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Antiretroviral drugs and liver injury

Soriano, Vincenta; Puoti, Massimob; Garcia-Gascó, Pilara; Rockstroh, Juergen Kc; Benhamou, Yvesd; Barreiro, Pabloa; McGovern, Barbarae

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doi: 10.1097/QAD.0b013e3282f0e2fd
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Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity, mortality and treatment discontinuation in HIV-infected patients [1]. Prevention and management of ARLI have emerged as major issues among HIV-infected patients in the era of HAART [2]. Virtually every licensed antiretroviral medication has been associated with liver enzyme elevations, although certain drugs may cause liver injury more frequently than others. In addition, certain comorbidities, such as chronic hepatitis B (HBV) or hepatitis C (HCV) infection, may predispose patients to ARLI [3]. Several major mechanisms of ARLI have been described, including metabolic host-mediated injury, hypersensitivity reactions, mitochondrial toxicity, and immune reconstitution phenomena. The management of ARLI should be based on its clinical severity and underlying pathogenic mechanism. Herein, we propose use of a universal standard for defining liver injury to enable comparisons between future studies. Novel mechanisms for hepatotoxicity are also discussed along with preventive measures to avoid the onset of ARLI.

Definition of antiretroviral drug -related liver injury

ARLI is defined by elevations in liver enzymes in serum, with alanine aminotransferase (ALT) characteristically greater than aspartate aminotransferase (AST). To date, there has been broad variability in the criteria used in clinical studies to categorize the severity of hepatotoxicity. Some studies have utilized ALT parameters as minimal as two times the upper limits of normal [4] while others have employed an absolute threshold (e.g., > 100 IU/ml), regardless of baseline liver function tests [5]. The clinical relevance of these elevations is uncertain.

More recently, the AIDS Clinical Trials Group (ACTG) has defined a grading scheme against the patient's baseline serum aminotransferase concentrations. For example, in patients with a normal pretherapy ALT or AST, hepatic injury is graded as moderate or severe based on a 5-fold or 10-fold increase in aminotransferases, respectively [6]. In patients with abnormal liver enzymes prior to therapy, a > 3.5-fold or a 5-fold increase in ALT or AST is considered indicative of moderate or severe hepatotoxicity, respectively [7].

Liver function test abnormalities require careful interpretation. On the one hand, some drugs (e.g., nevirapine and less frequently efavirenz) increase γ-glutamyl transpeptidase serum levels. This laboratory result is often misinterpreted as a marker of liver damage, when isolated elevation of this enzyme actually reflects enzyme induction. Similarly, hyperbilirubinaemia alone should not be equated with liver injury, since indirect hyperbilirubinaemia may be related to medications, such as indinavir or atazanavir [8–10]; this risk is increased in patients with underlying Gilbert's syndrome, a genetic disorder (Fig. 1). On the other hand, drug-induced liver injury that is associated with an elevated direct bilirubin and clinical jaundice portends a poor clinical outcome. A cholestatic profile should only be considered when there is an associated increase in serum alkaline phosphatase as well as bilirubin.

Fig. 1:
Interplay between bilirubin metabolism, Gilbert's genotype and atazanavir (ATV) or indinavir (IDV) use. UDT, UDP glucuronosyltransferase.

Elevated aminotransferases also need to be interpreted within their clinical context. For example, increased liver enzymes in a patient with chronic HBV infection do not necessarily imply drug injury but may reflect HBV-related hepatic flares, which often occur during the natural course of the disease.

Clinical relevance

With the widespread use of HAART and the availability of new antiretroviral medications, ARLI has gained prominent attention owing to its negative impact on clinical outcomes. Drug-associated hepatotoxicity also creates an economic burden on already strained medical budgets, since additional visits and hospital admissions are often required for appropriate patient care and management [1]. Furthermore, antiretroviral drug discontinuation hampers maintenance of HIV suppression.

