JAC Advance Access originally published online on January 25, 2007
Journal of Antimicrobial Chemotherapy 2007 59(3):342-346; doi:10.1093/jac/dkl524
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Reviews |
Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors
1 Sección de Enfermedades Infecciosas, Hospital Universitario Reina Sofía, Cordoba, Spain 2 Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario de Valme, Seville, Spain 3 Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Seville, Spain
* Corresponding author. Tel: +34-955011636; Fax: +34-955011636; E-mail: ariveror{at}saludalia.com
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Abstract |
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Top
Abstract
IntroductionLiver toxicity is one of the most relevant adverse effects of antiretroviral therapy. Within the non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz can be considered a safer drug for the liver than nevirapine. In fact, the frequency of severe increased liver enzymes in patients on efavirenz ranges from 1 to 8%, whereas in patients treated with nevirapine, it ranges from 4 to 18%. Likewise, nevirapine is more commonly associated than efavirenz with early acute hepatitis, which is produced by a hypersensitivity mechanism and has a defined risk profile that often makes it avoidable. Despite the fact that most cases of NNRTI-induced liver toxicity are asymptomatic, the rates of symptomatic events in patients treated with nevirapine are greater than in subjects on efavirenz. In any case, it is unusual for an NNRTI to be suspended due to liver toxicity.
Keywords: efavirenz , nevirapine , hepatotoxicity , HIV
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Introduction |
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Liver toxicity is one of the most relevant adverse effects of antiretroviral therapy (ART), owing to its frequency and the fact that it can lead to interruption of therapy, clinical hepatitis and death.1–3 It is well known that any antiretroviral drug can produce liver toxicity.
The data available on the exact incidence of liver toxicity related to ART are contradictory, probably due to different methodological problems.4 On the one hand, many episodes of liver toxicity attributed to ART do not fulfil the criteria necessary for a temporal relationship and for the exclusion of other causes of increased liver enzymes (ILE), such as alcohol, other drugs and immune recovery. On the other hand, studies evaluating the liver toxicity of ART have not used the same definition of this event and its different degrees. Most clinical trials define severe liver toxicity (grade 3 or 4) as a greater than fivefold increase in levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) above the upper limit of normal (ULN), following the criteria used by the AIDS Clinical Trials Group (ACTG).5 Nevertheless, this definition is limited, as it is more sensitive to increased transaminases in patients with high baseline values. Attempts have been made to solve this problem by varying the ACTG definition in those patients with high baseline transaminases. Therefore, the most widely accepted definition at present, which we will use in this article as an equivalent of severe hypertransaminasaemia, is a modified version of the ACTG definition.6 It defines ILE as any increase in ALT or AST levels above 200 IU/mL if baseline values are normal (
40 IU/mL), or more than 3.5-fold baseline levels if they are abnormal. Another explanation for the different findings of the studies that have evaluated the incidence of ART-induced liver toxicity is that ART is always administered in combination, which makes it extremely difficult to apportion the blame for ILE.
According to the different definitions used in each study, the overall frequency of hypertransaminasaemia of grade 3 or higher in HIV-infected adults receiving ART ranges from 1 to 18%,7–26 whereas this condition may be less frequent in HIV-infected children.27 Furthermore, the presence of the hepatitis C virus (HCV) increases by 2- to 10-fold the risk of developing ILE during ART.6,28
This article will examine liver toxicity associated with two frequently used non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz and nevirapine, in HIV-infected adults. We will consider the available data on acute liver toxicity related to both drugs, with special emphasis on their similarities and differences in areas such as mechanism of production and clinical impact of liver toxicity.
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Mechanisms of NNRTI-induced liver toxicity |
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Hypersensitivity
As with other antiretroviral drugs, such as abacavir and fosamprenavir,1,29,30 patients treated with efavirenz or nevirapine can develop hypersensitivity—in some cases with ILE—a few days or weeks after starting therapy.31–35 These cases of NNRTI-induced hypersensitivity hepatitis can present as part of the so-called DRESS syndrome,31–34 which includes skin rash, eosinophilia and systemic involvement (lymphadenopathy, interstitial nephritis, pneumonia and hepatitis), or in a clinical picture with the same systemic symptoms but without skin lesions or eosinophilia.32,35 Hypersensitivity reactions to efavirenz are less frequent than those related to nevirapine.32–35 Thus, in the specific case of nevirapine, the incidence of hepatitis due to hypersensitivity can reach rates of almost 3%.32 Furthermore, although most of these clinical pictures are resolved without suspending nevirapine or efavirenz, exceptionally, there may be episodes of acute hepatic insufficiency.17,36,37
Female sex and a high CD4 cell count are associated with a higher incidence of hepatitis due to nevirapine-induced hypersensitivity.37,38 Similarly, hypersensitivity to nevirapine seems to have a certain genetic component. Thus, patients who present the DRB1*0101 histocompatibility antigen and a baseline percentage more than 25% of CD4 cells/mm3 are more susceptible to developing this type of reaction, although larger studies are needed to assess the clinical utility of genetic screening prior to initiating therapy with nevirapine.39 On the contrary, the factors associated with developing a hypersensitivity reaction to efavirenz are much less well known.
