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HEPATITIS CHEPATITIS C
« on: /September/ 30, 2005, 08:39:48 AM »

DIAGNOSIS AND TREATMENT OF ACUTE HEPATITIS C INFECTION

INTRODUCTION

? Identification of patients with acute hepatitis C virus infection is uncommon since most patients are asymptomatic. Furthermore, the incidence of acute hepatitis C infection has declined. Nevertheless, occasional patients with acute infection continue to be recognized usually because of symptoms or during surveillance following a known exposure. Hepatitis C is estimated to account for approximately 20 percent of cases of acute viral hepatitis in the United States and many other countries.
An approach to patients with acute hepatitis C infection will be presented here. An overview of treatment recommendations for chronic hepatitis C is discussed separately.

DIAGNOSIS ? The presence of HCV RNA in serum or liver is the first biochemical evidence of HCV infection. HCV RNA is detectable in serum by PCR within days to eight weeks following exposure, depending in part upon the size of the inoculum [1,2]. In a series of 14 needle stick injuries, an early negative HCV PCR appears to have a high negative predictive value [3]. However, the minimal interval following suspected exposure after which a persistently negative HCV PCR test excludes infection has not been definitely established.

Serum aminotransferases become elevated approximately 6 to 12 weeks after exposure (range 1 to 26 weeks). Serum ALT levels are variable; in one of the largest series that included 44 patients, the mean ALT was 885 U/L (+/- 554 U/L) [4].

Anti-HCV-ELISA tests become positive as early as eight weeks after exposure . Approximately one-half of patients with symptomatic acute infection have detectable antibodies to HCV by ELISA when first presenting [1]. However, the development of HCV antibodies may be delayed in patients who have subclinical infection. This was illustrated in a study of 19 patients who acquired HCV from injection drug use, in whom HCV RNA was detectable in low levels in blood or peripheral blood mononuclear cells for an average of 41 months (range 13 to 94) prior to the development of antibodies [5]. In rare patients it may take several months for a positive antibody response. A positive anti-HCV-ELISA does not distinguish those who cleared the infection from those who are chronically infected.

Fluctuation of serum aminotransferases is common after the acute infection; the serum alanine aminotransferase (ALT) concentration may normalize in up to 40 percent of cases. However, actual resolution of infection, as determined by the persistent loss of HCV-RNA, occurs in fewer than 15 percent of patients. Furthermore, HCV-RNA may remain detectable in the liver even in patients in whom it is undetectable in serum, although its clinical significance is uncertain [6]. Thus, normalization of the serum ALT concentration after acute infection does not necessarily mean that the infection has cleared.

Recommendation following known exposure ? The timing of the events discussed above provides a rationale for testing for acute HCV infection following a known exposure. Patients should undergo:

Testing for HCV by PCR immediately and at weeks 4 and 12

Antibody testing using an ELISA immediately and at week 12

Serum aminotransferases (ALT and AST) immediately and at weeks 4 and 12


These recommendations are similar to those suggested by the National Institutes of Health, with slight differences in testing intervals.

Distinction from chronic infection ? The distinction between acute hepatitis C virus infection and newly discovered chronic infection may not always be straightforward since in both settings patients may have detectable HCV RNA, antibodies against HCV, and elevated serum aminotransferases. The pattern and timing of serologic markers, including HCV RNA and serum aminotransferases and antibodies with respect to a suspected exposure, can be helpful

However, in many cases, suggestive circumstantial evidence for new infection (such as a history of a recent exposure, new clinical features of acute hepatitis, and exclusion of other causes) must suffice as a substitute for a documented new anti-HCV-ELISA seroconversion in the presence of HCV PCR positivity. Symptoms suggesting acute viral hepatitis include anorexia, nausea, malaise, right upper quadrant discomfort, and uncommonly jaundice (occurring in less than 25 percent of patients). In patients who experience acute symptoms, the illness typically lasts for 2 to 12 weeks. Fulminant hepatic failure due to acute HCV infection is rare [7,8].

Development of chronic infection ? The risk of chronic infection after an acute episode of hepatitis C is high. In most studies, 80 to 100 percent of patients remained HCV RNA positive, while 60 to 80 percent had persistently elevated serum aminotransferases [2,9-12]. As a general rule, most patients who are destined to spontaneously clear HCV viremia do so within 12 weeks and usually no later than 20 weeks after the onset of symptoms [13,14]. Whether spontaneous clearance can occur after longer follow-up (as in the case of chronic hepatitis B) is unclear but is unlikely when considering long-term follow-up studies in patients with post-transfusion hepatitis.

Higher rates of spontaneous HCV RNA clearance (approximately 50 percent) have been described in some populations such as in children and those infected after Rh immunization [10,15,16]. There is also some evidence that the risk of developing chronic infection may be lower in patients presenting with symptomatic acute HCV infection [10-13]. In a study focusing on 51 patients, spontaneous clearance was observed in 52 percent of symptomatic patients compared to none of nine patients with asymptomatic infection [13]. Symptoms included jaundice (68 percent) nausea (34 percent) dark urine and white stool (39 percent), right upper quadrant pain (25 percent) and flu-like symptoms (55 percent). Asymptomatic patients had been diagnosed during testing after a known exposure. A rapid decline in HCV RNA was predictive of spontaneous viral clearance in two other series of 40 and 12 patients, respectively [14,17]. Host and viral factors that have an influence on rates of spontaneous viral clearance remain a topic of intensive investigation [18]. (See "Clinical features and natural history of hepatitis C virus infection").

