Editorial
Prevention of Liver Cancer With New Curative Hepatitis C Antivirals: Real-World Challenges Vicente Soriano
1
Ayalew Tefferi2
Although less than 15% of all human cancers are produced by viruses, the epidemiology and treatment paradigms of these neoplasms are unique.1,2 There are 6 oncogenic viruses that cause tumors in humans, including hepatitis B virus and hepatitis C virus (HCV; Table 1). Interestingly, although a large number of people in the world harbor at least 1 of these oncoviruses, only a small proportion of carriers go on to develop cancer. Human immunodeficiency virus (HIV) contributes indirectly to viral cancers by causing immune dysfunction, and this is why the AIDS virus is considered within the category of cancer viruses by the International Agency for Cancer Research.2 The current burden of HCV infection is enormous. Roughly 100 million persons worldwide have serological evidence of a current or past HCV infection, and this means that they are reactive for HCV antibodies. Because 30% would be aviremic after spontaneous HCV clearance, the estimate for chronic hepatitis C globally is 71 million people.3 Notably, approximately half of these people live in 5 countries (China, Pakistan, India, Egypt, and Russia). Hepatitis C causes globally more than 400,000 deaths each year. The prevalence is highest in low- and middleincome countries, in which a significant number of infections are iatrogenic and due to injections with contaminated, recycled needles. In contrast, in developed countries, infections are mainly caused by high-risk exposures and behaviors among specific populations, such as injection drug users and men having sex with men.4 In the United States, 3 million people are estimated to be infected with HCV, which causes more than 25,000 deaths annually, and new infections are on the rise, largely as a result of the resurgence of injection drug use.5 The advent of new HCV drugs known as direct-acting antivirals (DAAs), which provide unprecedented and very high curative rates (>95%) with short courses (8-12 weeks) of oral therapy,6 has transformed chronic hepatitis C into a curable condition. Therefore, hopes have been renewed, and the World Health Organization (WHO) has set up a roadmap for the elimination of viral hepatitis as a public health threat. Briefly, it aims to reduce new HCV infections by 30% by the year 2020 and by 90% by 2030. In parallel, HCV-associated deaths should decline 10% by 2020 and 65% by 2030.7 The WHO goals for hepatitis C should be interpreted in light of global projections for other major infectious diseases, such as HIV, tuberculosis, and malaria (Fig. 1A). Unfortunately, although mortality is declining for these infections, deaths due to HCV are rising globally,8 and in the United States, HCV has already surpassed HIV as a cause of mortality.9 Roughly 25% of individuals with chronic hepatitis C go on to develop cirrhosis at some point in their lives. The yearly risk for developing hepatocellular carcinoma (HCC) is 5% for patients with cirrhosis.10 A large intercontinental, collaborative study followed nearly 175,000 patients with chronic hepatitis C from 2001 to 2014, when DAAs replaced interferon-based therapies. A total of 2124 individuals developed HCC during the study period. Across all settings, the HCC burden increased, with older age being the strongest predictor of an HCC diagnosis. The median survival was very short: less than 1 year after the HCC diagnosis.11 These findings highlight the minimal impact of HCC prevention and management strategies during the interferon-based HCV treatment era, and they form the basis for evaluating the impact of DAA therapy in the coming years. It must be stressed that the benefit of curing HCV goes beyond the prevention of HCC in chronic carriers.12 A wide constellation of clinical complications, ranging from direct effects of hepatic damage causing decompensated cirrhosis to extrahepatic conditions such as cryoglobulinemia, insulin resistance and type 2 diabetes, and neuropsychiatric abnormalities, can improve after HCV is cured.12,13 Even cancers other than HCC (ie, some B-cell lymphomas) have been associated with persistent HCV infections and could also be prevented with successful DAA therapies.14 Corresponding author: Vicente Soriano, Infectious Diseases Unit, La Paz University Hospital, Madrid 28035, Spain;
[email protected] 1
Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain; 2Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
See referenced commentary on pages 1644-46, this issue. DOI: 10.1002/cncr.31291, Received: December 5, 2017; Accepted: January 13, 2018, Published online February 27, 2018 in Wiley Online Library (wileyonlinelibrary.com)
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Editorial TABLE 1. Human Oncoviruses Virus Epstein-Barr virus
Human papillomavirus
Hepatitis B, C, or D virus Human T-lymphotropic virus type 1 Human herpesvirus type 8
Polyomavirus
Cancer Burkitt lymphoma Diffuse large B-cell lymphoma Primary cerebral lymphoma Nasopharyngeal carcinoma Gastric carcinoma Anorectal cancer Cervical cancer Head and neck carcinoma Hepatocellular carcinoma Adult T-cell leukemia/lymphoma Kaposi sarcoma Multicentric Castleman disease Primary effusive lymphoma Merkel cell cutaneous carcinoma
In this issue of Cancer, Kantarjian and Paul15 stress that the current high prices of DAAs make treatment unaffordable for many. They correctly point out that major clinical complications and deaths due to HCV are largely avoidable because the viral infection is curable. However, the large revenues of pharmaceutical drug companies are only part of the true scenario that is challenging HCV eradication worldwide, and one should acknowledge the major challenges of diagnosis and referral to medical care.16 The poor contribution of DAAs to HCV control worldwide is largely explained by the fact that most infected people are not aware of their infection, and as such, most are not treated for reasons other than high drug costs. A recent conference held in Chicago by the Alliance to Eliminate HIV/HCV Coinfection (AEH2C), which included participants from the WHO and the US Centers for Disease Control and Prevention, emphasized that major efforts should be made to expand HCV screening.17 Guidelines and recommendations for HCV antibody testing have been released by both organizations. However, although the WHO emphasized new point-ofcare tools and rapid tests,18 the Centers for Disease Control and Prevention prioritized screening of baby boomers (those born between 1945 and 1965).19 Along with strategies to expand HCV testing, the AEH2C report concluded that in view of the HCV cascade, as shown in Figure 1B, the number of hepatitis C care givers must increase substantially.17 Because of the limited number of hepatologists and infectious diseases physicians, DAA prescriptions should not be restricted to these specialists so that others and general practitioners can treat hepatitis C. Other initiatives, including distinct telemedicine modalities (ie, Extension for Community Healthcare Outcomes [ECHO]), should be considered to widely expand access to hepatitis C therapies.20 In line with these thoughts, the Global Burden 1648
Figure 1. Burden and treatment cascade for hepatitis C: (A) deaths due to major infectious diseases worldwide and (B) hepatitis C treatment cascade. Ab indicates antibody; DAA, direct-acting antivirals; HCV, hepatitis C virus; HIV, human immunodeficiency virus.
of Disease collaboration has recently concluded that the achievement of WHO targets for the elimination of HCV would be possible only with a multifaceted approach that, in addition to expanding HCV screening, should increase treatment access for patients without liver fibrosis and gradually be scaled up to treat all HCV-infected persons.16 In summary, the recent advent of short-term, easyto-take curative oral therapies for hepatitis C has unveiled the huge efforts that must be implemented to translate into the real world the benefit of these new good medications. In addition to requests for affordable drug prices from pharmaceutical companies, global HCV eradication will demand a strong commitment by others and at different levels, with diagnosis and treatment referrals being among the most important considerations.16,21 Lessons can be taken from prior failures to eradicate other infectious diseases with effective preventive vaccines (ie, hepatitis B and polio) and, conversely, from the only success to date, the global elimination of smallpox. FUNDING SUPPORT No specific funding was disclosed.
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Prevention of Liver Cancer Curing HCV/Soriano and Tefferi
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
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