Fatty Liver in HIV
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Download the PDF here
There are 2 publications attached below + this link to report on NATAP.org. Some think NASH may have different path & mechanism in HIV+ leading to controversy around the utility of drugs currently in development or the 1 available & their efficacy in HIV+ since they are designed for HIV-. Here below are discussions around this and various drugs in development including those for HIV+. A lot more has to be done to sort out these questions. To begin with fatty liver & NASH is not at the top of the list of conditions to screen for in HIV+ & then what to do?? So it pays for PLWH to begin the discussion with their providers. PLWH with elevated liver functions tests - that is an indication for further examination: "all patients with chronically increased liver test panel results should be investigated for the presence of steatosis and then further risk-stratified using non-invasive assessments of fibrosis (figure 3)". We HIV+ have all the risk factors. Fibroscan is often used as an initial test to evaluate fatty liver, its a simple quick & easy ultrasound test that takes 5 minutes and tells you your CAP # which is the data used to evaluate the patient. But it certainly is not the final answer.
"Although the incidence of lipodystrophy is thought to be declining alongside the declining use of NRTIs, its prevalence remains relatively high, because effective treatment strategies are scarce. The absence of simple and clinically useful criteria for increased VAT or HIV-associated disorders of fat partitioning that can differentiate this syndrome from the heterogeneous patterns of fat distribution seen in the general population has considerably limited the study of these conditions. These fat distribution changes could be characterised as part of the spectrum of metabolic syndrome, because visceral adiposity is strongly associated with the development of dyslipidaemia and diabetes. However, the effects of the HIV infection and long-term exposure to ART probably further enhance these changes. The specific ways in which the HIV-associated syndrome differs from metabolic syndrome, and how HIV-associated hepatic fat accumulation and liver injury differ from that seen in patients without HIV, are not known.
Although the high prevalence of steatosis and steatohepatitis has been recognised in patients with HIV since the 1980s,6, 7, 8, 9 the previously uncertain effect of these syndromes on patient outcomes, difficulty with non-invasive diagnosis, and few therapeutic options have led to the under-recognition and under-treatment of NAFLD in these patients. However, as the prevalence of metabolic syndrome and NAFLD rise and a multitude of novel therapeutic agents are entering clinical trials for NAFLD (both in the general population and in patients with HIV), a more concerted effort to diagnose, stage, and treat these patients will be essential to combating the NAFLD epidemic."
Fatty Liver, NAFLD, NASH Definitions
VAT & Fatty Liver/Fibrosis - "Clinical Predictors of Liver Fibrosis Presence and Progression in HIV-Associated NAFLD" - (05/15/20)
New Drugs for NASH and HIV Infection: Great Expectations for a Great Need
The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, convened recently for a conference focused on nonalcoholic fatty liver disease (NAFLD) in people living with human immunodeficiency virus (PLWH).(1)NAFLD is defined as fat accumulation in more than 5% hepatocytes without a secondary cause such as alcohol consumption, and can be evaluated with noninvasive diagnostic tools such as ultrasound, transient elastography, computed tomography, and magnetic resonance imaging.
