Elevated liver enzymes in HIV monoinfected patients on HIV therapy: what are the implications?

Liver enzyme elevations (LEE) in patients infected with the human immunodeficiency virus (HIV) are common [1]. In some cases they are transient and of minor clinical interest, in other cases they are caused by alcohol consumption or by co-infection with other viral diseases, such as hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection. However, in an important number of patients the origin of liver enzyme elevation is not explained by an underlying liver disease or toxin and may occur either due to antiretroviral drug toxicity or the HIV infection itself.

As HIV patients benefit from their antiretroviral treatment (ART) and consequent immunological stabilisation [2,3], continuous long-term treatment is inevitable. Although ART clearly has prolonged survival benefit for patients, it has led to a number of unexpected drug-induced toxicities: lipodystrophy, insulin resistance, dyslipidaemia and direct hepatotoxic injury [4]. Transaminase elevations have been described during antiretroviral treatment by various mechanisms, leading to morbidity, mortality and drug discontinuation [5]. Consequently, prevention and management of antiretroviral drug-related liver injury have emerged as major issues among HIV-infected patients in the era of combination ART [6].

Chronic liver disease may occur due to altered lipid patterns, insulin resistance or mitochondrial toxicity, which may contribute to the development of steatosis and steatohepatitis. Even in the absence of another concomitant liver disease, steatohepatitis has the potential to progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [7,8].

In an era where the expected survival for HIV-infected persons has nearly reached that of healthy individuals [9], the right interpretation of liver enzyme elevation is crucial as it helps to define patients at risk of developing severe hepatic injury. The impact of LEE in HIV-monoinfected patients is therefore the subject of this article.

MECHANISMS OF ANTIRETROVIRAL DRUG TOXICITY

Virtually every licensed antiretroviral medication has been associated with liver enzyme elevations [10]. Depending on the study, the incidence after 6 months of treatment has been found to be between 2% and 18% [12-25].

As effective viral suppression is commonly reached by combination treatment (CART), the contribution of each particular drug to the development of hepatotoxicity is difficult to determine, and more than one drug with a toxic potential may be involved [11]. Moreover, the concomitant use of alcohol and/or illicit drugs might routinely confound treatment-associated enzyme elevations [12-16]. Nevertheless, drug or drug class-specific alterations have been described.

NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS (NRTIS)

NRTIs rarely lead to LEE with an onset between 3 and 13 months after treatment initiation [24,26,27]. NRTIs have been associated with liver injury through mitochondrial dysfunction, lactic acidosis, and subsequent hepatic steatosis. Of interest, nucleoside analogues differ widely in their propensity to induce mitochondrial toxicity. Potency estimations in vitro gave a descending hierarchy of their potency: zalcitabine, didanosine, stavudine, zidovudine and, finally, abacavir, as least toxic [28]. Abacavir has been linked to hypersensitivity reactions within 6 weeks of treatment initiation, including rare cases of hepatic failure [30].

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS)

NNRTIs such as efavirenz or nevirapine have been associated with hepatotoxicity mainly by two mechanisms. According to numerous publications, the likelihood of developing LEE seems to be higher with nevirapine [15,26,31,32]. Nevirapine is associated with an idiosyncratic hypersensitivity reaction in the patient within the first 6 weeks of treatment [15]. Although the mechanism is unclear, it seems to be related to higher CD4 cell counts (>250/mm3 in women and >400/[mm.sup.3] in men) [33] but has also occurred in healthy individuals. Nevirapine should therefore not be used in the setting of post-exposure prophylaxis [34]. Low body mass index [15] and genetic polymorphisms in the host (HLA-DRB1*0101 background) are risk factors for nevirapine hypersensitivity [35].

Secondly, hepatotoxicity may occur at 6-12 months of treatment. This type of drug toxicity seems to increase over time, and is thought not to represent an immune-mediated process [11]. Certain polymorphisms have been found to decrease the risk of NNRTI-associated drug toxicity [36,37].