There is no clear explanation of the mechanism of production of toxic hepatitis in patients receiving an NNRTI who do not show symptoms of a hypersensitivity reaction. Clinical presentation is the same as in other types of toxic hepatitis associated with ART, although it may appear later in therapy than hepatitis by hypersensitivity.13,16 In line with this observation, the possibility has been suggested of an accumulative or dose-dependent mechanism as the origin of these cases of liver toxicity, both with nevirapine and with efavirenz. As far as nevirapine is concerned, although some case-control studies observed an association between high plasma concentrations of nevirapine and liver toxicity,40 later studies with a larger sample size and better design have not confirmed this relationship.41–43 In the case of efavirenz, a recent study revealed an association between plasma levels of efavirenz and high transaminase levels during the first 6 weeks of treatment.43
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Frequency of NNRTI-induced liver toxicity |
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Currently available information on the frequency of liver toxicity related to efavirenz and nevirapine is extensive and comes from both clinical trials and cohort studies. The data from these studies show that efavirenz causes liver toxicity less frequently than nevirapine. Thus, in the different studies comparing the adverse effects of these drugs on the liver, the frequency of severe ILE in patients on efavirenz ranges from 1 to 8%,7–14 whereas in patients treated with nevirapine, it ranges from 4 to 18% (Figure 1).7,11–16
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Several clinical trials have provided information on the frequency of severe hypertransaminasaemia due to efavirenz, and they all follow the criteria proposed by the ACTG. Study GS 903 included 602 naive patients, who were randomized to receive tenofovir, or stavudine, in combination with lamivudine and efavirenz for 144 weeks.8 Of the patients included in each group, 5% and 6%, respectively, developed a grade 3 or 4 increase in ALT and/or AST levels. The results were almost identical in trial CNA30024,9 in which naive patients were randomized to abacavir or zidovudine, with lamivudine and efavirenz as common antiretrovirals. Six per cent of the patients included in both groups showed grade 3 or 4 liver toxicity. Trial GS 934 has recently been published.10 It compares the efficacy and safety of an antiretroviral regimen with tenofovir, emtricitabine and efavirenz, with another composed of zidovudine, lamivudine and efavirenz in 517 naive patients. Of the total number of patients included in the study, 7.5% presented ILE above grade 2 (>2.6 times the ULN). No patients needed to suspend therapy due to adverse liver effects.
In a Spanish prospective cohort study with 610 naive patients treated with nevirapine,16 12.5% of the patients analysed developed a severe episode of ILE (i.e. increase in transaminase levels greater than three times baseline during follow-up).
The clinical trials that have compared the frequency of efavirenz- and nevirapine-induced toxicity include 2NN.7 In this study, 1216 naive patients were assigned to receive nevirapine 200 mg/12 h, nevirapine 400 mg/24 h, efavirenz 600 mg/24 h or nevirapine 400 mg/day in combination with efavirenz 800 mg/day, for 48 weeks. The subgroup of patients treated with efavirenz presented hypertransaminasaemia of grade 3 or above, according to ACTG criteria, with the lowest frequency of all the arms (4.5%), whereas the patients treated with nevirapine-based ART, once and twice per day, presented frequencies of 13.2% and 7.8%, respectively. In this study, one patient assigned nevirapine twice daily died due to an episode of fulminant hepatitis attributed to the use of this antiretroviral drug. There were no liver-related deaths in those subjects treated with efavirenz.
The NEFA trial evaluated the strategy of replacing a protease inhibitor (PI) by nevirapine,11 efavirenz or abacavir in patients with suitable virological control. Only 0.6% of the patients who received efavirenz showed grade 3 or 4 ILE compared with 4% of those treated with nevirapine. This trial also evaluated the grade of ILE using the ACTG definition. None of the patients treated with efavirenz and 3% of those treated with nevirapine suspended therapy due to increased ALT and/or AST.
