Changes in incidence of hepatitis C virus reinfection and access to direct-acting antiviral therapies in people with HIV from six countries, 2010-19: an analysis of data from a consortium of prospective cohort studies.

BACKGROUND: Reinfection after successful treatment with direct-acting antivirals is hypothesised to undermine efforts to eliminate hepatitis C virus (HCV) infection among people with HIV. We aimed to assess changes in incidence of HCV reinfection among people with HIV following the introduction of direct-acting antivirals, and the proportion of all incident cases attributable to reinfection. METHODS: We pooled individual-level data on HCV reinfection in people with HIV after spontaneous or treatment-induced clearance of HCV from six cohorts contributing data to the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC) in Australia, Canada, France, the Netherlands, Spain, and Switzerland between Jan 1, 2010, and Dec 31, 2019. Participants were eligible if they had evidence of an HCV infection (HCV antibody or RNA positive test) followed by spontaneous clearance or treatment-induced clearance, with at least one HCV RNA test after clearance enabling measurement of reinfection. We assessed differences in first reinfection incidence between direct-acting antiviral access periods (pre-direct-acting antiviral, limited access [access restricted to people with moderate or severe liver disease and other priority groups], and broad access [access for all patients with chronic HCV]) using Poisson regression. We estimated changes in combined HCV incidence (primary and reinfection) and the relative contribution of infection type by calendar year. FINDINGS: Overall, 6144 people with HIV who were at risk of HCV reinfection (median age 49 years [IQR 42-54]; 4989 [81%] male; 2836 [46%] men who have sex with men; 2360 [38%] people who inject drugs) were followed up for 17 303 person-years and were included in this analysis. The incidence of first HCV reinfection was stable during the period before the introduction of direct-acting antivirals (pre-introduction period; 4·1 cases per 100 person-years, 95% CI 2·8-6·0). Compared with the pre-introduction period, the average incidence of reinfection was 4% lower during the period of limited access (incidence rate ratio [IRR] 0·96, 95% CI 0·78-1·19), and 28% lower during the period of broad access (0·72, 0·60-0·86). Between 2015 and 2019, the proportion of incident HCV infections due to reinfection increased, but combined incidence declined by 34%, from 1·02 cases per 100 person-years (95% CI 0·96-1·07) in 2015 to 0·67 cases per 100 person-years (95% CI 0·59-0·75) in 2019. INTERPRETATION: HCV reinfection incidence and combined incidence declined in people with HIV following direct-acting antiviral introduction, suggesting reinfection has not affected elimination efforts among people with HIV in InCHEHC countries. The proportion of incident HCV cases due to reinfection was highest during periods of broad access to direct-acting antivirals, highlighting the importance of reducing ongoing risks and continuing testing in people at risk. FUNDING: Australian National Health and Medical Research Council.

All-cause mortality before and after DAA availability among people living with HIV and HCV: An international comparison between 2010 and 2019.

BACKGROUND: Among people living with HIV and hepatitis C virus (HCV), people who inject drugs (PWID) have historically experienced higher mortality rates. Direct-acting antivirals (DAA), which have led to a 90 % HCV cure rate independently of HIV co-infection, have improved mortality rates. However, DAA era mortality trends among PWID with HIV/HCV remain unknown. Using data from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC), we compared pre/post-DAA availability mortality changes in three groups: PWID, men who have sex with men (MSM), and all other participants. METHODS: We included InCHEHC participants with HIV/HCV followed between 2010 and 2019 in Canada, France, the Netherlands, Spain, and Switzerland. All-cause mortality hazard was compared in the three groups, using Cox proportional hazards regression models adjusted for sex, age, advanced fibrosis/cirrhosis, and pre/post DAA availability. RESULTS: Of the 11,029 participants, 76 % were men, 46 % were PWID, baseline median age was 46 years (interquartile range [IQR] = 40;51), and median CD4 T-cell count was 490 cells/mm3 (IQR = 327;689). Over the study period (median follow-up = 7.2 years (IQR = 3.7;10.0)), 6143 (56 %) participants received HCV treatment, 4880 (44 %) were cured, and 1322 participants died (mortality rate = 1.81/100 person-years (PY) [95 % confidence interval (CI)=1.72-1.91]). Overall, PWID had higher mortality rates than MSM (2.5/100 PY [95 % CI = 2.3-2.6] vs. 0.8/100 PY [95 % CI = 0.7-0.9], respectively). Unlike women with other transmission modes, those who injected drugs had a higher mortality hazard than men who did not inject drugs and men who were not MSM (adjusted Hazard-Ratio (aHR) [95 % CI] = 1.3[1.0-1.6]). Post-DAA availability, mortality decreased among MSM in the Netherlands, Spain, and Switzerland and increased among PWID in Canada (aHR [95 % CI] = 1.73 [1.15-2.61]). CONCLUSION: Post-DAA availability, all-cause mortality did not decrease in PWID. Determinants of cause-specific deaths (drug-related, HIV-related, or HCV-related) need to be identified to explain persistently high mortality among PWID in the DAA era.

