, and SMFM all developed their current recommendations to initiate HCV screening during pregnancy. To make this successful, screening algorithms need to be simple and consistent across all society recommendations.

HCV antibody testing should always reflex to the diagnostic test (HCV PCR) to allow confirmation in those who test positive without requiring an additional blood test. Viremic mothers (those who are HCV positive on PCR) should be linked to a provider who can discuss prognosis, transmission, and treatment. The importance of screening the infant also must be communicated to the parents and pediatrician alike.

Dr. Reau has served as a director, officer, partner, employee, adviser, consultant, or trustee for AbbVie, Gilead, Arbutus, Intercept, and Salix; received research grants from AbbVie and Gilead; and received income from AASLD. Dr. Pacheco disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

Because hepatitis C virus (HCV) infection is typically asymptomatic, its presence can easily be overlooked without appropriate screening efforts. For those screening efforts to be effective, they must keep pace with the changing demographic face of this increasingly prevalent but treatable disease.

Perhaps the most dramatic shift in HCV demographics in recent years has been the increase of infections among those born after 1965, a trend primarily driven by the opioid epidemic. In addition, data from the National Notifiable Diseases Surveillance System show that cases of diagnosed HCV doubled among women of childbearing age from 2006 to 2014, with new infections in younger women surpassing those in older age groups.

With such trends in mind, the Centers for Disease Control and Prevention broadened their recommendations regarding HCV in 2020 to include one-time testing in all adults aged 18 years and older and screening of all pregnant women during each pregnancy, except where the prevalence of infection is less than 0.1%, a threshold that no state has yet achieved.

The US Preventive Services Task Force (USPSTF) subsequently followed suit in their own recommendations.

The American Association for the Study of Liver Diseases/Infectious Diseases Society of America have long advocated for extensive expansion in their screening recommendations for HCV, including pregnancy.

Although the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine did not immediately adopt these recommendations, they have since endorsed them in May 2021 and June 2021, respectively.
 

The hepatologist perspective

As a practicing hepatologist, this seems like an uncontroversial recommendation. Obstetricians already screen for hepatitis B virus in each pregnancy. It should be easy to add HCV testing to the same lab testing.

Risk-based screening has repeatedly been demonstrated to be ineffective. It should be easier to test all women than to ask prying questions about high-risk behaviors.

Given the increase of injection drug use and resultant HCV infections in women of childbearing age, this seems like a perfect opportunity to identify chronically infected women and counsel them on transmission and cure. And pregnancy is also unique in that it is a time of near-universal health coverage.

Let’s address some of the operational issues.

The diagnostic cascade for HCV can be made very easy. HCV antibody testing is our standard screening test and, when positive, can automatically reflex to HCV polymerase chain reaction (PCR), the diagnostic test. Thus, with one blood sample, you can both screen for and diagnose infection.

Current guidelines do not recommend treating HCV during pregnancy, although therapy can be considered on an individual basis. Linkage to a knowledgeable provider who can discuss transmission and treatment, as well as assess the stage of liver injury, should decrease the burden on the ob.gyn.

The impact on pregnancy is marginal. HCV should not change either the mode of delivery or the decision to breastfeed. The AASLD/IDSA guidance outlines only four recommendations for monitoring during pregnancy:

• Obtain HCV RNA to see whether the infection is active and assess liver function at initiation of prenatal care.
• Prenatal care should be tailored to the pregnancy. There is no modification recommended to decrease mother-to-child transmission (MTCT).
• Be aware that intrahepatic is more common with HCV.
• Women with have a higher rate of adverse outcomes and should be linked to a high-risk obstetrics specialist.

But of course, what seems easy to one specialist may not be true of another. With that in mind, let’s hear the ob.gyn. perspective on these updated screening recommendations.
 

The ob.gyn. perspective

Recent guidelines from the CDC, ACOG, and SMFM recommend universal screening for HCV in all pregnant women. The increased availability of highly effective antiviral regimens makes universal screening a logical strategy, especially to identify candidates for this curative treatment. What is questionable, however, is the recommended timing by which this screening should take place.

HCV screening during pregnancy, as currently recommended, provides no immediate benefit for the pregnant woman or the fetus/neonate, given that antiviral treatments have not been approved during gestation, and there are no known measures that decrease MTCT or change routine perinatal care.

