Antiviral therapy in hepatitis C virus cirrhotic patients in compensated and decompensated condition

The main goals of treating cirrhotic patients with antiviral therapy are to attain sustained viral clearance （SVR）, halt disease progression, and prevent reinfection of the liver graft. However, while the medical need is great, the use of interferon and ribavirin might expose these patients to severe treated-related side effects as a large proportion of them have pre-existing hematological cytopenias. We have reviewed potential benefits and risks associated with antiviral drugs in patients with liver cirrhosis, due to hepatitis C virus （HCV） infection. In cases presenting with bridging fibrosis or cirrhosis, current regimens of antiviral therapy have attained a 44%-48% rate of SVR. In cirrhotic patients with portal hypertension, the SVR rate was 22% overall, 12.5% in patients with genotype 1, and 66.7% in those with genotypes 2 and 3 following therapy with low doses of either Peg-IFN alpha- 2b and of ribavirin. In patients with decompensated cirrhosis, full dosages of Peg-IFN alpha-2b and of ribavirin produced a SVR rate of 35% overall, 16% in patients with genotype 1 and 4, and 59% in those with genotype 2 and 3. Use of hematological cytokines will either ensure full course of treatment to be accomplished with and prevent development of treatment-associated side effects. Major benefits after HCV eradication were partial recovery of liver metabolic activity, prevention of hepatitis C recurrence after transplantation, and removal of some patients from the waiting list for liver transplant. Several observations highlighted that therapy is inadvisable for individuals with poor hepatic reserve （Child-Pugh- Turcotte score ≥ 10）. Although SVR rates are low indecompensated cirrhotics due to hepatitis C, these patients have the most to gain as successful antiviral therapy is potentially lifesaving.     

Safety and efficacy of sofosbuvir/velpatasvir/voxilaprevir in post-liver transplant patients with previous direct-acting antiviral failure: Six case reports

BACKGROUNDDirect-acting antiviral (DAA) therapy regimens are highly effective at eliminating hepatitis C virus (HCV) infection but rates of sustained virologic response (SVR) are lower in patients with decompensated cirrhosis or hepatocellular carcinoma. Since many of these patients will be referred for liver transplant, they will require retreatment after transplantation. Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is recommended by guidelines as the preferred regimen to treat HCV in DAA-experienced patients following liver transplant however there is limited data.CASE SUMMARYWe present the cases of six liver transplant recipients who had previous treatment failure with sofosbuvir-based DAA therapy prior to transplantation and who then received SOF/VEL/VOX after transplant.CONCLUSIONThis case series demonstrate the real-world efficacy and safety of SOF/VEL/VOX in the post liver transplant setting. Treatment was successful with all patients achieving SVR, it was well tolerated, and there were minimal drug-drug interactions with their immunosuppressants.     

我国丙型肝炎肝硬化患者DAA治疗现状及短期预后的研究

目的了解丙型肝炎肝硬化患者直接抗病毒药物(DAA)治疗现状、短期预后和影响因素。方法选取2015年1月至2019年11月期间于瑞金医院感染科诊治的丙型肝炎肝硬化患者,收集其数据,研究基线特征、DAA方案及疗效和预后的关系。结果共入组161例,DAA治疗者149例;代偿组122例,失代偿组27例;两组在年龄、性别、HCV基因型及干扰素治疗史等方面无显著性差别;两组疗效与安全性均良好,其中SVR12率(99.17%比96.25%,P=0.325)和SVR24率(96.64%比92.0%,P=0.614)均无明显差异;基线肝硬化失代偿期患者中发生肝病进展的比例明显高于代偿期患者(50%vs.13.75%,P=0.000);基线肝硬化失代偿是DAA治疗后短期预后的独立危险因素(HR 6.765,95%Cl:2.866~15.969,P=0.000)。结论基线肝硬化失代偿是DAA治疗后短期预后的独立预测因素。     

Concise review: Interferon-free treatment of hepatitis C virus-associated cirrhosis and liver graft infection

Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.     

