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Hepatitis C       Transmission |  SX  |  DX  |  RX              

See also  hepatitis C_Rx_2011  | Hepatitis C_2011.pdf |  hepatitis C Rx options-2009.pdf  

Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States. Chronic liver disease is the tenth leading cause of death among adults in the United States. Population-based studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year.

DX - Hepatitis C Tests                                   
(Ref: Cleveland Clinic JM  Oct. 1999 - CA MAtteoni & ZM Younossi)

Diagnostic Testing for Hepatitis C - Am J Med Dec. 27, 1999;107 (6B):31S Michael Fried

Transmission of Hepatitis C:     

Sexual transmission:
15%-20% of patients with acute hepatitis C who have been reported to CDC's sentinel counties surveillance system, have a history of sexual exposure in the absence of other risk factors.  Two thirds of these have an anti-HCV-positive sex partner, and one third reported greater than 2 partners in the 6 months before illness (2).     Five of the studies of long-term spouses of patients with chronic HCV infection who had no other risk factors for infection have been conducted in the United States, involving 30-85 partners each, in which average prevalence of HCV infection was 1.5% (range: 0% to 4.4%) (56,82-85). Among partners of persons with hemophilia coinfected with HCV and HIV, two studies have reported an average prevalen ce of HCV infection of 3% (83,86). 

Household Contact Transmission:
In studies from other countries of nonsexual household contacts of patients with chronic hepatitis C, average anti-HCV prevalence was 4% (15). Although infected contacts in these studies reported no other commonly recognized risk factors for hepatitis C, most of these studies were done in countries where exposures commonly experienced in the past from contaminated quipment used in traditional and nontraditional medical procedures might have contributed to clustering of HCV infections in families (75,76,79).

Perinatal Transmission:
Perinatal. The average rate of HCV infection among infants born to HCV-positive, HIV-negative women is 5%-6% (range: 0%-25%), based on detection of anti-HCV and HCV RNA, respectively (89-101). The average infection rate for infants born to women coinfected with HCV and HIV is higher -- 14% (range: 5%-36%) and 17%, based on detection of anti-HCV and HCV RNA, espectively (90,96,98-104).

                                      

SX - Clinical Features and Natural History

Acute HCV Infection

60%–70% of patients have no discernible symptoms;
20%–30% might have jaun-dice; and
10%–20% might have nonspecific symptoms (e.g., anorexia, malaise, or abdominal pain) (13,114,115).

Clinical illness in patients with acute hepatitis C who seek medical care is similar to that of other types of viral hepatitis, and serologic testing is necessary to determine the etiology of hepatitis in an individual patient. In 20% of these patients, onset of symptoms might precede anti-HCV seroconversion. Average time period from exposure to symptom onset is 6–7 weeks (116,117,118), whereas average time period from exposure to seroconversion is 8–9 weeks (114; personal communication, HJ Alter, M.D., Chief, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, September 1998). Anti-HCV can be detected in 80% of patients within 15 weeks after exposure, in 90% within 5 months after exposure, and in ³97% by 6 months after exposure (14,114). Rarely, seroconversion might be delayed until 9 months after exposure (14,119).

The course of acute hepatitis C is variable, although elevations in serum ALT levels, often in a fluctuating pattern, are its most characteristic feature. Normalization of ALT levels might occur and suggests full recovery, but this is frequently followed by ALT elevations that indicate progression to chronic disease (14). Fulminant hepatic failure following acute hepatitis C is rare (120,121).

Natural History of Hepatitis C    AM J Med Dec.27, 1999; 107 (6B): 10S - Leonard Seeff  
It is now widely accepted that 85% or more of individuals with acute hepatitis C virus (HCV) infection progress to chronic hepatitis, and chronic hepatitis C is a known risk factor for cirrhosis and hepatocellular carcinoma (HCC). However, there has been much controversy about the inevitability of developing cirrhosis and HCC and the time frames in which they are likely to occur. The combined population data indicate that the disease progresses slowly over approximately 30 years, on average. Approximately 20% of infected individuals will progress to fibrosis and cirrhosis. Of these, approximately 20% will progress to HCC.   The likelihood of progression appears to be independent of genotype or viral load but increases with alcohol intake, male sex, age over 40 years at infection, and coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV).

