Man With Hepatitis C Infection: Making Treatment Decisions

April 1, 2006

Infection with hepatitis C virus (HCV) was recently diagnosedin a 45-year-old man when a positive enzyme-linked immunosorbentassay was followed by a polymerase chain reaction assaythat showed a viral load of 835,000 copies/mL. The patient probablyacquired the infection when he was using intravenous heroin, a practice he quit 10 yearsago. The patient is immune to both hepatitis A and hepatitis B viruses, and there is no coinfectionwith HIV. Liver biopsy shows moderate cellular inflammation (grade 3) and bridging fibrosis(stage 3) but no evidence of cirrhosis. Iron staining shows no abnormal iron deposition in theliver. The HCV genotype is 1A.

PATIENT PROFILE


Infection with hepatitis C virus (HCV) was recently diagnosedin a 45-year-old man when a positive enzyme-linked immunosorbentassay was followed by a polymerase chain reaction assaythat showed a viral load of 835,000 copies/mL. The patient probablyacquired the infection when he was using intravenous heroin, a practice he quit 10 yearsago. The patient is immune to both hepatitis A and hepatitis B viruses, and there is no coinfectionwith HIV. Liver biopsy shows moderate cellular inflammation (grade 3) and bridging fibrosis(stage 3) but no evidence of cirrhosis. Iron staining shows no abnormal iron deposition in theliver. The HCV genotype is 1A.

WHAT WOULD YOU DO NOW?


A.

Observe patient; check liver function tests(LFTs) regularly; repeat biopsy in 3 to 5 years.

B.

Recommend therapy with interferon andribavirin.

C.

Initiate standard therapy for HCV infection andscreen periodically for hepatocellular carcinoma.

D.

Offer alternative therapy with silymarin andvitamin E.

THE CONSULTANT'S CHOICE

Based on the liver biopsy results, the best choicehere is

B.

A biopsy provides 2 pieces of information thatare key to establishing a prognosis and making therapeuticdecisions: the grade of inflammation and the stage offibrosis. Because morbidity and mortality in HCV infectionare largely the result of cirrhosis, the extent of fibrosisis invaluable in estimating prognosis.

1

The grade of necroinflammatory activity is determinedby 2 parameters: the severity of periportal inflammationand the degree of parenchymal necrosis (Table 1).There is a 1.2% annual risk that cirrhosis will develop inpatients with mild inflammation. In those with moderateinflammation, this risk rises to 4.6% annually, and to 90%within 20 years of biopsy.

2

Cirrhosis develops within 10years in nearly all patients with severe inflammation.

2

 Table 1 - Histologic grading of chronic hepatitis C
Grade Histologic description

0 Inflammation is absent

1 Inflammation is confined to the portal tract

2 Both periportal (interface) inflammation and parenchymal injury are mild

Data from Rosenberg PM. Clin Infect Dis. 2001.

The stage of fibrosis is determined by Masson trichromestain (Table 2). On average, the condition progresses1 stage every 4 years in patients with HCV infection.

3

Those with HCV infection and compensated cirrhosishave a good prognosis (a 10-year survival rate over80%

4

); once complications of cirrhosis develop, however,the 5-year survival rate falls below 50%.

5

It may be reasonable to observe patients with mildinflammation and no fibrosis. This can be done by checkingaminotransferase levels regularly and repeating liverbiopsy in 3 to 5 years.

6,7

However, our patient has moderateinflammation and bridging fibrosis. There is a highlikelihood that his disease will progress to cirrhosis in thenext decade. Thus, it is appropriate to recommend therapywith interferon and ribavirin.Unless contraindicated, treatment is recommended forall patients in whom biopsy reveals at least grade 2 inflammationand stage 1 fibrosis. However, patients with decompensatedcirrhosis should not be treated.

1,8,9

(Treatment maybe of benefit to some patients with subclinical cirrhosis.)

 Table 2 - Histologic staging of chronic hepatitis C
Stage Histologic description

0 No fibrosis

1 Fibrous portal tract expansion

2 Periportal fibrosis

3 Bridging or septal fibrosis

4 Cirrhosis

Data from Rosenberg PM. Clin Infect Dis. 2001.

Hepatocellular carcinoma develops almost exclusively inpatients with cirrhosis--and at a rate of 1% to 4% per year.

10

Consequently, periodic screening with serum alpha-fetoproteinmeasurements and ultrasonography of the liver every 6to 12 months has been advocated in patients with HCV cirrhosis--despite the lack of long-term studies showing costeffectiveness.

11

However, our patient's disease has not yetprogressed to cirrhosis, making such screening unnecessary.The patient inquired about nonprescription therapiesfor HCV infection. Silymarin (milk thistle) is reported topossess antioxidant properties and is commonly used bypatients with HCV infection. Althoughtheoretically beneficial in preventingfibrosis, long-term data are limited.

12

Vitamin E may improve fibrinogenesisand decrease serum transaminaselevels.

13,14

However, there is far too littlesupportive evidence to recommendeither of these as sole therapy for apatient with serious liver disease.

