Hepatitis c Rev

8/14/2019 Hepatitis c Rev

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OCTOBER 2007 20(10) www.jaapa.com JAAPA 21

EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 42 and successfullycompleting the posttest on page 49. Successful completion is defined as a cumulative score of at least 70%correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME creditby the AAPA. The term of approval is for 1 year from the publication date of October 2007.

LEARNING OBJECTIVES Outline the epidemiology of hepatitis C, how it is transmitted, and what can be done to prevent it Describe the natural history, clinical presentation, and diagnosis of hepatitis C Discuss the standard of care for hepatitis C, how the disease is monitored, and what other

therapeutic options might become available

CME

Hepatitis C virus infection:A current reviewThe standard therapy for hepatitis C cures 40% to 50% of infections, but new treatmentsnow being studied in clinical trials may improve these numbers.

Douglas L. Senecal, PA-C; Joseph Morelli, MD

Hepatitis Cthe disease caused by infectionwith the hepatitis C virus (HCV)is the num-

ber one indication for liver transplantationand one of the most common causes ofchronic liver disease worldwide.1,2 HCV is a

positive, single-stranded RNA virus in the Flaviviridae familythat is transmitted through parenteral exposure. The virusdirectly infects the hepatocyte yet is proposed to be noncyto-pathic; hepatic parenchymal damage occurs as a conse-quence of the hosts immune response and subsequent devel-opment of an inflammatory infiltrate, as seen in Figure 1.HCV was first isolated in 1989; before this occurred, sero-logic evaluation for the virus was impossible, leaving peopleexposed to blood products at risk for infection. Fortunately,testing techniques have now evolved to the point that evenvery small levels of virus can be detected. Eleven HCVgenotypes have been identified, with prevalence dependingon geographic location. In the United States, genotypes 1, 2,3, and 4 are most common, with genotype 1 comprising 75%of US infections.2,3

Todays standard therapy, pegylated interferon combinedwith ribavirin, offers an overall cure rate of approximately40% to 50%.4,5 However, specifically targeted antiviral thera-pies, such as the protease and polymerase inhibitors now inclinical trials, may improve on the current standard of care.Because hepatitis C is being diagnosed more frequently andthe treatment regimens are complex, PAs play an integralrole in providing care.

EPIDEMIOLOGY AND PREVENTION

The CDC has estimated that 3.9 million Americans havebeen exposed to HCV and that 2.7 million Americans have

active chronic HCV infection.2,3 An estimated 26,000 infec-tions are acquired each year, and the 10,000 to 12,000 yearlydeaths occur in those whose infections progress to cirrhosisor hepatocellular carcinoma (HCC).2,3 Risk factors for HCVtransmission that should prompt screening at the primarycare level are listed in Table 1 (page 22).

As with all infectious diseases, prevention of viral transmis-sion is key. Some experts have suggested that sharing tooth-

brushes and razors poses greater risk than does monoga-

FIGURE 1. This liver biopsy specimen from a patient with

chronic hepatitis C shows an inflammatory infiltrate around the

portal tract.


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mous heterosexual intercourse. Sexual transmission hasundergone much scrutiny, however, as studies have quotedanywhere from 2% to 22% infection rates, depending onsexual practices.6,7 The American Association for the Studyof Liver Diseases (AASLD) states that sexual practices neednot be altered in monogamous heterosexual couples, as therisk of infection is minimal.6 However, advising couples touse barrier protection is reasonable.

NATURAL HISTORY

The natural history of HCV infection guides patient educa-tion and influences the decision of whether a patient shouldundergo therapy. In patients infected with HCV, 10% to 20%will have spontaneous clearance and chronic infection willdevelop in the other 80% to 90%.8 The chronic infection willprogress to cirrhosis (over a period of 20 to 30 years), inapproximately 20% to 30% of patients.8 The progression offibrosis is more rapid in patients who are older at the time ofinfection, nonwhite, infected with HIV, have hepatic steato-sis, or consume alcohol.9 Studies have shown that viral loaddoes not predict disease progression and can fluctuate as

22 JAAPA OCTOBER 2007 20(10) www.jaapa.com

CME Hepatitis Cmuch as one log in a days time, making this marker anunreliable gauge of disease progression.9 Serial testing ofquantitative HCV RNA is not recommended outside of thetreatment setting.

