New direct-acting antiviral therapies are highly effective at eliminating the Hepatitis C virus infection, according to a systematic evidence review by researchers at Oregon Health & Science University.
The review, published today in the Journal of the American Medical Association, informed a new recommendation by the U.S. Preventive Health Task Force for universal screening of Hepatitis C.
Until now, screening has been recommended for people born between 1945 and 1965 with risk factors such as injection drug use.
The evidence review found that new direct-acting antiviral therapies effectively target the virus with few side effects.
“This has really been a remarkable advance in treatment,” said corresponding author Roger Chou, M.D., director of the Pacific Northwest Evidence-based Practice Center at OHSU and a professor of medicine (general internal medicine and geriatrics) in the OHSU School of Medicine.
“Historically, Hepatitis C has been very difficult to treat, and the treatments were longer and difficult to tolerate,” Chou added. “The new treatments are more effective but also have few side effects and therapy is usually completed in 8 to 12 weeks, compared with around a year previously.”
Hepatitis C is the most common blood-borne virus in the United States with an estimated 2.4 million people affected. Left untreated, Hepatitis C can lead to severe complications including liver failure and liver cancer.
The new study updates a previous review conducted in 2013.
At that time, direct-acting antiviral therapies were just beginning to be used in combination with injections of interferon. Interferons ramp up the body’s overall immune response to suppress the virus, however the year-long treatment caused flu-like side effects. In the 2013 review, the first direct-acting antiviral medications had just been introduced.
In combination with interferon, the first-generation antiviral drugs were between 68% and 78% effective in driving the virus to undetectable levels in the blood following treatment.
New all-direct-acting antiviral regimens without interferon are more than 95% effective in eliminating the virus even in young people, the review found.
The review covered eight randomized controlled trials comparing direct-acting antiviral therapies to placebo or an outdated antiviral regimen, 48 other treatment studies, and 33 cohort studies with a total of almost 180,000 patients.
The research was funded under contract HHSA290201500009i, Task Order 7, from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, under a contract to support the U.S. Preventive Services Task Force.
In recent years, direct acting antiviral (DAA) treatments have replaced pegylated-interferon (PEG-IFN) and ribavirin (RBV) combination therapy (PR) as standard of care for patients with chronic hepatitis C (CHC) globally[1–3].
DAAs are associated with over 90% rates of sustained virologic response (SVR), fewer side effects, shorter treatment durations, and improved adherence compared to PR therapy.
Due to the substantial impact of hepatitis C virus (HCV) infection globally on patients, their families, and public health systems, the World Health Organization (WHO) has set HCV elimination goals that include reduction of HCV incidence by 80% and HCV-related mortality by 65% by 2030.
As part of the strategy to achieve these goals, the WHO included DAA therapies in its 2017 edition of List of Essential Medicines. Specifically, the latest (2018) WHO guidelines for HCV treatment make an updated recommendation of using pan-genotypic regimens for treating adult patients with chronic HCV infection.
Besides their proven high efficacy, pan-genotypic regimens enable cost saving and care pathway simplification by eliminating the need for pre-treatment genotyping, potentially reducing loss to follow up among patients.
Furthermore, the recommended pan-genotypic regimens, such as sofosbuvir/velpatasvir (SOF/VEL), enable most HCV patients to be treated with simple treatment strategies regardless of patients’ prior treatment experience or cirrhosis status, with minimal need for regimen adjustment or on-treatment monitoring.
As reflected in this recommendation by the WHO, the value of high-impact, curative treatment for HCV infection is wide-ranging and goes beyond clinical efficacy.
In China, the number of individuals infected with HCV is estimated at 10 million, with a seroprevalence of anti-HCV antibodies of 0.6% among the general population[7,8]. In addition to the large and growing number of HCV-infected individuals, there have been a diversification of HCV genotypes (GTs) and a broadening of the age spectrum among Chinese HCV patients; GT1b or GT2a HCV patients historically infected through blood transfusion are aging, while an increasing number of younger patients are becoming infected with GT3a, 3b and 6a HCV through injection drug use[9–11].