TREATMENT ? The high risk of chronic infection provided the rationale for studies aimed at reducing the incidence of chronic infection [4,19-25]. Multiple small studies have evaluated the efficacy of interferon monotherapy for acute hepatitis C infection. Most focused primarily on patients with transfusion-associated infection, were small, used interferon beta, treated for only a short duration, or did not measure outcomes based upon HCV RNA clearance. A meta-analysis of four randomized trials involving 141 patients with acute transfusion-acquired HCV found that patients treated with standard interferon monotherapy had a greater likelihood of having an end-of-treatment virologic response (42 versus 4 percent) and a sustained virologic response (32 versus 4 percent) [24].

A more recent trial that was not included in the meta-analysis involved 44 patients identified within four months of acute infection who were treated with interferon alfa monotherapy (5 MU subcutaneously daily for four weeks followed by 5 MU subcutaneously three times weekly for 20 more weeks) [4]. The majority of patients were infected with genotype 1 (61 percent). Twenty-four weeks after the end of treatment, 98 percent were HCV RNA negative, a rate of clearance that was much higher than would have been expected to occur spontaneously. Therapy was well-tolerated except in one patient who discontinued treatment. The incidence of adverse effects were similar to those observed during interferon treatment for chronic hepatitis C, and were not more severe during the initial four weeks of treatment compared to the subsequent 20 weeks. A subsequent report included 31 of the patients who were followed for a median of 135 weeks during which HCV RNA remained undetectable suggesting that the virologic response was durable [26].

The reason why the sustained virologic response rate was higher than the estimated response rate in the meta-analysis cited above [24] is unclear. One possible contributing factor may have been the relatively high dose of interferon used and the induction strategy, a hypothesis supported by the results of another study in which a high dose of interferon was also used [20].

Another study described 60 patients with acute HCV, 54 of whom were not treated immediately [13]. In this subgroup of patients, spontaneous clearance of HCV RNA was observed in 37 patients (68 percent) at a mean of eight weeks after diagnosis (range 1 to 26 weeks). However, relapse of HCV RNA occurred in 13 patients; thus only 24 of the 54 initially untreated patients (44 percent) remained persistently HCV RNA negative during a median follow-up of 27 months and were classified as having self-limited HCV infection.

Twenty patients who developed chronic infection were treated with interferon alone or in combination with ribavirin leading to a sustained virologic response in 16 (80 percent). The authors concluded that for patients with symptomatic acute HCV, a strategy of waiting for three months to evaluate for spontaneous clearance with treatment in those who continue to be HCV RNA positive would lead to a sustained virologic response rate in approximately 90 percent of patients while avoiding unnecessary treatment in those who would ultimately clear the virus spontaneously. The occurrence of spontaneous clearance of HCV before week 12 and a high sustained virologic response to early treatment have also been described in other smaller reports [14,27]. A meta-analysis of 16 trials concluded that later initiation of therapy yielded the same likelihood of response as early treatment [28].

A third study (also not included in the meta-analysis) focused on 30 patients with acute HCV who were randomly assigned to interferon therapy (natural interferon alfa 6 million units daily for four weeks) beginning eight weeks after the onset of acute hepatitis or after one-year of observation [29]. Patients who initially cleared the virus with treatment but then relapsed were treated with natural interferon therapy three times weekly for 20 weeks.

In the group receiving treatment at eight weeks, a sustained virologic response was observed in 13 of 15 patients (87 percent) after short-term therapy alone, and in all patients when considering the two who were continued for six months on adjunctive therapy for non response or relapse on short term therapy. In contrast, in the group receiving treatment after one year, only 6 of 15 patients (40 percent) responded after short-term therapy alone and two more (adding up to 53 percent) after adjunctive therapy for non response or relapse on short term therapy.

Pegylated interferon ? The efficacy of monotherapy with pegylated interferon was evaluated in an open-label trial (reported as an abstract) involving 79 patients with acute HCV [30]. Patients were identified mostly following surveillance after a known exposure. Patients received pegylated interferon alfa-2b (1.5 microG/kg) for 24 weeks beginning when acute infection was detected. Genotype 1 infection was present in 65 percent. The mean serum alanine aminotransferase concentration was 588 (range 24 to 2670 IU/L) and the average time from infection to detection was 73 days.

A sustained virologic response was observed in 67 percent of patients on an intention-to-treat basis. Of those who completed the treatment (ie, those who did not drop out) 27 of 29 had a sustained virologic response. There was no apparent difference in response rates based upon the levels of aminotransferases or the presence of signs or symptoms of acute hepatitis. Serious adverse events related to treatment included a patient who committed suicide.

The authors concluded that pegylated interferon is effective for acute HCV and can be given to patients with high serum aminotransferases. However, as noted above, there were several dropouts for various reasons, and one serious consequence from treatment. Thus, careful patient selection is necessary. Furthermore, the proportion of patients who may have cleared the virus spontaneously is uncertain. The authors are currently conducting a follow-up study in which treatment is delayed for 12 weeks to identify patients who may spontaneously clear the infection.

Such a treatment delay was allowed in another report (also in abstract form) of 16 patients with acute HCV who remained viremic after 12 weeks and were treated with pegylated interferon alfa 2b (1.5 mcg/kg per week) for six months [31]. An end of treatment virologic response was observed in 15 patients all of whom remained HCV RNA negative three months after discontinuing treatment. Six-month follow-up was available in 10 patients, nine of whom remained HCV RNA negative. Ten of the 16 patients had genotypes 2 or 3.

