A decade has passed since the cloning of the hepatitis C virus (HCV). 1 During this period, an incredible wealth of data has steadily accumulated concerning this world-wide infection, relating to its natural history and to its frequently dreadful consequences. At the same time, significant progress has been made in its management, initially through interferon monotherapy and, more recently, with the recommended systematic use of combination therapy involving interferon and ribavirin.
Keeping abreast of the exponentially accumulating literature has proved to be a formidable task, which has been led to several consensus conferences over the last five years. 2-5 In order to provide the Canadian medical community with the most up-to-date, judicious, evidence-based guidelines on the management of HCV, the Canadian Association for Study of the Liver (CASL) sponsored the 1999 Canadian Consensus Conference on the Management of Viral Hepatitis. In this edition of Hepatitis Update, I will present an all-too-common clinical scenario that will illustrate some of the broader guidelines and key recommendations concerning hepatitis C.
- 1 Clinical Presentation
- 2 Where do I stand? What will become of me?
- 3 Do I need a liver biopsy? What about getting an HCV RNA test?
- 4 What do you intend to use to treat me? What are the odds that therapy will be successful?
- 5 If I am treated with combination therapy, what can I expect? How much sicker will this make me before I get better?
- 6 Might I have unknowingly infected my husband and daughter?
- 7 Conclusion
A 31-year-old female legal secretary was found to have an elevated ALT of 2.1 times normal values on routine testing for life insurance purposes. Her history included a rather liberal early adulthood during which she had several different sexual partners, and used nasal and intravenous cocaine for a year. She married a successful young attorney five years ago and gave birth to a healthy daughter two years later.
She acknowledges slight fatigue, which she attributes to her busy work and homekeeping schedule. Otherwise, she has always enjoyed excellent health. She uses oral contraceptives and has two or three glasses of wine with dinner, three or four nights a week. Physical examination is unremarkable.
Further investigation performed by her family physician showed normal results for CBC, INR, albumin, total protein, creatinine and electrolytes, ANA, SMA, and abdominal ultrasound. Negative results were found for HBV and HIV while anti-HCV gave positive results on both EA-2 and confirmatory RIBA testing. Repeated measurements of ALT monthly, during the past three months, have shown values ranging from 1.8 to 2.6 times the upper limit of normal. She is now referred for consideration of further investigation and treatment.
While awaiting her referral appointment, she has read all of the information she could find on hepatitis C and has drawn up a list of questions she wishes to address.
Where do I stand? What will become of me?
Much accumulated experience with the natural history of HCV has, unfortunately, still not produced a reliable crystal ball. Although we cannot adequately predict which patients will do so, we do know that, over a matter of one or more decades, between 20% and 50% of patients with chronic hepatitis C will go on to develop cirrhosis. 6-13 The recognized risk factors for progression to cirrhosis are acquisition of infection after 40 years of age, male gender, consumption of even social amounts of alcohol 14-16 and evidence of significant inflammation or fibrosis on liver biopsy (see Table 1), 17-19 Once cirrhosis has developed, the estimated ten-year survival rate is 80% if liver function remains compensated. However, the odds of decompensation with ensuing complications during this same ten-year period are up to 40%. 12 Should that happen, the survival rate diminishes to 50% over the next five years. Furthermore, cirrhotics develop hepatocellular carcinoma, at a rate of 1% to 4% per year. 11-12
Recognized Risk Factors for Progression to Cirrhosis
– Acquisition of infection after 40 years of age
– Male gender
– Consumption of even “social” amounts of alcohol
– Significant inflammation or fibrosis on liver biopsy
Do I need a liver biopsy?
What about getting an HCV RNA test?
A liver biopsy is strongly recommended prior to institution of treatment, as it is the only reliable means of assessing how far along a patient is in the disease process. Should an adequately representative biopsy (showing at least 3 to 5 portal tracts) demonstrate only minimal or no inflammation or fibrosis, it may be appropriate to consider postponing treatment.
Testing for HCV RNA should be done in anti-HCV positive patients with repeatedly normal ALT levels. It is also useful to obtain such testing in immunosuppressed patients with unexplained elevated enzymes, as they could have a falsely negative anti-HCV test. However, in typical anti-HCV patients, it is neither essential nor necessary to proceed to either qualitative (Roche Amplicor TM or quantitative (Chiron Quantiplex TM bDNA, National Genetics Institute SuperQuant TM ,Roche Amplicor TM HCV Monitor TM ) HCV RNA testing prior to treatment. In typical cases, the odds of positive qualitative testing are so great that it is deemed superfluous to proceed to this test. As for quantitative assessment of the viral load, although offering some prognostic value, 20 the result will not alter the decision to treat a given patient, no matter how elevated the initial viral load may be.
HCV RNA testing will nonetheless eventually be required. Clearance of HCV RNA will, more definitely than the ALT levels, be the parameter defining therapeutic success. Such testing will first need to be performed after 24 weeks of combination treatment: persistence of detectable HCV RNA at that time would indicate treatment failure and justify terminating treatment. HCV RNA testing will also need to be performed six months after the end of planned duration of treatment. A negative result will thus define successful therapy.
What do you intend to use to treat me?
What are the odds that therapy will be successful?
