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AASLD Practice Guidelines: Diagnosis, management, and treatment of hepatitis C: An update, pdf attached
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Hepatology April 2009
Marc G. Ghany 1, Doris B. Strader 2, David L. Thomas 3, Leonard B. Seeff 4
individuals with unexplained elevations of the aminotransferase levels (alanine and/or aspartate aminotransferase; ALT/AST), those ever on hemodialysis, children born to HCV-infected mothers, or those with human immunodeficiency virus (HIV) infection should be tested for the presence of HCV infection
Other potential sources of HCV transmission include exposure to an infected sexual partner or multiple sexual partners, exposure among health care workers to HCV-contaminated blood and blood products, and tattooing
The liver biopsy has been widely regarded as the gold standard for defining the liver disease status, but it has drawbacks that have prompted questions about its value.[61][62] The procedure is not without risks (including pain, bleeding and perforation of other organs),[63][64] it is subject to sampling error,[65] it requires special expertise for interpreting the histopathology, it adds cost to medical care, and it is anxiety-provoking for the implicated person. Thus, efforts are underway to seek alternative means of establishing information on the extent of fibrosis by focusing on noninvasive blood marker panels.[66] These markers are useful for establishing the two ends of the fibrosis spectrum (minimal fibrosis and cirrhosis) but are less helpful in assessing the mid-ranges of fibrosis or for tracking fibrosis progression.[66] The recently developed transient elastography that uses ultrasound and low frequency elastic waves to measure liver elasticity[67] has improved the ability to define the extent of fibrosis without a liver biopsy, particularly when combined with other noninvasive markers.[68] However, it is not yet ready to replace the liver biopsy since it is not FDA approved, the failure rate is higher in obese patients, and there is now evidence that the transient elastography score can be unexpectedly increased in persons with acute hepatitis who have high necroinflammatory activity but no or minimal fibrosis
The two more common non-HCV conditions that might affect disease progression and possibly impede treatment response are steatosis[49][55][56] and excess hepatocellular iron.[57] Identifying either of these two features does not preclude initiating treatment, but their presence provides additional information regarding the likelihood of response to treatment.[58-60]
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).[99]
Treatment of HCV infection can be considered for persons even if they currently use illicit drugs or who are on a methadone maintenance program, provided they wish to take HCV treatment and are able and willing to maintain close monitoring and practice contraception (Class IIa, Level C)
Persons who use illicit drugs should receive continued support from drug abuse and psychiatric counseling services as an important adjunct to treatment of HCV infection


Because of the high prevalence of HIV/HCV coinfection, and because the management of each infection can differ in dually-infected persons, all HIV-infected persons should be tested for HCV and all HCV-infected persons with HIV risk factors should be tested for HIV. As in HIV-uninfected persons, the usual approach is to first test for anti-HCV and to confirm the positive results with a highly sensitive assay. However, approximately 6% of HIV-positive persons fail to develop HCV antibodies; therefore, HCV RNA should be assessed in HIV-positive persons with unexplained liver disease who are anti-HCV negative.[208][209]
The urgency for treatment of persons who are co-infected is greater than it is in those with HCV infection alone. Progression of liver disease is more rapid in HIV/ HCV-co-infected persons, in whom there is an approximately twofold increased risk of cirrhosis.[210][211] Successful treatment of HCV also might improve the tolerability of HAART by reducing the risk of hepatotoxicity.[212][213]
The likelihood of achieving an SVR is lower in HIV/HCV co-infected persons than in those with HCV monoinfection.[214-218] The reduced SVR likelihood appears to be due in part to higher HCV RNA levels in HIV-infected persons compared to those with just HCV infection.
Early Virological Response (EVR)
The absence of an EVR is the most robust means of identifying non-responders. Data from two retrospective analyses of multicenter trials indicated that failure to decrease serum HCV RNA by 2 logs or more at treatment week 12 correlated strongly with non-response in treatment-naive subjects with genotype 1 infection.[72][105] Ninety-seven to 100% of treatment-naive patients with HCV genotype 1 infection who did not reach an EVR failed to achieve an SVR. Thus, patients who do not have an EVR can discontinue therapy early without compromising their chance to achieve an SVR. In contrast, an EVR is less accurate in predicting an SVR since only 65% to 72% of subjects who achieved an EVR ultimately attained an SVR. A completely negative test for HCV RNA at week 12 (complete EVR) is a better predictor of an SVR than a 2-log reduction in HCV RNA, 83% versus 21%.[105] The clinical utility of an EVR is less helpful in persons with HCV genotype 2 and 3 infection since a majority of such individuals clear virus by week 12 and respond to therapy.
Rapid Virological Response (RVR)
Earlier time points have also been examined in the hope of limiting exposure to and the side effects of therapy. Achieving an RVR is highly predictive of obtaining an SVR independent of genotype and regardless of the treatment regimen.[107] However, only 15% to 20% of persons with HCV genotype 1 infection and 66% with HCV genotype 2 and 3 infections achieve an RVR.[107][114] In a retrospective analysis of the predictive value of an RVR in persons with HCV genotype 1 treated with peginterferon alfa-2a, those who achieved an RVR had an SVR rate of 91%, those who achieved a complete EVR had an SVR rate of 75%, and those who achieved an undetectable HCV RNA at week 24, had an SVR rate of 45%.[107]
Because of the rapid clearance of virus from serum, patients who achieve an RVR may be able to shorten the duration of treatment.[104][107] In contrast, because of a poor negative predictive value, the absence of an RVR should not be a basis for discontinuing treatment.
Utility of RVR in Patients with Genotype 1 Infection.
