Journal of Hepatology 44 (2006) S132S139

www.elsevier.com/locate/jhep

Hepatotoxicity of antiretrovirals: Incidence,

mechanisms and management
Marina Nunez*
Infectious Diseases, Instituto de Salud Carlos III, Madrid, Spain

One of the toxicities linked to the use of antiretrovirals is the elevation of transaminases. Liver toxicity is a cause of
morbidity, mortality, and treatment discontinuation in HIV-infected patients. While several antiretrovirals have been
reported to cause fatal acute hepatitis, they most often cause asymptomatic elevations of transaminases. Liver toxicity is
more frequent among subjects with chronic hepatitis C and/or B. The incidence of drug-induced liver toxicity is not well
known for most antiretrovirals. The contribution of each particular drug to the development of hepatotoxicity in a
HAART regimen is difficult to determine. Possible pathogenic mechanisms involved in hepatotoxicity are multiple,
including direct drug toxicity, immune reconstitution in the presence of HCV and/or HBV co-infections,
hypersensitivity reactions with liver involvement, and mitochondrial toxicity. Other pathogenic pathways may be
involved, such as insulin resistance caused by several antiretrovirals, which may contribute to the development of
steatohepatitis. The management of liver toxicity is based mainly on its clinical impact, severity and pathogenic
mechanism.
q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Antiretrovirals; Hepatotoxicity; Hepatitis C

1. Introduction In this review, the incidence and clinical impact of

antiretroviral liver toxicity are evaluated. Furthermore, the
Highly active antiretroviral therapy (HAART) has mechanisms involved are explored, with the aim of helping
dramatically changed the course of HIV infection, having with the management of this complication.
decreased the morbidity and mortality derived from
classical opportunistic infections. As a counterweight to
this positive impact, antiretroviral therapy (ART) carries
2. Clinical impact
along undesirable effects, which challenge the management
of HIV-infected patients to a great extent. Among these,
With the widespread use of HAART and the availability
liver toxicity deserves a special attention since it often leads
of more drugs, some of them perhaps more hepatotoxic,
to HAART discontinuation; particularly in hepatitis C
HAART-linked hepatotoxicity has been made evident over
(HCV) and/or hepatitis B (HBV) co-infected patients. The
the past few years. Liver toxicity generates medical visits,
mechanisms involved in HAART-derived liver toxicity are work-up exams, and frequent hospital admissions, all of
not well understood, which makes its management more which increase expenses. In addition, hepatotoxicity
difficult. hampers the maintenance of HIV suppression over time.
In a recent American study, which evaluated the causes
of death of HIV-infected individuals, discontinuation of
* Address: Enfermedades Infecciosas, Hospital Carlos III, C/Sinesio
Delgado, 10, 28029 Madrid, Spain. Tel.: C34 91 4532500; fax: C34 91 ART due to hepatotoxicity increased from 6% in 1996 to
7336614. 31.8% in 19981999 among those mortalities [1]. More
E-mail address: m_nunez_g@hotmail.com (M. Nunez). recently, Kramer and colleagues have highlighted the
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jhep.2005.11.027
 M. Nunez / Journal of Hepatology 44 (2006) S132S139 S133

