Carolyn Wester, MD, MPH is the Director of the Division of Viral Hepatitis (DVH) in the National Center for HIV, Viral Hepatitis, STD and TB Prevention at the Centers for Disease Control and Prevention (CDC).
Q. What is HCV viral-first testing? Is it the same as point of care HCV testing?
Traditionally, CDC has recommended following a two-step process beginning with a Hepatitis C virus (HCV) antibody test and, if that test is reactive, then testing for HCV RNA using a nucleic acid test (NAT).
The testing sequence has traditionally begun with antibody testing because compared to NAT testing for RNA, HCV antibody testing is less expensive and less complex for laboratories to conduct. However, HCV antibody remains reactive even after someone has cleared their infection (either naturally or as a result of curative treatment). As a result, all reactive HCV antibody results need to be followed up with a NAT for HCV RNA to distinguish between current versus resolved HCV infection.
Viral-first testing is an approach in which the initial diagnostic test looks directly for the presence of current infection using a viral test, such HCV RNA or HCV core antigen. Compared to starting with an antibody test, an advantage of viral-first testing is that it shortens the window period between infection and detectable markers of infection by at least 1 month.
CDC already recommends NAT for HCV RNA for people who might have been exposed to HCV within the past 6 months because an HCV antibody test may miss early HCV infection.
It’s important to note that viral-first testing is not always the same as point-of-care testing. Point-of-care refers to where the test is performed—typically near the patient, with results available quickly. Whereas viral-first testing refers to the testing sequence (e.g. utilizing HCV RNA or core antigen to detect HCV as an initial step in the testing algorithm).
Q. What are the potential advantages of HCV viral-first testing both for individuals and for public health efforts to eliminate Hepatitis C virus?
One problem with the antibody-first approach is incomplete testing wherein people with a reactive HCV antibody do not receive subsequent NAT for HCV RNA to diagnose HCV infection. CDC has been working to reduce incomplete testing by promoting the use of automatic HCV antibody to RNA reflex testing across laboratories. While most laboratories have moved away from stand-alone HCV antibody testing, a move to viral-first testing has the potential to substantially increase complete testing and thus increase HCV diagnoses.
Perhaps the greatest advantage of viral-first testing is the identification of early HCV infections that would otherwise be missed by antibody-first approaches. This is because it takes 7-8 weeks from the time of infection before anti-HCV is detectable; in contrast, viral tests can detect HCV infection within about 2 weeks of infection, thereby accelerating the diagnosis of HCV infection by more than 1 month compared to the current antibody-first testing approach.
This is especially relevant in populations that have a high incidence of HCV infection. For example, one study measuring Hepatitis C prevalence among people who inject drugs found that the nearly 10% of participants with HCV infection had early infection (before antibody was detectable). Detection of these early infections has individual and public health benefits. For the individual, diagnosing early HCV infection represents an opportunity to both treat and cure Hepatitis C in that individual and prevent HCV-related complications including cirrhosis, liver cancer, and death. Further, since a person with HCV infection may be most infectious during early infection, diagnosing early HCV infection presents an opportunity to interrupt onward HCV transmission.
Additionally, viral-first testing may have a role in general population screening: a cost-effectiveness analysis published earlier this year evaluated various approaches for diagnosing HCV infection among US adults. Compared with the current antibody-first testing approach, the study found that viral-first HCV testing strategies were potentially cost-effective, resulting in gains in diagnoses and health outcomes.
Q. Can you please provide a brief description of the objectives of a meeting on HCV viral-first testing that the US Centers for Disease Control and Prevention’s (CDC) Division of Viral Hepatitis and the Association of Public Health Laboratories (APHL) held on September 16-17, 2025.
The September APHL-led convening brought together experts from public health laboratories, clinicians, diagnostic manufacturers, policy makers, and community partners to establish a roadmap for the accelerated diagnosis and treatment of Hepatitis C in the United States. Our main objectives were to:
- Describe how to best implement existing diagnostics to meet the needs of patients across a variety of high-impact settings.
- Describe what new technologies are needed to fully build out the HCV diagnostic toolkit.
CDC and APHL collaborated to organize the discussion around 5 key questions:
Two related to HCV point-of care testing:
- What are the optimal settings to utilize POC HCV testing for same-day diagnosis of current HCV infection?
- What are the optimal POC HCV testing sequences and linkage to treatment strategies by setting?
Two related to laboratory-based HCV testing:
- What are the benefits of various laboratory-based viral-first testing strategies for the diagnosis of HCV infection in the U.S.?
- What barriers need to be overcome to implement laboratory-based viral-first HCV testing in the U.S.?
