Metabolic Syndrome's Link to Liver Fibrosis in Patients With HIV

Although incredible advances in the development and dissemination of antiretroviral therapy (ART) have enabled many individuals with HIV to avoid progressing to AIDS, the efficacy of this therapy means the population may now live long enough to succumb to diseases that often plague the non- HIV—infected population. Chief among these is liver disease, specifically nonalcoholic fatty liver disease (NAFLD), which is characterized by fatty deposits in the liver and can lead to liver fibrosis (stiffness), cirrhosis, or death.

In patients who do not have HIV, the primary driver of NAFLD is metabolic syndrome. According to the National Heart, Lung, and Blood Institute, metabolic syndrome pertains to a cluster of risk factors that predispose a person to heart disease, diabetes, and stroke, and its incidence is rising worldwide. Prominent among these risk factors is obesity concentrated in the abdominal area. Additional risk factors include hypertension, a high fasting blood glucose level, and high triglyceride and low high-density lipoprotein (HDL) cholesterol levels. Now, NAFLD driven by metabolic syndrome is becoming more common in individuals with HIV as well—approximately one-third have NAFLD, according to the authors of a new study on the link between liver fibrosis and metabolic syndrome in individuals living with HIV.

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The study was conducted by a European team that analyzed 405 HIV-monoinfected adults, mostly male, who appeared in a database of patients being followed for treatment at a Paris hospital. The subjects all had been diagnosed with HIV at least 5 years prior to the study, and none had a history of excessive alcohol consumption. Their average age was 53, and 203 had metabolic syndrome. Upon enrollment, each participant had the stiffness of his or her liver measured using transient elastography, a noninvasive method similar to an ultrasound. Blood samples also were taken after a 12-hour fast.

The team found that liver stiffness, along with cirrhosis, was measurably higher in patients who had markers of metabolic syndrome, including low HDL cholesterol and high triglycerides. The higher the patient’s body mass index (BMI), the higher the risk of fibrosis and cirrhosis. Patients with a BMI of at least 30 kg/m

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were especially likely to have fibrosis, as were patients whose blood work suggested insulin resistance. Overall, 25.1% of HIV-monoinfected patients who had metabolic syndrome had significant fibrosis, with 8.4% found to have cirrhosis. Among HIV-monoinfected patients without metabolic syndrome, fewer than 8% had fibrosis. Because fibrosis is a known marker of the severity of chronic liver disease, and because it has a proven association with deaths due to liver disease in individuals with NAFLD who don’t have HIV, these findings have important implications for the HIV community.

Liver disease has long been a concern in individuals living with HIV, especially as they’ve seen their lives extended thanks to ART. “Most of the time, patients with HIV develop liver fibrosis/ cirrhosis in a background of viral hepatitis (hepatitis B virus [HBV] or hepatitis C virus [HCV]) coinfection,” Maud Lemoine, a senior clinical lecturer at Imperial College London and the lead author of the study, told Contagion^®. “But in patients without HBV or HCV coinfection, metabolic syndrome [arises] mainly due to obesity inducing fat into the liver, which can progress to inflammation and fibrosis.”

Exactly how and why NAFLD and metabolic syndrome contribute to liver fibrosis in individuals living with HIV is not well understood. Researchers are unsure of the causative biological processes, but they have confirmed that HIV-monoinfected patients with metabolic syndrome experience changes in the levels of proteins emitted by fat tissue as well as higher levels of cells that induce an immune response. “The HIV infection itself is connected to a chronic inflammatory state,” Dr. Lemoine said, but added that scientists do not know whether HIV has a direct impact on the liver. “We analyze patients that are very well suppressed, with no detectable viral load.”

What she and her team do know is that adipose tissue from obesity is the main driver of this condition. “So far, it has been a neglected problem in HIV patients,” she said, noting that there have been many studies examining the role of obesity and metabolic disease in individuals without HIV.

Helping Patients Who Have HIV and Metabolic Syndrome

As it is now recognized that individuals living with HIV are becoming more likely to fall prey to non-AIDS—related maladies as their lifespans increase, the health care community needs to respond accordingly. The causes of obesity in individuals living with HIV, said Dr. Lemoine, include poor diet and lack of exercise—much as they do in the general population. Practitioners who treat individuals living with HIV must be aware of the impact of these factors and help patients create and adhere to strategies to lose weight, get more active, and control their diabetes and hypertension, if those conditions are present.

