Non-alcoholic fatty liver disease (NAFLD) is a major emerging health challenge for people living with HIV, according to a review of evidence by doctors from the department of internal medicine and infectious diseases, University Medical Centre Utrecht (UMCU), The Netherlands.
NAFLD occurs when fat accumulates in liver cells, in people with low alcohol consumption. In some people fat accumulation will cause no symptoms but in a minority of people with NAFLD, fat accumulation leads to more serious liver damage in the form of non-alcoholic steatohepatitis (NASH) and cirrhosis. Around 10% of people with NAFLD develop NASH, and approximately one-third of people with NASH will go on to develop fibrosis or cirrhosis, resulting in declining liver function.
Immune activation caused by HIV and a history of treatment with the first generation of antiretroviral drugs, as well as the classic risk factors of obesity and metabolic syndrome, may place people living with HIV at higher risk of developing NAFLD and NASH.
A systematic review and meta-analysis published in 2017 found a prevalence of NAFLD in people living with HIV (PLHIV) of 35%, compared to a general population prevalence of 25%. The prevalence of NAFLD is much higher in PLHIV with persistent liver enzyme elevations; studies found prevalence ranged from 57 to 72%. However, studies that have matched PLHIV with HIV-negative controls do not consistently find a higher prevalence in PLHIV and show that classic risk factors for NAFLD were more important than HIV-related factors.
Possible causes of NAFLD and NASH in HIV infection include: insulin resistance induced by HIV infection and by use of older protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) (especially stavudine) leads to triglyceride accumulation in the liver; mitochondrial toxicity caused by older NRTIs (stavudine, zidovudine) prevents liver cells from processing triglycerides, promoting accumulation; boosted protease inhibitors promote higher lipid levels; and insulin resistance and raised glucose levels encourages production of lipids in the liver.
Traditional risk factors are insulin resistance and type 2 diabetes, high body mass index and high waist circumference, hypertension and high triglycerides.
NAFLD is thought to predispose the liver to further injury from other sources such as antiretroviral drugs that cause mitochondrial toxicity, changes in the activity of adipose tissue due to metabolic syndrome or antiretroviral drugs, and inflammation caused by chronic HIV infection. But experts are still uncertain why NASH develops in some people with NAFLD.
As people with HIV age, the authors say, it is likely that traditional risk factors for NAFLD will become more important than HIV-related factors in determining the burden of NAFLD in PLHIV. One study found almost two-thirds of a cohort of PLHIV was either overweight or obese and therefore at risk of developing NAFLD.
Diagnosis of NAFLD and NASH, especially in epidemiological studies, remain problematic. Liver biopsy is the gold standard but cannot be used for screening owing to the potential risks of bleeding and pain. MRI scanning cannot be used for screening studies owing to its cost but a new addition to the Fibroscan non-invasive tool for measurement of liver stiffness called Controlled Attenuation Parameter (CAP) can be used to assess the extent of steatosis with a high degree of sensitivity at all stages.
European AIDS Clinical Society guidelines recommend ultrasound screening for NAFLD in all PLHIV with metabolic syndrome (defined as any three of impaired fasting glucose or type 2 diabetes, elevated triglycerides, low HDL cholesterol, high blood pressure, and increased waist circumference).
Potential treatment options for NASH include the following: NASH can be improved by weight loss of 10% or more; alcohol consumption should be confined to the recommended limits – high alcohol consumption raises the risk of liver cancer in people with NASH. The European Association for the Study of the Liver (EASL) recommends complete abstinence for anyone diagnosed with NASH; Pioglitazone has shown some efficacy against NASH but is associated with weight gain. EASL recommends an insulin sensitiser such as pioglitazone in people with type 2 diabetes whereas the American Association for the Study of Liver Diseases (AASLD) recommends an insulin sensitiser for anyone with NASH; Vitamin E can be considered for anyone without type 2 diabetes and without cirrhosis, EASL and AASLD recommend; and antiretroviral regimens associated with metabolic complications should be replaced with more benign regimens containing newer non-nucleoside reverse trancriptase inhibitors such as rilpivirine or doravirine and integrase inhibitors.
The burden of liver-related morbidity remains high among HIV-infected patients, despite advances in the treatment of HIV and viral hepatitis. Especially, the impact of non-alcoholic fatty liver disease (NAFLD) is significant with a prevalence of up to 50%. The pathogenesis of NAFLD and the reasons for progression to non-alcoholic steatohepatitis (NASH) are still not fully elucidated, but insulin resistance, mitochondrial dysfunction and dyslipidemia seem to be the main drivers. Both HIV-infection itself and combination antiretroviral therapy (cART) can contribute to the development of NAFLD/NASH in various ways. As ongoing HIV-related immune activation is associated with insulin resistance, early initiation of cART is needed to limit its duration. In addition, the use of early-generation nucleoside reverse transcriptase inhibitors and protease inhibitors is also associated with the development of NAFLD/NASH. Patients at risk should therefore receive antiretroviral drugs with a more favorable metabolic profile. Only weight reduction is considered to be an effective therapy for all patients with NAFLD/NASH, although certain drugs are available for specific subgroups. Since patients with NASH are at risk of developing liver cirrhosis and hepatocellular carcinoma, several non-antifibrotic and antifibrotic drugs are under investigation in clinical trials to broaden the therapeutic options. The epidemiology and etiology of NAFLD/NASH in HIV-positive patients is likely to change in the near future. Current guidelines recommend early initiation of cART that is less likely to induce insulin resistance, mitochondrial dysfunction and dyslipidemia. In contrast, as a result of increasing life expectancy in good health, this population will adopt the more traditional risk factors for NAFLD/NASH. HIV-treating physicians should be aware of the etiology, pathogenesis and treatment of NAFLD/NASH in order to identify and treat the patients at risk.
Berend J van Welzen, Tania Mudrikova, Ayman El Idrissi, Andy IM Hoepelman, Joop E Arends