Bouncing back or slowing down renal function decline after hepatitis C virus eradication

Hepatitis C virus (HCV) is both hepatotropic and lymphotropic in human bodies. Its cytopathic nature leads to a wide category of extrahepatic manifestations. The kidney is one of the target organs/systems that HCV involves. A poor renal function in chronic hepatitis C (CHC) patients may be due to immune complex depositions that causes glomerular or tubulointerstitial injuries. Increasing comorbidities than the general population, such as diabetes, may further compromise renal function. An early interferon-based cohort study in Taiwan has shown that antiviral treatment, regardless of successful viral eradication, may decrease the risk of end-stage renal disease (ESRD).¹ It raised the hope for possible halting or reversal of the deteriorated renal function in CHC patients.

In the current issue by Su et al.,² the authors discussed the short-term change in estimated glomerular filtration rate (eGFR) in CHC patients who were treated with sofosbuvir/velpatasivir. One of the rationality raised by the authors is the safety concern of sofosbuvir-based regimens in patients with chronic kidney disease stage 4 or 5 because of the concern of the overt accumulation and delayed excretion of the metabolite, GS-331007. We now clearly know that its use is very safe in patients whose eGFR was less than 30 mL/min/1.73 m² after the approval of the FDA in 2019. Among ESRD patients, GS-331007 was smoothly removed by regular hemodialysis, which was never detected throughout 1 month to 1 year after the end of sofosbuvir/velpatasivir treatment.³

The authors did not show the overall eGFR change after directly acting antivirals (DAAs) therapy. Rather, they observed an improvement of eGFR in patients with baseline eGFR ≤60 mL/min/1.73 m² but a decreased eGFR in patients with baseline eGFR >60 mL/min/1.73 m². This contradictory result was difficult to explain but have been reported in previous studies.^{4, 5} It should be noted that the MDRD equation may improperly judge a healthy subject with a high eGFR level.⁶ Moreover, a transient decrease in eGFR in patients with extremely high baseline levels shortly after DAA may not indicate deterioration of renal function. As eGFR declines with aging, age per se would be the confounder for the comparison of eGFR change. An ideal way is to compare the slope of coefficient difference of eGFR change between comparators.^{4, 7, 8} Recently, Liu et al. have shown a steeper slope of eGFR decline in patients who failed antiviral therapy compared with those who achieved a sustained virological response (SVR).⁹ Due to the lack of a control group (untreated or treatment failure patients) in the DAA era, another way is to observe the short-term dynamic change in eGFR immediately before and after DAA treatment as in this study. To elucidate the trend of eGFR change, using repeat measurement and multiple comparisons would be a better statistic⁴ than solely comparing the delta change of the parameter between two time points before and after DAA treatment.

Notably, using the binary categorization of renal function in the analysis may lead to misinterpretation. Actually, patients with lower baseline eGFR levels may have more room for renal function restoration after DAA treatment if patients were stratified by more subgroups based on their baseline renal function.⁴ We can imagine that with the increase in baseline eGFR, there would be a decrease in improvement of eGFR (delta change of eGFR) until a certain turning point where eGFR starts to decrease compared with the pretreatment status.

It is suggested that HCV eradication may slow down the speed of renal function decline.⁷ More importantly, we would like to see whether HCV eradication reduces the risk of ESRD. A study that included 1987 patients receiving both interferon-based and DAA regimens has shown that the incidence of ESRD in patients who achieved SVR was 0.06 per 100 person-years compared with that of 0.37 per 100 person-years in non-SVR patients. The achievement of SVR significantly reduces 76% of the risk of ESRD.⁹ Nevertheless, another larger nationwide cohort including 12 696 CHC patients receiving interferon-based therapy (T-COACH) in Taiwan did not observe a decrease in the incidence of ESRD in SVR patients compared with non-SVR ones after a longer and greater person-years follow-up.¹⁰ The index event, ESRD, in both studies was rare. The discrepant results between the two studies may in part due to the different patient characteristics. In conclusion, the benefit of achieving SVR in preserving renal function comes from the direct removal of the immune complex. Indirectly, the improvement of glycemic control in diabetic patients, reversal of atherosclerosis, and immune-medicated inflammation may also play a role in renal protection after HCV eradication. In the current DAA era, patients being allocated to treatment may possess more complex comorbidities including more risk factors and confounders for renal function deterioration. The net benefit of HCV eradication by DAAs in reducing ESRD opens the window for further exploration.

The authors delcaim no conflicts of interest.