|Year : 2021 | Volume
| Issue : 3 | Page : 151-156
Effect of direct-acting antiviral treatment on decompensated Hepatitis C Virus cirrhosis
Neha Jakhete1, Rati Deshpande2, Mary G Bowring2, Jessica Shay3, Jennifer Katzianer2, Shanti Seaman2, Ahmet Gurakar2, Christine M Durand2, Brittany Barnaba2, Kirti Shetty1
1 Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland; Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
2 Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
3 Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
|Date of Submission||05-Apr-2021|
|Date of Decision||28-Apr-2021|
|Date of Acceptance||10-May-2021|
|Date of Web Publication||05-Jul-2021|
Dr. Neha Jakhete
Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland Medical Center, Baltimore, Maryland
Source of Support: None, Conflict of Interest: None
Goals: The goal of the study is to assess the effect of direct-acting antivirals (DAAs) on the model for end-stage liver disease-sodium (MELD-Na) score and on specific decompensations related to hepatitis C virus (HCV) cirrhosis. The aim of our study was to identify a specific cohort of patients with cirrhosis, if any, that should be targeted for treatment with DAAs. Background: The development of DAAs has provided safe and well-tolerated treatment options for patients with advanced liver disease. However, controversy remains in terms of optimal timing of treatment and whether this treatment should be offered before or following liver transplantation. Methods: We identified all patients with HCV cirrhosis who initiated treatment with DAA therapy at Johns Hopkins Hospital between July 2014 and June 2016. We identified a subset of patients who had decompensated cirrhosis and recorded their MELD-Na scores and decompensations pre- and post-treatment. Results: Fifty-six patients achieved sustained virologic response with decompensated HCV cirrhosis. The group demonstrated a significant decrease in median MELD-Na score following treatment from 12 to 10.5. Furthermore, a significant percentage of patients experienced resolution of ascites following DAA therapy with 19 patients (35.2%) clearing their ascites posttreatment. Of the 19 patients who cleared ascites, MELD-Na score decreased from a median of 12 (interquartile range [IQR] 11–18) to 11 (IQR 8–14), P = 0.01. Conclusions: Our findings suggest that patients with ascites as their main decompensation should be considered for the treatment with DAAs, while awaiting liver transplant given that the MELD-Na score showed only modest improvement and thus would not affect liver transplant (LT) listing priority.
Keywords: Ascites, decompensated cirrhosis, direct acting antivirals, hepatitis C, model for end-stage liver disease purgatory
|How to cite this article:|
Jakhete N, Deshpande R, Bowring MG, Shay J, Katzianer J, Seaman S, Gurakar A, Durand CM, Barnaba B, Shetty K. Effect of direct-acting antiviral treatment on decompensated Hepatitis C Virus cirrhosis. Curr Med Issues 2021;19:151-6
|How to cite this URL:|
Jakhete N, Deshpande R, Bowring MG, Shay J, Katzianer J, Seaman S, Gurakar A, Durand CM, Barnaba B, Shetty K. Effect of direct-acting antiviral treatment on decompensated Hepatitis C Virus cirrhosis. Curr Med Issues [serial online] 2021 [cited 2022 Aug 10];19:151-6. Available from: https://www.cmijournal.org/text.asp?2021/19/3/151/320650
| Introduction|| |
Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and remains an important indication for liver transplantation in the United States. Direct-acting antivirals (DAAs) for the treatment of HCV have transformed care for all patients, even those with advanced cirrhosis who previously had limited treatment options. Conventionally, patients with decompensated cirrhosis were not considered for therapy given the severe side effects and low tolerability of interferon-based therapies, particularly neutropenia, fatigue, and depression. The development of DAAs has provided safe and well-tolerated oral treatment options for this special population of patients. However, controversy remains in terms of optimal timing of treatment and whether this treatment should be offered before or following liver transplant (LT). Viral eradication in HCV cirrhosis may not be accompanied by resolution of the complications of cirrhosis, while improving the biochemical parameters within the model for end-stage liver disease-sodium (MELD-Na) score, which is used in the United States for determining priority on the LT waiting list. This paradox renders patients less likely to be transplanted, a situation referred to as “MELD purgatory.” Limited data exist regarding whether specific decompensations of cirrhosis can be reversed or improved by DAA therapy. In addition, there are conflicting data on whether viral clearance impacts liver-related morbidity/mortality and need for LT.
