Drug reverses signs of liver disease in people living with HIV

Researchers at the National Institutes of Health and their colleagues at Massachusetts General Hospital (MGH) in Boston report that the injectable hormone tesamorelin reduces liver fat and prevents liver fibrosis (scarring) in people living with HIV.

The study was conducted by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute, both parts of NIH. The findings were published online today in The Lancet HIV

A microscopic image of liver tissue affected by non-alcoholic fatty liver disease (NAFLD). The large and small white spots are excess fat droplets filling liver cells (hepatocytes). Dr. David Kleiner, NCI

“Many people living with HIV have overcome significant obstacles to live longer, healthier lives, though many still experience liver disease,” said NIAID Director Anthony S. Fauci, M.D. “It is encouraging that tesamorelin, a drug already approved to treat other complications of HIV, may be effective in addressing non-alcoholic fatty liver disease.”

Non-alcoholic fatty liver disease, or NAFLD, frequently occurs alongside HIV, affecting as many as 25% of people living with HIV in the developed world. However, no effective treatments currently exist to treat the condition, which is a risk factor for progressive liver disease and liver cancer. Investigators led by Colleen M. Hadigan, M.D., senior research physician in NIAID’s Laboratory of Immunoregulation, and Steven K. Grinspoon, M.D., Chief of the Metabolism Unit at MGH, tested whether tesamorelin could decrease liver fat in men and women living with both HIV and NAFLD. Among the participants enrolled, 43% had at least mild fibrosis, and 33% met the diagnostic criteria for a more severe subset of NAFLD called nonalcoholic steatohepatitis (NASH). Thirty-one participants were randomized to receive daily 2-mg injections of tesamorelin, and 30 were randomized to receive identical-looking injections containing a placebo. Researchers provided nutritional counseling to all participants, as well as training in self-administering the daily injections. Researchers then compared measures of liver health in both groups at baseline and 12 months.

After one year, participants receiving tesamorelin had better liver health than those receiving placebo, as defined by reduction in hepatic fat fraction (HFF)—the ratio of fat to other tissue in the liver. The healthy range for HFF is less than 5%. Thirty-five percent of study participants receiving tesamorelin achieved a normal HFF, while only 4% of those on placebo reached that range with nutritional advice alone. Overall, tesamorelin was well-tolerated and reduced participants’ HFF by an absolute difference of 4.1% (corresponding to a 37% relative reduction from the beginning of the study). While nine participants receiving placebo experienced onset or worsening of fibrosis, only two participants in the tesamorelin group experienced the same. Additionally, levels of several blood markers associated with inflammation and liver damage — including the enzyme alanine aminotransferase (ALT) — decreased more among those taking tesamorelin compared to those on a placebo, particularly among those with increased levels at the beginning of the study.

Given these positive results, investigators suggest expanding the indication for tesamorelin to include people living with HIV who have been diagnosed with NAFLD. They also recommend additional research to determine if tesamorelin could contribute to long-term protection against serious liver disease in people without HIV.

“Our hope is that this intervention may help people living with HIV, as well as benefit HIV-negative people with liver abnormalities,” said Dr. Hadigan. “Further research may inform us of the potential long-term benefits of this approach and develop formulations that can benefit everyone with liver disease, regardless of HIV status.”

Egrifta (tesamorelin) was approved in 2010 by the U.S. Food and Drug Administration to reduce excess abdominal fat in HIV patients with lipodystrophy — a complication characterized by an abnormal distribution of body fat initially associated with older classes of HIV medications. The most commonly reported side effects in previous clinical trials evaluating Egrifta included joint pain (arthralgia), skin redness and rash at the injection site (erythema and pruritis), stomach pain, swelling, and muscle pain (myalgia). Worsening blood sugar control occurred more often in trial participants treated with Egrifta than with placebo.

“Because tesamorelin proved effective in treating abnormal fat build-up in the abdomens of people in the context of HIV and related medication use, we hypothesized that the drug might also reduce fat that accrues in the liver and causes damage in a similar population,” said Dr. Grinspoon.

While liver disease is often associated with heavy alcohol use, NAFLD occurs when excess fat builds up in the liver without alcohol as a contributing factor. This condition may progress to liver damage, cirrhosis or cancer that could be life-threatening and necessitate liver transplantation.

Previous studies have found that vitamin E supplements, weight loss and other lifestyle changes can improve outcomes among HIV-negative people with NASH. However, treatment options for NASH and NAFLD are often not tested in people with HIV and none are available for this group. Obesity and type 2 diabetes raise the risk of developing NAFLD regardless of HIV status, and people with HIV are at increased risk of NAFLD because some HIV medications and HIV itself are associated with gaining abdominal fat and may contribute to liver fat build-up.

WHO urges countries to invest in eliminating hepatitis

The World Health Organization has called on countries to take advantage of recent reductions in the costs of diagnosing and treating viral hepatitis and scale up investments in disease elimination.

A Visual Guide to Hepatitis. Photo credit: WebMD

Since 2011, WHO has been commemorating World Hepatitis Day on 28 July with an annual campaign as one of the 9 flagship annual health campaigns.

