Striking Hard to Overcome the Final “Fortress” of Antiviral Treatment for Hepatitis C

Editor's Note: The advent of direct-acting antiviral drugs (DAAs) for chronic hepatitis C has achieved virological clearance in antiviral treatment, a crucial step towards China's realization of the World Health Organization's (WHO) "2030 goal to eliminate viral hepatitis." Today, Dr. Huiying Rao from Peking University People's Hospital and Peking University Liver Research Institute delivered a specialized lecture on the "Challenges of Antiviral Treatment for Hepatitis C," analyzing in-depth the current difficulties facing hepatitis C prevention and control in China, along with strategies to address them. The following is a summary of the lecture for the benefit of colleagues and exchange of knowledge.

The WHO has set the goal of “eliminating viral hepatitis by 2030,” with a 90% reduction in the new infection rate, a 65% reduction in mortality, a 90% diagnosis rate, and an 80% treatment rate by then^[1]. How far are we globally from achieving this goal by 2030? Based on a literature review and disease burden models specific to HCV in 110 countries/regions^[2], it is estimated that in 2020, the global HCV infection was approximately 56.8 million, with a declining prevalence since 2015. However, efforts are still needed to expand screening and treatment to reach the 2030 elimination target (Figure 1).

Turning our focus back to China, in 2020, the estimated number of HCV infections was 9.487 million, with a diagnosis rate of 33% and a treatment rate of only 11%. At this rate, China is expected to achieve the WHO goal of eliminating hepatitis C only after 2051. In response, nine national ministries jointly issued a document guiding and supervising the action to eliminate hepatitis C, urging maximum efforts to curb new infections, effectively identify and cure patients, reduce the burden of the disease, and eliminate the public health hazards of hepatitis C^[3]. Here, we will delve into the current challenges facing antiviral treatment for hepatitis C in China and gradually unpack targeted strategies for addressing them.

Challenge 1: How to Identify and Treat?

Currently, various challenges exist at different stages of hepatitis C prevention and control in China:

1) In the prevention stage, there is a lack of detailed national-level planning and targets to eliminate the public health threat of hepatitis C. Public awareness and education about hepatitis C are limited, and there is a lack of strong preventive consciousness among the public.

2) In the screening stage, patients in China have weak awareness of the disease and lack proactive screening consciousness. Few actively seek screening, and HCV testing involves two steps, requiring multiple medical visits and blood draws.

3) In the diagnosis and treatment stage, due to limited public awareness of hepatitis C and insufficient understanding of its curability and the severity of complications, patients are unwilling or unable to seek medical attention. Additionally, high patient dropout rates occur due to multiple referrals and the inconvenience of distant medical institutions.

4) In the monitoring and evaluation stage, patients with chaotic lifestyles are at a high risk of reinfection, and some cirrhotic patients face a higher risk of HCC (hepatocellular carcinoma) and complications.

Therefore, the first issue we need to address is how to identify patients who need antiviral treatment and ensure that those in need can receive treatment. This is a crucial step in effectively controlling and preventing the spread of HCV. In June of last year, WHO released two policy documents on the diagnosis and service treatment of HCV-infected individuals, which may provide guidance for us. This WHO guidance update emphasizes both treatment plan updates and recommended service policy measures, highlighting the central theme of “simplicity.”

The updated WHO guidelines primarily focus on two aspects^[4]:

1) Simplifying HCV Diagnostic and Treatment Services, including decentralization (suggesting the provision of HCV testing and treatment services in secondary healthcare or community-based settings), resource integration (advising the integration of HCV testing and treatment with existing management services in secondary healthcare settings), and task sharing (suggesting non-specialist physicians and nurses provide HCV testing, management, and treatment to expand the coverage of diagnosis, management, and treatment).

2) Simplifying the HCV Diagnostic Pathway, recommending HCV core antigen testing and other high-sensitivity HCV RNA testing methods to enhance diagnostic efficiency and quality.

It is evident that eliminating hepatitis C requires improvement and optimization of various stages in the HCV diagnostic and treatment cascade (Figure 2). The management and diagnosis of HCV infection need further simplification and innovation to enhance the accessibility of HCV testing and management. For instance, in the prevention stage, strengthening control and screening for key high-risk populations, formulating different screening strategies based on local HCV epidemiology, optimizing diagnostic methods, achieving low-cost, simple, and rapid HCV diagnosis, and implementing diversified HCV treatment models to enhance treatment accessibility^[5].

Challenge 2: How to Achieve Cure?

