European Review for Medical and Pharmacological Sciences 2020; 24: 1435-1439 Primary biliary cholangitis development after hepatitis C virus eradication with direct acting antivirals: a case report and review of the literature

F. FIANCHI, F.R. PONZIANI, M. POMPILI

Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

Abstract. – We report the case of an 84-year- He was also affected by hypertension, hy- old man with asymptomatic chronic hepatitis pothyroidism, monoclonal gammopathy, ureteral C virus (HCV) infection treated with direct an- lithiasis and had a previous history of prostate tiviral agents. At the end of the antiviral thera- adenocarcinoma successfully treated with radi- py laboratory tests showed an abrupt increase ation therapy. The patient was on treatment with in cholestasis parameters and aminotransferas- es, associated with anti-mitochondria antibod- levothyroxine, ramipril, nitrosorbide, low-dose ies positivity. Therefore, primary biliary chol- aspirin, tamsulosin and propafenone. angitis (PBC) was diagnosed. The patient was Blood tests performed before starting antivi- treated with ursodeoxycholic acid achieving a ral therapy showed high serum HCV viral load good biochemical response. (HCV-RNA 17,000,000 IU/ml) but without any This is the second case described in litera- elevation in aspartate (AST) and alanine amino- ture of PBC onset after HCV eradication with an interferon-free antiviral regimen. In both cas- transferases (ALT) or gamma-glutamyl transpep- es an autoimmune damage of cholangiocytes tidase (GGT) or alkaline phosphatase (ALP). secondary to the immunological derangement After checking for the absence of drug inter- caused by virus clearance may be hypothesized. actions, the patient started and completed the Indeed, according to the hygiene hypothesis, course of DAAs therapy, without reporting any when two different triggers act simultaneously adverse event. At the 4th week of treatment course on the immune system they tend to be mutually HCV-RNA was undetectable, whereas serum lev- inhibitory, and an immune tolerance develops; th when one of these triggers disappears (as HCV els of GGT, AST and ALT were normal; at the 8 in this case), the immune system may mount a week of treatment only a slight increase of GGT response against self-antigens, causing autoim- was detectable (126 IU/L), and aminotransferases mune disorders such as PBC. were within the normal range. However, at the end of the antiviral therapy Key Words: HCV, Direct-acting antiviral drugs, Primary biliary laboratory tests showed a significant increase in cholangitis, Hygiene hypothesis, Anti-mitochondria cholestasis (GGT 313 IU/L, ALP 252 IU/L) and antibody. cytonecrosis indices [AST and ALT × 1.5 and × 2 upper limit of normal (ULN), respectively]; total bilirubin was normal (0.55 mg/dl) as long as hepatic synthesis indices (albumin 4.1 g/dl, Case Report INR 1.01): nevertheless, serum HCV-RNA was An 84-year-old man with chronic hepatitis C undetectable, and serology for major and minor virus (HCV) infection (genotype 1b, diagnosed hepatotropic viruses such as hepatitis B, A, and E in 2005, naive to antiviral therapy) was treated viruses, cytomegalovirus, Epstein Barr and Her- in our outpatient clinic with a 12-week course pes simplex 1 excluded a recent infection and/or of Elbasvir/Grazoprevir 50/100 mg orally once re-activation; the use of drugs potentially causing a day, a combination of direct-acting antiviral liver injury was also ruled out. An abdominal agents (DAAs) highly effective in the treatment ultrasound did not show any biliary tract obstruc- of genotypes 1 and 4 HCV infection1. tion or bile duct dilation.

Corresponding Author: Francesca Fianchi, MD; e-mail: [email protected] 1435 F. Fianchi, F.R. Ponziani, M. Pompili

Therefore, antibodies indicative of autoim- Discussion mune liver disease were tested. Serum levels of anti-nuclear, anti-smooth muscle and anti-liv- HCV clearance in patients with chronic infec- er kidney microsomes-1 antibodies were unde- tion is associated with a reduction in HCV-re- tectable, whereas anti-mitochondria antibodies lated complications, liver disease severity and (AMA) were positive with a titer of 1:40. mortality. A close monitoring of blood tests showed In the past, the standard of care for HCV in- a slight reduction in transaminase levels, but fection treatment was pegylated interferon alpha a progressive increase in cholestasis indices, (PEG-IFNα) and ribavirin3. Several reports4,5 in with GGT and ALP reaching a peak of 14-fold the literature have described the onset of PBC and the ULN (860 g/dl) and 4.2-fold the ULN (543 other autoimmune diseases during IFN-based g/dl) respectively at 6 weeks from the end of regimens. Indeed, IFN has well-known immu- therapy. A diagnosis of primary biliary cholan- nostimulating properties and is able to induce a gitis (PBC) was made according to the present great imbalance in the immune system, interfer- guidelines for the diagnosis and management of ing with T helper 1 (Th1) and T helper 2 (Th2) this disease2 and it was decided to avoid liver lymphocytes activity6. biopsy and start treatment with ursodeoxycholic On the contrary, the occurrence of autoim- acid at the dosage of 900 mg/day (13.5 mg/kg/ mune diseases after DAAs, which are now the weight), resulting in a rapid normalization of the gold standard for the treatment of HCV chronic aminotransferases and a progressive decrease in infection, is uncommon. To our knowledge, this GGT and ALP levels. is the second case described in literature of PBC At present, 6 months after the beginning of onset after HCV eradication with an IFN-free ursodeoxycholic acid, the serum levels of ALP antiviral regimen. and GGT have normalized (131 IU/L and 64 IU/L The first case was reported by Rendina et al7, respectively), as long as aminotransferases (ALT in which the authors postulated that PBC may 9 IU/L, AST 19 IU/L) (Figure 1). have been triggered by HCV clearance with A sustained viral response (SVR) was achieved a mechanism related to the ‘hygiene hypothe- and maintained 12 and 24 weeks after the end of sis’: in summary, when two different antigens DAAs treatment. act simultaneously on the immune system they