The efficacy of combination therapy with pegylated interferon plus ribavirin was evaluated in a prospective study that included 40 subjects with acute HCV who were treated with pegylated interferon plus ribavirin combination therapy (n=20) or pegylated interferon monotherapy (n=20) for 24 weeks [32]. Rates of SVR were compared to a group of 14 untreated controls. All patients were infected with genotypes 1 or 4. Treatment was initiated after an initial 12 week observation period; thus, all 40 of the treated patients had failed to recover spontaneously.

SVR was observed in 85 percent of the combination group and 80 percent of the monotherapy group. By comparison, only 5 of the 14 untreated patients achieved spontaneous recovery. Immunologic analysis showed that the breadth of the HCV-specific CD4 T helper 1 responses were significantly higher in the treated patients compared to untreated subjects with self-limited disease or those who evolved to chronic infection.

Consensus statements ? A consensus development conference on the treatment of hepatitis C convened at the National Institutes of Health [33]. A brief comment on treatment of acute hepatitis C was included (http://www.consensus.nih.gov/cons/116/116cdc_intro.htm):

"Studies of interferon treatment for acute hepatitis C have been very heterogeneous and limited by small sample size; lack of randomization; and variability in the timing of therapy after onset of infection, dose, schedule, end points, and follow-up. High SVR rates (83 to 100 percent) have been reported by small uncontrolled trials with interferon monotherapy. Accordingly, treatment of persons with acute hepatitis C is warranted, but the timing of therapy and the type of regimen to use remains to be determined from future trials."


The 1997 German consensus recommended treatment with interferon-alpha (5 to 6 million units three times weekly for three months) starting at diagnosis [34]. The recommendations were based upon the 41 percent sustained viral response rate described in a meta-analysis [22], a sustained response rate much lower than has been achieved in subsequent studies (see above). An update of these recommendations is not currently available.

A 2004 guideline issued by the American Association for the Study of Liver Diseases (AASLD) suggests that it is appropriate to consider use of pegylated interferon because of its improved ease of administration [35]. The decision to use ribavirin was recommended on a case-by-case basis. Delay of treatment for two to four months after acute onset was considered reasonable to determine whether spontaneous resolution will occur. No definitive recommendation regarding duration was offered, although at least six months of therapy was considered reasonable. (See "AASLD Guideline: Diagnosis, management, and treatment of hepatitis C: Part 1")

RECOMMENDATIONS ? The limited available evidence (most of which has been derived from uncontrolled trials) combined with the expense and side effects of interferon treatment leaves some controversy as to the optimal management of patients with acute hepatitis C [36]. None of the available treatments has been approved for treatment of acute HCV. Nevertheless, in aggregate, the data suggest that treatment with interferon-based regimens during acute infection can augment the rate of sustained virologic clearance beyond which might be expected from later treatment in the chronic phase. The magnitude of the benefit and the optimal selection of patients remain uncertain. Furthermore, it is possible that the overall benefit in published series reflects selection bias or underreporting of negative trials.

How to treat ? The majority of trials on acute HCV used interferon-alpha monotherapy. The best results in any single study used a regimen that began initially with 5 MU subcutaneously daily for four weeks followed by 5 MU subcutaneously three times weekly for 20 more weeks [4]. The sustained virologic response rate with this regimen was a remarkable 98 percent. The induction strategy and the use of a relatively high dose of standard interferon therapy may have been an important factor leading to the high sustained virologic success rate. Another study using a similar regimen also reported a high sustained virologic response rate [20]. In contrast, lower sustained virologic rates have been described in several studies using alternate day regimens.

Whether such a nearly complete response rate could be achieved with pegylated interferon has not been established, although emerging data suggest that the response rates in a subgroup of patients who completed pegylated interferon for six months may be similar [30-32]. As a result, some hepatologists have already begun using pegylated interferon. This option may be preferable since it is easier to administer, may be better tolerated and is in line with the 2004 practice guideline of the American Association for the Study of Liver Diseases. When using the induction regimen with standard interferon described above, it is reasonable to switch to pegylated interferon plus ribavirin in patients who continue to be HCV RNA positive three months after beginning the interferon induction therapy using standard interferon since such patients are likely to have developed chronic infection. We use this approach regardless of the HCV genotype.

When to start treatment ? The data presented above suggest that spontaneous HCV clearance following acute infection is most likely to be observed within 12 weeks (range 2 to 24 weeks) following the onset of symptoms. Spontaneous clearance appears to be more likely in patients who developed symptomatic hepatitis. Delaying treatment until after this period does not appear to decrease the likelihood of a sustained virologic response. Thus, it may be reasonable to assess HCV RNA status three months after symptom onset before beginning therapy. Patients who appear to have cleared HCV RNA should have subsequent determinations at three-month intervals for one year to assure that clearance was sustained. Possible exceptions to the above are those who are infected via a transfusion (an uncommon occurrence since the implementation of routine screening of the blood supply for HCV markers) and those with asymptomatic acute HCV; chronic infection appears to be highly likely in such patients, potentially warranting immediate treatment upon diagnosis.

