Antiviral therapy in HCV decompensated cirrhosis: To treat or not to treat?
Article Outline
Chronic hepatitis C virus (HCV) infection is the main cause of cirrhosis and hepatocellular carcinoma in the Western World and Japan. Patients with advanced liver disease due to chronic HCV infection are at risk of death and only liver transplantation (LT) is able to significantly increase patient survival. There are only a few studies assessing the efficacy of antiviral therapy in patients with decompensated cirrhosis; in these studies patients were awaiting LT and the endpoint of therapy was prevention of HCV infection recurrence after transplantation [1], [2], [3], [4]. Although the treatment strategies used in these studies varied greatly, the final results (i.e. prevention of HCV infection of the graft) were quite similar (Table 1).
Table 1. Antiviral therapy in HCV-infected patients awaiting liver transplantation (Refs. [1], [2], [3], [4])
Crippin (n =15) | Thomas (n=20) | Everson (n=124) | Forns (n=30) | |
|---|---|---|---|---|
| Treatment | IFN or IFN+RBV until LT | IFN 5MU/d until LT | IFN+RBV (LADR)a | IFN 3MU/d+RBV until LT |
| Duration (months) | 2 | 14 | 6–12 | 3 |
| Response | ||||
| VR n (%) | 5 (33) | 12 (60) | 57 (46) | 9 (30) |
| SVR n (%) | – | – | 30 (24) | – |
| Transplanted (n) | 2 | 20 | 47b | 30 |
| SVR after LT n (%) | – | 4 (20) | 12 (26) | 6 (20) |
aLADR, low accelerating dosage regimen. |
bOf 47 patients who underwent LT 15 were HCV-RNA negative at the time of LT (relapse after transplantation occurred in 3). |
Despite the above-mentioned series, there is very little information on the effects of antiviral treatment (and viral suppression) on liver function and clinical decompensation in advanced HCV-related cirrhosis. The potential benefits of an improvement in liver function would be to defer LT or, in patients in whom LT is not indicated, to increase survival. In the setting of decompensated hepatitis B virus (HBV) cirrhosis, interferon treatment is contraindicated due to the life-threatening flare-ups and infections [5]. However, several uncontrolled and controlled studies [6], [7], [8], [9] have shown that viral suppression (particularly with lamivudine) induces a significant improvement in liver function and more importantly, reduces the incidence of clinically relevant events (decompensation) and prolongs survival (or time to LT) when compared to historical controls. In patients with chronic hepatitis B progression to cirrhosis and hepatocellular carcinoma is strongly correlated with elevated HBV-DNA levels [10], [11]. Similarly, in HBV cirrhosis, high HBV replication (as indicated by the presence of HBeAg and elevated HBV-DNA concentrations) is associated with increased risk of hepatic decompensation and mortality [12]. All these studies strongly suggest that the reduction in viral replication and the decrease in necroinflammation obtained with nucleoside or nucleotide analogues explain the amelioration of liver function.
The study by Iacobellis et al. [13] is the first to specifically assess the effect of antiviral therapy on liver function in patients with decompensated HCV cirrhosis. The authors included a large cohort of HCV-infected cirrhotics who were admitted to the hospital for clinical decompensation. Patients were offered antiviral therapy; individuals who refused treatment served as controls. After a 24-week course of pegylated interferon and ribavirin, patients were followed for a median period of 30 months and clinical events and survival were assessed in the two groups. The most relevant finding was a significant reduction in the incidence of clinical decompensation (particularly ascites and hepatic encephalopathy) among treated patients compared to untreated controls during the follow-up period. Survival was not different between the two groups, but a post hoc analysis showed a survival benefit in patients who achieved sustained virological response (SVR). SVR was relatively high in patients infected with HCV genotype 2 but very low in those with genotype 1 infection. Regarding safety, the results of the study suggest a significantly higher incidence of overall infections in the treated group compared to controls during the treatment period (first 24 weeks). Variables independently associated with the infections were poor liver function (Child C) and a neutrophil count below 900, but not treatment itself. The authors concluded that in decompensated cirrhotics HCV clearance after antiviral therapy may be life-saving and may reduce the risk of decompensation. Thus, antiviral therapy should be encouraged in Child A and B patients (particularly if infected with genotype 2).
The results of the study are certainly relevant for the field, but there are a number of limitations that require attention. Despite the fact that control and treated patients appeared to be similar at baseline, a randomized assignment of patients would have minimized possible biases. The primary endpoints of the study were survival and clinical decompensation: although the cohort is large and the follow-up considerably long, the study does not prove a survival benefit in the treated group. In a sub-analysis the authors found an increased survival in individuals who achieved SVR. Although this is an important finding, the proportion of patients who achieved SVR was very low, particularly among those infected with genotype 1 (7%). Even though the prevalence of genotype 2 in this particular cohort was high (as it is in Italy), the predominance of genotype 1 most likely explains the lack of a survival benefit in the entire cohort, which would be the case in most parts of Europe, US and Japan, where HCV genotype 1 is very prevalent.