Nonalcoholic steatohepatitis (NASH) is a histological diagnosis defined by liver steatosis with hepatocyte ballooning and lobular inflammation, leading to progressive hepatocellular injury.(2) NASH affects 3%-7% of the general population,(2) and without interventions can progress to advanced liver fibrosis, cirrhosis, and related end-stage liver complications such as ascites, hepatic encephalopathy, variceal bleeding, hepatocellular carcinoma, and hepatic failure. In the general population, the disease burden is increasing so fast that currently NASH represents the second most common indication for liver transplantation in North America, with projections to become the leading indication over the next 10 years.(3) NASH is already the leading indication for liver transplantation in women.(4)
As PLWH live longer due to effective early treatment with antiretroviral therapy (ART), chronic noninfectious comorbidities (NICM) are an increasingly important aspect of the medical care in this aging population. As a result, there is interest in how chronic HIV infection and long-term drug treatment may affect the trajectory of aging-related conditions, such as liver and cardiovascular disease. Liver disease is a leading cause of non-acquired immune deficiency syndrome-related deaths in PLWH.(5) Although in the past co-infections with hepatitis C virus (HCV) and hepatitis B virus have driven this trend, NAFLD/NASH has become the most frequent liver disease in PLWH.(6)
Available data paint a fairly equivocal picture on the role of HIV and associated drug exposure on the development and progression of NAFLD/NASH in PLWH. However, there is also an increasing number of studies suggesting that metabolic disorders play a key role in the development of NAFLD/NASH as observed in patients without HIV.(7-9)
The purpose of this article is to discuss the current understanding on the interaction between HIV and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. We reviewed in detail the risk of drug-drug interactions (DDIs) between ART and NAFLD/NASH agents that are currently in phase 3 trials, and we suggest a model for trial design to include PLWH, strongly advocating for the scientific community to include this group as a subpopulation within studies.
A Way Forward for PLWH in NASH Trials
How can these lessons inform trial design for NASH in HIV? As in HCV/HIV, there are some data to support additional pathophysiological mechanisms in HIV-associated NASH, including ART effects on lipid metabolism, particularly, but not exclusively, with respect to those patients subjected to now-obsolete drugs strongly associated with lipodystrophy. However, because the clinical phenotype is so strongly associated with the metabolic syndrome, the pathways leading to liver injury, NASH, and fibrosis (e.g., insulin resistance, adipose-derived inflammation, and impaired lipid metabolism) remain those targeted by many current therapies under investigation. It would therefore be reasonable to expect similar response rates between those with and without HIV.
Therefore, for drugs for which there is a low probability of DDIs, PLWH may be included as a prespecified subgroup within a trial population. To allay concerns from the pharmaceutical industry about delays in licensing for the general population, PLWH can then be excluded from the interim analysis, much like other trials have included F1 fibrosis stage as a group of interest but focused on F2/3 in the interim analysis. Where significant uncertainty exists over potential DDIs, driven primarily by booster-containing regimens, small exploratory studies can be readily conducted to answer this question before proceeding to inclusion in larger trials.
This approach, in contrast to separate trials on HIV-associated NASH, is particularly important, as the requirement for a liver biopsy makes it very difficult to recruit into adequately powered trials. A prespecified subanalysis within a larger trial would enable exploration into some unanswered questions on the pathophysiology and efficacy of new drugs in HIV-associated NASH, while expediting the licensing of new therapies in this population.
Investigational Agents for NASH and Potential DDIs in the Context of HIV
As the clinical phenotype of NASH in PLWH increasingly mirrors that of the general population, it could be considered that the treatment of NASH in PLWH would likely have the same etiological targets as in the general population. An increasing number of agents are being investigated for the treatment of NASH, and many registrational trials are ongoing. In this setting, it is striking that PLWH have consistently been excluded from these studies. We are concerned that this may limit therapeutic options for NASH in PLWH. Pharma and sometimes regulatory agencies justify the exclusion of PLWH due to the risk of DDIs associated with concomitant chronic exposure to ART.
This concern can be addressed by conducting properly designed studies that aim to evaluate DDIs between compounds to treat NASH and ART. Furthermore, for some of these compounds available, pharmacological data allow researchers to predict the likelihood of having DDIs with ART. The DDI profiles of these compounds can be summarized in tables, thereby providing an overview of the DDI risk within a therapeutic class, similarly to what has been done with other drugs to treat NICMs (www.hiv-druginteractions.org; www.hep-druginteractions.org).
This section explores potential DDIs between ART and five drugs in the pipeline that are in phase 3 trials for NASH, thus being the most likely candidates to be approved for clinical use in the near future: aramchol, cenicriviroc, elafibranor, obeticholic acid, and resmetirom (MGL-3196).
