Role of the nurse practitioner in the management of patients with chronic hepatitis C

Purpose: To inform nurse practitioners (NPs) of the vital role they play in recognizing patients who may have hepatitis C. Data sources: Selected review of scientific literature. Conclusions: NPs involved in the management of patients with chronic hepatitis C are well positioned to provide supportive care and contribute to the development of effective treatment strategies that maximize the opportunity for successful treatment outcomes. Although peginterferon alfa plus ribavirin therapy is associated with a well-described series of side effects, effective measures are available for the management of these events that permit the continuation of treatment and enhance the likelihood of attaining sustained virologic response. NPs can play a pivotal role in ensuring that these measures are in place in a preemptive manner. For example, growth factor supplementation represents an alternative to dose reduction or treatment discontinuation in selected patients with neutropenia or anemia and may help to improve treatment adherence. Implications for practice: Hepatitis C is a widespread problem; approximately 3% of the global population is chronically infected with the virus. Awareness of risk factors for hepatitis C will help the NP to recognize at-risk patients, who should then be screened for the virus and referred for treatment based on specific criteria.     

Initial treatment for chronic hepatitis C: current therapies and their optimal dosing and duration

The main treatment goal in patients with chronic hepatitis C virus (HCV) infection is the prevention of progressive hepatic fibrosis by eradicating serum and intrahepatic virus. The current standard of care in previously untreated patients with chronic hepatitis C is combination therapy with pegylated interferon alfa and ribavirin. The duration of therapy and the dose of ribavirin should be determined according to the patient's HCV genotype. Adherence to the full dose of therapy for the prescribed treatment duration enhances the likelihood of sustained virologic response. Early virologic response is a good predictor of eventual sustained response for patients with HCV genotype 1 infection. Despite important gains in treating chronic hepatitis C, many treatment challenges remain.     

Future therapies for hepatitis C

Although pegylated interferon-alpha plus ribavirin has become the standard for treating chronic hepatitis C virus infection, a substantial number of patients do not tolerate therapy and require dose reduction or discontinuation, or do not respond to this combination therapy. Thus, new therapeutic options are needed. An increased knowledge of the hepatitis C virus and an understanding of its replication cycle, as well as advances in biotechnology, have stimulated the development of numerous new antiviral treatments for patients with hepatitis C virus infection. This review focuses on four classes of new agents: new interferons, ribavirin-like molecules, specific small-molecule hepatitis C virus inhibitors and new immune therapies, with particular emphasis on medications in the later stages of development.     

Treatment options for nonresponders and relapsers to initial therapy for hepatitis C

As treatment for chronic hepatitis C virus (HCV) infection has advanced over the past decade, efforts have evolved to retreat patients who did not achieve a sustained virologic response to previous antiviral regimens. Retreating nonresponders to interferon alfa monotherapy with a combination of interferon and ribavirin yields a sustained virologic response in 9% to 32% of patients, whereas retreatment with peginterferon alfa plus ribavirin yields a sustained virologic response in up to 30% to 40% of patients. Sustained virologic response is more likely in retreated patients with HCV genotype 2 or 3, low serum HCV RNA levels, and lack of response to prior interferon monotherapy. Retreatment of nonresponders to interferon-ribavirin combination therapy is associated with lower response rates (< or = 20%). Despite treatment advances, the efficacy of current antiviral regimens for nonresponders remains inadequate. The next few years will see more-targeted antiviral regimens for these patients and therapies focused on slowing the progression of liver disease rather than viral eradication.     

Comparative Effectiveness of Telaprevir-Based Triple Therapy in Patients With Chronic Hepatitis C