We also must not forget that a significant proportion of women in the United States, particularly those with limited resources, do not receive prenatal care at all. Most of them, however, will present to a hospital for delivery. Consequently, compliance with screening might be higher if performed at the time of delivery rather than antepartum.

Deferring screening until the intrapartum or immediate postpartum period, at least until antiviral treatment during pregnancy becomes a reality, was discussed. The rationale was that this approach might obviate the need to deal with the unintended consequences and burden of testing for HCV during pregnancy. Ultimately, ACOG and SMFM fell in line with the CDC recommendations.

Despite the lack of robust evidence regarding the risk for MTCT associated with commonly performed obstetric procedures (for example, genetic amniocentesis, artificial rupture of the membranes during labor, placement of an intrauterine pressure catheter), clinicians may be reluctant to perform them in HCV-infected women, resulting in potential deviations from the obstetric standard of care.

Similarly, it is likely that patients may choose to have a cesarean delivery for the sole purpose of decreasing MTCT, despite the lack of evidence for this. Such ill-advised patient-driven decisions are increasingly likely in the current environment, where social media can rapidly disseminate misinformation.
 

Implications for pediatric patients

One cannot isolate HCV screening in pregnancy from the consequences that may potentially occur as part of the infant’s transition to the care of a pediatrician.

Even though MTCT is estimated to occur in just 5%-15% of cases, all children born to HCV viremic mothers should be screened for HCV.

Traditionally, screening for HCV antibodies occurred after 18 months of age. In those who test positive, HCV PCR testing is recommended at 3 years. However, this algorithm is being called into question because only approximately one-third of infants are successfully screened.

HCV RNA testing in the first year after birth has been suggested. However, even proponents of this approach concur that all management decisions should be deferred until after the age of 3 years, when medications are approved for pediatric use.

In addition, HCV testing would be required again before considering therapy because children have higher rates of spontaneous clearance.
 

Seeking consensus beyond the controversy

Controversy remains surrounding the most recent update to the HCV screening guidelines. The current recommendation to screen during pregnancy cannot modify the risk for MTCT, has no impact on decisions regarding mode of delivery or breastfeeding, and could potentially cause harm by making obstetricians defer necessary invasive procedures even though there are no data linking them to an increase in MTCT.

Yet after extensive debate, the CDC, USPSTF, AASLD/IDSA, ACOG, and SMFM all developed their current recommendations to initiate HCV screening during pregnancy. To make this successful, screening algorithms need to be simple and consistent across all society recommendations.

HCV antibody testing should always reflex to the diagnostic test (HCV PCR) to allow confirmation in those who test positive without requiring an additional blood test. Viremic mothers (those who are HCV positive on PCR) should be linked to a provider who can discuss prognosis, transmission, and treatment. The importance of screening the infant also must be communicated to the parents and pediatrician alike.

Dr. Reau has served as a director, officer, partner, employee, adviser, consultant, or trustee for AbbVie, Gilead, Arbutus, Intercept, and Salix; received research grants from AbbVie and Gilead; and received income from AASLD. Dr. Pacheco disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

One of the most remarkable stories in medicine must be the relatively brief 25 years between the discovery of the hepatitis C virus (HCV) in 1989 to its eventual cure in 2014.

HCV afflicted over 5 million Americans and was the cause of death in approximately 10,000 patients annually, the leading indication for liver transplantation, and the leading risk factor for hepatocellular carcinoma, clearly signaling it as one of the era’s major public health villains. Within that span of time, it is the work beginning in the mid-1990s until today that perhaps best defines the race for the HCV “cure.”

In the early to mid-1990s, polymerase chain reaction techniques were just becoming commonplace for HCV diagnosis, whereas HCV genotypes were emerging as major factors determining response to interferon therapy. The sustained viral response (SVR) rates were mired at around 6%-12% for a 24- to 48-week course of three-times-weekly injection therapy. Severe side effects were common and there was a relatively high relapse rate, even in patients who responded to treatment.

By 1996, the addition of ribavirin to the interferon treatment was associated with a modest but significant improvement in SVR rates to above 20%. And by 2000, the use of pegylated interferon – allowing once-weekly injection therapy – along with ribavirin, improved SVR rates to above 50% for the first time. The therapy was still poorly tolerated but was associated with better compliance.