Because of the unresolved questions discussed above and the infrequency with which acute hepatitis C is detected, patients should preferably be treated within clinical trials.
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Re: HEPATITIS CHEPATITIS C
« Reply #1 on: /September/ 30, 2005, 08:44:05 AM »

Treatment of chronic hepatitis C virus infection: Recommendations


INTRODUCTION ? The hepatitis C virus (HCV) can cause both acute and chronic hepatitis. The acute process is self-limited, rarely causes hepatic failure, but usually leads to chronic infection. In contrast, chronic HCV infection often follows a progressive course over many years, and can ultimately result in cirrhosis and the need for liver transplantation or hepatocellular carcinoma.

This topic review will summarize general principles of management of chronic HCV infection. The epidemiology, diagnosis, and a review of the trials supporting the use of standard or pegylated interferon monotherapy or combination therapy with ribavirin are discussed in detail separately.

GENERAL MEASURES ? Although most patients with chronic HCV infection are asymptomatic at the time of diagnosis, they are faced with a looming threat to their health, which can have significant emotional and physical consequences. Counseling and screening for depression should be a major consideration upon diagnosis and on subsequent follow-up. Many patients benefit from participation in a support group.

Counseling should include discussion about the routes of transmission of the hepatitis C virus. In particular, most patients are concerned about sexual transmission and the risk of infecting household contacts

Diet ? Many patients are also concerned about dietary factors that could favorably or adversely affect the disease. Although no particular diet has been shown to be beneficial in patients with chronic HCV infection, it is clear that alcohol promotes the progression of chronic HCV. We recommend that alcohol consumption should be avoided.

It is reasonable to suggest supplementation with vitamin E since it is safe, and it impaired fibrogenesis in a pilot study, presumably by an effect on hepatic stellate cells [1]. Furthermore, in two small controlled studies it significantly reduced the serum alanine aminotransferase concentration [2,3]. However, vitamin E has no effect on viral replication, and its influence on the natural history of hepatitis C is unknown.

Fatigue ? Many patients complain of fatigue, the cause of which is uncertain and may be difficult to ascribe to liver disease alone (rather than to another illness such as depression). No specific treatment has been proven to be beneficial for treatment of fatigue in controlled trials. In a case report, ondansetron (4 mg twice daily) given in a double-blind crossover trial was helpful [4]. The rationale for its use was based upon the observation that serotonin is associated with fatigue in animal and human models [5]. Fatigue improves in some patients who have a sustained virologic response following interferon-based therapy; in one of the largest series addressing this issue, fatigue improved in 29 of 83 responders versus 75 of 348 nonresponders (35 versus 22 percent) [6].

Dose adjustments ? Prescription and over-the-counter medications usually do not require dose adjustment in patients who have normal hepatic function. Many patients voice concern about taking acetaminophen due to its association with liver injury. We recommend that the dose of acetaminophen should not exceed 2 g per 24 hours.

Vaccination ? Patients with chronic HCV infection should be vaccinated against hepatitis A if they lack hepatitis A antibody. This recommendation is based upon a study of 163 patients with chronic hepatitis B and 432 patients with chronic hepatitis C who were prospectively followed for seven years [7]. Hepatitis A superinfection occurred in 27 patients. An uncomplicated course occurred in 9 of the 10 patients with hepatitis B who acquired hepatitis A; one patient who also had preexisting cirrhosis developed marked cholestasis. In comparison, fulminant hepatic failure developed in 7 of the 17 patients with HCV who acquired hepatitis A; six of these patients died. Despite this recommendation, the cost-effectiveness of routinely vaccinating patients with chronic HCV has been questioned [8], although at least one decision-analysis found it to be cost-effective, particularly in young patients [9], while another found it to be cost-effective when given to patients with HCV who tested negatively for anti-HAV antibodies [10].

Patients who lack antibodies to hepatitis B virus should be vaccinated against hepatitis B. Pneumococcal vaccine and yearly influenza vaccination should be considered in patients who have developed cirrhosis

Screening for varices and hepatocellular carcinoma ? Patients with cirrhosis should be screened for the presence of esophageal varices by upper endoscopy. In addition, it is common practice to screen such patients for hepatocellular carcinoma with a right upper quadrant ultrasound and serum alfa fetoprotein concentration every six months.

SELECTION OF PATIENTS FOR TREATMENT ? The decision to treat patients with chronic hepatitis C infection is based upon several factors, including the natural history and stage of the disease and the efficacy and adverse effects related to therapy. As a general rule, patients who are considered for treatment should have histologic and virologic evidence of chronic infection (ie, HCV RNA detectable in serum) and an elevated serum ALT

A thorough evaluation for other types of liver disease should also be obtained, and other medical conditions should be investigated, since they may have bearing on the treatment plan. As examples:

Interferon is contraindicated in patients who have major depression because such patients are at risk for committing suicide during treatment. Ribavirin is contraindicated in women who are pregnant, contemplating pregnancy or unwilling to assure contraception.

Patients with underlying autoimmune disorders may also be at increased risk from therapy with interferon.

Other liver diseases can interact adversely with chronic hepatitis C. As an example, alcohol abuse reduces the responsiveness to interferon, accelerates disease progression, and increases the risk of hepatocellular carcinoma [11,12]. As a result, patients with chronic hepatitis C should be evaluated for other causes of chronic liver disease and counseled not to drink alcohol.

Certain underlying diseases can modify the treatment plan. Patients with concurrent hereditary hemochromatosis, for example, should first be treated with phlebotomy to reduce iron accumulation.

