Carta et al. published an interesting article on the use of some direct antiviral agents (DAAs) in renal transplant (RT) recipients affected by hepatitis C virus (HCV) infection.

The issue is relevant and presents several aspects that need to be highlighted.

The persistence of HCV infection after RT is a severe risk factor for graft and patient survival. Complications may involve the liver or the kidney.

The improved knowledge of the vital cycle of HCV and of the virus structure and its proteins allowed the development of highly efficient DAA (Figure 1).

To date, the DAAs may be divided into four classes according to the mechanism of action (Table 1). The first DAAs for the treatment of HCV were the protease inhibitors against NS3/SA, such as telaprevir and boceprivir (10, 11). These drugs are used for the treatment of genotype 1 in association with IFN and ribavirin. In 2013, three new DAAs were approved in the United States: simeprivir (IP-NS3/NS4A), daclatasvir (inhibitor of NS5A), and sofosbuvir (inhibitor of polymerase NS5B). The use of these DAAs allowed for avoiding the use of IFN. New strategies in the use of DAAs have been the use of combinations of DAAs (12), such as sofosbuvir and ledipasvir. More recently, new DAAs have been added, such as elbasvir, glecaprevir, ritonavir, ombitasvir, dasabuvir, and voxilaprevir (13, 14).

The introduction of these drugs allowed for obtaining efficacy against all genotypes, to reduce the duration of treatment, and to increase the safety and efficacy of the treatment (15).

The new KDIGO guidelines recommend that all patients with HCV who are candidates for kidney transplantation should be considered for DAA therapy, either before or after transplantation. The same recommendation applies to HCV candidates with a living donor (16).

Pharmacokinetic interactions are the most important, primarily because of the role of cytochrome P450 (CYP450). The interactions with glycoprotein P (P-gp) are also important in limiting the drug bioavailability (17, 18).

The use of drugs inducing CYP450 or P-gp carries the risk of reducing the DAA concentrations. On the other hand, the use of the protein inhibitor, NS3-4A, is contraindicated in patients with severe liver disease. Similarly, the use of the polymerase inhibitor, sofosbuvir, is not indicated in patients with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² because of its renal elimination (19).

In addition to inhibiting cytochrome CYP3A, cyclosporine (CyA) also inhibits the organ anion transporter family 1B1/3 (OATP1B1/3), the breast cancer resistance protein (BCRP), and P-gp. As a consequence, its administration with a protease inhibitor IPNSA3-4A is not recommended because of the increase in blood CyA. On the contrary, the administration of simeprevir with tacrolimus (TAC) causes only a small decrease of the latter and requires monitoring (20, 21).

The new combinations with an IPNS3-4A as grazoprevir–elbasvir or glecaprevir–pibrentasvir or sofosbuvir–ledipasvir–voxilaprevir may cause a mild TAC modification and require monitoring (22–24).

No data are available for the inhibitors of mammalian target of rapamycin (mTORIs).

Daclatasvir and sofosbuvir may be safely administered together with TAC and mTORIs (25).

The association between ombitasvir–paritaprevir–ritonavir and the immunosuppressants may be dangerous because ritonavir causes inhibition of CYP3A4 and of P-gp. This may cause an increase of the calcineurin inhibitors and of the mTORIs. In one study (26), CyA doses were reduced to one-fifth and TAC doses were reduced to 0.5 mg/week.

Table 2 shows the modifications of immunosuppressant doses in patients receiving DAA.

In conclusion, the availability of new IFN-free DAA offers the possibility of efficiently treating RT patients with HCV infection.

The possible important interactions between these drugs and the immunosuppressants often require strict monitoring to reduce the risks of rejection or immunosuppressants-related toxicity.

The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.