The real breakthrough in therapy came in the early 2000s with the discovery and availability of HCV protease inhibitors: telaprevir and boceprevir. These agents could induce a more rapid decline in viral replication than interferon but could not be administered alone owing to the rapid emergence of resistant HCV variants. Therefore, these agents were administered with interferon and ribavirin as a three-drug cocktail to take advantage of interferon to prevent emergence of resistant variants. Although SVR rates improved substantially to around 75%, adverse events also increased and limited its usefulness in patients with more advanced liver disease, precisely those who were most in need of better therapies.

Nonetheless, the incredible advances in understanding the replication machinery of HCV that led to the discovery of the protease inhibitors in turn led to further elucidation and unlocking of three additional classes of HCV protein targets and inhibitors: NS5A complex inhibitors (e.g., ledipasvir), the NS5B nonnucleoside inhibitors (e.g., dasabuvir), and NS5B nucleoside inhibitors (e.g., sofosbuvir). It quickly became apparent that the use of combinations of these direct-acting antivirals (DAAs) could limit emergence of resistant variants while also providing rapid and profound viral suppression. Because HCV required viral replication to persist in the hepatocyte, it became possible to induce HCV eradication, and thus cure, with combinations of DAAs.

In addition, investigators soon learned that the duration of therapy no longer needed to be the generally accepted 24-48 weeks for SVR, but instead could be reduced eventually to 8-12 weeks. This shortened treatment duration allowed for more rapid testing of new agents and combinations, and the field took a rapid step forward between 2011 and 2017. HCV cure rates rose to 90%-95%.

The competition for Food and Drug Administration approval of new agents among several pharmaceutical companies also meant that the time-honored process of issuing treatment guidelines every 3-5 years by societies would not be adequate. Therefore, in 2013, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America joined forces to establish more nimble and responsive online HCV guidance. This important resource debuted in January 2014 just as the FDA approved the first DAA therapies.

The high cost initially associated with many of these new therapies (up to $1,000 per pill) significantly limited uptake owing to insurance and health plan cost factors. Early on, the cost was also analyzed by price per cure, seemingly to justify the high cost by the high cure rate. However, advocacy and negotiations ultimately led to marked reductions in the cost of a course of therapy (with some therapies at $225 per pill), thus making these treatments now widely available.

By 2020, the HCV field has shifted from therapeutic development to improving the care cascade by enhanced identification and testing of unsuspected but HCV infected individuals. This is our current challenge.
 

Moving toward noninvasive tests

While curative therapy has revolutionized HCV management, innovation in diagnostics eliminated a significant barrier in access to therapy: the liver biopsy.

Staging, or accurately identifying advanced fibrosis in persons infected with HCV, is essential for long-term follow-up. The presence of advanced disease affects drug choices, especially before the approval of all-oral therapy. Historically, a liver biopsy was obligatory before treatment. Invasive with a significant risk for complications, this requirement effectively prevented treatment in those who were unwilling to undergo the procedure and deterred those at risk from even being tested.

Over the past 25 years, numerous methods to noninvasively assess for liver fibrosis have been used. Serum biomarkers can be either indirect (based on routine tests) or direct (reflecting components of the extracellular matrix). Although highly available, they are only moderately useful for identifying advanced fibrosis and thus cannot replace liver biopsy in the care cascade. The technique of elastography dates back to the 1980s, though the role of vibration-controlled transient liver elastography in the assessment of hepatic fibrosis in patients with HCV was not recognized until around 2005 and it was not commonly used for nearly another decade.

Yet, a paradigm shift in the care cascade occurred with the release of the AASLD/IDSA guidance document in 2014. For the first time in the United States, noninvasive tests were recommended as first-line testing for the assessment of advanced fibrosis. Prior guidelines specifically stated that although noninvasive tests might be useful, they “should not replace the liver biopsy in routine clinical practice.” Current guidelines recommend combining elastography with serum biomarkers and considering biopsy only in patients with discordant results if the biopsy would affect clinical decision-making.
 

The last frontier

Curative therapy has also allowed the unthinkable: willingly exposing patients to the virus through donor-positive/recipient-negative solid organ transplant. Traditionally, an HCV-infected donor would be considered only for an HCV-positive recipient; however, with effective DAA therapy, the number of HCV actively infected patients in need of transplant has dwindled.