The severity of ARLI may range from the absence of symptoms to liver decompensation, and the outcome can range from spontaneous resolution to liver failure and death [11,12]. In one study, severe hepatotoxicity with acute hepatic necrosis was recognized in 2% of HIV-infected patients dying from liver disease. Furthermore, in a large ACTG cohort of nearly 3000 patients initiating HAART, the most common grade 4 adverse events were liver related; this risk was increased in patients with underlying chronic viral hepatitis [13].

Fortunately, the vast majority of episodes of ARLI are asymptomatic, and most ALT elevations resolve spontaneously, as described for many other medications, probably through a process called ‘adaptation’ [14]. However, in a minority, drug-induced liver injury can be overt and have serious consequences. Therefore, it is critically important for the clinician to understand risk factors associated with poor outcomes and the pathogenic mechanisms of disease.

Incidence and risk factors

After initiating HAART, the reported incidence of severe liver toxicity ranges from 2 to 18% [3,5,7,15–22]. Differences in study outcomes may reflect heterogeneity in patient populations, frequency of liver enzymes determinations, other exogenous exposures (e.g., alcohol), medication prescribing patterns, prevalence of chronic viral hepatitis, and criteria used for defining severe hepatotoxicity. Table 1 summarizes some of the major studies that have examined ARLI in HIV-infected patients.

Table 1:
Risk and predictors of liver toxicity after initiating antiretroviral therapy.

Chronic hepatitis B and/or hepatitis C infection

ARLI, especially severe toxicity, is clearly more frequent in HIV-infected patients with underlying chronic HBV and/or HCV infection [3,7,15–22]. Moreover, a higher risk of hepatotoxicity has recently been described for patients infected with HCV genotype 3 in comparison with other HCV genotypes [23–25]. The vast majority of patients with chronic viral hepatitis, however, tolerate HAART well, and the clinician should not be deterred from initiating antiretroviral therapy when necessary [26].

In addition to drug injury, flares in serum transaminase concentrations in a patient with chronic HBV can be related to several different factors, including viral rebound after withdrawal of effective anti-HBV therapy, breakthrough of drug-resistant HBV strains or spontaneous flares of HBV viraemia [21,27–29]. The clinician must bear this in mind before misinterpreting hepatic flares as drug injury.

Other predisposing factors

Alcohol is a known hepatotoxin and its use has been associated with an increased risk of ARLI in the studies that have examined this variable [3]. Chronic use may also predispose to hepatocyte injury by increasing oxidative damage to mitochondrial DNA and depleting stores of glutathione, an important scavenger of free oxygen radicals [30].

Consumption of ecstasy and cocaine may also cause acute hepatitis. Interestingly, liver injury does not seem to be dose dependent nor related to duration of exposure to ecstasy [31,32], whereas cocaine may cause hepatotoxicity via a toxic oxidative metabolite, which induces mitochondrial damage [33,34].

Multiple studies have demonstrated that the risk of liver injury is increased in those with aminotranferase elevations prior to initiating HAART [16,18–20]. Other risk factors associated with ARLI include older age [3], female gender [20,35], first exposure to antiretroviral treatment [21] and significant CD4 cell gains following HAART initiation [7,36]. More recently, an association between the presence of advanced stages of liver fibrosis and greater risk of ARLI has been reported [37]. The mechanism for this observation is unclear, but it could be the consequence of compromised hepatic clearance with subsequent drug overexposure in patients with cirrhosis [38].

Mechanisms of drug-induced liver injury

Drug-induced liver injury can be considered predictable (high incidence) or unpredictable (low incidence) [39]. Liver injury may result from direct toxicity of the drug or its metabolites or may be an idiosyncratic response in persons with a characteristic genetic predisposition. The latency period between the initiation of therapy and the onset of liver disease provides clues to its aetiology.

Predictable hepatotoxic reactions are dose dependent and host independent, with the classic example being paracetamol (acetaminophen) toxicity [39]. Early-onset toxicity (within a few days) is strong evidence for direct drug toxicity, particularly if there has been no previous exposure. Unpredictable hepatotoxic reactions are host dependent and not dose related [40]. Unfortunately, the vast majority of drug reactions are unpredictable. They occur when the drug is transformed into an intermediate metabolite that is either toxic (host-mediated metabolism) or provokes an immunological response (hypersensitivity reaction).

