Complications of Hepatitis C

From Scripp Clinic’s 2009 “National Hepatitis B and C Training Program and Treatment Update” and“New Treatments in Chronic Liver Disease”

Educational Objectives

The goal of this program is to improve the management of hepatitis C. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the side effects of treatment of hepatitis C and how to manage them.

2.   Monitor patients for problems that may arise during treatment for hepatitis C.

3.   Demonstrate how insulin resistance and coexistent steatosis affect response to therapy in patients with hepatitis C.

4.   Distinguish between virally-mediated and host-mediated steatosis.

Utilize strategies available for improving response to treatment of hepatitis C.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committe to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Saab is on the Ad­visory Board or Speakers’ Bureau of Schering-Plough, Roche, Three Rivers, and Vertex. Dr. Pockros and the planning com­mittee reported nothing to disclose. In their lectures, Drs. Saab and Pockros present information that is related to off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Saab was recorded at 2009 National Hepatitis B and C Training Program and Treatment Update, held September 26, 2009, in Los Angeles, CA, and Dr. Pockros was recorded at New Treatments in Chronic Liver Disease, held April 4-5, 2009, in San Diego, CA; both conferences were sponsored by the Scripps Clinic. The Audio-Digest Foundation thanks the speak­ers and the Scripps Clinic for their cooperation in the production of this program.

Management of Side Effects of Therapy

Sammy Saab, MD, MPH, Associate Professor of Medicine and Surgery, David Geffen School of Medicine, Uni­versity of California, Los Angeles

Introduction: goals of therapy  —  cure viral infection and maintain quality of life (QOL); significant adverse effects seen with therapy (lasts 40 wk); patients must know what to expect; modifiable influences of sustained virologic re­sponse (SVR)  —adherence throughout therapy, but first 12 wk most important

Principles of side effect management: be proactive, ie, ask patient (speaker has patients fill out survey form); some adverse effects diminish with continued therapy (tachyphylaxis); monitor patient; certain patients may need psychi­atric consultation; support necessary (spouse, family, or friend should attend class with patient)

Treatment of hepatitis C virus (HCV) infection: interferon (IFN)  —  flu-like symptoms, nausea, diarrhea, hair loss, and thyroid problems; may spark autoimmunity (leukopenia and thrombocytopenia); ribavirin (RBV)  —  associated with cough, rashes, insomnia, anorexia, and birth defects; patient should not become pregnant during therapy and for 6 mo after completion; side effects  —  predictable and manageable; resolve with dose modification or discontin­uation of drug; flu-like symptoms most common; management of flu-like symptoms  —  acetaminophen acceptable (bedtime or early evening administration); recommend adequate intake of water and balanced meals; focus on pos­itive; nonsteroidal anti-inflammatory drugs (NSAIDs) contraindicated in patient with advanced disease (cirrhosis; lead to kidney failure and liver disease, and affect platelet function)

Fatigue: difficult to treat when caused by IFN; treatable if caused by anemia, thyroid disease, or depression; encour­age hydration and avoidance of strenuous activities; avoiding carbohydrates helpful; patients with HCV at risk for early diabetes or insulin resistance (IR); should rule out anemia (hemoglobin [Hb] <10 g/dL), problems with eat­ing, and thyroid problems; pharmacologic intervention (eg, modafinil [Provigil]) not helpful

Depression: some patients (20%-30%) depressed before starting therapy; use low threshold for starting antidepres­sant medication; should fit medication to type of depression; except for those with advanced cirrhosis, individuals with hepatitis C have normal metabolism of medications; in this case, start with low dose and gradually increase

Headaches: due to IFN; rule out sinus infection and tension headache; advise patients to use analgesics, limit expo­sure to bright light and loud sounds, avoid alcohol and certain foods, and limit caffeine intake; ensure adequate fluid intake; caffeine  —  beneficial to liver (reduces risk for liver cancer in cirrhosis); may dehydrate and cause fa­tigue

Insomnia: treat aggressively; use low threshold for starting pharmacologic therapy, but start with conservative mea­sures

Fever: improves over time; acetaminophen recommended; rarely necessary to use cooling packs; encourage fluids

Myalgia: acetaminophen, massages, whirlpool or warm soaks, and mild exercise recommended