ObjectiveTo examine the effectiveness and tolerability of triple therapy with pegylated interferon (p-IFN), ribavirin (RBV), and telaprevir in patients with chronic hepatitis C receiving treatment in an academic practice setting and in a more clinically diverse population compared with patients receiving treatment in phase 3 trials.Patients and MethodsA prospective database of all patients with viral hepatitis undergoing antiviral therapy from January 1, 2006, to July 1, 2012, was queried to identify treatment-naive and -experienced patients with chronic hepatitis C receiving dual and triple therapies. On-treatment response categories included rapid virologic response, extended rapid virologic response, early virologic response, and sustained virologic response. These patients were compared with matched controls, namely, patients who underwent dual therapy with p-IFN and RBV. Matching was performed for age, cirrhosis status, and prior treatment.ResultsThere were 55 patients who received triple therapy and met the eligibility criteria, consisting of treatment-naive (n=35) and -experienced patients (n=20: those with relapse, 9; those with nonresponse, 9; and those who terminated the treatment early, 2). Rapid virologic response was achieved in 41% of the patients, extended rapid virologic response in 41%, and early virologic response in 75%. Sustained virologic response was observed in 51% (18/35) of treatment-naive patients, 67% (6/9) of the patients with prior nonresponse, and 56% (5/9) of those with prior relapse. Corresponding results after dual therapy were 37% (23/62), 11% (2/18), and 27% (3/11), respectively. The mean decrease in the hemoglobin level at weeks 4, 8, and 24 of triple therapy was 2.8, 3.8, and 3.2 mg/dL compared with 2.4, 2.6, and 2.4 mg/dL with dual therapy (to convert mg/dL to mmol/L, multiply values by 0.0259).ConclusionTelaprevir-based triple therapy in clinical practice is considerably more effective than dual therapy with p-IFN and RBV despite the significant degree of anemia that complicated therapy, requiring RBV dose reduction and erythropoietin support.     

Role of genetic polymorphisms in hepatitis C virus chronic infection

AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C(CHC).METHODS: We conducted an electronic search on the Pub Med and MEDLINE(2000-2014) databases and Cochrane library(2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.RESULTS: Several studies associated polymorphisms in the interleukin 28 B gene on chromosome 19(19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon(PegIFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation. CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.     

Adverse effects of high-dose interferon-α-2a treatment for chronic hepatitis B

The aim of this study was to assess morbidity and the incidence of adverse effects during interferon (IFN)-α-2a treatment of patients with chronic hepatitis B. This prospective study included 48 consecutive patients with chronic hepatitis B who underwent IFN-α-2a treatment from January 2003 to August 2005. Adverse effects related to IFN treatment were recorded during this period and for 6 mo after treatment. Adverse effects that led to dose reduction or early discontinuation of IFN treatment were examined. Complete response was reported in 25% of patients. At least 1 adverse effect was documented in 88% of patients. Flu-like symptoms were the most frequently observed adverse effects (88%), and thrombocytopenia (63%), leukopenia (54%), and anemia (23%) were also reported. Bleeding occurred in 2 patients. Other adverse effects included neuropsychiatric signs (21%), alopecia (19%), weight loss (17%), thyroid disorders (19%), menstrual cycle irregularities (8%), skin lesions (8%), and dry cough (4%). Adverse effects that led to dose reduction or early discontinuation of IFN treatment occurred in 19% of patients and included impotence, depression, seizure, thyroid disorders, severe thrombocytopenia, and intestinal bleeding. These effects were found to be unrelated to treatment response. No relationship was detected between patient age, duration of treatment, and adverse effects of IFN. Although IFN-α-2a treatment induced various adverse effects in patients with chronic hepatitis B, most of these effects were reversible or could be ameliorated. Adverse effects that led to dose reduction or early discontinuation of IFN treatment were found to be unrelated to complete response.     

Clinical use of haematological growth factors in patients with human immunodeficiency virus (HIV-1) infection

HIV-infected patients commonly experience haematological disturbances including anemia, neutropenia or thrombocytopenia. Bone marrow failure may be caused by HIV itself, or by secondary involvement by opportunistic pathogens and malignancy. The need for multiple concomitant suppressive treatments may increase the risk of cytopenias. Strategy to reduce both anemia and neutropenia as well as to improve the haematological tolerance to myelotoxic agents have been developed by using haematological growth factors. So far, erythropoietin and granulocyte(macrophage) colony-stimulating factors have been successfully used in clinical trials including HIV-patients with either zidovudine-associated anemia or severe HIV or drug-induced neutropenia. However, according to the cost of these palliative approaches, there is a need for more reliable data showing that these growth factors could really have a major impact on the patient's compliance to therapy, reduction of hospitalization and infection rate and improvement of the overall survival.     