We therefore undertook this study with the overall objective of assessing the effect of DAA on not only the MELD-Na score but also specific decompensations related to HCV cirrhosis, including ascites, hepatic encephalopathy, and portal hypertensive/variceal hemorrhage. The aim of the study was to identify a specific cohort of patients, if any, that should be targeted for treatment with DAAs. Secondary aims were to assess the rates of virologic clearance, as well as to evaluate the safety and tolerability of these agents in a population with advanced liver disease.
| Methods|| |
Utilizing a database maintained by our specialty pharmacy (Thiergy®), we identified all patients with HCV cirrhosis who initiated treatment with DAA therapy at Johns Hopkins Hospital between July 2014 and June 2016. Cirrhosis was diagnosed by either a liver biopsy or noninvasive testing (such as the HCV Fibrosure® test or transient elastography). To identify patients with the highest risk of decompensated cirrhosis, we first utilized our electronic medical records system (Epic®) to generate a report of patients with platelet counts <150,000/ml. We utilized this platelet count threshold based on natural history studies which have demonstrated that clinically significant portal hypertension is uncommon in those with platelet counts over this threshold., From these patients, we identified a subset who had diagnostic codes consistent with the following decompensations at any time point before DAA therapy: ascites, hepatic encephalopathy, and/or portal hypertensive hemorrhage.
Patients were excluded if they underwent LT, died, or were lost to follow-up within 6 months of the end of DAA therapy. Co-infections with hepatitis B virus or the human immunodeficiency virus or a diagnosis of hepatocellular carcinoma were also exclusionary, as these confounding variables could affect the natural course of cirrhosis.
Demographic information was recorded at treatment initiation. Laboratory values for the MELD-Na score, including sodium, creatinine, total bilirubin, and International Normalized Ratio (INR), were collected pre- and post-treatment. We also assessed for the presence of decompensations of liver disease, defined as ascites, hepatic encephalopathy, and portal hypertensive hemorrhage in the 24-week posttreatment. Information regarding these decompensations was abstracted from progress notes before and after antiviral therapy. Pretreatment data were collected no more than 90 days before initiation of DAA therapy and posttreatment data collected at 12 and 24 weeks from the last day of treatment.
We used a two-sided α level of 0.05 to indicate a statistically significant difference. All analyses were performed using STATA/SE, version 15 (StataCorp). The goal was to compare pretreatment laboratories with 24-week posttreatment laboratories; when 24-week laboratories were unavailable, 12-week laboratories were used. Given that we had paired pre- and post-treatment values from each patient, we used McNemar's Chi-square test of paired data to determine statistically significant changes in the presence of each decompensation (dichotomous outcome) and Wilcoxon paired signed-rank test to determine changes in median MELD-Na (continuous outcome). Median and interquartile range (IQR) MELD-Na and overall prevalence of each decompensation are reported. Type, duration, and outcome (e.g. sustained virologic response [SVR], relapse) of DAA therapy were also reported. Finally, we compared pre- and post-treatment MELD-Na and decompensations among patients who achieved SVR and among those who relapsed [Figure 1].
| Results|| |
Patient characteristics and treatment regimen
Notably, there were 11 patients (16%) who were either nonresponders or relapsed [Table 1]. There were no differences noted in the characteristics of patients who achieved SVR versus nonresponse/relapse [Table 1]b. Since we were interested in evaluating for improvement in MELD-Na and decompensations if SVR was achieved, we only included the 56 patients who did achieve SVR in the final analysis [Table 1]b.
