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. 2020 Mar;10(3):a036913. doi: 10.1101/cshperspect.a036913

Hepatitis C Virus Epidemiology and the Impact of Interferon-Free Hepatitis C Virus Therapy

Jeffrey V Lazarus 1, Elena Roel 1,2, Ahmed M Elsharkawy 3
PMCID: PMC7050577  PMID: 31570385

Abstract

The public health impact of hepatitis C virus (HCV) infection has been realized only recently. Globally, 71 million people are living with HCV chronic infection. HCV prevalence is higher in some regions and countries, as well as in some subpopulations such as people who inject drugs, prisoners, or people living with HIV. In 2017, an estimated 580,000 people died from HCV, largely because of long-term complications of the disease. The advent of direct-acting antivirals (DAAs), which are highly effective in treating the infection and are well tolerated, led the World Health Organization (WHO) in 2016 to call for the elimination of HCV by 2030, which would be possible by meeting the numerical targets laid down by the organization. However, at present, only 12 countries are on track. Overall, only 20% of people with HCV have been diagnosed and only 7% of people diagnosed have initiated treatment, with major differences among countries. Underdiagnoses, a general lack of awareness, poor surveillance, and the prices of diagnostics and treatment remain major barriers to achieving the elimination goals. Comprehensive strategies, which include innovative models of care and the removal of reimbursement restrictions for treatment, are needed to overcome these public health and health system obstacles.

GLOBAL EPIDEMIOLOGY OF HEPATITIS C VIRUS

Infection with the hepatitis C virus (HCV) is a worldwide epidemic. Its prevalence across continents, the morbidity and mortality it causes, and poor rates of diagnosis and treatment are major public health challenges. In 2015, according to the Global Hepatitis Report (World Health Organization 2017a), 71 million people (i.e., 1% of the world's population) were chronically infected with HCV, yet only one out of five was aware of their status (World Health Organization 2018). Overall, in 2015 there were 1.75 million estimated new HCV infections, with an incidence of 23.7 per 100,000 population. The Global Burden of Disease Collaborative Network (2018) estimated that, in 2017, 580,000 people died from HCV, the vast majority from long-term complications (Roth et al. 2018). Complications of cirrhosis are the leading cause of mortality due to HCV (342,000 deaths) followed by hepatocellular carcinoma ([HCC]; 234,300 deaths). Although several studies point out that incidence rates may have been declining over the past decades, the burden of the disease has increased recently as the infection has a long incubation rate and diagnoses have begun to increase (World Health Organization 2017a; Roth et al. 2018). From 2000 to 2017, mortality from HCV-attributable cirrhosis increased by 17.4% and HCC by 30.4% (Roth et al. 2018). Additionally, because of the rapid spread of the epidemic in earlier decades in several low- and middle-income countries (LMICs), including high-burden settings like Egypt, Mongolia, and Pakistan, a large number of people will develop HCV-related complications in the coming years. Morbidity and mortality are expected to increase unless testing and treatment are greatly scaled up (World Health Organization 2017a). In 2016, only 1.76 million people received treatment for HCV infection, comparable to the number of newly infected in 2015 (World Health Organization 2018). As a global community, we are a long way from making a significant dent in the overall global HCV disease burden.

The distribution of HCV varies widely among World Health Organization (WHO) regions (World Health Organization 2017a). Overall, 75% of the people living with HCV live in LMICs (World Health Organization 2018), with the highest prevalence in the Eastern Mediterranean region followed by the European region (2.3% and 1.5%, respectively), as well as estimated incidence (61.8 and 62.5 new cases per 100,000, respectively), almost triple the global rate. The Western Pacific region and the region of the Americas have the lowest estimates for both prevalence and incidence. Nonetheless, the burden of HCV within the regions is heterogeneous. For instance, the country with the largest prevalence is Egypt with 6.3% of the population affected in 2015 (El-Akel et al. 2017). This is attributed to the use of nonsterile injections during a national campaign to treat schistosomiasis during the 1950s–1980s, the largest-ever recorded iatrogenic transmission of an infectious disease (Frank et al. 2000; Cooke et al. 2019). China has the largest number of people living with HCV (almost 10 million), followed by Pakistan (7.2 million) and India (6.2 million; World Health Organization 2018). Major differences can also be observed in the total amount of disability-adjusted life years (DALYs) with the highest burden of disease (combined hepatitis B and C) in the Western Pacific and Southeast Asia (Fig. 1). In the last years, DALYs have increased in all WHO regions in the world apart from Europe.