The role of hematopoietic growth factors in special populations with chronic hepatitis C: patients with HIV coinfection, end-stage renal disease, or liver transplantation

Certain populations with chronic hepatitis C face special challenges in attaining optimal adherence to antiviral therapy, including patients coinfected with human immunodeficiency virus, patients undergoing dialysis for end-stage renal disease, and liver transplant recipients. These patient groups may stand to gain particular benefit from the expanding use of hematopoietic growth factors to manage the cytopenic effects of antiviral therapy for hepatitis C. This article reviews the rationale, current evidence, and future prospects for the adjunctive use of growth factors in these special populations with hepatitis C.     

Combination therapy of IFN and ribavirin

Ribavirin is a purine nucleoside analog that inhibits the replication of a wide range of DNA and RNA viruses, although ribavirin treatment dose not significantly decrease serum virus load in patients with chronic hepatitis C. Several lines of evidence from the randomized large-scale studies of USA and Europe indicate that combination therapy with ribavirin significantly enhances the sustained response rate of IFN therapy in major patient types with chronic hepatitis C. A recent trial in Japan also proved that the combination therapy is superior to IFN monotherapy. Thus, IFN-ribavirin combination is likely to become the antiviral therapy of choice for chronic hepatitis C.     

Hepatitis B genotypes and response to antiviral therapy: a review

The aim of this review is to examine the impact of hepatitis B virus (HBV) genotypes on biochemical and virologic response to antiviral drugs (alfa-interferon and pegylated-interferon alfa-2b, lamivudine, and adefovir dipivoxil) actually used for the treatment of chronic hepatitis, HBV related. International literature evidences that HBV genotypes D and C are associated with a lower rate of favorable response to alfa-interferon and pegylated-interferon alfa-2b therapy than genotypes A and B. The rate of resistance to lamivudine was higher in patients with genotype A infection than in patients infected by genotype D, whereas no difference in the risk of lamivudine resistance is found between patients with genotype B and patients with genotype C. In regard to the new nucleotide analogue, adefovir dipivoxil, a preliminary trial appears to provide no evidence of any difference in virologic response among the different HBV genotypes. The current study has determined that the different HBV genotypes have a very important impact on response to antiviral therapy, in particular interferon treatment. For this reason, determining the HBV genotype could be helpful for predicting the outcome of antiviral therapy in patients affected by chronic hepatitis B.     

Managing hematologic toxicities in the oncology patient.

Myelosuppression associated with antineoplastic therapy may lead to neutropenia, anemia, or both, resulting in an increased risk for infection, fatigue, diminished quality of life, and reduced survival. Neutropenia can result in dose reductions and treatment delays. Hematopoietic growth factors have been used effectively as supportive therapy to reduce antineoplastic therapy-associated neutropenia and anemia. This article discusses management of neutropenia and anemia secondary to antineoplastic therapy, new medications, and nursing considerations.     

The hematologic system as a marker of organ dysfunction in sepsis

Sepsis with acute organ dysfunction (severe sepsis) results from a systemic proinflammatory and procoagulant response to infection. Organ dysfunction in the patient with sepsis is associated with increased mortality. Although most organs have discrete anatomical boundaries and carry out unified functions, the hematologic system is poorly circumscribed and serves several unrelated functions. This review addresses the hematologic changes associated with sepsis and provides a framework for prompt diagnosis and rational drug therapy. Data sources used include published research and review articles in the English language related to hematologic alterations in animal models of sepsis and in critically ill patients. Hematologic changes are present in virtually every patient with severe sepsis. Leukocytosis, anemia, thrombocytopenia, and activation of the coagulation cascade are the most common abnormalities. Despite theoretical advantages of using granulocyte colony-stimulating factor to enhance leukocyte function and/or circulating numbers, large clinical trials with these growth factors are lacking. Recent studies support a reduction in the red blood cell transfusion threshold and the use of erythropoietin treatment to reduce transfusion requirements. Treatment of thrombocytopenia depends on the cause and clinical context but may include platelet transfusions and discontinuation of heparin or other inciting drugs. The use of activated protein C may provide a survival benefit in subsets of patients with severe sepsis. The hematologic system should not be overlooked when assessing a patient with severe sepsis. A thorough clinical evaluation and panel of laboratory tests that relate to this organ system should be as much a part of the work-up as taking the patient's blood pressure, monitoring renal function, or measuring liver enzymes.     

