Antiviral Therapy in HCV-Infected Decompensated Cirrhotics

Decompensated cirrhosis has traditionally been considered a contraindication to interferon and ribavirin therapy. Whereas, the same may be true for advanced cirrhosis, which is only successfully amenable to liver transplantation (LT), there are reports in the literature in which antiviral therapy was given successfully in selected cases of early hepatic decompensation with an aim to attain sustained viral clearance, halt disease progression, and expect potential (though, often, partial) recovery of hepatic metabolic activity. Antiviral therapy may also be instituted to prevent hepatitis C recurrence after LT (it has even caused removal of some patients from the waiting list for LT). Thus, decompensation per se is no more an absolute contraindication to antiviral therapy. Nonetheless, considering that a large proportion of such patients have pre-existing hematological cytopenias, modifications in antiviral dose regimens and close monitoring is required in order to prevent worsening of the same. Although the final sustained virological response rates attained in these patients are relatively low, successful antiviral therapy is potentially lifesaving which explains the need to go for it. In this article, the pros and cons of antiviral therapy in decompensated liver cirrhosis are reviewed with special emphasis on how to avoid antiviral dose reductions/withdrawals secondary to the development of hematologic side effects by using hematopoietic growth factors.


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Thus decompensation per se is not an absolute contraindication for antiviral therapy. Although the final SVR rates attained in such patients are lower, 21,23 successful antiviral therapy is potentially lifesaving which supports the rationale for implementing HCV treatment in these patients.
In this chapter, the pros and cons of antiviral therapy in decompensated liver cirrhosis are reviewed with special emphasis on how to avoid antiviral dose reductions/ withdrawals secondary to the development of haematologic side effects by using haematopoietic growth factors (HGF's).

Therapeutic options in decompensated cirrhosis
In selected cases, HCV-infected decompensated cirrhosis may be treated surgically (i.e. with LT) &/or medically (i.e. with antiviral therapy).

Surgical option
LT: How feasible is this option? LT is not a feasible option in the great majority of cirrhotics. This is not only because of the limited number of organ donors available at a given time, but also because of the age-related cardiovascular, renal, and pulmonary derangements that practically make going for this option rather irrational at times. Additionally, old age (≥65 years) is generally considered an exclusion criterion for LT.

Medical option
Historical reasons for reluctance to institute medical therapy in decompensated cirrhotics: Historically, despite the known theoretical benefits of antiviral therapy (improvement in liver histology, partial reversal of established cirrhosis, and prevention of life-threatening complications), most decompensated cirrhotics have not been offered antiviral therapy. Primarily, this has been due to the concerns regarding the therapeutic efficacy and safety of antiviral therapy in such cases. Peginterferon-ribavirin combination therapy is known to have limited efficacy in decompensated cirrhotics. 4,5 Also, compared to non-cirrhotics, such patients are more prone to develop hematologic side effects (neutropenia, thrombocytopenia & anemia) with antiviral therapy. 6 In fact, patients who already have severe neutropenia or thrombocytopenia (neutrophil count <1500/mm 3 or platelets count <75,000/mm 3 ) are highly prone to develop life-threatening infections after starting antiviral therapy, particularly if they have Child-Pugh class C disease. 7,8 Also, it is generally thought that agerelated derangements in cardiovascular and pulmonary functions make the cirrhotic patients less tolerant to ribavirin-induced hemolytic anemia. Finally, there are concerns that decompensation may worsen with antiviral therapy as is the case with decompensated chronic hepatitis B cases. 9 Do the reasons for reluctance evidence-based: Current literature reviews shows that because of the unstandardized dosage schedules being administered over variable periods of time in the past studies, we may have actually under/ overestimated the potential benefits and risks of antiviral therapy respectively in decompensated cirrhotics. There are now several reports in the literature in which antiviral therapy was relatively well tolerated www.intechopen.com Antiviral Therapy in HCV-Infected Decompensated Cirrhotics 5 by decompensated cirrhotics with reasonable rates of attainment of end-of-treatment response (ETR) & sustained virological response (SVR): 4,7,10,11 1. In one study, 7 39% of the patients receiving low, accelerating regimen of non-pegylated interferon plus ribavirin experienced clearance of HCV-RNA, & 21% attained an SVR. Results with pegylated interferon are even better. In the first study 12 proving the benefits of antiviral therapy in cirrhotics with signs of portal hypertension, 51 cirrhotics received 1mg/kg/wk of pegylated-interferon alpha-2b plus oral ribavirin at a fixed dose of 800mg/d for 52 wks. By intention-to-treat analysis, SVR was achieved in 21.6% patients.