ADVERSE EFFECTS OFINTERFERON AND RIBAVIRIN

It is understandable that patientsfrequently inquire about alternativetreatments for HCV infection;interferon-œ and ribavirin can havevery serious adverse effects (Table3). In fact, such effects are seriousenough to necessitate withdrawalfrom therapy in up to 15% ofpatients.

15,16

It is important to discussthese with patients and to make surethere are no preexisting conditionsthat militate against therapy with eitherinterferon or ribavirin. Suchconditions include severe anemia,ischemic heart disease that may beworsened by anemia, renal insufficiency(creatinine clearance below50 mL/min), untreated or severedepression, coexisting autoimmunehepatitis (which may worsen withinterferon therapy), and pregnancyor the possibility of becoming or causing someone tobecome pregnant.

 Table 3 - Side effects of treatment with interferon-α and ribavirin
Frequency of side effects Interferon-α Ribavirin

> 30% (very common) Influenza-like symptoms Headache Fatigue Fever Rigors Myalgia Thrombocytopenia Induction of autoantibodies Hemolysis Nausea

1% – 30% (common) Anorexia Erythema at injection site Insomnia Alopecia Lack of motivation Inability to concentrate Irritability Emotional lability Depression Diarrhea Induction of autoimmune disease Leukocytopenia Taste perversion Anemia Nasal congestion Pruritus

< 1% (rare) Polyneuropathy Paranoia or suicidal ideation Diabetes mellitus Retinopathy Optic neuritis Hearing impairment Seizures Loss of libido Cardiotoxicity Gout

Data from Lauer GM, Walker BD. N Engl J Med. 2001.

Common side effects of interferon-œ include influenza-like symptoms, headache, fatigue, fever, myalgias, exacerbationof underlying autoimmune disease, reversiblealopecia, elevated uric acid, glucose intolerance, and cytopenias.Both hyperthyroidism and hypothyroidism mayoccur and are, at times, irreversible.

17

Ophthalmologic disorders(vascular thrombosis, hemorrhages, or cotton-woolspots) have also been reported,

18

and patients who are atrisk for retinal disease (such as those with diabetes or hypertension)need a baseline retinal examination.Psychiatric sequelae occur in at least 20% of patientstreated with interferon and can include irritability, emotionallability, depression, and even suicidal ideation.

19

These effects may represent exacerbation of antecedentpsychiatric disease or new problems; in either case theymay persist, even after interferon is discontinued. Considera pretreatment psychiatric consultation for any patientwith a history of psychiatric illness or substance abuse, afamily history of psychiatric disease, or other risk factorsfor depression (such as multiple comorbidities or use ofmedications that predispose to depression).Ribavirin often causes hemolysis, with decreases inhemoglobin levels of 2 g/dL to 4 g/dL. This complicationusually occurs in the first month of therapy. Other effectsinclude pruritus, nausea, and nasal congestion. Ribavirincan cause fetal abnormalities and must not be used by eithermen or women who cannot use reliable birth controlduring treatment and for at least 6 months thereafter.

15

A thorough history reveals no conditions in ourpatient that would contraindicate use of either interferonor ribavirin. Baseline thyroid-stimulating hormone(TSH) level, creatinine level, and results of a completeblood cell (CBC) count are normal. After discussingpotential adverse effects, the patient agrees to starttherapy.

WHAT WOULD YOU DO NOW?


A.

Initiate a 48-week course of interferon.

B.

Initiate a 24-week course of interferon andribavirin.

C.

Initiate a 48-week course of interferon andribavirin.

D.

Measure viral load; use this figure todetermine length of treatment regimen.

THE CONSULTANT'S CHOICE

The optimal choice here is

C.

Interferon alone producessustained response rates of just 10% to 20%

20,21

and,therefore, is indicated as monotherapy only in patientswith contraindications to ribavirin.The duration--and efficacy--of combination therapyare determined by a patient's HCV genotype, of whichthere are at least 6 distinct types. Genotypes 1, 2, and 3are found most often in the United States; genotype 1 isthe most common. Genotype 4 is largely confined to theMiddle East and northern Africa, genotype 5 to SouthAfrica, and genotype 6 to Asia.

22

Genotype is the most important predictor of responseto therapy. Patients infected with genotype 1 have a sustainedresponse rate (persistently normal aminotransferaseconcentrations and absence of viral RNA at the end oftherapy and for at least 6 months thereafter) approximatelyhalf that of patients infected with other genotypes.Genotype also affects the length of therapy. Patientsinfected with genotype 2 or 3 can be treated successfullywith 24 weeks of therapy. In those with genotype 1 infection,the percentage who demonstrate sustained responsecan be doubled by extending the duration of therapyfrom 24 to 48 weeks. A 48-week course of therapy is thereforerecommended for our patient, who is infected withgenotype 1A.Some studies have shown that patients with higherpretreatment viral loads may respond better to longertreatment regimens. However, because viral load fluctuatesover time and because assays of viral load are notstandardized, this variable is not currently used to determinelength of therapy.