Chronic HCV Infection     

After acute infection, 15%–25% of persons appear to resolve their infection without sequelae as defined by sustained absence of HCV RNA in serum and normalization of ALT levels (122; personal communication, LB Seeff, M.D., Senior Scientist [Hepatitis C], National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, July 1998).
Chronic HCV infection develops in most persons (75%–85%)(14,122,123,124), with persistent or fluctuating ALT elevations indicating active liver disease developing in 60%–70% of chronically infected persons (12–15,116,122–124). In the remaining 30%–40% of chronically infected persons, ALT levels are normal. No clinical or epidemiologic features among patients with acute infection have been found to be predictive of either persistent infection or chronic liver disease. Moreover, various ALT patterns have been observed in these patients during follow-up, and patients might have prolonged periods (12 months) of normal ALT activity even though they have histologic-confirmed chronic hepatitis (14). Thus, a single ALT determination cannot be used to exclude ongoing hepatic injury, and long-term follow-up of patients with HCV infection is required to determine their clinical outcome or prognosis.

The course of chronic liver disease is usually insidious, progressing at a slow rate without symptoms or physical signs in the majority of patients during the first two or more decades after infection. Frequently, chronic hepatitis C is not recognized until asymptomatic persons are identified as HCV-positive during blood-donor screening, or elevated ALT levels are detected during routine physical examinations. Most studies have reported that cirrhosis develops in 10%–20% of persons with chronic hepatitis C over a period of 20–30 years, and HCC in 1%–5%, with striking geographic variations in rates of this disease (124,125,126,127,128). However, when cirrhosis is established, the rate of development of HCC might be as high as 1%–4% per year. In contrast, a study of >200 women 17 years after they received HCV-contaminated Rh factor IG reported that only 2.4% had evidence of cirrhosis and none had died (129). Thus, longer term follow-up studies are needed to assess lifetime consequences of chronic hepatitis C, particularly among those who acquired their infection at young ages.

Although factors predicting severity of liver disease have not been well-defined, recent data indicate that increased alcohol intake, being aged >40 years at infection, and being male are associated with more severe liver disease (130). In particular, among persons with alcoholic liver disease and HCV infection, liver disease progresses more rapidly; among those with cirrhosis, a higher risk for development of HCC exists (131).

Furthermore, even intake of moderate amounts (>10 g/day) of alcohol in patients with chronic hepatitis C might enhance disease progression. More severe liver injury observed in persons with alcoholic liver disease and HCV infection possibly is attributable to alcohol-induced enhancement of viral replication or increased susceptibility of cells to viral injury. In addition, persons who have chronic liver disease are at increased risk for fulminant hepatitis A (132).

Extrahepatic manifestations of chronic HCV infection are considered to be of immunologic origin and include cryoglobulinemia, membranoproliferative glomerulonephritis, and porphyria cutanea tarda (131). Other extrahepatic conditions have been reported, but definitive associations of these conditions with HCV infection have not been established. These include seronegative arthritis, Sjögren syndrome, autoimmune thyroiditis, lichen planus, Mooren corneal ulcers, idiopathic pulmonary fibrosis (Hamman-Rich syndrome), polyarteritis nodosa, aplastic anemia, and B-cell lymphomas.

Ref: Niederau C, Lange S, Heintges T, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology 1998;28:1687-95.

     

Clinical Management and Treatment       See KP Intranet Guidelines for Rx of Hepatitis C 1998  

Boceprevir for Untreated Chronic HCV Genotype 1 Infection
N Engl J Med 2011; 364:1195-1206March 31, 2011 Fred Poordad, M.D., etc
The addition of boceprevir to standard therapy with peginterferon–ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir.

