The Risk of Hepatitis C Virus Recurrence in Hepatitis C Virus-infected Patients Treated With Direct-acting Antivirals After Achieving a Sustained Virological Response

A Comprehensive Analysis

Peng Huang; Yan Wang; Ming Yue; Zhijun Ge; Xueshan Xia; Andre J. Jeyarajan; Jacinta A. Holmes; Rongbin Yu; Chuanwu Zhu; Sheng Yang; Wenyu Lin; Raymond T. Chung


Liver International. 2021;41(10):2341-2357. 

In This Article


The widespread availability of pan-genotypic combination DAAs regimens has provided major individual and population level benefits for chronic hepatitis C infection.[59–61] The favourable effects of HCV antiviral therapy have been clearly demonstrated in patients who achieve SVR, in whom liver-related and all-cause mortality are significantly reduced.[9,62] However, SVR does not confer lifelong protection against reinfection with HCV. Furthermore, there is minimal data available describing the long-term durability of DAAs-induced SVR, particularly in patients with ongoing risk factors for transmission. In this paper, our findings reflect that the substantial majority of patients who achieved SVR following DAAs treatment maintain undetectable HCV RNA levels. Although there is a subgroup of patients that are at higher risk for HCV recurrence, the risk of recurrence was still low in these populations, suggesting that DAAs-induced SVR is durable.[11]

The current study demonstrates that HCV recurrence was 0.89/1000 PYFU in low-risk HCV-mono-infected patients but increased to 29.37/100 PYFU and 23.25/1000 PYFU in the high-risk HCV-mono-infected and HIV/HCV-coinfected populations, respectively. In addition, we calculated that the high-risk HCV-mono-infected and HIV/HCV-coinfected populations experienced a 10.79% and 9.60% increased risk of HCV recurrence, respectively, compared to the low-risk HCV-mono-infected population. Notably, these recurrences were largely driven by reinfection rather than late relapse. Rossi et al previously reported that reinfection rates were higher among PWID than in low-risk HCV-mono-infected patients following successful DAAs therapy likely due to the persistent risk of exposure.[21] Together these data re-emphasize the need for education and preventive measures in individuals with ongoing high-risk behaviours, as well as the need for ongoing HCV monitoring in these individuals.[63]

In our study, the estimated reinfection risk among PWID post-DAAs-induced SVR was 18.31/1000 PYFU (95% CI, 9.70–29.16). This estimate is lower than that reported in previous systematic reviews evaluating the rate of HCV reinfection among PWID (19-62 per 1000 person-years).[24,64,65] Previous systematic reviews were limited by the small number of included studies and lack of data on HCV reinfection post-SVR in the DAAs era. Furthermore, those studies examined the rate of HCV reinfection at the EOT, while in our analysis, studies with <6 months of follow-up post-SVR were excluded. As a result, our study provides the most comprehensive review of long-term HCV recurrence post-DAAs-induced SVR among low- and high-risk HCV-mono-infected and HIV/HCV-coinfected population groups.

Prior to the development of all-oral DAAs regimens, IFN-based therapy was the standard of care for the treatment of HCV. In contrast to DAAs that target-specific HCV proteins involved in viral replication, the mechanism of action of IFN was through broad antiviral effects and immune modulation.[36] Owing to the high potency of combination DAAs regimens, treatment is not only more effective (>95% SVR), but treatment durations are considerably shorter (8-12 weeks compared to 24–48 weeks of IFN plus RBV). Due to differences in the mechanism of action and potency between IFN plus RBV and DAAs, the timing of SVR assessment has also changed from 24 weeks after cessation of therapy with IFN-based therapy (SVR24), to 12 weeks of post-cessation of therapy with DAAs (SVR12). Therefore, the durability of SVR, with respect to late relapse and reinfection due to high-risk behaviours, has been of concern in patients receiving DAAs. Our integrated comprehensive analysis showed that there was no evidence for differential recurrence risks after achieving SVR with DAAs therapy compared to IFN-based therapy overall and among the three subpopulations. Consequently, SVR achieved with all-oral DAAs is durable, and importantly, as durable as that obtained through IFN-based therapy. Furthermore, due to the low risk of HCV recurrence even in the high-risk HCV mono-infection and HIV/HCV co-infection populations, there would appear to be no reason to withhold or defer DAAs therapy in patients who remain at risk for reinfection.[66–70]