There are four known mechanisms involved in the development of hepatotoxicity associated with the use of antiretroviral medications (Table 2). Multiple aberrant pathways may coexist within the same individual.

Table 2:
Mechanisms of drug-related liver injury in HIV-infected patients.

Metabolic host-mediated injury

Host differences in drug metabolism may lead to an excess of potentially harmful reactive drug metabolites when genetic polymorphisms affect critical metabolizing enzymes [41]. The latency of onset is long (from 2 to 12 months), which poses problems for patient monitoring [42]. Prototypical examples include isoniazid and troglitazone; these aberrant metabolic pathways may also underlie one form of drug injury seen in association with the nonnucleoside reverse transcriptase inhibitors (NNRTI) and the protease inhibitors (PI) [43,44].

Some drugs may potentiate the activation of T cell death receptors and/or intracellular stress pathways, leading to increased oxidative stress [45]. In response, hepatocytes promote mechanisms of cytoprotection, such as the formation of heat shock proteins, which protect the liver against toxic metabolites [41]. This cytoprotective response may explain the spontaneous normalization of liver enzymes that may occur despite maintenance of HAART (or other medications, such as isoniazid). Alternatively, the rise and fall of serum aminotransferase concentrations after initiation of medications may be related to a phenomenon of ‘adaptation’, whereby liver function tests normalize despite ongoing drug exposure [46].

Hypersensitivity reactions

Allergic phenomena are idiosyncratic to the host, have an intermediate onset of latency (from a few days to 8 weeks), and are not dose related. The incidence of hypersensitivity reactions is about 1 in 1000 in the general population but is more common in patients with HIV [47]. Prototypical examples include phenytoin and sulphonamides, which can cause rash, fever, eosinophilia and hepatitis. The temporal relationship between symptoms and signs and the initiation of the suspected culprit drug are helpful in distinguishing this type of drug reaction (Table 3). Clearly, rechallenges should be avoided if drug hypersensitivity is suspected.

Table 3:
Clinical presentation of antiretroviral-related liver toxicity.

Hypersensitivity reactions have been reported with nevirapine, abacavir and less frequently with amprenavir, both in HIV-infected patients and in subjects receiving HIV prophylaxis after potential exposure [48]. These immune-mediated drug reactions may involve the generation of neoantigens formed by the covalent bonding of liver proteins with reactive drug metabolites [41,49].

Mitochondrial toxicity

Mitochondria play a major role in energy production and glucose and fat metabolism, but they are also the main source of reactive oxygen species, which can lead to cellular demise. The most infamous example of severe mitochondrial damage occurred with the use of the nucleoside analogue fialuridine for the treatment of HBV. During the initial stages of the study, several participants developed lactic acidosis and hepatic failure [50]. Chronic therapy with nucleoside reverse transcriptase inhibitors (NRTI) for the treatment of HIV can also lead to mitochondrial toxicity after long-term exposure. This drug class selectively inhibits DNA polymerase-γ, which is responsible for replication of mitochondrial DNA. Diminished mitochondrial function may lead to a decrease in oxidative phosphorylation, which, in turn, leads to aberrations in pyruvate metabolism and accumulation of lactate [51].

The spectrum of mitochondrial toxicity of NRTI drugs ranges from nonspecific symptoms to lactic acidosis syndrome with fulminant hepatic failure [52,53]. Early on, patients may complain of fatigue, abdominal bloating, anorexia and weight loss. Lactic acidosis syndrome is manifested by nausea, vomiting and abdominal pain, rapidly progressing to tachypnoea with severe acidosis. Liver function tests may be modestly elevated in this setting, often with AST greater than ALT [54]. Late recognition of this syndrome usually is associated with death of the patient [55].