Patients with concurrent HIV infection have an accelerated rate of progression of HCV and the responsiveness to interferon is determined by the immune status.

In addition to the above considerations, the threshold for recommending treatment may be influenced by a number of other factors. As examples, the threshold for treatment may be increased in the elderly and in patients with only mild hepatitis on biopsy who have unfavorable treatment characteristics (such as genotype 1 and a high viral load). On the other hand, the threshold may be decreased in patients with genotype 2 or 3 and a low viral load since combination therapy is associated with a sustained virologic response as high as 65 to 80 percent in such patients.

Persistently normal serum ALT ? Up to 30 percent of patients with chronic hepatitis C infection have a persistently normal serum ALT. The optimal management for such patients remains controversial. As a group, these patients may have a better prognosis than those who have an elevated serum ALT [13]. However, some of these patients may have substantial inflammation on liver biopsy [14].

The 1997 National Institutes of Health Consensus Conference recommended that patients with normal serum ALT should not be treated with interferon even if there is evidence of chronic hepatitis on liver biopsy (see below) [15]. A revised consensus statement from 2002 suggested that many factors should be considered in deciding upon treatment including the genotype, findings on liver biopsy, patient motivation, symptoms, severity of comorbid illness, and age. (http://consensus.nih.gov/cons/116/116cdc_intro.htm). Similarly, a 2004 guideline issued by the American Association for the Study of Liver Diseases suggested that the decision to initiate therapy in patients with persistently normal aminotransferase values should be individualized based upon the severity of disease, the potential for side effects, the likelihood of response, and the presence of comorbid conditions [16].

Patients with a persistently normal serum ALT who acquired HCV under the age of 35 years, are women, do not drink alcohol, and have no or minimal fibrosis on liver biopsy may have a slow rate of hepatic fibrosis progression [17]. In such patients, it is reasonable to withhold treatment pending the results of ongoing clinical trials. In contrast, patients who do not fit this profile, and whose initial biopsy shows moderate activity or some degree of fibrosis may be at increased risk of disease progression. We offer therapy to such individuals after discussing that this approach is not scientifically proven. We usually treat such patients using combination therapy with pegylated interferon alfa plus ribavirin.

Role of liver biopsy ? Most patients undergo liver biopsy prior to treatment of chronic HCV infection, although the utility of a routine biopsy continues to be debated. Despite these concerns, a liver biopsy has many practical advantages in the care of patients with HCV in whom treatment is being considered [18]:

Liver histology is useful for predicting the stage and prognosis of the disease. Patients with cirrhosis should undergo periodic screening for hepatocellular carcinoma, and upper endoscopy to evaluate for varices.

Once treatment has started, the baseline liver histology can assist in decisions regarding medication adjustment in patients who experience adverse effects. As an example, the threshold to discontinue therapy may be relatively high in patients who have advanced histologic features.

A liver biopsy can establish the presence of concomitant diseases (such as hemochromatosis, alcoholic hepatitis, and hepatic sarcoidosis), and the degree to which these conditions contribute to the liver disease.


The initial 1997 National Institutes of Health Consensus Development Conference on Hepatitis C recommended liver biopsy in all patients with chronic hepatitis C prior to treatment [15]. In contrast, a revised NIH consensus statement from 2002 recognized that a liver biopsy may not be necessary in all patients prior to treatment. In particular, a biopsy may not be required prior to treatment of patients with genotype 2 or 3 (in whom the virologic response rate is as high as 80 percent) provided that other causes of liver disease have been excluded. (http://consensus.nih.gov/cons/116/116cdc_intro.htm).

We generally perform a liver biopsy prior to treatment. We do not perform a liver biopsy in patients who have had a sustained virologic response to treatment. Although there is little information on the appropriate interval for subsequent evaluations, a repeat liver biopsy in two years (some authorities use longer intervals) to evaluate for disease progression is reasonable in patients who do not respond or in those who declined treatment.

Proportion of patients eligible for treatment ? The issues discussed above limit the number of patients who are HCV antibody positive who are eligible for treatment. The proportion of HCV positive individuals who are treated has not been well studied. A case series suggested that it may be only a small subset of HCV positive patients [19]. Of 327 patients referred to a liver clinic in a metropolitan area, only 83 (28 percent) were ultimately treated. The most common reasons for exclusion were failure to adhere to evaluation procedures (37 percent), medical or psychiatric contraindications (34 percent), patient preferences (11 percent), absence of HCV RNA (10 percent), and normal liver enzymes (5 percent). Whether these observations represent the experience in other regions is unclear.

FACTORS ASSOCIATED WITH A RESPONSE TO INTERFERON AND RIBAVIRIN ? Several host and viral characteristics have been associated with a response to therapy. The most important predictors of a sustained virologic response following combination treatment with pegylated interferon plus ribavirin are the HCV genotype (ie, higher response in those with genotypes 2 and 3 compared with 1) and (to a lesser extent) viral load (ie, higher response in those with a viral load 2 X 10 (6) copies/mL [approximately 800,000 IU/mL]) (show table 2) [20].

Other predictors that have been associated with higher rates of a sustained virologic response include younger age, lower body weight, and absence of bridging fibrosis or cirrhosis. In addition, response is generally lower in African Americans. An interferon sensitizing region within the HCV genome has also been identified, but its role is less well established.

