Stebbing, Justin MD, MA, PhD, FRCPath, MRCP; Wong, Nick MD; Tan, Lionel MD; Scourfield, Andrew MD; Jiao, Long MD, FRCS; Shousha, Sami MD, FRCPath; Grover, Deepa MD; Bower, Mark MD, PhD, FRCP, FRCPath; Nelson, Mark MD
To the Editor:
Chronic liver disease causes substantial morbidity and mortality in HIV-positive patients, with chronic hepatitis B virus (HBV), hepatitis C virus (HCV) infection, alcohol consumption, and drug-related toxicity being commonly cited.1-3 In addition, some individuals with elevated liver enzymes without an obvious underlying etiology may still develop complications such as portal hypertension.4 In the context of HIV, this “cryptogenic” liver disease has previously been reported in association with prolonged didanosine exposure.4 We thus undertook a study to assess the association between prolonged antiretroviral therapy (ART) and cryptogenic liver disease (CLD).
We defined CLD as persistently elevated hepatic transaminase levels in the absence of replicative HBV or HCV infection or other common causes of chronic liver disease.4 The normal level of alanine aminotransferase (ALT) was ≤37 IU. We identified 90 patients from a cohort of 4500 HIV-positive patients attending the Chelsea and Westminster Hospital who underwent a liver biopsy between January 2004 and July 2007. We retrospectively reviewed the case notes including full ART history and laboratory results of these patients to exclude other causes of chronic liver disease including autoimmune hepatitis, Wilson disease, alpha-1 antitrypsin deficiency, and syphilis.
Each of the cases, which fulfilled our definition of CLD, were then matched for age, sex, race, duration of HIV diagnosis, and CD4 count with a control. Variables were compared using a Kruskal-Wallis test to assess for any association between ART and the development of CLD.
Of the 90 patients who had a liver biopsy during this 41-month period, 13 constituted our definition of CLD. All of these had persistently elevated ALT for greater than 6 months. There was no history of excessive alcohol use except for 1 patient who abstained from alcohol consumption for more than 1 year before liver biopsy. Syphilis serology and liver autoantibodies (antinuclear antibody [ANA], liver-kidney microsomal autoantibodies of type 1 [LKM-1]) were negative in all patients. Normal levels of alpha-1 antitrypsin, copper/ceruloplasmin, ferritin, and transferrin saturation excluded metabolic causes of liver disease. All patients had a negative HBV surface antigen and HCV antibody, and in addition, HBV DNA and HCV RNA levels (lower limit of detection was 500 copies/mL and 3200 copies/mL, respectively) were confirmed by polymerase chain reaction in most patients to exclude occult HBV and HCV infection.
Of the 13 patients with CLD, the mean age measured 45 years (range 39-65 years), and 10 were males (77%). The median CD4 count at biopsy was 187 cells per cubic millimeter [interquartile range (IQR) 190]. All patients had an undetectable HIV viral load at biopsy, except for 1 with a viral load of 356 copies per milliliter. All had normal ALT before commencing ART, and all were triple antiretroviral class experienced. The biopsy findings showed portal fibrosis in 9 (69%), cholangiopathy in 2 (15%), sclerosing cholangitis in 1 (7.7%), and Ishak stage 5 cirrhosis in 1 (7.7%). Biopsies of 2 patients with mild portal fibrosis were also suggestive of nodular regenerative hyperplasia (NRH).
The median duration of exposure with ART in CLD patients were as follows: nucleoside reverse transcriptase inhibitors as follows: (1) 10 patients on didanosine, 62 months (IQR 44.75), (2) 6 individuals receiving tenofovir, 47.5 months (IQR 10), (3) 8 on zidovudine, 43 months (IQR 60.5), (4) 8 on lamivudine, 29 months (IQR 33.25), (5) 6 on stavudine, 35.5 months (IQR 23.5), (6) 4 on abacavir, 11 months (IQR 23.25), and (7) 4 on emtricitabine, 3 months (IQR 7.5) and nonnucleoside reverse transcriptase inhibitors as follows: (1) 6 on efavirenz, 59 months (IQR 23.5) and (2) 5 on nevirapine, 39 months (IQR 26). The protease inhibitors received were as follows: (1) 2 individuals on nelfinavir, 52 months (IQR 1), (2) 6 on ritonavir (all on boosted dose), 18.5 months (IQR 7.75), (3) 3 on fosamprenavir, 13 months (IQR 10), (4) 5 on atazanavir, 14 months (IQR 13), (5) 3 on lopinavir, 8 months (IQR 9.5), (6) 4 on saquinavir, 8.5 months (IQR 8.25), and (7) 1 on indinavir, 5 months (Table 1).
Three patients (23%) developed portal vein thrombosis, 4 (31%) developed episodes of hepatic decompensation with ascites, and 2 (15%) developed portal hypertension. One patient subsequently died of hemorrhage from esophageal varices complicating their CLD. The case-control analysis revealed no significant association between ART and the development of CLD. In particular, there was no link with didanosine (P = 0.096) although this was most frequently used and for the longest duration.