increase in the number of cases of fulminant liver failure in
HIV/HCV-coinfected individuals during the HAART era,
even after excluding patients with advanced liver disease
and adjusting by alcohol intake [2].
The severity of liver toxicity ranges from the
absence of symptoms to liver decompensation; and
the outcome, from spontaneous resolution to liver
failure and death [3]. Although in a study severe
hepatotoxicity with acute hepatic necrosis was present
in 2% of HIVC patients dying due to hepatitis or
other liver diseases, mainly among those with prior
liver disease, most cases of liver toxicity is mild-to-
moderate and asymptomatic [4].
Drug liver toxicity has impacted on the recommendations
for antiretroviral therapy in certain scenarios. Thus, the use
of nevirapine (NVP) has been recommended to be avoided
as part of post-exposure prophylaxis regimens. The reason
for that was the occurrence of fulminant hepatitis in two
cases and severe liver toxicity in 12 other healthy subjects
who received a NVP-including HAART regimen after HIV
exposure [5,6]. However, NVP seems to be safe when
administered to mother and child as a single dose for
prevention of mother-to-child HIV transmission [7].
3. Definition of liver injury
The clinician thinks of liver damage when abnormalities
in the liver tests are seen. There is a broad variability among
studies in the criteria to categorize the severity of
hepatotoxicity. We propose as the most accepted one, the
AIDS Clinical Trials Group scale of liver toxicity [8].
According to it, patients with transaminases within normal
limits at baseline are considered to develop hepatotoxicity
when ALT and/or AST rise above the upper limits of normal
(ULN). Severe hepatic injury (the primary study outcome) is
defined as grade 3 or 4 change in AST and/or ALT levels
during antiretroviral treatment. If AST and ALT grades were
discordant, the highest should be used for classification
purposes.
Many drugs increase g-glutamiltranspeptidase (GGT)
levels. This is often misinterpreted as a marker of liver
damage, but the isolated elevation of this enzyme actually

Table 1
Risk and predictor factors of liver toxicity after initiating antiretroviral therapy

Author (Ref.) No. ART HCV/HBV (%) CD4a Incidence Predictor factors
b
Rodrguez-Rosado 187 PI-based 58 26 (14%) HCV
[10]
Saves [11] 748 PI-based 41 144 67 (9%) HCV, HBV, prior
cytolysis
1249 2 NRTIs 44 234 71 (6%) HCV, HBV, prior
cytolysis
Sulkowski [9] 211 PI-based 51 109 26 (12%) HCV, HBV, [
CD4, RTV
87 2 NRTIs 61 215 5 (6%) HCV, HBV, [
CD4
Den Brinker [12] 394 PI-based 22 150 70 (18%) HCV, HBV
Saves [13] 1080 PI-based 30 290 23 (2%) HCV, HBV
Nunez [14] 222 HAART (PI, 40 337 21 (9%) HCV, age, alcohol
NNRTI)
Bonfanti [15] 1477 PI-based y50 265c NAd HCV, RTV, prior
cytolysis
DArminioMon- 1255 HAART (mainly 57 327 61 (5%) HCV, HBV, prior
forte [16] PI) cytolysis, prior
non-HAART
therapy
Aceti [17] 1325 PI-based 59 y200 42 (3%) HCV, HBV, RTV,
no response to
HAARTe
Wit [18] 560 HAART (PI, 19 170 35 (6%)f HCV, HBV, prior
NNRTI) cytolysis, NVP,
RTV (full dose),
female sex, naive
a
Median values.
b
Hepatic injury defined as at least 2-fold ALT/AST increase above baseline values.
c
Mean.
d
Incidence rate for severe hepatotoxicity 2.7 [95% CI: 2.6-2.8]; Incidence for hepatotoxicity of any grade 8%.
e
Observed after 12 months of therapy.
f
Grade 4 hepatotoxicity.
S134 M. Nunez / Journal of Hepatology 44 (2006) S132S139

reflects enzyme induction. Only when associated with a 4.2. Antiretrovirals

proportional increase in alkaline phosphatase levels should
it be considered as a cholestatic lesion. Bilirubin should not
be considered itself as indicator of liver toxicicity it can be
elevated due to a variety of reasons, such as hemolysis,
fasting and certain drugs (e.g. indinavir and atazanavir) [9].
In addition to HAART-derived hepatotoxicity, some other
conditions or drugs used in HIV infection, can cause
elevations in the levels of liver enzymes and should be ruled
out.
The results of the studies that have evaluated the risk for
liver toxicity associated with the use of particular
antiretroviral drugs or families are conflicting. The
unbalanced and often insufficient representation of some
antiretrovirals in these series, make it difficult to determine
with accuracy the role of each particular drug in the
development of liver toxicity. In addition, the use of several
antiretrovirals combined makes it difficult to ascribe the
elevation of transaminases to single drugs.

