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.
“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.
More information: T Stanley et al. Effects of tesamorelin on nonalcoholic fatty liver disease in HIV: a randomized, double-blind, multicenter trial. The Lancet HIV, 2019.
Provided by NIH/National Institute of Allergy and Infectious Diseases
Nonalcoholic fatty liver disease (NAFLD) is now the second leading indication for liver transplantation in the United States and is projected to become the major etiology within the next decade.1
The prevalence of NAFLD among the US population is approximately 30%, with an estimated 25% of those individuals having nonalcoholic steatohepatitis (NASH), the more severe and progressive subtype. NAFLD is not only the most common etiology of chronic liver disease in the general population but also in individuals with HIV infection (See Figure 1).2–4
Prevalence of alcoholic and subtypes of nonalcoholic liver disease varies depending on the modality used for diagnosis, but is also attributable to varying definitions of alcohol abuse, variability of alcohol use, and social stigma; therefore, the true prevalence is unclear.
Since the development of effective antiretroviral therapy (ART), liver disease remains one of the leading causes of non-HIV-related mortality.5,6 HIV-related liver disease has a wide variety of etiologies, including coinfection with hepatitis B or C virus, NAFLD, alcoholic liver disease, medication-related hepatotoxicity, and potentially the virus itself.7
Subtypes of Fatty Liver and Fatty Liver Disease
The presence of fat in the liver does not automatically mean that liver disease is present. Indeed, normal physiologic processes include temporary storage of fat in the liver prior to processing and distribution. Longer-term storage of fat in hepatocytes may lead to increased cell turnover and subsequent development of an immune-mediated response, as well as fibrosis. Simple ste-atosis (fatty liver) can be distinguished from fatty liver disease by the presence of serum transaminase abnormalities (injury) or by the development of fibrosis. Fatty liver disease is broadly differentiated by its underlying etiology into alcoholic versus nonalcoholic forms. Alcoholic liver disease (ALD) and NAFLD are histologically similar; therefore, clinical history must be taken into consideration, which is often challenging when dealing with the stigma and misconceptions associated with alcohol use.
Alcoholic Fatty Liver Disease
ALD can range from alcoholic steatosis to alcoholic steatohepatitis (ASH) and, ultimately, advanced liver disease in the form of cirrhosis.
Alcoholic steatosis is simple steatosis, a direct consequence of alcohol oxidation, and is typically benign and reversible with abstinence.8 In the majority of cases, steatosis is macrovesicular in nature. However, the presence of mixed steatosis (macro- and microvesicular) has been associated with higher risk (28% vs 3%, respectively) of progression to cirrhosis over a median interval of 10.5 years than with purely macrovesicular steatosis.9
A proposed mechanism of progression of liver disease includes oxidative stress, which may promote the formation of giant mitochondria. The presence of giant mitochondria is also a histologic predictor of ALD progression to advanced fibrosis or cirrhosis.9
ASH is characterized by the presence of macrovesicular steatosis, Mallory-Denk bodies, neutrophilic infiltration, and hepatocyte ballooning, the latter of which distinguishes ASH from simple steatosis.
Ballooned hepatocytes, Mallory-Denk bodies, and lobular inflammation are primarily located in zone 3 (the pericentral portion of the liver lobule), promoting the eventual development of zone 3 fibrosis.
A differentiating feature of ASH is the predominant lobular infiltration of polymorphonuclear leukocytes, compared with portal tract infiltration of mononuclear cells in other types of hepatitis.8 Severe neutrophilic infiltration is often a feature of ASH.
ASH (often referred to as alcoholic hepatitis) is a clinical diagnosis based on development of jaundice plus aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations 5 to 10 times the upper limit of normal, with ALT classically being lower, in the setting of alcohol use within 8 weeks.10
There is a marked short-term mortality of up to 30%. In cases where alcohol use is unclear or there may be confounding etiologies, liver biopsy is utilized to confirm the diagnosis. In order to assist with prognostication, the Alcoholic Hepatitis Histologic Score was developed.11
Histologic features, including degree of fibrosis, degree of neutrophilic infiltration, type of bilirubinostasis, and presence of megamitochondria were associated with 90-day mortality (area under the receiver operating characteristic curve [AUROC], 0.77; 95% confidence interval, 0.71–0.83). In fact, features such as severe neutrophilic infiltration and presence of megamitochondria portended a better prognosis than do features of advanced fibrosis and canalicular with hepatocellular bilirubinostasis, which predicted higher mortality.11
In individuals with ongoing injury, cirrhosis will eventually develop. Those who progress to cirrhosis will have perivenular and perisinusoidal fibrosis with micronodular versus macronodular cirrhosis if they continue to actively use alcohol.8 In fact, fibrosis stage is the main long-term predictor of mortality in persons with compensated ALD, with a 10-year mortality of 45% in those with advanced fibrosis (Metavir score, F3/F4; P <.001).12
Alcohol use is prevalent among individuals with HIV infection and can lead to medication nonadherence, disease progression, and inadequate viral suppression. One large-scale study of more than 1000 participants found that 10% participated in hazardous alcohol use (defined as >14 drinks/week for men and >7 drinks/week for women or binge drinking).13 A longitudinal study of 231 individuals with HIV infection found that those who frequently used alcohol (defined as ≥2 drinks daily) were 2.91 times more likely to have a decline in CD4+ cell count to below 200/μL (P= .015) independent of ART use over time, baseline CD4+ cell count, viral load, sex, age, and duration of HIV infection. Persons who frequently used alcohol while on ART had higher viral loads after controlling for sex, age, and CD4+ cell count than those who did not use or moderately used alcohol (P=.04).14
Alcohol use causes suppression of the innate and acquired immune systems that not only augments disease susceptibility but can also accelerate HIV progression.15 Additionally, alcohol disrupts the gut barrier, increases enteric microbial burden, and causes bacterial translocation, which exacerbates HIV disease progression.16
Nutrient deficiencies accelerate HIV progression, and alcohol is well known to cause nutrient, particularly micronutrient, deficiencies.
