Vol. 9 Issue S1
On the cover: Official Journal of the Mexican Association of Hepatology and the Latin-American Association for the Study of the Liver. Practice Guidelines Diagnosis, Management, and Treatment of Hepatitis C
Hepatitis C virus is one of the most common causes of chronic liver disease and one of the principal indications for liver transplantation. The prevalence and incidence worldwide is variable, although there may be some similarities among different regions. Worldwide prevalence has been estimated around 3.1% or 170 million infected people. The Latin America region has one of the lowest prevalence around the world with an overall prevalence estimated around 1.23%, nevertheless it varies from country to country and even between regions of the same country. Although the principal route of transmission continues being blood transfusion, the epidemiological change around the world is affecting our region, increasing the virus transmission among intravenous drugs users. Also in Latin America the most prevalent genotype is 1 different from other regions like Africa and Asia. The knowledge of epidemiology of Hepatitis C in our region is basic for the prevention and treatment of this arising disease, and further research with greater general population based studies must be carried out.
Hepatitis C is one of the most common causes of chronic liver disease in Latin America. It is essential to understand the different mechanisms of transmission of the infection in order to design control measures. The pattern of transmission of the infection in our region suggests that the peak of the infection occurred 30 to 50 years ago. While most infections in Latin America seem to be the result of blood transfusion and unsafe therapeutic injection practices in the past, there is still a need to identify and notify infected blood donors. Intravenous drug use and sexually transmitted hepatitis C virus among human immunodeficiency virus-positive patients are current problems that need to be addressed.
The current optimal approach to detecting hepatitis C virus (HCV) infection involves screening people for risk factors and only testing selected individuals at risk. Blood transfusion from infectious donors, unsafe therapeutic injection practices, and illegal intravenous drug use have been the predominant modes of transmissiom of HCV infection. Virological markers that are currently used for the clinical management of patients with hepatitis C include serologic assays (ELISA or immunoblot assays), which detect specific antibodies (IgG) to HCV, and virological assays, which detect serum HCV RNA, by highly sensitive qualitative and quantitative techniques. The applicability of these tests is for the diagnoses and monitoring of the treatment but they have no role in the assessment of disease severity or prognosis. Patients diagnosed with HCV infection must be educated in order to avoid the spread of the disease to other people.
Major requirements for performance of liver biopsy (LB) are the benefits for the patient and the impossibility of having the same information by less invasive procedures. In the last two decades physicians have faced the difficult task of convincing a patient positive for hepatitis C, with minimal clinical or laboratory alterations to be submitted to LB in order to evaluate the status of the disease for therapeutic management. The characteristics of the needle used for percutaneous LB interferes with the accuracy of diagnosis. In chronic hepatitis C (CHC), validity is achieved with liver fragments about 25mm in length containing more than 10 portal tracts. Morbidity due to LB is mainly related to bleeding but death is very rare. Severe complications are also uncommon, increasing with number of passes and decreasing with experience of operator and ultrasound guidance. Although CHC is a diffuse disease, the various areas of the liver may not be equally affected and sampling errors are possible. Another potential limitation of LB is the discordance between pathologists in its interpretation. To replace LB, many panels of surrogate markers have been described, aiming to identify extent of fibrosis and inflammation. All of them have used LB as their gold standard. Liver biopsy continues to be the most reliable method to evaluate the possibility of therapy for CHC. Universal treatment of all patients with diagnosis of CHC would be ideal. But, there are mainly three drawbacks. Overall efficacy is as low as 50%, side effects are common and may be severe and treatment is prolonged and expensive. The acceptability of the biopsy by the patient is highly dependent on the physicians conviction of its usefulness.
HCV Infection is a global burden disease and it is related to the development of progressive liver fibrosis, cirrhosis and hepatocellular carcinoma. At least 80% of the persons that have an acute infection evolve to chronicity. This event affects the patient and their contacts for the risk of acquiring the infection. Once chronic HCV is present some factors accelerate progression: older age, obesity, alcohol consumption, etc. Severity of fibrosis is one of the most important factors to be analyzed before deciding to treat a patient. Pegylated interferon and ribavirin is the standard of care for this disease, however, it has many side effects, some of them life threatening. That is the reason why this treatment must be indicated in the right moment in the right patient. A complete medical evaluation must be done previously to initiate treatment. Other concurrent problems must be ruled out or treated. Decompensated cirrhosis, autoimmune diseases or other uncontrolled disease are contraindication to HCV treatment. Previous failure to treatment for HCV must be analyzed to identify the reasons for that event and consider retreatment. Cryoglobulinemia and membranoproliferative glomerulonephritis are indications for treatment independent from the severity of liver disease.