8

DRUGS AND DOSAGES

Combination therapy with interferon and ribavirin remainsthe standard of care for patients with HCV infection.Ribavirin, an oral nucleoside analogue, is activeagainst RNA and DNA viruses. Although it has little effectas monotherapy, it augments the efficacy of interferon.Pegylated interferon, which is created by attachinga molecule of polyethylene glycol to interferon, resultsin better bioavailability, a longer half-life, and better responserates than conventional interferon. Pegylated interferonwas approved by the FDA as monotherapy forhepatitis C in January 2001 and as combination therapywith ribavirin in August 2001. Sustained virologic andhistologic response to pegylated interferon monotherapyis superior to that seen with standard interferon andsimilar to that seen with standard interferon/ribavirintherapy.

23-25

However, since ribavirin also augments the effect ofpegylated interferon, combination therapy with these 2agents is the treatment of choice unless contraindicated.The average sustained response rate for conventional interferon/ribavirin is 40%; for pegylated interferon/ribavirin,60%. Patients infected with genotypes 2 and 3 havea sustained response rate with pegylated interferon/ribavirinas high as 88%; those infected with genotype 1 havea response rate of 48%.

26-28

Our patient can expect a sustainedresponse rate of 30% to 50%, depending on thetype of interferon used.The standard dosing regimen for conventional interferonis 3 million units subcutaneously 3 times per week;for pegylated interferon, 1.5 µg/kg subcutaneously onceweekly. Ribavirin is taken orally; 1200 mg/d for patientswho weigh at least 75 kg, and 1000 mg/d for those whoweigh less than 75 kg.

Our patient has begun therapy with conventionalinterferon (pegylated interferon was not available) andribavirin.

WHAT WOULD YOU DO NOW?


A.

Check CBC count, LFTs, and TSH regularly.

B.

Screen for depression regularly; also checkCBC count, LFTs, TSH, and viral load on aregular basis.

C.

After 24 weeks, screen for depression andcheck CBC count, LFTs, TSH, and viral load.

D.

Screen for depression regularly; checkCBC count, LFTs, and TSH on a regular basis;check viral load after 24 weeks.

THE CONSULTANT'S CHOICE

The best choice is

D.

Carefully monitor all patientswho are taking interferon and ribavirin--both to assurecompliance with therapy and to check for adverse reactions.Regular screening for depression using standard instruments(Beck Depression Inventory, Zung Self-RatingDepression Scale) is mandatory. If a patient shows signs ofdepression, selective serotonin reuptake inhibitors (SSRIs)may be appropriate. Because of the possible role of interferonin serotonin metabolism, SSRIs are the medicationsof choice for interferon-related depression.

19

Other optionsinclude the diminution or cessation of interferon therapy.Check CBC and LFTs at 1, 2, and 4 weeks, andmonthly thereafter. Measure TSH levels after 8 weeks oftherapy.It is also important to measure viral load after 24weeks of therapy. A detectable viral load at this time is areliable predictor of lack of response to a longer courseand allows for cessation of therapy.

8

Our patient reports flu-like symptoms after 8 weeksof treatment. At this time, his hemoglobin level hasdropped from a pretreatment level of 13.1 g/dL to 10.8g/dL, and he complains of mild exercise intolerance.

WHAT WOULD YOU DO NOW?


A.

Keep all dosages constant and continue tomonitor patient.

B.

Reduce dosage of ribavirin and continue tomonitor.

C.

Reduce dosage of both ribavirin and interferonand continue to monitor.

D.

Discontinue ribavirin.

THE CONSULTANT'S CHOICE

The wise choice here is A. Ribavirin frequently causeshemolytic anemia. In up to 10% of patients, the situationis serious enough to necessitate a reduction in dosage.

16

However, a reduction in ribavirin dosage is associatedwith a decreased virologic response

29

; thus, it is appropriateto reduce the dosage or discontinue the drug altogetheronly when necessary. A reduction in ribavirin dosageto 600 mg/d is advised when hemoglobin levels decrease2 g/dL or more over a 4-week period in patients with cardiacdisease, or when the level drops to less than 10 g/dLin all others.

30

Erythropoietin can limit ribavirin-associatedanemia and enable some patients to continue with thestandard dosage.

31

Permanent discontinuation of ribavirin may be necessaryin patients with cardiovascular disease whose hemoglobinlevel is persistently below 12 g/dL or in anyonewhose hemoglobin level is consistently below 8.5 g/dL.Flu-like symptoms are very common in patients receivinginterferon therapy. They usually abate as therapycontinues, and their presence does not justify a reductionin dosage or discontinuation of the medication.

Our patient remained on his initial treatmentregimen, and his hemoglobin level remained stable(without intervenion) for the duration of therapy. Aviral load measurement taken after 24 weeks revealedundetectable levels of HCV. The patient successfullycompleted 48 weeks of treatment, and a viral load measurementtaken 6 months post-treatment also showedundetectable levels.

In those who demonstrate a sustained virologic response,as our patient did, infection recurs in fewer than10% of patients during the subsequent 5 to 10 years. Histologicinjury also appears to improve over time.

32,33

References:

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