The resulting healthcare expenditures, as well as reduction in quality of life and loss of work productivity among the Chinese CHC population, are expected to have wide-ranging economic and societal implications.
In addition to the heavy disease burden, the management of the HCV epidemic has been compounded by a lag in adopting DAAs in China: up to early 2017, no DAA had been approved in China. To improve the availability of innovative treatments (including DAAs), China introduced policies that expedite the regulatory review process for drug registration. To date (March 2019), most of the mainstream DAA regimens used internationally have been approved in China, including daclatasvir plus asunaprevir (DCV + ASV), sofosbuvir plus simeprevir (SOF + SMV), SOF + DCV, the fixed-dose combination ombitasvir/paritaprevir/ritonavir with or without dasabuvir (O/P/r ± D), SOF/VEL, ledipasvir (LDV)/SOF, and elbasvir/grazoprevir (EBR/GZR). Glecaprevir/pibrentasvir (GLE/PIB) and SOF/VEL/voxilaprevir (VOX) are also pending approval.
While the rapid improvement in DAA availability is encouraging, China is still far from universal adoption of DAA-based therapies. In an initial step to address the issue of drug accessibility, the Chinese government included SOF/VEL in the latest (October 2018) National Essential Drug List as the first and only DAA treatment.
Nevertheless, DAAs are not covered by the National Medical Insurance scheme for reimbursement, and thus much less affordable compared with IFN-based therapies. As such, a considerable number of patients, such as those in rural and less-developed areas and those with limited financial means, would still have to resort to IFN-based therapies.
In light of how IFN-free DAA regimens have revolutionized treatment for HCV-infected patients, many countries are now aiming for elimination of the disease; the introduction of DAA regimens in China therefore, also provides the opportunity for potential hepatitis C elimination.
In the 2017–2020 National Viral Hepatitis Action Plan, the Chinese government emphasized the use of more efficacious treatment as part of the strategy to reduce the spread of HCV. The overarching Healthy China 2030 Plan also showed the Chinese government’s commitment to establish public health as the foundation for future economic and societal development.
In line with the country’s strategic approach to healthcare and hepatitis management, this article aims to comprehensively evaluate the value of curative HCV therapies in the dimensions of clinical, patient, economic and societal benefits, in the hope of providing useful references for various stakeholders and policy makers in China. Where possible, data from China have been used, supplemented with data from other Asian countries and from around the world when Chinese data are unavailable.
CLINICAL BENEFITS OF CURING HCV INFECTION
Impact of HCV infection and treatment on the liver
The principal impact of HCV is on the liver, the predominant site of HCV replication. While initial HCV infection resolves spontaneously in around 15%–25% of cases, the majority of patients will develop CHC.
The long-term outcomes of the liver inflammation caused by HCV infection include the development of fibrosis, compensated and decompensated cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease (ESLD).
Progression of CHC typically occurs over many years; it is estimated that 10%–20% of patients will develop cirrhosis and the annual risk of HCC in patients with cirrhosis is approximately 1%–4%. If left untreated, CHC patients would progress to more advanced disease stages, which in turn are associated with accelerated disease progression, elevated risks of developing HCC, and consequently lower survival rates.
A long-term retrospective cohort study in Japanese CHC patients showed that untreated F0/F1 patients have a 0.5% annual risk for HCC development, while this increased to 7.9% in F4 patients. A systematic review of CHC patients in Asia, including China, reported that the 5-year survival for cirrhotic CHC patients was 73.8%, but falls to 39.2% following progression to ESLD, wherein liver transplantation is required.
China has an estimated annual incidence of 53593 cases (95%CI: 16144–92466) of HCV-related HCC, with > 93000 cases of HCV-related liver cancer deaths recorded in 2005. The majority of Chinese HCV patients were infected through blood transfusion before 1993–1996, in whom age and duration of infection are significant risk factors for disease progression.
