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Non-alcoholic fatty liver disease predicts development of metabolic comorbidities in HIV-infected patients
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https://www.ddwnews.org/news/preview-ddw-2020-eposters-epapers-release-this-weekend/
from Jules: this is not really new information, we have known that fatty liver in HIV+ is associated with & there is causation around comorbidities, liver fibrosis & comorbidities, this is seen similarly in HIV-neg but may be in HIV+ the strength of this relationship is greater because HIV+ have such strong metabolic abnormalities, I have often said HIV is a fat disease, a metabolic disease.
CROI: NAFLD AND LIVER FIBROSIS PREDICT HIGH CARDIOVASCULAR RISK IN HIV-MONOINFECTED PATIENT (04/02/20)
Our study provides novel longitudinal data on the increased risk of T2DM, hypertension and dyslipidemia in PWH with NAFLD. This is consistent with findings in the general population with NAFLD.
This study, based on a cohort of HIV-infected patients consecutively screened for liver disease, shows that NAFLD predicts the development of important metabolic comorbidities, including T2DM and dyslipidemia. Furthermore, NAFLD severity, represented by suspected significant liver fibrosis, predicts development of T2DM. Our findings mirror what has already been reported in the general population and shape fatty liver as a central barometer of metabolic health also in PWH[28]. To the best of our knowledge, this is the first cohort study linking NAFLD with the development of important metabolic comorbidities.
Liver and cardiovascular disease are the primary non-AIDS related causes of morbidity and mortality in PWH[38]. While HCV coinfection has been driven much of the liver-related mortality in the past, the implementation of effective direct antiviral-agents has inverted this trend. The increasing burden of NAFLD in the HIV-infected population, combined with our findings of its impact on metabolic comorbidities, indicate that PWH with NAFLD may be at particularly high risk of cardiovascular morbidity and mortality.
In conclusion, our study suggests that NAFLD is an independent predictor for the development of important metabolic comorbidities in PWH. This finding configures NAFLD as a barometer for metabolic health also in the setting of HIV infection. Metabolic comorbidities might perpetuate the NAFLD spectrum and contribute to increased cardiovascular risk in PWH. In the context of HIV infection, patients with NAFLD should be closely monitored for the development of metabolic outcomes and modifiable risks be managed in a timely fashion. Our findings might be considered a further argument to advocate for screening for NAFLD in PWH, as it is the case for patients with diabetes[47]. Indeed, the European AIDS Clinical Society guidelines recommended screening for NAFLD in PWH with metabolic syndrome, and expansion of these criteria to PWH with any metabolic comorbidity has been proposed[48, 49]. Implications of our findings on long-term cardiovascular outcomes should be investigated in future studies.
NAFLD is increasingly recognized as the most frequent liver disease in people aging with HIV[13, 29-32]. A recent meta-analysis situates the prevalence of NAFLD in HIV mono-infected at 35%, higher than the global prevalence reported for the general population at 25%[1, 6]. In the same study, the pooled prevalence of significant liver fibrosis was 22%. One of the reason for this excess, may be that PWH present with particularly high frequency of metabolic conditions. A higher incidence of T2DM in the HIV-infected population has been well described, though the role of the liver in this process has not been investigated. A longitudinal study with a median follow-up of 4 years reported a cumulative incidence of T2DM of 10% in PWH, compared to 3% in uninfected controls[8]. A recent meta-analysis reported a pooled incidence rate for T2DM of 13.7 per 1000 PY of follow-up (95% CI 13-20)[33]. Frequent hypertension and a higher cardiovascular risk have also been consistently reported[10, 11]. Several virologic and ART-related factors have been implicated in the pathophysiology of T2DM and hypertension in HIV infection, including chronic inflammation, immune reconstitution and lipodystrophy[34]. Dyslipidemia is also common due to both HIV chronic infection and lifelong use of ART, particularly PIs[9]. CKD is a frequent complication of HIV infection, occurring in 3.5-48.5% of the patients, due to HIV infection itself and as a consequence of ART, such as tenofovir disoproxil fumarate[12, 27].
