Current Opinion in HIV & AIDS:
HIV AND AGING: Edited by Amy C. Justice and Julian Falutz
Liver fibrosis in HIV: which role does HIV itself, long-term drug toxicities and metabolic changes play?
Rockstroh, Jürgen K.; Mohr, Raphael; Behrens, Georg; Spengler, Ulrich
aDepartment of Medicine I, University Hospital Bonn
bGerman Centre for Infection Research (DZIF), partner site Bonn-Cologne, Bonn
cDepartment of Medicine, University Hospital Hannover
dGerman Centre for Infection Research (DZIF), partner site Hannover, Hannover, Germany
Correspondence to Professor Jürgen K. Rockstroh, Department of Medicine I, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Tel: +49 228 287 16558; fax: +49 228 287 15034; e-mail: email@example.com
Purpose of review: Liver disease is one of the main causes of non-AIDS death in HIV-infected individuals from Europe and North America and has been attributed mainly to coinfection with hepatotropic viruses. However, HIV-induced inflammation as well as long-term antiretroviral drug toxicity may also contribute to clinical relevant liver disease. Therefore, a better understanding of liver disease beyond viral hepatitis coinfection is urgently needed in HIV-infected individuals.
Recent findings: Cross-sectional fibroscan studies in HIV-infected patient populations have reported unexpectedly high rates of advance fibrosis in HIV-infected patients even without underlying viral hepatitis or alcohol abuse suggesting that HIV itself may contribute independently to liver disease. Finally, HIV therapy itself either through direct hepatotoxicity or long-term metabolic changes, such as dyslipidemia and/or insulin resistance, may additionally cause liver damage in life long treatment.
Summary: Therefore, aging of the liver in HIV may play a much more pivotal role in the future considering age-related effects, coinfection with hepatotropic viruses and the toxicity of long-term antiviral treatment. Thus, adequate monitoring of liver disease and development of management algorithms are clearly needed to optimize outcome and care of the aging liver in an HIV-infected individual.
With the introduction of combination antiretroviral therapy (cART), allowing life long suppression of HIV replication, survival of HIV-infected individuals has improved substantially. Indeed with better treatability of HIV, non-HIV-related conditions have become common causes of morbidity and mortality among HIV-infected patients in the developed world. In particular, liver disease has emerged as an increasingly significant contributor to morbidity and mortality among HIV-infected patients [1,2]. In a study analyzing 13 cohorts of HIV-infected individuals, hepatic mortality accounted for 7.1% of deaths, of which 56% were associated with hepatitis, indicating a significant proportion of non-hepatitis-related deaths independently of the severity of HIV infection . To date, only a few studies have examined the prevalence and potential risk factors for significant hepatic fibrosis among HIV-monoinfected patients [4–9]. The aim of this review is to summarize these findings and to describe the prevalence and contributing factors for development of fibrosis in HIV infection particularly with regard to the aging patient population as well as life-long antiretroviral therapy. This review also aims at addressing potential management strategies for these patients. Clearly, life long therapy in the context of an aging population raises concern of how the liver will change over decades of antiretroviral treatment, non-antiretroviral medications and HIV-induced inflammation. Eventually, prospective data from controlled trials will be necessary to identify the most liver-friendly HIV treatment over time.
LIVER DISEASE IN HIV
Progressive liver injury is a concern in HIV-infected patients due to coinfection with hepatitis B (HBV) or C (HCV) viruses, alcohol abuse and long-term exposure to antiretroviral drugs, which may be enhanced or influenced by direct cytopathic effects of HIV. Although, successful antiretroviral therapy can help to decrease the risk for hepatic decompensations and dying from liver disease in HIV/HCV coinfection, the overall risk of hepatic decompensations still remains higher than in HCV-monoinfected individuals [10,11▪▪]. Nonalcoholic fatty liver disease (NAFLD) as a result of obesity and metabolic abnormalities may be considered to be benign as plain steatosis. However, clinically silent lesions of nonalcoholic steatohepatitis (NASH) can result in fibrosis/cirrhosis and eventually lead to hepatocellular carcinoma in some patients. Several studies identified age as one independent factor contributing to this unfavorable evolution of NASH and fibrosis [12,13]. Two large cross-sectional studies using computed tomography scans or ultrasounds in HIV patients found NAFLD in 37% of 225 European and 31% out of 216 United States patients, respectively [14,15]. Similar to the general population, steatosis was associated with increased transaminases, male sex, markers of adiposity and/or blood metabolic abnormalities. Importantly, exposition to nucleotide reverse transcriptase inhibitors was identified as a risk factor of NAFLD in some [14,16] but not all  studies. In HIV-patients with NAFLD undergoing liver biopsy for persistent elevated transaminases, NASH was diagnosed in 16/55 (30%) and 17/26 (65%) of cases, respectively [15,16]. In a study by Ingiliz et al., 30 HIV-monoinfected patients with unexplained abnormal liver functions tests, 53% of patients had NASH and 63% had fibrosis.