Treatment of chronic hepatitis C in patients with decompensated cirrhosis

Cirrhosis due to chronic hepatitis C is now the leading indication for liver transplantation in the United States. Current data from existing clinical trials suggest that 41% of patients with genotype 1 hepatitis C virus infection (HCV) and 73% with genotype 2 or 3 infection with advanced fibrosis or early compensated cirrhosis can achieve sustained virologic response (SVR) to antiviral therapy. However, response to therapy declines with severity of liver disease and nonresponse to prior interferon-based regimens. Although SVR rates are low in patients with decompensated cirrhosis, on-treatment clearance of HCV from blood occurs in about 30% of those with genotype 1 infection and 80% of those with genotype 2 or 3. In addition, recent reports suggest that pretransplantation clearance of HCV RNA from blood may reduce the risk of HCV recurrence after transplantation. In the absence of a virologic cure, maintenance therapy with peginterferon may slow disease progression and reduce the rate of clinical decompensation.     

Hepatitis C virus treatment pre- and post-liver transplantation

Liver disease caused by the hepatitis C virus is the main indication for liver transplantation in Western countries. However, HCV re-infection post-transplantation is constant and recent data confirm that it significantly impairs patient and graft survival. Chronic HCV infection develops in 75-90% of patients, and 5-30% ultimately progress to cirrhosis within 5 years. Because of the impact of HCV recurrence on graft and patient survival, several treatment strategies have been evaluated. Antiviral therapy could be administered before transplantation to suppress viral replication and reduce the risk of recurrence. However, this approach is applicable in around 50% of patients and tolerance is poor, particularly in patients with decompensated cirrhosis. Pre-emptive therapy in the early post-transplant period is limited by the high rate of side effects. Frequently, antiviral therapy is initiated when HCV recurs to obtain viral eradication and/or reduce disease progression. Treatment of established graft lesions with Pegylated Interferon (PEG-IFN) and Ribavirin (RBV) combination therapy results in a sustained virological response (SVR) in around 30% of patients. The new classes of potent and direct antiviral agents (DAA) will certainly improve the results of pre- and post-transplant antiviral therapy. However, at the present time, no data are available on the use of these drugs in patients with decompensated cirrhosis or post-transplant hepatitis.     

Hepatitis C virus cirrhosis: prolonged sustained virological response in a patient after low-dose antiviral treatment

Hepatitis C virus (HCV) infection is the most frequent cause of chronic liver disease in the western world. The 'gold standard' treatment of chronic HCV infection currently involves the administration of pegylated interferon alpha (PEG-IFN) and ribavirin. The success of this therapy is demonstrated by sustained virological responses (SVR). Randomized trials and practice guidelines have reported that compensated HCV cirrhosis is an indication for treatment with PEG-IFN and ribavirin, not only to obtain SVR but also to increase survival and to reduce the development of cirrhotic sequelae. In particular, the literature has reported that antiviral treatment was associated with histological improvement of fibrosis in cirrhotic patients with SVR. Recently, the same authors have evaluated the efficacy and safety of different doses of antiviral treatment in patients with chronic HCV infection. The use of interferon has been limited due to associated side effects, particularly in cirrhotic patients. Consequently, therapeutic decisions should be made on an individual basis. The Authors report a case of a patient with compensated HCV liver cirrhosis, with associated severe thrombocytopenia and oesophageal varices, in which the administration of antiviral therapy at a dose lower than the therapeutic 'gold standard' has achieved SVR and consequently improved clinical status.     

The cost of treatment failure: resource use and costs incurred by hepatitis C virus genotype 1–infected patients who do or do not achieve sustained virological response to therapy

Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost‐effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium‐term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2 months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS ‘Payment by Results’ database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non‐SVR) with mean follow‐up of 3.5 (SVR) and 4.9 (non‐SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non‐SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5‐year post‐treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13‐fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56‐fold, equating to more than £10 000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real‐life data for future cost‐effectiveness analyses related to the treatment for chronic HCV infection.     

Treat chronic hepatitis C virus infection in decompensated cirrhosis – pre‐ or post‐liver transplantation? the ironic conundrum in the era of effective and well‐tolerated therapy

