Interferon treatment of chronic hepatitis C

Interferon treatment of chronic hepatitis C

Interferon GARY L. DAVIS, M.D., Treatment of Chronic Hepatitis C Gainesville,Florida The natural history of chronic hepatitis C is just beginning...

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Interferon GARY

L.

DAVIS,

M.D.,

Treatment of Chronic Hepatitis C Gainesville,Florida

The natural history of chronic hepatitis C is just beginning to be clarified, with its more common course being an insidiously progressive liver disease that often remains clinically inconsequential for many years or even decades. Although chronic hepatitis C progresses histologically, the impact on the clinical well-being of the patient is less evident. Interferon is an effective therapy for this disease because of its antiviral effect on the cytopathic hepatitis C virus, lowering serum alanine aminotransferase (ALT) levels, rather than because of any immune modulatory mechanism. Unfortunately, interferon therapy does not permanently eradicate hepatitis C virus in the majority of patients, and relapse with return of the serum ALT level to the pretreatment range occurs in approximately 70% of responding patients. Other interferon-treated patients continue to be viremic and are not considered to be responders. In addition, not all patients with chronic hepatitis C require treatment. A systematic approach to patient evaluation is necessary to determine the need for treatment, assess treatment response, identify side effects of therapy, and assist in other clinical decisions.

From the Department of Medicine, Section of Hepatobiliary Diseases, University of Florida College of Medicine, Gainesville, Florida. Requests for reprints should be addressed to Gary L. Davis, M.D., Department of Medicine, Section of Hepatobiliaty Diseases, University of Florida College of Medicine, Gainesville, Florida 3261C!-D214.

January

hronic hepatitis C is an extremely common infection that causes an insidiously progressive form of hepatic injury [l]. Unfortunately, for several reasons, the clinician is currently inadequately equipped to deal with patients with chronic hepatitis C. First, the natural history of chronic hepatitis is just beginning to be clarified. Second, our ability to intervene in this disease is limited by our lack of understanding of the pathogenesis of the disease. In fact, the only available treatment option, interferon, was shown to be effective before the agent responsible for the disease was even identified [2,3]. Finally, we do not know how to identify which patients to treat, when to intervene, how to monitor the effects of therapy, or when to discontinue therapy. The purpose of this article is to review our current understanding of the natural history of hepatitis C and how, under certain circumstances, this justifies a rational approach to therapeutic intervention.

C

NATURALHISTORYOF HEPATITISC Chronic hepatitis C evolves in 50-70% of patients who acquire acute infection [l]. Although as many as 40% of patients with acute hepatitis C currently relate no risk factor for infection, risk factors are present in about 80% of patients presenting with chronic hepatitis [4,5]. Most have parenteral risk factors, either a history of blood transfusion or intravenous drug use. Few give a history of acute hepatitis. Only approximately 50% of the patients with chronic hepatitis C have symptoms or signs of liver disease [6]. Furthermore, the serum alanine aminotransferase (ALT) level does not necessarily correlate with the histologic activity of the disease [6]. A chronic carrier state of this virus does exist [7,8]. Occasionally, the serum ALT level may be normal for prolonged periods of time in the face of viremia and active liver disease on biopsy. Thus, the disease activity may be underestimated by the clinical presentation of the patient. The natural history of chronic hepatitis C is just beginning to be clarified. The course is known to be variable. Although rapid progression to cirrhosis and hepatic failure over l-2 years can occur, the more common course is one of an insidiously progressive liver disease that often remains clinically inconsequential for many years or even decades [8101. In contrast to hepatitis B, in which approxi-

