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Experts warn widespread HCV screening harms may outweigh benefits
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Many organizations have endorsed expanding widespread screening of hepatitis C virus infection, 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.
Kenneth W. Lin
“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, 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.”
Harms to majority vs. benefits to minority
Lin and colleagues argue that because 80% to 85% of HCV-infected people never develop symptoms and die of nonhepatic 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 end-stage liver disease is common often have referral bias, with cohorts usually composed of sicker subpopulations of chronic HCV patients. Patients with chronic HCV infection also tend to die earlier from nonhepatic 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 nonhepatic causes cannot be assumed to be causative,” they wrote.
Furthermore, they said several studies indicate the risk for developing end-stage liver disease 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.”
Treatment efficacy uncertain
The researchers further argue that evidence for treatment efficacy is lacking. Well-designed randomized controlled trials using clinical outcomes are only available for interferon monotherapy, and their results were disappointing, they wrote. They also warn against the limitations of using surrogate markers such as sustained virologic response, serum enzyme activity and hepatic histological assessments, and question 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.”
Treatments can be harmful
Although newer drugs are considered safer and better tolerated due to fewer and less severe adverse effects, they can still cause serious adverse events resulting in disability, hospitalization or death, the researchers wrote. Some drugs are still combined with interferon, which can cause bone marrow suppression and death, and ribavirin, which can cause anemia, leucopenia, skin rashes, gastrointestinal upset and insomnia. Protease inhibitors can cause severe anemia, skin rashes and Stevens-Johnson syndrome. Although safety data are limited for the newest drugs, trials have shown that 3% of patients assigned sofosbuvir (Sovaldi, Gilead) had severe adverse events compared with 1% assigned peginterferon plus ribavirin; patients assigned sofosbuvir plus ledipasvir (Harvoni, Gilead) with or without ribavirin had a 0.5% to 2% severe adverse event rate; and according to FDA data “over 1 year telaprevir (Incivek, Vertex Pharmaceuticals) accounted for the single greatest number of reported severe and fatal skin reactions of any drug monitored.”
“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.
Large randomized controlled trials needed
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 hepatocellular carcinoma. “Such a large simple trial could be performed at a low cost in the US 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.”
Disclosure: The researchers report no relevant financial disclosures.
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