Hepatitis C virus (HCV) infection is a common infectious disease with a prevalence of 71 million HCV-infected individuals all over the world.1 Evidence has accumulated over the last two decades reporting a variety of extra-hepatic diseases induced by HCV; HCV-negative individuals have lower non-liver-related mortality compared to those who are chronically infected with HCV.2 The extra-hepatic activity of HCV is added to its action on the liver that manifest itself with cirrhosis and hepatocellular carcinoma, the main complications of chronic liver disease.

The kidneys are an important target of chronic HCV, the relationship between HCV and the kidneys has bidirectional nature and is complex. On one side, kidney failure supports the diffusion of HCV (mostly via dialysis environment) particularly in the developing world where the compliance to the infection control procedures against HCV spread within dialysis units is frequently missing. On the other, HCV increases the risk of renal impairment. In addition to conventional risk factors for chronic kidney disease (ageing, metabolic syndrome, arterial hypertension, and diabetes) HCV infection may be an additional risk factor.

The detrimental role of chronic HCV on the incidence and progression of chronic kidney disease in the general population has been recently emphasized. A meta-analysis of observational studies (n=40 studies, n=4,072,867 unique patients) demonstrated an association between positive anti-HCV serologic status and increased incidence of CKD.3 We found a significant association between positive anti-HCV serologic status and increased frequency of proteinuria, adjusted risk of proteinuria associated with HCV across the surveys, 1.633 (95% CI, 1.29; 2.05). Test for homogeneity of the adjusted risk of proteinuria across the ten studies gave a Q value of 37.47 (I2=75.9%) (P=0.0001). That is, the homogeneity assumption was rejected.3

The advent of the direct-acting antiviral agents (DAAs) is dramatically changing the management of HCV in the general populations including the ‘difficult-to-treat’ groups such as CKD patients. According to the guidelines provided by the AASLD/IDSA, two regimens based on DAAs have been suggested for HCV in advanced CKD.4 On the contrary, various combinations have been recommended in patients with mild-to-moderate renal impairment.4,5 However, the data in the medical literature regarding the use of DAAs in patients with stage 1–3 chronic kidney disease are extremely limited.6–9

The aim of this study is to evaluate efficacy and safety of therapy with DAAs for HCV in patients with mild-to-moderate chronic kidney disease in a ‘real-life’ clinical practice. Various regimens based on DAAs have been retrospectively reviewed including the most recent combinations.

Most RCTs of DAAs in the general population included patients with intact kidneys and the majority of studies with CKD patients (such as C-SURFER, RUBY-1, and EXPEDITION-4) involved individuals with advanced CKD.12–14 The aim of this study is to evaluate the efficacy and safety of DAAs for treatment of HCV among patients with mild-to-moderate CKD in a ‘real-world’ setting. We have evaluated the activity of various combinations of DAAs (such as PrOD or sofosbuvir-based regimens) in a large cohort of patients with stage 1–3 CKD followed at some outpatient clinics all over the world. We found a high viral response (>95%) and this occurred irrespective of viral features, demographic and clinical characteristics. The viral response was great despite our cohort was a difficult group to cure- many patients had advanced liver fibrosis, treatment-experience, and a high rate of co-morbidities (such as arterial hypertension and diabetes); genotypes other than 1 and 4 were frequently found.

Another important point was tolerance to DAAs. This was satisfactory as no drop-outs or hospitalizations occurred; dose reduction or discontinuation of RBV was made in a minority of patients only. Worsening of kidney function was experienced in a few individuals (all having stage 3 CKD at baseline). This fact appears to confirm what has been already observed in the HCV-TARGET database, where patients with eGFR <45mL/min more frequently experienced worsening of kidney function compared with a control group with eGFR >45mL/min per 1.73m2.7 No difference in serum creatinine and eGFR levels at the beginning vs. EOT was observed in the whole population.