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mately 10% of patients will evolve into a nonreplicative stage each year [ll], spontaneous remission is either extremely rare or does not occur in patients with chronic hepatitis C. When considering therapeutic intervention, it is important to consider what would happen to a particular patient if no treatment were given. In other words, one must consider the individual’s probable natural history. For example, patients with presumed autoimmune hepatitis who have chronic persistent hepatitis on liver biopsy have been considered to have a very low chance of disease progression over time [12]. Corticosteroids, the treatment of choice in autoimmune hepatitis, are usually not indicated in such cases. Unfortunately, the ability to make similar estimations of prognosis is limited in cases of hepatitis C and, indeed, in viral hepatitis in general. It has been clearly demonstrated through anecdotal reports and retrospective reports that patients with mild chronic hepatitis on biopsy will evolve, not infrequently, to more severe degrees of inflammation or cirrhosis [1,13]. A recent Italian study estimated that progression from chronic persistent hepatitis to chronic active hepatitis occurs over a 2-year period of time in 25% of patients [14]. Takahashi, in a large Japanese study [13], demonstrated frequent histologic progression in patients with chronic hepatitis C. Over a mean period of 8 years, 42% of patients developed cirrhosis. The prospect of progressive liver injury over 10 years was greater in patients with mild or moderately severe chronic active (periportal) hepatitis than in those with chronic persistent (portal) hepatitis (63% vs 71% vs 50%, respectively) [13]. A total of 19 patients eventually developed hepatocellular carcinoma [ 131. Although it seems clear that chronic hepatitis C progresses histologically, the impact on the clinical well-being of the patient is less evident. On the one hand, it is generally estimated that liver-related mortality from chronic hepatitis C is 5-10% [lo] and hepatic failure develops in approximately 25% of patients who have progressed to cirrhosis [8]. Chronic hepatitis C is the major indication for liver transplantation among adults in the United States. However, a recent study by Seeff and colleagues [lo] has suggested that the long-term prognosis may not be as bad as previously assumed. This study looked at a large number of patients who participated in the transfusion studies in the 1970s in which immunoglobulin was used in hopes of preventing non-A, non-B posttransfusion hepatitis; >20 years later, chronic hepatitis was clinically apparent in 32% of the surviving patients who had previously developed acute posttransfusion hepatitis. Most of these had detectable antibody to hepatilA-42S

tis C virus (HCV). Overt or symptomatic liver disease, usually clinical evidence of cirrhosis, was present in only approximately 6%. Although liverrelated deaths were two- to threefold increased in the patients who had previously developed posttransfusion hepatitis, this accounted for only a small proportion of the total mortality [lo]. Alcohol consumption appeared to be a significant cofactor for hepatic failure and death in this study. The results of the Seeff study should not be interpreted as evidence that this disease has a “benign” course, however. It is important to remember that the study group had acute hepatitis and only 50-‘70% of the patients would be expected to have developed chronic hepatitis. Additionally, only 50% of the study group was available for long-term follow-up. Fully 50% of the patients died shortly after the initial study, due, presumably, to the conditions that necessitated their blood transfusions. A similar, but smaller, study at the National Institutes of Health (NIH) Blood Bank found that ~20% of patients developed cirrhosis after posttransfusion hepatitis, and 25% of these died of liver failure [l]. The overall mortality was 5% [l]. The major point of these studies is that clinical progression usually occurs over a very long period of time. This is clearly not a rapidly evolving disease in most patients. The discrepancy between the generally good prognosis and the observation that hepatitis C accounts for a large proportion of patients presenting with cirrhosis and hepatic failure is explained by the sheer number of patients who are infected with the HCV. A further liability of chronic HCV infection is the risk of developing hepatocellular carcinoma [13]. The magnitude of this risk has not been clarified, but, as with other liver diseases, it appears to be confined primarily to those individuals with cirrhosis.

TREATMENT Clinical Trials

The first report of interferon as effective therapy for non-A, non-B hepatitis was from the NIH in 1936 [21. In that pilot study of 10 patients, low doses of interferon were used, relative to the dosing that at that time was being utilized in hepatitis B therapy. The observed response was quite different from what had been previously observed for hepatitis B. Specifically, the serum ALT levels did not flare during treatment but declined rather precipitously with the beginning of interferon therapy [2]. This is now believed to be due to the fact that interferon works by virtue of its antiviral effect on the primarily cytopathic HCV, rather than through an