The presence of chronic HCV infection, which is quite prevalent in HIV-infected patients, may increase a patient's susceptibility to antiretroviral drug-related mitochondrial stress and damage [56]. HCV core protein causes mitochondrial injury, leading to excessive production of reactive oxygen species [57–59]. This leads to oxidative stress, which is enhanced in the presence of tumour necrosis factor, alcohol or nucleoside analogues. Consequently, exposure to any nucleoside analogues, either for the treatment of HIV (e.g., didanosine) or for HCV [e.g., tribavirin (ribavirin)] may further enhance mitochondrial toxicity [60].

Immune reconstitution phenomena

ARLI associated with HAART-induced CD4 T cell recovery has been attributed to immune reconstitution phenomena, particularly in the setting of chronic HBV and occasionally in patients with chronic HCV.

Hepatitis B

Cell-mediated immunity plays a central role in the pathogenesis of chronic HBV [61]. For example, in an HIV/HBV coinfected patient with advanced immunosuppression, HBV replication generally increases but HBV-related liver inflammation lessens and transaminase levels decline [62]. Conversely, when HAART is initiated, improved cellular immunity can lead to flares in liver enzymes [63] and spontaneous seroconversion [64], even in the absence of any anti-HBV active drug [65]. Liver enzyme flares in HIV/HBV-coinfected patients taking antiretroviral therapy need to be carefully interpreted, with concomitant evaluation of serum HBV DNA, in order to assign causality correctly. Liver enzyme elevations in HIV/HBV-coinfected patients following initiation of antiretroviral therapy can be caused by (i) direct drug-related liver injury; (ii) immune reconstitution in patients positive for HBV surface antigen (HBsAg), (iii) seroconversion in patients positive for HBV ‘e’ antigen and/or HBsAg, (iv) HBV reactivation in inactive carriers and occasionally in those with resolved HBV infection.

Hepatitis C

The concept of HCV-related immune reconstitution was initially proposed in 1998 when it was reported that three patients had developed liver enzyme elevations and regained HCV antibody after initiation of HAART [66]. However, antibody responses to HCV do not necessarily correlate with reconstitution of cellular immune function, and initiation of HAART does not imply restoration of HCV-specific T cell responses [67]. Moreover, the role that cellular immunity plays in the pathogenesis of chronic HCV is not as clear as for HBV [61]. Finally, conflicting results have been reported on whether gains in absolute numbers of CD4 T cells correlate with flares of transaminases [7,19,68,69]. Although immune reconstitution remains an attractive theory, and may certainly explain clinical events in a subset of HIV patients with HCV [70,71], more evidence needs to be gathered before any conclusions can be drawn.

Novel potential mechanisms for antiretroviral drug-related injury: hepatic steatosis

HIV-infected patients are at risk for hepatic steatosis, which may play an important role in facilitating liver injury. Insulin resistance, hyperlipidaemia and visceral adiposity are the metabolic and morphological abnormalities that have been intrinsically linked to the development of hepatic steatosis in the general population [72]. These same metabolic and morphological aberrations coexist in a high percentage of HIV-infected patients, and are know as the lipodystrophy syndrome [73]. Several studies have found that hepatic steatosis is highly prevalent in HIV-seropositive patients, particularly in those with chronic HCV and/or receiving NRTI drugs with high mitochondrial toxicity profiles [74,75].

These epidemiological associations are important, because it is highly possible that fatty liver may play an important role in ARLI. Hepatic steatosis produces substrates for lipid peroxidation; this results in the basal formation of potentially harmful reactive oxygen species, which can lead to liver injury [30]. Oxidative stress occurs when there is an imbalance between increased production of reactive oxygen species and depleted antioxidant defences, such as glutathione, that prevent damage from these oxygen radicals [76]. When antioxidants are depleted, excess reactive oxygen species can damage mitochondrial DNA and oxidize fat, causing a perpetual cascade of increased lipid peroxidation, oxidative stress and hepatocellular injury [77].