As these patients grow older and enter their third or fourth decade of infection, the occurrence of decompensated cirrhosis (DCC), HCC and ELSD will rise. On the other hand, China has seen a recent increase in younger patients with GT3 HCV[10,22]. A study in Shanghai reported evidence that GT3 patients undergo faster disease progression, with GT3 patients < 50 years of age showing significantly more advanced fibrosis than their non-GT3 counterparts. If left untreated, considerable numbers of liver sequelae will develop in these younger GT3 patients in future.
Antiviral treatment and resultant SVR improve the long-term clinical outcome of HCV patients[23–28]. The beneficial effects of IFN-based treatment and SVR on reducing cirrhosis progression, HCC, and mortality have been well documented, and this is reflected by the recently published results from two large-scale studies in Asia and two Chinese cohort studies[29–32].
Similar clinical benefits have been observed with SVR to DAA-based treatment. In a large-scale, retrospective study in Japan, GT1 HCV patients who achieved SVR to all-oral DAA regimens had a lower cumulative incidence of HCC than non-SVR patients at 2 years post-treatment (Figure (Figure11). Furthermore, a recent Chinese prospective study in DAA-treated and case-matched PR-treated patients showed no difference in the risk of developing HCC post-SVR.
DAA treatment was also associated with a 32% reduction in liver-related mortality relative to no treatment, and DAA-mediated SVR conferred reductions in all-cause mortality relative to non-SVR in patients with or without advanced liver disease by 79% and 56%, respectively[23,24].
A meta-analysis of 31 studies in predominantly GT1 HCV-infected patients (including Asian patients) showed that achieving SVR conferred survival benefit irrespective of patients’ clinical characteristics, with difficult-to-treat populations such as cirrhotic patients experiencing the largest extent of reduction in 5-year mortality compared to no SVR.
Nonetheless, the hepatic and survival benefits of achieving SVR are maximized by treating patients in earlier disease stages[31,35]. For instance, for Asian cirrhotic patients who achieved SVR, despite a reduction in cumulative risk of HCC by 25.5 percentage points relative to cirrhotic patients without SVR, the associated risk of HCC was still higher than non-cirrhotic patients with SVR (0.54 vs 0.37).
Thus, the WHO guidelines recommend treating all HCV-infected patients without disease stage-based restriction or prioritization, with an emphasis on minimizing treatment delay after diagnosis.
Although SVR to either IFN- or DAA-based treatment reduces liver disease progression, the impact of IFN-based treatment would be limited due to low SVR rates (40%–75%)[4,36]. In a meta-analysis of 12 studies involving 25497 CHC patients on IFN-based therapy, although SVR achievement led to a 76% reduction in HCC risk, only 36% of patients achieved SVR. PR treatment also has numerous contraindications and side effects, such as RBV-induced hemolytic anemia and various neuropsychiatric, autoimmune, ischemic, and infectious disorders that may be caused or aggravated by IFN[38,39].
In the nationwide CCgenos study, 56.7% of untreated Chinese HCV patients were IFN-ineligible. In contrast, DAA regimens confer high real-world SVR rates of 90%–100%, and extend HCV cure to patient populations that could not be effectively treated in the PR era, such as patients with DCC and/or liver transplant, and patients with concomitant renal impairment or psychiatric disorders (although the eligible patient populations and efficacy profiles do differ among DAA regimens).
As such, DAAs would have a greater impact than IFN-based therapy in significantly reducing HCV-related liver sequelae and deaths at the population level. Evidence for such populational benefits associated with expanded DAA use is emerging internationally, and various countries are promoting the use and reimbursement of DAAs as a key strategy towards the goal of HCV elimination. For example, in England, a national 40% scale-up of DAA provision in 2015 was followed by reductions in the incidence of HCV-related cirrhosis (42%), liver transplantations (32%), and deaths (8%). In 2018, Canada is progressively removing the eligibility criterion of F2+ fibrosis for DAA reimbursement.