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SYMPOSIUMON HEPATICDISEASE/ DAVIS

immune modulatory mechanism that was thought to be required for its effect in hepatitis B virus infection. This pilot study prompted large multicenter studies in the United States and Europe [15-171. The largest of these, the U.S. multicenter study, involved 166 patients with chronic non-A, non-B hepatitis (these studies were initiated before identification of the HCV) who were randomized into one of three arms, interferon given at a dose of either 1 or 3 x lo6 U subcutaneously, three times per week for 6 months, or no treatment [15]. In comparison to the dosing regimen utilized in this study, the dose used in chronic hepatitis B is greater and the duration of treatment is longer (5 x lo6 U daily for 4 months for hepatitis B) [18]. The endpoint in this study was termed a complete response, wherein the serum ALT levels declined to within the normal range during the course of treatment and remained normal at the end of treatment [15]. Spontaneous improvement in the serum ALT to normal levels occurred in 4% of the untreated patients. In the lo6 U regimen, 16% of patients returned to normalized serum ALT levels [15]. Finally, in the 3 x lo6 U dose group, 38% returned to normalized serum ALT levels by the end of treatment [151. The improvement in serum ALT occurred very early; all patients who had a complete response had normalized ALT values within the first 8 weeks of treatment [19]. This is the basis for the subsequent recommendation that patients who have not normalized their ALT level by 12 weeks should be considered treatment failures, and interferon should be discontinued in these patients. Histologic improvement occurred in 68% of patients in the U.S. multicenter trial who were treated with the 3 x lo6 U dose of interferon. This improvement was most striking in the reduction of lobular and periportal hepatitis [ 151. Two French randomized controlled studies utilized a protocol identical to the U.S. multicenter study. The results of these studies were nearly identical to the study described previously. In patients treated with 3 x lo6 U three times per week for 24 weeks, 39% [16] and 43% [1’71 achieved complete response (compared with 38% in the U.S. study) and histologic improvement was seen in approximately 90% of patients [171. In fact, a recent review by Tine and colleagues [20] demonstrated that the responses in all of the randomized controlled studies of interferon cy for chronic hepatitis C are similarly consistent, despite geographic differences and subtle variations in the design of the studies with respect to dose and duration of treatment. In summary, spontaneous resolution or improvement in disease is unusual; however, complete

biochemical response occurs in approximately of patients during treatment.

40%

Relapse Unfortunately, interferon therapy does not permanently eradicate HCV in the majority of patients, even in those patients who normalize their liver tests during treatment. Relapse with return of the serum ALT level to the pretreatment range occurs in approximately 70% of patients who had previously demonstrated complete response to treatment [16,20]. This raises the obvious question as to whether treatment should be discontinued after 6 months or continued for a longer period of time. The current rationale for ceasing treatment after 6 months rests on the fact that 20-30% of the patients who respond to therapy have a sustained response and do not relapse [15,16,20]. These patients can be spared from the necessity of a longer period of treatment. Additionally, longer courses of interferon have not been shown to increase the response rate or decrease the likelihood of relapse [21,22]. Since interferon appears to be suppressive rather than curative in the majority of responsive patients, finite courses of therapy are not likely to eradicate the virus, and long-term therapy is likely required to control the disease activity. This, of course, means that in most circumstances patients who relapse after discontinuation of interferon therapy should be retreated. Approximately 70% of patients will again achieve remission with retreatment [23]. There are currently no data on what therapeutic regimen to use for retreatment or how long to continue therapy. The obvious options include longterm maintenance treatment with either a fixed dose or a dose titrated to the serum ALT level, or retreatment with 6-month cycles every time the patient relapses. There are potential benefits and disadvantages to each of these options. Continuous treatment might encourage development of interferon antibodies or interferon-resistant mutations of the virus, although there is currently no evidence that either of these occurs. Reliance on repeated 6-month courses of interferon risks the possibility that the flares in disease associated with each episode of relapse will lead to progressive liver damage, similar to what is observed with discontinuation of steroid therapy in patients with autoimmune hepatitis. The various options for retreatment need to be tested in a prospective study. Nonresponders to Interferon Only approximately 40% of patients will normalize their liver tests and lose detectable HCV RNA