INowadays the standard of care for hepatitis C therapy is based on Pegylated interferon alpha and ribavirin (Peg IFN/RBV). This combination has led to a sustained virological response rate (SVR) of 50 to 80% depending on genotype. This is still low, considering the side effects, overall costs and duration of therapy. So far, strategies to foresee SVR have been described such as genotype, fibrosis stage, viral load and gammaglutamyltransferase. In addition, new data has recently been provided on predictive factors of SVR like genetic polymorphism related to race, insulin resistance and viral kinetics. This review aims to discuss these predictive factors of therapy that might help the decision about starting or discontinuing therapy in chronic HCV infected patients.
The effect of interferon alfa against hepatitis C virus has been well documented. However, clinical efficacy is low due to the short interferon residence in the body. To prolong half-life, interferon molecules have been bound to the biologically inert polymer, polyethyleneglycol. Pegylated interferons exhibit a longer residence time with an improved clinical efficacy, although the rate of therapeutic failure is still important. Addition of ribavirin to interferon, either pegylated or not, significantly increases efficacy. Therefore, the combination of a pegylated interferon with ribavirin has become the standard treatment of chronic hepatitis C. As the efficacy and safety of such combinations are not yet optimal, different drugs, including other types of long-acting interferons and ribavirin analogs, are presently been investigated.
Hepatitis C (HCV) is a major public health problem worldwide and it is considered that there are about 180 millions of infected people. The natural history of hepatitis C shows that, of those individuals affected by a primo-infection, 55 to 95% evolve into chronicity. The objective of treatment for chronic hepatitis C is to prevent in the long term the complications and death that this disease may cause. In a short term the most important aim is the sustained virological response (SVR), considered a virological response, normalization of the serum ALT level, histological improvement, improvement in patients quality of life and the risk of transmission reduction. The association Peginterferon alpha Ribavirin (PEG IFNa-RBV), at the moment, is the standard of care of patients with chronic hepatitis C and compensated cirrhosis. Two PEG IFNa are licensed, PEG IFNa 2a and PEG IFNa 2b. Pegylation is a procedure that allows the union of polyethylene glycol moieties (PEG) to pharmacologic active proteins; in this case, IFNa. Pegylation of the IFNa 2a and 2b provoke important modifications in these proteins: slower absorption, different distribution, slower elimination, and longer half life with major exposure to the drug and lesser antigenicity. The two pegylated interferons available are dissimilar between them. The SVR in chronic hepatitis C patients who were treated with PEG IFNa-RBV in registration trials was 54 to 61%. Patients with genotypes 1 and 4 must be treated 48 weeks and those with genotypes 2 and 3, 24 weeks. In some situations patients could be treated lesser or longer time. Results obtained from the association of PEG IFNa - RBV - Amantadine in chronic hepatitis C patients are controversial. Meta-analysis comparing both PEG IFNs alpha shows a better SVR with PEG IFNa 2a. Therapies in patients with mild chronic hepatitis C have a similar SVR that those with more advanced liver disease and could be treated in this phase of the disease.
IApproximately 30% of patients with chronic HCV infection have persistently normal alanine aminotransferase levels (PNALT). Most of these patients have minimal or mild inflammation and absent or minimal fibrosis, although occasionally cirrhosis and hepatocarcinoma may be seen. Overall, liver histology is significantly less severe than in patients with elevated ALT levels, and most follow-up studies have reported stability of the disease, with minimal fibrosis progression over years, and thus a disease with a favorable prognosis. Nevertheless, a few studies have shown more recently that many patients with PNALT, may have elevations in ALT over time, and almost 20-30% have a significant progression of fibrosis, being eligible for antiviral therapy. During the last decade it has been demonstrated that in chronic HCV infection with PNALT, combination antiviral therapy with peg interferon-alpha plus ribavirin is efficacious, safe, and associated with significant improvements in health-related quality of life, and the decision whether to treat or not this patients should be based on multiple factors including: age, HCV genotype, histology, patients motivation and adherence, symptoms and comorbidity, rather than on ALT levels alone. (182 words).