Clinical application of hematopoietic growth factor (IL-3, G-CSF, GM-CSF, and EPO)]

Hematopoietic growth factors were found as factors stimulating hematopoietic colony formation in in vitro culture system using bone marrow cells as a source of hematopoietic progenitor cells. Erythropoietin, a growth factor stimulating erythroid lineage has now been clinically used as an therapeutic agent for anemia of chronic renal failure. Macrophage colony-stimulating factor (M-CSF), a growth factor stimulating the production of leukocytes including monocytes and neutrophils has been clinically used as an agent for leukopenic patients after anti-cancer therapy. M-CSF improves a survival rate after bone marrow transplantation (BMT) through the reduction of mortality rate associated with BMT such as bleeding, engraftment failure and GVHD. M-CSF accelerated platelet production when injected to thrombopenic patients with solid tumor after anticancer therapy. Granulocyte CSF (G-CSF) is a most powerful agent for various kinds of neutropenia such as neutropenia after anti cancer therapy, neutropenia after BMT, aplastic anemia, chronic neutropenia of children and myelodysplastic syndrome. However, since G-CSF stimulates growth of leukemic cells in vitro, careful observations should be required when clinically used on leukemic patients. Clinical studies of granulocyte-macrophage CSF (GM-CSF) and interleukin 3 (IL-3) are now in progress, in which a promoting activity of leukocyte production of these factors is evaluated.     

Persistence of mixed cryoglobulinemia despite cure of hepatitis C with new oral antiviral therapy including direct-acting antiviral sofosbuvir: A case series

Objective. Obtaining a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) can decrease hepatic complications and be curative, however, extrahepatic manifestations including mixed cryoglobulinemia (MCN) may persist with interferon-based therapy. Our objective was to review our experience in treating patients with new oral antiviral agents and to assess common factors associated with MCN persistence despite SVR. Methods. We analyzed a case series of five patients with genotype one chronic HCV complicated by MCN who had persistence of cryoglobulins despite completion of triple therapy with oral antiviral agents (boceprivir, telaprivir or sofosbuvir). Results. Patients with cirrhosis appear to have a decreased ability to clear immune complexes. We observed that early viral response by week 8 of therapy and longer periods of undetectable virus on treatment correlated with eventual clearance of serum cryoglobulins in patients without cirrhosis. Two patients were treated with anti-B-cell agent rituximab prior to starting therapy for HCV; this did not lead to a more effective clearance of cryoglobulins. Conclusions. We suggest that a longer treatment course than the standard 24 weeks with triple therapy could aid in the clearance of these immune complexes and cryoglobulins in cirrhotics. More studies to determine the ideal duration of treatment for chronic HCV and coincident MCN are needed, especially in light of the new all oral direct-acting antiviral regimens that are now recommended for HCV treatment.     

The H63D mutation of the hemochromatosis gene is associated with sustained virological response in chronic hepatitis C patients treated with interferon-based therapy: a meta-analysis

The hemochromatosis (HFE) gene encodes the HFE protein that regulates iron absorption. HFE mutations lead to the hemochromatosis disease of excessive iron absorption. HFE mutations may also influence the sustained virologic response (SVR, long-term virus suppression) in chronic hepatitis C patients treated with interferon-based antiviral therapy. We performed a meta-analysis of all English and Chinese language studies of HFE mutations and SVR in interferon-treated chronic hepatitis C patients indexed in the Medline, PubMed, Embase, and China National Knowledge Infrastructure databases to November 2011. Seven studies involving 605 patients with HFE mutations (homozygous or heterozygous mutation of C282Y, H63D or S65C) and 1279 with wild-type HFE (no mutation of C282Y, H63D or S65C for both alleles) were analyzed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the fixed- or random-effect models. HFE mutations were associated with significantly higher SVR rate (vs. wild-type: OR = 1.56, 95% CI: 1.23-1.97, P < 0.001), indicating that mutation carriers were likely to achieve SVR in response to interferon-based antiviral therapy. Stratification analysis by HFE mutation type revealed that the H63D mutation was associated with a significantly higher SVR rate (OR = 1.60, 95% CI: 1.09-2.34, P = 0.020), while the C282Y mutation was not (OR = 1.19, 95% CI: 0.71-1.98, P = 0.510). Our meta-analysis results indicate that the H63D mutation in HFE is associated with a higher SVR rate in chronic hepatitis C patients treated with interferon-based antiviral therapy.     