In China, DAAs achieved high SVR rates in pivotal clinical studies (Table (Table1).1). Evaluated genotype-specific regimens (DCV + ASV, LDV/SOF, EBR/GZR, and O/P/r + D) all achieved SVR12 rates ≥ 92% in GT1 or GT1b patients[45–48]. Pan-genotypic regimens evaluated in clinical studies included SOF + RBV ± PEG-IFN and SOF/VEL. For SOF + RBV ± PEG-IFN, cirrhotic patients achieved lower SVR12 rates than non-cirrhotic patients (Table (Table11). For SOF/VEL, the only patient population with an SVR12 rate below 90% was GT3b cirrhotic patients (Table (Table1),1), who also exhibited a high prevalence of baseline A30K + L31M substitutions[50,51]. Due to the short period of DAA application, real-world efficacy data in China are only emerging. Majority of the early real-world studies focused on SOF-based regimens (reviewed by An et al); two examples are shown in Table Table1,1, where SOF-based regimens demonstrated high efficacy in difficult-to-treat patients[53,54].
Clinical efficacy of direct acting antiviral in major empirical studies in China
|Study Information||Study regimen||SVR12||Ref.|
|Pivotal phase 3; TN patients; GT1b||DCV + ASV||Non-cirrhotic: 92%|||
|Pivotal phase 3b; TN and TE patients; GT1, 2, 3, 6||SOF + RBV ± PEG-IFN||Non-cirrhotic GT1/2/3/6: 96%/93%/97%/100%|||
|Cirrhotic GT1/2/3/6: 84%/88%/88%/50%|
|(GT6 with cirrhosis: n = 2)|
|Pivotal phase 3b; TN and TE patients; GT1b||LDV/SOF||100%|||
|Pivotal phase 3; TN and TE patients; GT1b, 2, 3, 6||SOF/VEL||GT1b/2/3/6: 100%/100%/83%/100% (Subgroup SVR12: GT3a: 91%; GT3b non-cirrhotic/cirrhotic: 96%/50%)|||
|Pivotal phase 3; TN patients; GT1, 6||EBR/GZR||GT1/6: 97%/80% (GT1: 140/146 patients were GT1b; GT6: n = 5)|||
|Pivotal phase 3; TN and TE patients; GT1b||O/P/r + D||99%–100%|||
|Prospective cohort; TE; GT1b||SOF + DCV||100% (SVR24)|||
|PEG-IFN + RBV||28% (SVR24)|
|Real-world study; TN and TE HCV patients with DCC||SOF-containing regimens||90%; with significant improvement in hepatic function among SVR patients|||
ASV: Asunaprevir; DCC: Decompensated cirrhosis; DCV: Daclatasvir; EBR: Elbasvir; GT: Genotype; GZR: Grazoprevir; HCV: Hepatitis C virus; LDV: Ledipasvir; O/P/r + D: Ombitasvir/paritaprevir/ritonavir plus dasabuvir; PEG-IFN: Pegylated-interferon; RBV: Ribavirin; SOF: Sofosbuvir; SVR: Sustained virologic response; TE: Treatment experienced; TN: Treatment naïve; VEL: Velpatasvir.
Using China-specific SVR data where available, modeling studies predicted that compared to PR, DAA treatment would markedly reduce the HCV-associated long-term disease burden and mortality. A
study simulating the national-level disease burden of CHC in China predicted that with no treatment, the prevalence of HCV would continue increasing and reach 28.1 million in 2050, with 2.4 million liver-related deaths, mostly attributable to DCC and HCC.
The model predicted that using PR therapy would not be able to revert the trend of increase in HCV prevalence. In contrast, universal adoption of DAAs from 2021 onward would significantly reduce the HCV prevalence.
Furthermore, compared to using PR therapy, universal DAA adoption would reduce the cases of incident DCC, HCC, liver transplants, and liver-related deaths by 61%, 45%, 50%, and 61%, respectively. Similarly, simulations of 10000 Chinese CHC patients over a lifetime horizon predicted that various DAA regimens would significantly reduce the incidence of HCV-related liver sequelae and mortality compared to PR therapy[56,57].