These in-vitro observations are supported by histological data that demonstrate the presence of mild to moderate degrees of hepatic steatosis in patients experiencing ARLI [54,68,78]. Furthermore, HCV genotype 3 infection, which induces hepatic steatosis through a virally mediated cytopathic effect, has been associated with an increased risk of ARLI [23–25]. These studies suggest that liver steatosis itself may be a predisposing factor for drug-related toxicity. The role of steatosis in liver injury will be an important area of future research.

Antiretroviral medications and their role in liver injury

Studies that have evaluated the risk of liver injury associated with a particular antiretroviral agent or class are often conflicting. The effect of a specific drug is difficult to ascertain because of the widespread use of combination therapy. However, some general observations can be made, as discussed below.

Nucleoside reverse transcriptase inhibitors

Mechanisms of drug injury observed with NRTI mainly include mitochondrial toxicity and hypersensitivity reactions. Early clinical trial data from the late 1980s demonstrated that NRTI may be associated with high rates of moderate to severe hepatotoxicity, ranging from 7% with zidovudine, 9–13% with stavudine and 16% with didanosine [79]. Newer NRTI such as emtricitabine, abacavir and tenofovir are associated with a low incidence of mild asymptomatic aminotransferase elevations [80].

Mitochondrial toxicity is an infrequent but distinctive type of hepatotoxicity associated with the use of NRTI that may evolve to acute liver failure with severe hepatomegaly and lactic acidosis [51]. This complication generally occurs after several weeks or months of NRTI treatment. However, nucleoside analogues differ widely in their propensity to induce mitochondial toxicity. Potency estimations in vitro gave a descending hierarchy of their potency: zalcitabine, didanosine, stavudine, zidovudine and, finally, abacavir, as least toxic [80]. In-vitro data support additive or synergistic mitochondrial toxicity of some NRTI combinations [81], such as stavudine and didanosine [81–83].

Hypersensitivity reactions have been linked to abacavir and are characteristically seen in patients with HLA-B*5701 background [84]. Reexposure to abacavir can be fatal.

Incidents of unexplained liver disease in HIV-infected individuals have recently been reported in which clinical manifestations of portal hypertension are often predominant. Didanosine exposure seems to be involved in almost all and nodular regenerative hyperplasia is a frequent histological finding [85,86]. Ongoing studies will clarify the real impact of this condition, its predisposing factors and how to manage it adequately.

Nonnucleoside reverse transcriptase inhibitors

Although registration trials of nevirapine or efavirenz demonstrated acceptable toxicity profiles, postmarketing reports of severe ARLI associated with nevirapine have focused attention on this particular agent. Two distinct patterns of drug injury associated with nevirapine use have emerged: hypersensitivity reactions and direct drug-related toxicity [87].

Hypersensitivity reactions

In patients taking nevirapine, the overall incidence of symptomatic events involving the liver enzymes is approximately 5% [44,88]. However, severe liver toxicity, occurring with early latency, has been reported in HIV-infected and HIV-seronegative individuals. Warnings against the use of nevirapine for postexposure prophylaxis were issued after some individuals developed hepatic failure requiring liver transplantation [89]. In an HIV treatment trial assessing the efficacy and safety of emtricitabine, a higher incidence of hepatotoxicity was observed in patients assigned to the nevirapine arm than in those in the efavirenz arm [90]. Hepatotoxicity predominated in black women, often in association with rash and fever, and was consistent with a drug hypersensitivity reaction. Further analysis revealed that these events appeared to be linked to nevirapine use in women with CD4 cell counts > 250 cells/μl, emphasizing the importance of host immunity and neoantigen recognition in hypersensitivity reactions [91].

Boehringer-Ingelheim subsequently released a warning on the risk of severe liver toxicity, in some occasions with fatal outcome, and currently only recommends the use of nevirapine in women with a CD4 cell count < 250 cells/μl and in men with < 400 cells/μl. Interestingly, a recent study has refuted the role of immunocompetence as a risk factor for nevirapine toxicity [92].

Other risk factors for nevirapine-associated hepatotoxicity include low body mass index [93] and host genetics; persons with an HLA-DRB1*0101 background have an increased propensity for developing nevirapine-associated hypersensitivity [94–96].

