Hepatitis C virus (HCV) infection remains the leading cause of liver cirrhosis or hepatocellular carcinoma [1
], and has a substantial negative impact on patients’ quality of life and functioning [2
]. HCV infection can be classified as acute or chronic infection. The acute infection was defined as a new infection occurring from the time of exposure up through six months of infection [5
]. Approximately 26% (95% confidence interval [CI]: 22–29%) of the acute-infected individuals would spontaneously clear infection, otherwise the chronic infection would subsequently develop [5
People who inject drugs (PWID) were one of the most at-risk populations for HCV [1
]. In 2017, there were an estimated 15.6 million PWID aged 15–64 years worldwide, and among them 52% (95% CI: 42–62%) were infected with HCV [7
], accounting for 8% of current HCV infections globally [1
]. PWID also accounted for the biggest proportion (estimated 23%) of acute HCV infections worldwide [1
], and were at an increased risk of reinfection from HCV and excess mortality from drug overdose [8
To eliminate HCV, the World Health Organization (WHO) put forward a 2030 target that 80% of diagnosed HCV cases would be treated, and suggested that PWID should be prioritized for treatment [10
]. China has the largest number of PWID in the world, with an estimated HCV seroprevalence of 67.0% [11
], and approximately 25% new infection [12
]. Oral direct-acting antivirals (DAAs) regimen and the Peg-interferon (IFN)-based regimen are two types of antiviral drugs for the treatment of HCV. Due to the expensive nature of DAAs, in China and many other resource-limited settings where DAAs are newly or not yet approved, PegIFN-based regimen is still the frontline HCV therapy [14
]. PegIFN as a monotherapy is the frontline therapy for acute HCV infection, while combining PegIFN with ribavirin (RBV) is the frontline therapy for chronic HCV infection [14
]. In April 2017, the combination of Daclatasvir (DCV)+Asunaprevir (ASV) as the first generic DAAs was approved in China, and it represented a treatment option for chronic HCV genotype 1b infection [15
], the predominant genotype (56.8%) in China [16
Due to economic issues and limited health care infrastructure in China, as in other resource-limited settings, policy makers should determine which subgroup should be prioritized for HCV treatment. Regarding acute HCV infection among PWID [11
], PegIFN and DAAs therapies have already been demonstrated to be with higher efficacy and shorter-duration than treating chronic HCV infection [17
]. However, current clinic practice recommends deferring treatment to the chronic stage or monitoring patients with acute HCV for at least 12–24 weeks [5
]. On one hand, treating acute HCV infection may lead to unnecessary additional costs and over-treatment, because some individuals would spontaneously clear infection and have no symptoms [6
]. On the other hand, the cost-effectiveness of early treatment of acute infection was not confirmed. Only one modeling-based study from the United States suggested that treatment of acute HCV infection under the DAAs regimen was cost-effective compared with deferring treatment to the chronic stage, but it did not include HCV reinfection in the model [5
]. This may result in underestimating or overestimating the benefits of treatment for acute infection among PWID patients. What’s more, the results might not necessarily be applied to the developing countries as the cost-effectiveness of HCV treatment was influenced by the cost of treatment and the risk of reinfection [18
]. Therefore, it is necessary to confirm the cost-effectiveness of initiating therapy in the acute vs. deferring until the chronic phase of HCV infection, among PWID patients, especially in developing countries.
Regarding chronic HCV infection among PWID, the WHO recommends “treat all” based on previous cost-effectiveness studies, which suggested initiating treatment for chronic HCV regardless of the fibrosis stages [1
]. However, these cost-effectiveness analyses were all conducted in developed countries, such as Australia [19
], the Netherlands [22
], the United Kingdom [23
] and Italy [26
]. Evidence on the cost-effectiveness of expanding treatment to the early fibrosis stage related to access to HCV treatment was substantially more limited in developing countries. Only one study in Egypt [27
] suggested that immediate treatment of patients with early fibrosis stage was less expensive and more effective than delaying treatment, but it did not include the possibility of HCV reinfection in the model. This omission may result in underestimating or overestimating the benefits of early treatment for chronic infection [1
]. In China, the oral DAAs have been confirmed to be cost-saving and cost-effective compared with the PegIFN-based regimen [28
], but the cost-effectiveness of initiating treatment at an early fibrosis stage compared with advanced fibrosis stage was not reported. Furthermore, previous studies in developed and developing countries focused only on either DAAs or PegIFN-based therapy for HCV. They did not indicate how to adjust treatment strategy to local conditions in the presence of both drugs.
Thus, this study used the case of China to conduct a model-based analysis to examine the cost-effectiveness of different treatment timings under DCV+ASV and PegIFN-based regimens, respectively. With a hypothesis that early treatment was more effective, we first compared treatment at acute with deferring treatment until stage F0, to determine the cost-effectiveness of treating acute HCV, under DCV+ASV and PegIFN-based regimens, respectively. Then, we compared treatment at stage F0 with until stage F3, to assess the cost-effectiveness of early treatment for chronic HCV among PWID, under DCV+ASV and PegIFN-based regimens, respectively.