REF:  hepatitis_C_2011 Rx.pdf    

Interferon and Ribavirin Combination Therapy  (REF:  ACP Medicine 06-2004)

Beginning in late 1998, the combination of interferon alfa-2b and ribavirin became the standard therapy for chronic HCV infection in patients with no contraindications.    

The 1998 studies of interferon and ribavirin combination therapy showed important differences in the outcome based on genotype; that is, approximately 30% of patients with genotype 1 and approximately 65% with genotype 2 or 3 had sustained virologic responses. In addition, patients with genotype 1 had higher rates of sustained virologic response with 48 weeks of combination therapy than with 24 weeks of therapy, whereas patients with other genotypes achieved no additional benefit beyond 24 weeks of therapy.   These studies have led to the practice of administering therapy for 12 months to patients with genotype 1 but for only 6 months to those with genotype 2 or 3. Factors in addition to genotype are known to predict the likelihood of successful therapy with ribavirin and interferon

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In two trials using pegylated interferon and ribavirin, SVR (Sustained Viral Response)  rates of 42 and 46 percent were achieved in patients with genotype 1 compared to rates of 76 and 82 percent in patients with genotypes 2 and 3. In a recent, as yet unpublished study, a 24-week course of pegylated interferon and ribavirin was found to be as effective as a 48-week course in patients with genotypes 2 and 3 (SVR rates of 73 to 78 percent), but not in patients with genotype 1 (SVR rates of 41% with 24 weeks and 51% with 48 weeks). Similarly, a reduced ribavirin dosage of 800 mg daily appeared to be adequate for patients with genotypes 2 and 3, but the higher, standard dosage of 1000 to 1200 mg daily yielded better response rates in patients with genotype 1. Thus, 24 weeks of treatment and an 800 mg dose of ribavirin appears to be sufficient for persons with genotypes 2 and 3, while patients with genotype 1 need 48 weeks of treatment and standard doses of ribavirin.m
Management of Hepatitis C: 2002  June 10-12, 2002  Vol. 19, No. 1  (NIH Consensus)        

Interferon Therapy
Use of Interferon for prevention of hepatocellular Carcinoma in cirrhotic patients with Hep. B or Hep. C
(AIM Nov. 2, 1999;131:696 - Vicky Vaffis, etc.)

HCV-positive patients should be evaluated for presence and severity of chronic liver disease (133). Initial evaluation for presence of disease should include multiple measurements of ALT at regular intervals, because ALT activity fluctuates in persons with chronic hepatitis C. Patients with chronic hepatitis C should be evaluated for severity of their liver disease and for possible treatment (133,134,135).

Indications for Antiviral therapy:   patients with chronic hepatitis C who are at greatest risk for progression to cirrhosis (133).

[When is interferon Rx indicated for HCV? - American Liver Foundation 7-1999     
Patients with

are eligible for therapy. Patients who have a risk factor for HCV (blood transfusion, needle-stick exposure or illegal intravenous drug use) usually do not need to have the HCV result confirmed by additional testing. However, patients without such a risk factor should have a second test: either the RIBA test, to confirm the presence of the antibody, or the PCR test, which detects the presence of the virus. Liver biopsy is helpful in the diagnosis of viral hepatitis, assessing liver damage prior to treatment. Patients with acute infection, complications from cirrhosis, other major medical problems or autoimmune liver disease should not be treated with interferon. ]

In patients with less severe histologic changes, indications for treatment are less clear, and careful clinical follow-up might be an acceptable alternative to treatment with antiviral therapy (e.g., interferon) because progression to cirrhosis is likely to be slow, if it occurs at all. Similarly, patients with compensated cirrhosis (without jaundice, ascites, variceal hemorrhage, or encephalopathy) might not benefit from interferon therapy. Careful assessment should be made, and the risks and benefits of therapy should be thoroughly discussed with the patient.

Patients with persistently normal ALT values should not be treated with interferon outside of clinical trials because treatment might actually induce liver enzyme abnormalities (136).   Patients with advanced cirrhosis who might be at risk for decompensation with therapy and pregnant women also should not be treated. Interferon treatment is not FDA-approved for patients aged <18 years, and more data are needed regarding treatment of persons aged <18 years or >60 years. Treatment of patients who are drinking excessive amounts of alcohol or who are injecting illegal drugs should be delayed until these behaviors have been discontinued for 6 months.