Figure 1.

Figure 1.

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Trends of disability-adjusted life years (DALYs) per 1000 due to hepatitis C virus (HCV)-related cirrhosis and HCV-related liver cancer by World Health Organization (WHO) regions, 2000–2017. (Courtesy of the Global Burden of Disease Collaborative Network [GBD 2017] results; reprinted, with permission, from the Institute for Health Metrics and Evaluation [IHME] 2018.)

Epidemiology of HCV in Specific Population Groups

People Who Inject Drugs

Regardless of the region or country, prevalence is almost always higher in high-risk populations, which is strongly correlated with the mode of acquisition. HCV is transmitted mainly through parenteral and, to a lesser extent, sexual exposure, with the major risk factors for transmission being injection drug use (needle- and syringe-sharing), unsafe health-care practices, and sexual contact (usually between men who have sex with men [MSM]). The main sources of transmission differ among and within regions in correlation with socioeconomic conditions. Injection drug use is the leading cause of HCV infection in high-income countries, whereas unsafe health-care practices account for the largest proportion of new infections in LMICs (World Health Organization 2017a).

Generally, people who inject drugs (PWID) have the highest prevalence of chronic HCV infection. Globally, an estimated 15.6 million people aged 15–64 years are PWID (Degenhardt et al. 2017). A systematic review estimated that, in 2015, 8.5% of people with HCV chronic infection (6.1 million) were PWID with a history of recent (in the previous year) injection drug use (Grebely et al. 2018b). Overall, 39.2% of recent PWID were living with HCV infection and 52% of PWID were HCV antibody–positive (Degenhardt et al. 2017). HCV viremic prevalence in recent PWID showed large disparities across regions, ranging from 16.3% in sub-Saharan Africa to 48.6% in Eastern Europe (Fig. 2). The true burden of HCV chronic infection among this population subgroup is presumably underestimated, considering the scarcity of reliable statistics among this population and the significant barriers they encounter in accessing health-care facilities (e.g., stigma, criminalization of drug use) and, consequently, to testing, linkage to care, and treatment. Furthermore, the majority of available epidemiological data rely on HCV antibody positivity, which does not necessarily reflect active viremia.

Figure 2.

Figure 2.

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Estimated prevalence of hepatitis C virus (HCV) viremic infection among people with recent injection drug use by country. (Reprinted, with permission, from Grebely et al. 2018b, © Wiley.)

People Living with HIV

People living with the human immunodeficiency virus (HIV) are also a risk population for HCV infection, mainly because both viruses share the same routes of transmission—for example, injection drug use and, to a lesser degree, sexual transmission—and because coinfection with HIV reduces the probability of spontaneous clearance of the virus and accelerates liver disease progression in untreated individuals (Pineda et al. 2005). In 2015, among the estimated 36.9 million people living with HIV worldwide, 6.2% (2.3 million) had HCV chronic infection and 59% of these were PWID (UNAIDS 2018). HCV prevalence is also higher among MSM, particularly HIV-positive MSM. The main risk factor for HCV acquisition in MSM, as well as in individuals living with HIV, is drug use. However, another relevant source of transmission among this population that should be considered in the response is sexual exposure, particularly certain sexual practices that may lead to the exchange of blood (Gorgos 2013; Jin et al. 2017).

People in Closed Settings

Closed settings, such as prisons, have a high burden of HCV. Imprisoned individuals are a key population as a result of a unique conjunction of environmental risk factors, such as the high prevalence of injection drug use, high-risk sexual behaviors, poor hygienic conditions, sharing of personal care items, and scant prevention programs to reduce HCV infection in prisons. HCV incidence among incarcerated people has been reported at 30 new cases per 100 prisoners/year in Australia, and prevalence ranges between 1.8% and 20.6% worldwide (Cooke et al. 2019).