The treatment of patients with cirrhosis has the following purposes: to prevent the complications of the disease; to allow for the regression of cirrhosis; and to prevent reinfection in the graft in patients undergoing liver transplantation. When the sustained viral response is evaluated in patients with cirrhosis, especially in those with decompensated disease, it is noted to be lower than that of patients with chronic hepatitis, and with a higher possibility of complications of the treatment. Based on a review of the literature, we conclude that we should treat patients with compensated cirrhosis, probably also those with portal hypertension, and patients with decompensated cirrhosis only when included on the transplant list, as long as Child B with HCV genotype 2 (possibly 3) and preferably after clinical compensation.
Recurrent hepatitis C after liver transplantation is universal. Graft reinfection occurs rapidly, with chronic hepatitis and rapid evolution from end-stage liver disease. Within 5 years until 30% of patients with recurrent disease ultimately progress to cirrhosis, and survival of transplanted patients with recurrent hepatitis C virus has been shown to be lower than of patients transplanted for other indications. Antiviral therapy in this patient population is generally recommended, but indication, optimal timing, dose and duration of therapy are not clearly defined. There are two major indications of therapy in that patients: pre-transplant antiviral therapy aiming to prevent reinfection, and post-transplant therapy with the goal of eradicating the recurrent infection. The first is limited by poor tolerance and drug side effects, and the second achieves only sustained virologic response in 25-45% of patients. Combination therapy with PEG INF and ribavirin shown the better results. Dose reduction and interruption of therapy occurs in 30 to 60% by side effects. There are no prospective randomized trials with confidence of results. More efficacious and better tolerable antiviral therapies are needed.
Hepatitis C is, at present, a worldwide health problem and is the most common cause of liver transplantation. Its prevalence in pregnant women is similar to that of the general population. In the absence of cirrhosis and portal hypertension, most HCV-infected pregnant women do not have obstetric complications. Screening of pregnant women that are asymptomatic and do not have risk factors is not cost effective. A high hepatitis C viral load reportedly increases vertical transmission and is higher in women who are coinfected with HIV or who are intravenous drug users. Prolonged rupture of the membrane for more than 6 h, amniocentesis, and perineal lacerations increase the potential risk of perinatal transmission. Although the hepatitis C virus can be transmitted intrapartum, prevention by caesarean delivery is not generally indicated. The HCV virus can be found in maternal milk; however, breast feeding is not contraindicated. In conclusion, there are no antiviral treatment recommendations for HCV-infected women during pregnancy, or guidelines for the prevention of vertical transmission.
Infection with hepatitis C virus (HCV) is a worldwide health problem with more than 170 million infected individuals. In children, since 1992 almost all infections occurred through vertical transmission from an infected mother to her newborn infant. Natural history of HCV infection in children is not yet well defined, most children are asymptomatic and may remain so for decades. Most infected individuals (60-80%), regardless of their age at infection, become chronically infected with HCV. Spontaneous resolution in children appears to be infrequent. Positive HCV antibody implicate that patient has been exposed to the virus (EIA test). To discriminate between active or resolved HCV viral infection it is necessary to perform HCV RNA (PCR). Liver biopsy assess degree of liver injury and exclude concurrent diseases. HCV chronic infection is slow progressive in childhood. Progression of fibrosis seems to be a function of infection duration. Treatment objective is clearance of HCVRNA. IFNa is recognized as the drug approved for hepatitis C treatment in pediatric population. Combination therapy with IFNa or pegylated IFNa plus ribavirin is recently approved by US FDA and EMEA and clinical trials are in progress.
Hepatitis C signifies a highly prevalent infection in patients with end stage renal disease. Most frequently it is associated to glomerulonephritis, patients on hemodyalisis and renal transplants. The prevalence of HCV antibodies in hemodialysis patients varies between 5-70% depending on the geographical location of the patients. Factors associated with the prevalence of anti HCV in patients with hemodialysis include: age, blood transfusions, tattoos, use of illegal drugs, time in hemodialysis, more than two hospitalizations, treatment in multiple hemodialysis units or a kidney transplant. In some of the reported outbreaks of hepatitis in hemodialysis units, the phylogenetic analysis indicate that the transmission of HCV could relate to failures or breaches in general precautions in the management of these type of patients resulting in nosocomial transmission owed to sharing equipment or instruments employed in the hemodialysis or by transmission from professional members of the hemodialysis units. Antiviral treatment may be affected by a number of co-factors and co-morbidities, it consist mainly of non pegylated interferon or pegylated interferon. The treatment with interferon after a renal transplant is associated with an increase in the number of rejections; reason enough to recommended that treatment should be administered before the transplant.
