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Weighing the Wisdom of Expanded HCV Screening
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Many organizations, including the CDC, have endorsed expanding widespread screening for hepatitis C virus, but experts writing in The BMJ warn that physicians should resist screening until more evidence on the risk-benefit ratio and long-term clinical improvements with antiviral therapy becomes available.
“Expanding screening for hepatitis C to the entire population of persons born between 1945 and 1965 is based on two unproven assumptions: that the benefits of treatment of screen-detected persons will outweigh the harms, and that the 3- or 6-month surrogate outcomes (viral suppression) observed in trials of new treatments will translate into long-term reductions in morbidity and mortality from liver disease,” Kenneth W. Lin, MD, MPH, associate professor of family medicine at Georgetown University School of Medicine, told Healio Gastroenterology. “We need more data to support these assumptions before recommending or mandating that primary care physicians like me start indiscriminately testing millions of older adults.”
John Ward
The CDC, however, is holding firm in its position, according to John Ward, MD, director of the Division of Viral Hepatitis in the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. “We believe it is critical that everyone with hepatitis C know their status, have access to effective care, and discuss with their provider whether treatment is right for them,” he said. “Nearly 3 million Americans are infected with hepatitis C, and at least half don’t know it — and, therefore, don’t realize that their livers are slowly and silently being damaged.”
Jonathan Fenkel, MD, director of the Jefferson Hepatitis C Center and associate medical director of liver transplantation at Thomas Jefferson University Hospital, tried to strike balance on the subject. “I agree with Ward that knowing HCV status is important and I believe screening will impact long-term health outcomes positively, but it is too early to estimate any impact from the CDC’s recommendation for baby boomer screening on mortality, reduction in hepatocellular carcinoma cases, or prevention of liver transplantation,” he said. “We will probably need at least 5 years before this could even be assessed, but if we aren’t screening now, we will never have the ability to obtain this data.”
Healio Gastroenterology spoke to these and other experts about myriad topics related to screening, including the ability of the health care system to handle an increasing influx of patients, the financial implications thereof and what it all means for the practicing clinician. However, it may be helpful to start in the clinic.
End-Stage Liver Disease
Lin and colleagues argue that because 80% to 85% of people with HCV never develop symptoms and die of non-hepatic causes, exposing them to the harms of treatment may outweigh the benefits for the minority (< 0.6%) who develop end-stage liver disease. They said studies suggesting ESLD is common often have referral bias, with cohorts composed of sicker subpopulations of patients with chronic HCV. Patients with chronic HCV infection also tend to die earlier from non-hepatic causes compared with other people, they added, and life expectancy may be further reduced by reasons that led to infection. “Thus, the association between hepatitis C infection and increased risk of death from non-hepatic causes cannot be assumed to be causative,” they wrote.
Furthermore, they said several studies indicate the risk for developing ESLD is low for the first 30 years, but data for risk beyond that point are limited. Likelihood of HCV progression also is influenced by IV drug use, alcohol abuse, obesity or steatosis, older age, genetic factors and coinfection with HIV, so “there may be possibilities for nondrug interventions to prevent hepatic complications.”
Dawn M. Sears, MD, associate professor at the Texas A&M College of Medicine, chief of hepatology at Baylor Scott & White, Temple Division, GI Fellowship Program, said she thinks differently.
Dawn M. Sears
“We are finding more patients at earlier stage of liver disease,” Sears said. “Therefore, we are curing folks and getting patients off of alcohol and soda and back on coffee. These people otherwise would not have known that they had any liver issues. It is too early to tell if we are preventing liver cancers, but we do know that hepatitis C viremia does increase all-cause mortality. Because of this, we are optimistic that we are making a positive impact in many ways that we do not yet appreciate.”
Risks of Therapy
Although newer drugs are considered safer and better tolerated due to fewer and less severe adverse effects, Lin and colleagues noted that interferon is still a component of some regimens. First-generation protease inhibitors have been associated with severe anemia, skin rashes and Stevens-Johnson syndrome and are rarely used today, according to Fenkel. Although safety data are limited for the newest drugs, trials have shown that 3% of patients assigned Sovaldi (sofosbuvir, Gilead Sciences) had severe adverse events compared with 1% assigned peginterferon plus ribavirin; patients assigned Harvoni (sofosbuvir/ledipasvir, Gilead Sciences) with or without ribavirin had a 0.5% to 2% severe adverse event rate.
“Unfortunately, we cannot weigh the risk vs. the benefit at this time because we have no data on the precise benefit (if any),” the researchers wrote.
Lin and colleagues said clinical trials are needed to determine treatment outcomes in screen-detected patients and long-term harms of antiviral drugs.
To evaluate cohort screening, they propose a randomized trial of HCV testing in a large number of participants born from 1945 to 1965 in the United States with a primary outcome of death from liver disease or HCC. “Such a large simple trial could be performed at a low cost in the U.S. by using a simple point of entry approach,” they wrote.