Unsafe Blood and Health-Care Practices

Another important driver of the epidemic is unsafe health-care practices. Blood transfusion and infected health-care injections were globally the leading causes of transmission before HCV testing of blood donations became available, although other sources of iatrogenic transmission have been described (Defendorf et al. 2018), such as surgery, dental care, and solid organ transplantation from infected donors. Before the 1990s, almost all patients with inherited blood disorders (e.g., hemophilia) acquired HCV infection due to transfusion of contaminated blood products, and 80% became chronically infected (Van De Putte et al. 2014). Hemodialysis patients are also a high-risk population, as these patients tend to have had multiple potentially unscreened blood transfusions in the past, and nosocomial infections still occur in many dialysis units worldwide. Fortunately, major advances have been made to reduce this route of transmission, although unevenly across regions. Between 2000 and 2010, injection-associated HCV infection decreased by 83%, mainly because of the widespread use of single-use syringes and needles (Pépin et al. 2014). Although most high-income countries have established systems to ensure safe health-care practices, in LMICs, blood screening coverage is insufficient and up to 5% of health-care injections are unsafe (World Health Organization 2017b). They remain a significant source of transmission, particularly in the WHO Eastern Mediterranean region (World Health Organization 2017a).

In summary, HCV chronic infection is a global epidemic and a significant cause of liver disease, with a higher burden in certain countries and high-risk populations. However, reliable high-quality epidemiological data are scarce, particularly in LMICs, as well as in some subgroup populations with a higher risk of HCV infection (World Health Organization 2017a; Cooke et al. 2019). Statistics on HCV are, thus, frequently based on estimations. Incidence is often modeled from prevalence rates, as collecting direct incidence data poses several challenges: acute infections remain undiagnosed because they are frequently asymptomatic, most countries do not have surveillance systems for acute hepatitis, and there is no specific diagnostic test that dates the infection accurately. Accurate prevalence rates are also challenging because individuals remain asymptomatic for years and screening programs are not universally rolled out. As for HCV-related mortality, it remains underestimated as a result of underreporting on death certificates. A substantial proportion of the deaths attributed to HCC or cirrhosis are also likely related to HCV infection, considering that 80% of people with HCV are unaware of their status (World Health Organization 2017a). Hence, the real burden of the disease remains poorly defined.

HCV TREATMENT WITH DIRECT-ACTING ANTIVIRALS

Unlike other chronic infectious diseases, such as HIV, HCV can be treated and cured. A cure consists of achieving a sustained virological response (SVR), defined as undetectable HCV RNA in serum or plasma by a sensitive assay (lower limit of detection ≤15 IU/mL) 12 weeks (SVR12) or 24 weeks (SVR24) after completing treatment (European Association for the Study of the Liver 2018). Late relapse is extremely low, so SVR strongly correlates with a definitive cure.

Treatment with Interferon-Based Therapies

Before 2012, pharmacological treatments for HCV were interferon-based. The recommended therapy included a modified (pegylated) form of interferon α combined with ribavirin. In 2012, protease inhibitors (boceprevir and telaprevir) were added to these treatment regimens, although these were effective only for genotypes 1 and 4. SVR varied greatly, depending on the HCV genotype, which was the strongest predictor of clearance. Before 2013, SVR rates were high (up to 80%) for genotypes 2 and 3 but remained inadequate for genotypes 1 and 4 with cure rates of ∼50%–60% (Ansaldi et al. 2014). The long duration of therapy, ranging from 24 to 48 weeks, complexity of the dosage regimens, and frequent adverse events led a large number of patients to abandon treatment, meaning that the true cure rates were lower than those quoted. Further, many patients remained untreated because of comorbidities/interactions with other drugs or the high costs. Globally, treatment coverage ranged from <1% to 5% of individuals with HCV chronic infection. Hence, although all HCV-infected patients were, in principle, potential candidates for undergoing treatment, only a small percentage were successfully treated (Dore and Feld 2015).

Advent of Direct-Acting Antivirals

The advent of direct-acting antivirals (DAAs) in the past decade has totally revolutionized the HCV panorama (Fig. 3; Dore and Feld 2015; Burstow et al. 2017). In 2013, the approval of sofosbuvir and simeprevir by the U.S. Food and Drug Administration, followed by the European Medicines Agency in January 2014, led to the beginning of interferon-free therapies (Dore and Feld 2015). DAAs have since been continually evolving (Dore and Feld 2015; Baumert et al. 2019), and at present, several different combinations and schemes of DAAs are available. Globally, five single-component DAAs and six fixed-dose combinations have been approved by at least one reliable authority (World Health Organization 2018).