Aramchol is a fatty acid-bile acid conjugate-inhibiting stearoyl coenzyme A desaturase 1 (SCD1), an enzyme that plays a role in lipid metabolism. The inhibition of this DDI results in decreasing synthesis of fatty acids, with consequent decrease in storage triglycerides and other esters of fatty acids. This reduces liver fat, including triglycerides and free fatty acids, resulting in an improvement in insulin resistance.(44)
Information on the potential of aramchol to cause DDIs is currently not available, although there is an ongoing trial evaluating CYP3A4 inhibition of by-aramchol.(45) Thus, the risk for DDIs with drugs undergoing primarily hepatic metabolism cannot be established currently.
Cenicriviroc is a CCR5 and CCR2 CCR5/CCR2 antagonist. CCR5 and CCR2 are chemokine receptors expressed on circulating monocytes as well as on Kupffer cells. Activation of these receptors induces migration of macrophages into the liver.(44) It was initially developed as an HIV drug,(46) but it was shown to reduce the rates of hepatic fibrosis.
Cenicriviroc is currently investigated in patients with NASH due to its anti-inflammatory and antifibrotic potential at an oral dosage of 150 mg daily.
Cenicriviroc is metabolized by CYP3A4 and CYP2C28 and is a substrate of P-glycoprotein. Cenicriviroc is devoid of strong inhibitory or inducing effects on drug metabolizing enzymes. DDI studies with dolutegravir (50 mg once daily) showed no significant effect on dolutegravir exposure, whereas cenicriviroc exposure was reduced by 29%.(47) It is currently unclear whether this decrease in exposure would require a dosage adjustment of cenicriviroc. The coadministration with atazanavir/ritonavir (300/100 mg once daily) increased cenicriviroc (50 mg once daily) exposure by 289%. Hyperbilirubinemia was observed following coadministration of atazanavir/ritonavir with cenicriviroc. Similarly, coadministration with darunavir/ritonavir (800/100 mg once daily) increased cenicriviroc (50 mg once daily) exposure by 213%, although no clinically relevant laboratory abnormalities were observed.(48) Finally, coadministration with efavirenz (600 mg once daily) reduced cenicriviroc (200 mg once daily) exposure by 43%, although cenicriviroc exposure was not significantly reduced when doubling cenicriviroc dose (400 mg once daily).(49)
Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in lipid metabolism. PPARs are implicated in fatty acid catabolism. Elafibranor is a PPAR-alpha/PPAR-delta agonist. PPAR-alpha activation increases lipolysis cellular lipid uptake. In animal models, PPAR-delta activation leads to fatty acid consumption in skeletal muscle and adipose tissue.(44)
Information on the metabolic pathway of elafibranor is not available from the public domain, except the fact that elafibranor is metabolized to GFT1007.(50)
Obeticholic acid (Ocaliva) is a bile acid analogue that is conjugated with glycine or taurine in the liver and secreted into the bile. Obeticholic acid is a semisynthetic farnesoid X nuclear receptor (FXR) agonist. Farnesoid X nuclear receptor is a bile acid receptor that regulates lipid and glucose metabolism, and its activation leads to reduction in serum and hepatic triglyceride levels.(44)
Concomitant medications to obeticholic acid that inhibit canalicular membrane bile acid transporters, such as bile salt export pump, may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver, which may cause clinical symptoms. Thus, in case of coadministration with bile salt export pump inhibitors,(51) serum transaminases and bilirubin should be monitored (Ocaliva product label). Although obeticholic acid was shown to inhibit CYP3A4 in vitro , a DDI study has demonstrated no clinically significant inhibition of CYP3A4 at the doses of obeticholic acid in clinical use.(52) Obeticholic acid is not expected to significantly inhibit or induce other cytochromes or drug transporters (Ocaliva product label).
