Road Less Traveled; By Lana Gramlich.Specific clinical recommendations for Hepatitis C :
Persons with HCV infection should be vaccinated against hepatitis A and B
Abstinence from alcohol is recommended for persons with chronic HCV infection
Persons with chronic HCV infection and cirrhosis should avoid hepatotoxic drugs
For persons with chronic HCV infection and cirrhosis, surveillance for hepatocellular carcinoma should be considered.
Who Should Not Treat Hepatitis C ?
Contraindications To Treatment
2010 Guidelines:
Absolute contraindications to treatment of HCV infection include active alcohol or substance abuse, active autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin, known hypersensitivity to medications used to treat HCV infection, and pregnancy or lack of compliance with adequate contraception.
Other absolute contraindications to treatment of HCV infection are severe concurrent cardiopulmonary disease; uncontrolled major depressive illness, psychosis, or bipolar disorder; and untreated hyperthyroidism. Relative contraindications to treatment of HCV infection include laboratory values suggesting decompensated cirrhosis, and baseline hematologic and biochemical indices.
For ribavirin only, renal failure is an absolute contraindication
Treatment with ribavirin should be avoided in patients with ischemic cardiovascular and cerebrovascular disease and in patients with renal insufficiency.
Why Should I Treat HCV ?
Justification for Treatment
Treatment goals in patients with HCV infection are to delay or prevent progression of fibrosis and to prevent the development of cirrhosis.
Natural history studies indicate that 55% to 85% of individuals who develop acute hepatitis C will remain HCV-infected. Spontaneous resolution is more common among infected infants and young women than among persons who are older when they develop acute hepatitis.
Chronic HCVinfection has relevance for the infected persons as well as for their contacts: the former are at risk for progression to cirrhosis and/or HCC, the latter are at risk of acquiring the infection through exposure to the virus.
The risk of developing cirrhosis ranges from 5% to 25% over periods of 25 to 30 years.
Prospective studies of women and children infected at a young age and followed for 20 to 30 years report low rates of cirrhosis, 1% to 3%.
Retrospective studies of patients referred to tertiary care facilities document higher rates of cirrhosis, 20% to 25%, but this figure may be inflated by referral bias.
Progression to cirrhosis may be accelerated in persons who are of older age, who are obese, who are immunosuppressed (e.g.,HIV co-infected), and who consume more than 50g of alcohol per day, although the precise quantity of alcohol associated with fibrosis progression is unknown. Persons with HCV-related cirrhosis are at risk for the development of hepatic decompensation (30% over 10 years) as well as hepatocellular carcinoma (1% to 3% per year).
Identifying individuals at risk for developing progressive disease is difficult. Presently, the preferred approach is to assess the degree of fibrosis on liver biopsy, using avalidated staging system such as the Ishak, IASL, Metaviror Batts-Ludwig staging systems.
Persons with no or minimal fibrosis (Ishak stage 0-2; Metavir, IASL andBatts-Ludwig stage 0-1) have a low risk for liver-related complications and liver-related death (over the next 10 to 20 years). Infection with HCV can also cause extrahepatic diseases including mixed cryoglobulinemia, types II and III. Indeed, symptomatic cryoglobulinemia is an indication for HCV antiviral therapy regardless of the stage of liver disease.
However, the presence of bridging fibrosis (for example Metavir stage 3, ) is an important predictor of future progression to cirrhosis and therefore an indication for treatment.
What Does My METAVIR Score Mean?
The fibrosis is graded on a 5-point scale from 0 to 4.
The activity, which is the amount of inflammation (specifically, the intensity of necro-inflammatory lesions), is graded on a 4-point scale from A0 to A3.
Fibrosis
Stages of fibrosis (F)
F0 = no fibrosis
F1 = portal fibrosis without septa
F2 = portal fibrosis with few septa
F3 = numerous septa without cirrhosis
F4 = cirrhosis
Activity score:
Amount of inflammation (A for activity)
A0 = no activity
A1 = mild activity
A2 = moderate activity
A3 = severe activity
Other scoring systems are available, such as the Knodell score (also called the histologic activity index, or HAI). However, the METAVIR score is simple to use and is popular in many clinics
Scoring system for chronic hepatitis C (the Metavir Score System).