An important finding of the study was the decreased incidence of decompensation episodes (particularly ascites and hepatic encephalopathy) in the treated group compared to controls during the follow-up period. Regretfully, precise definitions of clinical events (i.e. reappearance of ascites) are not included in the manuscript and this makes the analysis a little more difficult. Nevertheless, the reduction in decompensation episodes may be the consequence of a decrease in necroinflammation (and even in liver fibrosis) in treated patients, which may ultimately lead to a reduction in portal pressure. Rincón et al. [14] have recently shown that antiviral therapy in HCV-infected cirrhotics was associated with a significant decrease in portal pressure when compared to historical controls; importantly, the reduction in portal pressure was associated with end-of-treatment virological response and biochemical response (Fig. 1). Similarly, we have recently shown a significant reduction in portal pressure in HCV-infected liver transplant recipients undergoing antiviral therapy; the reduction in portal pressure was associated with ALT normalization (biochemical response) and early virological response (Forns et al., unpublished observation). Moreover, the interim analysis of the COPILOT trial strongly suggests that low dose pegylated interferon maintenance treatment in HCV cirrhosis is associated with a significant decrease in decompensation episodes in treated patients compared to controls [15]. It would be interesting to know if in the study of Iacobellis et al. the reduction in clinical events was associated with biochemical and on-treatment virological responses. This would allow the selection of individuals in whom prolongation of therapy might be beneficial. Despite the decreased incidence of clinical decompensation episodes, the Child–Pugh score worsened in treated patients who did not clear HCV. As shown in the study of Everson et al. [2], liver function improved only in patients who achieved SVR, strengthening the fact that the maximum benefit of treatment is obtained in patients who clear HCV.
Fig. 1.
Effect of pegylated interferon plus ribavirin on portal pressure in HCV cirrhotics. Overall changes in hepatic venous gradient pressure (HVPG) in (a) patients who underwent antiviral treatment and (b) a group of historical controls. HVPG values are expressed in mmHg and depicted in box plots at baseline and immediately after treatment (or after a 12-month period in controls) [14].
The reduction in the incidence of clinical decompensation did not translate into an increased survival in treated patients. The low HCV clearance rate (as stated above), and the election of a short treatment regimen (24 weeks) might have influenced the results. It is important to state, however, that tolerability of interferon-based therapy is poor and the incidence of potentially severe adverse events is high in decompensated cirrhosis. Prolongation of treatment and use of higher interferon doses would most likely be associated with a higher drop-out rate and an increased incidence of severe adverse events. This is particularly important in this study, since antiviral treatment was not aimed at preventing hepatitis C recurrence after LT, but to assess a possible effect of therapy on liver function and survival.
Safety is always a concern in patients with advanced liver disease. In this study, the authors found an increased incidence of infections in the treated group compared to controls, though deaths related to infection were not significantly different between the two groups. These are certainly relevant data when antiviral treatment is considered, but the results have some limitations, particularly because the study was not specifically designed to assess the incidence of bacterial infections. Relevant data are lacking: (1) the past history of bacterial infections, mainly spontaneous bacterial peritonitis (SBP), (2) whether the patients were or not on antibiotic prophylaxis for SBP, (3) if they received antibiotic prophylaxis during episodes of gastrointestinal bleeding, and (4) if the proportion of patients under prophylaxis was similar between the treatment group and the controls. Moreover, definitions of proven and possible bacterial infections and the methodology used for the diagnosis are not clear [16]. Infections were considered severe if they required hospitalization or treatment discontinuation, hampering the comparison between treated patients and controls, since the latter obviously did not require treatment discontinuation. Finally, it would be relevant to know the type of bacteria causing infections to allow a better understanding of the mechanisms favoring infections and to propose adequate prophylaxis. As expected, the incidence of infections was significantly higher in individuals with poor liver function (Child C), but the study does not permit to conclude that among them, the incidence increased in treated compared to untreated patients. Therefore, the recommendation not to treat Child C patients (due to an increased risk of severe infections) should be taken as a warning (probably true), but is not conclusive. Treatment itself was not an independent predictor of infection.
As often happens with the first studies on a particular topic, the authors generate great enthusiasm and open new areas to explore. This is the case of this relevant publication by Iacobellis and collaborators. Although the study has a number of shortcomings, the results strongly suggest that viral clearance slows disease progression and increases survival in HCV decompensated cirrhosis. The latter would encourage treatment of decompensated cirrhotics (at least Child B) with a good virological profile (infected with genotypes 2 and 3) even in patients who do not fulfill criteria for LT. The effect of treatment on liver function in patients who do not achieve SVR (and particularly those infected with genotype 1) requires further investigation. Since the new antiviral drugs against hepatitis C (protease and polymerase inhibitors) are still not available, this study might be the basis to design a randomized controlled trial to validate the results obtained.
Acknowledgements
This work was supported in part by CIBER HEPAP, Instituto de Salud Carlos III (Spain).
References
- . A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl. 2002;8:350–355
- Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology. 2005;42:255–262
- Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation. J Hepatol. 2003;39:389–396
- . Infection with chronic hepatitis C virus and liver transplantation: a role for interferon therapy before transplantation. Liver Transpl. 2003;9:905–915
- . Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology. 1993;104:1116–1121
- Effect of lamivudine treatment on survival of 309 North American patients awaiting liver transplantation for chronic hepatitis B. Liver Transpl. 2002;8:433–439
- Clinical course of lamivudine monotherapy in patients with decompensated cirrhosis due to HBeAg negative chronic HBV infection. Am J Gastroenterol. 2004;99:57–63
- A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology. 2001;33:424–432
- . Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology. 2001;34:411–416
- . Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–686
- Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73
- . Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43(2 Suppl. 1):S173–S181
- Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: A controlled study. J Hepatol. 2007;46:206–212
- Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis. Am J Gastroenterol. 2006;101(10):2269–2274
- Colchicine versus PEG-Intron long term (COPILOT) trial: Interim analysis of clinical outcomes at year 2. Hepatology. 2004;40:239A;(Abstract)
- Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club. Gut. 2005;54:718–725
PII: S0168-8278(06)00623-4
doi:10.1016/j.jhep.2006.11.001
© 2006 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
