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01 April 2023: Editorial  

Editorial: Effective Direct-Acting Antiviral Treatments Support Global and National Programs to Eliminate Hepatitis C

Dinah V. Parums1A*

DOI: 10.12659/MSM.940519

Med Sci Monit 2023; 29:e940519



ABSTRACT: Eliminating an infectious disease aims to result in no residual disease in a specific geographic area due to deliberate efforts, which may require ongoing control measures to prevent the re-establishment of infection transmission. Currently, no effective vaccines prevent hepatitis C virus (HCV) infection. However, during the past decade, oral direct-acting antivirals (DAAs) have been developed and approved for the treatment of HCV that result in a ‘cure’ in more than 95% of people infected. Morbidity and mortality from untreated hepatitis C result from liver failure, cirrhosis, and HCC and can be prevented by curative treatment with DAAs, which also prevents HCV transmission. Morbidity and mortality from untreated hepatitis C result from liver failure, cirrhosis, and HCC and can be prevented by curative treatment with DAAs, which also prevents HCV transmission. In May 2016, the World Health Assembly of the World Health Organization (WHO) proposed the first global health initiative on viral hepatitis, which proposed the elimination of hepatitis B and C by 2030. In March 2023, the US President announced that in the 2024 fiscal year budget proposal, a 5-year program was approved to eliminate hepatitis C in the US, using a screening and treatment approach. This Editorial aims to present the development of effective and curative DAA treatments for hepatitis C that support the WHO and US Federal programs for disease elimination.

Keywords: Editorial, Hepatitis C, elimination, Infection Control, hepatitis C virus, eradication, Humans, Antiviral Agents, Hepacivirus, Carcinoma, Hepatocellular, Hepatitis C, Chronic, Liver Neoplasms, Liver Cirrhosis, Liver failure

During the past three years, the COVID-19 pandemic has diverted global public health resources and policy on viral testing, genomic surveillance, clinical trials of antiviral agents, and vaccine development for SARS-CoV-2 infection [1]. The pandemic has also highlighted inequalities in healthcare between low-income and high-income countries in response to the pandemic and has raised awareness of the importance of global investment in healthcare and disease prevention [1]. Although attention may have been diverted away from other important diseases, new proposals have been developed to eliminate viral infections with effective treatments, even without effective vaccines. A new paradigm for this approach for improved and more widely available diagnosis and treatment comes from recent initiatives for the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) to eliminate hepatitis C virus (HCV) disease [2–4].

Hepatitis C is an acute or chronic liver inflammation caused by infection with HCV. Transmission of HCV is bloodborne, usually through exposure to blood from contaminated transfusions or needles and sexual transmission of HCV [2]. Infection with HCV may cause a spectrum of disease, from mild acute illness, in approximately 30%, to severe and chronic or lifelong hepatitis in 70% of patients infected with HCV [2]. Chronic HCV infection has a risk of cirrhosis that ranges from between 15% and 30% within 20 years [2]. Chronic HCV infection also increases the risk of developing hepatocellular carcinoma (HCC) [2]. The World Health Organization (WHO) estimates that in Europe and the Eastern Mediterranean region, 12 million people have chronic HCV infection; 10 million in South-East Asia and the Western Pacific region; 9 million in the African region; and 5 million people in North and South America have chronic HCV infection [2].

The severity of chronic hepatitis C in terms of patient morbidity and mortality should not be underestimated, even in developed and high-income countries, such as the US [5,6]. In 2019, hepatitis C was identified as an underlying or contributing cause of death in 14,242 death certificates in the US [5]. Annual death rates from hepatitis C are increasing in the US from new infections associated with the nation’s opioid crisis [5]. Drug treatment is now available and effective, and can result in a ‘cure.’ Therefore, everyone aged 18 years or older should be tested at least once, and people with ongoing risk factors should be tested regularly [5]. However, patients with recent HCV infections are unlikely to be tested if they are asymptomatic, and testing is usually done in patients with chronic liver disease [2]. Diagnostic testing is for anti-HCV antibodies in the serum, followed by a nucleic acid test for HCV RNA, which identifies which patients require treatment [2]. The severity of liver disease is also used to guide patient management [2].