Figure 3.

Figure 3.

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The evolution of direct-acting antiviral (DAA) therapies. (IFN) interferon, (RBV) ribavirine, (TVR) telaprevir, (BOC) boceprevir, (SMV) simeprevir, (SOF) sofosbuvir, (LDV) ledipasvir, (OBV) ombitasvir, (PTV) paritaprevir, (R) ritonavir, (DSV) dasabuvir, (DCV) daclatasvir, (VEL) velpatasvir, (EBR) elbasvir, (GZR) grazoprevir, (VOX) voxileprevir, (G) glecaprevir, (P) pibrentasvir.

DAA therapies are highly effective, well-tolerated, and have short treatment durations, ranging from 8 to 12 weeks. They act by directly inhibiting protein functions involved in the life cycle of HCV. They achieve SVR in ≥95% of patients, irrespective of HCV genotype, removing the absolute requirement to perform genotype testing before starting treatment in all but confirmed cirrhotic patients in which G3 disease merits special consideration (this is a minority of patients required to achieve HCV elimination in a global setting). This means that DAAs can be more widely prescribed, especially in resource-limited environments in which genotype testing can be challenging and costs can be prohibitive. Further, advanced liver disease, comorbidities, and concomitant medication are not contraindications to treatment with DAAs. They remain highly effective among special populations, such as patients with chronic kidney disease (Ridruejo et al. 2018), hemoglobinopathies (Origa et al. 2017), HIV/HCV-coinfected individuals (Bhattacharya et al. 2017; Hézode 2018), PWID (Grebely et al. 2017, 2018a), older individuals (Conti et al. 2017), and those with advanced liver disease (Holzmann et al. 2018). In real-life conditions, also, DAAs are highly effective (Cornberg et al. 2017; Puenpatom et al. 2017; Ji et al. 2018). Overall, DAAs are significantly more effective, better tolerated, and easier to take than previous treatments.

After the introduction of DAAs, their use grew spectacularly in a short span of time. In 2015, only half the people treated for HCV received DAAs, whereas in 2016, 86% did (World Health Organization 2018). However, treatment reached only a small proportion of those living with HCV, with higher annual treatment rates in high-income countries. In 2016, HCV cases treated with DAAs ranged from 0.1% in sub-Saharan Africa to 8.1% in North America, and differences were even greater across other countries (e.g., 0.0015% in Kenya and 50% in Iceland) (Hill et al. 2017). Only four countries with a high prevalence had treatment rates above 10%: Australia (16%), Japan (12%), Netherlands (12%), and Egypt (12%). Particularly noteworthy is the case of Egypt, which reportedly accounted for almost 40% of people treated globally in 2016 and is a leading country in the hepatitis C elimination drive, despite being the one with the highest prevalence (World Health Organization 2018).

Obstacles to Treatment with DAAs

Low rates of and inequities in HCV treatment coverage are largely explained by major gaps in screening and diagnosis coverage, along with financial barriers. In 2017, only 20% of people living globally with HCV were estimated to have been diagnosed with vast disparities throughout regions; in high-income countries and LMICs, 57% and 92% of people living with HCV, respectively, remained undiagnosed (World Health Organization 2018). Early diagnosis is critical for preventing complications and reducing ongoing transmission of HCV, yet remains challenging. HCV infection is often asymptomatic for years and HCV testing requires resourcing, which can be challenging in some settings, as it usually requires serological testing for HCV antibodies followed by a confirmatory HCV RNA test. Between screening and confirmatory testing, there is often a gap in linkage to care (Cooke et al. 2019). Diagnosing HCV epidemics requires setting up screening strategies, either for the general population or targeting key populations at higher risk (e.g., PWID and prisoners). However, screening programs, although increasing globally, are not yet adequate and key at-risk populations remain ill-defined in regions in which epidemiological data are lacking. Additionally, establishing screening programs, as well as surveillance systems, can be expensive, considering all the associated costs (test kits, health-care training, human resources, and quality monitoring).