Interestingly, we also found that the lower rate of HCV recurrence post-SVR following antiviral treatments (IFN-based and DAAs) were associated with longer follow-up duration. By inference, the recurrence risk is greatest soon after achieving SVR. Another explanation may be loss to follow-up or bias resulting from the differences in follow-up duration as there were few PYFU among those with early HCV recurrence post-SVR. In the future, studies to determine the rate of HCV recurrence will require sufficient follow-up duration and strategies to enhance adherence to ensure there are adequate person-years of post-SVR follow-up to minimize the potential for bias.

The advent and widespread use of DAAs with high SVR rates and low adverse events has been one of the major advances in clinical medicine in recent decades and makes it possible to eliminate hepatitis C and significantly reduce HCV-related morbidity and mortality.[59–61,71] It provides an opportunity for broad treatment up-scaling thereby increasing the potential to meet the WHO 2030 targets. However, in order to meet both the reduction in incidence and mortality targets, all patients, including individuals who may be high-risk for HCV recurrence, need to be treated. This is particularly important considering the fact that the majority of new HCV infections are acquired in PWID,[72] which remains an ongoing challenge towards achieving global HCV elimination. However, the high prevalence and incidence in these high-risk groups, as well as our data demonstrating a low HCV recurrence rate, highlight the critical importance of treating these individuals to restrict the HCV transmission pool. It also encourages the adoption of additional strategies to prevent HCV reinfection and manage high-risk and HIV/HCV-coinfected populations. This should occur at the individual level as well as at the state and federal level if the WHO viral hepatitis targets are to be met.[73,74]

The strength of our systematic review is that it is the first quantitative and comprehensive analysis for HCV recurrence in the DAAs era accounting for populations of different risk levels. However, there are several limitations of this study. First, the mean follow-up period for 36/44 (82%) studies was relatively short (<26 months). Longer follow-up durations would be more appropriate as one previous study evaluating the incidence of late relapse in low-risk HCV-mono-infected patients with genotype 1b who achieved SVR with daclatasvir and asunaprevir,[36] found that late relapse was a rare event that occurred within 26 months after SVR. Since the follow-up duration contributes to PYFU, a study with a short follow-up period also results in wide CIs for the risk estimate of HCV recurrence. In addition, it possibly leads to a miscalculation of the true recurrence rate. Second, complete records on patients who dropped out of long-term follow-up were not available, and it is possible that people lost to follow-up and not included in the studies also experienced recurrence events. This would lead to potential selection bias which limits interpretation of the results. Long-term follow-up adherence might also be potentially important when considering late relapse.

Although there is a low likelihood of viral relapse after SVR particularly in high-risk populations,[17,75] HCV sequencing should ideally be performed in individuals with late recurrent viraemia, to distinguish between HCV reinfection and late relapse in terms of assessing recurrence type. In those studies not utilizing sequencing methods but rather genotyping or author judgement, bias may have been introduced by the tendency to classify either late relapse or reinfection. Therefore, the HCV recurrence risks calculated may not be accurate. Finally, our study did not include patients who had acute HCV or spontaneously cleared acute HCV. There is evidence demonstrating that HCV recurrence can occur not only in the chronic stage but also in acute HCV or after spontaneous clearance.[76,77] Since these patients are often asymptomatic, this is a difficult cohort to amass, and there are extremely limited data available. As a result, if these patients were captured and followed, the calculated HCV recurrence rates may have been higher.

In conclusion, the risk of HCV recurrence following SVR achieved with all-oral DAAs therapy is low. Although recurrence rates in high-risk HCV-mono-infected and HIV/HCV-coinfected populations are significantly higher than those in low-risk populations, the rates are still low. These data demonstrate that SVR rates achieved with all-oral DAAs therapy are comparable to that observed with IFN therapy. Given these data, we believe the ambitious HCV elimination targets set by the WHO are achievable and that high-risk patients should not be excluded from treatment algorithms and government policies if these targets are to be met.