Currently, no effective vaccines prevent HCV infection [7]. However, during the past decade, oral direct-acting antivirals (DAAs) have been developed and approved for the treatment of HCV that result in a cure in more than 95% of infected people [2,5]. The recent clinical development of highly effective DAA agents has changed the clinical approach and outcomes for patients with hepatitis C from management to ‘cure’ [8.9]. Generic DAAs have the potential to ‘cure’ hepatitis C and reduce the burden of liver disease, including in poorly resourced countries [10]. DAAs target several HCV-encoded proteins required for viral replication [8,9]. Approved DAAs and those in the late stages of drug development include inhibitors of NS3/4A protease (glecaprevir, grazoprevir, simeprevir, paritaprevir, and voxilaprevir), NS5B polymerase inhibitors (sofosbuvir), and inhibitors of the NS5A protein (elbasvir, ledipasvir, ombitasvir, pibrentasvir, velpatasvir, and daclatasvir), which are highly effective in treating hepatitis C [8,9]. Importantly, the pan-genotypic NS5A inhibitor, velpatasvir, and the NS5B inhibitor, sofosbuvir, are now co-formulated (Epclusa®, Gilead, Foster City, CA, USA) to be given as a single tablet effective against HCV genotypes 1 to 6, with approval in the USA and Europe, including for children [11].

More than 2 million people in the US are estimated to have chronic HCV infection [3]. Current DAA treatment programs require that patients comply with their treatment regimen for between eight and 12 weeks [3]. In the US, DAAs are unavailable to all infected patients, resulting in more than 15,000 annual deaths from HCV [3,6]. However, the most widely used low-cost pan-genotypic DAA regimen recommended by the WHO is sofosbuvir and daclatasvir [2]. Although there have been attempts to prevent transmission of HCV by public health primary prevention measures, these have not reduced the global burden of chronic HCV infection [2]. Recently, the WHO has recommended that HCV diagnosis and management should be provided by trained non-specialist nurses and doctors in low-income countries [2,10].

In the history of human viral infection elimination and eradication, one major success has been the global elimination of smallpox. In 1980, the World Health Assembly declared that smallpox was eliminated, and no cases of naturally occurring smallpox have occurred since [12]. Due to the control of viral transmission by public health measures and a successful vaccination program, the last natural smallpox outbreak was reported in the United States in 1949 [12]. In 1996, the Forum on Emerging Infections was established by the US CDC and the National Institutes of Health (NIH) to evaluate ongoing research on detecting, preventing, and managing emerging infectious diseases to guide public health policy [13]. At that time, it was acknowledged that the success of smallpox elimination was due to the ability to control viral transmission through public awareness of improved hygiene, the lack of an animal reservoir of infection, and the availability of an effective, safe, and long-lasting vaccine [13,14].

Eliminating an infectious disease aims to result in no residual disease in a specific geographic area due to deliberate efforts, which may require ongoing control measures to prevent the re-establishment of infection transmission [14]. Eradication aims to result in no residual disease globally due to deliberate efforts to remove the infectious organism, which means that control measures will no longer be needed [14]. The criteria used to assess the feasibility of eliminating an infectious disease can be regarded as scientific and social [14]. Scientific feasibility includes infection with no non-human reservoir, ease of diagnosis, naturally occurring immunity, an available vaccine or curative treatment, and demonstration of the feasibility of geographic elimination [10]. The required social and political support includes the recognition of the severity of the disease, the cost burden of the disease compared with that of elimination programs, and the recognition of the requirement for elimination rather than control [14].