The prices of and reimbursement restrictions for DAAs also hinder scaling up of testing and diagnosis, as the lack of access to treatment makes the ethics of testing questionable. Although DAAs were initially expensive, overall prices have decreased substantially, largely as a result of issuing voluntary licenses that enable the production of generic DAAs. Countries capable of acquiring less expensive generic DAAs account for >60% of individuals chronically infected with HCV (Fig. 4; World Health Organization 2018). Many national governments in high-income countries have also reached agreements with the pharmaceutical industry to reduce DAA costs. For example, Australia negotiated a risk-sharing arrangement with pharmaceutical companies for a 5-year unlimited treatment access for a fixed price (McCall 2016). Currently, prices vary considerably among countries, and the total costs of a complete DAA treatment regimen range from less than US$100 to US$40,000 (Douglass et al. 2018).

Figure 4.

Figure 4.

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Number of people living with HCV with possibility to access generic direct acting antiviral (DAA) therapy, by country income group, 2017. (HIC) high-income countries, (LIC) low-income countries, (LMIC) low- and middle-income countries, (UMIC) upper- and middle-income countries. (Courtesy of the World Health Organization 2018; reprinted, with permission.)

As a result of the high list price of DAAs, public authorities and other payers initially prioritized patients with a higher risk of complications, those “most in need”—that is, with advanced liver disease typically measured by stage of fibrosis or clinically significant extrahepatic manifestations or relevant comorbidities such as HBV and HIV. In 2017, almost half of the European countries restricted treatment to high-risk patients, and up to 17% required abstinence from recent alcohol or other drug use (Marshall et al. 2018a). Similar restrictions were in place in other countries such as the United States. Such restrictions are not evidence-based, as treatment is recommended in all HCV patients without contraindications, regardless of disease severity or drug consumption history (American Association for the Study of Liver Diseases, Infectious Diseases Society of America 2014; European Association for the Study of the Liver 2018). Progressively, countries are removing those restraints and, in 2018, most European countries extended treatment access to all patients (Marshall et al. 2018b).

The inherent features of DAAs (i.e., easy to prescribe, short-duration regimens, mild side effects) open the door to wider prescribing. However, constraints may be set by payers, limiting DAA prescription to specialists, usually gastroenterologists, hepatologists, or infectious disease specialists. Such restrictions hinder treatment uptake, particularly in some population subgroups, such as individuals in rural areas or PWID, who are more reluctant to attend traditional health-care facilities. In fact, there are no significant differences in cure rates between specialist and nonspecialist prescribers and, therefore, moving toward decentralized models of care can be achieved without endangering the effectiveness of DAAs (Kattakuzhy et al. 2017). These kinds of models are particularly important for accessing hard-to-reach risk populations. There are several examples of innovative models of care (Cooke et al. 2019; Roncero et al. 2019), including integrated multidisciplinary models, models focused on difficult-to-engage populations such as PWID or settings-based models (e.g., prisons, harm-reduction/drug treatment centers), peer-based models (Remy et al. 2016; Ford et al. 2017; Cooke et al. 2019), primary health-care-based models (e.g., Australia; Kirby Institute 2018), and nontraditional settings such as community pharmacies (e.g., Scotland, the United Kingdom; Radley et al. 2018). However, rigorous clinical trials evaluating such models of care are still lacking, particularly in LMICs (Ford et al. 2017; Cooke et al. 2019).

DIRECT-ACTING ANTIVIRALS: PAVING THE ROAD TO HCV ELIMINATION

Global Health Sector Strategy on Viral Hepatitis, 2016–2021

Hepatitis C, once a deadly infection, is the only chronic viral infection that can be cured, which means that it can be eliminated, as long as testing and treatment are accessible. In 2016, WHO published its first Global Health Sector Strategy on Viral Hepatitis (GHSS), which called for the elimination of viral hepatitis “as a major public health threat by 2030” (World Health Organization 2016). The Strategy comprises a series of ambitious time-bound numerical targets for elimination of infection with hepatitis B virus (HBV) and HCV. For HCV, the key impact targets are to achieve an 80% reduction in new infections and a 65% reduction in liver-related mortality by 2030. To attain those targets, 90% of those chronically infected should be diagnosed and 80% treated by 2030 (Fig. 5). Additional targets include 100% screening of blood donations, 90% safe health-related injections, and 300 sterile needles and syringes provided per year per person who injects drugs.