*Note F1-F4 On Figure
Conversion ; FibroTest and fibrosis stages
Conversion between FibroTest and fibrosis stages using METAVIR, Knodell and Ishak fibrosis scoring systems (upper panel).
Conversion between ActiTest and activity grades using METAVIR, Knodell and Ishak necroinflammatory activity scoring systems (lower panel).
Hepatic Consequences
Individuals with CHC (Chronic Hepatitis C) are at increased risk of liver related morbidity and mortality.
HCV infection was associated with 27% of all US liver transplants performed in 2007, and US-based studies demonstrated that up to 51%–55% of HCC patients have anti-HCV antibodies. There is also a link between steatosis and liver fibrosis in HCV-infected patients, as well as a potential association between HCV infection and HCC or, as described more recently, of intrahepatic cholangiocarcinoma (ICC). In some ethnic groups such as Latinos the course of HCV infection is more aggressive, with a higher risk of cirrhosis than other ethnic groups. Furthermore, disease progression is more rapid in patients who are coinfected with HCV and HIV. Coinfected patients have approximately double the risk of cirrhosis or decompensation than those infected with HCV alone.
Fibrosis and Cirrhosis
Progressive hepatic fibrosis leading to cirrhosis is the major complication of chronic HCV infection and accounts for almost all HCV-related morbidity and mortality. Early studies suggested little, if any, fibrosis progression during the first decade of infection, followed by a slow, regular progression during the next 15 years, increasing to an intermediate rate during the subsequent decade.
In a German cohort study of 1833 women infected with HCV-contaminated immunoglobulin, 0.5% of patients developed cirrhosis after 25 years. Similarly, in a study of 376 HCV-infected women conducted by the Irish Hepatology Research Group, 51% of patients had fibrosis after 17 years, but only 2% had probable/definite cirrhosis. These estimates of cirrhosis rates are considerably lower than those from the US multicohort study and the widely cited US military study (approximately 35%). Fibrosis outcomes of 184 women from the same cohort were followed up for the subsequent 5 years; 49% showed no change in fibrosis, 24% showed regression, and 27% showed progression.
Recent data reinforce the potential for severe liver disease to develop in some patients. Among 485 plasma donors infected during the early 1970s, 34% had stage F3/F4 fibrosis (bridging fibrosis), cirrhosis, or HCC after 31 years; their 35-year cumulative survival was 84% versus 91%–95% for the general population. Similarly, a study of 300 black and white Americans with untreated HCV infection found that 29% of patients had stage F3/F4 fibrosis after 20 years, and 4.7% had confirmed cirrhosis. It should be noted, however, that these studies could have selected patients with severe disease.
The nonlinear progression of fibrosis was recently confirmed in a meta-analysis of 111 HCV studies. The mean annual stage-specific transition probabilities were for stage F0 to F1, for F1 to F2, 0.120 for F2 to F3, and 0.116 for F3 to F4. Although the estimated prevalence of cirrhosis was 16% after 20 years, there was wide variation between studies, suggesting that fibrosis is a highly unpredictable process.
Infection duration is a major risk factor for severe fibrosis, with the progression rate in a 50-year-old being almost 3 times that in a 20-year-old. Age at time of infection is also important. In a biopsy analysis of 247 treatment-naïve HCV patients, progression rates were 0.13, 0.14, 0.27, and 0.36 fibrosis units/year for patients aged ≤19, 20–24, 25–36, and >36 years at infection, respectively. Age >36 years (vs ≤36 years) at time of infection was independently associated with faster progression. Men infected before age 50 have been identified as comprising the majority of cases of cirrhosis today (73.6%), whereas men aged >50 years when infected have faster disease progression compared with other age groups.
Several other factors, including sex, baseline fibrosis, HCV genotype, HIV/HBV coinfection, and alcohol consumption, also influence fibrosis progression . Identifying these factors can be useful when determining prognosis and advising patients on minimizing liver damage. Indeed, a recent study suggested that HCV genotype 3 might pose a particularly high risk of progressive fibrosis.