They also said a large study is needed to collect long-term patient outcomes data on the newer drugs and their combinations. “Although 171 interventional studies of new drugs for hepatitis C have been registered on clinicaltrials.gov, most have fewer than 100 participants and follow-up is short, thereby offering no insight into clinical outcomes or the sustainability of virological outcomes,” they wrote.
“Given the converging recommendations from major organizations for widespread screening, the pressure on practitioners to adopt this policy is mounting,” the researchers concluded. “We have a limited window of opportunity to collect appropriate evidence on whether this is a good idea. Until then, physicians should not be pressured to enforce birth cohort screening strategies out of enthusiasm for new treatments that have not yet been shown to cause long-term clinical improvement.”
A final point from Lin and colleagues pertains to the question of whether high percentages of sustained response translate into long-term clinical benefit. “We need to stop separating patients infected with hepatitis C according to sustained response and think about them as those who will, or will not, develop end-stage liver disease,” they wrote. “Sustained virological response is not a cure.”
Handling the Influx
With media attention on HCV at an all-time high, millions of patients are expected to flood the system, raising questions about the capacity of health care systems to support the needs.
“We are able to handle the influx,” Sears said. “Having all-oral, short-course therapy with hardly any side effects and little monitoring means that curing hepatitis C has become similar to curing a bad sinus or bone infection.”
In the post-interferon era, psychiatry clearance and weekly blood draws are no longer required, according to Sears. “The time and intensity of the provider visits for treatment and cure of HCV is about 20% what it used to be,” she said. “We can easily handle increased capacity.”
The real manpower issue is that of pre-authorization and actual drug acquisition, she added. “We used to spend the majority of our resources on the patient — assuring safety, adherence and highest quality of life during difficult side effects,” Sears said. “Now we spend our resources on insurance payers, specialty pharmacies and drug assistance program paperwork.”
The large price tag for novel direct-acting antiviral therapies is largely responsible for this shift. “However, we did a cost analysis on our patients and found that each cure, when we included extra visits, blood work, complications and side effect management, was between $125,000 and $152,000,” Sears said. “With this in mind, the price of $60,000 to $100,000 per cure is a nice bargain that doesn’t include the societal gain of productivity, higher quality of life and increased confidence in cure that we previously did not have with old therapies.”
Jonathan Fenkel
Fenkel looked to the future. “We have the capacity for treating more patients currently, but will probably need more treaters in the next 5 years as more patients are diagnosed and seek care,” he said. “There are many providers who have treated hepatitis C in the past that stopped treating as a result of the complexity associated with protease inhibitor-based triple therapy, but these doctors are starting to reactivate. I like to call it an accordion effect.”
Many experts predict that primary care providers will share an increasing proportion of the HCV treatment load. “It may be worthwhile to develop a certificate program for HCV treatment as there is for HIV treatment,” Fenkel said, but he echoed the comment from Sears that prior authorization has proved prohibitive.
Cost-effectiveness of Screening
New data published in the Canadian Medical Association Journal suggest that screening all Canadians aged 25 to 64 years would be cost-effective and save lives.
Source:Wong WWL
“The screening programs that we evaluated would identify people with chronic [hepatitis C virus] infection who are asymptomatic, which would in turn allow medical treatment to be offered, if needed, according to published guidelines, ideally before development of advanced liver disease,” wrote William W.L. Wong, PhD, of the Toronto Health Economics and Technology Assessment Collaborative and the Leslie Dan Faculty of Pharmacy at the University of Toronto, and colleagues.
Wong and colleagues created a model to evaluate cost-effectiveness of four screening methods: no screening; screening and treating with interferon and ribavirin; screening and treating with interferon and ribavirin, with DAAs; or screening with the same treatment options except for patients with genotype 1 infection, who receive an interferon-free regimen with DAAs.
They found that the screen-and-treat strategies for adults aged 25 to 64 years were more costly than no screening, but they also were effective. For every 10,000 people screened, there would be approximately 63 cases of HCV identified, of which 37 (59%) would be eligible for treatment. Treating these cases would avert nine HCV-related deaths if interferon and ribavirin were used, and 18 HCV-related deaths if DAAs were used.
The researchers broke down the cost-effectiveness of each treatment regimen by quality-adjusted life-years, or QALY, as shown in the Table.
When considering only the population aged 45 to 64 years, the cost-effectiveness ratios increased from $34,359 per QALY for treatment with interferon and ribavirin to $35,562 per QALY for treatment with interferon-free treatment with DAAs to $44,034 for interferon, ribavirin and DAA therapy.
“Early recognition of infected individuals and linkage of these people with care, treatment, alcohol and other lifestyle counseling, and other forms of support could reduce the large pool of undiagnosed HCV infections, save and prolong the lives of people with such infections, and avert the lengthy hospital stays and costs associated with HCV-related end-stage liver disease, liver transplant and hepatocellular carcinoma,” the researchers wrote.