Figure 5.

Figure 5.

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Cascade of care for HCV infection and 2030 targets. (Data from the World Health Organization 2017a.)

Viral Hepatitis and the Sustainable Development Goals

The GHSS was developed in response to the United Nations’ Sustainable Development Goals (SDGs), adopted by all member states in 2015 (United Nations 2015). The SDGs aim to promote worldwide social development and health. Each of the 17 goals to be reached by 2030 includes several targets. Target 3.3 of Goal number 3 specifically mentions “combating hepatitis,” reflecting the relevance of viral hepatitis worldwide.

Goal 3 includes other targets closely related to the burden of HCV, such as halting the AIDS epidemic, reducing the prevalence of noncommunicable diseases (which include cirrhosis and HCC), and preventing and treating substance-abuse disorders. Particularly relevant is the aim to achieve universal health coverage (UHC), which means ensuring that all individuals have access to the health-care services they require without financial consequences. In this regard, WHO aligns the response to HCV within the framework of UHC with the fight against viral hepatitis contributing to achieving UHC and other targets. In fact, the GHHS recommends that countries include in their national health insurance systems essential interventions for HCV, such as treatment and prevention strategies, harm-reduction services, and blood safety.

Reaching the Elimination Goals: Failures and Successes

Despite these ambitious goals, by January 2018 only 12 countries were on track to meeting the WHO targets: Australia, Egypt, France, Georgia, Iceland, Italy, Japan, Mongolia, the Netherlands, Spain, Switzerland, and the United Kingdom (The Polaris Observatory 2018). These countries are treating at least 7% of the affected population in their country every year, and all of them provide unrestricted access to DAAs. Globally, the number of treated individuals increased from 1.8 to 2.1 million between 2016 and 2017, although it decreased in many high-income countries because of a lack of patients, both because of the rates of undiagnosed individuals and many individuals previously diagnosed are not linked to care for various reasons. In Japan, treated patients per year decreased by 57% (from 87,900 to 38,000), in the Netherlands by 40% (2000–1200), and in Australia by 31% (32,400–22,300).

However, there are examples of success. In Australia, from 2016 to 2018, 26% of the estimated people living with HCV (58,280 individuals) initiated treatment with DAAs, and 27% of them were prescribed by a general practitioner (Kirby Institute 2018). Australian national strategy includes unrestricted treatment access, programs targeting specific settings and models of care (e.g., prisons), harm-reduction services, nurse-led care, and health promotion and education programs. Currently, 80% of the estimated number of people living with HCV have been diagnosed, which is one of the highest diagnoses rates worldwide (Cooke et al. 2019).

The case of Egypt is also exemplary. The Egyptian national plan to eliminate hepatitis C aims to enhance testing and treatment, as well as to improve prevention while maintaining sustainability. The government achieved a 97% reduction in the price of DAAs through negotiations with pharmaceutical companies; currently, a 12-week treatment regimen with sofosbuvir/daclatasvir costs ∼$80 (Cooke et al. 2019). All testing and treatment costs are covered by the state without reimbursement restrictions. An online registration website to enroll patients (El-Akel et al. 2017) has led to an enormous increase in DAA prescriptions. Reportedly, by May 2018, almost 25% of the infected population (two million people) had been treated (Cooke et al. 2019). Underdiagnosis is now the biggest issue in tackling HCV, and a national screening program tested 4.5 million people in 2017 (The Polaris Observatory 2018).

Spain is also on track to meet the WHO goals and initiated its national strategy to eliminate HCV in 2015. Initially, treatment was reimbursed only in patients with advanced liver disease because of the high prices of DAAs. The government reached an agreement to lower the prices and, in 2016, removed reimbursement restrictions. The prevalence of HCV then was ∼1.2% (∼470,000 people) (Ministry of Health Social Services and Equality 2015). Since that year, more than 120,000 people have been treated, with cure rates >95% (Ministerio De Sanidad Consumo y Bienestar Social 2019). Furthermore, an economic study showed that, in Spain, DAAs are cost-effective, given the savings accrued by avoiding the long-term complications of HCV chronic infection (cirrhosis and HCC), even without considering the probable additional benefits derived from the increase in labor productivity in treated patients (Turnes et al. 2017). However, the lack of diagnoses in the country remains a major gap to stay on track to achieve the HCV targets by 2030.