After many years of relying on interferon monotherapy as the only treatment option available, recent studies have clearly shown that the combined use of interferon alpha 2b (3 mu T1W) and ribavirin has greatly improved the odds of successful therapy. 20-22 Ribavirin, a guano sine analog, is given orally in a dose of 1000 mg for patients weighing less than 75 kg. Or 1200 mg for heavier patients. The overall sustained response rate in naïve patients is in the order of 40%, more than twofold better than can be achieved using interferon monotherapy (see Figures 1 & 2). Interferon monotherapy is now reserved for ribavirin intolerate patients.
Both the duration of treatment and the odds of successful therapy are related to the genotype of HCV virus. Patients with genotypes 2 or 3 stand about a 65% chance of attaining sustained response and need to be treated for only 24 weeks. 20, 22 In contrast, patients with genotype 1 have a 30% sustained response rate and require 48 weeks of combination therapy, as do patients with genotypes other than 2 or 3. 20, 22 It therefore stands to reason that genotyping must be made available to patients before therapy starts, so that the treatment can be planned.
Superior efficacy of combination therapy has also been demonstrated in an international study of interferon monotherapy relapsers that showed an overall, highly significant, 49% sustained response rate following 24 weeks of combination therapy. 23 An analysis of individual patient data, from six controlled trials comparing interferon monotherapy (147 patients) vs combination therapy (197 patients) for a period of six months, has also demonstrated definite superiority of combination therapy in sustained response rates achieved in previously untreated patients, without or with cirrhosis, be they of genotype 1 or of genotypes 2 or 3. 24 Clinically relevant superiority was also seen in interferon monotherapy relapsers and nonresponders (although the response to combination therapy in monotherapy nonresponders is still just 6% in genotype 1 and 21% in genotype 2 or 3). 24
Data is accumulating suggesting that sustained responders enjoy a durable response for a number of years. Not only do the ALT levels return to normal, but responders also have a lower rate of cirrhosis and of hepatocellular carcinoma, as well as improved survival, 25-26 Unfortunately, there are currently no proven treatment options for those patients who fail on combination therapy. Newer therapeutic agents – protease and helicase inhibitors, dominant negative mutants, ribozymes, or antisense nucleotides – may, in the future, provide a valid alternative in these cases.
If I am treated with combination therapy, what can I expect?
How much sicker will this make me before I get better?
The Clinical Presentation on page 1, profiles a candidate with an ALT level greater than 1.5 times the upper limit of normal (ULN) on at least three consecutive monthly measurements. As well, the list of indications (see Table 2) and contraindications (see Table 3) suggests treatment, providing that the impending liver biopsy shows significant inflammation and/or fibrosis.
It is important that patients be highly motivated to undergo treatment, as their determination and cooperation will be crucial. Throughout the treatment they must abstain completely from any alcohol intake, and maintain stringent contraceptive measures during their treatment and for at least six months following. It is imperative that both men and women use effective contraception as ribavirin is potentially teratogenic.
Patients are expected to comply with an established follow-up schedule of once weekly visits and blood work, which can be reduced to monthly following the first four weeks. As well, patients should be made aware of the myriad side effects possible with ribavirin and interferon therapy, and should be advised to inform their physician of any overt symptoms or depressive feelings. Fatigue will be the number one battle these patients face, and they should be encouraged to anticipate significantly less energy than they have experienced.
Might I have unknowingly infected my husband and daughter?
Based on a very thorough review of the literature, 28 and on some even more recent data, 29-33 interspousal transmission is rare in the absence of parentera risk factors in the partner: less than 5%, if a figure must be given. 28 Promiscuity and coinfection with HIV or HSV-2 are factors that increase this risk. 34-35 Sexual transmission has consistently been negligible in sex partner studies, 28 and recent data have not clearly established that the odds of transmission between partners increase with age or with decades of marriage. 32-36
Patients should inform their sexual partners, who should be offered testing. Infected people should avoid sharing personal hygiene items, and refrain from intercourse during menstrual periods. Condoms should be used in short-term sexual relationships; their use is left to the discretion of informed couples enjoying stable monogamous relationships.
The risk of mother to newborn transmission of HCV has been said to range between 5% to 6%, 28 or as little as 0% to 3% 37-40 according to different studies. Coinfection with HIV, and high maternal viral load, clearly increase the risk of vertical transmission, 37-40 Since breastfeeding transmission has never been documented, it is not contraindicated.
Establishing the HCV status in the neonatal and infancy period must rely on HCV RNA testing. Conventional antibody testing should not be performed before 18 months of age, so as to avoid detection of persistent maternal antibody that might have been passively transferred across the placenta.
As for household transmission of HCV, it has been shown to be very unlikely 41 and need not be considered.
The 1999 Canadian Consensus Conference on the Management of Viral Hepatitis has offered guidance for all Canadian gastroenterologists and hepatologists, in a rapidly changing field. These recommendations will help to guide the treatment of patients such as the one presented here, and all of the other people infected with the hepatitis C virus.
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The opinions expressed in this publication are those of the authors and do not imply endorsement by Schering Canada Inc. or Science & Medicine Canada Inc. This update has been made possible under an unrestricted educational grant from Schering Canada Inc.
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