Change in model for end-stage liver disease-sodium posttreatment
Overall, MELD-Na decreased from a median of 12 (IQR 10.5–16.5) pretreatment to 10.5 (IQR 8–14.5) posttreatment (P = 0.001) [Figure 2] among the entire study population. At the patient level, 33 patients (58.9%) experienced a decrease in MELD-Na (median of 3 [IQR 2–6] MELD-Na points), 11 patients (19.6%) experienced an increase (median of 3 [IQR 1–5] points), and 12 patients (21.4%) experienced no change in MELD-Na.
|Figure 2: Pretreatment versus posttreatment model for end-stage liver disease and decompensations in patients who achieved sustained virologic response. *P values based paired Wilcoxon rank-sum tests for model for end-stage liver disease and McNemar's Chi-squared test of paired data for changes in the prevalence of ascites, hepatic encephalopathy, and portal hypertensive bleed; Ascites, hepatic encephalopathy, and portal hypertensive bleed only available for 54|
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Among the 32 patients for whom MELD-Na decreased posttreatment and we had complete follow-up data, there was a statistically significant change in proportion with ascites (59.4% pre vs. 18.8% post, P = 0.0002), and there was nonstatistically significant change in proportion with HE (37.5% pre vs. 21.9% post, P = 0.06) and with portal hypertensive bleeding (6.3% pre vs. 0% post, P = 0.5).
Change in decompensations posttreatment
The prevalence of ascites decreased from 59.3% pretreatment (n = 32) to 27.8% posttreatment (n = 15) (P < 0.001). At the patient level, 19 patients (35.2%) cleared ascites posttreatment, 2 (3.7%) developed ascites, 13 (24.1%) maintained their ascites, and 20 (37.0%) remained without ascites posttreatment.
Of the 19 patients who cleared ascites, MELD-Na decreased from a median of 12 (IQR 11–18) to 11 (IQR 8–14), P = 0.01.
The prevalence of hepatic encephalopathy decreased from 37.0% (n = 20) to 25.9% (n = 14), and although this was not a statistically significant decrease, it is approaching significance (P = 0.07); 7 patients (13.0%) cleared, 13 patients (24.1%) maintained, 1 developed (1.9%), and 33 (61.6%) remained without hepatic encephalopathy.
The prevalence of portal hypertensive bleed decreased from 9.3% pre-DAA treatment (n = 5) to 1.9% post-DAA treatment (n = 1), although this was not statistically significant (P = 0.12); 4 patients (7.4%) did not have any new bleeding posttreatment, 1 patient (1.9%) had an episode of portal hypertensive bleeding pre- and post-DAA treatment, 0 (0%) developed, and 49 (90.7%) remained without portal hypertensive bleed posttreatment.
| Discussion|| |
Our study found that patients with decompensated HCV cirrhosis treated with DAAs had a significant decrease in median MELD-Na score following treatment, suggesting that viral clearance may lead to an improvement in overall hepatic synthetic function. Furthermore, a significant percentage of patients experienced resolution of ascites following DAA therapy. DAA treatment was well tolerated, with no discontinuations noted. The rate of relapse/nonresponse in our study (16%) was higher than in other treatment studies of decompensated cirrhosis, which may be attributable to differences in study populations., We did not specifically assess compliance, but this may have been a contributing factor in our population.
SVR has been demonstrated to result in a decrease in the hepatic venous pressure gradient, explaining the improvement seen in portal hypertension-related complications. Ascites is the most frequent and earliest decompensation of cirrhosis and has been found to be an independent predictor of mortality. Resolution or decrease in ascites has also been associated with improved quality of life (QOL). Our finding that the resolution of ascites is associated with only a modest decrease in MELD score is important, as transplant priority could be preserved in parallel with the improvement in patient survival and QOL. This is consistent with the findings of other studies looking at DAA therapy in decompensated HCV cirrhosis. A multicenter European experience on DAAs in decompensated cirrhosis also reported improvement in ascites, including refractory ascites after 24 weeks. Similar improvement in ascites has been reported by Romano et al.