Once therapy has been started, the likelihood of a sustained virologic response can be predicted based upon the virologic response at 12 weeks of therapy.

NIH GUIDELINES ? Guidelines for the selection of patients for treatment with interferon monotherapy were initially proposed at the National Institutes of Health (NIH) Consensus Development Conference on Hepatitis C in 1997 [21]. Because of development of better treatment and a more detailed understanding of the natural history of the disease, the guidelines were revised in 2002 to include a broader range of potentially eligible patients [22]. (http://consensus.nih.gov/cons/116/116cdc_intro.htm).

The Consensus Panel recommended that all patients with chronic hepatitis C should be considered as potential candidates for antiviral therapy. Treatment should be recommended for patients who are at increased risk for progression to cirrhosis. Such patients are characterized by the presence of measurable HCV, a liver biopsy showing portal or bridging fibrosis, and at least moderate inflammation and necrosis; the majority of these patients have persistently elevated serum ALT values.
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Re: HEPATITIS CHEPATITIS C
« Reply #2 on: /September/ 30, 2005, 08:44:27 AM »

The Consensus Recommendations recognized that the risks and benefits of therapy are less clear in other patient populations. Treatment in such cases should be determined on an individual basis or in the context of clinical trials. Patients with ongoing injection drug use, alcohol abuse, older age, and comorbid medical or psychiatric illness have generally been excluded from trials. The NIH recommended that efforts should be made to increase the availability of the best current treatment to these patients. Similarly, better strategies are needed to prevent, diagnose, and treat individuals who are incarcerated.

The following sections represent NIH comments in particular settings.

Mild liver disease ? Patients who have persistent elevation in serum ALT but do not have fibrosis and have minimal necroinflammatory changes are likely to have only slow disease progression. Such patients can be monitored periodically. However, the decision to treat should be individualized.

Advanced liver disease ? The efficacy of treatment in patients with advanced fibrosis or compensated cirrhosis has been derived mostly from subgroup analysis of larger clinical trials. These have suggested that the response is lower than in patients without cirrhosis. Patients with decompensated cirrhosis should be referred for clinical trials until the safety and efficacy data of treatment are established. The main treatment option for such patients is liver transplantation.

Recurrence after transplantation ? Disease progression following transplantation is accelerated compared to immunocompetent patients with HCV infection. In addition, the risk of complications is higher in post-transplant HCV patients with cirrhosis compared to immunocompetent patients with cirrhosis. Recurrence correlates with HCV RNA levels at the time of transplantation, the age of the organ donor, and the degree of immunosuppression in the post-transplant period.

Children ? There are relatively few data on treatment of children and adolescents. Sustained virological response rates with interferon monotherapy are similar or better than those in adults. Studies of combination therapy in children are ongoing.

Acute infection ? The Consensus panel recognized that studies of interferon for acute HCV have been small, heterogeneous, and lacked randomization. The panel recommended that treatment of persons with acute hepatitis C is warranted, but the timing of therapy and the type of regimen to use remains to be determined from future trials.

Injection drug users ? Management of HCV-infected intravenous drug users can be enhanced by linkage with drug-treatment programs. HCV therapy can be successful even when patients have not been abstinent from continued drug use or are on daily methadone [23].

Coinfection with HIV ? All HIV infected persons should undergo screening for HCV. Coinfection is associated with an accelerated course of HCV disease. While no therapies have been specifically approved for coinfected patients, such patients should be considered for treatment. Preliminary data suggest better responses to pegylated interferon plus ribavirin compared to standard interferon plus ribavirin.

Alcohol ? Alcohol is an important cofactor in HCV disease progression. While a history of alcohol abuse is not an absolute contraindication to therapy, continued alcohol use decreases the response to therapy. Thus, treatment should be performed along with efforts to treat the alcohol abuse. The amount of alcohol that is safe during treatment is unknown.


AASLD GUIDELINES ? Guidelines issued by the American Association for the Study of Liver Diseases (AASLD) are consistent with the NIH guidelines but provide additional details. The AASLD recognizes three categories of patients: those in whom therapy is widely accepted, those in whom therapy should be individualized, those in whom therapy is contraindicated.

Persons for whom therapy is widely accepted ? The AASLD recommends that therapy is widely accepted in patients with the following characteristics;

At least 18 years of age

Abnormal serum ALT values

Liver biopsy with chronic hepatitis with significant fibrosis (more than portal fibrosis (Metavir score 2, or Ishak score 3).

Compensated liver disease (total serum bilirubin <1.5 g/dL; INR <1.5; albumin >3.4 g/dL; platelet count >75,000 k/mm(3); and no evidence of hepatic encephalopathy or ascites).

Acceptable hematological and biochemical indices (hemoglobin >13 g/dL for men and >12 g/dL for women; neutrophil count >1.5 k/mm(3); creatinine < 1.5 mg/dL)

Willing to be treated and to conform to treatment requirements.


Patients who fulfill these criteria had have been treated previously for HCV infection can also be considered. Those with a history of depression but the condition is well controlled can also be considered for treatment.

Persons for whom therapy should be individualized ? The AASLD recommends that therapy should be individualized for patients:

With persistently normal ALT values

Who failed prior treatment (nonresponders and relapser) consisting of either interferon given alone or in combination with ribavirin, or consisting of peginterferon given alone

Current users of illicit drugs or alcohol but willing to participate in a substance abuse program (such as a methadone program) or alcohol support program

Liver biopsy evidence of either no or only mild fibrosis (portal fibrosis: Metavir score <2; Ishak score <3)

Acute hepatitis C

Coinfection with HIV

Less than age 18

Chronic renal disease (on or not on hemodialysis)

Decompensated cirrhosis

Recipient of a liver transplant.