And a final key question:
- Is it time to move to viral-first HCV testing guidance for clinicians and laboratorians in the U.S.?
Through these questions, convening participants:
- Reviewed the strengths and limitations of existing HCV diagnostic technologies, including how they are being implemented to improve Hepatitis C diagnosis and treatment
- Identified the potential benefits of viral-first testing, as well as the barriers and opportunities to bringing viral-first diagnostics to the United States, and
- Charted a short-term path forward to advance HCV diagnostics that support the scale-up of early diagnosis and rapid treatment initiation in the U.S.
Q. What were some important takeaway points from the 5 key questions mentioned above?
A key takeaway is that HCV testing and treatment approaches need to be tailored across the full range of settings where people with Hepatitis C receive care. These approaches should be tailored in a way that maximizes the likelihood of diagnosis and initiation of treatment, while minimizing cost.
For example, most clinical settings like primary care offices and emergency departments with access to phlebotomy and laboratory testing may find it easier to maintain laboratory-based testing practices. These settings may serve communities with a low HCV prevalence and encounter mostly low-risk patients who may be likely to seek follow-up care. This reduces the need for point of care diagnosis and immediate linkage to treatment and favors laboratory-based testing.
Conversely, non-clinical settings like syringe service programs or brief encounter settings like jails or mobile health units may serve high prevalence populations, and/or patients who are unlikely to seek follow up care. This favors point-of-care testing for ease of sample collection and rapid, on-site diagnosis that can be paired with linkage to treatment.
Laboratory-based testing offers high throughput, lower cost testing and accounts for the vast majority of Hepatitis C testing in the U.S. However, its longer turnaround time, driven largely by to the need to transport a specimen from collection site to the laboratory, can delay results and contribute to loss to follow up. These operational limitations affect both traditional two-step and viral-first laboratory approaches, which is why it will be important to tailor testing strategy to setting.
Although antibody testing is generally cheaper than NAT, a recently published cost-effectiveness study showed two viral-first testing strategies to be cost-effective when compared to the current antibody-first two step approach. Unfortunately, the diagnostic tools needed to support widespread viral-first testing in U.S. laboratories either do not have the appropriate (viral-first) regulatory authorizations or are not currently accessible in the U.S. market.
In comparison to laboratory-based testing, point-of-care testing offers faster results and opportunities to rapidly initiate treatment, but widespread implementation is currently limited by cost, test complexity, and limited throughput. In the context of point-of-care testing, there was robust discussion around using one-step RNA testing versus the two-step antibody-first strategy. Despite the advantage of HCV RNA POC testing being able to detect early infection, which is particularly important in populations with active transmission, panelists emphasized that the two-step antibody-first approach is preferrable in many instances given that currently available POC antibody tests are more cost effective and have shorter run times than RNA POC tests, resulting in a maximization of resources and more clients receiving their test results during the initial visit.
Overall, there was widespread recognition of the utility of viral-first testing in advancing earlier diagnosis of HCV infection, and support for viral-first testing as an alternative to two-step testing sequences. At the same time, it was emphasized that any changes in testing guidance should be mindful not only of what diagnostic tools currently exist but also of what tools are needed.
Lastly, there was a clear message about the importance of rapid treatment initiation. While co-location of treatment at the site of HCV testing is ideal, there are newer models of care that use innovative strategies to expand access to treatment where co-location of Hepatitis C treatment is not feasible. This includes the use of telehealth, mobile health units, and peer-led navigation and coordination to provide Hepatitis C care in a variety of high-impact settings at scale.
Q. What changes/advances in technology, policy, practice, and infrastructure would be necessary in order to expand the availability of HCV viral-first testing in the U.S.?
A focus on several priorities will help advance viral-first testing:
- First, CDC has been working on updating its HCV testing guidance to laboratorians and clinicians. Providing guidance to support viral-first testing with HCV RNA or concurrent antibody/core antigen testing will signal the need for these options with manufacturers, leading to their eventual authorized use in the United States.
- Second, as an increasing number of testing and treatment strategies become available, there is a need to provide education, training, and support for the implementation of best practice testing and treatment strategies tailored to specific high-impact settings. CDC will explore opportunities to accomplish this through existing resources as well as plan a larger training and implementation network should we receive additional funding for Hepatitis C elimination.
- Third, there is a need to create a supportive environment for HCV elimination by reducing restrictive barriers to testing and treatment. This includes updating test reimbursement frameworks, streamlining prior authorization requirements and modernizing data systems to enhance interoperability and ensure that HCV test results from all settings can be used for surveillance purposes and to enhance continuity of care. These steps will strengthen the system needed to advance HCV elimination goals.