Chronic Hepatitis C patients with normal ALT  [Am J Med Dec. 27, 1999;107 (6B):53S  Adrian Bisceglie]  
A substantial proportion of patients with chronic hepatitis C virus (HCV) infection (HCV RNA positive) have persistently normal serum alanine aminotransferases (ALT). These patients currently pose a therapeutic dilemma, as it is not clear how best to deal with them. Response rates to interferon are low, and in some cases interferon therapy has been associated with an increase in serum aminotransferases. Therefore, the NIH Consensus Conference recommended against treating them with interferon. Although most patients with persistently normal serum ALT levels have mild disease on liver biopsy, the consensus panel did think it appropriate to do liver biopsies in these subjects.   Few data are available on therapy with the combination of interferon and ribavirin for such patients.   At Saint Louis University, 24 patients with normal ALT were treated with interferon/ribavirin.   Preliminary analysis of the results shows that 33% of the patients had a sustained response 24 weeks after therapy.  Thus, uncertainties remain about patients with chronic HCV infection and persistently normal serum ALT with the currently available therapies. However, if a more effective and better tolerated therapy were to become available, such patients might best be treated to eliminate the chronic viral infection.

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Contraindications to treatment with interferon include major depressive illness, cytopenias, hyperthyroidism, renal transplantation, and evidence of autoimmune disease.

Most clinical trials of treatment for chronic hepatitis C have been conducted using alpha-interferon (134,135,137,138). When the recommended regimen of alpha-interferon 3 million units subc. 3 times/week for 12 months is used, approximately 50% of treated patients have normalization of serum ALT activity (biochemical response), and 33% have a loss of detectable HCV RNA in serum (virologic response) at the end of therapy. However, 50% of these patients relapse when therapy is stopped. Thus, 15%–25% have a sustained response as measured by testing for ALT and HCV RNA 1 years after therapy is stopped, many of whom also have histologic improvement. For patients who do not respond by the end of therapy, retreatment with a standard dose of interferon is rarely effective. Patients who have persistently abnormal ALT levels and detectable HCV RNA in serum after 3 months of interferon are unlikely to respond to treatment, and interferon treatment should be discontinued. These persons might be considered for participation in clinical trials of alternative treatments. Decreased interferon response rates (<15%) have been found in patients with higher serum HCV RNA titers and HCV genotype 1 (the most common strain of HCV in the United States); however, treatment should not be withheld based solely on these findings.

Therapy for hepatitis C is a rapidly changing area of clinical practice. Combination therapy with interferon and ribavirin, a nucleoside analogue, is now FDA-approved for treatment of chronic hepatitis C in patients who have relapsed following interferon treatment and might be approved soon for patients who have not been treated previously.   Studies of patients treated with a combination of ribavirin and interferon have demonstrated a substantial increase in sustained response rates, reaching 40%–50%, compared with response rates of 15%–25% with interferon alone (139,140). However, as with interferon alone, combination therapy in patients with genotype 1 is not as successful, and sustained response rates among these patients are still <30%.

Ref: Combination interferon & ribavirin Rx ; Part 2

Most patients receiving interferon experience flu-like symptoms early in treatment, but these symptoms diminish with continued treatment. Later side effects include fatigue, bone marrow suppression, and neuropsychiatric effects (e.g., apathy, cognitive changes, irritability, and depression). Interferon dosage must be reduced in 10%–40% of patients and discontinued in 5%–15% because of severe side effects. Ribavirin can induce hemolytic anemia and can be problematic for patients with preexisting anemia, bone marrow suppression, or renal failure. In these patients, combination therapy should be avoided or attempts should be made to correct the anemia. Hemolytic anemia caused by ribavirin also can be life-threatening for patients with ischemic heart disease or cerebral vascular disease. Ribavirin is teratogenic, and female patients should avoid becoming pregnant during therapy.