At the beginning of 2018, in England, 76% of the 35,634 registered patients with HCV had started treatment, with SVR rates of ∼90% for patients with recorded outcomes (Harris et al. 2018; Williams et al. 2018). To overcome underdiagnoses, the United Kingdom (including Wales and Scotland) has based its strategy on community case finding, with testing and treatment delivered in the community and prisons. An innovative English national elimination procurement deal with the main pharmaceutical companies in the field is on the verge of being agreed upon and will involve the companies investing in case finding and linkage to care.

Impact of DAAs

Impact on Morbidity and Mortality

The increase in availability of DAA treatment for HCV is starting to make an impact on morbidity and mortality. Before the era of the new DAAs, HCV was the leading cause of liver transplantation in the United States and Western Europe. In the United States, cirrhosis due to HCV infection has decreased substantially in past years, and HCV is no longer the most frequent cause of liver transplantation (Goldberg et al. 2017; Cholankeril and Ahmed 2018). DAA treatment has also been associated with higher survival rates (Butt et al. 2017), confirming previous studies showing that the risk of mortality is reduced in people treated with DAAs achieving SVR, including cirrhotic patients (Simmons et al. 2015). In Europe, in June 2017, the proportion of HCV-related liver transplantation had declined significantly, from 22.9% before the advent of DAAs to 17.4%, with a reduction in both cirrhosis-related (13.2%–8.0%) and HCC-related (9.5%–9.4%) liver transplantation (Belli et al. 2018). Further, survival rates among liver transplant recipients with HCV have increased substantially, likely attributable to the effect of DAAs (Belli et al. 2018). In the United Kingdom, between 2013 and 2016, the proportion of HCV patients on the liver transplantation waiting list decreased from 10.5% to 4.7%, and those registered for transplantation with HCV-associated HCC decreased from 46.4% to 33.7% (Vaziri et al. 2018). In Spain, the National Institute of Statistics reported that viral hepatitis mortality diminished by 30% between 2015 and 2018 because of treatment with DAAs (AEHVE Alianza para la Eliminación de las Hepatitis Víricas en España 2019). In France, a large prospective cohort study comparing individuals treated with DAAs versus nontreated patients found that DAAs are associated with a significant decrease of 34% in HCC incidence, 61% in liver-related mortality, and 52% in all-cause mortality after adjusting for confounding variables (Carrat et al. 2019).

Impact on Transmission

DAAs may also play a role in reducing ongoing HCV transmission. Cure prevents the long-term complications of HCV and reduces onward transmission, as cured individuals are no longer infectious. Treating individuals is therefore an important disease-prevention strategy, as modeling studies have suggested (Hajarizadeh et al. 2016). In the United Kingdom, scaling up treatment to 26 per 1000 PWID per year could reduce chronic HCV prevalence by 15%–50%. In France, chronic HCV prevalence is expected to diminish from 43% to 25% in 10 years because of treatment with DAAs. Prevalence is expected to decrease among HIV-infected MSM as a result of treatment with DAAs, not only because of infected patients being cured but also because of reductions in new HCV cases. In Iceland, modeling studies show that treatment with DAAs will reduce the incidence by 72% without even considering the added effect of the prevention of reinfection in high-risk groups because of the progressive reduction of the number of infected people or other prevention interventions like harm-reduction services (Gottfreðsson et al. 2017).

Impact on Subpopulations

The impact of DAAs is also noticeable in subpopulations. One novel approach to reaching the WHO goals is microelimination, which consists of tackling the epidemic by targeting specific subpopulations, settings, or geographical areas with a higher prevalence (Lazarus et al. 2018). Such populations include PWID, HCV/HIV-coinfected individuals, birth cohorts with high HCV prevalence, hemodialysis patients, people with inherited blood disorders requiring frequent transfusion, and migrants from high-prevalence countries, among others. Settings could include prisons or harm-reduction centers, and a geographical area could be a city, a region, or even a small country.