There are no well established treatment guidelines about acute hepatitis C (AHC), leaving physicians to make several challenging decisions, such whether to treat, when to treat and what treatment regimens to use. This article examines the diagnosis of acute infection and critically appraises the various treatment regimens.
Insulin resistance (IR) is a common pathophysiological condition where higher-than-normal concentrations of insulin are needed to maintain a normal glycemia and adequate glucose utilization in insulin target tissues. A high proportion (50-80%) of patients chronically infected with the hepatitis C virus (HCV) exhibit evidence of IR. Basic and clinical studies have disclosed a complex bidirectional relationship between IR and HCV infection that has important clinical implications. HCV infection may promote IR through direct viral- dependent mechanisms or due to activation of the inflammatory response resulting in increased production of Tumor Necrosis Factor-a and other cytokine-related molecules. These abnormalities may act synergistically with pre-existing metabolic risk factors and result in the development of hepatic steatosis and type 2 diabetes mellitus (T2DM) which are frequently found in the setting of HCV infection. Moreover, in addition to underlying metabolic abnormalities leading to its development hepatic steatosis also exhibit genotype-specific pathogenic mechanisms. A number of studies have shown that hepatic steatosis is associated to fibrosis progression in patients with HCV and that IR has a negative impact on the response rates to interferon-a-based therapy. Thus, modification of these factors through life-style changes or pharmacological agents may represent an undervalued specific target of therapy aiming to improve sustained virological response rates and reduce HCV related-morbidity and mortality.
Chronic hepatitis C virus infection is a well-recognized risk factor for occurrence of hepatocellular carcinoma (HCC). In Europe, Oceania and America, chronic hepatitis C and alcoholic cirrhosis are the main risk factors for HCC. In Latin America, a few retrospective and one prospective study have also shown the predominant role played by hepatitis C in this setting. Furthermore, the incidence of HCC has been increasing in industrialized countries in the last decades; partially as a consequence of the increase in HCV-related cirrhosis (as the long-term sequel of the peak of infections occurring 2-4 decades ago). The main risk factor for HCC development in patients with hepatitis C is the presence of cirrhosis. Among patients with hepatitis C and cirrhosis, the annual incidence rate of HCC ranges between 1-8%, being higher in Japan (4-8%) intermediate in Italy (2-4%) and lower in USA (1.4%). Some studies have also found that HCC may be the first complication to develop and the more frequent cause of death in the compensated HCV-associated cirrhosis. Other risk factors for HCC occurrence are older age at infection, male gender, decreased platelet count, esophageal varices, presence of porphyria cutanea tarda, liver steatosis or diabetes, infection with genotype 1b, coinfection with hepatitis B virus or with HIV and chronic alcoholism. Many studies and also meta-analysis have reported that antiviral therapy based on interferon may reduce the incidence of HCC in chronic hepatitis C, especially in patients with sustained virologic response. Patients with HCV-related cirrhosis should undergo surveillance for HCC.
We are at the cusp of significant new alternatives for the treatment of chronic hepatitis C. Among more than 100 drugs in development, some are ready to be approved and in the market as soon as next year. The protease inhibitors Telaprevir and Boceprevir, will change the SOC treatment to triple therapy, (combined with peg IFN and RBV), with duration of treatment guided by rapid virological response. In this article we present the data supporting the approval of Telaprevir and Boceprevir, and information on polymerase inhibitors and IFN free proof of concept trials. Finally we discuss which patients should wait for DAA based therapies and which should be considered for peg IFN/RBV now. In the next 5 years our patients can expect higher response rates and truncated duration of therapy. They can expect drug cocktails or combos but for the next years these novel drugs will still require peg IFN and RBV. Also, a new era of resistance as a barrier to therapy will require sub typing and more viral monitoring. Overall, improved outcomes will come at the expense of more adverse events and increased costs of treatment.
Hepatitis C is a major public health issue. It infects about 200 million people worldwide and is a major cause of chronic liver disease. Its transmission in medical facilities is a topic of increased concern, as outbreaks of the disease had raised the attention of media and medical authorities. To date, evidence suggests that infection from in which a health-care worker is involved is mostly result of bad injecting practices as well as the result of shared medical devices. Furthermore, the infection caused by physicians is rare and very few well documented cases exist on the literature. Among countries, different definitions and legislation exist, in that mode that the responsibility of this issue almost is a an obligation of individual institutions. Nonetheless, Hepatitis C virus transmission in medical facilities is an important source of new cases, and as treatments options are very limited, its recommendable that institutions as well as governments implement policies to avoid Hepatitis C spread in a almost fully preventable setting.