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Nonalcoholic Fatty Liver Disease in HIV-Infected Persons: Epidemiology and the Role of Nucleoside Reverse Transcriptase Inhibitors

Guaraldi, Giovanni MD*; Stentarelli, Chiara MD*; Orlando, Gabriella MD, PhD*; Zona, Stefano MD*; Carli, Federica MD*; Ballestri, Stefano MD*; Lonardo, Amedeo MD*; Squillace, Nicola MD†; Loria, Paola MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: February 2010 - Volume 53 - Issue 2 - p 278
doi: 10.1097/QAI.0b013e3181c990ed
Letters to the Editor

*University of Modena and Reggio Emilia, Modena, Italy; and †San Gerardo Hospital, University of Milan-Bicocca, Monza (MI), Italy.

To the Editors:

We appreciated the article written by Dr. Crum-Cianflone et al,1 which provides liver histopathologic insight into HIV-associated nonalcoholic fatty liver disease (NAFLD) and allows one not only to estimate NAFLD but also to estimate nonalcoholic steatohepatitis (NASH) prevalence in HIV-infected patients. Previous to this article, only Lemoine et al2 provided a liver biopsy study in HIV people with NAFLD; they were able to detect NASH in 6 of 9 insulin-resistant lipodystrophic patients and in 2 of 5 noninsulin-resistant patients with HIV infection. Evidence of liver fibrosis was found in patients with NAFLD. The NASH prevalence rate of 6%-10% of HIV patients without viral hepatitis (B or C) coinfection or excessive alcohol use identified in the work by Crum-Cianflone et al1 is greater than that found in the general population3 and suggests a possible unique pattern in the progression from NAFLD to NASH associated with HIV infection. Determinants of the evolution of the natural history of this metabolic disease are poorly understood even in the general population,3 but we can hypothesize that HIV patients may have additional risks regarding immunologic and inflammatory factors, including those associated with antiretroviral (ARV) drug toxicity. NASH is a progressive organ disease eventually leading to fibrosis, cirrhosis, and hepatocellular carcinoma,3 and it is clinically relevant to identify the proportion of NAFLD patients who have a high risk of developing NASH to study prevention and treatment strategies. The number of NASH cases in this series is too small to identify any difference from the NAFLD group.1

We were impressed by how closely data of Crum-Cianflone agreed with ours4: their prevalence rate of biopsy-proven NAFLD was 36%, whereas ours was 36.6%. In our study, NAFLD was diagnosed with computed tomography (CT) scan, an objective noninvasive imaging technique that can discriminate between zero-to-mild and moderate-to-severe hepatic steatosis with a sensitivity and specificity of 0.833 and 0.815, respectively.5 We believe this concordance between ultrasound and CT results may encourage a wider use of noninvasive imaging to diagnose steatosis in the HIV-infected population.

The main difference between study of Crum-Cianflone et al1 and ours4 was their inability to identify any particular ARV class as an independent predictor of NAFLD. Contrary to this, we found that exposure to nucleoside reverse transcriptase inhibitors (NRTIs) was an independent risk factor for NAFLD, with an 11% increase in the odds ratio for each year of use.4 This discrepancy may be based on the different population settings, raising possible controversy due to the limitations intrinsic to cross-sectional studies, where association does not prove causation.

In addition, Crum-Cianflone et al1 did not include data on cumulative exposure to NRTIs and NAFLD risk. Given the observational nature of both of these studies, neither of the 2 is able to demonstrate a pathogenetic association between drug exposure and liver damage.

We did not find any association between cumulative exposure to single ARV drugs, single NRTIs, or commonly prescribed dual-NRTI combinations and NAFLD.4 To establish an association between cumulative drug exposure and NAFLD, we agree that prospective studies are needed.

Giovanni Guaraldi, MD*

Chiara Stentarelli, MD*

Gabriella Orlando, MD, PhD*

Stefano Zona, MD*

Federica Carli, MD*

Stefano Ballestri, MD*

Amedeo Lonardo, MD*

Nicola Squillace, MD†

Paola Loria, MD*

*University of Modena and Reggio Emilia, Modena, Italy

†San Gerardo Hospital, University of Milan-Bicocca, Monza (MI), Italy

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1. Crum-Cianflone N, Dilay A, Collins G, et al. Nonalcoholic fatty liver disease among HIV-infected persons. J Acquir Immune Defic Syndr. 2009;50:464-473.
2. Lemoine M, Barbu V, Girard PM, et al. Altered hepatic expression of SREBP-1 and PPARgamma is associated with liver injury in insulin resistant lipodystrophic HIV-infected patients. AIDS. 2006;20:387-395.
3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221-1231.
4. Guaraldi G, Squillace N, Stentarelli C, et al. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin Infect Dis. 2008;47:250-257.
5. Iwasaki M, Takada Y, Hayashi M, et al. Noninvasive evaluation of graft steatosis in living donor liver transplantation. Transplantation. 2004;78:1501-1505.
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