Resmetirom is an agonist of the thyroid hormone receptor-β.(53) There is no information on the metabolic pathway of resmetirom, except that it is taken into the liver by hepatic transporters. Thus, potential DDIs with boosted ART regimens cannot be excluded. DDI studies have shown no significant effect of resmetirom on statins exposure, suggesting that resmetirom is unlikely to affect ART.(54)
Table 2 summarizes the predicted risk of DDIs between selected antiretrovirals and drugs to treat NASH.
In the absence of randomized clinical studies, it is difficult to predict which therapeutic strategies would be more suitable in PLWH. From a theoretical point of view, it can be hypothesized that lean NAFLD associated with d-drug exposure would benefit more from a drug strategy focused on anti-oxidative stress aiming to improve mitochondrial dysfunction. On the other side, the pathogenesis and thus therapeutic target for NAFLD/NASH in PLWH with obesity and/or diabetes mellitus, may be similar to the general population. With this regard, a number of studies of animal models and human trials have evaluated the effects of glucagon-like peptide-1 receptor agonist on liver fat content and suggest that the treatment could represent a new alternative for NAFLD management.(55) However, the hypothesis that such treatments have a direct effect on hepatocytes is still questionable and there is no evidence that the positive effect of glucagon-like peptide-1 receptor agonists is linked to the presence of glucagon-like peptide-1 receptor on hepatocytes.(56) In HIV setting, there is an ongoing randomized double-blinded, placebo-controlled trial to assess effect of semaglutide on visceral and ectopic fat in HIV-associated lipohypertrophy.(57)
With regard to dyslipidaemia, frequently PLWH with NAFLD are qualified for statin therapy. It is hypothesized that treatment with statins may have beneficial effects on NAFLD and its liver-related complications, exerting systemic pleiotropic mechanisms that collectively may concur in improving steatosis, sterile inflammation, fibrosis and tumorigenesis; nevertheless, these evidences are still lacking.(58)
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in patients with HIV
Thus, all patients with chronically increased liver test panel results should be investigated for the presence of steatosis and then further risk-stratified using non-invasive assessments of fibrosis (figure 3)
Direct impact of HIV
HIV infection itself is also implicated in the development of metabolic syndrome and therefore risk of hepatic steatosis. The degree of HIV viraemia has been associated with hypertriglyceridaemia, dyslipidaemia, and insulin resistance in patients with untreated HIV, and HIV-associated mitochondrial damage has been implicated in systemic immune activation in the pathogenesis of diabetes.
Additionally, the virus might promote hepatic steatosis by interacting with sterol regulatory element-binding-protein 1 and peroxisome proliferator-activated receptor γ, which are key regulators of lipogenesis and insulin signalling, respectively.
Evidence indicates that HIV influences the activation of hepatic stellate cells, and thus causes hepatic collagen deposition and fibrogenesis.
Finally, although not well studied in the patients with HIV mono-infection, preliminary evidence indicates that HIV treatment with viral suppression might decrease the risk of steatosis development and progression.
In a study of 222 patients with HIV-HCV co-infection-which involved the assessment of paired liver biopsy samples to identify risk factors for steatosis progression-cumulative exposure to ART between biopsy samples and high CD4+ T-cell counts were associated with reduced progression of steatosis.
Treatment of NAFLD
An improved understanding of the complex pathogenesis of NAFLD has enabled the identification of many therapeutic approaches, including weight loss, decreasing fatty acid accumulation, decreasing inflammation and oxidative stress, inhibiting or resolving fibrosis, and manipulating the intestinal microbiome.
Most recommendations are based on studies in patients with NAFLD who do not have HIV, and since most studies include only short-term follow-up, long-term safety and efficacy data for therapeutic interventions are not available. General recommendations specific to patients with HIV include ensuring adequate suppression of viral load and modification of the ART regimen to avoid agents with a negative impact on the patients' metabolic profile if possible. Avoidance of stavudine and didanosine is preferable, and all patients with HIV-HCV co-infection should be treated for HCV.
