Reactivation of autoimmune hepatitis during budesonide monotherapy ...

JOURNAL OF HEPATOLOGY benefitting may decline (i.e. 109 vs. 136 patients in the NORDynamIC trial). In addition, practical, pharmacokinetic, and technical problems may arise: (1) it is essential to take an early assessment of viral kinetic measurements of HCV RNA viral load from blood drawn exactly at day 7 and directly before the next PEG-interferon injection because viral load may fluctuate significantly during the initial phase of viral decline. This may be less of a problem 4 weeks after initiation of antiviral therapy. Indeed, in our study we found that when retesting a large number of samples at week 4, undetectable HCV RNA and viral levels below 15 IU/ml had identical predictive values for sustained virologic response in genotype 1 and 2/3 infected patients [6]. (2) Differences may be present between the two pegylated interferons alfa 2a and 2b because of different pharmacokinetics (65 vs. a 28 h elimination half-life, respectively). For pegylated interferon alfa 2b, a more step-wise viral decline is well known. After one week of therapy a flat or even slightly increasing viral load kinetics may be seen while a more continuous viral decline is observed with pegylated interferon alfa 2a. With identical rapid virologic response rates for both pegylated interferons at week 4 of treatment (IDEAL study 11.4% vs. 11.9% for pegylated interferon alfa 2a vs. 2b, respectively) [7] algorithms with later assessments of virologic response may be better applicable for these differences. (3) Finally, despite standardization of IU HCV RNA viral loads measured with different commercially available assays, these are not comparable and this is already a problem for the determination of low vs. high baseline viral load. For a measurement at day 7 as proposed by Lagging et al., for example 1000 IU/ml by the Cobas TaqMan assay in genotype 1, 2, 3 infected patients equals approximately 300, 1000, and 600 IU/ml by realtime HCV and 300, 600, and 500 IU/ml by the bDNA assay [8–11]. Moreover, a significant intra- and inter-assay variability especially for lower viral loads (0.04–0.13 log10 SD) may make it difficult to establish a general and precise rule with just one HCV RNA measurement taken early during therapy [10]. Herein, determination of undetectable HCV RNA levels with a highly sensitive assay may be superior because all new assays have lower detection limits between 5 and 10 IU/ml (Cobas TaqMan, realtime HCV, TMA). All these parameters have to be taken into account for the current standard of care. In the era of direct antiviral agents that display strong antiviral activities, highly individualized and tailored treatment durations will be established. The determination of virologic response with or without additional parameters (baseline viral load, IL28B polymorphisms etc.) very early during therapy (i.e. between day 3 and week 4) will most likely be required for the selection of super responders that may benefit from very short treatments (24 weeks or shorter for genotype 1 and perhaps even below 12–16 weeks for genotype 2/3 infected patients).

Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, Heintges T, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005;129: 522–527. [2] Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609–2617. [3] Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyannis SJ, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006;43: 954–960. [4] Diago M, Shiffman ML, Bronowicki JP, Zeuzem S, Rodriguez-Torres M, Pappas SC, et al. Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40 KD) plus ribavirin. Hepatology 2010;51:1897–1903. [5] Lagging M, Alsiö A, Hellstrand K, Norkrans G. Is HCV RNA analysis at day 7 cost-effective in deciding the duration of therapy in chronic hepatitis genotype 2/3 infection?. J Hepatol 2011;54:836–837. [6] Sarrazin C, Shiffman ML, Hadziyannis SJ, Lin A, Colucci G, Ishida H, et al. Definition of rapid virologic response with a highly sensitive real-time PCRbased HCV RNA assay in peginterferon alfa-2a plus ribavirin responseguided therapy. J Hepatol 2010;52:832–838. [7] McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580–593. [8] Chevaliez S, Bouvier-Alias M, Brillet R, Pawlotsky JM. Overestimation and underestimation of hepatitis C virus RNA levels in a widely used real-time polymerase chain reaction-based method. Hepatology 2007;46:22–31. [9] Michelin BD, Muller Z, Stelzl E, Marth E, Kessler HH. Evaluation of the Abbott RealTime HCV assay for quantitative detection of hepatitis C virus RNA. J Clin Virol 2007;38:96–100. [10] Vermehren J, Kau A, Gartner BC, Gobel R, Zeuzem S, Sarrazin C. Differences between two real-time PCR based assays (RealTime HCV, Cobas AmpliPrep/ Cobas TaqMan) and one signal amplification assay (Versant HCV RNA 3.0) for HCV RNA detection and quantification. J Clin Microbiol 2008;46:3880–3891. [11] Sarrazin C, Gärtner B, Sizmann D, Babiel R, Mihm U, Hofmann WP, et al. Comparison of conventional PCR with real-time PCR and branched DNAbased assays for hepatitis C virus RNA quantification and clinical significance for genotypes 1 to 5. J Clin Microbiol 2006;44:729–737.