Alcohol, too, may play a role in the development of liver fibrosis, which physicians and other providers should address. “Excess alcohol consumption is definitely a risk factor for fibrosis, and any discussion about fibrosis must make note of this reversible cause,” Benjamin Young, MD, PhD, senior vice president and chief medical officer of the International Association of Providers of AIDS Care (although not an author of this study), told Contagion

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. “Alcohol consumption and dependency should be assessed and addressed, and for those with chronic hepatitis or liver fibrosis, a harm reduction approach should be used to support reduction and cessation.”

According to the National Institute on Drug Abuse, alcohol and drugs are significant problems for individuals living with HIV: one of 3 used drugs or binged on alcohol between 2005 and 2009, and 24% have a problem serious enough that they should be in a substance-abuse treatment program.

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Patients with HIV also need to be screened for hepatitis, traditionally a major driver of liver disease in this population. “Diagnosis, treatment, and—in the case of hepatitis C—cure, of viral hepatitis should be done, and for uninfected individuals, vaccinations to prevent hepatitis A and B should be administered,” Dr. Young said.

What role, if any, does ART play in the development of liver fibrosis? “This has not been clearly demonstrated,” Dr. Lemoine told Contagion

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. “Probably [there is] an indirect role…but in our study, the role of ART was not significant.”

A more accurate question might be which drugs used in ART pose the most risk rather than whether ART itself is problematic, as the medical community recognizes that the risks of forgoing ART are greater than the potential risks of administration. “It’s generally appreciated that treating HIV with antiretrovirals reduces the risk of liver fibrosis,” said Dr. Young. “Yet there remains controversy as to whether any particular antiretroviral drug might increase the risk over others.” Older drugs, such as d4T (stavudine) and azidothymidine (AZT), Dr. Lemoine said, seem to be more toxic than newer therapies and might best be avoided. Other studies have shown, for example, that when HIV-infected patients with NAFLD switch from efavirenz to raltegravir, liver steatosis is significantly improved.

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Treatment for NAFLD remains a work in progress. A recent study out of Case Western Reserve University in Cleveland, Ohio, examined whether statins are an appropriate therapy for people living with HIV who have NAFLD, as they have been suggested as a viable NAFLD treatment option for people without HIV.4 Interestingly, the HIV-positive subjects treated with statins experienced an increase in their liver fat scores after 96 weeks compared with the liver fat scores of the HIV-positive placebo takers. Therefore, it would seem that although statins are effective at reducing cardiovascular risks, they cannot be relied upon to treat fatty liver disease—and in fact may be counterproductive.

This study had a few limitations, including its use of a noninvasive method to scan for liver fibrosis and the absence of histological confirmation of this diagnosis with liver biopsies. A small percentage of participants (13%) had invalid transient elastography results that could not be used. The participants were overwhelmingly male, which could have skewed the findings as a previous study found that women living with HIV have significantly lower levels of liver steatosis, or fatty liver, than women without HIV. Also, as this was a cross-sectional study, follow-up is necessary to examine rates of morbidity and mortality in this population. The authors hope the medical community engages in further research to learn more about the exact mechanisms that lead patients with HIV to experience liver fibrosis and how this can be prevented.

Ms. Saloman, MS, is a health writer with more than 20 years of experience working for both consumer- and physician-focused publications. She is a graduate of Brandeis University and the Medill School of Journalism at Northwestern University. She lives in New Jersey with her family.

References:

1. Lemoine M, Lacombe K, Bastard JP, et al. Metabolic syndrome and obesity are the cornerstones of liver fibrosis in HIV-monoinfected patients. AIDS. 2017;31(14):1955-1964. doi: 10.1097/QAD.0000000000001587.
2. National Institute on Drug Abuse. Drug and alcohol use - a significant risk factor for HIV. NIH website. drugabuse.gov/related-topics/trends-statistics/infographics/drug-alcohol-use-significant-risk-factor-hiv. Updated April 2015. Accessed on October 14, 2017.
3. Macias J, Mancebo M, Merino D, et al. Changes in liver steatosis after switching from efavirenz to raltegravir among human immunodeficiency virus-infected patients with nonalcoholic fatty liver disease. Clin Infect Dis, online edition. DOI: 10.1093/cid/cix467.
4. El Kamari V, Hileman CO, Mccomsey G. Fatty liver disease in HIV: Predictors and response to statin therapy. Open Forum Infectious Diseases, 2017 Fall; 4(Suppl 1): page S58. DOI: 10.1093/ofid/ofx162.136.