Chronic pain: due to IFN; tends to exacerbate “old” pains (eg, chronic fatigue syndrome, reflux sympathetic dystro­phy, previous injury); be aggressive with therapy

Hair loss: usually occurs during second half of therapy and tends to persist £2 mo after therapy completed; rule out thyroid disorder; advise patients to avoid harsh hair products and hair dryers, use mild shampoos and conditioners, and avoid hair coloring and permanents

Nausea: predictable and manageable; due to RBV; advise patients to avoid acidic, spicy, or greasy foods, and to eat small meals; rule out other causes (eg, gastroesophageal reflux disease); low threshold for over-the-counter or pre­scription medications (eg, ondansetron, prochlorperazine); RBV  —  new formulation of 400-mg or 600-mg capsules associated with less nausea

Pruritus: not common and rarely necessitates discontinuation of therapy; advise patients to use soothing baths and lotions and to avoid perfumed soaps and lotions

Anorexia: assess for depression; control nausea; monitor weight

Cough: rule out infection; ensure pulmonary function intact; IFN  —  increases bronchial reactivity and exacerbates asthma; also causes pulmonary fibrosis; cough and shortness of breath (SOB) worrisome (speaker refers to lung specialist)

Injection-site reactions: seen in »25% of patients; ice applied to injection site before injection; let alcohol dry after swabbing site; inject at room temperature; massage of injection site not recommended; rotate injection site

Monitoring patient: check for anemia, bone marrow toxicity, pulmonary disorders, pancreatitis, and psychiatric is­sues; IFN can cause eye (retinal) problems; if patient has vision problems during therapy, refer to ophthalmologist; check for pregnancy during clinic visits; laboratory monitoring  —  complete blood count, liver tests, thyroid tests, and aggressive (monthly) monitoring of virus levels; decision whether to continue therapy based on week 12 data; the faster patient becomes HCV RNA-negative, the better the chances for cure (motivating for patient)

Neutropenia: occurs in »20% of patients on therapy; be concerned if absolute neutrophil count (ANC) <500 cells/mm³ or <750 cells/mm³ in patients with cirrhosis; serious infections not associated with lower ANC; in gen­eral, infections do not occur at time of ANC nadir; management  —  decrease dose of IFN; can use growth factors, eg, granulocyte colony-stimulating factor (G-CSF; filgrastim [Neupogen]); however, associated with more side ef­fects than IFN (eg, myalgia, arthralgia); limited to patients with advanced disease in whom risk of developing neu­tropenia and consequences greater

Thrombocytopenia: less common than neutropenia (occurs in 2%-5% of patients); all patients on therapy have de­creased platelet count, although worse with cirrhosis; clinical implication depends on baseline level of platelets and degree of liver damage; for neutropenia, filgrastim used (off-label); for anemia, epoetin alfa (Procrit) used (off-la­bel); platelet growth factor  —  approved by Food and Drug Administration for idiopathic thrombocytopenic pur­pura; small molecule, safe, and first in its class; in study, given to patients with hepatitis C and cirrhosis to determine whether platelet counts would increase enough to start IFN; platelet count too low to start IFN indicates significant liver damage and decreased likelihood of cure (<20%); associated with more side effects and poor re­sponse; if thrombocytopenia present, monitor platelet count regularly; depending on drug used, may intervene at different time if platelet count drops dramatically due to autoimmune phenomena (eg, bleeding of gums or nose); if using peg-IFN alfa-2a or peg-IFN alfa-2b and platelet count decreases to <50 x 10³/μL, consider reducing dose of IFN by 50%; different thresholds for lowering IFN therapy; speaker concerned if platelet count <30 x 10³/μL (cir­rhosis likely present; screen patient for varices and liver cancer)

Anemia: due to RBV; seen in 15% to 20% of patients; risk »30% in those with liver transplantation, even with nor­mal kidneys; risk higher if coinfected with hepatitis B or if renal insufficiency present; study showed almost linear relationship between RBV dose and cure rate; increasing dose of RBV increases risk for anemia and nausea; small risk for anemia with IFN alone; IFN inhibits reticulocyte response; anemia affects QOL; options include dose re­duction, using growth factors, waiting for therapeutic options (eg, taribavirin) under development, and transfusion; avoid dose reduction, particularly in first 8 wk; threshold for using growth factor Hb <10 g/dL or <10 g/dL plus symptoms; if Hb >10 g/dL, growth factors may cause increased risk for clotting