Several cohort studies have provided comparative data on the liver toxicity induced by both NNRTIs. The first, from the Johns Hopkins University in Baltimore, USA,12 prospectively analysed the incidence of severe liver toxicity in 568 patients treated with efavirenz or nevirapine. Of those who received efavirenz, 8% had severe ILE, compared with 15.8% in the nevirapine group. Of the 298 patients included in the Spanish cohort from the Hospital Carlos III, who had received NNRTI-based ART,13 six of the 136 (4%) patients receiving efavirenz and 20 (12%) of the 162 receiving nevirapine developed severe hypertransaminasaemia.
In a prospective cohort study carried out in Italy,14 in which patients treated with either of the two NNRTI were followed up for 18 months, 17% and 52% of patients who received efavirenz and nevirapine, respectively, presented increased levels of ALT and/or AST of at least twice baseline. In this study, none of the patients who received efavirenz suspended therapy due to liver toxicity, compared with 9 (3%) patients treated with nevirapine who did. Finally, in a study which evaluated severe ART-associated liver toxicity in 692 patients included in eight different clinical trials carried out in Thailand,15 the incidence of severe ILE in the group who received nevirapine-containing regimens was 18.6 episodes per 100 person-years, compared with 2.4 events per 100 person-years in the group who used efavirenz-containing ART. In this study, severe ILE was defined as any greater than fivefold increase above ULN in ALT and/or AST, or an increase of more than 100 IU/mL of ALT levels above baseline.
In randomized clinical trials comparing the incidence of severe liver toxicity induced by NNRTI with that of protease inhibitors (PIs), the rate of grade 3 or 4 ILE-associated with efavirenz was similar to that of atazanavir (3% versus 4%), nelfinavir (6% versus 3%) and indinavir (5% versus 5%),22–24 whereas the percentage of patients developing an episode of severe hypertransaminasaemia due to nevirapine was greater than in those who received nelfinavir (10% versus 7%) and indinavir (9% versus 4%).25,26 At present, no randomized clinical trials have compared the incidence of efavirenz or nevirapine-induced liver toxicity with that of other PIs. As far as cohort studies are concerned, the rates of severe ILE observed in patients receiving the oldest PIs, such as indinavir, saquinavir and nelfinavir, are generally higher than those observed with efavirenz and similar to those described with nevirapine.18 On the contrary, the frequency of severe liver toxicity associated with the most commonly used PIs at the moment, such as lopinavir, atazanavir and fosamprenavir, seems to be in the range recorded for patients on efavirenz and substantially lower than that of patients who are treated with nevirapine.19–21
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Risk factors related to NNRTI-induced liver toxicity |
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The risk factors associated with NNRTI-induced liver toxicity are similar to those of the other antiretroviral drugs. HCV co-infection is the most determining factor, since it increases by two- to sevenfold the risk of developing an ILE episode of grade 3 or higher in patients treated with these drugs.12,13,16,38,44 Similarly, in most studies, co-infection by the hepatitis B virus, concomitant use of PI and high alcohol consumption has been related to a greater frequency of severe NNRTI-induced liver toxicity.12,13,38,44 Furthermore, both female sex and an increase in CD4 of more than 50 cells/mm3 during therapy have been associated with NNRTI-induced liver toxicity in some studies,12,13 although these have not been confirmed in all of them.12,13,16,38,44
With regard to nevirapine in particular, some factors are clearly associated with severe liver toxicity during therapy. Thus, the risk of nevirapine-induced hepatitis increases 12-fold in women with more than 250 CD4 cells/mm3 and fivefold in males with more than 400 CD4 cells/mm3.37,38 These circumstances have led the FDA to issue a warning, accepted by the producer of the drug, stating that therapy with nevirapine should not be started in women with CD4 >250 cells/mm3 or in men with CD4 > 400 cells/mm3 if another option is available.37 Finally, both high baseline ALT levels, and prolonged ART experience before starting therapy with an NNRTI have been associated with the development of severe nevirapine-induced liver toxicity.16,38
Particularly interesting is the fact that the severity of the hepatic lesions associated with HCV before starting ART determines the risk of NNRTI-induced liver toxicity. This is also the case with other antiretrovirals, such as nelfinavir.45 Thus, in a prospective study involving 107 HIV/HCV-coinfected patients who received ART after a liver biopsy, the frequency of severe ILE observed in those patients with advanced fibrosis (F3–F4) and on efavirenz was 18%, compared with 7% in those who did not have advanced fibrosis (F1–F2).46 The same was true of nevirapine, since severe liver toxicity appeared in 5% and 25% of patients with F1–F2 and F3–F4, respectively. Among patients with non-advanced fibrosis, the incidence of severe ILE was similar in those who received any of the NNRTI and those treated with other ART regimens, at around three episodes of severe ILE per 100 person-years. Nevertheless, the presence of advanced fibrosis led to an increase in the incidence of severe ILE in the efavirenz group, which reached 8.6 events per 100 person-years, and in that of nevirapine, with 11.7 episodes per 100 person-years.