Christoph Sarrazin J.W. Goethe-University Hospital, Medizinische Klinik I, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany E-mail address: [email protected]

Reactivation of autoimmune hepatitis during budesonide monotherapy, and response to standard treatment To the Editor: The large European trial of budesonide therapy suggests that budesonide might be better than prednisone in the treatment of newly diagnosed autoimmune hepatitis [1]. These results were based on the sensible combination of azathioprine and steroid,

but already physicians have started using budesonide monotherapy, or combinations of budesonide and prednisone or prednisolone. We wish to report a case of autoimmune hepatitis (AIH), who experienced reactivation of disease activity during treatment with 3 3 mg budesonide per day and tapering doses

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Letters to the Editor Table 1. Laboratory findings at presentation and at four time points of treatment.

At first presentation

End of Budesonide-treatment

Increase of Prednisolone

Treatment initiation

Azathioprine and Prednisolone combination regime

Prednisolone

IgG [g/L] ALT [U/L ]

15 mg + 9 mg Budesonide



5 mg + 75 mg Azathioprine

15.06 1168

79

10.98 217

11.11 47

9.04 20

160

24

33

27

11

Bilirubin [mg/dl] AP [U/L]

1.3 121

0.7 52

0.6 89

0.6 65

0.3 51

SMA-Titer

1 : 320

-

-

-

1 : 160

-GT [U/L]

of prednisolone, and at the same time suffered from significant steroid side-effects. Institution of standard therapy with prednisolone tapering and azathioprine leads to rapid remission and disappearance of side-effects. The 22-year-old female patient first presented in May 2009 to her general practitioner for a check-up due to non-specific mild symptoms, at which time point markedly elevated transaminases (aspartate aminotransferase (AST) 841 U/L, alananine aminotransferase (ALT) 1357 U/L and gamma-glutamyl-transferase (c-GT) 155 U/L) were noted (Table 1). Further laboratory findings showed a slightly elevated level of total bilirubin (1.3 mg/dl) and IgG was found to be at the upper limit of normal (15.06 g/L). Autoantibody testing did only show positivity for antibodies to smooth muscle antigen (SMA) – titre 1:320 – (antinuclear antibodies (ANAs), anti-mitochrondrial antibodies (AMAs), liver-kidney microsomes (LKM), and soluble liver antigen/liver pancreas (SLA/LP) were all negative). Metabolic liver disease such as Wilson’s Disease and Hemochromatosis were excluded (coeruloplasmin levels, urine copper, serum iron, and serum transferrin saturation were within normal range and eye-examination was inconspicuous). Viral markers for Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus were negative. The patient did not show any history of alcohol abuse nor did she recently use any known hepatotoxic drugs. Liver biopsy was not performed at this time point, because the treating physicians considered the diagnosis of autoimmune hepatitis as sufficiently confirmed. Treatment was started with prednisolone at a starting dose of 60 mg/d (corresponding to 1.3 mg/kg body weight), with a dose reduction every four days (Fig. 1). Vitamin D and Calcium supplementation were prescribed. Due to steroid specific side effects, the patient started feeling agitated and suffered from sleep disorder. Prednisolone was gradually reduced to a level of 20 mg/d. As after an initial fall, transaminases increased again somewhat after 7 weeks of prednisolone induction therapy, and in view of the steroid side-effects, the patient was put on additional budesonide at a dose of 3 mg three times daily, while prednisolone was slowly tapered down to 2.5 mg/d. The patient tolerated budesonide well and transaminases decreased slightly, however, without reaching normal levels. Steroid-specific side-effects continued, but changed their character, as she now gained weight (5 kg in 8 weeks) and developed facial-rounding and hirsutism.