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in serum during treatment [24]. Early trials described a so-called partial response wherein the serum ALT level remained elevated but decreased to ~50% of the pretreatment level [15]. Such patients usually continue to be viremic and, for practical purposes, are no longer considered to be responders. Lack of response can be identified early in the course of treatment. Since complete responders demonstrate response by 8-12 weeks, it is reasonable to assume that patients who have not had a significant reduction in the serum ALT after 12 weeks will not respond. Interferon can be discontinued in such individuals. The reason for the lack of response to interferon in these patients is not known. Possible explanations include an inadequate interferon dose, high levels of virus replication, interferon-resistant HCV strains, or development of neutralizing interferon antibodies. Doses of interferon >3 x lo6 U have not been shown to increase treatment response significantly [25,26]. Similarly, escalation of the dose in patients who have not responded has only a lo-15% chance of inducing response [26,2’7]. However, this marginal increase in response rate is at the expense of increased drug cost and side effects. It is probably reasonable to reserve the option of increasing drug dose to those patients who had severe histology on their initial biopsy and had not yet responded to therapy. Recent quantitative assays for HCV RNA have shown that patients with low levels of the virus are most likely to achieve and sustain a complete response to interferon [28]. High levels of HCV RNA do not appear to preclude response, but they are almost always associated with relapse following discontinuation of treatment [28]. There is also evidence that viral strain or subtype may influence response. The Okamoto type 3, common in Japan but unusual (approximately 3% of HCV cases) in the United States, has a high rate of response to interferon, and the response is often sustained [29311. Finally, although neutralizing antibodies have been reported to cause a loss of response in patients treated @th interferon for hairy cell leukemia or hepatitis R, there is little evidence to suggest that these antibodies are detrimental in patients with hepatitis C [32,33]. Neutralizing antibodies develop in approximately 15% of patients with hepatitis C treated with interferon a-2b, but the titers are low and a relationship of antibody development to loss of response has not been shown [ 151. A much higher proportion of patients treated with interferon a-2a develop neutralizing antibodies, but there is currently little evidence that these are of clinical significance in patients with chronic hepatitis C [32]. lA-44S

PATIENTSELECTION Not all patients with chronic hepatitis C should be treated. Certain subgroups of patients-such as those with decompensated cirrhosis, significant cytopenia, associated autoimmune diseases, or psychiatric disorders-should not be treated because of the potential for adverse effects [34,35]. The safety of interferon therapy in patients with decompensated cirrhosis and transplant recipients has not been established. Several facts make careful selection of patients for interferon treatment critical. First, chronic hepatitis is usually a slowly progressive liver disease and, depending on the initial severity of histologic injury, leads to cirrhosis in a variable proportion of patients over a period of years or decades [10,13]. Second, interferon therapy is initially effective in normalizing liver tests in only 40% of patients [20] and, because of the common occurrence of relapse, retreatment or chronic maintenance therapy is usually required [15]. This difficult decision involves weighing the costs and benefits of treatment in each patient. Arguments for treatment include the risk of progression to cirrhosis or hepatic failure; the potential for infectivity; and incapacitation by symptoms. Arguments against treatment include the chance of response; side effects of therapy; the fact that therapy may be long-term; the potential cost of therapy; and other factors, such as age and general health, that would preclude a long-term beneficial effect of even successful treatment. Unfortunately, the lack of data to facilitate a concrete prediction of the natural history and treatment response makes this important clinical decision a subjective one. Several attempts have been made to identify pretreatment factors that could identify patients most likely to respond to interferon. Age, gender, body weight, source of infection, duration of disease, and degree of ALT elevation do not predict a response to treatment [19,36]. The amount of HCV and the viral subtype may be better predictors of response to interferon. Recent data suggest that patients with levels of viremia <350,000 genomes/mL (a relatively low level) are more likely to achieve and sustain a complete response to therapy [28]. Patients who have the so-called type 3 strain of the HCV appear to be more likely to respond to treatment [29]. Unfortunately, this viral subtype, while common in Japan, is not prevalent in the United States. At the present time, techniques for quantitation and subtyping of the HCV are only available in a few specialized research laboratories. A more helpful tool in assessing the need and likelihood of response to treatment is the liver bi-