The issue of whether DAA should be offered before or following LT is controversial. Belli et al. found that DAA treatment resulted in one in three patients being inactivated, and one in five patients being delisted over 60 weeks after treatment with DAAs given improvement/resolution in liver decompensation. In general, the greatest improvement in MELD score is seen within the first 12 weeks from the start of therapy, and benefit is most marked in those with lower MELD scores. However, eradication of HCV before LT potentially complicates the option of utilizing HCV-positive donor livers. In addition, Markov modeling has demonstrated that treating HCV before LT increased life expectancy if MELD was ≤27 but could decrease life expectancy at higher MELD scores.
Our findings suggest that patients with ascites as their main decompensation should be considered for treatment with DAAs, while awaiting liver transplant. Even though there was a statistically significant decrease in MELD score among our group of patients who cleared ascites, this decrease was a modest one point and would not affect liver transplant priority. Therefore, our study suggests that in those patients with baseline low MELD scores, which are not in the transplantable range, DAA therapy could not only improve ascites with resultant improvement in QOL but may even enable LT to be avoided or delayed by improved MELD score. An added benefit to pretransplant HCV treatment would be less risk of transmitting HCV to the operating team if a liver transplant is needed. However, those patients with higher MELD scores (>27) would not be benefited from DAA treatment pretransplant and may even be harmed by DAA therapy pre-LT given the utilization of HCV-positive donor organs in this population has been shown to decrease waiting time on the transplant list. This group would therefore be best served by delaying HCV treatment until after liver transplant. Of note, our study did not find significant improvement in hepatic encephalopathy pre- and post-treatment as reported by others, likely due to the limited sample size of our study and the small number of these decompensation occurrences.
There is uncertainty regarding the duration of clinical improvement with ascites; however, there is one study that has followed patients for 2 years and reported 30.9% of patients were able to be delisted following clinical improvement after treatment with DAAs, with 79.5% having complete regression of ascites. Clinical and biochemical factors may help predict which patients will benefit the most from DAA therapy. El-Sherif et al. developed a predictive score using several baseline factors, including body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin, which can also aid in decision-making about whether DAA treatment should be pursued.
This study was a retrospective study, with a limited sample size, and our data collection method was reliant on chart review which could have impacted accuracy. Natural history studies have demonstrated that those with platelet counts over 150,000/ml are unlikely to have significant portal hypertension,, and we therefore used this as a screening criterion for the identification of those with decompensated cirrhosis. However, it is possible that we excluded patients with other clinical presentations of decompensated cirrhosis, limiting our sample size even further. In addition, medications and doses were not recorded in this study, given inconsistent reporting and documentation in the chart. This will be important to note in future studies given the impact on symptom control as well. Finally, our study ended at 24 weeks post-SVR, and thus, patients were not followed for long enough to understand the impact on liver transplant listing.
| Conclusion|| |
In summary, our urban population with decompensated cirrhosis treated with DAAs derived benefit in terms of ascites improvement, as well as decline in MELD score. Importantly, improved ascites were accompanied by only a modest decrease in MELD score, hence preserving the option of LT and obviating the issue of “MELD purgatory.” Further studies are needed to study patients with more advanced liver disease and higher MELD scores receiving DAA therapy pretransplant and the clinical course post-SVR, including impact on transplant listing. It will also be important to define factors that predict hepatic recovery associated with SVR and longer-term outcomes in this patient population.
Research quality and ethics statement
All authors of this manuscript declare that this scientific study is in compliance with standard reporting guidelines set forth by the EQUATOR Network. The authors ratify that this study required Institutional Review Board / Ethics Committee review, and hence prior approval was obtained by the Institutional Review Board at the Johns Hopkins Hospital (IRB 00172526). We also declare that we did not plagiarize the contents of this manuscript and have performed a Plagiarism Check.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]