Interestingly, hepatotoxicity to either efavirenz or nevirapine appears not to increase the risk on exposure to the alternative NNRTI [38,39]. The recently approved NNRTI, etravirine, has not shown increased liver toxicity but further investigations need to be made in the clinical setting.

PROTEASE INHIBITORS (PIS)

All PIs are metabolised in the liver by the cytochrome P450 3A system [40] and can cause liver enzyme elevation. Full-dose ritonavir has the highest risk of liver toxicity [24] but is rarely used in the clinical setting. This observation has not been made when ritonavir is used for pharmacokinetic boosting of other PIs [41]. Tipranavir is associated with an increased risk of hepatotoxicity, including fatal outcomes [42,43], possibly linked to the higher ritonavir doses required. All other PIs, including darunavir, have a safer liver toxicity profile [23,44-50].

As the metabolism of ritonavir seems to be impaired in advanced fibrosis [11], dose adjustment might be necessary in this specific group of patients.

Of note, atazanavir and indinavir are often associated with an isolated elevation of indirect bilirubin, which is not a sign of liver injury and does not require treatment interruption [11].

NEW DRUG CLASSES

The impact of newly licensed drugs on the liver has yet to be evaluated through long-term observations. However, the fusion inhibitor, enfuvirtide, has so far shown little liver toxicity [51]. The first approved integrase inhibitor, raltegravir, has been associated with mild transaminase elevations but no severe hepatotoxicity has been described so far [52]. The CCR5 antagonist, maraviroc, appears to have a safe liver profile [53] and reports on liver toxicity related to vicriviroc have not been published.

HAART-ASSOCIATED NASH (NON-ALCOHOLIC STEATOHEPATITIS)

A study conducted by our group examined HIV monoinfected individuals on antiretroviral therapy with chronic transaminase elevation [53]. All patients had a long history of HIV infection (median 13 years) and long-term treatment with NRTIs, NNRTIs and PIs. These patients also had a high rate of liver problems that included fibrosis, cirrhosis, steatosis and steatohepatitis. Steatohepatitis was the most common finding and its emergence was associated with insulin resistance. Other groups seem to confirm these findings [54,55]. In our study, mitochondrial toxicity did not play a role in the development of hepatic steatosis, although all patients had a long history of NRTI intake. Neither a particular drug nor a drug class was linked to the development of steatohepatitis or steatosis. However, other groups have shown an association with stavudine use [56,57].

The prevalence of hepatic steatosis in the HIV-monoinfected population is unknown because liver biopsy cannot be routinely performed in this setting for ethical reasons [56]; however, it does remain the best diagnostic tool to assess this condition so far [58]. According to the study, the observed collective prevalence data for hepatic steatosis range from 3% to 57% [59,60]. Classical risk factors are metabolic abnormalities associated with insulin resistance and the lipodystrophy syndrome (visceral obesity, diabetes, dyslipidaemia) [61].

Transcription factors regulating lipid metabolism such as SBREP-1, PPAR[gamma]1 and PPAR[gamma]2 seem to play a major role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) or NASH in the HIV-infected population [62]. Lemoine et al. [63] compared HIV-infected patients with lipodystrophy (with or without insulin resistance), non-HIV -infected patients with NAFLD and healthy controls. Steatosis, steatohepatitis and fibrosis were common in HIV-patients with insulin resistance and steatosis was associated with an overexpression of SREBP-1 and a downregulation of PPAR[gamma]1 and PPAR[gamma]2; the latter were also inversely related to fibrosis.

THE TREATMENT OR THE VIRUS?

In the pre-HAART (highly active antiretroviral therapy) era changes in the lipid profile of HIV-positive patients had already been reported. High triglyceride levels and reduced cholesterol and HDL cholesterol seem to be related to the inflammatory state with elevated cytokines such as interferon-[alpha] [64]. These findings have been historically described with bacterial, parasitic and viral infections and were linked to cytokines (TNF-[alpha], IL-1, IL-6, interferons) that mediate the host immune response [65]. In conclusion, the development of hepatic steatosis might be caused by dyslipidaemia and therefore by the viral infection itself. Insulin resistance was poorly investigated in the pre-HAART era but one study did show increased insulin sensitivity in HIV-infected patients [66].