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opsy. As discussed previously, mild degrees of histological inflammation (chronic persistent or mild chronic active hepatitis) are less likely to progress to cirrhosis, although this change may still occur in lo-20% of patients after a period of 10 years [13]. In contrast, 40-70% of patients with moderate-tosevere inflammation will progress to cirrhosis, and, therefore, these patients have a greater chance of developing hepatic failure as a result of their disease [13]. Thus, the liver biopsy is a helpful tool in estimating the probable natural history of the infection in the individual patient. The necessity of treating patients with mild chronic hepatitis is controversial. Reasonable arguments supporting treatment in this group of patients include the risk, albeit small, of progressive liver injury and the high chance of response to interferon. The U.S. Multicenter Study of interferon a-2b treatment demonstrated that patients with chronic persistent hepatitis had a 62% chance of having a complete response, whereas those patients with chronic active or cirrhosis had approximately a 35% chance of responding (G. L. Davis, unpublished data). Arguments against treating these patients include the lower risk of histological progression and the high relapse rate with a need for long-term therapy. Together these factors make it unlikely that therapy will have a significant impact on the natural history of the disease. However, if therapy is not undertaken in such patients, serial liver biopsies are required to assess for progression of liver injury. At the present time, there is inadequate information to make firm recommendations regarding the necessity or advisability of therapy in all patients. This decision must be reached on an individual basis after the physician and patient have completely considered the risks and benefits of treatment.

PATIENTMONITORING A systematic approach to patient evaluation is necessary, to determine the need for treatment, assess treatment response, identify side effects of therapy, and assist in other clinical decisions. The diagnosis of chronic hepatitis C should be confirmed serologically, and other causes of liver disease, especially autoimmune hepatitis, should be ruled out. All patients should have a pretreatment liver biopsy to serve as a baseline for later comparison and to evaluate histological severity as it pertains to selection for therapy. Baseline liver tests, blood counts, and thyroid function tests are essential. Significant leukopenia, neutropenia, or thrombocytopenia may preclude interferon therapy [15]. Thyroid dysfunction, which is common in patients with

chronic hepatitis, should be treated before initiation of interferon therapy. Liver tests and blood counts should be serially monitored during therapy to assess treatment response and drug-related cytopenia, which may occasionally require dose adjustment [El. Thyroid tests should be repeated midway and at the end of the 6-month course of therapy since hypothyroidism or, less commonly, hyperthyroidism occurs in approximately 2% of patients. Determination of a treatment response is made by the observation that serum ALT levels have normalized. A repeat liver biopsy is not usually required to confirm normalization. However, biopsy may be helpful in some circumstances. For example, one might be convinced to continue therapy in a patient who had severe inflammation on the initial liver biopsy, even if the liver tests did not decline completely to normal, when the repeat biopsy demonstrated a reduction in inflammation. Although confirmation of loss of detectable virus from serum and liver is not currently part of patient monitoring, it will likely become part of the routine end-of-treatment assessment when these techniques become more widely accessible [24,37]. Liver tests should be closely monitored for several months after discontinuation of the initial g-month course of interferon therapy, since relapse, if it occurs, will generally become evident within the first few months [El. In general, liver biopsy is not required before reinitiating interferon for treatment of relapse. However, it may be indicated in certain situations. For example, if the patient tolerated interferon poorly during the initial 6 months of treatment, rebiopsy could be used to determine if the disease severity still requires treatment.

CONCLUSION There have been great strides in the treatment of chronic hepatitis C. Normalization of liver enzymes can be achieved in approximately 40% of patients, and this response is associated with histologic reduction in inflammation and loss of detectable HCV in serum and liver [21]. Procollagen 3 and transforming growth factor production decrease, suggesting that fibrogenesis may be retarded [38]. It is probable that HCV infection is actually eradicated in the small proportion of patients with sustained response [15,37]. Despite these significant accomplishments, many problems remain and our therapeutic strategy continues to evolve. The most appropriate criteria for selection of patients for treatment remain controversial. Relapse with reappearance of abnormal liver tests and HCV RNA occurs in the majority of patients who respond to treatment [15]. The best therapeutic approach to the

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patient with relapse is still not known. It is assumed that long-term maintenance of response will decrease the chance of histologic progression, but this remains to be demonstrated in clinical studies.