Sustained weight loss through diet and exercise is the first-line treatment for NAFLD, and up to 10% reduction in weight is required for substantial histological improvement in necroinflammation.
Unfortunately this weight loss is rarely achieved without additional intervention, and the impact of lifestyle modifications on NAFLD among patients with HIV has not been established. Reduced alcohol consumption should also be strongly recommended, as should sufficient control of diabetes and components of metabolic syndrome.
If liver test results do not considerably improve following lifestyle interventions, the recommended first-line therapy for patients without diabetes who have biopsy-proven NASH is vitamin E. This recommendation is based on several trials, including the randomised controlled PIVENS trial, which compared the impact of vitamin E, pioglitazone, or placebo treatment on liver histology in 247 patients without diabetes or cirrhosis who had biopsy-proven NASH. Patients given vitamin E 800 IU daily for 96 weeks were significantly more likely to achieve a reduction of at least 2 points in the NAFLD activity score (NAS) than were patients given placebo (42% vs 19%, p<0·001). However, given the criteria for entry into studies of the efficacy of vitamin E in NASH, the impact of vitamin E in patients with diabetes, cirrhosis, NAFLD without NASH, or HIV is uncertain. Additionally, concerns have been raised about the safety of long-term vitamin E use, including in meta-analyses reporting increased all-cause mortality among patients on high-dose vitamin E (although other studies have not found this association) and perhaps an increased risk of prostate cancer.
These risks must be weighed against the potential benefits for each individual patient. With new therapies now possibly on the horizon, vitamin E might soon be used less frequently. In the PIVENS trial, pioglitazone use also improved liver histology, although only 34% of patients achieved at least a 2-point reduction in the NAS. Additionally, the long-term safety and efficacy of pioglitazone in patients without diabetes is not well established.
Although few effective pharmacological interventions are available, many clinical trials are investigating treatments for steatosis, steatohepatitis, and NAFLD-related fibrosis, and several agents are now in phase 3 clinical trials.
Obeticholic acid-a bile acid derivative that is a potent activator of the farnesoid X nuclear receptor (FXR) and was recently approved for use in patients with primary biliary cirrhosis-has shown promising efficacy in patients with biopsy-proven NASH.
When bound to FXR, obeticholic acid promotes insulin sensitivity, decreases hepatic gluconeogenesis, and decreases circulating concentrations of triglycerides, and it has thus been tested in various clinical settings, including in patients with NAFLD. In a phase 2 trial in which patients were randomly assigned to groups receiving 72 weeks of either 25 mg obeticholic acid or placebo daily, those who received obeticholic acid were significantly more likely to achieve a 2-point reduction in the NAS without worsening fibrosis than were patients who received the placebo (45% vs 21%, p<0·0001). A larger phase 3 trial is now ongoing (NCT02548351); however, no data on the use of obeticholic acid in patients with HIV have been published to date.
Pilot studies investigating the use of rifaximin to alter the gut microbiota and diminish the translocation of bacterial components, including endotoxin, have been reported both in patients with NAFLD or NASH who do not have HIV and in patients with HIV who do not show an immune response to ART.
These studies have shown only modest changes in the levels of markers of bacterial translocation in the short term, although manipulation of the microbiome in both disease states is of great interest.
Additionally, at least two ongoing clinical trials are investigating treatments for NAFLD specifically in patients with HIV (NCT03296831, NCT02684591). Tesamorelin, a synthetic growth-hormone-releasing hormone, is FDA approved for the treatment of excess visceral adiposity in patients with HIV.
Tesamorelin is administered by subcutaneous injection and induces the pulsatile secretion of growth hormone. In a small randomised trial to assess the impact of tesamorelin on hepatic fat content, 60 patients with HIV received either 2 mg tesamorelin or placebo daily for 12 months.
Hepatic fat content was modestly but significantly reduced, as quantified by MRS, and visceral adiposity was also significantly reduced in patients receiving tesamorelin compared with those receiving the placebo.
