**3.3 Antiviral drugs and regimens**

The optimal dose and duration of antiviral treatment in transplant patients are unknown, and the same regimens are usually followed as those applied to immunocompetent patients (Otón et al, 2006).

Adverse effects are the main reason for dose reduction (50%), particularly with ribavirin, and premature treatment interruption (25%). The most usual adverse effects involve haematological alterations, mainly anaemia (60-80%), neuropsychiatric disorders (around 10-15%), thyroid disorders, asthenia (60-70%) and infections (15-25%). The use of

eliminate the HCV before the hepatic lesion appears. Nevertheless, this early antiviral therapy has numerous limitations, such as the degree of post-transplant immunosuppression present in these patients; their clinical situation after the transplant, which affects their tolerance to treatment; their high viral load, partly related with the degree of immunosuppression, and the corresponding reduction in therapeutic success plus the high risk of episodes of rejection, which advise delaying treatment until a more suitable time from the immunological standpoint (Sheiner et al, 1998, Chalasani et al, 2005, Sugawara

This strategy is, however, applicable to all patients who receive a transplant due to HCV infection, including those who have no aggressive rejection episode and remain stable, with minimum hepatic lesions for whom antiviral therapy would perhaps not otherwise be

The viral response experienced, according to the various studies published, ranges from 1% to 13%. However, treatment had to be withdrawn early in 35% of the patients treated, due to adverse effects (Shergill et al, 2005). The application of this treatment regimen could perhaps be considered in those patients who receive a further transplant due to aggressive HCV

This consists of applying treatment once the histological recurrence of the HCV is well established, with the aim of preventing rapid progression of the hepatic lesion. The period of treatment application is from 2 to 7 months after the transplant, or according to the histological lesions seen on liver biopsy. Using this strategy, the patient has a lower and better controlled degree of immunosuppression, has recovered from the surgery, and alterations present prior to the transplant have been corrected, such as anaemia, thrombocytopoenia or the nutritional status, all of which favour greater tolerance and

The rate of sustained viral response seen with this schedule is from 20% to 40% (2,21-22,25); the rate of premature interruption of treatment is around 28% and that of dose reduction 73%. The results, though, are still worse than those found in immunocompetent patients

In all cases management should be personalized, and consideration given to such factors as renal function, concomitant diabetes, a prior history of rejection and genotype (Aymant et

The optimal dose and duration of antiviral treatment in transplant patients are unknown, and the same regimens are usually followed as those applied to immunocompetent patients

Adverse effects are the main reason for dose reduction (50%), particularly with ribavirin, and premature treatment interruption (25%). The most usual adverse effects involve haematological alterations, mainly anaemia (60-80%), neuropsychiatric disorders (around 10-15%), thyroid disorders, asthenia (60-70%) and infections (15-25%). The use of

et al, 2004, Shergill et al, 2005).

infection or in coinfected (HIV) patients.

**3.2.2 Late post-transplant antiviral therapy** 

indicated.

applicability.

(Berenguer, 2008).

(Otón et al, 2006).

**3.3 Antiviral drugs and regimens** 

al, 2010).

erythropoietin and colony-stimulating factors (G-CSF) helps avoid the need for dose reduction and thus increases the possibility of reaching a sustained viral response. Though these drugs clearly permit better tolerance to antiviral treatment, no data yet exist to confirm improved efficacy. (Berenguer et al 2006b, 2008).

The development of acute cellular rejection represents another possible complication, with an incidence of around 6% (0-35%). It is related with the state of the patient's immunosuppression, the time since transplantation, the concomitant use of ribavirin and the use of pegylated interferon (more than with conventional interferon). Cases of chronic rejection (<1%) have, however, been reported in patients who achieve a viral and biochemical response. In this situation it has been attributed to improved hepatic function with the resulting change in metabolism of the immunosuppressive drugs, which could determine a reduction in their blood levels (Berenguer, 2008, Otón et al, 2006). Accordingly, close vigilance and monitoring of the immunosuppression are necessary during treatment, as well as histological study in the event of unexplained laboratory findings.

#### **3.4 Factors predicting response to antiviral therapy**

Factors predicting antiviral response in the patient who undergoes liver transplantation due to HCV infection are mostly similar to those seen in the immunocompetent patients. Factors associated with a worse response include advanced donor age, advanced fibrosis, the presence of genotype 1, a high initial viral load and the presence of the metabolic syndrome. Obtaining a rapid viral response (4 weeks after starting antiviral therapy) and an early viral response at 12 weeks of treatment predict a sustained viral response, as seen with HCV treatment in non-transplant patients (Berenguer et al, 2006; Jiménez et al, 2010).

Polymorphisms in interleukin (*IL-28B*) (chromosome 19), related with response to antiviral therapy in immunocompetent patients (Fukuhara et al, 2010), are also related to response in transplant patients. Polymorphisms in rs 1127354 (chromosome 20), which determines the activity of inosine triphosphatase, have been associated with the possibility of predicting a predisposition to the development of haemolytic anaemia in relation to ribavirin (Fellay, 2010).Another important factor to consider that is associated with a greater sustained viral response concerns treatment adherence; at least 80% compliance should be aimed for.