Persons in whom therapy is contraindicated ? The AASLD recommends that therapy is currently contraindicated in persons:

With major, uncontrolled depressive illness

Who received a renal, heart, or lung transplant

With autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin

Untreated hyperthyroidism

Pregnant or unwilling/unable to comply with adequate contraception


Severe concurrent disease such as severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, obstructive pulmonary disease

Younger than 3

Known hypersensitivity to drugs used to treat HCV.


CAUTIONS ? Interferon monotherapy and combination therapy with ribavirin are associated with several adverse effects, and may be contraindicated or should be used with extreme caution in patients with certain preexisting conditions. These include significant cytopenia, pregnancy, severe depression or other psychiatric conditions, cardiac diseases, poorly controlled diabetes, seizure disorders, and autoimmune or potentially immune-mediated diseases.

COST-EFFECTIVENESS ? Although interferon monotherapy is expensive, the costs appear to be justified [24,25]. At least four analyses on combination therapy with interferon and ribavirin suggested it was also cost-effective in patients who have never been treated and those who relapsed following interferon monotherapy [9,26-29].

Another cost-effectiveness analysis focusing on patients with mild histologic disease compared strategies of immediate treatment versus surveillance with a liver biopsy every three years [30]. Immediate therapy was found to be cost-effective with a cost-effectiveness ratio of $7000. Immediate therapy was associated with an increase of at least 0.8 quality-adjusted life-years compared with biopsy management after accounting for age, sex, genotype, compliance, and variable rates of disease progression. At least two cost-effectiveness analyses concluded that combination therapy with pegylated interferon was cost-effective as initial treatment, and that the incremental cost-effectiveness ratio compared with standard interferon plus ribavirin was in an acceptable range [31,32].

A somewhat different approach was taken in another study in which the cost-effectiveness of therapy was considered in various patient groups with different potentials for disease progression [33]. The authors estimated that the probability of developing cirrhosis over a 30-year period ranged from 13 to 46 percent for men and from 1 to 29 percent for women. The incremental cost-effectiveness of combination therapy with pegylated interferon plus ribavirin varied considerably depending upon the likelihood of disease progression. Overall, the greatest benefits were mostly related to improvement in health-related quality of life rather than in improved survival. The authors concluded that the cost-effectiveness of treatment depends upon an appraisal of the likelihood of disease progression and the degree to which chronic infection will impair quality-of-life. As a practical matter, however, neither of these parameters are easy to determine on an individual patient basis.

RECOMMENDATIONS ? General health measures (such as vaccination) for patients with chronic HCV and the selection of patients for treatment are discussed above. Once the decision has been made to treat, the recommended approach varies depending upon clinical setting. The efficacy and safety of the different interferon preparations are reviewed in detail separately.

The clinical trials supporting the use of combination therapy and the details of its administration are also presented elsewhere.

Acute HCV ? Treatment of acute HCV is discussed separately.

Initial therapy ? Combination therapy with pegylated interferon plus ribavirin is superior to interferon monotherapy and to standard interferon/ribavirin combination therapy. Combination therapy should be administered for 48 weeks using standard doses of ribavirin in patients with genotype 1 or 4 (ie, 1,000 mg for those 75 kg in weight and 1,200 mg for those more than 75 kg). Quantitative HCV RNA should be determined before the initiation of therapy and at week 12. Treatment can be discontinued in those who do not achieve an early virologic response (ie, at least a 2-log decline from baseline of the HCV RNA level) at week 12, although the decision should be individualized depending upon how well therapy has been tolerated, the severity of the underlying liver disease, and demonstration of some degree of biochemical and/or virologic response [16].
In contrast, 24 weeks of therapy using a lower dose of ribavirin (800 mg daily in divided doses) appears to be as effective as longer courses of therapy (using the standard higher dose of ribavirin) in patients infected with genotype 2 and 3.

These recommendations are consistent guidelines published by the AASLD

Relapsers and nonresponders ? The NIH consensus statement recommends that decisions regarding the retreatment of patients who failed to achieve a sustained virologic response to initial treatment should be based upon the following considerations: (http://consensus.nih.gov/cons/116/116cdc_intro.htm)

The previous type of response

The previous therapy and the difference in the potency of the new therapy

The severity of the underlying liver disease

Viral genotype and other predictive factors of response

Tolerance and compliance with previous therapy


Similar recommendations have been issued by the AASLD [16].

The following represents our approach in various common settings and are consistent with the consensus statements from the NIH and the AASLD.

Relapsers after interferon monotherapy ? Patients who relapse after an initial response to interferon monotherapy should receive combination therapy with ribavirin (1000 to 1200 mg/day) plus pegylated interferon rather than a repeat course of interferon alfa.

Nonresponders to interferon monotherapy ? Patients who did not respond to interferon monotherapy have a relatively poor response to combination therapy compared to those who relapsed [34]. However, it is reasonable to offer a trial of combination therapy (with pegylated interferon plus ribavirin) to patients who otherwise tolerated interferon monotherapy who have moderate to advanced histologic features.