4. Incidence and risk factors 4.2.1. Protease inhibitors

The reported incidence of severe liver toxicity after
initiating HAART ranges from 2 to 18% [1019].
Differences in the study populations, as well as in the
methods used probably account for the wide range. In
Tables 1 and 2, which summarize the main trials assessing
liver toxicity in patients taking antiretroviral therapy, the
risk factors are recorded.
4.1. Hepatitis B and C co-infections
Liver toxicity, especially severe toxicity (grades 3 and 4),
is clearly more frequent in HCV and/or HBV co-infected
individuals treated with HAART [1019]. In one study, a
higher risk of hepatotoxicity was found in patients carrying
HCV genotype 3 (HCV-3) compared to other genotypes
[20]. More recently, other authors have obtained similar
findings [21]. The clinical implications of this finding are
2-fold. On one hand, the presence of HCV-3 may impact on
the selection of HAART regimen, choosing those with less
potential for hepatotoxicity. On the other hand, since
genotype 3 shows a higher response to a-interferon (IFN)
and ribavirin (RBV), anti-HCV treatment should be given if
no major contraindication is present.
The phenomenon of hepatotoxicity became more evident
after the introduction of ART of high activity, which
initially included invariably a protease inhibitor (PI).
However, none of the studies has been able to prove the
higher potential for liver toxicity of this particular family of
drugs. Among the PI, in some studies full-dose ritonavir
(RTV) has been found to be more hepatotoxic
[10,16,18,19,22], although these results have not been
confirmed by others [17,23]. In certain cases, RTV has
caused fatal acute hepatitis [24]. Several cases of liver
toxicity associated with the use of indinavir (IDV) and
saquinavir (SQV) have also been reported [25,26].
Nelfinavir was found to be less hepatotoxic than the other
PI anlyzed (RTV, IDV, SQV y amprenavir (APV)) in study
evaluating 1052 patients [27].
The use of two PI, which often includes RTV at low
doses as a booster for the second PI, does not seem to
increase the risk of toxicity for the liver [28,29]. The
incidence of liver toxicity with lopinavir (LPV), which is
given with low doses of RTV (200 mg/day) is low
[26,30,31]. Atazanavir, marketed more recently, seems
also to have a good safety profile regarding the liver, even
if used with low-dose RTV [32,33]. Tipranavir, recently
approved, appears to be more hepatotoxic, most probably

Table 2
Severe hepatotoxicity in patients treated with NNRTIs: incidence, timing and risk factors

Study (Ref.) NNRTI No. VHC/VHB (%/%) Incidence (%) Timing Risk factors
a
Martnez [31] NVP 610 46/9 12.5 4% at 3 months HCV, prolonged
ART
Palmon [33] NVP 141 12/9 1.4 (NZ3): days
EFZ 91 1.1 16, 98 and 468
DLV 40 0
Sulkowski [35] NVP 256 43/8 15.6 Md. 137 days NVP,HCV, HBV,
EFZ 312 8b Md. 100 days PI, [ CD4
Martn-Carbonero NVP 162 45 12 vs. Md. 5,5 months NVP, HCV
[36] EFZ 136 4%b Md. 5,5 months female sex, alcohol
De Maat [34] NVP 174 3.4% HBV, PI