Inadequate viral suppression is thought to be secondary to ineffective ART metabolism; the 2 proposed mechanisms are enzymatic inhibition from acute alcohol use competing with cytochrome p450 isozymes, and enzymatic induction from chronic alcohol use. Patients should be screened for high-risk alcohol use behaviors and extensively counseled on this modifiable risk factor.
Nonalcoholic Fatty Liver Disease
NAFLD constitutes a spectrum of disease encompassing nonalcoholic fatty liver (NAFL), NASH, and advanced fibrosis or NASH cirrhosis. NAFL, otherwise known as simple steatosis, is the accumulation of steatosis in more than 5% of hepatocytes, with or without mild lobular inflammation, in the absence of substantial alcohol intake.17
Steatosis is often macro- and microvesicular. Unlike alcoholic steatosis, microvesicular steatosis has a nonzonal distribution in the parenchyma, which can lead to higher grades of steatosis and progressive disease.18
Mild lobular inflammation with mononuclear cells, particularly lymphocytes, is typically found even in cases of simple steatosis.
The hallmark of NASH is the presence of ballooned hepatocytes, reflecting hepatocellular injury, which are required to make the diagnosis. Given the prognostic implications of differentiating NAFL from NASH in clinical trials, the NAFLD Activity Score (NAS; a histologic scoring system) was designed by pathologists to be a semiquantitative scoring system for defining NASH.
The NAS focuses on scoring each of the following histologic changes: steatosis, lobular inflammation, and hepatocellular ballooning. An NAS of 5 or higher correlates with a diagnosis of NASH, and a score of below 3 indicates the absence of NASH.19
Notably, fibrosis is not included in the score. Steatosis, inflammation, and hepatocellular ballooning tend to be centrilobular in location. Without a clinical history, it can often be difficult to histologically differentiate NASH and ASH; however, certain features, such as presence of large Mallory-Denk bodies, canalicular cholestasis, chronic portal inflammation, and perivenular fibrosis, are observed more frequently in ASH than NASH.18
Unfortunately, no histologic features are pathognomonic to distinguish ALD from NAFLD, making a clinical history imperative.
NASH is a more severe and progressive subtype of NAFLD; therefore, more aggressive modification risk factors is warranted in individuals with NASH. Individuals with NASH are at not only at higher risk of liver-related mortality but also all-cause malignancy and, most of all, cardiovascular disease (13%–30%).20
Hepatocellular carcinoma (HCC) can occur in the absence of cirrhosis, a finding exemplified by the fact that cirrhosis was present in only 50% of participants in a multicenter study that compared NAFLD with hepatitis C virus (HCV)-related HCC.21 This observation is concerning, as persons without cirrhosis are generally not undergoing HCC surveillance. Therefore, HCC can present with higher tumor burden due to delayed diagnosis.21 Ultimately, fibrosis stage and not NAS has been shown to be predictive of long-term mortality.22–24 In a large retrospective study examining participants over a period of 20 years, 12.1% of those with F3 fibrosis and 45% of those with F4 fibrosis developed decompensated liver disease.22
Although the prevalence of NAFLD in individuals with HIV infection varies depending on the study, a prospective biopsy-proven study found that 55% of individuals with chronically elevated liver enzymes had NASH, corroborating the importance of NAFLD screening in this patient population.7
The gold standard for distinguishing NASH from NAFL and assessing fibrosis stage is via liver biopsy. However, the inherent invasive nature, cost, and potential complications of liver biopsy preclude universal use. Alternative modalities for distinguishing NASH from NAFL include transient elastography (TE) with controlled attenuation parameter (CAP) and magnetic resonance elastography (MRE), each of which have been well studied. MRE and transient elastography assess degree of fibrosis. The addition of CAP to transient elastography and proton density fat fraction (PDFF) to MRE allow for the measurement of steatosis.
A prospective cross-sectional study of more than 100 persons with biopsy-proven NAFLD compared the accuracy of TE to MRE for assessment of fibrosis and of CAP to magnetic resonance imaging-derived PDFF (MRI-PDFF) for assessment of steatosis.25 MRE was superior to transient elastography (AUROC, 0.82 vs 0.67) for diagnosing any stage of fibrosis and was significantly more accurate (P=.0116).
However, no significant difference was found between the 2 modalities for diagnosing dichotomized stages of fibrosis. Notably, this study did use the extra-large (XL) probe during transient elastography, to account for high rates of obesity in the United States.25 MRI-PDFF was also superior to CAP (AUROC, 0.99 vs 0.85) in diagnosing any degree of steatosis, with significantly more accuracy (P= .0091), and in diagnosing dichotomized stages of steatosis (P=.0017 and P=.0238).25
The main limitations of MRE and MRI-PDFF are institutional availability, technical expertise required to perform and interpret results, cost, and claustrophobia for some patients.26
Therefore, some experts recommend that MRI-PDFF be considered mainly for individuals at high risk for NASH for whom an intervention is planned.26 Because of the acceptability of the AUROC for CAP in the study mentioned above and others plus the ability of transient elastography to rule out advanced fibrosis, transient elastography remains a viable option for most patients.