With the increasing availability of noninvasive fibrosis determinations, such as transient elastography (Fibroscan; Echosense) or aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and FIB-4 score, cross-sectional and prospective studies, which evaluate prevalence and incidence of liver fibrosis in HIV-infected individuals, have become possible. Interestingly, all of these tests have been demonstrated to be acceptable in predicting the presence or absence of mild fibrosis (liver fibrosis > or = 2) and the absence of advanced fibrosis (liver fibrosis = 2) . Indeed, in 2013 several studies were presented on this topic for the first time. Table 1[4–9] summarizes the cross-sectional studies performed up-to-date as well as their main findings.
In a first cross-sectional pilot study, HIV-infected patients from the HIV outpatient clinic in Bonn who had transient elastography (FibroScan) and routine blood tests between August 2009 and December 2011 were examined with regard to prevalence of significant liver fibrosis . A cutoff of at least 7.1 kPa in liver stiffness measurement (LSM) by Fibroscan was defined as significant fibrosis and at least 12,5 kPa as severe fibrosis/cirrhosis. Overall, 333 patients were examined of whom 18% had significant fibrosis and 7.5% had severe fibrosis. Main causes of significant fibrosis or cirrhosis in the study population were chronic hepatitis B or C and alcohol abuse. Most interestingly, 11% (22 of 202) of patients without hepatitis coinfection or alcohol abuse had significant fibrosis and 2% (4 of 202) had severe fibrosis. cART [containing azidothymidine, d4T and especially didanosine (ddI)], was associated with higher rates of liver toxicity and appeared to influence fibrogenesis. Other studies more recently, only examined HIV-monoinfected patients without any history of liver disease and again found surprising high rates of abnormal liver fibrosis between 11 and 47% [5,6]. Clearly, the magnitude of liver fibrosis was dependent on the cutoffs used to define abnormal liver fibrosis. In the study by Han et al. from South Korea, 93 asymptomatic HIV-monoinfected patients with normal alanine aminotransferase (ALT) and total bilirubin levels who had consistently been undergoing cART for more than 12 months received LSMs. In this study, to overcome the confounding effect of coinfection with hepatitis virus, the authors adopted cutoff LSM values derived from healthy individuals . LSM values more than 5.3 kPa were defined as abnormal and thereby much lower than the cutoffs used in other studies partially explaining the very high rate of abnormal LSM values. Indeed, 39 individuals (41.9%) had abnormal LSM values, overall. Interestingly, in multivariate logistic regression analysis, the cumulative exposure duration of boosted-protease inhibitors and γ-glutamyltranspeptidase levels were identified as the independent predictors, which showed a negative and positive correlation with abnormal LSM values, respectively [odds ratio (OR), 0.941; 95% confidence interval (CI), 0.889–0.997; P = 0.039 and OR, 1.032; 95% CI, 1.004–1.060; P = 0.023]. These results would suggest a protective effect of low-dose ritonavir, which would be surprising in face of the metabolic changes associated with boosted protease inhibitor use. Clearly, longer follow-up is needed to substantiate these findings. In a study from Spain, the prevalence and risk factors for abnormal LSM values without coinfection were also evaluated but using the cutoff LSM value of 7.2 kPa . With this higher cutoff, the authors reported a prevalence of liver damage of 11.2%. Further, risk factor analyses for the development of liver damage identified long-term exposure to ddI as a major risk factor for abnormal LSM values. So far, three studies exist, which used noninvasive laboratory fibrosis scores namely either the AST-to-APRI or the FIB4 index [7,9,18]. Among 432 HIV-monoinfected patients enrolled in the Center For AIDS Research Database between November 1999 and May 2008, significant fibrosis by APRI was identified in 36 (8.3%; 95% CI, 5.9–11.4%) patients. After controlling for all other hypothesized risk factors as well as active alcohol use and site, detectable HIV viremia (adjusted OR, 2.56; 95% CI, 1.02–8.87) and diabetes mellitus (adjusted OR, 3.15; 95% CI, 1.12–10.10) remained associated with significant fibrosis by APRI. The observation that detectable HIV-viremia increased the risk for significant fibrosis emphasizes the impact of direct cytopathic effects of HIV. In a large North American study in four groups of women (HCV monoinfected, HIV monoinfected, HIV/HCV coinfected and HIV-seronegative/HCV-seronegative women) again HIV RNA level was associated with increased FIB-4 score in the absence of hepatitis B, hepatitis C, antiretroviral therapy (ART) or alcohol use, also suggesting a potential relationship between HIV infection and hepatic fibrosis in vivo. Finally, a first study from Africa in 500 HIV-infected participants in an HIV care programme in rural Rakai, using a LSM cutoff value of 9.3 kPa for diagnosing significant fibrosis, concluded that the burden of liver fibrosis among HIV-infected rural Ugandans is high and that the prevalence of significant fibrosis in HIV-infected individuals was significantly higher than non-HIV-infected individuals (17 vs. 11%, P = 0.008) . Fibrosis was associated with male sex [adjusted prevalence risk ratio (adjPRR) 1.4, 95% CI 1.0–1.9; P = 0.045], herbal medicine use (adjPRR 2.0, 95% CI 1.2–3.3; P = 0.005), heavy alcohol consumption (adjPRR 2.3, 95% CI 1.3–3.9; P = 0.005), occupational fishing (adjPRR 2.5, 95% CI 1.2–5.3; P = 0.019) and chronic HBV infection (adjPRR 1.7, 95% CI 1.0–3.1; P = 0.058). Among HIV-infected participants, ART reduced fibrosis risk (adjPRR 0.6, 95% CI 0.4–1.0; P = 0.030) again highlighting the importance of shutting off HIV replication also with regard to liver fibrosis progression in HIV.