Figure 1. Kinetics of liver enzymes in the patient during and after HCV treatment. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma glutamyltranspeptidase; HCV, hepatitis C virus; ULN, upper limit of normal.

1436 Primary biliary cholangitis after HCV eradication with DAAs tend to be mutually inhibitory, but when one of after the end of treatment22. Indeed, DAAs have these stimuli disappears, the immune system dramatically changed the treatment of HCV not may mount a response against self-antigens, only for their high antiviral efficacy, but also causing autoimmune disorders8. This explana- for their ability to awake the immune system tion may also be applied to our patient, who by releasing it from the burden of chronic anti- abruptly developed alteration of cholestasis and gen load. These effects of DAA agents may be cytonecrosis parameters soon after HCV-RNA relevant not only in determining the response eradication. to therapy, but also in the modulation of the Another interesting case was described in immune response. 2018 by Matsumoto et al9, reporting the onset Other effects of the immune modulation oc- of autoimmune hepatitis during DAA treatment curring during DAA treatment for HCV infec- for HCV infection. HCV affects the human im- tion have already been described, including hep- mune system via several mechanisms in order to atitis B virus (HBV) reactivation and recurrence escape surveillance and hinder the elimination of HCC10. In fact, it has been postulated that by the host. Specific changes in the innate and abrupt changes in the immune surveillance can adaptive immune responses that promote the be responsible in some cases for HBV reactiva- persistence of the infection are described10,11. tion in patients with inactive or resolved HBV One of these mechanisms is the ability to reduce infection23,24 and for the recurrence of hepatocel- the activity of cells responsible for the elimi- lular carcinoma (HCC) in patients with previous nation of virus-infected cells, in particular the successfully treated cancer25,26. Also in these exhaustion of cytotoxic T lymphocytes (CTLs) cases, the modification of the immunological [the so-called “exhausted phenotype”]12,13. Fur- milieu and the different behavior of the immune thermore, during chronic HCV infection, natu- cells after the HCV eradication with DAAs are ral killer (NK) cells become activated but their the mechanisms most probably involved27. typical responses are disordered, preventing the elimination of the virus and leading to chronic hepatitis14. Prezzi et al15 have also suggested Conclusions that an imbalance between the Th1 and Th2 responses may be involved in the development In summary, when an abrupt increase in of chronic hepatitis C, with a depressed Th1 and cholestasis indices and/or aminotransferases oc- overactive Th2 response. curs during or immediately after the end of treat- Conversely, dynamic changes in the innate ment with DAAs, it is important to look for the immune response during DAA therapy for onset of an autoimmune disorder that may have HCV infection have been described16-19. In par- remained silent until HCV eradication. ticular, immunological analyses have revealed Indeed, the profound immunological chang- the reversal in the exhaustion of CTLs with es occurring during treatment with DAAs can a restoration of HCV-specific CD8+ T cell potentially be responsible for the unmasking of function in patients treated with DAAs16,17. The a silent autoimmune disease, that becomes clin- viral load decline during treatment reduces ically relevant as a consequence of the immune serum levels of NK cell-stimulating cytokines system reconstruction. We did not test our patient and causes correction of the altered NK cell for AMA before starting anti-HCV therapy, but it phenotype observed in chronic HCV patients20. is well known that liver autoantibodies in asymp- Moreover, HCV treatment has demonstrated to tomatic patients may precede the subsequent de- induce lymphocytes polarization towards Th1 velopment of overt autoimmune disease by many over Th2 phenotype, a mechanism implicated years. For further investigation, it will be useful in the pathogenesis of PBC21. A biological proof to establish if the development of an autoimmune of concept of these important immunomodula- disease after HCV eradication with DAAs can be tory effects of HCV treatment with DAA is the predicted by the presence of autoantibodies prior so-called “end of treatment (EOT)+/SVR”: a to the start of therapy. fraction of chronic HCV patients treated with DAAs achieve SVR despite having detectable viremia at the EOT. This observation has been related to reversal of CTLs exhaustion induced Conflict of Interest by DAAs, which is able to clear the infection The Authors declare that they have no conflict of interests.

1437 F. Fianchi, F.R. Ponziani, M. Pompili

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