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alpha interferon (rlFN) treatment in patients with chronic hepatitis C. IAbstr.1 Hepatology 1990; 12: 905. 20. TinC, F, Magrin S, Craxi A, Pagliaro L. Interferon for non-A, nob chronic hepatitis: a meta-analysis of randomized clinical trials. J Hepatol 1991; 13: 192-9. 21. GomezRubio M, Porres JC, Castillo I, Quiroga JA, Moreno A, Carreno V. Pre longed treatment (18 months) of chronic hepatitis C with recombinant alphainterferon in comparison with a control group. J Hepatol 1990; 1 l(Suppl 1): S63-7. 22. Metreau JM, Calmus Y, Poupon R, et al. Twelve-month treatment, compared to 6-month treatment, does not improve the efficacy of alpha-interferon in NANB chronic active hepatitis. IAbstr.1 Hepatology 1991; 14: 72A. 23. Liaw YF, Sheen IS, Lin SM, Chen TJ, Chu CM. Effects of prednisolone pretreatment in interferon alfa therapy for patients with chronic noc-A, nob (C) hepatitis. Liver 1993; 13: 46-50. 24. Shindo M, Di Bisceglie AM, Cheung L, et al. Decrease in serum hepatitis C viral RNA during alpha-interferon therapy for chronic hepatitis C. Ann Intern Med 1991; 115: 700-4. 25. Lindsay KL, Davis GL, Schiff ER, et al. Long-term response to higher doses of interferon alfa-2b treatment of patients with chronic hepatitis C: a randomized controlled multicenter trial. Hepatology 1993; (in press). 26. Marcellin P, Pouteau M, Boyer N, et al. Absence of efficacy of an increasing dosage schedule on the response rate during and after recombinant alpha interferon therapy in chronic hepatitis C. fibstr.1 Hepatology 1991; 14: 71A. 27. Feinman SV, Willems B, Minuk G, et al. Treatment of chronic non-A, non-B hepatitis blood related and sporadic with recombinant interferon A. IAbstr.1 Hepatology 1991; 14: 71A. 26. Lau JYN, Davis GL, Kniffen J, et al. Significance of serum hepatitis C virus RNA levels in chronic hepatitis. Lancet 1993; 341: 1501-4. 29. Okada SI, Akahane Y, Suzuki H, Okamoto H, Mishiro S. The degree of variability in the amino terminal region of the E2/NSl protein of hepatitis C virus correlates with responsiveness to interferon therapy in viremic patients. Hepatology 1992; 16: 61924. 30. Okamoto H, Sugiyama Y, Okada S, et al. Typing of hepatitis C virus by polymerase chain reaction with type specific primers: application to clinical surveys and tracing infectious sources. J Gen Virol 1992; 73: 673-9. 31. Lau JYN, Davis GL, Ohno T, et al. Application of hepatitis C virus subtyping in the United States. Hepatology 1993; 18: 149A. 32. Lok ASF, Lai CL, Leung EKY. Interferon antibodies may negate the antiviral effects of recombinant alpha-interferon treatment in patients with chronic hepatitis B virus infection. Hepatology 1990; 12: 1266-70. 33. Steis RG, Smith JW, Urba WJ, et al. Resistance to recombinant interferon alfb2a in hairy-cell leukemia associated with neutralizing anti-interferon antibodies. N Engl J Med 1988; 318: 1409-13. 34. Papo T, Marcellin P, Bernuau J, Durand F, Poynard T, Benhamou JP. Autoimmune chronic hepatitis exacerbated by alphtinterferon. Ann Intern Med 1992; 116: 51-3. 35. Renault RF, Hoofnagle JH, Park Y, et al. Psychiatric complications of long-term interferon alpha therapy. Arch Intern Med 1987; 147: 1577-80. 36. Farrell GC, Lin R, Coverdale S. Prediction of response to interferon in patients with chronic active hepatitis C and evidence that this improves hepatic metabolic function. Gastroenterol Jpn 1991; 26(Suppl 3): 243-6. 37. Diamond DA, Davis GL, Qian K-P, Lau, JYN. Detection of hepatitis C viral sequences in formalin-fixed, paraffin-embedded liver tissue: effect of interferon alpha therapy. J Med Virol 1993; (in press). 36. Castilla A, Prieto J, Faust0 N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med 1991; 324: 933-40.

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