Unfortunately as a consequence of the opioid epidemic, the HCV-exposed donor population has blossomed. Given that HCV therapy is near universally curative, using organs from HCV-viremic donors can greatly expand the organ transplantation pool. Small studies[1-5] have demonstrated the safety and efficacy of this approach, both in HCV-positive liver donors as well as in other solid organs.
 

A disease pegged for elimination

In the past 25 years, HCV has evolved from non-A, non-B hepatitis into a disease pegged for elimination. This is a direct reflection of improved therapeutics with highly effective DAAs. Yet, without improved diagnostics, we would be unable to navigate patients through the clinical care cascade. These incredible strides in diagnostics and therapeutics allow us to push the cutting edge through iatrogenic infection of organ recipients, while recognizing that the largest hurdle to elimination remains in finding those who are chronically infected. Ultimately, the crux of elimination remains unchanged over the past 25 years and resides in screening and diagnosis with effective linkage to care.

Donald M. Jensen, MD, is a professor of medicine at Rush University Medical Center, Chicago. He was previously the director of the Center for Liver Disease at the University of Chicago until 2015. His research interest has been in newer HCV therapies. He recently received the Distinguished Service Award from the AASLD for his many contributions to the field.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the AASLD and the IDSA, as well as educational chair for the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.
 

References

Woolley AE et al. Heart and lung transplants from HCV-infected donors to uninfected recipients. N Engl J Med. 2019;380:1606-17.

Franco A et al. Renal transplantation from seropositive hepatitis C virus donors to seronegative recipients in Spain: A prospective study. Transpl Int. 2019;32:710-6.

Goldberg DS et al. Transplanting HCV-infected kidneys into uninfected recipients. N Engl J Med. 2017;377:1105.

Kwong AJ et al. Liver transplantation for hepatitis C virus (HCV) nonviremic recipients with HCV viremic donors. Am J Transplant. 2019;19:1380-7.

Bethea E et al. Immediate administration of antiviral therapy after transplantation of hepatitis C–infected livers into uninfected recipients: Implications for therapeutic planning. Am J Transplant. 2020;20:1619-28.

This article first appeared on Medscape.com.

One of the most remarkable stories in medicine must be the relatively brief 25 years between the discovery of the hepatitis C virus (HCV) in 1989 to its eventual cure in 2014.

HCV afflicted over 5 million Americans and was the cause of death in approximately 10,000 patients annually, the leading indication for liver transplantation, and the leading risk factor for hepatocellular carcinoma, clearly signaling it as one of the era’s major public health villains. Within that span of time, it is the work beginning in the mid-1990s until today that perhaps best defines the race for the HCV “cure.”

In the early to mid-1990s, polymerase chain reaction techniques were just becoming commonplace for HCV diagnosis, whereas HCV genotypes were emerging as major factors determining response to interferon therapy. The sustained viral response (SVR) rates were mired at around 6%-12% for a 24- to 48-week course of three-times-weekly injection therapy. Severe side effects were common and there was a relatively high relapse rate, even in patients who responded to treatment.

By 1996, the addition of ribavirin to the interferon treatment was associated with a modest but significant improvement in SVR rates to above 20%. And by 2000, the use of pegylated interferon – allowing once-weekly injection therapy – along with ribavirin, improved SVR rates to above 50% for the first time. The therapy was still poorly tolerated but was associated with better compliance.

The real breakthrough in therapy came in the early 2000s with the discovery and availability of HCV protease inhibitors: telaprevir and boceprevir. These agents could induce a more rapid decline in viral replication than interferon but could not be administered alone owing to the rapid emergence of resistant HCV variants. Therefore, these agents were administered with interferon and ribavirin as a three-drug cocktail to take advantage of interferon to prevent emergence of resistant variants. Although SVR rates improved substantially to around 75%, adverse events also increased and limited its usefulness in patients with more advanced liver disease, precisely those who were most in need of better therapies.

Nonetheless, the incredible advances in understanding the replication machinery of HCV that led to the discovery of the protease inhibitors in turn led to further elucidation and unlocking of three additional classes of HCV protein targets and inhibitors: NS5A complex inhibitors (e.g., ledipasvir), the NS5B nonnucleoside inhibitors (e.g., dasabuvir), and NS5B nucleoside inhibitors (e.g., sofosbuvir). It quickly became apparent that the use of combinations of these direct-acting antivirals (DAAs) could limit emergence of resistant variants while also providing rapid and profound viral suppression. Because HCV required viral replication to persist in the hepatocyte, it became possible to induce HCV eradication, and thus cure, with combinations of DAAs.