Apart from the global eradication of smallpox, further eradication and elimination of major infectious diseases have not been achieved. In 1986, the World Health Assembly of the WHO aimed to eliminate dracunculiasis, due to Guinea worm infestation (dracunculiasis), as a global goal [14]. In 1988, the World Health Assembly aimed to eradicate poliomyelitis [14]. Although dracunculiasis and poliomyelitis occur very rarely, after two decades the goals set by the WHO still need to be achieved, which highlights the challenges [14]. There have also been previous failed attempts to eliminate malaria, yaws, and hookworm [14]. In May 2016, the World Health Assembly proposed the first global health initiative on viral hepatitis for 2016–2020, which proposed the elimination of hepatitis B and C by 2030 [15]. The WHO proposed a 90% reduction in new cases of chronic infections and a 65% reduction in patient mortality compared with the 2015 data [15]. In May 2022, the 75th World Health Assembly of the WHO proposed integrated global health strategies for viral hepatitis, human immunodeficiency virus (HIV), and sexually transmitted infections (STIs) for 2022–2030 [16]. Other countries have followed the WHO to develop national hepatitis programs and infection elimination strategies [17,18].

In March 2023, the US President announced that in the 2024 fiscal year budget proposal, a 5-year program was approved to eliminate hepatitis C in the US, using a screening and treatment approach [3,4]. Morbidity and mortality from untreated hepatitis C result from liver failure, cirrhosis. HCC can be prevented by curative treatment with DAAs, which also prevents HCV transmission [19]. The US Federal program of HCV elimination will prevent costly medical treatments for liver failure and HCC [3,4]. A major reason for this Federal initiative is that although the effectiveness of DAAs to cure HCV infection is established, many people with hepatitis C in the US have limited access to health care [6]. In the US, hepatitis C disproportionately affects low-income patients, those without health insurance, and illicit drug users [6].

In 2020, a report from the US Preventive Services Task Force (USPSTF) showed that only 40% of patients with chronic hepatitis C were aware that they might be infected with HCV [20]. Therefore, screening for HCV is recommended by the USPSTF and the CDC for all adults, pregnant women, and individuals with known risk factors for HCV infection [5,20]. Despite these clinical guidelines and recommendations, screening for HCV has needed more compliance. Treatment for hepatitis C does not commence until two diagnostic steps have been completed, which include an antibody test to detect prior infection and a test for HCV RNA to identify active infection [2]. The laboratory testing results can take several weeks, with a return visit to commence treatment [2]. Also, only about one-third of people diagnosed with hepatitis C have health insurance, and the cost of treatment with DAAs is high [6].

In 2017, the findings of a study from the US Department of Veterans Affairs (VA) that treated more than 92,000 veterans with HCV infection from 2014 identified cure rates in more than 90% of patients [21]. This study also highlighted the importance of managing the cost of medications and ensuring accurate and rapid diagnosis [21].

Therefore, the US Federal 5-year program was developed by including government, patient, and physician groups [3,4]. The 5-year US program aims to expand screening, testing, treatment, prevention, and monitoring of hepatitis C infections by focusing on populations most at risk for hepatitis C [3,4]. There are three main program priorities [3,4]. The first aim is to accelerate the availability of point-of-care (POC) diagnostic tests for HCV, including RNA diagnostic tests and a test-and-treat initiative that can be undertaken at a single hospital or clinic visit [3,4]. The 5-year Federal program’s administration will be undertaken by collaborating with the US Food and Drug Administration (FDA) and the NIH to accelerate clearance or approvals of diagnostic tests [3,4]. The second aim is to provide broad access to curative treatments for hepatitis C medications with a national subscription model to purchase DAAs for those who lack health insurance [3,4]. Also, the pharmaceutical industry might expect more revenue for DAAs from high-risk patient groups than it currently receives, but at a much lower per-patient cost [3,4].