Idiosyncratic drug-related toxicity

In other studies, a different pattern of drug injury with nevirapine use has emerged, with onset of liver enzyme elevations occurring beyond 16 weeks of therapy, consistent with direct or idiosyncratic host-mediated liver injury [35,36,97]. This late onset of hepatotoxicity with NNRTI is more common in patients with underlying chronic viral HBV and/or HBC infection, as has been described with many other antiretroviral agents. In patient populations that vary in terms of chronic viral hepatitis prevalence, NNRTI-associated liver injury can vary from 15% [36] to as low as 3% [98]. Specific genetic polymorphisms of metabolizing enzymes and drug transporters may also increase the risk of this complication [44,99].

It should be highlighted that hepatotoxicity with either nevirapine or efavirenz does not appear to increase the risk of developing liver injury on exposure to the alternative NNRTI [100,101]. Table 4 summarizes the main studies that have assessed the risk and predictors of NNRTI-associated hepatotoxicity.

Table 4:
Incidence and predictors of severe hepatotoxicity using NNRTI.

Protease inhibitors

The phenomenon of ARLI became more evident after the introduction of PI drugs. Rates of hepatotoxicity from registration trials of various PI have ranged from 1% to 9.5%, but few patients had serious liver-related outcomes [102]. In comparison with other drugs in its class, full-dose ritonavir has consistently been shown to be more hepatotoxic [7,18,21]. However, the use of low-dose ritonavir for pharmacokinetic boosting of other PI drugs appears to be safe [103].

Although there are a few case reports of liver-related toxicity with indinavir, these were in association with advanced liver disease; dose reduction is recommended in patients with cirrhosis. Several cases of clinical hepatitis and hepatic decompensation, including some fatalities, have been associated with the use of tipranavir, particularly in patients with chronic HCV infection [104,105]. Nelfinavir, saquinavir, atazanavir, fosamprenavir, lopinavir and darunavir are associated with a relatively safer liver toxicity profile [106–113]. Amprenavir has occasionally been associated with drug-related hypersensitivity reactions but only sporadically with severe hepatotoxicity [114].

New antiretroviral drug families

The clinical development of aplaviroc, a CCR5 antagonist, was halted in 2005 after the occurrence of severe hepatotoxicity [115]. In contrast, maraviroc and vicriviroc appear to have safer hepatotoxicity profiles. Enfuvirtide, the only approved fusion inhibitor, has demonstrated a consistent safety record in terms of liver toxicity [116]. Data on integrase inhibitors are still scarce, but to date MK-0518 has not been associated with any significant liver toxicity [117].

Therapeutic management

When should antiretroviral drugs be discontinued?

Clinical decision making regarding drug discontinuation is often a balancing act. Stopping medications at the very first sign of mild injury can prevent serious consequences. However, this approach can sacrifice potentially important therapy for a large number of patients. Continuing with therapy, however, can lead to untoward outcomes. For patient safety, several important principles need to be emphasized.

  • Symptomatic hepatitis is of much greater concern than asymptomatic elevations of transaminases. The longer a patient continues to take a drug after onset of symptomatic hepatitis, the more likely the outcome will lead to serious liver injury [3].
  • ARLI associated with overt jaundice with increased direct bilirubin levels has a high mortality rate [11,12]. Medications should be immediately discontinued.
  • If a patient complains of symptoms consistent with mitochondrial toxicity in association with an elevated lactate level, medications should be immediately discontinued.
  • If the patient has symptoms consistent with drug hypersensitivity, the medication should be stopped immediately; readministration can be fatal.
  • Medications should be discontinued promptly if plasma ALT or AST is greater than 10 times the upper limit of normal (grade 4), even if the patient is asymptomatic [79,118,119]. For patients with advanced liver disease, more conservative management should be exercised to avoid hepatic decompensation [68].
  • Special caution is warranted for newly marketed drugs since the hepatotoxic potential may not have been recognized in premarketing clinical studies (e.g., darunavir).
  • Always consider alternative causes for hepatitis including viral hepatitis, cholecystitis, opportunistic infections and alcohol or cocaine use.