Treatment of viral hepatitis - 2001

Chronic viral hepatitis may now be controlled and, in many cases, permanently eradicated. Rapid advances in the antiviral therapy of chronic hepatitis C infection have resulted in a greater than 50% sustained response rate, with genotypes 2 and 3 now considered ‘curable diseases.’ Current hepatitis B therapy leads to significant improvement in liver histology and overall survival. These advances, coupled with the fact that 8% of the world population is chronically infected with viral hepatitis, has sparked considerable interest in this condition on the part of the pharmaceutical industry. In 2001, the most effective therapy for chronic hepatitis C is the combination of pegylated interferon alpha and oral ribavirin. The treatment of hepatitis B consists of either interferon alpha or oral lamivudine, while newer nucleoside/nucleotide analogues, alone or in combination with existing therapy, are being explored.     

Treatment of viral hepatitis--2001

Chronic viral hepatitis may now be controlled and, in many cases, permanently eradicated. Rapid advances in the antiviral therapy of chronic hepatitis C infection have resulted in a greater than 50% sustained response rate, with genotypes 2 and 3 now considered 'curable diseases.' Current hepatitis B therapy leads to significant improvement in liver histology and overall survival. These advances, coupled with the fact that 8% of the world population is chronically infected with viral hepatitis, has sparked considerable interest in this condition on the part of the pharmaceutical industry. In 2001, the most effective therapy for chronic hepatitis C is the combination of pegylated interferon alpha and oral ribavirin. The treatment of hepatitis B consists of either interferon alpha or oral lamivudine, while newer nucleoside/nucleotide analogues, alone or in combination with existing therapy, are being explored.     

Iron depletion before HCV antiviral therapy: A pilot,randomized, controlled trial

It is not known whether iron depletion before pegylated IFN or combination treatment improves sustained virological response (SVR) rate in patients with chronic hepatitis C, despite its use in clinical practice in this setting. We aimed to investigate whether blood letting improves the efficacy (SVR) and tolerability of PEG‐IFNα2b + Ribavirin in chronic hepatitis C patients. Patients with chronic hepatitis C and ferritin >100 ng/mL were randomized to: (1) repeated phlebotomies to obtain a ferritin level <50 ng/mL followed by pegylated‐Interferon α2b + ribavirin (active arm); or (2) pegylated‐Interferon α2b + ribavirin (control arm). Primary endpoint was SVR rate, secondary endpoint was frequency of clinical and laboratory grade 3–4 adverse events. Thirty‐three patients were enrolled in the study (19 in active arm, 14 in control arm). The 19 patients in the active arm underwent a median of 5 phlebotomies (range: 1–9) to achieve the targeted ferritin (<50 ng/mL). Phlebotomies significantly reduced ferritin, iron, transferrin saturation, aspartate aminotransferase, alanine aminotransferase, and hemoglobin levels. Platelet count significantly increased, whereas HCV‐RNA levels remained unchanged. After antiviral therapy overall SVR was 31.6% in active arm and 21.4% in control arm (P = 0.698). Considering only the 18 patients who were naive to antiviral therapy, SVR was 60% in active arm versus 25% in control arm (P = 0.188). Tolerability, drug dose reduction or withdrawal were similar in the two arms. In conclusion phlebotomies do not increase the overall efficacy of antiviral therapy. However, the strong trend to higher SVR in naive patients undergoing phlebotomies warrants further investigation. J. Clin. Apheresis 2009. © 2009 Wiley‐Liss, Inc.     

Advances in treatment of chronic hepatitis C: 'pegylated' interferons

New regimens consisting of pegylated interferons plus ribavirin may produce a sustained virologic response in more than 50% of cases of chronic hepatitis C. In contrast, the combination of standard interferon alfa and ribavirin, which was the standard of care until recently, produced a sustained virologic response in 35% to 40% of cases. As the efficacy of newer regimens improves, additional steps to adequately manage their side effects and maximize adherence may become crucial.