So far, only one study has prospectively evaluated the incidence and risk factors for the development of liver damage of uncertain origin (LDUO) in HIV-infected patients not coinfected with HCV/haemoglobin [21▪▪]. This longitudinal study with 6-monthly Fibroscan measurements included HIV-infected patients free of previous liver damage and viral hepatitis B or C coinfections. Abnormal liver stiffness (ALS) was defined as a liver stiffness value greater than 7.2 kPa at two consecutive measurements. For patients who developed ALS without any specific cause of liver disease, liver biopsy was proposed. One hundred and ninety-eight patients completed the study. After a median follow-up of 18 (interquartile range 12–26) months, 21 of 210 patients (10.6%) developed ALS. Of these, 15 patients were diagnosed as LDUO. The incidence of LDUO was 7.64 cases/100 patient-years. Additional histological studies were performed on 10 (66.6%) patients, and all showed liver steatosis. A higher homeostatic model assessment-insulin resistance value and BMI were independently associated with the development of LDUO. These results clearly raise the question whether metabolic liver disease may be enhanced in HIV-infected individuals and warrant further research in this area.
DIRECT HIV EFFECTS ON THE LIVER
A recent study examined whether HIV-related liver stiffness was associated with markers of immune activation or microbial translocation . In this African retrospective case–control study, individuals with evidence of liver stiffness as defined by a transient elastography stiffness measurement at least 9.3 kPa (cases = 133) and normal controls (n = 133) were included. Higher sCD14 levels were associated with a 19% increased odds of liver stiffness (adjusted matched odds ratios (adjMOR) = 1.19, P = 0.002). In HIV-infected individuals, higher sCD14 levels were associated with a 54% increased odds of having liver stiffness (adjMOR = 1.54, P < 0.001); however, the opposite was observed in HIV-negative individuals (adjMOR = 0.57, P = 0.001). No other biomarker was significantly associated with liver stiffness, and only one individual was found to have detectable lipopolysaccharide (LPS). The increased sCD14 levels were concluded to be indicative of monocyte activation in the absence of viral hepatitis or microbial translocation, suggesting that HIV may be directly involved in liver disease.
Chemokine (C-C motif) receptor 5 (CCR5) and cysteine-X-cysteine receptor 4 (CXCR4), the two major coreceptors required for HIV entry into cells, are expressed on activated hepatic stellate cells (HSCs), the principle fibrogenic cell type in the liver. Through in-vitro experiments, it has been shown that the laboratory-adapted viruses HIV-IIIB (CXCR4-tropic or X4) and HIV-BaL (CCR5-tropic or R5) and primary HIV isolates can infect both a human stellate cell line, LX-2 and primary human HSCs . Interestingly, HIV infection promoted HSC collagen I expression and secretion of the proinflammatory cytokine monocyte chemoattractant protein-1. These findings underscore the direct HIV effects on liver cells and their implications for fibrogenesis in the setting of uncontrolled HIV replication.
More data suggesting direct HIV-induced effects on the pathogenesis of fibrosis generation have come from HIV and HCV coinfection. Indeed, faster fibrosis progression has been described in coinfected individuals mostly in the context of CD4-count decline . It has been recently demonstrated that CD4+ T cells are able to stimulate anti-fibrotic natural killer (NK) cell activity via interleukin-2 (IL-2)-mediated upregulation of NKG2D. HIV-induced loss of CD4+ T cells together with an impaired activity of CD4+ T cells, therefore, may contribute to accelerate progression of liver fibrosis observed in coinfection [25▪]. Changes in NK cell function in HIV altogether may contribute to fibrosis pathogenesis in liver disease of various origins.