The third aim of the US Federal program includes a public health initiative to identify, inform, and treat people with hepatitis C so that they seek testing and treatment [3,4]. The 5-year Federal program to eliminate hepatitis C in the US will support universal screening as part of routine care, establish testing locations through networks of pharmacies, and increase training programs for clinicians [3,4]. There is also the possibility that this program might stimulate HCV vaccine research following recent developments in mRNA vaccine platforms [7].

In support of the new hepatitis C elimination program, in January 2023, data from a systematic review and meta-analysis study showed that when compared with laboratory-based standard-of-care (SOC) HCV viral load testing, the use of point-of-care (POC) assays was associated with reduced time from antibody test to treatment initiation and increased treatment uptake [22]. The effect of POC viral load testing was most significant when used as part of a simplified care model in which testing and treatment are provided at the same site and on the same day [22]. POC HCV RNA viral load testing is now recommended in WHO guidelines as an alternative to laboratory-based viral load testing for HCV [19]. Australia, Malaysia, Cambodia, and Myanmar have begun to use POC assays in their national screening programs for hepatitis C [23].


Recently, the development and approval of oral DAAs for the treatment and ‘cure’ of patients with hepatitis C has driven both the WHO and the US Federal government to accelerate programs to eliminate this viral disease, which are also supported by POC assays that accelerate patient diagnosis.


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2. World Health Organization (WHO), Factsheet: Hepatitis C June 24, 2022 Available at: https://www.who.int/news-room/fact-sheets/detail/hepatitis-c

3. Fleurence RL, Collins FS, A National Hepatitis C Elimination Program in the United States: A historic opportunity: JAMA Mar 9, 2023, doi: 10.1001/jama.2023.3692 Epub ahead of print

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13. Knobler S, Lederberg J, Pray LAInstitute of Medicine (US) Forum on Emerging Infections: Considerations for viral disease eradication: Lessons learned and future strategies: Workshop summary, 2002, Washington (DC), National Academies Press (US) Available at: https://www.ncbi.nlm.nih.gov/books/NBK98112/pdf/Bookshelf_NBK98112.pdf

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15. World Health Organization (WHO), Combating hepatitis B and C to reach elimination by 2030: Advocacy Brief May, 2016 Available at: http://apps.who.int/iris/bitstream/handle/10665/206453/WHO_HIV_2016.04_eng.pdf

16. World Health Organization (WHO): Global health sector strategies on, respectively, HIV, viral hepatitis and sexually transmitted infections for the period 2022–2030 July 18, 2022 Available at: https://www.who.int/publications/i/item/9789240053779

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18. Gountas I, Yiasemi I, Kyprianou E, Planning the hepatitis C virus elimination in Cyprus: A modeling study: World J Gastroenterol, 2021; 27(31); 5219-31

19. Kwo PY, Puenpatom A, Zhang Z, Initial uptake, time to treatment, and real-world effectiveness of all-oral direct-acting antivirals for hepatitis C virus infection in the United States: A retrospective cohort analysis: PLoS One, 2019; 14(8); e0218759

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21. Belperio PS, Chartier M, Ross DBD, Curing hepatitis C virus infection: Best practices from the US Department of Veterans Affairs: Ann Intern Med, 2017; 167(7); 499-504

22. Trickey A, Fajardo E, Alemu D, Impact of hepatitis C virus point-of-care RNA viral load testing compared with laboratory-based testing on uptake of RNA testing and treatment, and turnaround times: A systematic review and meta-analysis: Lancet Gastroenterol Hepatol, 2023; 8(3); 253-70

23. World Health Organization (WHO): Newsletter. New WHO study: Making diagnosis of hepatitis C more accessible and closer to the community using point-of-care HCV viral load assays January 24, 2023 Available at:https://www.who.int/news/item/24-01-2023-new-who-study-making-diagnosis-of-hcv-more-accessible-and-closer-to-the-community-using-poc-hcv-viral-load-assays

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