As far as ART is concerned, cirrhotic patients are a particularly difficult population to manage. Plasma concentrations of efavirenz and nevirapine in this group are usually high, which could be associated with higher levels of liver toxicity.47 In this sense, the information available on NNRTI-induced liver toxicity in cirrhotic patients is very limited. In a small series of cirrhotic patients,48 in fact in the only one in which this aspect has been evaluated, the frequency of severe ILE in patients treated with efavirenz was lower (28%) than that of those who received nevirapine (60%) or lopinavir (50%). We clearly need more information on the hepatic safety of NNRTIs in patients with cirrhosis.
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Clinical presentation of NNRTI-induced toxic hepatitis |
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Despite the fact that most cases of NNRTI-induced liver toxicity are asymptomatic, even when transaminase levels are very high, there are differences between the two drugs. Thus, whereas cases of efavirenz-induced symptomatic hepatitis have only been reported occasionally, the rates of symptomatic events in patients treated with nevirapine are greater, and in some studies reach more than 2% of the patients who have received this drug.7–14,16 In any case, it is unusual for an NNRTI to be suspended due to liver toxicity.
Furthermore, in patients treated with nevirapine, fulminant hepatitis has been more common than in patients on efavirenz. Thus, in trial FTC-302,17 17% of patients treated with nevirapine developed grade 3 or 4 ILE, according to the ACTG definition. Two women, i.e. 4% of those who developed liver toxicity, died from liver failure, and none of those on efavirenz presented severe liver toxicity or fulminant liver failure. According to these data, only one death due to fulminant liver failure after starting efavirenz-based ART has been reported to date in the literature (source: PubMed; search terms: efavirenz and liver).36 Furthermore, in this case we cannot rule out completely that nucleoside analogue-induced hyperlactataemia, rather than severe efavirenz-induced liver toxicity, was the cause of the liver failure, since the patient was taking stavudine and had moderately high levels of lactate in plasma.
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Management of NNRTI-induced liver toxicity |
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At present, there is no agreement on how to manage patients suffering from ART-associated liver toxicity. An algorithm has been proposed, which indicates different schedules of behaviour depending on the presence of clinical symptoms, the magnitude of the hypertransaminasaemia and its mechanism of production.49 According to this algorithm, it is recommended that ART be suspended in the case of grade 3 or 4 ILE, regardless of the symptoms the patient presents. Nevertheless, this attitude may be questionable. With regard to NNRTI-induced liver toxicity in particular, it is more reasonable to suspend either of these two drugs in any case of acute symptomatic hepatitis, when the patient presents systemic evidence of a hypersensitivity reaction or if hypertransaminasaemia reaches more than 10 times the ULN (grade 4 ILE). In the case of grade 3 ILE, the patient should be followed up and re-assessed weekly or fortnightly, and treatment with efavirenz or nevirapine should be suspended only when any of the above-mentioned criteria appear. Thus, the vast majority of grade 3 ILE will not lead to suspension of these antiretrovirals, since they normally resolve without further problems and without clinical symptoms.
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Conclusions |
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Within the NNRTI, efavirenz can be considered a safer drug for the liver than nevirapine. In fact, the incidence of severe efavirenz-induced hypertransaminasaemia is lower than that observed with nevirapine. The latter is more commonly associated than efavirenz with early acute hepatitis, which is produced by a hypersensitivity mechanism and has a defined risk profile that often makes it avoidable. In any case, the vast majority of episodes of toxic hepatitis by both nevirapine and efavirenz are asymptomatic and self-limiting; therefore, they generally do not require the drug to be suspended. Finally, data on the safety of NNRTI are necessary in HIV/HCV-coinfected patients with liver cirrhosis.
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Transparency declarations |
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Antonio Rivero reports having received consulting fees from Bristol-Myers Squibb, Abbot, Gilead, Roche Pharma and Boehringer Ingelheim Pharmaceuticals. José A. Mira has received a research grant from GlaxoSmithKline and has received consulting fees from Bristol-Myers Squibb. Juan A. Pineda reports having received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbot, Gilead and Boehringer Ingelheim Pharmaceuticals. He has received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Abbot and Boehringer Ingelheim Pharmaceuticals and has received lecture fees from GlaxoSmithKline, Roche Pharma, Abbot, Bristol-Myers Squibb and Boehringer Ingelheim.
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