JAC Advance Access published online on October 2, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn416
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Research letter |
Autoimmune hepatitis induced by pegylated interferon in an HIV-infected patient with chronic hepatitis C
1 Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain 2 Department of Pathology, Hospital Ramón y Cajal, Madrid, Spain
* Corresponding author. Tel: +34-91-4532500; Fax: +34-91-7336614; E-mail: mvispo{at}gmail.com
Key Words: autoimmunity , liver fibrosis , liver biopsy
Autoimmunity is a pathophysiological mechanism that leads to chronic inflammatory diseases in a broad array of organs. Autoimmune hepatitis (AIH) results in a chronic inflammatory process in the liver; it is associated with hypergammaglobulinaemia and the occurrence of autoantibodies. Diagnosis of AIH often represents a clinical challenge as its clinical presentation is quite heterogeneous. The association of AIH and hepatitis C virus (HCV) infection is well known and when present it generally complicates definitive diagnosis. Difficulties are greater when AIH coexists with both HCV and HIV. Although this is a rare situation, the need for long-term immunosuppressive therapy gives special relevance to this subset of patients.
A young Caucasian woman on regular follow-up at our HIV clinic for more than 15 years initiated treatment for chronic HCV infection in 2006. She had been engaged in intravenous drug addiction practices in her twenties and had acquired an HCV genotype 4 infection. General blood tests (haemoglobin, platelet count and kidney profile) gave normal values. She presented with mild hepatic cytolysis [Aspartate aminotransferase (AST) 167 IU/L and alanin aminotransferase (ALT) 189 IU/L], with a normal liver function (albumin 3.25 mg/dL and prothrombin activity 92%). Plasma HCV-RNA was 155 000 IU/mL. Liver fibrosis was measured using transient elastometry (FibroScan®) and was determined to be mild (estimate Metavir F2). She had been on antiretroviral therapy for more than 12 years and currently was receiving tenofovir, emtricitabine and atazanavir/ritonavir as a fourth-line therapy. Plasma HIV-RNA was <50 copies/mL, and CD4 counts were 634 cells/mm3. Her past gynaecological history evidenced two spontaneous abortions. The patient had been vaccinated for hepatitis B virus (HBV) in the past, developing a satisfactory immunological response [hepatitis B surface-antigen antibody (HBsAb) titre 78 IU/mL].
On February 2006, she began treatment with pegylated interferon-
2b (100 µg weekly) plus weight-adjusted ribavirin (1000 mg daily). She did not achieve a rapid virological response, but HCV-RNA was undetectable at week 12 of therapy and until completion of 15 months of treatment. No serious adverse events were reported during therapy. Fifteen days after ending hepatitis C treatment, the patient complained of asthenia, arthralgias, myalgias and low-grade fever. Serum blood biochemistry showed a 10-fold increase in aminotransferases (AST and ALT) and mild non-icteric cholestasis with a normal liver function [international normalized ratio (INR) 1.04 and albumin 3.6 mg/dL]. Serum HCV-RNA remained undetectable (<10 IU/mL). The patient was admitted at the hospital for more thorough evaluation. After ruling out the involvement of hepatotoxic drugs, alcohol consumption, infection with other hepatotropic viruses [hepatitis A virus (HAV), HBV, Epstein–Barr and cytomegalovirus] and metabolic liver disorders (haemochromatosis, Wilson's disease and 1-antitrypsin deficit), tests for autoimmunity revealed polyclonal immunoglobulin G elevation and anti-nuclear antibodies (ANAs) at titres of 1/20 000. Other types of autoantibodies (anti-smooth muscle antibody, anti-liver and kidney microsome type 1, anti-liver cytosol type 1 and anti-mitochondrial antibody) were all negative, as were plasmatic cryoglobulins. Autoimmune tests had been negative before initiating hepatitis C therapy. During hospital admission, serum HCV-RNA reappeared with low values (800 IU/mL) in May 2007, rose to 48 000 IU/mL in June 2007 and decreased to 18 000 IU/mL in July 2007. HCV genotyping was repeated and no change was found in HCV variant, which could have suggested re-infection. However, spontaneous HCV clearance occurred subsequently and until now 15 months later (Figure 1).