Ribavirin: RBV prodrugs have same efficacy as RBV, but less tendency to cause anemia; RBV alone has limited an­tiviral activity and requires IFN for efficacy; study data  —  looked at effect of dose of RBV; in patients with geno­type 1 taking 800 mg of RBV for 40 wk, cure rate 41%; with larger dose, cure rate 52%; study showed that exposure to RBV in first 12 wk predicts cure; at <80% of expected exposure to RBV, chances of cure £41% (<60%, 35%); if patient grossly anemic, may stop drug temporarily; exposure to RBV predicts not only likelihood of achieving early virologic response (EVR), but also predicts cure rate

Depression: other issues (eg, family, mental health) may coexist; »23% of patients with hepatitis C had depression at time of presentation (more common than in general population); studies looking at treating depression in patients on therapy for hepatitis C found favorable response to selective serotonin reuptake inhibitors (SSRIs); adverse ef­fects may occur; substance abusers  —  in most patients, HCV acquired through drug use; should abstain from recre­ational drugs for ³6 mo; patient on methadone can be treated for hepatitis C; if side effects occur, increase dose of methadone; no increased side effects or compromise in SVR rate seen with methadone

Steatosis and Hepatitis C

Paul Pockros, MD, Head, Division of Gastroenter-ology/Hepatology and Director, Liver Disease Center, Scripps Clinic, La Jolla, CA

Introduction: of 8 studies looking at SVR in patients with fatty liver and HCV, 7 showed lower SVR rates in patients with fatty liver than in those without; peg-IFN alfa-2a and peg-IFN alfa-2b show same diminished response in pa­tients weighing >85 kg

Impact of insulin resistance (IR) on VR: homeostatic model assessment (HOMA) score  —  obtained by multiplying fasting insulin and fasting glucose in mmol/L, then dividing by 22.5; determined in overweight or obese patients; if score normal, chance for SVR good (»60%); if patient diabetic and score >4, chance 20%; IR important predictor; study showed direct correlation between HOMA score and SVR rate (as HOMA score increases, SVR decreases); key question whether patient can achieve high SVR if IR cleared

Response to therapy in patients with coexistent steatosis: question of whether fat in liver causing blockade of re­sponse or IR or both; study found more fat in liver associated with 50% reduction in probability of SVR; large body mass index (BMI) negative predictor of response in genotypes 1, 2, 3, and 4

Metabolic syndrome: defined as waist circumference >40 in men (>35 in for women); blood pressure (BP) >130/85 mm Hg; elevated fasting blood glucose (>100 or >110 mg/dL); most likely to have nonalcoholic steatohepatitis (NASH) and underlying IR concomitant with hepatitis C; mechanism unknown, but distribution of IFN clearly plays role; diminished distribution of other drugs also seen in patients with significant truncal obesity; constant and consistent pressure on key immune processes required for effectiveness of peg-IFN (possibly blocked by too much fat); population subgroup with steatosis, obesity, and HCV end up with IR and altered immune response; patient’s response to therapy also altered by leptin; increased leptin levels seen in patients with HCV, compared to controls (possibly influenced by virus); patients also have decreased SVR; unclear whether due to altered immune response or altered hepatocyte function (end result same)

Steatosis: host-mediated  —  seen in overweight or obese patients and in alcoholics; virally-mediated  —  seen only with genotype 3; related to levels of viremia; if virus cleared with IFN, steatosis resolves; probably not same blockade to therapy seen in host-mediated steatosis; steatosis present in »50% of all patients with hepatitis C; in virally-medi­ated steatosis, core protein (NS5) in virus blocks trafficking of fat, resulting in inhibition of microsomal triglycer­ide transfer, which, in turn, reduces very low-density lipoprotein levels; treatment reduces level of core protein, resulting in reduction of virus-specific inhibition of triglyceride metabolism

