The end of the hepatitis C burden: Really?
Authors: Jean‐Michel Pawlotsky
Journal: Hepatology (2016)

Chronic infection with the hepatitis C virus (HCV) is a leading cause of chronic liver disease and its complications, including cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC), and death. Approximately 170 million individuals are infected worldwide. The development of new HCV direct-acting antiviral (DAA) drugs paved the way to the approval of all-oral, interferon (IFN)-alpha-free combination regimens that proved safe and highly efficacious in both large-scale clinical trials and in the real world, with an over 95% cure of infection rate when used according to international liver society guidelines.1, 2 Although better therapies are anticipated for certain groups of patients (e.g., those with genotype 3 infection, advanced chronic kidney disease, decompensated cirrhosis, HCC, etc.), tools exist that could theoretically eradicate HCV from the earth. In the current issue of Hepatology, Chhatwal et al.3 used a validated model and assumptions based on the current HCV treatment situation in the United States to project the effect of DAA-based therapies on the burden of HCV infection up to 2030. Their conclusion is that the HCV-associated disease burden will still remain substantial in the era of oral DAAs, unless HCV screening and treatment capacity are dramatically increased. Definitive eradication of a highly prevalent chronic viral infection that took centuries to adapt and spread over human populations is unlikely to occur. Controlling the infection, that is, making chronic hepatitis C a rare disease with limited morbidity and mortality, is possible with the current available tools. Four conditions must be met to achieve this ambitious goal: (1) Infected patients must be identified; (2) patients with a confirmed diagnosis of HCV infection must have access to a convenient cascade of care; (3) treatment must be simple; and (4) treatment must be affordable. The vast majority of infected patients are unaware of their infection, which is, in most cases, asymptomatic. Finding them is thus challenging. It requires a strong political willingness, often refrained by the implicit acceptance that treatment costs will have to be covered for individuals found with the infection. Once decided, large-scale HCV testing should take place within the framework of national or state action plans. Sensitive and specific tools must be used, while well-defined strategies for screening and confirmation of infection are put in place. HCV testing is generally based on the detection of antibodies to the hepatitis C virus (anti-HCV) antibodies in plasma or serum collected by venous puncture, by means of enzyme immunoassay performed in a central laboratory. Confirmation of infection is based on HCV RNA detection by means of a real-time molecular biology-based technique. A number of tools have been developed to increase patient access to HCV testing. They include rapid diagnostic tests that can use serum or plasma, but also fingerstick capillary whole blood and, for some of them, saliva (crevicular fluid) as matrices. Dried blood spots are also useful to collect and store whole blood samples for subsequent central testing for anti-HCV antibodies and/or HCV RNA. Both approaches have been validated, but the assays must be carefully chosen, given that their performances are variable.4, 5 The choice of the HCV testing approach is crucial. Based on national epidemiology data, the U.S. Centers for Disease Control and Prevention recommended to screen a birth cohort (i.e., all individuals born between 1945 and 1965). Some reports suggested that this approach was successful. For instance, among 24,966 people from 104 health care sites in 21 cities in the United States tested, 2,900 (11.6%) were found to be positive for anti-HCV antibodies. Approximately half were HCV RNA positive, the majority of whom were referred to care.6 However, among 4,221,135 birth cohort veterans receiving care within the Veterans Administration health system between 2000 and 2013, significant variation in testing (7%-83%) was observed, suggesting that implementation of birth cohort testing for HCV failed to be "universal" as initially planned.7 The model presented by Chhatwal et al. further emphasizes the limitations of the birth cohort strategy, estimating that, under the current standard of care, 597,000 (95% confidence interval [CI], 542,000-891,000) of an estimated 834,000 remaining viremic subjects (72%) will be unaware of their infection in 2020 in the United States.3 France adopted a different strategy. Three national action plans for prevention were implemented by the French Ministry of Health. A risk-based testing strategy was launched in 2001, targeting a large variety of risk factors. In 2004, 57% of the estimated 232,196 (95% CI, 167,869-296,523) chronically infected HCV patients were aware of their status.8 Among them, less than 20% were diagnosed for risk exposure, whereas 57% were diagnosed during systematic screening, such as check-up, blood donation, etc. Ten years later, the number of patients unaware of their infection has decreased by only 27%, leaving an estimated 74,102 undiagnosed individuals in the country (plausible range, 64,920-83,283), including 45.4% of men aged 18-59 years.8 This suggests that risk-based strategies tend to plateau after the first few years. A new French complementary screening strategy was recommended in 2014, consisting of one-time simultaneous HCV, hepatitis B virus, and human immunodeficiency virus (HIV) testing in men aged 18-60 years and in women during the first trimester of pregnancy. In the United States, recent studies also suggested that a universal one-time testing might be more effective than birth cohort testing, especially in high-risk urban settings.9 Once infected patients have been identified, reducing the burden of HCV infection can be achieved only if full access to a convenient cascade of care is guaranteed. This would still not be the case in a large number of low- to middle-income areas, where the majority of HCV-infected patients live. Thus, large-scale HCV testing is useless in these regions. Even in places where medical standards are high, there is heterogeneity linked to the type of medical insurance coverage. Most European countries have a national social security system, whereas in the United States private insurers play a greater role. In their article, Chhatwal et al. show a beneficial effect of aging of the HCV population and of the Affordable Care Act, which increased the proportion of patients enrolled in Medicare from 18% to 24% and decreased the proportion of uninsured patients from 26% to 19% between 2010 and 2015. They predict that the number of viremic patients will be highest in the uninsured population by 2019 because of their lower access to treatment.3 Heterogeneous accessibility to expert treating centers and physicians is also key. The expertise and experience of doctors initiating therapy (hepatologists, infectious disease physicians, gastroenterologists, general practitioners, etc.) and their working environment (general practice, primary, secondary or tertiary care center, availability of treating nurses, etc.) greatly vary. Interestingly, large-scale, real-world studies revealed slightly better global efficacy of DAA-based regimens in less-specialized facilities than in tertiary referral centers, probably reflecting the fact that the latter patients have more-advanced, more-complex, thus more difficult-to-cure disease. Access to care has been limited by many institutional or private payers attributed to the high cost of HCV therapies. Initially, mostly patients with advanced liver disease (F3 or F4 fibrosis) and/or severe comorbidities (extrahepatic manifestations, HIV coinfection) were granted access to therapy, whereas treatment was not reimbursed for many infected patients with more-benign disease despite the availability of the very efficient regimens. Appearance of prioritization for therapy in the recommendations for treatment of hepatitis C published by the American Association for the Study of Liver Diseases/Infectious Disease Society of America and by the European Association for the Study of the Liver1, 2 raised considerable emotion in the community that considered treatment was denied to a substantial proportion of individuals with the need and the right to receive it. Both societies now recognize that treatment should be proposed to all patients with HCV viremia who wish to be treated. Accordingly, the French Minister of Health recommended universal treatment for HCV-infected patients in May 2016. However, because of the large number of HCV-infected individuals and the limited health care capacities, not everybody can be treated within a few months. Thus, there remains a need to identify patients who need urgent treatment versus those who can wait for subsequent access to therapy. In the United States, Chhatwal et al. estimate that 1.85 million individuals (95% CI, 1.30-2.32) would receive HCV treatment between 2014 and 2030.3 It is obvious that not all of them can be treated the first year. In 2015, 923,000 patients with insurance were candidates for treatment, including 42% with advanced fibrosis or cirrhosis. Treating these patients first is a priority given that this will maximize the effect on the burden of disease. The model by Chhatwal et al. suggests that prioritization will still be required until 2016-2022, according to the treatment uptake scenario (with 500,000-150,000 patients treated each year, respectively), then patients will be treated irrespective of their fibrosis score as the demand for treatment decreases below the treatment capacity.3 An important condition for optimal access to care is simplicity of therapy. In spite of the high rates of infection cure achieved with the new DAA-based regimens, their use remains complex. Characteristics that inform treatment option selection include HCV genotype and subtype, severity of liver disease, patients' comorbidities, pharmacokinetic treatment profile, potential drug-drug interactions, past treatment experience, and, for some regimens, pretreatment assessment of HCV resistance.1, 2 These parameters are required to choose the ideal drug combination, length of treatment, use of ribavirin, and management of efficacy and tolerability. Simplifying HCV therapy is thus mandatory. Suboptimal treatment regimens should be clearly identified and removed from treatment recommendations. Decision to treat and choice of the optimal regimen should be based on a small number of parameters, such as genotype/subtype, fibrosis stage, and past treatment. Resistance testing before first-line therapy should not be recommended, because optimization of therapy is possible without this parameter.10 Monitoring should be simplified. For instance, it is possible to assess efficacy of therapy with a simple HCV RNA or HCV core antigen test performed at treatment initiation and 12 weeks posttreatment, negativity at the latter time point indicating sustained virological response.11 Future approval of drug combinations with pangenotypic effectiveness may even make pretreatment genotype determination dispensable in the future. These simple measures can only increase treatment uptake and results, moving the hypotheses raised by Chhatwal et al. toward the most favorable numbers. The last condition for global control of HCV infection is the affordability of treatment regimens. The high cost of current HCV treatment combinations has been seen as a major obstacle to broader access to care. Although current drug regimens were reported to be cost-effective, nothing justifies the current prices, except financial considerations on the drug makers' side. On the one hand, one could consider that the money saved on liver disease-related expenses is not truly saved. Being cured from HCV and not dying from its complications will not prevent the same individual from dying from another cause at a very high cost, likely to feed the same drug manufacturers who sell current HCV drugs. On the other hand, the debate is complicated by the fact that payers negotiate with drug companies based on predefined volumes of prescriptions, but the result of these negotiations are not made public. For instance, in many European countries, the actual price national social insurance systems pay for HCV treatment is not known by the patients, the medical community, or the public. The strong need for transparency weighs heavily on democratic societies today, to the extent that this weight of obligation seems dictatorial. It therefore seems quite odd that citizens and the medical world are in the dark as to the cost of medication to their respective governments. More commercial competition is expected in a few months. At the end, the cost of HCV treatments will have to be reduced to a more reasonable level, including the use of generic drugs when necessary, making them affordable and cost-effective at the global level. In conclusion, the article by Chhatwal et al. is an important contribution that raises reasonable hypotheses, suggesting that the burden of HCV-associated disease will remain substantial in the era of IFN-free, DAA-based therapies in the United States and, by extension, in other industrialized countries. In order to decrease this burden, increasing HCV screening, treatment capacity, access to care, simplifying therapy, and making its cost reasonable are essential to further decrease the HCV burden. Only those countries able to take such measures will be able to control HCV. In addition, specific strategies should be put in place to tackle the issue of HCV infection in low- and middle-income areas, where most of the HCV-infected patients live. Otherwise, global eradication of HCV will remain a fantasy. Jean-Michel Pawlotsky, M.D., Ph.D.1,2 1National Reference Center for Viral Hepatitis B, C and D Department of Virology Henri Mondor Hospital University of Paris-Est Créteil, France 2INSERM U955 Créteil, France