Insulin resistance has been linked with fibrosis, and several studies have reported that this relationship remains significant, irrespective of HCV genotype.
In addition, serum aminotransferase level elevations and the degree of hepatocellular necrosis/inflammation on biopsy have been found to predict fibrosis progression. Genetic factors might also play a role in fibrosis progression. Recent data indicate that the cirrhosis risk score, which is based on the association of 7 host genes, might help to differentiate HCV patients at high versus low risk of progressing toward cirrhosis, including those with early or mild CHC. Steatosis has also been linked to fibrosis progression, as has regular cannabis use. There is evidence of an association between cigarette smoking and hepatitis fibrosis, but not all studies have verified such an association.
Hepatocellular Carcinoma
The greatest increase in US cancer deaths from 1995–2004 was in those caused by cancers of the liver and bile duct, of which HCC comprised about 76%. This might be attributed to the increasing incidence of HCV-related HCC because rates for HBVrelated and alcohol-related HCC have remained stable during recent years. The incidence of HCV-related HCC in the United States is projected to peak in 2019 at 14,000 cases/year. In a large US database, the proportion of HCV-related cases of HCC among HCC patients aged ≥65 years doubled from 11% in 1993–1996 to 21% in 1996–1999. During the past decade, the fastest increase in HCC incidence has affected Hispanics and whites. In multivariate analysis HCV infection was an independent predictor for the development of HCC.
Furthermore, maintenance therapy with peginterferon did not reduce the 5-year incidence of HCC in the HALT-C cohort.Comparisons of US and Japanese HCV strains suggest that the US HCV epidemic began about 2 to 3 decades after that in Japan. This has led to speculation that the burden of HCC in the United States might eventually equal that currently seen in Japan as HCV-infected individuals age and their infection duration increases. In Japan, HCV-related HCC accounts for 80% of all HCC cases, and the rate of HCC among HCV-infected men has risen from 17.4/100,000 in 1972–1976 (32,335 deaths) to 27.4/100,000 in 1992–1996 (109,365 deaths).
A recent Italian study of 214 HCV-infected patients with Child–Pugh class A cirrhosis showed that HCC developed at a rate of almost 4%/year. HCC was the first complication to occur in 55 (27%) patients; after 17 years, HCC had developed in 68 (32%) patients.
In another cohort of 416 patients with uncomplicated Child–Pugh class A HCV-related cirrhosis, the incidence of HCC was 13.4% at 5 years, and the 5-year HCC death rate was 15.3%, with the hazard rate of HCC tending to increase over time.
Several factors influence the risk of HCC in patients with HCV-related cirrhosis.
Generally, HCC risk is increased in patients aged >50 years or those infected when aged >50 years, patients with longer duration of infection, men, overweight or diabetic patients, and patients with advanced cirrhosis or elevated alpha-fetoprotein Other possible risk factors include the presence of steatosis, HCV genotype 1b, Asian/African American race and occult HBV infection. As for hepatic fibrosis, an association between cigarette smoking and HCV-related HCC has been suggested in some studies but not others. Chronic HCV-related inflammation might increase HCC risk by shifting hepatocytic transforming growth factor– beta signaling from tumor suppression to fibrogenesis.
HCC generally develops after cirrhosis is established, signifying the likely importance of long-standing necrosis and regeneration, an environment of extensive scarring, in its pathogenesis. HCV might influence hepatocarcinogenesis through the oncogenic effects of its core protein, which might augment oxidative stress. It might also alter the signaling cascade of mitogen-activated protein kinase and activating factor 1, thereby activating cellcycle control. Liver angiogenesis and the neovascular response, plus genomic changes that deregulate components of the Jak/STAT pathway in early carcinogenesis, might also promote HCV-related hepatocarcinogenesis. Additional mechanisms have also been proposed.
Starting Treatment
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How Will I Know If Treatment Is Working ?
Your doctor will look at several kinds of lab results to keep track of your treatment response.
A viral load test or PCR will be used to see how much hepatitis C virus is in your blood, it's the most common way to evaluate hepatitis C treatment.
A PCR/viral load test will be given at baseline(start of treatment) , 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, follow up at 4 weeks, 12 weeks, 24 weeks and one year. (depending on treatment duration).