In addition, investigators soon learned that the duration of therapy no longer needed to be the generally accepted 24-48 weeks for SVR, but instead could be reduced eventually to 8-12 weeks. This shortened treatment duration allowed for more rapid testing of new agents and combinations, and the field took a rapid step forward between 2011 and 2017. HCV cure rates rose to 90%-95%.

The competition for Food and Drug Administration approval of new agents among several pharmaceutical companies also meant that the time-honored process of issuing treatment guidelines every 3-5 years by societies would not be adequate. Therefore, in 2013, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America joined forces to establish more nimble and responsive online HCV guidance. This important resource debuted in January 2014 just as the FDA approved the first DAA therapies.

The high cost initially associated with many of these new therapies (up to $1,000 per pill) significantly limited uptake owing to insurance and health plan cost factors. Early on, the cost was also analyzed by price per cure, seemingly to justify the high cost by the high cure rate. However, advocacy and negotiations ultimately led to marked reductions in the cost of a course of therapy (with some therapies at $225 per pill), thus making these treatments now widely available.

By 2020, the HCV field has shifted from therapeutic development to improving the care cascade by enhanced identification and testing of unsuspected but HCV infected individuals. This is our current challenge.
 

Moving toward noninvasive tests

While curative therapy has revolutionized HCV management, innovation in diagnostics eliminated a significant barrier in access to therapy: the liver biopsy.

Staging, or accurately identifying advanced fibrosis in persons infected with HCV, is essential for long-term follow-up. The presence of advanced disease affects drug choices, especially before the approval of all-oral therapy. Historically, a liver biopsy was obligatory before treatment. Invasive with a significant risk for complications, this requirement effectively prevented treatment in those who were unwilling to undergo the procedure and deterred those at risk from even being tested.

Over the past 25 years, numerous methods to noninvasively assess for liver fibrosis have been used. Serum biomarkers can be either indirect (based on routine tests) or direct (reflecting components of the extracellular matrix). Although highly available, they are only moderately useful for identifying advanced fibrosis and thus cannot replace liver biopsy in the care cascade. The technique of elastography dates back to the 1980s, though the role of vibration-controlled transient liver elastography in the assessment of hepatic fibrosis in patients with HCV was not recognized until around 2005 and it was not commonly used for nearly another decade.

Yet, a paradigm shift in the care cascade occurred with the release of the AASLD/IDSA guidance document in 2014. For the first time in the United States, noninvasive tests were recommended as first-line testing for the assessment of advanced fibrosis. Prior guidelines specifically stated that although noninvasive tests might be useful, they “should not replace the liver biopsy in routine clinical practice.” Current guidelines recommend combining elastography with serum biomarkers and considering biopsy only in patients with discordant results if the biopsy would affect clinical decision-making.
 

The last frontier

Curative therapy has also allowed the unthinkable: willingly exposing patients to the virus through donor-positive/recipient-negative solid organ transplant. Traditionally, an HCV-infected donor would be considered only for an HCV-positive recipient; however, with effective DAA therapy, the number of HCV actively infected patients in need of transplant has dwindled.

Unfortunately as a consequence of the opioid epidemic, the HCV-exposed donor population has blossomed. Given that HCV therapy is near universally curative, using organs from HCV-viremic donors can greatly expand the organ transplantation pool. Small studies[1-5] have demonstrated the safety and efficacy of this approach, both in HCV-positive liver donors as well as in other solid organs.
 

A disease pegged for elimination

In the past 25 years, HCV has evolved from non-A, non-B hepatitis into a disease pegged for elimination. This is a direct reflection of improved therapeutics with highly effective DAAs. Yet, without improved diagnostics, we would be unable to navigate patients through the clinical care cascade. These incredible strides in diagnostics and therapeutics allow us to push the cutting edge through iatrogenic infection of organ recipients, while recognizing that the largest hurdle to elimination remains in finding those who are chronically infected. Ultimately, the crux of elimination remains unchanged over the past 25 years and resides in screening and diagnosis with effective linkage to care.

Donald M. Jensen, MD, is a professor of medicine at Rush University Medical Center, Chicago. He was previously the director of the Center for Liver Disease at the University of Chicago until 2015. His research interest has been in newer HCV therapies. He recently received the Distinguished Service Award from the AASLD for his many contributions to the field.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the AASLD and the IDSA, as well as educational chair for the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.
 