NNRTI, non-nucleoside reverse transcriptase inhibitors; NVP, nevirapine; TAR, antiretroviral therapy; EFZ, efavirenz; DLV, delavirdine; Md, median; IP,
protease inhibitors.
a
Hepatotoxicity defined as an increase in ALT or ASTR3-fold above baseline values.
b
Statistically significant differences.
 M. Nunez / Journal of Hepatology 44 (2006) S132S139
because it is given with higher doses of RTV (400 mg/
day) [34].
4.2.2. Nucleoside analogues reverse transcriptase inhibitors
(NRTI)
Some authors have found a lower incidence of
hepatotoxicity with lamivudine (3TC) and tenofovir
[15,17]. However, the majority of the NRTI can induce
mitochondrial damage, and, therefore, have a potential for
the development of liver injury, as it will be explained
below [35]. Cases of hepatic failure have been reported in
patients taking zidovudine, but didanosine and stavudine
have been most often involved in severe hepatotoxicity [36
39]. Abacavir (ABC) and tenofovir (TDF), with low
potential for mitochondrial damage, seem to have a safer
profile regarding the liver. In patients with chronic hepatitis
B, the removal of 3TC may be accompanied by a flare of
HBV replication, translated into an increase in
transaminases.
4.2.3. Non-nucleoside analogues reverse transcriptase
inhibitors
The risk of liver toxicity associated with the non-
nucleoside analogues reverse transcriptase inhibitors
(NNRTI) is variable and involves several aspects and
mechanisms. Several cases of severe liver toxicity, some of
them fatal, in subjects receiving NVP as part of a post-
exposure prophylaxis regimen [5,6]. Likewise, in a trial
assessing the NRTI emtricitabine (FTC), a higher incidence of
hepatotoxicity was observed among patients taking NVP [40].
Of interest, in both series, the post-exposure prophylaxis and
the FTC trial, hepatotoxicity developed early into treatment,
and predominated among black women in the FTC study.
These data suggest a hypersensitivity reaction causing the
liver abnormalities. However, in other reports, the hepato-
toxicity of NVP-containing regimens had a later onset
(beyond the 4th month), with an increase in the cumulative
incidence over time [41,42]. Therefore, it looks like there is a
second mechanism through which NVP causes liver toxicity,
much more common than the hypersensitivity syndrome.
Several retrospective studies have evaluated the develop-
ment of hepatotoxicity linked to the use of NNRTI
(Table 2). In some series, the incidence of liver toxicity is
not higher compared to other antiretrovirals [41,43,44]. This
is especially true in populations with a low prevalence of
chronic HCV infection [43]. While some authors have found
a higher risk of liver toxicity for NVP compared to efavirenz
(EFZ) [45,46], others have failed to do so [43]. More
recently, in a randomized clinical trial comparing NVP
twice a day, NVP once a day and EFZ, higher incidences of
severe hepatotoxicity were seen in the NVP groups (13.8%
once a day and 7.2% twice a day) compared to the EFZ arm
[47]. However, only the differences between the once a day
NVP arm and the EFZ arm were statistically significant.
It is interesting that one of the studies did not find cross-
hepatotoxicity between NVP and EFZ [45]. In the same
S135
study, the morbidity and mortality derived from liver
toxicity among patients taking NVP or EFZ was similar.
Moreover, in a study assessing NVP hepatotoxicity,
transaminases decreased in many of the patients who
continued taking the same treatment [41].
Taken together, all these data suggest that NNRTI have a
greater risk to induce immunoallergic reactions involving
the liver soon after initiation of therapy. With prolonged
therapy, especially in HBV and/or HCV co-infected
subjects, NNRTI have a trend to cause a slight increase in
the cumulative incidence of hepatotoxicity, which may
spontaneously abate over time. Only in rare occasions is
liver toxicity serious. In particular, morbidity and mortality
linked to the use of NVP has not been proven to be superior
to those of other antiretrovirals.
4.2.4. Other factors
Heavy alcohol intake has also been identified as a risk
factor for severe hepatotoxicity in patients taking anti-
retrovirals [15,46]. Several authors have identified other risk
factors for the development of HAART-derived liver
toxicity, such as the prior presence of transaminase
elevation [12,16,17,19], older age [15], female sex
[18,46], prior monotherapy [17], first antiretroviral treat-
