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Vitamin E is an effective treatment for nonalcoholic
steatohepatitis in HIV mono-infected patients
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Poster pdf attached for better viewing
AIDS Feb 1 2020 - Giada Sebastiania,b, Sahar Saeedc, Bertrand Lebouchea, Alexandra de Pokomandya, Jason Szaboa, Louis-Patrick Haraouia, Jean-Pierre Routya,d, Philip Wongb, Marc Deschenesb, Peter Ghalib, Marina Kleina, for the LIVEHIV Study Group
aChronic Viral Illness Service, bDivision of Gastroenterology and Hepatology, McGill University Health Centre (MUHC),
Montreal, cDepartment of Epidemiology, Biostatistics and Occupational Health, McGill University, and dDivision of Hematology,
MUHC, Montreal, Quebec, Canada.
In conclusion, vitamin E treatment seems safe and reduces ALT, CAP and CK-18, leading to rapid and sustained normalization of ALT and reduction of hepatic steatosis in a significant number of HIV mono-infected patients with a noninvasive diagnosis of NASH. This effect may be related to the importance of oxidative stress in NASH pathogenesis in HIV infection. Considering the epidemic of NAFLD in HIV-infected patients, as well as their exclusion from current clinical trials of antifibrotic molecules for NASH, vitamin E should be regarded as a therapeutic option. Larger studies, also based on liver histology, are needed to confirm these promising results, define optimal treatment duration and long-term benefits. There are several reasons why an intervention proved to be effective in the general NASH population requires ad hoc validation in HIV-infected patients. First, the pathogenesis of HIV-associated NASH is more complex. Elevated oxidative stress is a hallmark of HIV-infected patients and may predict all-cause mortality [14,15]. This could be both a consequence of HIV itself and of ART, which interferes into the redox system, mainly by reducing the antioxidant defenses [16]. Second, because of its pathogenetic complexity, HIV-associated NASH might be less responsive to interventions. Finally, vitamin E may be not well tolerated in all settings. An increased risk of cardiovascular events, bleeding and prostate cancer has been suggested [17,18].
In the ART era, liver disease is emerging as a major driver in morbidity and mortality of HIV-infected patients [1]. Increasing rates of metabolic disorders among aging HIV-infected patients are contributing to this trend [3,9,28,29]. Insulin resistance is highly prevalent among HIV-infected patients, because of inflammation, aging and specific ART regimens [29]. Dyslipidemia and hypertension are also common [28]. Other risk factors unique to this population may contribute to the epidemic of liver disease. First, ART is used lifelong and is known to elevate ALT and induce oxidative stress in hepatocytes [8]. Second, HIV viremia from ART treatment interruptions is a risk factor for elevated ALT and liver cirrhosis. HIV is believed to have immune-activating and pro-apoptotic effects on hepatocytes [8]. These multiple metabolic and HIV-related hepatotoxic hits represent pathogenetic triggers for NASH, a severe liver condition eventually leading to liver cirrhosis and related end-stage complications. Currently, NASH represents the second most common indication for liver transplantation in North America and it is projected to become the leading indication over the next 10 years [30]. NASH is more frequent in HIV-infected persons, with reported prevalence up to 57.1% in those with chronically elevated ALT and at 10% in patients attending a routine screening program [7,31,32].
Few interventions can alter the natural history of the disease and improve NASH. Life-style changes, characterized by a combination of dietary restriction and increase in aerobic exercise/resistance, are the first-line treatment and can result in significant regression of liver fibrosis and NASH [13]. However, this intervention is seldom implemented by patients and has not been tested for HIV-associated NASH [33]. Waiting until end-stage liver complications arise will result in the need for transplant, which is not a viable option being particularly challenging and not widely available for HIV-infected patients [34]
Vitamin E is a lipophilic antioxidant acting as a regulator of the activity of genes controlling apoptosis, inflammation and collagen deposition [36]. The role of vitamin E in the treatment of NASH is based on its activity as a free radical scavenger. Two large randomized controlled trials concluded that vitamin E is an effective treatment to reduce transaminases and to ameliorate liver histology in HIV-negative NASH [11,12]. Guidelines recommend vitamin E as a first-line pharmacotherapy for patients with NASH [13,37]. In this trial, we observed a rapid change in ALT, already significant at month 1, which further continued with a mean reduction of -27 IU/l at week 24. As a result, the proportion of patients with elevated ALT dropped from 74% at baseline to 15% at the end of treatment. Elevated ALT has been repeatedly associated with significant liver fibrosis, high proportions of histologic NASH and mortality in HIV-infected patients [38]. The effect of vitamin E on ALT observed in this trial is similar to that reported in the PIVENS trial, where the mean ALT change at 96 weeks was -37 IU/L [11]. Furthermore, we observed a change in both CAP and CK-18, as surrogate markers of hepatic steatosis and apoptosis. A reversal of hepatic steatosis by CAP was observed in 22% of cases. Because of the role of apoptosis in NASH pathogenetic cascade, the reduction in hepatocyte apoptosis suggests an improvement in NASH [10].