References

Woolley AE et al. Heart and lung transplants from HCV-infected donors to uninfected recipients. N Engl J Med. 2019;380:1606-17.

Franco A et al. Renal transplantation from seropositive hepatitis C virus donors to seronegative recipients in Spain: A prospective study. Transpl Int. 2019;32:710-6.

Goldberg DS et al. Transplanting HCV-infected kidneys into uninfected recipients. N Engl J Med. 2017;377:1105.

Kwong AJ et al. Liver transplantation for hepatitis C virus (HCV) nonviremic recipients with HCV viremic donors. Am J Transplant. 2019;19:1380-7.

Bethea E et al. Immediate administration of antiviral therapy after transplantation of hepatitis C–infected livers into uninfected recipients: Implications for therapeutic planning. Am J Transplant. 2020;20:1619-28.

This article first appeared on Medscape.com.

One of the most remarkable stories in medicine must be the relatively brief 25 years between the discovery of the hepatitis C virus (HCV) in 1989 to its eventual cure in 2014.

HCV afflicted over 5 million Americans and was the cause of death in approximately 10,000 patients annually, the leading indication for liver transplantation, and the leading risk factor for hepatocellular carcinoma, clearly signaling it as one of the era’s major public health villains. Within that span of time, it is the work beginning in the mid-1990s until today that perhaps best defines the race for the HCV “cure.”

In the early to mid-1990s, polymerase chain reaction techniques were just becoming commonplace for HCV diagnosis, whereas HCV genotypes were emerging as major factors determining response to interferon therapy. The sustained viral response (SVR) rates were mired at around 6%-12% for a 24- to 48-week course of three-times-weekly injection therapy. Severe side effects were common and there was a relatively high relapse rate, even in patients who responded to treatment.

By 1996, the addition of ribavirin to the interferon treatment was associated with a modest but significant improvement in SVR rates to above 20%. And by 2000, the use of pegylated interferon – allowing once-weekly injection therapy – along with ribavirin, improved SVR rates to above 50% for the first time. The therapy was still poorly tolerated but was associated with better compliance.

The real breakthrough in therapy came in the early 2000s with the discovery and availability of HCV protease inhibitors: telaprevir and boceprevir. These agents could induce a more rapid decline in viral replication than interferon but could not be administered alone owing to the rapid emergence of resistant HCV variants. Therefore, these agents were administered with interferon and ribavirin as a three-drug cocktail to take advantage of interferon to prevent emergence of resistant variants. Although SVR rates improved substantially to around 75%, adverse events also increased and limited its usefulness in patients with more advanced liver disease, precisely those who were most in need of better therapies.

Nonetheless, the incredible advances in understanding the replication machinery of HCV that led to the discovery of the protease inhibitors in turn led to further elucidation and unlocking of three additional classes of HCV protein targets and inhibitors: NS5A complex inhibitors (e.g., ledipasvir), the NS5B nonnucleoside inhibitors (e.g., dasabuvir), and NS5B nucleoside inhibitors (e.g., sofosbuvir). It quickly became apparent that the use of combinations of these direct-acting antivirals (DAAs) could limit emergence of resistant variants while also providing rapid and profound viral suppression. Because HCV required viral replication to persist in the hepatocyte, it became possible to induce HCV eradication, and thus cure, with combinations of DAAs.

In addition, investigators soon learned that the duration of therapy no longer needed to be the generally accepted 24-48 weeks for SVR, but instead could be reduced eventually to 8-12 weeks. This shortened treatment duration allowed for more rapid testing of new agents and combinations, and the field took a rapid step forward between 2011 and 2017. HCV cure rates rose to 90%-95%.

The competition for Food and Drug Administration approval of new agents among several pharmaceutical companies also meant that the time-honored process of issuing treatment guidelines every 3-5 years by societies would not be adequate. Therefore, in 2013, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America joined forces to establish more nimble and responsive online HCV guidance. This important resource debuted in January 2014 just as the FDA approved the first DAA therapies.

The high cost initially associated with many of these new therapies (up to $1,000 per pill) significantly limited uptake owing to insurance and health plan cost factors. Early on, the cost was also analyzed by price per cure, seemingly to justify the high cost by the high cure rate. However, advocacy and negotiations ultimately led to marked reductions in the cost of a course of therapy (with some therapies at $225 per pill), thus making these treatments now widely available.