Spontaneous improvement in transaminases despite drug continuation

In assessing drug toxicity, mild elevations of serum transaminases are commonly seen and often improve despite administration of the same drug [120]. This has also been observed with the antiretroviral medications, particularly with PI use [17,21]. Based upon these data, some authors have suggested that PI-containing HAART does not need immediate adjustment but simply careful monitoring [66]. It should be emphasized that most of these patients had asymptomatic elevations of transaminases.

Cumulative effects of antiretroviral drug-related injury

Another aspect of antiretroviral therapy that requires much more research is the issue of cumulative liver injury, particularly for NRTI [85,86]. In one study of patients with biopsy-proven chronic viral hepatitis, ARLI led to marked increases in necroinflammatory scores on repeat histological sampling [70]. In contrast with this concern, a recent study has suggested that persistent mild serum elevations in liver enzymes do not seem to be deleterious [121]. However, the long-term implications of recurrent liver injury remain unknown.

The role of liver biopsy in ARLI

Unfortunately, the liver biopsy often does not contribute substantially to patient management or assigning causality [118]. On occasion, histology can be helpful if eosinophils or granulomas are found, which suggest drug hypersensitivity [7,68]. If mitochondrial toxicity is suspected, then histology and electron microscopy can help to determine if microvesicular steatosis and evidence of mitochondrial injury is present [122].

Prevention of antiretroviral drug-related injury

The most effective approach to drug-induced liver disease is primary prevention. However, since most drug-induced hepatotoxicity is difficult to predict, the clinician must be aware of the patient's predisposing risk factors for ARLI, which may help to guide monitoring and patient management.

Assessment of baseline liver status

The treatment of patients with cirrhosis must be carefully undertaken since an episode of severe hepatotoxicity may lead to hepatic decompensation [70]. If advanced liver disease is clinically suspected, assessment of liver fibrosis using noninvasive tools (e.g., elastometry) or a liver biopsy may be considered in selected patients prior to drug initiation. The rationale for this approach is to make a firm diagnosis of cirrhosis and consider using dosages of antiretroviral drugs appropriately for advanced liver disease.

The critical role of patient education

Long-term clinical experience with drugs such as isoniazid has shifted the primary focus away from laboratory monitoring to increased emphasis on patient education and medical assessment [123]. Although often neglected by HIV care providers, it is critically important to educate the patient about the symptoms of hepatitis, including fatigue, nausea, vomiting, right upper quadrant pain and jaundice. Patient education is particularly important when considering hypersensitivity reactions, which occur early and can be devastating if the offending drug is continued. Patients need to be instructed to contact their medical provider immediately should these symptoms occur. In resource-poor countries, regular laboratory monitoring is often not feasible owing to cost constraints; therefore, patient education takes on even greater importance.

Frequency of monitoring: a patient-tailored approach

Decisions on the frequency of monitoring may be determined by the patient's individual risk profile and particular drug choice. For example, a patient who is prescribed nevirapine should be monitored within 1 to 6 weeks, since most reactions occur early after drug initiation. Similarly, a patient who is HCV seropositive with abnormal aminotransferases at baseline requires closer monitoring than one who is HCV seronegative and has normal liver function tests. Patients with cirrhosis require the closest supervision, with additional attention paid to any increases in total bilirubin or prothrombin time.

Reevaluation of the antiretroviral regimen

Cumulative exposure to NRTI drugs is an important factor in the development of mitochondrial toxicity. Since hepatotoxicity related to NRTI may progress silently, it is prudent to consider stopping older generation NRTI with a high mitochondrial toxicity profile (e.g., didanosine or stavudine) and switching to alternative NRTI drugs whenever possible [75,85,86]. Figure 2 summarizes graphically which antiretroviral drugs show a safer liver profile.