In the general population, rates of CLD are below 0.01%4 with a prevalence of 5%-30% amongst cirrhotic patients.5 Estimates within the HIV-positive population are limited, with a prevalence of 17 of 3200 (0.5%) in 1 case-control study.4 In our cohort, only 13 of 90 liver biopsies performed from a cohort of 4500 HIV-positive patients during a 31-month period were compatible with a diagnosis of CLD. An undetectable HIV viral load in 12 of 13 indicates that HIV itself is unlikely to be the cause of hepatic dysfunction. All had normal ALT before commencing ART, suggesting that ART may be responsible for hepatic inflammation. Although didanosine was used most frequently and for the longest duration, in the case-control analysis, there was no correlation between specific antiretroviral drugs and CLD. This contradicts a previous case-control study, in which the only independent predictor of the developing CLD was long-term didanosine exposure.4 Furthermore, in another study of 27 HIV-positive patients with CLD receiving didanosine who discontinued this drug, clinical and laboratory improvement occurred in 13 patients (48%) after 12 months.6 Mitochondrial damage associated with didanosine may be the underlying mechanism for the development of CLD,4 however, the lack of correlation with other nucleoside analogues known to cause mitochondrial toxicity does not support this hypothesis.
Two of our patients had evidence of NRH, a condition in which there are small, diffuse, regenerative nodules in the absence of significant fibrosis.7 A review of 8 HIV-positive patients with CLD and NRH on biopsy revealed that all were receiving didanosine.8 The authors speculate that NRH may be due to a combination of HIV, ART with didanosine, and also a prothrombotic state leading to intrahepatic thrombosis and NRH.8 Two further case reports of patients who had been on either nevirapine and didanosine9 or didanosine followed by nevirapine10 and a case series of 6 patients, with 5 on didanosine,11 have presented similar findings and suggest that either HIV or ART are associated with NRH. Both of our patients with NRH were white and had been on didanosine for a duration of 59 months and 102 months, respectively; in addition, both also had treatment experience with nevirapine.
Patient numbers here were small, though similar to other studies, and indicative of how uncommon this diagnosis seems to be. Despite this, we have demonstrated that there does not seem to be an association between antiretroviral use and the development of CLD. Inaccuracies and observer bias may have occurred due to the retrospective collection of some data. In addition, we did not perform a thrombophilia screen on the patients with a histological diagnosis of NRH and thus could not confirm the presence of a prothrombotic state as indicated by the previous literature.8,11
With greater experience of long-term ART and the availability of new drugs in existing and novel classes, ART-related toxicity is of increasing concern. Although acute liver failure is clearly documented with some drugs such as nevirapine4 and coinfection with HCV and concomitant ART may lead to a progression in fibrosis,12 there has been limited assessment of the long-term consequences of ART on the liver. In conclusion, our study does not confirm an association between the development of CLD and the prolonged use of antiretroviral drugs.
We would like to thank Charlotte Wing for her help in data collection and Sundhiya Mandalia for her help with the statistics.
Justin Stebbing, MD, MA, PhD, FRCPath, MRCP
Nick Wong, MD
Lionel Tan, MD
Andrew Scourfield, MD
Long R. Jiao, MD, FRCS
Sami Shousha, MD, FRCPath
Deepa Grover, MD
Mark Bower, MD, PhD, FRCP, FRCPath
Mark Nelson, MD
Imperial College School of Medicine
Chelsea and Westminster Hospital
Charing Cross Hospital
London, United Kingdom
1. Lewden C, Salmon D, Morlat P, et al. Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol. 2005;34:121-130.
2. Salmon-Ceron D, Lewden C, Morlat P, et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatology. 2005;42:799-805.
3. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis. 2001;32:492-497.
4. Maida I, Nunez M, Rios MJ, et al. Severe liver disease associated with prolonged exposure to antiretroviral drugs. J Acquir Immune Defic Syndr. 2006;42:177-182.
5. Caldwell S, Oelsner D, Iezzoni J, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664-669.
6. Maida I, Garcia-Gasco P, Sotgui G, et al. HIV associated hepatopathy-a new clinical condition: prevalence, eitiology and outcome. Presented at: 3rd International Workshop on HIV and Hepatitis co-infection; June 7-9, 2007; Paris, France. Abstract 45.
7. Colina F, Alberti N, Solis JA, et al. Diffuse nodular regenerative hyperplasia of the liver (DNRH). A clinicopathologic study of 24 cases. Liver. 1989;9:253-265.
8. Mallet V, Blanchard P, Verkarre V, et al. Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV infected patients. AIDS. 2007;21:187-192.
9. Sandrine PF, Sylvie A, André E, et al. Nodular regenerative hyperplasia: a new serious antiretroviral drugs side effect? AIDS. 2007;21:1498-1499.
10. Arey B, Markov M, Ravi J, et al. Nodular regenerative hyperplasia of liver as a consequence of ART. AIDS. 2007;21:1066-1068.
11. Garvey LJ, Thomson EC, Lloyd J, et al. Response to Mallet et al., ‘Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients’. AIDS. 2007;21:1494-1495.
12. Pineda JA, Macías J. Progression of liver fibrosis in patients coinfected with hepatitis C virus and human immunodeficiency virus undergoing antiretroviral therapy. J Antimicrob Chemother. 2005;55:417-419.
© 2009 Lippincott Williams & Wilkins, Inc.