838

In November 2009, when prednisolone dose had been tapered to 2.5 mg for 6 weeks, and during continued therapy with 3 3 mg budesonide/d, the patient experienced reactivation of her AIH with transaminase levels up to 217 U/L ALT. At this stage, a liver biopsy was performed to confirm reactivation of AIH and exclude other liver disease including steroid-induced nonalcoholic staetohepatitis (NASH). Histology showed moderately severe interface hepatitis (HAI-score 8/18) with dense infiltrates predominantly of plasma cells and lymphocytes. Periportal lymphocytic piecemeal necrosis with moderate fibrosis without biliary lesions was identified. Histology thus demonstrated the picture of moderately active AIH, despite six months of adequately dosed budesonide. The patient was advised by her treating gastroenterologist to discontinue the intake of desogestrel as oral contraceptive. Probably, as a consequence of that, considerable hair loss was triggered as additional unpleasant side-effect. The treating physicians considered the patient to be treatment refractory, and prednisolone dose was again raised to 20 mg/d, and then slowly decreased down to a maintenance dose of 10 mg/d. At this stage, in February 2010, the patient first presented to our department. At this time point disease was considered only mildly active with transaminases at the upper limit of normal, IgG within the normal range, SMA titre of 1:160, and mild symptoms of fatigue. Subjective well-being was quite impaired due to steroid side-effects under the combination therapy with 10 mg prednisolone daily and 3 3 mg budesonide daily, and in view of the hair loss. We decided to stop budesonide and start treatment with azathioprine with an initial dose of 50 mg/d (1 mg/ kg) and an increase after two weeks to 75 mg/d. Prednisolone was then reduced first to 7.5 mg/d and after 12 weeks to 5 mg/ d. Azathioprine was well tolerated and the patient responded quickly to the new combination regimen. Liver enzymes decreased continuously and normalized for the first time. At the same time, steroid side-effects disappeared. At the moment the patient is feeling well under azathioprine and low-dose prednisolone treatment. It is planned to phase out the steroids completely within the next few months. She is no longer suffering from any treatment-related side effects. She reintroduced the administration of an oral contraceptive and the hair loss is no longer apparent. This case demonstrates that in some patients 3 3 mg budesonide is insufficient to induce and/or maintain remission in autoimmune hepatitis, and in this case appeared less effective than


JOURNAL OF HEPATOLOGY

Prednisolone (mg)

60

Budesonide 9 mg 100 75 50 25 0

40 20 0

Azathioprine (mg)

Prednisolone Budesonide Azathioprine

40 35 1225

30

ALT IgG

20

35

IgG [g/L]

ALT [U/L]

25

15 10 5 0

ne Ju

ay M

ril Ap

ch M

ua br

ar

ry

y ar Fe

nu

em ec D

Ja

be

be em

N

ov

ct O

r

r

er ob

be

r

st

em pt

Se

Au

gu

ly Ju

ne Ju

M

ay

1

2009

2010

Fig. 1. Time course of ALT and IgG during treatment showing reactivation despite therapy with 3 3 mg/day budesonide.

prednisolone. In addition, steroid side-effects were considerable, and these did only change their character when budesonide was introduced into the treatment. Our group has reported in the past, that remission can be induced in more than 90% of AIH within six months by using a starting dose of 1 mg/kg prednisolone and introducing azathioprine early at a dose of 1–1.5 mg/kg body weight [2]. These data were recently confirmed in a second large patient cohort [3]. These data and the present case should caution us in the use of budesonide in the treatment of autoimmune hepatitis, and further critical evaluation of clinical data will be needed to define its exact place in the management of patients with autoimmune liver disease [4]. Diagnosis should be confirmed by biopsy, and azathioprine should be standard treatment in all confirmed cases of AIH who can tolerate the drug.

Conflict of interest The authors who have taken part in this study declared a relationship with the manufacturers of the drugs involved. AWL took part in the trial of budesonide in AIH (Manns et al; Gastroenterology 2010) sponsored by Falk Pharma, and gives lectures paid for by Falk foundation.

References [1] Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, et al. European AIH-BUC-Study Group. Budesonide induces remission more effectively than prednisone in a controlled trialog patients with autoimmune hepatitis. Gastroenterology 2010;139:1198–1206. [2] Kanzler S, Galle PR, Meyer zum Büschenfelde KH, Lohse AW. Long term management and prognosis of autoimmune hepatitis (AIH): a single centre experience. Z. Gastroenterol. 2001;39:339–348. [3] Schramm C, Weiler-Normann C, Wiegard C, Hellweg S, Müller S, Lohse AW. Treatment response in patients with autoimmune hepatitis. Hepatology 2010;52:2247–2248. [4] Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology 2010;139:58–72.

Ansgar W. Lohse Hannah Gil I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Germany Tel.: +49 7410 53910; fax: +49 7410 58531 E-mail addresses: [email protected], [email protected] (A.W. Loshe)


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