Evidence-based pharmacotherapy of HCV infection in decompensated cirrhotics
Child-Pugh (sometimes called Child-Turcotte-Pugh [CTP]) scoring -see table 1 -helps determine the need and utility of instituting antiviral therapy: 1. The ideal candidate for antiviral therapy remains a patient with Child-Pugh class A disease in whom the risk of drug-induced side effects is almost identical to that of the controls. Nonetheless, all cirrhotic patients with a CTP score ≤9 and a decompensated event that abated with routine management may be considered for antiviral therapy. 2. Whether or not to institute antiviral therapy in Child-Pugh class B patients should be individualized on case-to-case basis giving due consideration to factors like genotype (2 & 3 better than 1) & pre-treatment viral loads (< 800,000 IU/mL better than higher loads). In all such cases, antiviral therapy probably should be discontinued after 4 or 12 weeks if there is no virological response. 3. Patients with Child-Pugh class C (CTP score ≥10 or MELD score 18 [

NB:
1. If the patient has had dialysis at least twice in the past week, then the value for serum creatinine used should be 4.0 2. Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used). This helps prevent the occurrence of scores below 0 (the natural logarithm of 1 is 0, and any value below 1 would yield a negative result). Ln = natural logarithm

Rapid virologic response (RVR)
Qualitative HCV RNA assay done at 4 weeks comes back to be negative (<50IU/mL)

Early virologic response (EVR)
Quantitative HCV RNA assay done at 12 weeks:  Comes back to be negative -called early virologic clearance (EVC) or aviremic response  Shows a decline in the HCV RNA titre (compared with the pretreatment assay) of ≥ 2 log -called partial virologic response (PVR) or viremic response

Nonresponders
Quantitative HCV RNA assay done at 12 weeks showing either no decline in the HCV RNA titre (compared with the pre-treatment assay) or a decline of < 2 log

End of treatment response (ETR)
Qualitative HCV RNA assay done on completion of the recommended duration of the treatment course comes back to be negative

Sustained virologic response (SVR)*
Qualitative HCV RNA assay done 24 weeks after completion of the recommended duration of the treatment course comes back to be negative

Relapsers
Qualitative HCV RNA assay done on completion of the recommended duration of the treatment course was negative (ETR achieved), but 24 weeks later it becomes positive again (SVR not achieved). .  Positive and negative predictors of therapeutic response: 1. Positive predictors: As otherwise, attainment of a rapid/ early virological response and genotypes 2 & 3 are the most robust predictors of viral clearance with antiviral therapy. 10,12 Child-Pugh class A and lower pre-transplantation viral loads (< 800,000 IU/mL) are other positive predictors. 2. Negative predictors: A reduction in the viral load of ≤2 l log 10 between baseline & week 4, Child-Pugh class C or MELD >18 have a strong negative predictive value. In the absence of a ≥2 log 10 reduction in HCV RNA at week 4, probably the best approach to reduce the risk of complications is to stop antiviral therapy at this point.
The exact treatment protocol instituted in a given patient depends upon the genotype. Genotypes 2&3 are more responsive to interferon therapy than genotype 1 and therefore the recommended duration of antiviral therapy in former is 06 months as compared to one year in the latter. Although more data and experience is needed to establish definite protocols in genotypes 4, 5 & 6 cases, current evidence suggests treating them as genotype 1 cases. 23  shown to improve responses in such cases, but it is too premature to recommend it. † The newly recommended week 4 qualitative HCV RNA assay helps modify the duration of the therapy based on viral kinetics. On one hand, this approach helps maximize the SVR rates and on the other hand, limits the toxicities and cost associated with the extended treatment courses. Achievement of RVR means that we can consider shortening the treatment course. ‡ With the shortened treatment courses in subjects who show RVR, SVR rates of 80-100% have been reported in genotype 2 cases and 77-85% in genotype 3 cases. ∂ In case of relapse, retreatment with the standard 24 weeks course is recommended. ∆ SVR rates achieved in this subgroup are poor, particularly in genotype 3 cases -41-58%. In genotype 2 cases, the results are relatively better -50-89%. Because of the poor SVR rates, prolonged therapy (>24 weeks) may be considered in this subgroup, although more evidence is needed at this time for a definite recommendation. Previously treated with non-pegylated interferon: Treat with peginterferon and ribavirin. If EVR is not achieved at week 12, stop the treatment Previously treated with pegylated interferon: Retreatment is not indicated even if a different type of peginterferon is administered. Consensus interferon has shown to improve responses in such cases, but it is too premature to recommend it. † Old age (>50yrs); male gender; African American race; obesity; alcoholism; HIV confection or immunosuppression; more-than-portal fibrosis on liver biopsy (Metavir ≥2 or Ishak ≥ 3); a pretreatment viral load of >800,000IU/mL. ‡ SVR rates of 80-89% can be achieved in this subgroup. ∂ In case of relapse, retreatment with the standard 48 weeks course is recommended. Monitoring the antiviral therapy not only involves asking repeat HCV RNA assays at specific intervals to determine therapeutic response, but also a battery of other blood tests to rule out the development of any adverse effects (see table 7).