Mortality in hepatitis C virus-cured vs. hepatitis C virus-uninfected people with HIV.

OBJECTIVE: It is unknown whether hepatitis C virus (HCV)-cured people with HIV (PWH) without cirrhosis reached the same mortality risk as HCV-uninfected PWH. We aimed to compare mortality in PWH cured of HCV by direct-acting antivirals (DAAs) to mortality in individuals with HIV monoinfection. DESIGN: Nationwide hospital cohort. METHODS: HIV-controlled participants without cirrhosis and HCV-cured by DAAs started between September 2013 and September 2020, were matched on age (±5 years), sex, HIV transmission group, AIDS status, and body mass index (BMI) (±1 kg/m 2 ) to up to 10 participants with a virally suppressed HIV monoinfection followed at the time of HCV cure ±6 months. Poisson regression models with robust variance estimates were used to compare mortality in both groups after adjusting for confounders. RESULTS: The analysis included 3961 HCV-cured PWH (G1) and 33 872 HCV-uninfected PWH (G2). Median follow-up was 3.7 years in G1 [interquartile range (IQR): 2.0-4.6], and 3.3 years (IQR: 1.7-4.4) in G2. Median age was 52.0 years (IQR: 47.0-56.0), and 29 116 (77.0%) were men. There were 150 deaths in G1 [adjusted incidence rate (aIR): 12.2/1000 person-years] and 509 (aIR: 6.3/1000 person-years) in G2, with an incidence rate ratio (IRR): 1.9 [95% confidence interval (CI), 1.4-2.7]. The risk remained elevated 12 months post HCV cure (IRR: 2.4 [95% CI, 1.6-3.5]). Non-AIDS/non-liver-related malignancy was the most common cause of death in G1 (28 deaths). CONCLUSIONS: Despite HCV cure and HIV viral suppression, after controlling on factors related to mortality, DAA-cured PWH without cirrhosis remain at higher risk of all-cause mortality than people with HIV monoinfection. A better understanding of the determinants of mortality is needed in this population.

Treatment as prevention effect of direct-acting antivirals on primary hepatitis C virus incidence: Findings from a multinational cohort between 2010 and 2019.

Background: Broad direct-acting antiviral (DAA) access may reduce hepatitis C virus (HCV) incidence through a "treatment as prevention" (TasP) effect. We assessed changes in primary HCV incidence following DAA access among people living with HIV (PLHIV). Methods: We used pooled individual-level data from six cohorts from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC). Follow-up started from the first recorded negative HCV antibody test date and ended at last negative antibody test or estimated infection date. Follow-up was restricted to 2010-2019. We used segmented Poisson regression to model trends across pre-, limited- (i.e., restrictions on access) and broad-DAA access periods. Findings: Overall, 45,942 participants had at least one HCV antibody negative result and follow-up between 2010 and 2019. We observed 2042 incident HCV infections over 248,189 person-years (PY). Pooled incidence decreased from 0.91 per 100 PY in 2015 to 0.41 per 100 PY in 2019. Compared to the average pre-DAA period incidence (0.90 per 100 PY), average incidence was similar during the limited-DAA access period (Incidence rate ratio [IRR] = 0.98; 95%CI = 0.87, 1.11), and 52% lower during the broad-DAA access period (IRR = 0.48; 95%CI = 0.42, 0.52). The average annual decline in HCV incidence was 2% in the pre-DAA period; an additional 9% annual decline in incidence was observed during the limited-DAA access period (IRR = 0.91; 95%CI = 0.82, 1.00) and a further 20% decline in the broad-DAA access period (IRR = 0.80, 95%CI = 0.73, 0.89). Interpretation: Our findings suggest that broad DAA access has a TasP effect on primary HCV incidence among PLHIV. Based on the initial years of DAA availability, the countries in the InCHEHC collaboration are on track to meet the World Health Organization's 80% HCV incidence reduction target for PLHIV by 2030. Funding: This study was funded by the Australian Government National Health and Medical Research Council (Grant number GNT1132902).