METABOLIC CHANGES IN HIV AND UNDER COMBINATION ANTIRETROVIRAL THERAPY
Insulin resistance, a risk factor for fatty liver disease, is increasingly seen in persons infected with HIV. In those affected, it is unclear whether insulin resistance is a direct result of HIV infection alone, as the development of insulin resistance has also been established as a complication of antiretroviral therapies. Some HIV protease inhibitors, such as indinavir or lopinavir/r or nucleoside analogues, such as ddI, are culpable [26–28]. However, there are significant differences in the impact of different protease inhibitors on glucose metabolism with newer protease inhibitors, such as atazanavir and darunavir, showing no impact on glucose metabolism. Circulating levels of microbial products, such as LPS, are increased in HIV infection. Microbial translocation promotes insulin resistance, and dyslipidemia in other settings. Recent studies evaluating LPS levels in HIV-infected patients had higher level of LPS compared with age-matched healthy controls (64 vs. 50 pg/ml, P = 0.002) [29▪]. Likewise, HIV-infected patients had higher triglycerides, low-density lipoprotein and fasting insulin as well as evidence of lower insulin sensitivity compared with controls. Further studies have documented an association between vitamin D insufficiency and insulin resistance among nondiabetic HIV-infected women . As low vitamin D levels are typically seen in HIV, this may further contribute to changes in glucose metabolism. Finally, dyslipidemia is seen with many different antiretrovirals in particular ritonavir associated increases in triglycerides and has been discussed extensively in recent overviews . Additionally, patients with lipodystrophy syndrome were found to be at risk of NAFLD/NASH as reported by Lemoine et al.. Next to age and adiposity, additional deleterious mechanisms may worsen the development of NAFLD/NASH. Mitochondrial toxicity induced by stavudine and didanosine has been identified as factors of NAFLD and fibrosis [14,16,33], and recent experimental data suggest that inhibition of hepatic autophagy through thymidine analogues might contribute to the development of liver steatosis . In general, avoidance of drugs with known potential for causing insulin resistance or dyslipidemia should be avoided in patients with existing – or being at risk for the development of – fatty liver disease. Unfortunately, so far data on age-related fibrosis and risk for development of NAFLD in HIV are lacking. However, age-related reduction in liver size, hepatic blood flow and hepatic drug-metabolizing enzyme activity causing a decrease in hepatic drug clearance need to be highlighted as particularly in HIV patients with increased probability of polypharmacy age-related changes in the liver will also need to be discussed .
The European AIDS Clinical Society guidelines recommend with regard to liver disease assessment of HIV-positive persons in addition to viral hepatitis screening an initial determination of ALT/AST, alkaline phosphatase and bilirubin upon HIV diagnosis for all patients as well as every 3–12 months on subsequent clinic visits (see www.eacssociety.org). Risk factors for chronic liver disease include alcohol, viral hepatitis, obesity, diabetes, insulin resistance, hyperlipidaemia and hepatotoxic drugs. More frequent monitoring prior to starting and on treatment with hepatotoxic drugs may be warranted in patients with increased risk for liver disease. Patients with dyslipidemia and/or insulin resistance should be switched to ART regimens, which at best are metabolically neutral (for example, rilpivirine or an integrase inhibitor as third agent within cART). Preexisting resistance mutations need to be considered prior to switching to guarantee continuous virological suppression. Clear evaluation algorithms for patients with persistently elevated liver enzymes (wherein viral hepatitis and alcohol abuse have been ruled out) do not exist. In our practice, we perform annual noninvasive fibrosis stage assessment through Fibroscan and/or biochemical markers, such as APRI or FIB-4 score. In case of significant fibrosis, at least F3 and/or differing results between fibroscan and noninvasive blood markers liver biopsy is discussed in order to obtain liver fibrosis stage and receive further information on the underlying cause of liver disease. Referral to a hepato-biliary specialist in case of significant fibrosis is also recommended. The diagnosis of cirrhosis would warrant further diagnostic work-up (diagnostic work-up of portal hypertension and potential oesophageal varices is required). In patients who develop diabetes or dyslipidaemia manage metabolic disease following the practical management algorithms from the European AIDS Clinical Society.
In the future, aging of the liver in HIV will become increasingly important considering age-related effects, coinfection with hepatotropic viruses and the toxicity of long-term antiviral treatment. Thus, adequate monitoring of liver disease and development of management algorithms are clearly needed to optimize outcome and care of the aging liver in an HIV-infected individual. In sight of the lack of prospective data, more research in this focus area is urgently needed.
This work was supported by the DZIF TTU HIV Project 05.803, and the German Center for Infection Research (DZIF).
Conflicts of interest
R.M., G.B. and U.S. have no conflicts of interest. J.R. has received honoraria for speaking at educational events or consulting from Abbvie, Bionor, BMS, Boehringer, Gilead, Janssen, Merck, Tibotec and ViiV.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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HIV; liver fibrosis; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis
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