Patients with NAFLD were older, more likely to be Caucasian and had higher BMI. Moreover, they had longer time since HIV diagnosis. Finally, they had higher prevalence of hypertension, lower HDL cholesterol, higher triglycerides and glucose, higher ALT and AST, higher albumin and higher liver stiffness measurement. At baseline, patients with NAFLD had higher prevalence of hypertension and dyslipidemia (Table 1), while those with suspected significant liver fibrosis had higher prevalence of all metabolic comorbidities (Fig. 2).
Incidence and predictors of metabolic comorbidities
Patients were followed for a median of 40.1 months (IQR 26.5-50.7). There were 68, 86, 190, and 84 patients with T2DM, hypertension, dyslipidemia, and CKD, respectively, who were excluded from the longitudinal analysis for having the outcome at baseline. Overall, incidence rates of T2DM, hypertension, dyslipidemia and CKD were 2.2 (95% CI 1.6-3.3), 4.2 (95% 3.2-5.5), 5.3 (95% CI 4.0-7.1) and 2.7 (95% CI 1.9-3.8) per 100 PY, respectively. Table 2 reports incidence rates of metabolic comorbidities by NAFLD and suspected significant liver fibrosis status.
Patients with NAFLD had higher incidence rate of T2DM and dyslipidemia as compared to those without NAFLD (Fig. 3a and 3c). There was also a tendency for a higher incidence rate of hypertension (Fig. 3b), while there was no difference for CKD (Fig. 3d). Patients with suspected significant liver fibrosis had a higher incidence rate of T2DM, while no difference was found for hypertension, dyslipidemia and CKD (Fig. 4). Supplemental Table S1 depicts the characteristics of patients who developed metabolic comorbidities during the follow-up period. Compared to the whole cohort, patients who developed T2DM were more likely to be females and of black ethnicity, and had a higher BMI. They were also less likely to be MSM and to be on NRTIs. Patients who developed dyslipidemia were more likely to be on NRTIs. Those who developed CKD were more likely to be diabetic and to have higher liver stiffness measurement. During the follow-up period, there were a total of 8 deaths, of which three were related to non-liver cancer, two to infections and two were not known. The corresponding incidence rate was 0.4 (95% CI, 0.2-0.9) per 100 PY.
After adjustments, NAFLD and pre-existing hypertension were independent predictors of T2DM development (Table 3). Incident hypertension was independently predicted by older age. NAFLD and current use of PIs as ART regimen were independent predictors of development of dyslipidemia. Incident CKD was independently predicted by older age and pre-existing T2DM. We also conducted a multivariable analysis including suspected significant liver fibrosis as exposure. After adjusting for age (per 10 years; aHR 1.14, 95% CI 0.78-1.67), male sex (aHR 0.84, 95% CI 0.35-1.97), and black ethnicity (aHR 2.15, 95% CI 0.93-4.97), independent predictors of T2DM development were suspected significant liver fibrosis (aHR 2.71, 95% CI 1.11-6.61; p=0.029) and pre-existing hypertension (aHR 4.22, 95% CI 1.81-9.80; p=0.001). There was no effect of suspected significant liver fibrosis on development of other metabolic comorbidities (results not shown). We also conducted a sensitivity analysis for the subgroup of patients with available BMI. The relative univariable Cox regression analysis showed HR of 1.20 (95% CI, 0.99-1.45; p=0.05) for incident T2DM, 1.18 (95% CI, 0.99-1.41; p=0.06) for incident hypertension, 1.01 (95% CI, 0.87-1.17; p=0.91) for incident dyslipidemia and 1.24 (95% CI 0.99-1.55; p=0.06) for incident CKD.