By 2020, the HCV field has shifted from therapeutic development to improving the care cascade by enhanced identification and testing of unsuspected but HCV infected individuals. This is our current challenge.
 

Moving toward noninvasive tests

While curative therapy has revolutionized HCV management, innovation in diagnostics eliminated a significant barrier in access to therapy: the liver biopsy.

Staging, or accurately identifying advanced fibrosis in persons infected with HCV, is essential for long-term follow-up. The presence of advanced disease affects drug choices, especially before the approval of all-oral therapy. Historically, a liver biopsy was obligatory before treatment. Invasive with a significant risk for complications, this requirement effectively prevented treatment in those who were unwilling to undergo the procedure and deterred those at risk from even being tested.

Over the past 25 years, numerous methods to noninvasively assess for liver fibrosis have been used. Serum biomarkers can be either indirect (based on routine tests) or direct (reflecting components of the extracellular matrix). Although highly available, they are only moderately useful for identifying advanced fibrosis and thus cannot replace liver biopsy in the care cascade. The technique of elastography dates back to the 1980s, though the role of vibration-controlled transient liver elastography in the assessment of hepatic fibrosis in patients with HCV was not recognized until around 2005 and it was not commonly used for nearly another decade.

Yet, a paradigm shift in the care cascade occurred with the release of the AASLD/IDSA guidance document in 2014. For the first time in the United States, noninvasive tests were recommended as first-line testing for the assessment of advanced fibrosis. Prior guidelines specifically stated that although noninvasive tests might be useful, they “should not replace the liver biopsy in routine clinical practice.” Current guidelines recommend combining elastography with serum biomarkers and considering biopsy only in patients with discordant results if the biopsy would affect clinical decision-making.
 

The last frontier

Curative therapy has also allowed the unthinkable: willingly exposing patients to the virus through donor-positive/recipient-negative solid organ transplant. Traditionally, an HCV-infected donor would be considered only for an HCV-positive recipient; however, with effective DAA therapy, the number of HCV actively infected patients in need of transplant has dwindled.

Unfortunately as a consequence of the opioid epidemic, the HCV-exposed donor population has blossomed. Given that HCV therapy is near universally curative, using organs from HCV-viremic donors can greatly expand the organ transplantation pool. Small studies[1-5] have demonstrated the safety and efficacy of this approach, both in HCV-positive liver donors as well as in other solid organs.
 

A disease pegged for elimination

In the past 25 years, HCV has evolved from non-A, non-B hepatitis into a disease pegged for elimination. This is a direct reflection of improved therapeutics with highly effective DAAs. Yet, without improved diagnostics, we would be unable to navigate patients through the clinical care cascade. These incredible strides in diagnostics and therapeutics allow us to push the cutting edge through iatrogenic infection of organ recipients, while recognizing that the largest hurdle to elimination remains in finding those who are chronically infected. Ultimately, the crux of elimination remains unchanged over the past 25 years and resides in screening and diagnosis with effective linkage to care.

Donald M. Jensen, MD, is a professor of medicine at Rush University Medical Center, Chicago. He was previously the director of the Center for Liver Disease at the University of Chicago until 2015. His research interest has been in newer HCV therapies. He recently received the Distinguished Service Award from the AASLD for his many contributions to the field.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the AASLD and the IDSA, as well as educational chair for the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.
 

References

Woolley AE et al. Heart and lung transplants from HCV-infected donors to uninfected recipients. N Engl J Med. 2019;380:1606-17.

Franco A et al. Renal transplantation from seropositive hepatitis C virus donors to seronegative recipients in Spain: A prospective study. Transpl Int. 2019;32:710-6.

Goldberg DS et al. Transplanting HCV-infected kidneys into uninfected recipients. N Engl J Med. 2017;377:1105.

Kwong AJ et al. Liver transplantation for hepatitis C virus (HCV) nonviremic recipients with HCV viremic donors. Am J Transplant. 2019;19:1380-7.

Bethea E et al. Immediate administration of antiviral therapy after transplantation of hepatitis C–infected livers into uninfected recipients: Implications for therapeutic planning. Am J Transplant. 2020;20:1619-28.

This article first appeared on Medscape.com.