A larger multicentre trial investigating the efficacy of tesamorelin in patients with HIV-associated NAFLD is now ongoing (NCT03296831). Additionally, arachidyl amido cholanoic acid, a fatty acid-bile acid conjugate that both decreases fatty acid synthesis and increases hepatic cholesterol efflux, has been shown to decrease hepatic fat content, as measured by MRS, in a small trial of patients with NAFLD.
Arachidyl amido cholanoic acid is now entering a phase 2B trial in patients with NAFLD and HIV (NCT02684591). Finally, the CCR2/CCR5 antagonist cenicriviroc, a novel HIV treatment that inhibits viral entry, is now also in early trials for the treatment of NAFLD (NCT02217475).
Cenicriviroc could thus represent a novel approach to treating or preventing NAFLD among patients with HIV and multiple NASH risk factors.
Ultimately, combination therapies that target the specific pathology observed in each individual patient is likely to be required to optimise outcomes. This will include modifying secondary causes of steatosis with particular consideration of an individual patient's phenotype-ie, whether the patient is obese or lean, and insulin-resistant or normoglycaemic, and whether the patient has steatosis or steatohepatitis, and fibrosis or no fibrosis.
Although the high prevalence of steatosis and steatohepatitis has been recognised in patients with HIV since the 1980s,6, 7, 8, 9 the previously uncertain effect of these syndromes on patient outcomes, difficulty with non-invasive diagnosis, and few therapeutic options have led to the under-recognition and under-treatment of NAFLD in these patients. However, as the prevalence of metabolic syndrome and NAFLD rise and a multitude of novel therapeutic agents are entering clinical trials for NAFLD (both in the general population and in patients with HIV), a more concerted effort to diagnose, stage, and treat these patients will be essential to combating the NAFLD epidemic.
In the modern ART era, despite a shift away from the most hepatotoxic agents, NAFLD remains highly prevalent in patients with HIV, and estimates range from 13% to 55% depending on the population sampled and the assays used to diagnose NAFLD.
Steatosis is likely to be more common among patients with HIV-HCV co-infection than among patients with HCV mono-infection, suggesting an important effect of HIV in the pathogenesis of steatosis. Additionally, the presence of steatosis might be more strongly associated with more advanced fibrosis among patients with HIV-HCV co-infection than among patients with HCV mono-infection...steatosis might be more strongly associated with more advanced fibrosis among patients with HIV-HCV co-infection.
Insulin resistance, obesity, and polymorphisms of the PNPLA3 gene were significantly associated with the risk of NASH and fibrosis in this cohort, although the baseline characteristics of patients with NAFLD and those with non-specific findings considerably overlapped, highlighting the need for the use of liver biopsy samples to diagnose NAFLD in many cases. Similar findings were reported in a smaller series of 30 patients who underwent liver biopsy after 6 months of showing elevation in a panel of liver test results (including aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and serum γ-glutamyl transferase) in the absence of viral hepatitis, autoimmune disease, and metabolic liver diseases: of the total patient cohort, 60% had steatosis, 53% had NASH, and 20% had bridging fibrosis or cirrhosis.
Although the incidence of lipodystrophy is thought to be declining alongside the declining use of NRTIs, its prevalence remains relatively high, because effective treatment strategies are scarce. The absence of simple and clinically useful criteria for increased VAT or HIV-associated disorders of fat partitioning that can differentiate this syndrome from the heterogeneous patterns of fat distribution seen in the general population has considerably limited the study of these conditions. These fat distribution changes could be characterised as part of the spectrum of metabolic syndrome, because visceral adiposity is strongly associated with the development of dyslipidaemia and diabetes. However, the effects of the HIV infection and long-term exposure to ART probably further enhance these changes. The specific ways in which the HIV-associated syndrome differs from metabolic syndrome, and how HIV-associated hepatic fat accumulation and liver injury differ from that seen in patients without HIV, are not known.