Liver disease is common among patients infected with HIV. The proportion of deaths caused by liver-related causes has increased between 8-fold and 10-fold in the postantiretroviral therapy (ART) era whereas AIDS-related mortality has fallen more than 90-fold [1]. Nonalcoholic fatty liver disease (NAFLD) is an important contributor to this trend [2-5]. NAFLD is a fatty infiltration of the liver and the first pathological step for nonalcoholic steatohepatitis (NASH), a progressive disease characterized by inflammation leading to liver fibrosis and cirrhosis. NASH affects 3-7% of the general population [6]. Higher rates of the disease are reported in HIV-infected patients, ranging from 7.3 to 57.1% [7]. This is likely because of both high frequency of metabolic conditions underlying the pathogenesis of NASH and ART-related hepatotoxicity [3,8,9]. Despite the disease burden, therapeutic options for NASH are limited in the general population and there are no proven treatments to reduce HIV-associated NASH. There are several reasons why an intervention proved to be effective in the general NASH population requires ad hoc validation in HIV-infected patients. First, the pathogenesis of HIV-associated NASH is more complex. Elevated oxidative stress is a hallmark of HIV-infected patients and may predict all-cause mortality [14,15]. This could be both a consequence of HIV itself and of ART, which interferes into the redox system, mainly by reducing the antioxidant defenses [16]. Second, because of its pathogenetic complexity, HIV-associated NASH might be less responsive to interventions. Finally, vitamin E may be not well tolerated in all settings. An increased risk of cardiovascular events, bleeding and prostate cancer has been suggested [17,18].
At week 24, severe steatosis was observed in only 41% of patients, as compared with 67% at baseline. resolution of hepatic steatosis was observed in 22% of cases. The proportion of patients with significant liver fibrosis by liver stiffness measurement remained the same between baseline and week 24 (41%). Among the four patients with available liver histology, normalization of ALT was observed in 100% of cases, whereas one case presented steatosis resolution, from baseline CAP of 350-235 dB/m at week 24. there was no change in triglycerides, total cholesterol, HDL cholesterol and HOMA-IR between baseline and week 24 (results not shown).
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Vitamin E is an effective treatment for nonalcoholic steatohepatitis in HIV mono-infected patients
Abstract
Objective:
HIV-infected patients are at increased risk of nonalcoholic steatohepatitis (NASH). Vitamin E is recommended for treatment of NASH in the general population. However, its safety and efficacy among HIV-infected patients remain unknown.
Design:
Single-centre, phase IV, open-label, single arm clinical trial.
Methods:
HIV mono-infected patients without significant alcohol intake or viral hepatitis coinfection were included. The diagnosis of NASH was based on the co-existence of fatty liver, diagnosed by controlled attenuation parameter (CAP) at least 248 dB/m and significant hepatocyte apoptosis, defined by the serum biomarker cytokeratin 18 (CK-18) greater than 130.5 U/L. Participants were treated with 800 IU daily of oral vitamin E (alpha-tocopherol) for 24 weeks, and followed for an additional 24 weeks postdiscontinuation. Generalized linear mixed effects models were used to evaluate changes in alanine aminotransferase (ALT), CAP and CK-18 at the completion of treatment and end of follow-up, controlling for pretreatment trends.
Results:
A total of 27 patients were included. Four (15%) had a pretreatment liver biopsy, which confirmed the diagnosis of NASH in all cases. Compared with baseline, 24 weeks of vitamin E treatment improved ALT [-27 units/l; 95% confidence interval (CI) -37 to -17], CAP scores (-22 dB/m; 95% CI -42 to -1) and CK-18 (-123 units/l; 95% CI -201 to -46). Conversely, there was no change in BMI. No serious adverse event was reported and no patient was lost to follow-up.
Conclusion:
In this first clinical trial, we showed that vitamin E is an effective and well tolerated treatment for NASH in HIV-infected patients.