The natural history of patients with HCV-induced cirrho-sis is quite alarming. Once this condition has been diag-nosed, the risk is as high as 3.9% per year that decompensa-tion of underlying cirrhosis will occur and be accompanied

by HCC, ascites, bleeding from varices, jaundice, hepaticencephalopathy, or renal/pulmonary dysfunction.10 Fortu-nately, only 20% to 25% of all patients with cirrhosis willever decompensate and require transplantation.10 When de-compensation does occur, the overall 5-year survival is ap-proximately 50%, and recent studies show the major causeof death in this population to be HCC.10 Because the riskfor HCC is relatively high, screening patients with cirrhosisevery 6 to 12 months with abdominal imaging and alpha-fetoprotein levels is recommended.11,12

CLINICAL PRESENTATION AND DIAGNOSIS

Hepatitis C has historically been a silent disease, and mostpatients with acute infection do not present with the symp-toms or extrahepatic effects listed in Table 2. Patientswho have established cirrhosis are more commonly symp-tomatic because of the manifestations of advanced liverdisease.13

Acute hepatitis C The incubation period of HCV is 2 to26 weeks, and only about 20% of patients with acute HCVinfection develop clinical signs and symptoms.14 Serum HCVRNA has been found to be the most sensitive marker ofacute infection, and the level will be positive 7 days to 8weeks after infection (often well before antibody production

begins, which occurs approximately 50 days after infec-tion).14 Nevertheless, an HCV antibody test should beordered along with testing for HCV RNA to ensure that thepatient did not have pre-existing chronic hepatitis with anoth-er acute hepatitis superimposed. Acute HCV infection isdefined by a positive result on HCV polymerase chain reac-tion (PCR) testing two times in a row.15 Spontaneous clear-ance is represented by a negative result on PCR testing per-formed monthly for 3 months, along with formation ofHCV antibodies.15

Medical knowledge

Interpersonal & communication skills

Patient care

Professionalism

Practice-based learning and improvement

Systems-based practice

KEY POINTS Hepatitis C is the number one indication for liver transplantation and one of the most com-

mon causes of chronic liver disease worldwide.

Understanding the natural history of HCV infection is paramount because this understanding

guides patient education and influences therapy.

Most acute HCV infections go unnoticed; the viral incubation period is between 2 and 26 weeks,

and only about 20% of patients with acute infection develop clinical signs and symptoms.

The standard definition of chronic HCV infection is the persistence of HCV RNA in the serum

for longer than 6 months.

Therapy with pegylated interferon combined with ribavirin offers an overall cure rate of

approximately 40% to 50%; rates are higher for some genotypes of HCV. Specifically target-

ed antiviral therapies, now in clinical trials, may improve on the current standard of care.

COMPETENCIES

TABLE 1. Risk factors for hepatitis C

Birth to a mother with positive antibodies for HCV

Blood transfusion before 1992

Hemodialysis

History of cocaine use

History of tattoos

IV drug use

Multiple sexual partners

Needlestick or mucosal exposure (in a health care worker)

Organ transplant before 1992

Sex with an HCV-infected patient

Treatment with clotting factor for hemophilia before 1987

Unexplained elevations of liver enzymes


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Continued on page 24

Chronic hepatitis C The standard definition ofchronicHCV infectionis the persistence of HCV RNA in the serumfor longer than 6 months. Initial HCV antibody testing isusually prompted by a history of risk factors or elevated liver

enzymes. Unfortunately, false-negative results are often seenin patients undergoing hemodialysis or in immunocompro-mised patients; furthermore, those who spontaneously clearthe virus will still produce antibodies to HCV.14 In eithercase, confirmatory testing with quantitative HCV RNAwould be preferred over a qualitative test because responseto therapy can be predicted based on viral load along withother factors such as HCV genotype.16

MANAGEMENT

In patients with acute infection, the benefits of treatmentalmost always outweigh the risk, but patients with confirmedHCV infection should be assessed for the relative barriers totreatment noted in Table 3. Next, the HCV genotype and

potential duration of infection should be determined; thisinformation will indicate whether obtaining a liver biopsy willyield information that will affect the decision to treat. Severalsubgroups of patients, such as those infected with genotypes 2or 3 and patients with clinical findings of cirrhosis, may notrequire liver biopsy as it will rarely influence management.Most would agree that patients infected with HCV genotypes2 and 3 should undergo therapy unless there are major barri-ers to treatment. On the other hand, patients infected withHCV genotype 1 with relative barriers to therapy may benefitfrom liver biopsy, which allows the provider to tailor the deci-sion to treat based on the histologic findings. For instance, apatient with advanced fibrosis on biopsy should have aggres-sive therapy to halt disease progression, whereas a patientwith minimal disease has the option of awaiting more effica-cious therapies with fewer side effects.