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Non-alcoholic fatty liver disease predicts development of metabolic comorbidities in HIV-infected patients
The Journal of Infectious Diseases,
06 April 2020
Krahn T1, Martel M1, Sapir-Pichhadze R2, Kronfli N3, Falutz J3, Guaraldi G4, Lebouche B3,5, Klein MB3, Wong P1, Deschenes M1, Ghali P1, and Sebastiani G1,3
Key-Points:
• People with HIV are at high risk for non-alcoholic fatty liver disease (NAFLD)
• NAFLD is associated with incident metabolic complications
• Diabetes and dyslipidemia develop at more than double rate in people with HIV and NAFLD compared to those without NAFLD
Abstract
Background
Cardiovascular and liver disease are main contributors to mortality in people with HIV (PWH). In HIV-uninfected patients, non-alcoholic fatty liver disease (NAFLD) is associated with incident metabolic complications. We investigated the effect of NAFLD on development of metabolic comorbidities in PWH.
Methods
We included PWH undergoing a screening program for NAFLD using transient elastography. NAFLD was defined as controlled attenuation parameter ≥248 dB/m and exclusion of other liver diseases. Incident diabetes, hypertension, dyslipidemia and chronic kidney disease were investigated using survival analysis and Cox proportional hazards.
Results
485 HIV mono-infected patients were included. During a median follow-up of 40.1 months (interquartile range 26.5-50.7), patients with NAFLD had higher incidence of diabetes (4.74, 95% confidence interval [CI] 3.09-7.27 vs. 0.87, 95% CI 0.42-1.83 per 100 person-years [PY]) and dyslipidemia (8.16, 95% CI 5.42-12.27 vs. 3.99, 95% CI 2.67-5.95 per 100 PY) compared to those without NAFLD. On multivariable analysis, NAFLD was an independent predictor of diabetes (adjusted hazard ratio [aHR] 5.13, 95% CI 2.14-12.31) and dyslipidemia (aHR 2.35, 95% CI 1.34-4.14) development.
Conclusions
HIV mono-infected patients with NAFLD are at higher risk of incident diabetes and dyslipidemia. Early referral strategies and timely management of metabolic risk may improve outcomes.
Introduction
Non-alcoholic fatty liver disease (NAFLD), defined as fat accumulation in the liver in the absence of excessive alcohol consumption, is an epidemic entity affecting approximately 25% of the world’s population[1]. In the general population, NAFLD is not only associated with liver-related morbidity and mortality related to cirrhosis and hepatocellular carcinoma, but has also been linked with increased mortality from extra-hepatic diseases, particularly cardiovascular disease[2]. Moreover, NAFLD is strongly associated with the metabolic syndrome, and has been linked with increased risk of developing diabetes, hypertension, dyslipidemia, and chronic kidney disease (CKD)[3-5].
NAFLD is expected to increasingly comprise the burden of liver disease in people with HIV (PWH) due to the widespread availability and effectiveness of direct-acting antivirals for the treatment of chronic hepatitis C. The prevalence of NAFLD in HIV mono-infection is currently estimated to be at least 35%[6]. The prolonged exposure to HIV infection and antiretroviral therapy (ART), as well as increased intestinal dysbiosis and bacterial translocation, are thought to contribute to the development of NAFLD in PWH in addition to risk factors shared with the general population, including obesity, insulin resistance, and dyslipidemia[7].
Importantly, the classic metabolic risk factors for NAFLD are more frequent in PWH. In HIV positive men, a four times higher prevalence of type 2 diabetes mellitus (T2DM) has been described vs. HIV negative men[8]. Dyslipidemia is also common due to both HIV chronic infection and lifelong use of ART[9]. Hypertension and a higher cardiovascular risk have also been consistently reported[10, 11]. HIV-infected patients are also at higher risk for CKD[12].
