To the Editors:
We appreciate the interest of Guaraldi et al in our recent article on nonalcoholic fatty liver disease (NAFLD) among HIV-infected persons.1 Both our study and a recent article by their group demonstrate the high prevalence (31%-37%) of NAFLD among HIV-positive persons.1,2 Because NALFD is often a “silent disease” and patients frequently have normal liver tests,1,3 the diagnosis of NAFLD usually relies on radiographic imaging using ultrasound, computed tomography (CT), or magnetic resonance imaging.4 As pointed out by Guaraldi et al, CT and ultrasound may be similar in their detection of NAFLD. Prior reports have shown that ultrasound has a similar sensitivity (80%-100%)5-7 to that cited for CT, and a recent study suggested that ultrasound may be even more sensitive than CT in detecting steatosis in the setting of concurrent fibrosis among patients with nonalcoholic steatohepatitis (NASH).7 These data, along with our study findings, suggest that ultrasound may be useful as an initial screening tool for detecting NAFLD.
Because NALFD may lead to liver complications (eg, cirrhosis, hepatocellular cancer) and may be correlated with other significant medical conditions,8-11 understanding the factors associated with liver steatosis is important. In both our study and the recent investigation by Guaraldi et al, the factors associated with NAFLD were nearly identical: elevated body mass index, greater waist circumference, low high-density lipoprotein levels, and high triglyceride levels (or the use of fibrates).1,2 These factors mirror those in the general population.8 These data suggest that weight and lipid level control may be important strategies in preventing NALFD, although prospective trials are needed to confirm this finding.
A critical issue is the role of antiretroviral medications in the development of NAFLD given the increasing use of HIV therapy by the recent guidelines.12 In our study, we examined two specific nucleoside reverse transcriptase inhibitors (NRTIs), didanosine and stavudine, based on their possible pathogenic mechanisms, and because some (but not all) studies among HIV/hepatitis C virus-coinfected persons showed they were potentially related to steatosis.13-17 We explored both the categorical use of these individual drugs as well as the duration of use and found no significant associations with NAFLD in our multivariate models.1 We also evaluated our participants who had undergone a liver biopsy and found no association between these two agents and NAFLD, although our sample size was smaller (Table 3).
Guaraldi et al showed that the duration of NRTI use was significantly associated with NAFLD; however, individual or dual NRTI (including stavudine and didanosine) use had no significant associations in their models.2 We examined the duration of NRTI use and NAFLD by steatosis level based on ultrasound (using the model shown in Table 1 of our original paper) and by liver biopsy (Table 3), but found no significant associations (odds ratio 1.0 per year, P = 0.11 and odds ratio 1.0 per year, P = 0.52, respectively). We also examined NRTI use as a categorical variable and noted no significant relationships.
Differences in study findings may be the result of several factors. First, the composition of study populations may differ by coexisting factors such as diabetes, visceral obesity, physical activity, and host genetics. Second, the duration and types of antiretroviral medication use may be dissimilar. For example, our cohort was less antiretroviral drug-experienced than the cohort used by Guaraldi, which required participants to have used antiretroviral medications for at least 2 years before study enrollment, whereas 28% of our cohort had never received HIV medications. Moreover, the duration of NRTI use differed: mean of 110 to 124 months versus 66 months, respectively.1,2 Perhaps a population “at risk” for NAFLD exposed to a long duration of NRTIs could have higher odds for developing liver steatosis.
Further studies will be needed to clarify the precise role of NRTIs in the development of NAFLD. Investigation of the impact of specific antiretroviral drugs is of vital importance because these data would be useful in determining which, if any, antiretroviral drugs should be avoided in patients with HIV already at risk for NAFLD. Prospective trials are needed to better define the risk factors for NAFLD, because liver disease is now a major cause of morbidity and mortality among HIV-infected persons.18
Nancy Crum-Cianflone, MD, MPH*†‡
Angelica Dilay, MPH‡
Gary Collins, MS§
Dean Asher, MD‖
Richard Campin, MD‖
Sheila Medina, MPH*†
Zach Goodman, MD¶
Alan Lifson, PhD§
Mary Bavaro, MD*†
Braden Hale, MD, MPH*†
*HIV Clinic, Naval Medical Center San Diego, San Diego, California
†Infectious Disease Clinical Research Program (IDCRP), Bethesda Maryland
‡School of Public Health, San Diego State University, San Diego, California
§Biostatistics Division, School of Public Health, University of Minnesota, Minneapolis, Minnesota
‖Radiology Department, Naval Medical Center San Diego, San Diego, California
¶Armed Forces Institute of Pathology, Washington DC
1. Crum-Cianflone N, Dilay A, Collins G, et al. Nonalcoholic fatty liver disease among HIV-infected persons. J Acquir Immune Defic Syndr
2. 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
3. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology
4. Schwenzer NF, Springer F, Schraml C, et al. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol
5. Joseph AE, Saverymuttu SH, al-Sam S, et al. Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. Clin Radiol
6. Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology
7. Tobari M, Hashimoto E, Yatsuji S, et al. Imaging of nonalcoholic steatohepatitis: advantages and pitfalls of ultrasonography and computed tomography. Intern Med
8. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology
9. Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology
10. Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis
11. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systemic review. J Hepatol
12. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009;1-161. Available at: www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
. Accessed December 3, 2009.
13. McGovern BH, Ditelberg JS, Taylor LE, et al. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin Infect Dis
14. Sulkowski MS, Mehta SH, Torbenson M, et al. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS
15. Marks KM, Petrovic LM, Talal AH, et al. Histological findings and clinical characteristics associated with hepatic steatosis in patients coinfected with HIV and hepatitis C virus. J Infect Dis
16. Bani-Sadr F, Carrat F, Bedossa P, et al. Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors. AIDS
17. Zeremiski M, Talal AH. Dideoxynucleoside analogues should be used cautiously in patients with hepatic steatosis. Clin Infect Dis
18. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med