Some investigators are looking into the efficacy of measur-ing fibrosis using noninvasive methods. Serologic assays have

been found to be helpful only when fibrosis is either minimalor advanced; their predictive value for patients with middle-stage fibrosis is poor.17 Ultrasound elastography is currently

being investigated as another assessment tool, but factorssuch as body mass index and ascites appear to limit its sensi-tivity and specificity.18

Once the appropriate data have been considered and thedecision to treat has been made, patients should be coun-seled on treatment side effects and be reassured that all sideeffects will regress once medications are withdrawn. The sideeffects associated with pegylated interferon are fatigue, low-grade fever, myalgia, arthralgia, headache, hair loss, diarrhea,and weight loss. The side effects associated with ribavirin areheadache, pruritus, rash, and cough. These side effects canoften be minimized if the patient is premedicated with aceta-minophen and/or diphenhydramine and remains well hydrat-ed throughout therapy. The potential adverse events notedin Table 4 should be emphasized so the patient is aware ofassociated risks before committing to therapy.


TABLE 2. Signs and symptoms of hepatitis C

Anorexia

Arthralgia

Autoimmune thyroiditis

Essential mixed cryoglobulinemia

Fatigue

Leukocytoclastic vasculitis

Membranoglomerulonephritis

Myalgia

Nausea

Polyarteritis nodosa

Porphyria cutanea tarda

Right upper quadrant pain

TABLE 3. Relative barriers to treatment

Active substance abuse

Adherence issues

Baseline hematologic abnormalities

Established cirrhosis

Financial issues

Pre-existing autoimmune disease

Social support concerns

Uncontrolled psychiatric disease

Uncontrolled thyroid disease

TABLE 4. Adverse events associated with therapy

Anemia

Cardiac decompensation

Decompensation of underlying cirrhosis

Exacerbation of autoimmune disease

Exacerbation of thyroid disease

Neutropenia

Pancreatitis

Pulmonary toxicity

Retinal disease

Thrombocytopenia

Worsening psychiatric disease


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Therapy Pegylated interferon is available in two forms,peginterferon alfa-2a, which is initiated at a fixed dosage of180 mcg/wk SC, and peginterferon alfa-2b, which is dosed at1.5 mcg/kg/wk SC. Contraindications to these agents include

decompensated cirrhosis, an absolute neutrophil count lessthan 1,000 cells/L, a platelet count less than 50,000 cells/L,severe depression, active substance abuse, retinopathy, anduntreated autoimmune or thyroid disease. For patients infect-ed with HCV genotypes 1, 4, 5, or 6, ribavirin is dosed at1,000 mg/d for those weighing less than 75 kg and at 1,200mg/d for those weighing more than 75 kg. For patients infect-ed with HCV genotypes 2 or 3, ribavirin is dosed at 800mg/d regardless of weight. Contraindications to ribavirin area hemoglogin less than 10 g/dL, coronary artery disease,renal insufficiency, and active or potential pregnancy. If preg-nancy might occur during or 6 months following therapy,two modes of contraception should be used.

The current AASLD guidelines for acute HCV infection

suggest treatment with full-dose pegylated interferon mono-therapy for 6 months after the patient has been given 2 to 4months to spontaneously clear the virus and has not doneso.19,20 With this therapy, rates of curecalled a sustained viro-logic response (SVR)have been cited at 81% to 91%.19,20

The current therapeutic regimen for chronic HCV infec-tion is derived based on genotype. For infection with HCV

24 JAAPA OCTOBER 2007 20(10) www.jaapa.com

CME Hepatitis Cgenotypes 1, 4, 5, or 6, the current regimen consists of pegy-lated interferon and weight-based ribavirin for 12 weeks, atwhich time HCV RNA should be measured to assess forearly virologic response (EVR) (EVR is defined as a two-log

drop from baseline). Should the patient achieve an EVR,then therapy should be continued for a total of 48 weeks.4,5

Those who have not achieved an EVR at 12 weeks have aless than 3% chance of achieving SVR and should be takenoff therapy.4,5 Once therapy is complete, HCV RNA testingis done to assess whether an end-of-treatment (EOT) re-sponse has been achieved; this is defined by a negative HCVRNA at the end of therapy. Lastly, HCV RNA should bemeasured 24 weeks later to assess for SVR. After 48 weeksof therapy, the estimated SVR for genotype 1 patients isapproximately 50%4,5 (see the algorithm).