Given that HIV infection and NAFLD independently increase the risk of metabolic comorbidities, the aim of this study was to investigate the effect of NAFLD on development of T2DM, hypertension, dyslipidemia and CKD in a cohort of PWH by means of transient elastography with associated controlled attenuation parameter (CAP)[13]. This diagnostic tool for NAFLD and associated liver fibrosis has been validated against liver biopsy in both HIV uninfected and HIV-infected patients[14-16].
Discussion
This study, based on a cohort of HIV-infected patients consecutively screened for liver disease, shows that NAFLD predicts the development of important metabolic comorbidities, including T2DM and dyslipidemia. Furthermore, NAFLD severity, represented by suspected significant liver fibrosis, predicts development of T2DM. Our findings mirror what has already been reported in the general population and shape fatty liver as a central barometer of metabolic health also in PWH[28]. To the best of our knowledge, this is the first cohort study linking NAFLD with the development of important metabolic comorbidities.
NAFLD is increasingly recognized as the most frequent liver disease in people aging with HIV[13, 29-32]. A recent meta-analysis situates the prevalence of NAFLD in HIV mono-infected at 35%, higher than the global prevalence reported for the general population at 25%[1, 6]. In the same study, the pooled prevalence of significant liver fibrosis was 22%. One of the reason for this excess, may be that PWH present with particularly high frequency of metabolic conditions. A higher incidence of T2DM in the HIV-infected population has been well described, though the role of the liver in this process has not been investigated. A longitudinal study with a median follow-up of 4 years reported a cumulative incidence of T2DM of 10% in PWH, compared to 3% in uninfected controls[8]. A recent meta-analysis reported a pooled incidence rate for T2DM of 13.7 per 1000 PY of follow-up (95% CI 13-20)[33]. Frequent hypertension and a higher cardiovascular risk have also been consistently reported[10, 11]. Several virologic and ART-related factors have been implicated in the pathophysiology of T2DM and hypertension in HIV infection, including chronic inflammation, immune reconstitution and lipodystrophy[34]. Dyslipidemia is also common due to both HIV chronic infection and lifelong use of ART, particularly PIs[9]. CKD is a frequent complication of HIV infection, occurring in 3.5-48.5% of the patients, due to HIV infection itself and as a consequence of ART, such as tenofovir disoproxil fumarate[12, 27].
Our study provides novel longitudinal data on the increased risk of T2DM, hypertension and dyslipidemia in PWH with NAFLD. This is consistent with findings in the general population with NAFLD. A large meta-analysis including 19 observational studies and 296,439 individuals followed for at least 1 year reported a twofold increased risk of incident T2DM in patients with NAFLD[4]. A community study including 3,869 NAFLD subjects and 15,209 controls followed for a median of 7 years found that a subject with NAFLD and without T2DM, hypertension or dyslipidemia was over two times (relative risk 2.62, 95% CI 5 2.31-2.96) more likely to develop one or more of these comorbidities than an age- and sex-matched control[35]. In our study, we found that PWH with NAFLD were more likely to develop T2DM and dyslipidemia, with aHR of 5.13 (95% CI 2.14-12.31) and 2.35 (95% CI 1.34-4.14), respectively. Moreover, suspected significant liver fibrosis was an independent predictor of T2DM development, with an aHR of 2.71 (95% CI 1.11-6.61). A recent cross-sectional study of factors associated with liver fibrosis and steatosis in patients with HIV mono-infection demonstrated an association of T2DM with liver fibrosis (odds ratio 3.78, 95% 1.48-9.68)[36]. Our finding suggests a possible link between the progression of NAFLD-associated liver disease and insulin resistance in the context of HIV infection. Current use of PIs was an independent predictor of developing dyslipidemia. This class of ART is associated with a less favorable lipid profile, in particular elevated triglycerides and total cholesterol, especially when boosted with ritonavir[37]. We also observed a trend for NAFLD to predict development of hypertension. Conversely, we did not observe any link between NAFLD and incident CKD. In the general population, a cohort study of 41,430 adults in Korea reported an aHR for NAFLD diagnosed by ultrasound of 1.22 (95% CI 1.04-1.43) for the development of CKD. We speculate that the pathogenesis of CKD in PWH may be more complex, and HIV-related factors may overcome the effect of NAFLD in this setting[3].
