CATIE News

16 January 2020 

Can vitamin E help fight fatty liver disease in HIV-positive people?

  • Some health conditions in HIV-positive people increase the risk of fatty liver disease
  • Montreal researchers studied the effect of vitamin E in HIV-positive people with fatty liver
  • Liver enzyme levels were restored to normal in 85% of participants who took vitamin E daily

The widespread availability of potent combination HIV treatment (ART) has significantly reduced AIDS-related deaths and illness in Canada and other high-income countries. The power of ART is so profound that scientists increasingly predict that many ART users will have a near-normal life expectancy.

HIV causes excess inflammation and activation of the immune system; these problems are reduced but not eliminated by ART. As many of the immune system’s cells are widely distributed throughout the body, issues that affect the immune system can also affect other systems as well as organs. Thus, chronic inflammation and immune activation have the potential over decades to affect the health of vital organs such as the brain, bones, heart, liver, kidneys and so on.

An emerging issue—fatty liver

Scientists at McGill University in Montreal have noted that fatty liver disease is an emerging issue in people regardless of their HIV status. Here is some information about fatty liver disease from the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

NAFLD (non-alcoholic fatty liver disease)

In this condition, excess fat is stored in the liver. NAFLD can be subdivided into two categories:

  • Simple fatty liver – this is a form of NAFLD in which there is excess fat in the liver but minimal levels of inflammation. Additionally, NIDDK states that “simple fatty liver typically does not progress to cause liver damage or complications.”
  • NASH (non-alcoholic steatohepatitis) – with this form of NAFLD there is both excess fat and inflammation in the liver. Furthermore, due to the underlying disease process in NASH, healthy liver cells are gradually replaced with scar tissue. NASH can lead to severe liver injury and, in some cases, increase the risk for liver cancer.

NASH and HIV

Scientists at McGill University have completed a small exploratory study of NASH in 27 people who have HIV infection. They found that 24 consecutive weeks of vitamin E supplementation was able to reduce inflammation as well as the excess death of liver cells. All of these changes are indicative of improved liver health. Vitamin E supplementation was generally safe. Larger and longer studies are needed to confirm the promising results from this study.

Study details

All participants were taking ART and had a viral load that was less than 50 copies/mL for at least six months prior to entering the study.

Participants did not have any of the following factors that can cause liver injury:

  • hepatitis B virus or hepatitis C virus
  • significant consumption of alcohol
  • use of street drugs

Liver health was assessed with the following tests and procedures:

  • a specialized ultrasound scan called FibroScan (made by Echosens in Paris, France) – the data captured by the scans were assessed by software with the capacity to grade fatty liver
  • CK-18 (cytokeratin-18) – this is a protein released into the blood when liver cells die. Excess levels of CK-18 indicate abnormal liver health and that liver cells are dying.
  • ALT (alanine aminotransferase) – this is a liver enzyme. Higher-than-normal levels of ALT strongly suggest there is inflammation of the liver.

These and other tests were done throughout the study.

The study lasted for 72 weeks and was divided into the following three 24-week portions:

  • Period 1 – participants were monitored, had blood tests, FibroScan and other assessments
  • Period 2 – participants took vitamin E 800 IU once daily, were monitored and underwent assessments
  • Period 3 – participants were monitored and underwent study tests and assessments

Results

During the period of vitamin E supplementation, the values of the three liver assessments improved. Here are some of the findings of the McGill scientists after 24 weeks of vitamin E supplementation:

  • 85% of participants had their ALT levels fall to within the normal range, suggestive of decreased liver inflammation. After cessation of vitamin E, the normalization of ALT levels continued in these participants.
  • The proportion of participants with a large degree of fat accumulation in the liver decreased from 67% at the start of the study to 41%.
  • Fatty liver disease resolved in 22% of participants.

As mentioned earlier, all of the main measures used to assess liver health were non-invasive and indirect. However, in four participants, doctors removed a tiny portion of liver tissue before and after the study. Analysis of these tissue samples directly confirmed resolution of fatty liver disease.

Safety

In the study, 11 people reported adverse events—these were mild or moderate in severity. As this trial did not have a control group that received placebo or other interventions, scientists cannot be certain as to the cause of the adverse events, which were as follows:

  • tiredness – 2 people
  • nausea and abdominal cramps – 2 people
  • blurred vision – 2 people
  • headache – 2 people
  • dizziness – 2 people
  • itching – 1 person

An American placebo-controlled study of vitamin E taken at a dose of 800 IU/day in HIV-negative people with NASH found it to be generally safe (with similar adverse effects to those taking placebo) and effective when taken for 96 weeks.

In the larger society

The Montreal scientists expect that liver injury arising from fatty liver disease will increasingly become an issue in the coming decade among HIV-negative people. This increase is very likely driven by growing trends such as overweight/obesity as well as pre-diabetes and diabetes. However, it is important to note that in some circumstances lean people can also develop NAFLD/NASH. In such cases, factors such as genetics, insufficient exercise, problems with maintaining normal blood sugar levels, diets high in sugar, and problems with thyroid and other hormones likely play a role.

Fatty liver disease in HIV-positive people

The McGill scientists and scientists at other institutions stated that there may be multiple factors contributing to the problem of fatty liver disease in HIV-positive people today, such as the following:

  • pre-diabetes and diabetes
  • abnormal levels of cholesterol
  • higher-than-normal blood pressure
  • chronic inflammation arising from HIV (this appears to affect the liver)
  • exposure to older anti-HIV drugs such as ddI (stavudine, Zerit) and d4T (didanosine, Videx) and efavirenz (in Atripla, Sustiva and Stocrin)
  • interruption of ART

It is important to note that trends that are happening in the larger society of HIV-negative people—overweight/obesity and problems with regulating blood sugar—are likely also happening with HIV-positive people.