This study used a Markov model to assess the cost-effectiveness of treating acute HCV and early treatment for chronic HCV, under DCV+ASV and PegIFN-based regimen, respectively. This study demonstrated that treatment at an acute stage compared with deferring until chronic stage was highly cost-effective or cost-saving, for both DCV+ASV and PegIFN-based regimens. With the threshold of one-time per capita GDP of China, early treatment at F0 stage was cost-effective compared with delayed treatment at F3 stage using DCV+ASV but not cost-effective when using the PegIFN-based regimen. When the threshold was set at three-times per capita GDP of China, early treatment at F0 stage was cost-effective for both the DCV+ASV and PegIFN-based regimens. This provided new evidences for improving current treatment guidelines that suggested deferring treatment to the chronic stage for an acute infection. This was the first study which included the risk of HCV reinfection in the model to assess the cost-effectiveness of early treatment vs. delayed treatment among chronic HCV in developing countries.
Treatment at the acute stage was the most cost-effective option, especially using DCV+ASV. In line with a study conducted in the United States [5
], treatment at an acute stage was highly cost-effective and cost-saving regardless of the reinfection rate or the costs of treatment. Actually, estimates for the efficiency and costs of acute treatment in this study were likely to be conservative, and treating acute HCV in developing countries may in fact be more cost-effective than we predicted. Thus, acute-infected individuals should not be deprived of being treated since spontaneous clearance of the virus may occur in some patients. It may be time to revise treatment guidelines to recommend treating acute HCV rather than deferring treatment to the chronic stage, regardless of the population (such as PWID, general population), the regimen (DAAs or PegIFN-based), and the setting (resource-limited settings and resource-abundant settings). However, early diagnosis was hard to reach, especially for PWID, because of discrimination, criminalization, and stigma associated with abusing drugs [49
]. Optimizing the impact of effective treatment might require more interventions to facilitate access to early HCV detection, including promoting health awareness, addressing discrimination and stigma, regular testing for HCV, and so on [50
Consistent with previous cost-effectiveness studies of treating chronic HCV among PWID in developed countries [18
], we found that early treatment at F0 was slightly effective and more expensive than delayed treatment at the F3 stage. Whether early treatment was cost-effective or not compared with delayed treatment depended on the national per capita GDP. For example, in Australia, early treatment at F0 was considered cost-effective compared with delayed treatment at F3 with the threshold of AUD$
50,000 per QALY, no matter using DAAs [19
] or PegIFN+RBV regimen [20
]. In this study, with the threshold of one-time per capita GDP of China (US$
9765 per QALY), early treatment at F0 compared with delayed treatment at F3 stage was considered as cost-effective using DCV+ASV but not cost-effective when using the PegIFN-based regimen. This result could provide evidence for China and other resource-limited countries to optimize the allocation of medical resources. In those resource-limited settings, especially for low- and middle-income countries, when DAAs were not available, prioritized treatment for chronic patients with advanced-stage fibrosis may be a better option.
Moreover, this study confirmed that the cost-effectiveness of early treatment for chronic patients was sensitive to “reinfection rate after clearing virus” and “reinfection reduction rate from treatment”, which were two input variables for the model. The lower the reinfection rate, the more cost-effective “treat at F0” was. The reduction rate reflected the potential for reducing the risk of reinfection and secondary transmission from other infected individuals [18
]. We also found that with the improvement of the potential, “treat at F0” was more cost-effective. This also suggested that expanding access to HCV treatment should be combined with harm reduction programs such as needle exchange and opiate substitute treatment, since they would complement HCV treatment by reducing reinfection risk for PWID [18
]. The cost-effectiveness of early treatment in chronic patients was also subjected to treatment costs, but early treatment was still highly cost-effective even when the weekly costs of DCV+ASV was US$
431.4. Actually, the price of highly effective DAAs has decreased substantially [18
]. Early treatment using DAAs might be more cost-effective in the future.
This study has some limitations. First, some of the model inputs were obtained from literatures published worldwide, which may not reflect China-specific data. Second, our model focused on the overall simulation on population-level natural history, thus individual heterogeneity was only represented by varying some parameters in sensitivity analyses. Third, the model did not consider those patients with repeated treatment due to poor response. Fourth, we did not consider other genotype patients, and other DAAs approved in China, such as ombitasvir/paritaprevir/ritonavir+dasabuvir for genotype 1b, and sofosbuvir+velpatasvir/daclatasvir for all genotypes [28
]. The efficiency and costs of these regimens were similar to DCV+ASV, but their treatment course was shorter. Therefore, the cost-effectiveness of other DAAs regimens for treating HCV in PWID would be consistent with DCV+ASV. Fifth, indirect medical costs were not considered, which may overestimate the cost-effectiveness of HCV treatment in PWID. Finally, our model only considered the patients mono-infected with HCV, excluding those coinfected HBV or HIV. Despite these limitations, we believe the conclusion would not be changed regardless.