Two analyses suggest that patients with HCV genotype 1 who achieve an RVR may be able to shorten the duration of therapy from 48 to 24 weeks. A post hoc analysis was conducted of a trial in which patients with chronic HCV infection were treated with peginterferon alfa-2a plus ribavirin either with a fixed dose (800 mg per day) or a weight-based dose (800-1,200 mg per day) for 24 or 48 weeks.[73] Overall, 24% of patients with HCV genotype 1 infection in the two 24-week treatment arms achieved an RVR. The SVR rate was 89% in patients who achieved an RVR and 19% in those who did not achieve an RVR, and was similar among those treated for 24 or 48 weeks.[104] Features predictive of an RVR were a low baseline viral load (<200,000 IU/mL) and HCV subtype 1b.
In another study, patients with HCV genotype 1 infection and a low viral load (<600,000 IU/mL) were treated with peginterferon alfa-2b, 1.5 ug/kg/week plus ribavirin 800 to 1,400 mg daily for 24 weeks.[115] Overall an SVR occurred in 50% of patients.[115] However, a subanalysis of patients who achieved an RVR, 47%, reported an SVR rate of 89% compared to 20% among those who did not achieve an RVR. These results suggest that HCV genotype 1 patients who achieve an RVR can be successfully treated with a 24-week course of therapy.
Utility of an RVR in Persons with Genotypes 2 and 3 Infections.
Four trials have evaluated the usefulness of an RVR in shortening the duration of therapy from 24 weeks to 12 to 16 weeks in patients with chronic HCV genotypes 2 and 3 infection.[116-119] Although not directly comparable because of the use of different inclusion criteria, treatment regimens and trial designs, the data from these trials suggest that patients with genotypes 2 and 3 infection who achieve an RVR can shorten their treatment duration to 12 to 16 weeks, because the SVR rates at 12 to 16 weeks (62%-94%) were comparable to the SVR rates at 24 weeks (70%-95%), (Table 9). The one shortcoming of this approach is that the relapse rate more than doubles from 3% to 13% in those treated for 24 weeks, to 10% to 30% for those treated for 12 to 16 weeks. Importantly, patients with HCV, genotypes 2 and 3 who relapse after a short course of treatment almost always achieve an SVR when re-treated with a standard 24-week course of therapy. No predictors of an RVR were identified in multivariate analysis in the single study that performed this analysis.[117] Predictors of an SVR among these studies were HCV genotype 2 infection, a low baseline HCV RNA level (<800,000 IU/mL), and the absence of bridging fibrosis or cirrhosis.[118] Patients with genotype 2 and 3 infections who fail to achieve an RVR (mostly patients with HCV genotype 3 infection with high viral loads and bridging fibrosis or cirrhosis) have poor SVR rates with 24 weeks of therapy and may benefit from longer duration of treatment, but this has not been prospectively evaluated.
Based on these results, it appears that patients with HCV genotype 2 or 3 infections who achieve an RVR can shorten their duration of therapy to 12 to 16 weeks. However, a recent large multicenter, multinational trial that included 1,469 patients with genotype 2 and 3 infection has challenged this concept. Patients were randomized to receive peginterferon alfa-2a, 180 ug / week plus 800 mg of ribavirin for either 16 or 24 weeks without stratification based upon RVR. In contrast to previous studies, the results demonstrated that treatment for 24 weeks was superior to treatment for 16 weeks (SVR rate 76% versus 65%, respectively, P <0.001), even in those who achieved an RVR (85% versus 79%, respectively).[114] One possible explanation for this varying result was that a fixed dose of ribavirin (800 mg) was used in this trial whereas weight-based ribavirin was used in the other trials.
Thus, patients with HCV genotypes 2 and 3 who are intolerant of a planned 24-week course of therapy can have their therapy discontinued between weeks 12 and 16 if they had achieved an RVR. However, patients should be informed of the higher relapse rate associated with this strategy and be advised that re-treatment with a 24 to 48 week course of therapy may be required. Patients with HCV genotype 3 and a high viral load have lower response rates than do patients with HCV genotype 3 and a low viral load and patients with genotype 2 infections. Therefore, a longer duration of therapy should be considered for such patients. Comparable data are not available in difficult-to-treat populations such as African Americans, those with cirrhosis and those with HIV-HCV coinfection, and therefore this strategy cannot be recommended for these patient populations.
Treatment of Persons with Psychiatric Illnesses
Patients with chronic HCV infection have a higher prevalence of psychiatric illness compared to the general U.S. population. The prevalence of chronic HCV infection in patients with mental or psychiatric diseases ranges from 8% to 31%, which is 4 to 20 times that of the U.S. population (1.8%). Mental or psychiatric disease represents a significant barrier to treatment in patients with chronic HCV infection. The argument against treatment of this population stems from the neuropsychiatric side effects associated with interferon and ribavirin therapy such as depression, irritability, suicidal ideation, mania, mood swings and relapse of drug or alcohol abuse.[389][402] Persons with mental or psychiatric disorders are felt to be at higher risk for these side effects.[402] Significant depressive symptoms occur in 21% to 58% of interferon-treated patients. However, a recent prospective controlled trial demonstrated that these patients may be successfully treated with a multidisiplinary approach to management of adherence and neuropsychiatric side effects. Using this approach, they can achieve SVR rates that are similar to patients without psychiatric disorders.[403]
Most psychotropic agents are thought to be safe for use in the management of patients with chronic HCV infection and psychiatric disease. However, consideration should be given to drug-drug interactions and dose modification in patients with advanced liver disease. Despite the clinical challenges of HCV treatment in patients with mental and psychiatric disease, the available evidence is that interferon and ribavirin can be safely administered provided there is comprehensive pretreatment psychiatric assessment, a risk benefit analysis is conducted, and there are provisions for ongoing follow-up of neuropsychiatric symptoms during antiviral therapy by a multidisciplinary team.
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