From a historical point of view, the purpose of antiviral therapy towards HCV has been to treat and prevent liver-related complications such as cirrhosis, HCV and liver-related death. The World Health Organization 1 has recently proposed the universal treatment of HCV, regardless the liver disease stage, and this recommendation is in keeping with the recent evidence showing that antiviral treatment of HCV prevents the development or deterioration of diabetes, cardiovascular disease, and chronic kidney disease. Survival studies performed in patients with intact kidneys or dialysis population have shown the association between positive anti-HCV serologic status and higher cardiovascular mortality.15,16 The detrimental role of chronic HCV on the incidence and progression of CKD in the adult general population has been repeatedly emphasized. In addition to the role of HCV in the development of glomerular disease, several biological mechanisms have been advocated to explain the kidney injury in HCV-positive patients; it can be given by endothelial dysfunction with is promoted by enhanced oxidative stress, pro-inflammatory cytokines, peripheral and hepatic insulin resistance, or non-alcoholic steatohepatitis (NASH).17–20

The findings from the current study have some limitations. First, some regimens (such as EBR/GZR or GP) have been administered in a few cases only as these have been recently introduced in the market. The retrospective nature of the current study may have led to incorrect reporting of AEs but we reviewed with accuracy the clinical records of our series and felt that many AEs were associated with the typical comorbidities of these patients. A subgroup of patients was excluded from the safety analysis because the information on AEs was incomplete. The aetiology of CKD was not addressed in our cohort and a few patients had undergone kidney biopsy; this commonly occurs in the ‘real-life’ clinical practice. Finally, we included patients with CKD identified by calculating eGFR, proteinuria measurements have not been considered for the diagnosis of CKD in our population. This is in analogy with what reported approach in prior studies8 as quantitative proteinuria assessment is still infrequent in HCV-infected individuals in the ‘real-world’ activity. Another limitation of the current study is that the post-treatment data are available only over a short follow-up (12 weeks). Studies are in progress in order to evaluate the effects of HCV eradication on the incidence and progression of CKD over longer periods of time.

In summary, various interferon-free combinations of DAAs are currently available for patients with early stage chronic kidney disease. These have given excellent safety and efficacy. What we need now is to accumulate data on the new treatments for HCV able to provide shorter treatment durations, lower pill burden, and no ribavirin use. In addition, studies are under way to assess the link between the eradication of HCV and better renal and cardiovascular survival among patients with CKD.

AASLD, American Association for the Study of Liver Diseases; AEs, adverse events; AH, arterial hypertension; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD-EPI, chronic kidney disease epidemiology collaboration; DAAs, direct-acting antiviral agents; DDIs, drug-drug interactions; DM, diabetes mellitus; EOT, end-of-treatment; eGFR, estimated glomerular filtration rate; gamma-GT, gamma glutamyltranspeptidase; GI, gastrointestinal; HCV, hepatitis C virus; IDSA, Infectious Disease Society of America; INR, international normalized ratio; ITT, intention-to-treat; MDRD, Modification of Diet in Renal Disease; NA, not available; OLT, orthotopic liver transplant; PKD, polycystic kidney disease; SAEs, serious adverse events; SVR, sustained virological response; W12, week 12 (12 weeks after the end of treatment).

DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GP glecaprevir/pibrentasvir; GZR, grazoprevir; SOF, sofosbuvir; IFN, interferon; LDV, ledipasvir; OBV, ombitasvir; pegIFN, pegylated interferon; PrOD, ritonavir-boosted paritaprevir, ombitasvir and dasabuvir; PTV, paritaprevir; r, ritonavir; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; VEL, velpatasvir.

No sources of funding were used for the preparation of this manuscript.

Ezequiel Ridruejo: advisor/lecturer for Bristol-Myer Squibb, Gilead, MSD. Manuel Mendizabal: advisor/speaker for BMS, AbbVie; grants from AbbVie and MSD. Marcelo Silva: advisor/speaker for MSD, AbbVie, BMS, Gilead; grants from MSD, AbbVie, BMS. Fabrizio Fabrizi: consultant/advisor to AbbVie, Merck & Co.