Factors Associated with Spontaneous Clearance of Chronic Hepatitis C Virus Infection: a Retrospective Case Control Study.
Bulteel N et al
J Hepatol 2016, May 4 (Epub ahead of print).

Background & Aims: Spontaneous clearance of chronic HCV infection (CHC) is rare. We conducted a retrospective case control study to identify rates and factors associated with spontaneous clearance of CHC.

Methods: We defined cases as individuals who spontaneously resolved CHC, and controls as individuals who remained chronically infected. We used data obtained on HCV testing between 1994 and 2013 in the West of Scotland to infer case/control status. Specifically, untreated patients with ≥ 2 sequential samples positive for HCV RNA ≥ 6 months apart followed by ≥ 1 negative test, and those with ≥ 2 positive samples ≥ 6 months apart with no subsequent negative samples were identified. Control patients were randomly selected from the second group (4/patient of interest). Case notes were reviewed and patient characteristics obtained.

Results: 25,113 samples were positive for HCV RNA, relating to 10,318 patients. 50 cases of late spontaneous clearance were identified, contributing 241 person-years follow-up. 2,518 untreated, chronically infected controls were identified, contributing 13,766 person-years follow-up, from whom 200 controls were randomly selected. The incidence rate of spontaneous clearance was 0.36/100 person-years follow-up, occurring after a median 50 months infection. Spontaneous clearance was positively associated with female gender, younger age at infection, lower HCV RNA load and co-infection with hepatitis B virus. It was negatively associated with current intravenous drug use.

Conclusions: Spontaneous clearance of CHC occurs infrequently but is associated with identifiable host and viral factors. More frequent HCV RNA monitoring may be appropriate in selected patient groups.

Expert's Commentary

« Following acute hepatitis C on average 25% of patients can clear HCV infection spontaneously. Clearance rates are higher in patients with symptomatic (jaundice and markedly elevated aminotransferases) acute HCV infection. Previous studies have suggested that the interleukin 28B (IL28B) rs8099917 genotype is related to spontaneous clearance of HCV in Caucasian and Japanese patient populations (1). More recently, the toll-like-receptor (TLR) TLR9 rs187084 C allele has also been associated with spontaneous virus clearance in women (2). Once HCV RNA is detectable for six months chronic HCV infection is diagnosed. Clearance of hepatitis C virus (HCV) infection without treatment occurs rarely once chronic infection has been established. In the current study, 50 cases of late spontaneous clearance were identified from a very large Scottish patient cohort. Overall, this was a very rare event with an incidence rate of spontaneous clearance of 0.36/100 person-years follow-up, occurring after a median of 50 months of HCV infection. The late clearance patients were then compared to non-clearance patients. Most interestingly, spontaneous clearance was positively associated with female gender, younger age at infection, lower HCV RNA load and co-infection with hepatitis B virus. This suggests that even in chronic HCV late clearance can occur in the setting of favorable host or viral factors. Unfortunately, no testing for established markers such as IL2B CC genotype was possible. Clearly, this would be very interesting to better understand which patients would be most likely to clear HCV by themselves over time. Noteworthy, occasional late spontaneous clearance has been described for HIV/HCV coinfected patients after starting cART (combined antiretroviral therapy) and achieving immune reconstitution, which again was associated with the favorable IL28B CC genotype (3). Similarly, IL28B has also been shown to play a role in spontaneous clearance in HBV/HCV dually infected subjects. Interestingly, in this paper HBV coinfection was also associated with higher chances for spontaneous clearance possibly related to favorable host factors (4). Beyond, the identification of individuals whose immune system eventually takes control of HCV infection this paper has some very important clinical implications. As late spontaneous clearance may occur, a HCV viral load determination prior to HCV DAA-based therapy initiation appears advisable in order to make sure that the patient still shows sign of chronic HCV infection before starting the costly HCV therapy. The novel finding of a negative association with ongoing IDU remains unclear, as reinfections cannot be precluded and warrants further investigations. »

Pr Jürgen Rockstroh, University of Bonn

1. Ikezaki H et al. Association of IL28B rs8099917 genotype and female sex with spontaneous clearance of hepatitis C virus infection: a Japanese cross-sectional study. Arch Virol. 2016;16:641-8.
2. Fischer J, et al. Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection. Gut. 2016 Apr 21. [Epub ahead of print]
3. Stenkvist J, et al. Occasional spontaneous clearance of chronic hepatitis C virus in HIV-infected individuals. J Hepatol. 2014;61:957-61.
4. Coppola N, et al. Role of interleukin 28-B in the spontaneous and treatment-related clearance of HCV infection in patients with chronic HBV/HCV dual infection. Eur J Clin Microbiol Infect Dis. 2014;33:559-67.