An example of the success of microelimination among a key population can be found in Ireland in patients with hemophilia. From the 1970s to 1991, 240 individuals with hemophilia were infected with HCV because of contaminated blood products. By 2015, 37 patients still living with HCV were prioritized for the provision of DAAs. By the end of 2016, hepatitis C was eliminated in this subgroup (Irish Haemophilia Society 2016). Slovenia achieved the same recently (Maticic et al. 2018). In the 1990s, all patients with congenital bleeding disorders were screened for HCV. Patients living with HCV were identified from the national registry, and all of those chronically infected initiated therapy. Sixty-two of 63 people who had initiated treatment achieved cure; there is no hepatitis C among hemophilia patients.

Prison programs are also good examples of this approach. In Spain, a prison located in Cantabria achieved elimination through a program comprising universal screening and treatment (Cuadrado et al. 2018). Between May 2016 and July 2017, testing and treatment was offered to all inmates with expected stays longer than 30 days. All the prisoners with HCV initiated treatment with DAAs, and SVR rates were 92.4%. The prevalence of HCV infection in the prison was 0%, and there were no new cases of HCV infection at time of study.

Finally, Iceland, with a population size of ∼340,000 and an estimated 880–1330 people with HCV chronic infection (0.3% of the population), most of them PWID, exemplifies elimination in a small territory. In 2016, the country launched the Treatment as Prevention for Hepatitis C program focused on PWID, which included harm-reduction services, case finding, and access to treatment with DAAs for all people covered by the national health insurance. Fifteen months later, 526 individuals had initiated treatment and achieved high SVR rates (Olafsson et al. 2018).

CONCLUSIONS

Clinical Impact of DAAs

The increase in availability of DAA therapy for HCV infection is starting to make an impact on morbidity and mortality. Before the era of the new DAAs, HCV was the leading cause of liver transplantation in the United States and Western Europe. In the United States, cirrhosis due to HCV infection has decreased substantially in the past years, and HCV is no longer the most frequent cause of liver transplantation (Goldberg et al. 2017; Cholankeril and Ahmed 2018). Also in the United States, DAA treatment has been associated with higher survival rates (Butt et al. 2017). In several European countries, it has been shown that the number of HCV patients on the liver transplantation waiting list has also decreased (Vaziri et al. 2018), as has mortality due to viral hepatitis. DAA treatment also correlated with a reduction in HCC, liver-related mortality, and overall mortality in patients with cirrhosis (Carrat et al. 2019). Further, cure with DAAs is an important disease-prevention strategy as cured people do not transmit the infection (Hajarizadeh et al. 2016).

Elimination of HCV: What Is Needed

Eliminating hepatitis C requires extending DAA treatment coverage to all people living with HCV. However, the current situation lags far behind the WHO elimination goals. Only 20% of those chronically infected are aware of their status (target: 90%) and only 7% of those diagnosed are being treated (target: 90%) with major differences across and within countries (World Health Organization 2017a). Enhancing HCV treatment uptake is crucial but major obstacles to scaling up treatment remain (such as underdiagnoses, financial constraints, prescribing by specialists). At present, meeting the WHO goals by 2030 seems difficult.

The Way Forward

There is a need for comprehensive strategies in countries, and where relevant at the subnational level, that encompass all the steps along the HCV cascade of care, from testing and diagnosis to treatment initiation, linkage to care, and long-term follow-up. Such strategies should be adapted to the epidemiological and socioeconomic context of each country and/or region, and at-risk populations should receive special attention. New models of care are valuable tools to reach difficult-to-engage populations, which account for the largest part of the HCV burden in many settings. However, the lack of epidemiological data, particularly in LMICs, remains a major constraint to accurately characterizing high-risk populations and monitoring and evaluating efforts toward elimination. Without robust and adequate data, HCV elimination will remain out of reach. The prices of DAAs remain unaffordable for many countries and still hinder equitable access to treatment for all, even without accounting for the additional expenses of setting up interventions for screening, testing, and long-term follow-up. Strong government commitment is required to address these barriers and achieve elimination of hepatitis C.

Footnotes

Editors: Arash Grakoui, Jean-Michel Pawlotsky, and Glenn Randall

Additional Perspectives on Hepatitis C Viruses: The Story of a Scientific and Therapeutic Revolution available at www.perspectivesinmedicine.org

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