However, since the introduction of HAART, the frequent association between treatment and lipodystrophy and insulin resistance has been recognised [67]. Some antiretroviral agents (e.g. stavudine) and a longer exposure to antiretroviral therapy have been implicated in the development of hepatic steatosis [56,68] while other studies did not confirm these findings [69,70]. Soriano et al. described a trend towards the exposure to NRTIs and severe hepatic steatosis, claiming possible mitochondrial toxicity as the underlying state [61].

Treatment with protease inhibitors has been clearly linked to features of the metabolic syndrome such as lipid alterations and insulin resistance [71], both risk factors for the development of hepatic steatosis and steatohepatitis. Moreover, some PIs have increased SREBP-1 levels in animal and cellular models [63], which might be linked to the development of hepatic steatosis.

Mallet et al. described nodular regenerative hyperplasia (NRH) as the underlying cause in HIV patients on HAART presenting with LEE and/or clinical signs of portal hypertension [72]. The group postulated NRH as a possible explanation for cryptogenic liver disease in HIV, and all of their patients had a history of didanosine use. Other groups have shown that didanosine intake was statistically associated with the occurrence of cryptogenic liver disease in HIV patients and the duration of didanosine exposure was a significantly associated variable [73].

CONCLUSIONS

Antiretroviral treatment has dramatically reduced morbidity and mortality in HIV-infected patients. Therefore long-term treatment strategies are the only option for this population at the moment. Liver disease has emerged as the major clinical pitfall in the last few years and will possibly keep this place in the future, as classical HIV-associated pathologies such as opportunistic infections become more and more irrelevant for a large number of patients in settings where treatment is broadly accessible.

Nevertheless, serologic and histological hepatic alterations in HIV patients are mainly associated with viral hepatitis B or C co-infection, to alcohol or illicit drug use.

However, all anti-HIV drugs have the potential to induce hepatic injury mainly by direct drug toxicity. It seems evident that the longer patients will be treated with antiretroviral drugs the more toxicity will occur over time.

In the clinical setting, the most evident routine markers of hepatic injury are elevated liver enzymes.

Hepatic steatosis is the most common expression of hepatic injury in HIV patients. It can possibly be caused by the viral inflammatory state itself, by mitochondrial impairment, or by metabolic alterations linked to antiretroviral treatment: dyslipidaemia, insulin resistance, lipodystrophy syndrome. Steatosis can progress to steatohepatitis, which has the potential to induce fibrosis, cirrhosis and hepatocellular carcinoma. Of note, other causes of cryptogenic liver disease, for example NRH, have to be taken into consideration if a patient presents with cryptogenic liver disease.

Clinicians need to be aware of laboratory or clinical signs of liver injury when treating HIV-positive patients, even in the absence of a concomitant liver disease.

As fibrosis progression is the common final path in all hepatopathies, non-invasive assessment of liver fibrosis such as transient elastography (Fibroscan) or serum markers (i.e. Fibrotest) should be routinely performed in these patients. As liver biopsy is the only method to detect histological alterations, it still plays a major role to rule out conditions like NASH or NRH. It should therefore have its place in the clinical toolkit for the assessment of liver damage of HIV patients.

Unfortunately, medical options are scarce in this setting and treatment interruptions did not turn out to be an alternative strategy. Whether treatment of insulin resistance, for example with thiazolidinediones, may help to treat steatohepatitis needs to be established in clinical trials. In some cases, the withdrawal of certain drugs (i.e. didanosine, stavudine) might be an option. If liver damage progresses, liver transplantation might remain the sole alternative.

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Correspondence to: Patrick Ingiliz, Vivantes Auguste-Viktoria Klinikum, Rubensstr 125, 12157 Berlin, Germany.

Email: [e-mail]