Public health officials are looking to knock out hepatitis C virus (HCV) with a one-two punch that includes near universal screening of adults and a simplified “treat all” approach for those with infection. The goal is to get most infected patients cured or halt their disease progression, dramatically reducing mortality and decreasing costly care for advanced liver disease.
“We now have such effective treatments,” said George M. Abraham, MD, MACP, ACP's President and immediate past chair of the Infectious Disease Board of the American Board of Internal Medicine. “You can essentially achieve cure, 80% to 90% or more in most patients, and you could prevent the progression to cirrhosis. We don't have enough livers to transplant; we don't even have enough partial livers to transplant. People die waiting for livers to transplant.”
The World Health Organization (WHO) has set a goal of eliminating viral hepatitis as a public health problem by reducing new viral hepatitis infections by 90% and reducing deaths from viral hepatitis by 65% by 2030. In the United States, the National Academies of Sciences, Engineering, and Medicine has called for a target of reducing HCV-related deaths by two-thirds over the next decade.
Screening recommendations expand
These efforts got a boost from the U.S. Preventive Services Task Force (USPSTF) in March 2020, when it expanded the population eligible for one-time screening for hepatitis C. The new grade B recommendation calls for screening all asymptomatic adults ages 18 to 79 years without known liver disease by using an anti-HCV antibody test followed by confirmatory polymerase chain reaction testing. The Task Force also called for periodic screening of those with continued risk for HCV.
The USPSTF offered a few reasons for its screening expansion, noting that direct-acting antiviral (DAA) regimens are safer, more effective, and less expensive than in the past and that the prevalence of HCV is increasing, especially in individuals younger than age 40 years.
During 2019, there were 4,136 acute HCV cases reported to the CDC, according to the agency's viral hepatitis surveillance report. That corresponds to an estimated 1.3 cases per 100,000 population, a 63% increase over the rate of 0.8 case per 100,000 reported in 2015. Of the cases reported in 2019, 63% were among people ages 20 to 39 years. For chronic HCV, the highest rate of newly reported cases was among individuals ages 30 to 39 years.
The USPSTF recommendation is in sync with the CDC's screening advice, which recommends that hepatitis C screening be conducted at least once in a lifetime for all adults at least 18 years of age, except in settings where the prevalence of HCV infection is less than 0.1%. The CDC also recommends screening for all pregnant women except where the prevalence of HCV infection is less than 0.1%; testing of anyone with risk factors, regardless of age or setting prevalence; and periodic testing if those risk factors are present. Additionally, testing should be made available to anyone who requests it regardless of known risk factors since patients may be reluctant to disclose “stigmatizing risks,” according to the CDC. The CDC also notes that screening should be universal when HCV prevalence is not known.
If you missed the USPSTF recommendations, you aren't alone. The new advice, which debuted in March 2020, came as most clinicians were dealing with the first wave of COVID-19 infections and nationwide lockdowns. “It was totally lost to COVID,” Dr. Abraham said.
But even if the timing had been better, Dr. Abraham noted, it often takes several years for screening changes to become integrated into standard practice. He pointed to cholesterol screening and hemoglobin A1c as other examples where “it took years to change habits.”
The new screening recommendation represents a significant shift from the current approach of most primary care physicians. Individuals are usually identified for HCV screening based on abnormal liver function, or risk behaviors that come up during a patient history, Dr. Abraham said.
This shift to age-based screening is positive, Dr. Abraham said, because it allows physicians to capture HCV-infected patients who have normal liver function and no abnormal tests, as well as those who are reluctant to share risk history. The availability of multiple DAAs also means that clinicians have effective treatment options when there is a positive test.
But Dr. Abraham also acknowledged several challenges to expanding the screening population. For instance, the number needed to screen to find a single person in need of treatment is high, especially in areas of low HCV prevalence. At the same time, the USPSTF's recommendation for one-time screening, as opposed to periodic screening, has the potential to miss people who engage in risk behaviors after screening. Finally, the stigma associated with HCV makes screening more complicated for this condition, he said.
“As a physician, when I say to a patient that the guidelines say I should screen you for hepatitis C, they all raise their hackles,” he said. “The immediate connotation is, ‘Are you assuming that I'm an injection drug user?’ This is the same dilemma we run into in teenagers when we talk to them about STD screening. It's a huge challenge from that standpoint.”
Stigmatization is just one of many factors that could be keeping this recommendation from taking hold more quickly, according to K. Rajender Reddy, MD, director of hepatology and medical director of liver transplantation at the University of Pennsylvania in Philadelphia and a member of the HCV guidance panel for the American Association for the Study of Liver Diseases (AASLD).
“One [barrier] is perhaps a lack of awareness of the recommendation, a lack of awareness of the magnitude of the problem amongst the entire medical community,” Dr. Reddy said. “Two, it's voluntary and does raise a concern of their insurance status and stigmatization if they are hepatitis C positive. Lastly, linkage to care. You've found a patient who is positive. How sure are you in getting them the treatment? What if they are not insured? Who pays for it? That's a big concern.”
He noted that obtaining insurance approval for treatment can also place a significant burden on medical practices. “The busy primary care physician who is dealing with hypertension and diabetes … does he or she have the resources to put in the paperwork?”
But Paul J. Pockros, MD, FACP, director of the Liver Disease Center at Scripps Clinic in La Jolla, Calif., said the USPSTF move may help to break down some of the barriers by easing the way for improved insurance coverage and by spurring medical centers to add HCV screening as a reminder in electronic health record systems.