These simulations took into consideration the composition of different HCV genotypes, treatment history and cirrhotic status of the patient population, thus, pan-genotypic regimens (SOF/VEL and GLE/PIB) were predicted to achieve higher overall SVR rates and greater reduction in disease progression than genotype-specific DAA regimens (Table (Table22)[56,57].
Model predicted long-term clinical outcomes of using direct acting antivirals in China
|Study Information||Regimens compared||Predicted reduction in liver sequelae relative to PR therapy|
|DCC||HCC||Liver transplant||Liver-related death|
|Simulating 10000 Chinese CHC patients over a lifetime horizon;||GLE/PIB||-95%||-90%||-95%||-92%|
|DCV + ASV||-51%||-48%||-51%||-49%|
|O/P/r + D||-59%||-55%||-59%||-57%|
|GT1b, 2, 3, 6|
ASV: Asunaprevir; CHC: Chronic hepatitis C; DCC: Decompensated cirrhosis; DCV: Daclatasvir; EBR: Elbasvir; GT: Genotype; GZR: Grazoprevir; HCC: Hepatocellular carcinoma; O/P/r + D: Ombitasvir/paritaprevir/ritonavir plus dasabuvir; PR: Pegylated-interferon plus ribavirin; RBV: Ribavirin; SOF: Sofosbuvir; VEL: Velpatasvir.
Besides the direct impact on the liver, HCV-infected patients may experience liver-unrelated symptoms that, depending on epidemiological evidence, are considered extrahepatic manifestations (EHMs) associated or possibly associated with HCV infection[58,59]. The most documented EHMs are mixed cryoglobulinemia/ cryoglobulinemic vasculitis and B-cell non-Hodgkin’s lymphoma.
A diverse range of other conditions also occur at higher prevalence in HCV-infected patients, including type 2 diabetes mellitus, renal diseases, fatigue, cardiovascular disease, and lichen planus (LP), to name a few. EHMs can occur in > 70% of CHC patients, and can be present before advancement into ESLD. Underlining the impact of EHMs on HCV patients, a Taiwanese study reported a cumulative 18-year EHM-related mortality of 19.8% in patients with chronic HCV infection, much higher than the non-liver-related mortality in those without HCV infection (12.2%). Published studies on EHMs in China are few, and there is currently a lack of clinical data on the prevalence and management of EHMs among Chinese patients.
A recent meta-analysis investigated the extrahepatic benefit of antiviral treatment and SVR in HCV patients. Achieving SVR significantly reduced extrahepatic mortality (vs no SVR, OR 0.44, 95%CI: 0.28–0.67), was associated with improvements in cryoglobulinemic vasculitis and B-cell lymphoproliferative diseases, and reduced the incidence of insulin resistance and diabetes.
Concordantly, IFN-based treatment induced favorable immunologic response in Chinese cryoglobulinemic patients with HCV infection, and IFN-based SVR reduced the risk for type 2 diabetes mellitus among Japanese HCV patients[63,64]. Of note, IFN-based treatment may exacerbate symptoms of cryoglobulinemic vasculitis, likely due to the immune-stimulatory effects of IFN[65,66]. IFN also induces lichenoid inflammation, and is thus contraindicated to LP.
Emerging data support the extrahepatic benefit of successful DAA treatment for HCV patients. In two prospective studies on patients with HCV-related mixed cryoglobulinemia, SOF-based regimens conferred 100% SVR rates and clinical improvement or resolution of mixed cryoglobulinemia-associated vasculitis[68,69].
In a retrospective study on 46 CHC patients with lymphoproliferative disorders, DAA treatment (mostly SOF-based) achieved an SVR rate of 98%, together with a lymphoproliferative disease response rate of 67% and survival benefit. In a prospective Japanese study, 7 patients with HCV-related oral LP all achieved resolution or improvement of oral LP lesions and cutaneous LP upon DAA-based SVR.