Other treatments, including corticosteroids, ursodiol, and thymosin, have not been effective. High iron levels in the liver might reduce the efficacy of interferon. Use of iron-reduction therapy (phlebotomy or chelation) in combination with interferon has been studied, but results have been inconclusive. Because patients are becoming more interested in alternative therapies (e.g., traditional Chinese medicine, antioxidants, naturopathy, and homeopathy), physicians should be prepared to address questions regarding these topics.

Management of interferon relapsers
The American Journal of Medicine Dec. 27, 1999, 107:6B 62-66 - Ira Jacobson

Relapse as defined today means an elevation in alanine aminotransferase (ALT) levels and reappearance of HCV RNA in serum after having an end-of-treatment response consisting of normalized ALT levels and disappearance of HCV RNA from serum. However, when interpreting clinical trials, it should be remembered that early trials conducted before the development of assays for HCV RNA defined a response simply as normalization of ALT.
Relapse in patients who have evidenced an initial response to a course of interferon monotherapy for chronic hepatitis C virus (HCV) infection has been a major frustration. At least 70% of responders will relapse after a 6-month course of treatment and more than 50% will relapse after a 12-month course of treatment, usually within the first 3 to 6 months after treatment discontinuation. At most, half of patients relapsing after an initial 6-month course will have a sustained response to a second, 12-month course of interferon monotherapy. A more promising second-line regimen is the combination of interferon plus ribavirin. A recent multicenter international trial has shown that this regimen results in a sustained virologic response rate of nearly 50%, fully 10-fold higher than the sustained response rate observed with a second 6-month course of interferon alone (49% vs 5%, respectively). In patients with non-1 genotype and viral levels no greater than 2 million copies/mL, the likelihood of sustained response to the second course of combination therapy was 100%. Biochemical and virologic responses (normalization of liver enzymes and disappearance of HCV RNA from the serum) were frequently accompanied by histologic improvement. HCV-RNA levels 2 million copies/mL and non-1 viral genotype predicted treatment response, whereas age, gender, body weight, source of infection, type of interferon used for the first round of treatment, and elapsed time since first treatment had no effect. Based on these data, combination therapy with interferon and ribavirin is now considered the treatment of choice for relapsers. It is not clear whether 12 months of combination therapy might have produced even better rates of viral eradication in relapsed patients.

   

Postexposure Prophylaxis and Follow-Up

Available data regarding the prevention of HCV infection with IG indicate that IG is not effective for postexposure prophylaxis of hepatitis C (67,141). No assessments have been made of postexposure use of antiviral agents (e.g., interferon) to prevent HCV infection.

The immediate postexposure setting provides opportunity to identify persons early in the course of their HCV infection. Studies indicate that interferon treatment begun early in the course of HCV infection is associated with a higher rate of resolved infection (143).

     

Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy
E Anthony Jones - Lancet Volume 354, Number 9176 31 July 1999

A woman with chronic hepatitis C and profound fatigue became symptomfree when treated long-term with ondansetron 4 mg twice daily. Altered central serotoninergic neurotransmission may contribute to fatigue complicating chronic liver disease.

Department of Gastrointestinal and Liver Diseases, Academic Medical Center, 1105 AZ Amsterdam-ZO, Netherlands (E A Jones FRCP) Correspondence to: Dr E Anthony Jones (e-mail: E.A.Jones@amc.uva.nl)

     

11142001 

Conclusions: Treatment of acute hepatitis C with interferon alfa-2b prevents chronic infection.
NEJM Volume 345:1452-1457, November 15, 2001 Number 20      Editorial  

Management of Hepatitis C: June 2002  (NIH)    

The following points may be especially useful for primary care physicians:

The entire supplement can be accessed on the Hepatology website free of charge. In addition, the conference's summary statement is available on the NIH website free of charge.  Management of Hepatitis C: 2002  June 10-12, 2002  Vol. 19, No. 1

— Allan S. Brett, MD

Published in Journal Watch December 3, 2002

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2011