Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection--the InC3 Study

Abstract

Background: We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance.

Methods: Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test. Those with positive results of an HCV RNA test following viral suppression were investigated for reinfection. Viral sequence analysis was used to identify reinfection (defined as detection of heterologous virus with no subsequent detection of the original viral strain).

Results: Among 591 participants with acute primary HCV infection, 118 were investigated for reinfection. Twenty-eight participants were reinfected (12.3 cases/100 person-years; 95% confidence interval [CI], 8.5-17.8). Peak HCV RNA level was lower during reinfection than primary infection (P = .011). The proportion of individuals with reclearance 6 months after reinfection was 52% (95% CI, 33%-73%). After adjustment for study site, females with the IFNL4 (formerly IFNL3 and IL28B) rs12979860 CC genotype detected were more likely to have reclearance (hazard ratio, 4.16; 95% CI, 1.24-13.94; P = .021).

Conclusions: Sex and IFNL4 genotype are associated with spontaneous clearance after reinfection.

Keywords: IFNL4; cohort study; hepatitis C; injecting drug use; re-infection; sex; viral resolution.

Figure 1.

Timing and classification of hepatitis C virus (HCV) primary infection, viral suppression, spontaneous clearance, and reinfection. A, Flowchart for determining the estimated date of primary HCV infection. B, Estimated dates of and times to primary clearance and viral suppression. All timelines represent participants with confirmed primary HCV infection followed by either viral suppression or primary clearance. The timelines begin at the estimated date of primary infection. After primary infection, HCV RNA test results are depicted on the timeline by squares. Black squares represent HCV RNA–positive test results, and white squares represent HCV RNA–negative test results. Primary clearance is distinguished from viral suppression by the number of HCV RNA–negative test results (white squares). The top timelines (i and ii) depict primary clearance (as indicated by the 2 consecutive HCV RNA–negative test results), and the bottom timelines (iii and iv) depict viral suppression (defined as 1 HCV RNA–negative test result). In timelines ii and iv, HCV RNA was undetectable at the time of primary infection detection, as indicated by the white initial squares (HCV RNA tests) in the timelines. The estimated date of primary clearance is illustrated using a white triangle, and the estimated date of viral suppression is illustrated using a gray triangle. These dates are both estimated as follows: if HCV RNA is detectable at the time of detection of primary infection (i and iii), the estimated date of primary clearance or viral suppression is the midpoint between the HCV RNA–positive test result prior to primary clearance or viral suppression and the first HCV RNA–negative test result.

Figure 1.

If HCV RNA is undetectable at the time of detection of primary infection (ii and iv), the estimated date of primary clearance or viral suppression is the midpoint between the estimated date of primary infection (the beginning of the illustrated timeline) and the first HCV RNA–negative test result. In all 4 cases, the time to primary clearance or viral suppression is the time from the estimated date of infection until the estimated date of primary clearance or viral suppression. C, Estimated dates of and times to reinfection. Both timelines represent participants with confirmed primary HCV infection followed by either viral suppression or primary clearance and confirmed reinfection. The timelines begin at the estimated date of primary clearance or viral suppression. HCV RNA test results are depicted on the timeline by squares. Black squares represent HCV RNA–positive test results, and white squares represent HCV RNA–negative test results. Primary clearance is distinguished from viral suppression by the number of HCV RNA–negative test results (white squares). The top timeline (i) depicts primary clearance (as indicated by the 2 consecutive HCV RNA–negative test results), and the bottom timeline (ii) depicts viral suppression (define as 1 HCV RNA–negative test result). The estimated date of reinfection is the midpoint between the last HCV RNA–negative test result and the first HCV RNA–positive test result. The time to reinfection is defined as the time from the estimated date of primary clearance or viral suppression until the estimated date of reinfection. D, Flowchart of reinfection classification. *Primary HCV infection outcome unknown; **Reinfection outcome unknown: includes five cases with insufficient follow-up to determine outcome and three cases with change in genotype after reinfection.

Figure 2.

Timeline of reinfection events from the estimated date of primary hepatitis C virus (HCV) infection. Timelines illustrate results of HCV RNA tests and HCV genotyping for the 28 participants with reinfection. Each box represents 1 HCV RNA test. Empty boxes are tests in which HCV RNA was undetectable, whereas filled boxes (black or colored) indicate that HCV RNA was detectable. HCV genotyping results are indicated using color and box labels. Within individuals, distinct strains within a single viral genotype and subtype that were confirmed by viral sequencing are illustrated using different shades of the same color. Reinfection events (R) are defined by the appearance of a new viral genotype, viral subtype, or distinct strain confirmed by viral sequencing following a period during which HCV RNA was undetectable. HCV from the primary infections of participants UFOVT0134 and AUS206 was serotyped.