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During her hospital admission, abdominal ultrasound only evidenced homogeneous hepatosplenomegaly. Liver biopsy was performed in July 2007 and showed important periportal inflammatory lymphoplasmocytic infiltrates, piecemeal necrosis and moderate periportal fibrosis (Metavir A3-F2), all being compatible with the histological pattern of AIH. The patient was discharged from the hospital with grade 3 liver enzyme elevations. After a 3 month interval with negative serum HCV-RNA, she began treatment for AIH with 1 mg/kg prednisone. Liver enzymes rapidly normalized and her clinical status improved. After 9 months of steroids, HIV infection was still well controlled (HIV-RNA <50 copies/mL and CD4 count 675 cells/mm3) under the same initial antiretroviral therapy, and liver enzymes had normalized with stepwise decline in steroid dose treatment.
AIH is a chronic inflammatory liver disease with an estimated prevalence of 1/5000 to 1/10 000.1 As with most autoimmune diseases, the cause is unknown. Nevertheless, multiple factors have been involved, with the general understanding that in a predisposing genetic background [histocompatibility leukocyte antigen (HLA)-DR3 and DR4], environmental, pharmacological or infectious agents may trigger the condition. Several cases of AIH in HIV-infected patients have been communicated, suggesting that HIV infection may be one of such triggers.2–4 AIH is more common in middle-aged women. A history of other autoimmune diseases (rheumatoid arthritis, lupus and thyroiditis) is common. Our patient had suffered two spontaneous abortions, which has occasionally been linked to the antiphospholipidic syndrome. AIH often presents with mild symptoms accompanying liver enzyme elevations, but some patients may develop severe acute or fulminant hepatitis. The diagnosis of AIH is made based on a revised scoring system made by a group of experts,5 recently simplified to four criteria.6 Accordingly, our patient had 14 points (probable AIH) for the standard score and 7 points (definite AIH) for the simplified score.
There is an association between AIH and HCV. Up to 38% of patients with chronic hepatitis C show ANA. In contrast, nearly one-third of patients with AIH have positive HCV antibodies.7 This link often complicates the diagnosis, and liver biopsy remains the only definite procedure to establish AIH. Interface hepatitis, piecemeal necrosis without biliary lesions, as reported in our patient, is the most characteristic finding of AIH. To complicate things more, prolonged exposure to anti-HCV therapy with interferon has been implicated in the induction or worsening of autoimmune diseases.8,9 In our patient, autoimmune events appeared 15 months after starting anti-HCV therapy. This lag between drug initiation and the onset of AIH symptoms has also been highlighted (up to 44 months) in other cases.10 Interferon enhances the expression of HLA class I and II antigens on cell membranes, promoting T cell activation and the subsequent release of cytokines. A predominance of Th1 (T helper cells) may favour organ-specific autoimmune phenomena.11,12
There are at least two other reports of AIH in HCV/HIV co-infected patients,13,14 but still it seems to be a rare condition given the high prevalence of HCV/HIV co-infection. Autoimmune diseases are infrequent in HIV subjects, perhaps due to the general attenuation of immune responses in HIV disease. However, the preservation of a good immunological status by an early initiation of antiretroviral therapy may lead to a change in the clinical behaviour of HIV-positive subjects, resembling that of their HIV-negative counterparts. Furthermore, there is one recent report that has linked AIH with the immune reconstitution inflammatory syndrome.15 However, this is not the case for our patient as she was treated for her HIV infection for a long time and presented a good immunological response. Treatment of AIH mainly consists of the use of immunosuppressive agents; steroids are the drugs of choice for induction of remission but azathioprine may be used as maintenance therapy. Recent reports have shown no risk of using this type of drug in HIV-positive patients,2 especially regarding an enhanced risk of opportunistic infections. Therefore, in the HIV setting, the most advisable recommendation for the treatment of AIH is the use of single steroid therapy tapered to the lowest dose required to maintain normal aminotransferase levels. Treatment should be given for at least 2–3 years, and interruption only considered when biochemical and histological remission has been demonstrated.16
We do not have a clear explanation for the transient relapse in serum HCV-RNA we saw upon completion of hepatitis C therapy. The flare in liver enzymes preceded this rise and most likely resulted from the autoimmune damage of the liver, as confirmed in the biopsy. Hypothetically, substantial hepatic cytolysis might have induced the release of residual viral debris. Alternatively, the exacerbated immune activation of AIH could have helped to resolve chronic hepatitis C, removing HCV from the liver and/or extrahepatic reservoirs.
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This work was supported in part by grants from Fundación Investigación y Educación en SIDA (IES), Red de Investigación en SIDA (RIS, ISCIII-RETIC RD06/006), Agencia Lain Entralgo and the European VIRGIL and NEAT networks.
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None to declare.
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