For infections with HCV genotypes 2 or 3, the currentstandard of care is 24 weeks of pegylated interferon and non-weight-based ribavirin. HCV RNA is measured at EOT and

24 weeks after EOT to assess for SVR, which is achieved inapproximately 76% to 81% of patients.4,5

For treatment of patients with both hepatitis C and HIVinfection, the same regimens are used, bearing in mind thatthese patients have a lower SVR.21-23 Before treatment isstarted, HIV disease must be well-controlled, as evidenced

by suppressed viremia and a CD4+ cell count of greater

ALGORITHM. Treatment of hepatitis C

Check HCV RNA at EOT and 24 weeksafter therapy to assess for SVR

Key: EOT, end of treatment; HCV, hepatitis C virus; SVR, sustained virologic response.

HCV infection confirmed with HCV RNA

Determine HCV genotype and viral load

Genotypes 1, 4, 5, 6 Genotypes 2, 3

Treat for 12 wk with pegylated interferonand weight-based ribavirin

Treat for 24 wk with pegylated interferonand ribavirin, 800 mg/d

2 log drop

Continue therapy to48 wk


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than 250 cells/L. In patients receiving highly active anti-retroviral therapy, screening for drug interactions beforetreatment and monitoring during treatment are essential.

Monitoring Baseline studies prior to therapy should include

a CBC with differential, AST, ALT, alkaline phosphatase,total bilirubin, albumin, thyroid-stimulating hormone, freethyroxine, prothrombin time/international normalized ratio,

beta-human chorionic gonadotropin in women, and quantita-tive HCV RNA with HCV genotyping. Once baseline valuesare established and therapy is initiated, patients should have

blood drawn for a CBC twice a week for the first 8 weeks; ifno cytopenia is noted, a monthly CBC should suffice. Every3 months, liver and thyroid function should be assessed.

Patients who experience aggressive cytopenia should beconsidered for dose reduction or treatment with epoetin alfaor filgrastim. A dose reduction of pegylated interferon is rec-ommended when the WBC count drops to less than 1,500cells/L or the absolute neutrophil count drops to less than

750 cells/L. Bone marrow stimulation with filgrastim is initi-ated when the WBC count drops to less than 1,000 cells/Lor the absolute neutrophil count drops to less than 500cells/L. The dosage of filgrastim is 300 mcg 1 to 3 timesweekly, depending on hematologic response, with a goal of anabsolute neutrophil count greater than 1,000 cells/L. Dosereduction of ribavirin is recommended when the hemoglobindrops more than 2 g/dL in a 4-week period. Bone marrowstimulation with epoetin alfa is initiated at 40,000 units andtitrated up to 60,000 units every 7 to 10 days, depending onresponse. Therapy is initiated if the hemoglobin drops to lessthan 11 g/dL or falls more than 3 g/dL from baseline. Thetarget hemoglobin is in the range of 10 to 12 g/dL.

POTENTIAL NEW THERAPIES

The most promising new therapies for hepatitis C are theprotease/polymerase inhibitors, which are currently undergo-ing clinical trials. Additional compounds being studied in-clude a ribavirin analog, taribavirin, to address the hemolyticanemia associated with standard ribavirin and longer-actinginterferon; and albumin-interferon alpha, which will offer

biweekly as opposed to weekly dosing of interferon.24,25

Although supporting data are limited, the clinician maysometimes find it appropriate to tailor therapy based on rapidvirologic response(RVR), defined as a negative HCV RNAafter 4 weeks of therapy.26 Some clinicians are using longercourses of therapy in patients with genotype 3 HCV infec-tion and a high viral load, or in patients with genotypes 1 or3 HCV infection who do not obtain an RVR. Studies to sup-port this have been done for genotype 1, but there are nodata for genotype 3.26 Additionally, shortening therapy ingenotype 2 and 3 patients who have an RVR has been ex-amined, but the data have yet to be evaluated and confirmedin large, controlled trials.27 JAAPA

Douglas Senecal and Joseph Morelli practice in the Department of

Hepatology, University of Florida College of Medicine, Gainesville. They have

indicated no relationships to disclose relating the content of this article.


DRUGS MENTIONEDAcetaminophen Peginterferon alfa-2a (Pegasys)Albumin-interferon alpha (Albuferon)* Peginterferon alfa-2b (PEG-Intron)Diphenhydramine Ribavirin (Copegus, Rebetol)Epoetin alfa (Epogen, Procrit) Taribavirin (Viramidine)*

Filgrastim (Neupogen) *Investigational agent

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