The management of hepatitis C virus (HCV) infection in patients with decompensated cirrhosis has evolved dramatically over the past few years mainly due to the availability of all‐oral antiviral regimens. The currently approved all‐oral direct‐acting antivirals (DAA) containing sofosbuvir, ledipasvir, daclatasvir and ribavirin, in various combinations, have shown to be safe and effective in patients with decompensated cirrhosis with sustained virological response (SVR) rates nearly comparable to those with well‐compensated liver disease. Unique issues yet remain such as the challenges with renal insufficiency, tolerability of ribavirin and risk of further hepatic decompensation with a protease inhibitor‐based regimen. While most patients who achieve SVR have demonstrated improvement in hepatic synthetic function over the short course of follow, the long‐term beneficial effects are unknown. Further, the baseline predictors of improvement in hepatic function have not been well delineated and thus have left us in a quandary as to what we might expect with successful therapy and thus we are at a loss to well educate our patients. The major concern, in potential liver transplant candidates, is of unintended ‘harm’ by achieving SVR but without improvement in hepatic function to an extent where the patients might function well. As HCV therapies are as effective in liver transplant recipients, there is a growing sentiment in some of the transplant quarters that those with decompensated liver disease and awaiting liver transplant be treated for HCV after liver transplant. This strategy would thus eliminate any concern of leaving a patient in ‘no person's’ land by treating HCV successfully pretransplant but not to the point of functional normalcy, while also would maintain the risk of HCC. Yet a contrarian view would be that not all patients have access to liver transplantation (LT), cannot bear the cost, have comorbidities or contraindications to LT. While the debate continues, it is essential that we develop robust predictors of improvement in liver function so that we can carefully select our patients for therapy in the context of liver transplantation.     

Antiviral therapy for hepatitis B virus‐related decompensated cirrhosis

Antiviral therapy is important in patients with hepatitis B virus (HBV)‐related decompensated cirrhosis. This therapy is beneficial in most patients for the stabilization or improvement of liver disease; however, advanced cirrhosis with a high Child–Pugh or model for end‐stage liver disease (MELD) score may have progressed and does not benefit from antiviral therapy. It is important to identify patients with severe decompensated cirrhosis who will not improve under antiviral therapy and who require liver transplantation as early as possible. Entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is the first‐line therapy for nucleos(t)ide analogue (NA)‐naive patients with decompensated cirrhosis due to their potent and prompt HBV suppressive effect and low rate of drug‐resistant mutations. Patients on antiviral therapy should be monitored for virological and clinical response, compliance, drug resistance and adverse effects as well as surveillance for hepatocellular carcinoma (HCC). Additional studies of TDF and ETV are necessary to determine the optimal agent(s) for treating naive patients and those with drug‐resistant decompensated cirrhosis. In order to evaluate the effectiveness of NA for the treatment of decompensated cirrhotic patients in the real world, high quality observational studies such as registration studies of antiviral therapy for HBV‐related cirrhosis and a long‐term follow‐up in China, where a large number of such patients are found, are recommended.     

Clinical drivers in naïve patient eligibility for treatment of chronic hepatitis C

Hepatitis C virus (HCV) infection represents a major health problem, being a leading cause of cirrhosis and liver transplantation worldwide. Viral eradication achieved by Peginterferon and Ribavirin therapy is the only therapeutic option that can prevent fibrosis progression in chronic hepatitis and liver-related complications in cirrhotic patients. Unfortunately, the occurrence of potentially serious side effects argues against universal treatment of HCV-infected patients. Indeed most scientific societies suggest that eligibility for therapy be based on baseline factors, the so called clinical drivers for treatment eligibility. Current international guidelines recommend focusing on the severity of liver disease, likelihood of treatment response in terms of chances of sustained virological response (SVR) to antiviral therapy and risk of serious adverse events when making treatment decisions. However, evidence exists that treatment may benefit also patients with mild fibrosis and that baseline predictions of a SVR are inaccurate because of the key role of HCV kinetics while on-therapy. An extended treatment programme is further supported by the fact that an increase in the number of patients treated would ultimately result in a long-term reduction of liver-related deaths.     

Impact of new treatment options for hepatitis c virus infection in liver transplantation

Liver transplant candidates and recipients with hepatitis C virus(HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens(e.g.,pegylated-interferon plus ribavirin with or without first generation protease inhibitors,boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents(DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir,daclatasvir,and combination of other DAA. Possible interactions should be monitored,especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals.     

Approach to the patient with chronic hepatitis B and decompensated cirrhosis

Patients with chronic hepatitis B virus (HBV) can develop progressive fibrosis, cirrhosis and hepatocellular carcinoma. Patients with chronic HBV and cirrhosis are at risk of developing hepatic decompensation and have high mortality without antiviral therapy and/or liver transplantation. Treatment of chronic HBV with antiviral therapy is indicated in all patients with cirrhosis whatever the HBe‐antigen status and serum alanine aminotransferase (ALT), so that hepatic decompensation can be prevented. Initiating antiviral therapy in patients with decompensated cirrhosis can improve liver function, Child‐Turcotte‐Pugh (CTP) and model for end‐stage liver disease (MELD) scores, as well as the need for liver transplantation and mortality. Patients with chronic HBV and cirrhosis who do not respond to antiviral therapy with normalization of ALT may have a co‐existent liver disorder. One of the most common co‐existent liver disorders present in patients with chronic HBV is non‐alcoholic fatty liver disease (NAFLD). Patients with chronic HBV, NAFLD and cirrhosis may be at risk of developing decompensated cirrhosis and require a liver transplant. If patients with chronic HBV require liver transplantation, infection of the liver graft with HBV can be prevented with antiviral therapy.     