Commentary on Cost-effectiveness
“Making hepatitis C a disease of the past comes with a price, but it will save lives and money in the long term,” Ward said. “Recent CDC analyses indicate hepatitis C testing linked to the new highly effective treatments is cost-effective and can save over 320,000 persons from hepatitis C-related deaths. We also found that the benefits of HCV testing and treatment is comparable to the prevention of many other diseases and the costs of these benefits will decrease as the price of HCV drugs fall.”
Fenkel raised the question of who would benefit from the cost savings. “With the absence of a universal payer in the U.S., the only payers who can truly realize the downstream cost-savings associated with universal screening are Medicare and the VA,” he said. “Commercial plans and Medicaid may not have a subscriber long enough to see that benefit. This is the fundamental reason why screening has not been more adopted and promoted, not a lack of data.”
Sears addressed a different kind of cost. “As we know, liver cancer is exploding, as Gary L. Davis, MD, predicted 5 to 10 years ago,” she said. “The only cure for liver cancer is a $250,000 to $500,000 liver transplant. We know that curing hepatitis C decreases the risk of liver cancer (not eliminating it completely, unfortunately). That, combined with the fact that 70% of those with hepatitis C do not know that they carry the virus and we can now cure 95% of patients with pills supports universal screening. Therefore, yes, I believe that we will find that universal screening will be cost-effective.”
In Clinical Practice
Another area of question is exactly who will be conducting all of these HCV tests, regardless of how effective they may ultimately be. Sears voiced a sentiment expressed by many clinicians, which is that the last thing they need is one more task to accomplish when seeing patients.
It was with this in mind that she and colleagues offered a viral hepatitis test to 500 individuals aged 50 to 65 years who were undergoing a colonoscopy. More than half of the cohort (n = 365) underwent HCV testing. “It is possible to screen patients for viral hepatitis during visits for routine colonoscopy,” the researchers concluded. “This approach can identify individuals with undiagnosed chronic HBV and HCV infections who could benefit from education, vaccination, or therapy.”
Fenkel noted that colon cancer screening is on the radar of most primary care providers. “If they are referred for a screening colonoscopy, they are usually Baby Boomers,” he said. “GI doctors know what to do with the results of a hep C test and could easily screen for hep C at the time of a colon cancer screening referral.”
“Barrett’s esophagus has a median age at diagnosis of 55,” Fenkel added. “Again, firmly within the baby boomer cohort. Patients referred for Barrett’s and colon cancer screening could get a triple cancer screen for esophageal, colon and liver cancers. GI doctors can and should play a bigger role in screening for HCV among patients referred for these conditions.”
Sears suggested that a point of service test such as Oraquick may be the best way for such an approach to become mainstream. “If incentives were added, then this would be likely to occur,” she said. “Bundling things in our mind helps us remember to do them.”
Until HCV testing is tied to pay for performance or considered a Physician Quality Reporting Initiative or meaningful use measure, primary care providers may be unlikely to adopt HCV screening, according to Fenkel. “There are so many things for PCPs to worry about in a short office visit and this is just one more thing,” he said. “There are pockets of doctors who have heeded the call, but they are the minority at this point.”
Moving forward, then, clinicians are encouraged to adhere to CDC recommendations for testing as much as possible. “Implementation of the recommendations is still in the early stages, and CDC is continuing to work to make implementation a reality,” Ward said. “As seen in the implementation of previous recommendations, we have found it always takes time for a new health recommendation to have an impact.”
Fenkel added that these recommendations are not “paramount to previously identified CDC risk factors for HCV acquisition.”
“Don’t forget about younger patients with traditional HCV risk factors like injection drug use,” he said. – by Adam Leitenberger and Rob Volansky
References:
Koretz RL, et al. BMJ. 2015;doi:10.1136/bmj.g7809.Sears DM, et al. Am J Gastroenterol. 2013;doi:10.1038/ajg.2013.50.
Wong WWL, et al. CMAJ. 2015;doi:10.1503/cmaj.140711.
For more information:
Jonathan Fenkel, MD, can be reached at 132 S. 10th St., Suite 480, Philadelphia, PA 19107; email: Jonathan.Fenkel@jefferson.edu.Kenneth W. Lin, MD, MPH, can be reached at 1020 Kearny St. NE, Washington, DC, 20017; email: Kenneth.Lin@georgetown.edu.
Dawn M. Sears, MD, can be reached at Scott and White Memorial Hospital, Department of Medicine, 2401 S. 31st St.,Temple, TX 76508; email: DSEARS@sw.org.
John Ward, MD, can be reached through the Division of Viral Hepatitis email: NCHHSTPMediaTeam@cdc.gov.
Disclosures: Fenkel reports associations with AbbVie, Bristol-Myers Squibb, Gilead and Janssen. Lin, Sears and Ward report no relevant financial relationships.