Monday, October 8, 2012

Insulin Resistance and Hepatic Fibrosis in HIV/Hepatitis C


Insulin Resistance Is Associated With Progression to Hepatic Fibrosis in a Cohort of HIV/Hepatitis C Virus-Coinfected Patients

Mark W. Hull; Kathleen Rollet; Erica E.M. Moodie; Sharon Walmsley; Joseph Cox; Martin Potter; Curtis Cooper; Neora Pick; Sahar Saeed; Marina B. Klein

Posted: 10/08/2012; AIDS. 2012;26(14):1789-1794. © 2012 Lippincott Williams & Wilkins

Discussion Only

Full text at Medscape

Insulin resistance was present in a majority of HIV/HCV-coinfected cohort participants with 56% having a baseline HOMA-IR of at least 2 and a significant proportion having very high levels of insulin resistance (27% having HOMA-IR score ≥4). As we excluded those receiving oral hypoglycaemics or insulin, this finding suggests that a substantial number of coinfected persons are not recognized as having impaired glucose tolerance and are, thus, at risk for common complications of insulin resistance.[3,4,20] Presence of insulin resistance was associated primarily with classic and potentially modifiable risk factors: elevated BMI and waist circumference. Although fasting glucose was higher among those having HOMA-IR of at least 2, all had values within the normal range; thus, fasting insulin levels are required to identify individuals with insulin resistance.

To understand whether insulin resistance contributes to the development of hepatic fibrosis, longitudinal studies in persons not having fibrosis or advanced liver disease are required. Ours is the first such longitudinal study to examine this question in coinfected patients. We found insulin resistance was strongly associated with development of hepatic fibrosis. In adjusted analyses, the risk of developing fibrosis was nearly eight times greater in the presence of insulin resistance and was independent of BMI. Furthermore, for each doubling in HOMA-IR score there was a 48% increase in risk for progression to fibrosis. This finding suggests that efforts to improve insulin sensitivity may potentially reduce rates of fibrosis progression among coinfected persons. Given the rise of ESLD morbidity and mortality among HIV/HCV-coinfected persons, the identification of this potentially modifiable risk factor for liver disease progression is of enormous relevance.

The prevalence of insulin resistance in our Canadian cohort is somewhat greater than that reported in other populations. Among 170 coinfected patients from France, the prevalence of insulin resistance was 37%.[17] In 1041 HIV-infected Spanish patients, the prevalence was 48% among 373 HIV/HCV-coinfected patients compared with 33% in those without HCV infection.[11]

We could not demonstrate an association of specific antiretroviral agents with the presence of insulin resistance at baseline. Particularly, certain protease inhibitors and cumulative exposure to nucleoside reverse transcriptase inhibitors, especially stavudine, have been implicated in previous studies.[21–24] In contrast, there has been no clear association of specific drug class or duration of ART exposure and insulin resistance in coinfected populations.[9,10] The lack of association between ART exposure and insulin resistance in our study and others may be due to a lack of power, given the relatively small numbers of individuals analysed to date, or may reflect more complex effects of ART on HCV-related disease.[25,26]

Prior cross-sectional studies in coinfected persons have not identified a clear relationship between insulin resistance and presence of hepatic fibrosis.[12,17] In contrast, in a cross-sectional study of 330 coinfected patients undergoing transient elastography, 64% of those with HOMA-IR of at least 4 had measures of at least 9 kPa compared with 39% of those with HOMA-IR less than 4 (P < 0.0001), and HOMA-IR of at least 4 was an independent predictor of elevated liver stiffness (adjusted odds ratio 5.33, 95% CI 2.70–10.49).[27] Insulin resistance has been associated with higher estimated fibrosis progression rates in monoinfected populations[1] but not in a small study of coinfected patients.[12] Finally, in HCV monoinfection, HOMA-IR more than 2 has been associated with decreased sustained virologic responses (SVRs) to HCV therapy. In coinfected patients, however, studies on the impact of insulin resistance on SVR have been contradictory.[18,28,29]

Mechanisms by which insulin resistance occur in HCV-infected patients have not been fully elucidated, but include effects of inflammatory cytokines such as tumour necrosis factor alpha,[30] other cytokine signalling pathways (e.g. upregulation of suppressor of cytokine signaling-3 protein)[31] and effects on insulin–receptor substrate which interferes with insulin signalling.[32] Whether HIV directly plays a role remains unclear.

Our study has some potential limitations. Overall, a significant proportion lacked fasting glucose and insulin values and, therefore, was excluded from analysis. This limited our power to determine associations between insulin resistance and such factors as specific antiretroviral drug classes or HCV genotype. The large number of excluded patients also potentially could have introduced a selection bias. Use of HOMA-IR in the evaluation of insulin resistance in HCV-infected patients is well established,[33] and we used a HOMA-IR score of at least 2 to define significant insulin resistance, as used in other North American and European coinfected populations,[5,17,18,34] although other cut-offs have been used.[12] We used the APRI score as a surrogate marker for hepatic fibrosis rather than liver biopsy. APRI has been validated against liver biopsy in our cohort as well as others and is widely accepted as a surrogate marker and is highly specific for fibrosis stages equal to or greater than F2 Metavir score (significant fibrosis, few septa).[14] A limitation of not using serial biopsies is the potential interplay between insulin resistance and hepatic steatosis, itself a consequence of insulin resistance, which may contribute to fibrosis progression.[17]

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