Advances in hepatitis C therapy: What is the current state-what come's next?

Chronic hepatitis C virus (HCV) infection affects 80-160 million people worldwide and is one of the leading causes of chronic liver disease. It is only a few years ago that standard treatment regimes were based on pegylated interferon alpha and ribavirin. However, treatment of HCV has undergone a revolutionary change in recent years. The admission of the nucleotide polymerase inhibitor Sofosbuvir enabled an interferon-free regimen with direct antiviral agents (DAA). Meanwhile seven DAAs are available and can be applied in several combinations for 8 to 24 wk depending on HCV genotype and patient characteristics such as cirrhosis and chronic renal failure. High rates of sustained virological response (SVR) rates can be achieved with these novel drugs. Even in difficult to treat populations such as patients with liver cirrhosis, HCV-human immunodeficiency virus co-infections, after liver transplantion, or with chronic kidney disease comparable high rates of SVR can be achieved. The anticipated 2^nd generation DAAs are strikingly effective in patients so far classified as difficult to treat including decompensated liver cirrhosis or post-transplant patients. These 2^nd generations DAAs will have higher resistance barriers, higher antiviral effects and a pan-genotypic spectrum. This review highlights the current state of the art of antiviral treatment in hepatitis C and gives an outlook for upcoming therapies.     

Treatment of hepatitis C virus infection in patients with end-stage renal disease

Hepatitis C virus (HCV) infection is a major health problem in patients with end‐stage renal disease (ESRD). The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk of nosocomial transmission. Following acute HCV infection, most patients develop chronic HCV infection, and a significant proportion develop chronic hepatitis, cirrhosis, and even hepatocellular carcinoma. Overall, chronic hepatitis C patients on hemodialysis bear an increased risk of liver‐related morbidity and mortality, either during dialysis or after renal transplantation. Interferon (IFN) therapy is modestly effective for the treatment of HCV infection in ESRD patients. Conventional or pegylated IFN monotherapy has been used to treat acute hepatitis C in ESRD patients with excellent safety and efficacy. Regarding chronic hepatitis C, approximately one‐third of patients can achieve a sustained virological response (SVR) after conventional or pegylated IFN monotherapy. The combination of low‐dose ribavirin and conventional or pegylated IFN has further improved the SVR rate in treatment‐naïve or retreated ESRD patients in clinical trials. Similar to the treatment of patients with normal renal function, baseline and on‐treatment HCV virokinetics are useful to guide optimized therapy in ESRD patients. Of particular note, IFN‐based therapy is not recommended at the post‐renal transplantation stage because of the low SVR rate and risk of acute graft rejection. In conclusion, ESRD patients with HCV infection should be encouraged to receive antiviral therapy, and those who achieve an SVR usually have long‐term, durable, virological, biochemical, and histological responses.     

Hepatitis C and End-stage Liver Disease

Cirrhosis secondary to infection with hepatitis C virus (HCV) is one of the leading causes of end-stage liver disease worldwide. The World Health Organization estimates that about 3% of the world population is chronically infected with HCV, with about 4 million infected individuals in the United States. Despite the declining US incidence of HCV, the complications of chronic HCV infection are rising rapidly. The cirrhosis can be classified as compensated or decompensated based on clinical complications. Compensated HCV-related cirrhosis can be treated safely per American Association for the Study of Liver Diseases guidelines. Treatment of decompensated HCV-related cirrhosis is challenging secondary to increased risk of complications and adverse effects during the course of antiviral therapy. The recommended treatment is the low, but accelerating dose regimen. HCV-related cirrhosis is associated with complications including ascites, variceal bleeding, renal insufficiency, hepatic encephalopathy, and hepatocellular carcinoma. Because of its poor prognosis, liver transplantation is the only definitive therapy for decompensated cirrhosis.     