A patchwork of insurance requirements varies by payer and by state, according to Joshua M. Liao, MD, MSc, FACP, an internal medicine physician and associate professor of medicine at the University of Washington School of Medicine in Seattle. Just a few years ago there were widespread coverage limits that were based on disease severity, requirements for abstinence from drugs and alcohol before treatment initiation, and requirements that prescribing be done only by subspecialists. Some states, like California, have removed those hurdles, though other states maintain some of the restrictions, and prior authorization is still widespread.
“There's been an overall shift to relaxing those restrictions,” Dr. Liao said, noting the incremental change in some state Medicaid programs. “But it's by no means fixed.”
For example, a recent analysis published in the Journal of Urban Health in February 2020 looked at how Medicaid managed care organizations in New York handled prior authorization after New York State fee-for-service Medicaid eliminated access restrictions based on liver disease stage, active alcohol and substance use, and prescriber limitations in 2016. The researchers found that prior authorization treatment delays decreased but were still present after the policy shift. Rather than delays associated with liver staging criteria, practices now reported issues with medication formularies.
But Dr. Liao noted that while continued insurance restrictions create frustrations for clinicians and patients, Medicaid programs in particular have fiscal challenges in covering these medications, even as costs come down. “The time in which you see benefit with these medications is years, but the budgets for Medicaid programs are annual and have to be balanced,” he said. “It's complex. The complexity is that the coverage of these medications may mean less coverage somewhere else.”
Simplified treatment regimens
The expanded screening recommendation was in part a reaction to improvements in the treatment of HCV, namely the availability of four classes of direct-acting antivirals. These oral treatments can typically achieve cure in 8 to 16 weeks and require minimal upfront testing and monitoring. The cost has also come down significantly, from $1,000 per pill just a few years ago to $10,000 to $15,000 for an entire course of treatment today, experts said.
In a January 2021 Best Practice Advice paper, ACP highlighted the World Health Organization's “treat all” approach to HCV using a combination of DAAs in uncomplicated HCV patients.
“What we wanted to do was provide information to clinicians in the United States about how the WHO guideline applies to the U.S. population because an estimated 2.4 million Americans are living with hepatitis C,” said Amir Qaseem, MD, PhD, FACP, Vice President of Clinical Policy at ACP and a coauthor on the paper. “Primary care physicians play a major and critical role to manage patients with uncomplicated hepatitis C virus.”
The paper spells out how internists can take a pangenotypic approach (i.e., using regimens that achieve a rate of sustained virologic response >85% across all major HCV genotypes) to treating all uncomplicated HCV patients with little monitoring and no invasive testing.
Successful treatment is defined by the WHO and others as having an undetectable viral load 12 weeks after completing therapy, and pangenotypic DAA regimens have pooled rates greater than 85% to 90% for sustained virologic response, according to the ACP paper. The regimens are typically well tolerated with mild adverse effects, but clinicians are cautioned to be aware of the increased risk for hepatitis B reactivation during treatment and the potential for drug interactions with proton-pump inhibitors, statins, antidepressants, and antiretroviral therapy, which can cause some DAAs to be less effective.
“The key here is the ‘treat all’ approach,” Dr. Qaseem said. “The simplification, safety, and effectiveness of the new treatments and reduction in their costs gives us an opportunity to improve hepatitis C care.”
Most HCV patients can be treated with either sofosbuvir-velpatasvir for 12 weeks or glecaprevir-pibrentasvir for 8 to 16 weeks. Some complicated patients—those with decompensated cirrhosis, hepatitis B or HIV co-infection, those with chronic kidney disease, pregnant women, and those who have been previously treated with DAAs—should be treated in consultation with a subspecialist and will likely require more careful lab monitoring, according to the Best Practice Advice paper.
Guidelines from the AASLD and the Infectious Diseases Society of America (IDSA), updated in January 2021, endorse a similar simplified strategy in which primary care physicians can treat most uncomplicated HCV patients using DAA combinations without genotype testing and with limited monitoring.
Under the AASLD/IDSA guidelines, simplified treatment is appropriate for adults with chronic HCV of any genotype who do not have cirrhosis and have not previously been treated. Either glecaprevir-pibrentasvir for eight weeks or sofosbuvir-velpatasvir for 12 weeks is recommended. During treatment, the guidelines recommend monitoring for hypoglycemia in patients taking diabetes medication and monitoring for subtherapeutic anticoagulation in patients taking warfarin.
“Patients who are eligible for simplified treatment are the ideal patients to be treated by a primary care physician,” Dr. Pockros said. “All the other patients who are not eligible should get referred to a gastroenterologist or a hepatologist.”
While viral genotyping is not necessary when dealing with patients eligible for simplified treatment, Dr. Pockros said, there are some simple noninvasive tests, including quantitative HCV RNA, an HIV test, a hepatitis B antigen test, and a pregnancy test, which are important to conduct before starting a treatment regimen.
For internists who have treated patients with HIV, these regimens will be even easier to incorporate into practice, Dr. Pockros said. “It's quite simple.”
Dr. Abraham agreed that the new regimens typically do not require subspecialty care. “The treatments are pretty much so standardized and so simplified and so narrow, in terms of the intricacies of it, that an average internist or primary care physician can potentially treat patients on their own and not require subspecialty care, except in isolated cases,” he said.