In this regard, HIV and metabolic expert Giovanni Guaraldi, MD, from the University of Modena in Italy, who reviewed the results of the Montreal study noted that nearly 80% of participants were overweight or obese.

He also noted that older anti-HIV drugs such as ddI and d4T are no longer used in high-income countries. Furthermore, integrase inhibitors are now widely used. Guaraldi stated that one integrase inhibitor, raltegravir (Isentress), has been found in two clinical trials to be associated with a reduction in fatty liver. However, other more widely used integrase inhibitors, such as bictegravir (in Biktarvy) and dolutegravir (in Dovato, Juluca and Triumeq), have not been formally assessed for their impact on fatty liver.

In the Montreal study, 93% of participants were taking an integrase inhibitor with two nucleoside analogues. However, as most participants had been diagnosed with HIV for about 23 years, it is likely that they had taken different anti-HIV drugs over the years. We do not know when participants first developed fatty liver disease. These issues make it difficult to be certain about the potential impact of ART (or specific classes of ART) on the development of fatty liver.

The role of vitamin E

Dr. Guaraldi sees vitamin E as a possible “bridge therapy” that can be used to stabilize liver health in some HIV-positive people with fatty liver until a more effective treatment emerges. Due to the increased risk for fatty liver disease in the HIV-negative population, pharmaceutical companies are testing many compounds for their potential use for this condition. However, clinical trials of such drugs exclude HIV-positive people, as generally companies want to get a drug to market as fast as possible and HIV-negative people are a much larger target population.

Well-designed studies to explore safety and potential drug interactions between different anti-HIV regimens and experimental drugs being tested for fatty liver disease would be a necessary first step before such experimental drugs would be considered for wider use in HIV-positive people. Thus, the Montreal scientists estimate that, in a business-as-usual scenario, it could take between seven and 10 years before these drugs are available for use by HIV-positive people. They also see vitamin E as a useful option for HIV-positive people with fatty liver disease.

Exercise and diet have a tremendous impact

The earlier point about overweight/obesity is an important one. There have been clinical trials of exercise (as simple as walking) and reduced intake of calories and carbohydrates in HIV-negative people with fatty liver. Dr. Guaraldi points out that such trials can have a dramatic impact. For instance, he states that “a 7% to 10% reduction in body weight alone leads to NASH resolution in 64% to 90% of cases,” depending on the study. What’s more, Dr. Guaraldi points out that “physical activity in HIV-negative people with NAFLD has been proven to reduce mortality from all causes [and in particular] death associated with cardiovascular disease and diabetes.”

For the future

The vitamin E trial by the scientists at McGill University is a very good first step in trying to find a way to help HIV-positive people with NAFLD/NASH. The scientists now have sufficient data to write a grant proposal for a larger, randomized trial from which firm conclusions can be drawn about the effectiveness and safety of vitamin E in HIV-positive people (Gaida Sebastiani, MD, written communication).

—Sean R. Hosein

REFERENCES:

  1. Sebastiani G, Saeed S, Lebouche B, et al. Vitamin E is an effective treatment for nonalcoholic steatohepatitis in HIV mono-infected patients. AIDS. 2020 Feb 1;34(2):237-244.
  2. Guaraldi G, Milic J. Vitamin E as a ‘bridge’ therapy for nonalcoholic steatohepatitis in HIV: what is waiting on the other side of the bridge? AIDS. 2020;34(2):317–319.
  3. Lerner AM, Eisinger RW, Fauci AS. Comorbidities in persons with HIV: The lingering challenge. JAMA. 2020;323(1):19-20.
  4. Leng SX, Margolick JB. Aging, sex, inflammation, frailty, and CMV and HIV infections. Cellular Immunology. 2020; in press.
  5. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. New England Journal of Medicine. 2010;362(18):1675–1685.
  6. Banasch M, Frank J, Serova K, et al. Impact of antiretroviral treatment on (13) C-methionine metabolism as a marker of hepatic mitochondrial function: a longitudinal study. HIV Medicine. 2011;12(1):40–45.
  7. Sanyal AJ. Past, present and future perspectives in nonalcoholic fatty liver disease. Nature Reviews Gastroenterology and Hepatology. 2019;16(6):377–386.
  8. Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nature Medicine. 2019;25(12):1822–1832.
  9. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nature Reviews Gastroenterology and Hepatology. 2018;15(1):11–20.
  10. Wong VW, Adams LA, de Lédinghen V, et al. Noninvasive biomarkers in NAFLD and NASH – current progress and future promise. Nature Reviews Gastroenterology and Hepatology. 2018;15(8):461–478.
  11. Saitta C, Pollicino T, Raimondo G. Obesity and liver cancer. Annals of Hepatology. 2019;18(6):810–815.
  12. El-Agroudy NN, Kurzbach A, Rodionov RN, et al. Are lifestyle therapies effective for NAFLD treatment? Trends in Endocrinology and Metabolism. 2019;30(10):701–709.
  13. Allen AM, Hicks SB, Mara KC, et al. The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity – a longitudinal cohort study. Journal of Hepatology. 2019;71(6):1229–1236.
  14. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367–378.
  15. Oates JR, McKell MC, Moreno-Fernandez ME, et al. Macrophage function in the pathogenesis of non-alcoholic fatty liver disease: The Mac Attack. Frontiers in Immunology. 2019;10:2893.