HCV clearance after direct-acting antivirals in patients with cirrhosis by stages of liver impairment: The ITAL-C network study

BackgroundSustained virological response (SVR12) rates at 12 weeks after treatment for HCV-infected patients with decompensated cirrhosis are used when referring to those with moderate functional impairment, while few data are available for those with more severe impairment. The use of the cirrhosis staging system proposed by D’Amico might provide new insights on timing for antiviral therapy.MethodsWe investigated efficacy (SVR12), safety, and post-treatment variations in clinical and laboratory parameters in 2612 patients with advanced fibrosis (n = 575) or cirrhosis (n = 2037). Cirrhosis was in the compensated phase (without/with varices) or had previously been in the decompensated stage. Different direct-acting antiviral (DAA) regimens were administered in accordance with scientific guidelines.ResultsThe SVR12 rate was 97.6% in patients with advanced fibrosis. For patients with cirrhosis, the rate was 96.5% in stage 1, 95.1% in stage 2, 100% in stage 3, 95.7% in stage 4, and 93.6% in stage 5. These rates were independent of gender, age, HCV genotype, and treatment schedule. Positive changes in biochemical parameters and CPT classes following therapy were evident in compensated and previously decompensated patients.ConclusionOur findings support the use of DAAs in patients with advanced cirrhosis (stages 3–5) who are at greatest risk and have the most to gain from therapy.     

Hepatitis C infection in hemodialysis patients: A review

Hepatitis C virus(HCV)-related liver disease is a significant cause of morbidity and mortality in patients with end-stage renal disease(ESRD) who is treated with dialysis or kidney transplantation(KT). The survival rate for HCV-infected renal transplant recipients is better than that for HCV-infected hemodialysis patients on transplant waiting lists. Early diagnosis and treatment HCV infection prior to KT prevents complications posttransplantation and reduces mortality. In addition to screening for anti-HCV antibodies and detecting HCV RNA, percutaneous liver biopsy is particularly valuable for assessing the stage of liver damage in HCV-infected patients, because the stage of fibrosis is importantdetermining optimal treatment for HCV. Studies have been demonstrated that with conventional interferon(IFN) monotherapy or pegylated IFN monotherapy are similar efficacy and safety in HCV-infected hemodialysis patients. Sustained viral responses(SVRs) with these monotherapies have ranged approximately 30% to 40%. Limited reports support the use of IFN and ribavirin combination therapy as antiviral treatment for ESRD patients or patients on hemodialysis. Ribavirin can be started at low dose and careful monitoring for side effects. Patients that show SVR after treatment are strong candidates for KT. It is also generally accepted that ESRD patients with decompensated cirrhosis and portal hypertension should be referred to the liver transplant team for consideration of combined liver-KT.     

Hepatitis C Management in Patients with Hepatitis C and HIV Co-infection

Co-infection with HIV and hepatitis C (HCV) is common due to similar risk factors. Twenty-five to thirty percent of HIV+ patients are co-infected with HCV. HCV infection in HIV+ patients is associated with higher rates of fibrosis, progression to cirrhosis and decompensated liver disease, and liver-related mortality. The ultimate HCV treatment goal is viral eradication, or sustained virologic response (SVR) which results in decreased liver-related morbidity and mortality. Prior therapies were suboptimal in co-infected patients. However, the new HCV direct-acting antiviral agents provide excellent treatment options in co-infected patients with response rates and adverse events similar to the HCV mono-infected population. Drug interactions between HIV treatments and HCV treatments can be challenging and must be taken into consideration. To optimize outcomes, co-infected patients should be managed by experienced providers or in the setting of a collaborative multidisciplinary approach. This article will review the current treatment rationale and recommendations for HIV-HCV-co-infected patients.     

Does SVR Prevent Transplant in HCV?

Sustained virologic response significantly reduces the risk of cirrhosis, hepatic decompensation, hepatocellular carcinoma, mortality, and the need for liver transplantation in patients with chronic hepatitis C. Thus, broad treatment prior to hepatic decompensation will likely prevent the need for transplant in many individuals. With emerging data on the use of direct acting antiviral regimens in patients with decompensated cirrhosis, it is now also feasible to successfully treat many of these high-risk patients, leading to improvement in liver function as measured by MELD score and Childs-Turcotte-Pugh class in some cases. However, identifying the subgroup of patients who will achieve stabilization or regression of their disease such that experience long-term transplant-free survival remains a clinical challenge. Thus, HCV treatment in the context of decompensated cirrhosis should remain individualized.