Week 4:
Qualitative HCV RNA assay at week 4 in both genotype 1 and 2&3 cases to assess for RVR

Every month:
Pregnancy assay in a sexually-active female of child bearing age

Ribavirin-induced hemolytic anemia
The minimum effective dose of ribavirin appears to be 10.6 mg/kg/day. In case hemolytic anemia develops, it is recommended to first reduce the dose of ribavirin to the minimum effective level. If no or little improvement in hemoglobin (Hb) level occurs, initiating concomitant erythropoietin (EPO) therapy may be considered. 17,18 Possible indications: 1. Fall in Hb level by >4 g/dL.
2. Hb levels of <8g/dL. 3. Development of symptoms and signs attributable to anemia (palpitations, dyspnea, easy fatigability, pallor). 21,22 Dosage regimens: 1. 20,000-40,000IU/week given in three divided doses subcutaneously (max. 60,000IU/week) with an aim to achieve & maintain Hb level of ≥10g/dL (return to the pretreatment level is NOT the aim). 23 2. Another study suggested starting EPO therapy at a lower dose of 4,000IU subcutaneously thrice weekly (12,000IU/week) and then increasing the dose depending upon the response. 24 Table 8.

Erythropoietin (EPO) therapy
Monitoring EPO therapy: The first evidence of response to the thrice weekly EPO administration is an increase in the reticulocyte count within 10 days. 25 Since erythroid progenitors take several days to mature, a clinically significant increase in hematocrit is usually not observed in less than 2 weeks and may require up to 6 weeks in some patients. 26 If the rate of rise of hemoglobin is greater than 1 g/dL over 2 weeks, it generally warrants decreasing EPO dose. This is because a greater than 1 g/dL rise in any 2 weeks during the course of the therapy has been associated with an increased risk of thromboembolic phenomenon, predisposing to myocardial infarction, stoke and even death. 27 Also, according to manufacturer's recommendations, a Hb level of greater than 12g/dL should not be aimed, the reason being potentially increased risk of thromboembolic phenomenon. 28 Once adequate Hb level (≥10g/dL) is achieved, ribavirin dose can be increased to the optimum level. 20 Once started, adjunct EPO therapy may be required until the end of the treatment. In one study, 24 the median duration of EPO treatment was 24 weeks (range 6-39).

Interferon-induced neutropenia/ thrombocytopenia
The minimum effective dose of pegylated interferon appears to be 1 μg/kg/wk. It is recommended to reduce IFN dose to the minimum effective level if neutrophil count falls to <0.5x10 9 /L, and discontinue it if it falls to <0.3x10 9 /L. 17 Regarding platelet count, IFN dose should be reduced to the minimum effective level if platelet count falls to <30x10 9 /L, and discontinued if it falls to <20x10 9 /L. 17 If no or little improvement in neutrophil/ platelet counts occur, initiating concomitant granulocyte-colony-stimulating-factor (G-CSF) or granulocyte-monocyte-colony-stimulating-factor (GM-CSF) therapy may be considered 19,20 with an aim to avoid using the suboptimal drug doses.

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Possible indications: 1. Neutrophil count <0.5x10 9 /L. 2. Platelet count <30x10 9 /L Dosage regimens: 3. 30MU subcutaneously once weekly and then adjusting the dose as per the response/ requirement. Table 9. Granulocyte-colony-stimulating-factor (G-CSF) therapy Monitoring G-CSF therapy: Complete blood counts should be requested twice or thrice weekly and response to therapy judged. Once adequate neutrophil count is achieved, IFN dose can be increased to the optimum level. 21 Once started, adjunct G-CSF therapy may be required till the end of the treatment. In one study, 24 the median duration of G-CSF therapy was 20 weeks (range 9-45).

Pharmacotherapy of superadded infections
Norfloxacin prophylaxis has been shown to reduce the incidence of superadded infections. 15,16 In cases of established nosocomial SBP (often caused by bacteria resistant to 3rd-generation cephalosporins and/or amoxicillin-clavulanic acid), broad-spectrum antibiotics like carbapenems or glycopeptides should be prescribed.
Although it is not yet clear how much survival benefit antiviral therapy confers, a standardized mortality rate analysis in one study reported a lower liver-related mortality among cirrhotics with SVR (0.6: CI: 0.0-3.1) compared to untreated patients. 29 In post-liver transplant cases, avoidance of allograft failure due to recurrence of HCV infection has also been reported in the literature although it needs further studies and validation. 30

Conclusion
One thing that has become increasingly clear from the existing trials data is that cirrhotic patients who are treated with antiviral therapy and who achieve SVR are less likely to develop liver-related complications as compared to the non-responders. Despite the many encouraging studies on this subject, data on the long-term disease progression, avoidance of transplantation, and most importantly, improvement of life expectancy is however still sparse. Although liver functions have clearly been shown to improve with antiviral therapy (as indicated by significant reductions in CTP and MELD scores), the same are more likely to deteriorate within a few years in patients with advanced cirrhosis thus explaining the need to accumulate data on the possible survival benefit conferred by antiviral therapy in cirrhotic patients.

References
[1] Fattovich G, Giustina G, Degos F, Diodati G, Tremolada F, Nevens F, et al. Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in