ment [19], lack of response to HAART (only observed at 12
months) [18], and an increase in the CD4 count after
HAART initiation [10,45]. An association between
advanced degrees of liver fibrosis and liver toxicity
secondary to NNRTI has been recently reported [48].
5. Mechanisms of liver toxicity
Despite the numerous published studies on antiretrovirals
and hepatotoxicity, many unanswered questions still
remain, in particular those related to the mechanisms
involved. The possible mechanisms involved in the
development of hepatotoxicity associated with the use of
antiretrovirals are summarized in Fig. 1. It is probable that
multiple pathogenic pathways simultaneously concur in
ALT
Direct
Mitochondrial
toxicity
toxicity Immune
reconstitution
Methadone
HBV HCV
Hypersensitivity Alcohol
reactions Insulin
resistance
Steatosis
ART
Mitochondrial
Other drugs toxicity
Concurrent HIV
diseases
Fig. 1. Mechanisms of hepatotoxicity linked to antiretroviral therapy.
HCV, Hepatitis C virus; HBV, Hepatitis B virus; ART, Antiretroviral
therapy. [This figure appears in colour on the web.]
S136 M. Nunez / Journal of Hepatology 44 (2006) S132S139
some patients, being difficult to identify the exact
mechanisms involved in the development of hepatotoxicity.
5.1. Direct toxicity
Antiretrovirals, as any other drug, can induce direct
toxicity in the liver. Drugs metabolized in the liver through
the cytocrom pathways may cause liver toxicity when there
are polymorphisms in the enzymes [49]. Since many of the
antiretrovirals are metabolized in the liver through the
cytocrome pathways, idiosyncratic polymorphisms of the
enzymatic complexes might lead to significant heterogen-
eity in drug metabolism, predisposing to the development of
hepatotoxicity in certain individuals. Some drugs may
potentiate the activation of death receptors and/or intra-
cellular stress pathways [50]. Hepatocytes promote mech-
anisms of cytoprotection against the oxidative stress caused
by drug metabolism. Heat-shock proteins, induced by
various forms of stress including drugs, may exert
cytoprotective functions helping to tolerate potentially
damaging toxicants [49]. An increase in heat-shock proteins
in individuals with polymorphisms may help the liver adapt
to and minimize drug toxicity. Anti-oxidation stress
mechanisms might explain the spontaneous normalization
in the levels of transaminases despite maintenance of
HAART, as it occurs with INH. Although still early in its
development, pharmacogenomics is a new approach, which
may be very valuable to predict the risk for hepatotoxicity in
each individual after initiation of ART [51].
5.2. Hypersensitivity reactions
Hypersensitivity reactions are idiosyncratic reactions of
the host, not related to the dose of the drug. Sulphas are
prototypical drugs inducing these immune-mediated
reactions involving the liver. They usually become apparent
within the first 46 weeks of treatment. In patients taking
NVP, the incidence of symptomatic events involving the
liver has been reported to be of 4.9% [52]. The company
marketing NVP has released a warning on the risk of severe
toxicity, in some occasions with fatal outcome, linked to the
use of NVP in women with CD4 counts O250 cells/mm
within 6 weeks after initiation of treatment, due to
hypersensitivity reactions. According to a recent analysis,
a low body mass index is an independent risk factor for this
type of events [53].
Immune mediated drug reactions seem to involve the
generation of neoantigens formed by the reaction of liver
proteins with reactive drug metabolites [49]. Assays
examining in vitro activation of peripheral blood mono-
nuclear cells against a drug or its metabolites are currently
under research. These assays are a promising approach to
identify susceptible individuals [54]. On the other hand,
individuals with the HLA-DRB1*0101 marker, especially if
they have !25% CD4 cells, have been shown to be at
greater risk of developing NVP-induced hypersensitivity
reactions [55].
Hypersensitivity reactions have been reported relatively
often with NVP and abacavir (ABC), both in HIV-infected
patients and in subjects receiving prophylaxis after HIV-
exposure [5660], but also with other antiretrovirals such as
zalcitabine (ddC) [61].
5.3. Mitochondrial toxicity
It is infrequent but a distinctive type of hepatoxicity that
may evolve to acute liver failure. Mitochondrial toxicity is