Nonresponders to standard interferon ribavirin combination therapy ? Options for patients who did not respond to combination therapy with standard interferon and ribavirin include observation, enrollment into a study, or a trial of pegylated interferon plus ribavirin. Preliminary data suggest that the response in such patients to pegylated interferon plus ribavirin is in the range of 11 to 20 percent (with higher rates in patients infected with genotypes 2 or 3 and those who relapsed to therapy and lower rates in patients with cirrhosis) [35-38]. Treatment should be administered for 48 weeks.

Nonresponders to pegylated interferon ribavirin combination therapy ? Options for patients who did not respond to combination therapy with pegylated interferon and ribavirin include observation, enrollment into a clinical trial, or maintenance pegylated interferon therapy. The decision should be based upon a number of factors including patient preference, histologic severity, and access to clinical trials. A repeat biopsy may be warranted in selected patients since significant histologic improvement may occur even in the absence of a sustained virologic response, and appropriate decisions can be predicated on the results of the liver biopsy.

Extrahepatic manifestations of HCV infection ? Interferon alfa has been used with reasonable success for the treatment of extrahepatic manifestations of HCV infection such as essential mixed cryoglobulinemia and glomerulonephritis [39]. Although the role of combination therapy with ribavirin has not been well-studied, it is reasonable to treat with pegylated interferon plus ribavirin provided that there is no renal dysfunction.

Decompensated cirrhosis ? Patients with decompensated cirrhosis should be referred for consideration of liver transplantation. Experienced hepatologists may consider treatment in those with mild degrees of decompensation [16]. Use of growth factors (such as erythropoietin and granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor) may be helpful during treatment of such patients by limiting the need for reductions in the dose of antiviral therapy.

Immunocompromised patients ? The response to interferon monotherapy in immunocompromised patients (such as patients with human immunodeficiency virus infection) depends upon the status of the immune system. The role of combination therapy in this setting is being investigated

Active users of illicit drugs ? Whether treatment with interferon-based regimens should be offered to patients who are actively using illicit drugs is controversial [40,41]. Treatment of such patients should be individualized. A guideline issued by the AASLD recommends that treatment should not be withheld from those who currently use illicit drugs or those on a methadone maintenance program provided that they wish to be treated and are willing and able to maintain close monitoring and practice contraception [16]. An important adjunct to treatment is continued support from drug abuse and psychiatric counseling services.

Renal disease ? Issues related to treatment of HCV in patients with underlying kidney disease are discussed separately.

Persistently normal ALT ? Patients with a persistently normal serum ALT who acquired HCV under the age of 35 years, are women, do not drink alcohol, and have no or minimal fibrosis on liver biopsy may have a slow rate of hepatic fibrosis progression. In such patients, it is reasonable to withhold treatment pending the results of ongoing clinical trials. In contrast, patients who do not fit this profile, and whose initial biopsy shows moderate activity or some degree of fibrosis may be at increased risk of disease progression. We offer therapy to such individuals after discussing that this approach is not scientifically proven. We usually treat such patients using combination therapy with pegylated interferon alfa plus ribavirin.
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eman
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Re: HEPATITIS CHEPATITIS C
« Reply #3 on: /October/ 15, 2005, 03:17:25 PM »

asalamo alikom please dr cleo md i answer my Q? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?            what are the maximum duration of ttt of HCV patient? his case is simple have good lab tests? good pcr? ?liver enz? ?no comlications?? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?                   ?do you know about the new ttt which is discoverd? by dr here in mansoura which is named HV FREE   if it succeced it will be good as it is cheap and natural ?? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?                                                          ARE there any bad complication for long use of interferon &ribavirin?? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?               ARE thE antibodies of HCV are not protective?when it dissapear from pt blood?? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? THANK? YOU
« Last Edit: /October/ 15, 2005, 03:20:39 PM by eman » Logged
 
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Re: HEPATITIS CHEPATITIS C
« Reply #4 on: /October/ 20, 2005, 06:58:10 PM »

Dr Eman,
? ? ? ? ? ? ?Your first question- Duration of treatment

The optimal duration of treatment varies depending on whether interferon monotherapy or combination therapy is used, as well as by HCV genotype. For patients treated with peginterferon monotherapy, a 48-week course is recommended, regardless of genotype. For patients treated with combination therapy, the optimal duration of treatment depends on viral genotype. Patients with genotypes 2 and 3 have a high rate of response to combination treatment (70 to 80 percent), and a 24-week course of combination therapy yields results equivalent to those of a 48-week course. In contrast, patients with genotype 1 have a lower rate of response to combination therapy (40 to 45 percent), and a 48-week course yields a significantly better sustained response rate. Again, because of the variable responses to treatment, testing for HCV genotype is clinically useful when using combination therapy.




The new medication you are talking about .
To be honest with you Dr Eman everyday we hear a drug is effective in countries where regulations are not optimal . I mean I can come up with water as a treatment for AIDS and sell it to those wishing for a cure and cant find it .
I will only believe in this drug can be used if large scale double blinded randomized studies were done , the safety has been tested long enough and receives agreement by those respected in the field of this drug.
So , i really dont pay much attention to drugs like HV FREE until I actually see valid data/proof of both efficacy and safety.


Side effects of ribavarin and interferon are multiple

Anti HCV is not protective - As a matter of fact Anti-HCV is detected by enzyme immunoassay (EIA) which is a routine test for HCV infection state

« Last Edit: /October/ 26, 2005, 06:14:38 PM by cleo_md » Logged
 
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