Introduction
Liver disease is common among patients infected with HIV. The proportion of deaths caused by liver-related causes has increased between 8-fold and 10-fold in the postantiretroviral therapy (ART) era whereas AIDS-related mortality has fallen more than 90-fold [1]. Nonalcoholic fatty liver disease (NAFLD) is an important contributor to this trend [2-5]. NAFLD is a fatty infiltration of the liver and the first pathological step for nonalcoholic steatohepatitis (NASH), a progressive disease characterized by inflammation leading to liver fibrosis and cirrhosis. NASH affects 3-7% of the general population [6]. Higher rates of the disease are reported in HIV-infected patients, ranging from 7.3 to 57.1% [7]. This is likely because of both high frequency of metabolic conditions underlying the pathogenesis of NASH and ART-related hepatotoxicity [3,8,9]. Despite the disease burden, therapeutic options for NASH are limited in the general population and there are no proven treatments to reduce HIV-associated NASH.
In addition to insulin resistance, oxidative stress plays a key role in the pathogenesis of NASH [6,10]. Vitamin E is a lipophilic antioxidant essential for human health, which protects cell membranes from oxidation and regulates apoptotic pathways. Two randomized controlled trials, PIVENS in adults [11] and TONIC in children [12], demonstrated that vitamin E effectively reduces transaminases and ameliorates liver histology in HIV-negative patients with NASH. As a result, vitamin E at daily dose of 800 IU/day is recommended as first-line pharmacotherapy of NASH in the general population by guidelines of the European
Association for the Study of the Liver and of the American Association for the Study of Liver Diseases (AASLD) [6,13].
There are several reasons why an intervention proved to be effective in the general NASH population requires ad hoc validation in HIV-infected patients. First, the pathogenesis of HIV-associated NASH is more complex. Elevated oxidative stress is a hallmark of HIV-infected patients and may predict all-cause mortality [14,15]. This could be both a consequence of HIV itself and of ART, which interferes into the redox system, mainly by reducing the antioxidant defenses [16]. Second, because of its pathogenetic complexity, HIV-associated NASH might be less responsive to interventions. Finally, vitamin E may be not well tolerated in all settings. An increased risk of cardiovascular events, bleeding and prostate cancer has been suggested [17,18].
Given the high prevalence of NASH among HIV-infected patients and the lack of therapeutic options, this clinical trial was aimed to investigate the effect of vitamin E treatment on NASH diagnosed through noninvasive tools.
Discussion
In this first trial, we showed that 24 weeks of vitamin E treatment decreased ALT, the degree of hepatic steatosis and hepatocyte apoptosis in HIV mono-infected patients with NASH. The intervention was both effective and well tolerated, with no patient lost to follow-up and no serious adverse event reported. HIV-infected patients are currently excluded from registrational clinical trials of new antifibrotic molecules for the treatment of NASH, and this poses an ethical and clinical dilemma. Vitamin E represents an available therapeutic option.
In the ART era, liver disease is emerging as a major driver in morbidity and mortality of HIV-infected patients [1]. Increasing rates of metabolic disorders among aging HIV-infected patients are contributing to this trend [3,9,28,29]. Insulin resistance is highly prevalent among HIV-infected patients, because of inflammation, aging and specific ART regimens [29]. Dyslipidemia and hypertension are also common [28]. Other risk factors unique to this population may contribute to the epidemic of liver disease. First, ART is used lifelong and is known to elevate ALT and induce oxidative stress in hepatocytes [8]. Second, HIV viremia from ART treatment interruptions is a risk factor for elevated ALT and liver cirrhosis. HIV is believed to have immune-activating and pro-apoptotic effects on hepatocytes [8]. These multiple metabolic and HIV-related hepatotoxic hits represent pathogenetic triggers for NASH, a severe liver condition eventually leading to liver cirrhosis and related end-stage complications. Currently, NASH represents the second most common indication for liver transplantation in North America and it is projected to become the leading indication over the next 10 years [30]. NASH is more frequent in HIV-infected persons, with reported prevalence up to 57.1% in those with chronically elevated ALT and at 10% in patients attending a routine screening program [7,31,32].
Few interventions can alter the natural history of the disease and improve NASH. Life-style changes, characterized by a combination of dietary restriction and increase in aerobic exercise/resistance, are the first-line treatment and can result in significant regression of liver fibrosis and NASH [13]. However, this intervention is seldom implemented by patients and has not been tested for HIV-associated NASH [33]. Waiting until end-stage liver complications arise will result in the need for transplant, which is not a viable option being particularly challenging and not widely available for HIV-infected patients [34]. Although new antifibrotic molecules are currently being studied in HIV-negative NASH in randomized controlled trials, as HIV-infected patients are excluded, it is estimated that it will take at least 7-10 years for them to become available for the HIV-infected community [35]. As such, there is a clear need for a simple and well tolerated intervention for NASH in HIV-infected patients over the next years.