After identifying and ensuring that patients receive standardized treatment, the second challenge we face is how to ensure that patients undergoing antiviral treatment can achieve cure. The goal of hepatitis C treatment is to clear HCV, and achieving sustained virological response (SVR) is the ideal treatment endpoint. SVR is defined as the absence of detectable HCV RNA in the serum or plasma using sensitive testing methods (detection limit ≤15 kU/L) 12 or 24 weeks after the completion of antiviral treatment. In recent years, with the advent of direct-acting antiviral (DAA) drugs (Table 1), hepatitis C has become the first chronic viral infectious disease in human history that can be completely cured. Various DAA drugs have shown SVR rates of over 90% in patients with chronic hepatitis C, with viral clearance rates exceeding 98%.

Results from a multicenter, open-label phase 3 clinical trial in China^[8] indicate that the 12-week single-tablet regimen of sofosbuvir/velpatasvir is an effective and safe treatment option for Asian patients with chronic HCV infection. Particularly, it demonstrates excellent efficacy for HCV genotypes 1, 2, and 6, achieving a 100% SVR rate. However, in patients with genotype 3b and concomitant liver cirrhosis, the efficacy may be lower, with only a 50% SVR rate (Figure 3). In fact, over the past decade, there has been a noticeable shift in the distribution of HCV genotypes in China^[9]. The proportion of genotypes 1 and 2 has decreased, while genotypes 3 and 6 have become new challenges, especially HCV genotype 3b (Figure 4).

Compared to other genotypes, patients infected with HCV genotype 3 tend to experience faster progression of liver disease, are younger in age, and have been considered challenging cases in the era of direct-acting antivirals (DAAs), especially for those with cirrhosis and prior treatment failure. Results from a retrospective study at the Second Affiliated Hospital of Chongqing Medical University^[10] show that the overall SVR12 rate for HCV genotype 3 patients receiving various antiviral treatment regimens is 93.2%. Specifically, the SVR12 rates for the sofosbuvir (SOF) group, sofosbuvir/daclatasvir (SOF/DCV) group, and sofosbuvir/daclatasvir ± ribavirin (SOF/DCV±RBV) group all reached 100% (Figure 5). For patients with HCV genotype 3b, the SVR12 rate was 92.1% (35/38), with overall good safety and no occurrence of severe adverse events or treatment interruptions due to adverse events.

A real-world study from Xinjiang delved into the efficacy and safety of sofosbuvir/velpatasvir ± ribavirin (SOF/VEL±RBV) in patients with genotype 3 and cirrhosis. The data showed^[11] an overall SVR12 rate of 87.9% (compensated cirrhosis: 93.8%, decompensated cirrhosis: 82.4%). The Child-Pugh-Turcotte (CTP) score significantly improved 12 weeks after treatment. In patients with compensated and decompensated cirrhosis, levels of total bilirubin, albumin, alanine aminotransferase, and hepatic encephalopathy significantly improved, and there were no drug-related adverse events or treatment interruptions due to adverse events during the treatment process (Figure 6). Another real-world study from Yunnan reached similar conclusions^[12]. HCV genotype 3 patients receiving SOF/VEL±RBV achieved an overall SVR12 rate of 93.5%. Compared to baseline, average ALT (74 U/L vs. 22 U/L) and AST (64 U/L vs. 26 U/L) significantly decreased 12 weeks after treatment, and liver stiffness also significantly decreased (11.7 kPa vs. 8.25 kPa), with good safety (Figure 7).

In May of this year, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) jointly updated and released guidelines for the detection, management, and treatment of HCV infection^[13]. Clear recommendations were provided for the treatment regimens for treatment-naïve patients with HCV genotype 3 without cirrhosis or compensated cirrhosis (Table 2).

Conclusion

Currently, antiviral treatment for chronic HCV infection has entered the era of pan-genotypic treatment with direct-acting antivirals (DAAs). Pan-genotypic regimens without interferon are preferentially recommended, achieving sustained virological response (SVR) rates of over 90% in HCV-infected individuals with known major genotypes and subtypes. However, pan-genotypic regimens do not cover all genotypes, and for a small number of genotypic subtypes and special populations that have not undergone clinical trials with DAAs or have not achieved SVR rates above 90% in existing trials, standardized clinical trials are still needed to determine appropriate treatment regimens. Especially for genotype 3 patients, selecting a safe and efficient genotype-specific regimen requires further support from multicenter real-world studies.

TAG: Perspective; Hepatitis C