High-risk populations: Latinos, obese individuals, blacks, Southeast Asians, HIV-HCV coinfected, immunosup­pressed, diabetics, and hyperlipidemics at high risk for increased steatosis in hepatitis C; cluster of poor prognostic features often seen in one patient; one of goals for new drugs to stratify results for high-risk populations; goal of drug development to offer new drug that overcomes barriers in high-risk populations with special needs; Virahep-C trial  —  400 participants (50% black, 50% white); all genotype 1 and treated with standard-of-care therapy; if virus not cleared by week 24, therapy stopped; found that blacks had statistically higher BMI and higher percentage of diabetes and hypertension; also higher incidence of metabolic syndrome, which may act as blockade to response to therapy; genetic factors (single nucleotide polymorphisms [SNPs]) identified that predict poor response in this pop­ulation; blacks  —  deposit fat differently and have less visceral fat than Latinos; possible reason why fatty liver but less fibrosis seen in blacks; rapid VR (RVR), EVR, end-of-treatment (EOT) response, and SVR rates »50% that of whites; study  —  267 Latino subjects compared to 300 non-Latino whites; treated with standard-of-care therapy; percentage of patients with BMI >27 higher in Latino group; at initiation of study, not yet known that IR negative predictor of response, so fasting glucose and fasting insulin levels not obtained; found that SVR rates in Latinos significantly lower than that of non-Latino whites, although not as poor as in blacks

Determinants of poor response: viral factors; disease characteristics; host factors; therapy generally not withheld based on weight, unless BMI >40 (morbidly obese); strategies to improve response  —  exercise and weight loss; control of comorbid conditions (eg, diabetes, hypertension, hyperlipidemia); use of antioxidants and ursodeoxycho­lic acid not beneficial; insulin-sensitizing agents; alternative dosing strategies (extending duration or increasing dose)

Insulin-sensitizing agents: study  —  looked at pioglitazone and EVR in genotype 1 patients; 10 lean and 20 obese pa­tients; lean group had good response to therapy (peg-IFN and RBV) in first 28 days; obese group had diminished response, but when given pioglitazone, caught up with lean group within 28 days, with similar reduction in viral load; question of whether starting pioglitazone early results in improved VR (large trial ongoing); study  —  looked at pioglitazone in genotype 1 patients with HOMA scores >2 (average score 5.8); group that received peg-IFN and RBV had SVR rate of 45%, EOT rate of 50%, with steatosis improved in 30%; those who received peg-IFN, RBV, and pioglitazone had better EOT response, with improvement in steatosis on biopsy seen in more patients; SVR rate same in both groups; Treatment of Naive Genotype 1 Chronic Hepatitis C Patients with Insulin Resistance (TRIC-1) trial  —  metformin vs placebo; all patients received peg-IFN alfa-2a and RBV; all had IR (mean HOMA score 4.3) and similar viral load; by week 72, SVR rate 29% in peg-IFN and RBV group (58% in metformin group); dramatic improvement and decrease in HOMA score in those who received metformin; not validated in larger trial

Suggested Reading

Afdhal NH et al: Proactive Study Group. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology. 126:1302, 2004; Berg T et al: Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 130:1086, 2006; Bowen DW et al: Blurred vision: cause? Retinopathy secondary to interferon treatment. Gut 55:211,  2006; Conjeevaram HS: Virahep-C Study Group. Peginterferon and ribavirin treatment in African American and Cauca­sian American patients with hepatitis C genotype 1. Gastroenterology 131:470, 2006; Davila JA et al: Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 54:533, 2005; Fartoux L et al: Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut 54:1003, 2005; Hick­man IJ et al: Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 51:89, 2002; Moucari R et al: Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 134:416, 2008; Omata M et al: Japanese C-Viral Hepatitis Network. A large-scale, multicentre, double-blind trial of ursodeoxycholic acid in patients with chronic hepatitis C. Gut 56:1747, 2007; Piche T et al: Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study. Gut 54:1169, 2005; Rodriguez-Torres M et al: Latino Study Group. Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C. N Engl J Med 9 360:257, 2009; Rubbia-Brandt L et al: Steato­sis affects chronic hepatitis C progression in a genotype specific way. Gut 53:406, 2004; Shah T et al: Resolution of hepa­titis C virus-induced steatosis improves tolerability of antiretroviral drugs associated with hepatotoxicity in an HIV-infected individual. J Infect Dis 197:932, 2008; Sulkowski M et al: Peginterferon alfa-2a does not alter the pharmacokinetics of methadone in patients with chronic hepatitis C undergoing methadone maintenance therapy. Clin Pharmacol Ther 77:214, 2005; Vartany E et al: Adult respiratory distress syndrome after treatment with pegylated interferon alpha-2a and ribavirin. Heart Lung 37:153, 2008.