Fig. 2:
Hepatic safety profile of antiretroviral drugs. RTV, ritonavir (*at full doses, not when used as booster); ddI, didanosine; d4T, stavudine; AZT, zidovudine; ABV, abacavir; TDF, tenofovir; 3TC, lamivudine; FTC, emtricitabine; NVP, nevirapine; EFV, efavirenz; TPV, tipranavir; APV, amprenavir; DRV, darunavir; ATV, atazanavir; LPV, lopinavir; SQV, saquinavir; NFV, nelfinavir; T20, enfuvirtide; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitors.

Address modifiable risk factors

If hepatic steatosis is present, predisposing conditions should be addressed (i.e., obesity, alcohol, hyperglycaemia, dyslipidaemia). Other potentially modifiable risk factors include HCV genotype 3 infection, which is associated with steatosis and an increased risk of drug injury [23–25]. This is particularly relevant given that HCV treatment is highly effective in patients with genotype 3 infection and should be actively undertaken [124].

Recent studies have demonstrated that anti-HCV therapy may improve the overall hepatic tolerance of antiretroviral therapy in coinfected patients, particularly in subjects who resolve their infection [125–127].

A liver protective role for antiretroviral therapy

Observational data suggest that the initiation of HAART is associated with slower progression of HCV-related liver injury [128–131]. This may be mediated by immune restoration, or by ameliorating the deleterious effect of HIV-associated cytokines (e.g., tumour necrosis factor) on liver fibrosis progression.

Given the large benefit of HAART, which clearly outweighs its potential risks for liver toxicity, it is unjustifiable to defer antiretroviral therapy in HIV treatment candidates. Clinicians need to educate the patient regarding symptoms and signs of hepatotoxicity, assess risk factors for drug injury, address those factors that can be modified, and be vigilant for the earliest signs of drug injury.

Future directions

Several initiatives will help to promote better research collaboratives, a comprehensive understanding of pathogenesis and improved patient management. Pharmacogenomics may provide great value for predicting undesirable drug reactions; some of these tools are already available for use [132–134]. For example, implementation of HLA typing for the HLA-B*5701 allele may significantly reduce the risk of abacavir hypersensitivity [135]. Knowledge of polymorphisms at isoenzyme 2B6 of cytochrome P450 may identify persons at risk for hepatic intolerance to efavirenz [136,137]. Typing of P-glycoprotein and/or the gene for UDP glucuronosyltransferase, along with plasma drug level monitoring, may permit adjustment of dosage and thus reduce hyperbilirubinaemia associated with atazanavir [138]. Techniques currently under investigation include in-vitro activation of peripheral blood mononuclear cells against a drug or its metabolites as a tool for identifying risk [49]. Serum biomarkers are also being developed to help to predict hepatic idiosyncratic reactions [139].

The role of liver steatosis as a mechanism of, and as predisposing factor for, ARLI should be investigated. Hepatic steatosis is highly prevalent in this patient population and its presence is influenced by chronic nucleoside analogue use, HCV genotype 3 infection and metabolic aberrations such as insulin resistance [75]. Even a modest interaction between hepatic steatosis and drug injury would have significant implications in this patient population.

Finally, the use of standard definitions for ARLI is needed in order to improve comparisons across studies. An absolute threshold of elevation of aminotransferases should be abandoned in favour of a system of measuring fold-changes against the patient's baseline values. In addition, the degree of elevation is an important parameter, since modest increases of ALT/AST may reflect the ‘waxing and waning’ of chronic viral hepatitis or drug ‘adaptation’. Therefore, we propose that a minimum requirement of a 5-fold change over a normal baseline or a 3.5-fold change over an abnormal baseline should be universally used as the minimum criteria for assessing significant drug-related injury. We also propose that ARLI should be considered when hepatic decompensation has occurred, regardless of the level of ALT/AST; in this setting, and serum levels of antiretroviral medications and lactate should be obtained. With a universal approach, further advances can be made in this critical field of research.


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antiretroviral drugs; hepatitis C; hepatotoxicity; HIV; liver; toxicity

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