Response Guided Therapy
Treatment will be response guided which is done by viral load monitoring during treatment. This is intended to enable the physician to determine the duration of combination therapy based on a patients viral response. The quantitative HCV RNA level (viral load test) is used to assess response to therapy and as a guide to discontinue treatment.
A negative viral load test after "four weeks" of therapy is predictive of sustained virologic response. In contrast, failure to achieve a 100-fold reduction in viral load by week 12 of therapy has a strong negative predictive value for sustained virologic response and suggests that treatment is likely ineffective and should be stopped."
Changes in viral load are sometimes expressed in terms of logs: a 1-log change means a 10-fold increase or decrease; a 2-log change is a 100-fold increase or decrease.
What Is A 2 Log Drop?
Example: 2 log drop = 15,000,000 IU/Ml to 150,000 IU/mL; a viral load that starts at 15,000,000 IU/mL and does not decrease to 150,000 IU/mL or lower.
A "sustained virologic response" means that the virus remains undetectable 6 or more months after you complete treatment.
Additional Information;
In SOC = pegylated interferon and ribavirin Laboratory evaluations to monitor during treatment
What Kind Of Doctor Should I See?
Before choosing a physician ask him/her how many patients they have treated with HCV and for how long. If possible go through a teaching hospital/university which is on the cutting edge of these therapies. You should use a Gastroenterologist or a Hepatologist. .
;What is a Gastroenterologist? .
A Gastroenterologist is a physician with dedicated training and unique experience in the management of diseases of the gastrointestinal tract and liver.
What Is A Hepatologist ?
A physician who successfully completes a hepatology fellowship is considered a hepatologist. Most hepatologists, although not all, are also gastroenterologists. These doctors have successfully completed both a hepatology and a gastroenterology fellowship. Occasionally, gastroenterologists who have not completed a fellowship in hepatology nonetheless focus their medical practice primarily on the diagnosis and treatment of people with liver disease. While these physicians do not have a separate diploma in the field of liver disease, they may also be considered hepatologists.
Read More Here; What Is A Hepatologist ? What Is A Gastroenterologist?
Liver Biopsy, Should I or Shouldn't I ?
According to the 2010 Guidelines: a liver biopsy should be considered in patients with chronic hepatitis C infection if the patient and health care provider wish information regarding fibrosis stage for prognostic purposes or to make a decision regarding treatment. Currently available noninvasive tests may be useful in defining the presence or absence of advanced fibrosis in persons with chronic hepatitis C infection, but should not replace the liver biopsy in routine clinical practice .
Also See: Liver Biopsy and Noninvasive Tests For Fibrosis
Noninvasive tests for liver disease, fibrosis, and cirrhosis: Is liver biopsy obsolete?
Tests before and during HCV therapy:
You will be asked to give a medical history and have a complete medical examination; including but not limited to an eye examination, an EKG (a tracing by machine that shows how well your
heart is working), and/or a cardiac stress test, if the provider thinks they are needed.
A pregnancy test for female patients
*Note; It is also recommended that men and women should not consider pregnancy for 6 months after discontinuation of the drug.
Thyroid function should be monitored every 12 weeks while on treatment.
Genotype test; Viral genotyping is used to determine the kind, or genotype, of the virus. There are 6 major types of HCV; the most common in the U.S. and difficult to treat is (genotype 1), genotypes 2 or 3 have a better response rate to HCV treatment. Genotyping is often ordered before treatment is started to give an idea of the likelihood of success and how long treatment may be needed.
PCR=Viral Load or Quantitative HCV tests measure the number of viral RNA particles in your blood. Viral load tests are often used before and during treatment to help determine response to treatment .
As mentioned above; A PCR (viral load test) is at baseline , 4 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. (depending on treatment duration).
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The IL28B Gene
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Updated; As reported On Feb 25 2011
Scripps Health ;IL28B Genetic Testing to Hepatitis C Patients Now Available
.In the last two years there has been notable research on the IL28B gene in relation to treatment response. However at this time the protocol for pre-testing has not been established.
How is the IL28B gene related to Hepatitis C ?