Liver and cardiovascular disease are the primary non-AIDS related causes of morbidity and mortality in PWH[38]. While HCV coinfection has been driven much of the liver-related mortality in the past, the implementation of effective direct antiviral-agents has inverted this trend. The increasing burden of NAFLD in the HIV-infected population, combined with our findings of its impact on metabolic comorbidities, indicate that PWH with NAFLD may be at particularly high risk of cardiovascular morbidity and mortality. Indeed, cardiovascular events are the leading cause of mortality in patients with NAFLD, and PWH have higher cardiovascular risk than the general population[39-41]. This is thought to be as a result of the effects of systemic inflammation and endothelial dysfunction, as well as the disproportionate presence of the traditional risk factors of insulin resistance and dyslipidemia. Additionally, the effect of NAFLD on long-term outcomes in the HIV-infected population is still not completely understood. Importantly, in HIV-negative patients NAFLD the severity of liver fibrosis impacts not only on liver-related, but also on all-cause mortality[39]. As such, guidelines recommend cardiovascular risk stratification for all patients with NAFLD, and particularly those with liver fibrosis[42, 43]. Management of NAFLD in HIV infection may include treating modifiable metabolic risk factors, diet and exercise, nutritional supplements as well as considering optimizing HIV-related factors and ART[44-46].
The main strength of our study is the longitudinal design, able to capture dynamics over time and providing novel data regarding the effects of NAFLD on development of metabolic comorbidities in PWH. Moreover, we included only consecutive patients as part of an ongoing screening program for liver disease at a single center. We wish to acknowledge several limitations of our study. First, the study was retrospective. Second, we did not have more robust diagnostic tools to diagnose hepatic steatosis, such as liver biopsy or magnetic resonance[14, 32]. However, it would be costly and time-consuming to use these approaches in a large prospective cohort. Moreover, transient elastography has not been widely validated against liver biopsy in the context of HIV infection. Although CAP >248 dB/m has a good sensitivity for detection of any grade steatosis, higher cut-off values have been proposed and its accuracy for grading steatosis is lower[14]. Third, we could not correlate our findings with actual cardiovascular outcomes. Fourth, given the limited number of outcomes, we were unable to study the influence of specific ART drugs and to include all metabolic comorbidities in the multivariable models. Fifth, BMI was missing for 22% of cases, so we could not account for its effect on multivariable models, although we found a tendency to predict incident T2DM, hypertension and CKD in univariable model. BMI might be an easy predictor to classify patients at risk of metabolic complications in clinical practice. Sixth, the observational design of this study does not allow for conclusions regarding causality. Specifically, our findings do not necessarily implicate NAFLD as a cause of diabetes. Finally, shared risk factors could contribute to both NAFLD, T2DM and dyslipidemia, including medication effects, genetics, type of diet and other lifestyle factors.
In conclusion, our study suggests that NAFLD is an independent predictor for the development of important metabolic comorbidities in PWH. This finding configures NAFLD as a barometer for metabolic health also in the setting of HIV infection. Metabolic comorbidities might perpetuate the NAFLD spectrum and contribute to increased cardiovascular risk in PWH. In the context of HIV infection, patients with NAFLD should be closely monitored for the development of metabolic outcomes and modifiable risks be managed in a timely fashion. Our findings might be considered a further argument to advocate for screening for NAFLD in PWH, as it is the case for patients with diabetes[47]. Indeed, the European AIDS Clinical Society guidelines recommended screening for NAFLD in PWH with metabolic syndrome, and expansion of these criteria to PWH with any metabolic comorbidity has been proposed[48, 49]. Implications of our findings on long-term cardiovascular outcomes should be investigated in future studies
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