explained in another article. The main feature of the hepatic
lesion is the accumulation of microvesicular steatosis in
liver cells and mitochondrial depletion. This early lesion
may evolve to macrovesicular steatosis with focal necrosis,
fibrosis, cholestasis, proliferation of biliary ducts, and
Mallory bodies, a clinical picture resembling alcohol-
induced liver toxicity, pregnancy steatosis or Reyes
syndrome [49]. Of interest, the underlying liver disease
does not predispose to this type of lesion [49]. The ability of
NRTI to inhibit mitochondrial DNA synthesis in vitro is in
the following order: ddC, ddI, d4T, AZT, 3TCZABCZ
TDF [62]. Hydroxyurea, used as coadjuvant treatment with
ddI to enhance its activity, seems to increase the toxic effect
of some NRTI, due to the rise of intracellular levels of
5 0 tryphosphates products [63,64]. It is believed that the
cumulative exposure to NRTI is an important factor for the
development of lactic acidosis, since it usually appears after
prolonged treatment, usually years, and correlates with the
number of concomitant NRTI. In vitro data support an
additive or synergistic long-term mitochondrial toxicity
with some NRTI combinations [65].
5.4. Metabolic abnormalities
Steatohepatitis may cause hypertransaminasemia. Insulin
resistance is believed to be the metabolic hallmark of
predisposition to non-alcoholic steatohepatitis (NASH).
HAART may cause, in the context of the lipodystrophy
syndrome, marked abnormalities in the metabolism of both
lipids and glucose, including insulin resistance [66]. Mild-
to-moderate degrees of steatosis have been found in the liver
of patients experiencing HAART-derived hepatotoxicity
[67]. Thus, in some patients receiving HAART, insulin
resistance and NASH may contribute to the development of
liver toxicity.
5.5. Immune reconstitution in HCV and/or HBV-infected
patients
Liver damage induced by chronic HCV and HBV
infection is mainly immune-mediated. The immune deficit
caused by HIV infection is responsible for the attenuation of
the inflammatory reaction in the liver of co-infected
subjects. The inhibition of HIV replication with HAART
 M. Nunez / Journal of Hepatology 44 (2006) S132S139
leads to immune reconstitution, and consequently the
immune response to HCV and/or HBV antigens exposed
in the liver cell is also restored. Thus, HAART therapy may
induce the development of hypertransaminasemia and even
symptomatic hepatitis in patients with HCV [11,6872] or
HBV co-infection [73,74].
The immune reconstitution syndrome as a mechanism of
liver toxicity is controversial, but there are several data
supporting it. Markers of HCV-specific immune responses
(HCV core-specific IGG antibody), T-cell activation and
inflammation, have been found to correlate with liver
damage and immune reconstitution [75]. Some authors have
identified an increase in O50 CD4 cells per mm3 after
initiating HAART as an independent risk factor for
hepatotoxicity [10,45]. Liver histology has shown exacer-
bated viral hepatitis in some patients developing severe
hypertransaminasemia while on HAART [67]
6. Therapeutic management
The three main considerations necessary for the manage-
ment of transaminase elevation after the introduction of
HAART are severity, clinical impact and etiologic
mechanisms. Suspicion of hypersensitivity reactions or
lactic acidosis, and the presence of liver decompensation,
are all reasons to stop treatment [76]. Severe liver toxicity
(grades 34), even in the absence of symptoms warrants
discontinuation of the antiretroviral therapy.
In the remaining cases, decisions should be made on an
individual basis. If liver steatosis is present, it is indicated to
pursue the removal of predisposing factors. If the patient is
taking an antiretroviral with higher hepatotoxic potential,
substitution of that particular drug is an available option.
Regarding the continuation of the same regimen, spon-
taneous decrease of transaminases levels has been reported
[77]. However, the elevation of transaminases can persist,
and the long-term consequences are unknown. In that
regard, the finding of an association between NVP use and
hepatic fibrosis is worrisome [78]. Nevertheless, this is a
single study, and its results should be confirmed by other
investigations.
Acknowledgements
Financial support: Instituto de Salud Carlos III (file#
02/3040); AIES; and Red Tematica de Investigacion en
SIDA (RIS).
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