A new study by WHO, published in Lancet Global Health, has found that investing US$6bn per year in eliminating hepatitis in 67 low- and middle-income countries would avert 4.5 million premature deaths by 2030, and more than 26 million deaths beyond that target date.

“Today 80% of people living with hepatitis can’t get the services they need to prevent, test for and treat the disease,” said WHO Director-General Dr Tedros Adhanom Ghebreyesus.

Dr. Ghebreyesus also calls for bold political leadership, with investments to match, and imploring all countries to integrate services for hepatitis into benefit packages as part of their journey towards universal health coverage.”

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“Hepatitis is an inflammation of the liver. The condition can be self-limiting or can progress to fibrosis (scarring), cirrhosis or liver cancer. Hepatitis viruses are the most common cause of hepatitis in the world but other infections, toxic substances (e.g. alcohol, certain drugs), and autoimmune diseases can also cause hepatitis.

There are 5 main hepatitis viruses, referred to as types A, B, C, D and E. These 5 types are of greatest concern because of the burden of illness and death they cause and the potential for outbreaks and epidemic spread. In particular, types B and C lead to chronic disease in hundreds of millions of people and, together, are the most common cause of liver cirrhosis and cancer.

Hepatitis A and E are typically caused by ingestion of contaminated food or water. Hepatitis B, C and D usually occur as a result of parenteral contact with infected body fluids. Common modes of transmission for these viruses include receipt of contaminated blood or blood products, invasive medical procedures using contaminated equipment and for hepatitis B transmission from mother to baby at birth, from family member to child, and also by sexual contact.

Acute infection may occur with limited or no symptoms, or may include symptoms such as jaundice (yellowing of the skin and eyes), dark urine, extreme fatigue, nausea, vomiting and abdominal pain.” —WHO

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WHO says a total of US$58.7 billion is needed to eliminate viral hepatitis as a public health threat in these 67 countries by 2030. This means reducing new hepatitis infections by 90% and deaths by 65%, adding that by investing in diagnostic tests and medicines for treating hepatitis B and C now, countries can save lives and reduce costs related to long-term care of cirrhosis and liver cancer that result from untreated hepatitis.

NIH study finds gut microbiome can control antitumor immune function in liver

Scientists have found a connection between bacteria in the gut and antitumor immune responses in the liver.

Their study, published online May 24 in Science, was led by researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI). It showed that bacteria found in the gut of mice affect the liver’s antitumor immune function. The findings have implications for understanding the mechanisms that lead to liver cancer and for therapeutic approaches to treat them. NCI is part of the National Institutes of Health.

“What we found using different tumor models is that if you treat mice with antibiotics and thereby deplete certain bacteria, you can change the composition of immune cells of the liver, affecting tumor growth in the liver,” said Tim Greten, M.D., of NCI’s CCR, who led the study. “This is a great example of how what we learn from basic research can give us insight into cancer and possible treatments.”

The microbiome is the collection of bacteria and other microorganisms that live in or on the body. In humans, the greatest proportion of the body’s total microbiome is in the gut. Despite extensive research into the relationship between the gut microbiome and cancer, the role of gut bacteria in the formation of liver cancer has remained poorly understood.

To investigate whether gut bacteria affect the development of tumors in the liver, Dr. Greten and his team carried out a series of experiments with mice. They used three mouse models of liver cancer, and found that when they depleted gut bacteria using an antibiotic “cocktail,” the mice that had the antibiotics developed fewer and smaller liver tumors and had reduced metastasis to the liver.

The investigators next studied the immune cells in the liver to understand how the depletion of gut bacteria suppressed tumor growth in the liver of the antibiotic-treated mice. Antibiotic treatment increased the numbers of a type of immune cell called NKT cells in the livers of the mice. Further experiments showed that, in all three mouse models, the reduction in liver tumor growth that resulted from antibiotic treatment was dependent on these NKT cells. Next, they found that the accumulation of the NKT cells in the liver resulted from an increase in the expression of a protein called CXCL16 on cells that line the inside of capillaries in the liver.

“We asked ourselves, why do mice treated with antibiotics have more CXCL16 production in these endothelial cells?” Dr. Greten said. “That was the critical point, when we found that bile acids can control the expression of CXCL16. We then did further studies, and found that if we treat mice with bile acids, we can actually change the number of NKT cells in the liver, and thereby the number of tumors in the liver.”

Bile acids are formed in the liver and help break down fats during digestion.

Finally, the investigators found that one bacterial species, Clostridium scindens, controls metabolism of bile acids in the mouse gut — and ultimately CXCL16 expression, NKT cell accumulation, and tumor growth in the liver.

Dr. Greten explained that while many studies have shown an association between gut bacteria and immune response, this study is significant in that it identifies not just a correlation, but a complete mechanism of how bacteria affect the immune response in liver. In the same study, the researchers found that bile acids also control the expression of the CXCL16 protein in the liver of humans and wrote that, though these results are preliminary, the novel mechanism described in this study could potentially apply to cancer patients.