Variations in the IL28B gene have recently been linked to better treatment response among people with chronic hepatitis C virus
From HCV Advocate : The gene is a variation of IL28B (interleukin 28B) which triggers our body to make more of a type of natural interferon called lambda interferon. This natural interferon has also been found to help naturally suppress the hepatitis C virus. In people who take interferon plus ribavirin therapy the presence of a certain variation of IL28B gives them a two-fold increased chance of achieving a sustained virological response (HCV RNA negative 24-weeks post treatment) compared to those who do not have this gene variation.
Additional Information; IL28B At HCV New Drug Research and Liver Health
IL28B Gene Patterns and Liver Transplant Outcomes in Hepatitis C Patients
Do IL28B Gene Variations Affect Liver Disease Progression in People with Hepatitis C ?
If You Have Cirrhosis And Achieve SVR
However, patients who achieve an SVR but who have cirrhosis are at risk for comlications including HCC and therefore should continue to be monitored periodically.
Also See; (See AASLD guidelines on Management ofHepatocellular Carcinoma).
There is no role for a post treatment liver biopsy among those who achieve an SVR.
After treatment is completed;
A PCR is given at 4 weeks, 12 weeks, 24 weeks and one year.
Side Effects:
Consequently, telaprevir has been combined with pegylated-interferon and ribavirin in clinical trials. This triple combination is more effective but has a higher rate of adverse events (notably rash) than the standard of care, despite the shorter duration of therapy. In boceprevir anemia has been seen during clinical trials.
Addtional Information; For SOC
Hepatitis C Treatment Adverse Event Monitoring
Hepatitis C: White Blood Count During Therapy
Hepatitis C: Anemia And Other Side Effects During Treatment
New Drugs
Telaprevir and Boceprevir/Less Side Effects?
Tips:
Needle Stick Risk; If a family member will be injecting the medication; Please use caution and replace the cap on the syringe as soon as you withdraw the needle.
Injection Guide
Dealing with Used Sharps Responsibly:
A Guide for Patients Improper disposal of needles and other medical sharps can cause needle-stick injuries, especially for garbage collectors. Please throw your used needles away safely. Needles, sharps or sharps containers should not be included in your household trash. Collection programs for these items are available in many locations throughout the country. You may also return the full sharps container to your physician.
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Treating with telaprevir or boceprevir
Telaprevir and Boceprevir Understanding The Chance For A Cure
Tip From Dr. Pockros;
Hepatitis C New Drugs:Telaprevir,Boceprevir Potential for Misuse Is ‘Huge’
The designs of the phase III trials on which the Food and Drug Administration approval will be based, as well as the resulting treatment regimens, are fairly complex, said Dr. Pockros, "so there will be lots of opportunities to screw things up." For example, he hypothesized, "I am sure that some patients are going to be put on telaprevir for 44 weeks with a 4-week pegylated interferon/ribavirin lead-in [even though the lead-in strategy was evaluated for boceprevir, not telaprevir], and other patients might be put on boceprevir for 12 weeks with no lead-in." For optimal safety and efficacy, Dr. Pockros stressed, physicians must have a good understanding of the treatment regimens, particularly in special populations, and they must actively and frequently monitor for antiviral resistance.
Additionally, physicians should anticipate problems with adherence, which is already an issue for some patients on standard therapy, he said, noting that – despite the shorter treatment duration – adding a third drug with its own set of side effects to the mix may not be realistic for patients with a history of poor compliance. The objective for physicians should be "to keep our eyes on the ball," said Dr. Pockros. "Our primary goal moving forward with all of the new drugs is going to be eradicating the virus." Paul J. Pockros, M.D., is head of the division of gastroenterology/hepatology and director of the Liver Research Consortium at the Scripps Clinic in La Jolla, Calif. He disclosed relationships with Vertex and Tibotec, which are involved in the development of telaprevir, and Merck, which manufactures boceprevir.
Source;
http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/
http://www.medscape.com/viewarticle/723197
http://www.coloradoguidelines.org/guidelines/hepbc.asp ttp://www.aasld.org/practiceguidelines/Pages/NewUpdatedGuidelines.aspx
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