In short, existing data on DAAs are in line with data from the IFN era, showing that SVR attainment aids the amelioration of HCV-associated EHMs. While further research is needed on the effect of DAAs on EHMs, the higher virologic efficacy, fewer side effects, and shorter treatment durations of DAAs would likely amplify the health benefit of reducing disease burden associated with extrahepatic complications.
Prevention of HCV transmission
Effective treatment of diagnosed patients is an integral part of a comprehensive approach to preventing HCV transmission, which also requires public education to raise disease awareness and efficient screening and linkage to care. HCV prevention strategies also need to be aligned with the predominant mode of transmission.
There is substantial regional variation in risk factors for HCV infection in China. In regions outside Southern China, blood transfusion is the major route of HCV transmission, accounting for 57.5%–69.3% of existing HCV-infected patients.
Infection through surgery or dental treatment is more common in Northern China than in other areas, whereas HCV transmission via high-risk behavior such as intravenous drug abuse is more prevalent in Southern and Western China.
Within each broad geographical region, the modes of HCV transmission may also show urban–rural differences. Current HCV prevention measures in China include screening of all blood donors, as well as harm reduction services for high-risk groups like injection drug users (IDUs)[3,73].
In addition to existing prevention measures, treating HCV infection with highly effective therapy can function as a prevention strategy [treatment as prevention, TasP] by essentially removing individuals in key populations from the pool of transmitters.
Numerous TasP modelling studies predicted that HCV treatment of sufficient effectiveness and accessibility would help reduce the incidence and chronic prevalence of HCV infection among IDUs, prisoners, and men who have sex with men (MSM).
For example, in Melbourne, with HCV prevalence among IDUs at 50%, increasing uptake of DAA treatment to 40 per 1000 IDUs annually is expected to halve HCV prevalence rates within 15 years; while scaling up treatment to 54 per 1000 IDUs annually could cut prevalence rates by as much as 75%.
Empirical evidence verifying these positive projections are currently scarce, but some real-world programs are underway, reflecting confidence in the potential of HCV TasP. In Australia, a world-first HCV surveillance and treatment program assessing the use of SOF/VEL for HCV TasP in prisons is expected to be completed by 2019.
Notably, high real-world efficacy of SOF/VEL has been demonstrated among HCV-infected, treatment-adherent IDUs with recent injection, lending confidence to the notion that treatment scale-up and adherence management would effectively control HCV transmission among IDUs.
In 2016, Iceland (with a population of 340000) launched the nationwide program of Treatment as Prevention for Hepatitis C (“TraP Hep C”), offering universal access to DAAs for HCV-infected patients, with an emphasis on treating high-risk transmitters such as IDUs.
International guidelines also recognized the benefit of reduced transmission with successful HCV treatment[1,2,79]. Guidelines by the European Association for the Study of the Liver and the WHO further highlighted that HCV screening and treatment should be prioritized in individuals at high-risk of transmitting HCV such as IDUs[2,79].
With the regional variations in HCV epidemiology in China, tailored strategies at the provincial or even district/city level will be necessary for HCV prevention and control. Suitable measures targeting specific modes of transmission will facilitate HCV ‘micro-elimination’ within certain populations: such is the strategy adopted by many countries for HCV elimination, and can form part of a realistic approach in China towards accomplishing the goals in the National Viral Hepatitis Action Plan.
In particular, China has a documented IDU population of 2.95 million, among whom the estimated HCV prevalence is 50.4%[81,82]. In this key population, efficacious HCV treatments, together with targeted education campaigns, continued harm reduction measures, and efficient diagnosis and linkage to care, would be required to reduce the prevalence and transmission of HCV[14,15].
More information: Roger Chou et al, Screening for Hepatitis C Virus Infection in Adolescents and Adults, JAMA (2020). DOI: 10.1001/jama.2019.20788