Vitamin E is a lipophilic antioxidant acting as a regulator of the activity of genes controlling apoptosis, inflammation and collagen deposition [36]. The role of vitamin E in the treatment of NASH is based on its activity as a free radical scavenger. Two large randomized controlled trials concluded that vitamin E is an effective treatment to reduce transaminases and to ameliorate liver histology in HIV-negative NASH [11,12]. Guidelines recommend vitamin E as a first-line pharmacotherapy for patients with NASH [13,37].
In this trial, we observed a rapid change in ALT, already significant at month 1, which further continued with a mean reduction of -27 IU/l at week 24. As a result, the proportion of patients with elevated ALT dropped from 74% at baseline to 15% at the end of treatment. Elevated ALT has been repeatedly associated with significant liver fibrosis, high proportions of histologic NASH and mortality in HIV-infected patients [38]. The effect of vitamin E on ALT observed in this trial is similar to that reported in the PIVENS trial, where the mean ALT change at 96 weeks was -37 IU/L [11]. Furthermore, we observed a change in both CAP and CK-18, as surrogate markers of hepatic steatosis and apoptosis. A reversal of hepatic steatosis by CAP was observed in 22% of cases. Because of the role of apoptosis in NASH pathogenetic cascade, the reduction in hepatocyte apoptosis suggests an improvement in NASH [10].
Unlike the PIVENS trial, in our study, we did not observe a significant change in insulin resistance or HDL-cholesterol. HIV-infected patients have multiple hits for oxidative stress [16]. Supplements of vitamin E have been previously shown to reduce oxidative stress in HIV and produce a trend towards a reduction in viral load [39]. Our results with vitamin E treatment, combined with these pathogenetic considerations and the lack of metabolic changes in our study, suggest that oxidative stress may have a greater importance in the pathogenesis of NASH in the specific context of HIV infection and could be one of the drivers of the high prevalence of NASH in this setting. Importantly, the stability of BMI throughout the study period, despite counselling on life style modifications, suggest that, as already observed in HIV-negative NASH, the uptake of such recommendations are suboptimal also in HIV-infected patients [33].
We wish to acknowledge several limitations of this study. First, the study period was relatively short. As such, these trial results should be regarded as exploratory. Nevertheless, we observed clinically significant changes over a 24-week course of vitamin E treatment, which also persisted at week 48, posttreatment discontinuation, suggesting a carry-over effect. It would be important to know whether continued treatment would lead to longer benefit. Second, we based the diagnosis of NASH on noninvasive tests instead of liver biopsy, which is still considered the gold standard. However, both CAP and CK-18 have been previously validated against liver biopsy in the specific setting of HIV infection [31,40]. CAP has been already employed in HIV-infected patients to study changes in hepatic steatosis during the course of an interventional trial [41]. Importantly, we previously showed a relatively high rate of patient refusal or ineligibility to liver biopsy in HIV [31]. Third, this trial was not designed to have a control arm. However, we did leverage existing historical data and quasi-experimental methodology to emulate a control group, which we confirmed with a sensitivity analysis of seven control individuals from another study. Fourth, we did not observe a reduction in liver stiffness measurement as a surrogate of liver fibrosis regression. This observation mirrors the findings of the PIVENS trial, where improvements in steatosis and necroinflammation were observed, whereas there was no improvement in fibrosis. It is also possible that the short study duration was not sufficient to allow fibrosis regression. Finally, given the small numbers, we were unable to conduct a subgroup analysis on the 12 diabetic patients included in the present trial, which could have been valuable since the PIVENS trial excluded them. In an exploratory univariate analysis, we found similar changes in ALT, CAP and CK-18 between diabetic and nondiabetic patients (data not shown).
In conclusion, vitamin E treatment seems safe and reduces ALT, CAP and CK-18, leading to rapid and sustained normalization of ALT and reduction of hepatic steatosis in a significant number of HIV mono-infected patients with a noninvasive diagnosis of NASH. This effect may be related to the importance of oxidative stress in NASH pathogenesis in HIV infection. Considering the epidemic of NAFLD in HIV-infected patients, as well as their exclusion from current clinical trials of antifibrotic molecules for NASH, vitamin E should be regarded as a therapeutic option. Larger studies, also based on liver histology, are needed to confirm these promising results, define optimal treatment duration and long-term benefits.
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