Clinical Syndromes and Consequences of
Marina Nu ´n ˜ez
Highly active antiretroviral therapy (HAART)-related hepatotoxicity complicates the man-
agement of patients infected with human immunodeficiency virus (HIV), increases medical
costs, alters the prescription patterns, and affects the guideline recommendations. Among
the clinical consequences derived from HAART-related liver toxicity, hypersensitivity reac-
tions and lactic acidosis are recognized as acute events with potential to evolve into fatal
cases, whereas there seems to be other syndromes not as well characterized but of equal
concern as possible long-term liver complications. Belonging to the latter category of syn-
drome, HAART-related nonalcoholic steatohepatitis, liver fibrosis, portal hypertension,
and nodular regenerative hyperplasia are discussed in this review. Updated information on
liver toxicity of current antiretroviral drugs, including the most recently licensed, is pro-
vided. Management and prevention of liver toxicity among HIV-infected patients treated
with HAARTare reviewed as well. (HEPATOLOGY 2010;52:1143-1155)
preted and managed. New hepatic problems which
might be related to the use of highly active antiretrovi-
ral therapy (HAART) continue to be revealed. In addi-
tion, new antiretrovirals have been licensed for which
information on liver safety is limited. I refer to past
reviews for previous information on the subject.1-8Af-
ter those publications, prescription patterns and guide-
line recommendations have continued to evolve, and
physicians treating HIV in 2010 manage new antire-
troviral drugs and new aspects of the epidemics.9This
review focuses on the clinical consequences of liver
toxicity associated with HAART, updates information
on the subject, and includes liver safety data of most
recently approved antiretroviral drugs. This article
hysicians treating human immunodeficiency vi-
rus (HIV)-infected patients often deal with ami-
notransferase elevations which have to be inter-
aims to help health care providers prevent and handle
antiretroviral toxicity within contemporary manage-
ment of patients with HIV.
accepted definition of drug hepatotoxicity or drug-
induced liver injury, another term used to refer to the
liver disturbances caused by drugs. Although alkaline
phosphatase elevation can be also a marker of liver
toxicity (and it is very prominent in cases with a
mixed or cholestatic pattern), aminotransferase eleva-
tion reflecting hepatocellular injury is more commonly
used as definition of hepatotoxicity.10The AIDS Clini-
cal Trials Group criteria11grades it according to the
following score system: grade 1 (1.25?-2.5? upper
limit of the normal range [ULN]); grade 2 (2.6?-5?
ULN); grade 3 (5.1?-10? ULN); and grade 4
(>10? ULN). Some authors have proposed to score
HAART-related hepatotoxicity according to baseline
levels in subjects having abnormal liver enzyme values
at baseline: grade 1 (1.25?-2.5? baseline); grade 2
(2.6?-3.5? baseline); grade 3 (3.6?-5? baseline);
and grade 4 (>5? baseline).12The presence of jaun-
dice along with high aminotransferase levels is associ-
ated with a poor prognosis (?10% mortality), a phe-
nomenon known as ’’Hy’s rule’’ in honor of the
pioneer researcher Hyman Zimmerman. The validity
of Hy’s rule, first proposed in the 1970s has been con-
firmed by more recent studies.13
isnot anuniformand internationally
Abbreviations: ALT, alanine aminotransferase; d-drug, dideoxynucleoside
drug; FDA, U.S. Food and Drug Administration; HAART, highly active
antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV,
human immunodeficiency virus; HLA, human leukocyte antigen; NASH,
nonalcoholic steatohepatitis; NNRTI, non-nucleoside reverse transcriptase
inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease
inhibitor; ULN, upper limit of the normal range.
From the Wake Forest University Health Sciences, Winston Salem, NC
Address reprint requests to: Marina Nu ´n ˜ez, M.D., Ph.D., Department of
Internal Medicine, Section on Infectious Diseases, Wake Forest University
Health Sciences, Medical Center Boulevard, Winston Salem, NC 27157.
E-mail: firstname.lastname@example.org; fax: 336-716-3825.
View this article online at wileyonlinelibrary.com.
Potential conflict of interest: Nothing to report.
C 2010 by the American Association for the Study of Liver Diseases.
Challenges in Causality Assessment
There is difficulty discerning and dissecting out the
number of individual factors that may contribute collec-
tively to liver damage in patients receiving antiretroviral
therapy. Several drugs are combined in a given HAART
regimen making difficult the attribution of hepatotoxic-
ity to a particular drug. Moreover, HIV-infected
patients may be receiving concurrent medications with
potential for liver toxicity as well, such as antimycobac-
terial drugs, lipid-lowering agents, antifungals, antibiot-
ics, and anticonvulsants. It is also difficult to make com-
parisons among reported cohorts, because individuals
often differ on the factors predisposing to elevations of
liver enzymes, like the presence/absence of concurrent
viral hepatitis. Biochemical, pharmacokinetic/dynamic,
and pathological correlations of HAART hepatotoxicity
have been poorly characterized, which makes it often
difficult to determine the true incidence of drug-
induced liver injury. In many instances, the hepatotoxic
potential of a drug has been recognized only after post-
marketing experience with the drug.
Risk Factors for HAART-Related
reported to increase the risk of severe HAART hepato-
toxicity (relative risk ¼ 2.1).14There is an estimated
2.7-fold to 5-fold increased risk of severe alanine ami-
notransferase (ALT) elevation on HAART with hepati-
tis C virus (HCV) coinfection.15-17Chronic hepatitis
B virus (HBV) infection appears to also carry a higher
risk, with a 9.2 hazard risk of grade 4 liver enzyme ele-
vations reported in one study.17The same authors also
observed that discontinuing lamivudine, an antiretrovi-
ral also active against HBV, was a factor associated
with aminotransferase elevation in HIV/HBV-coin-
fected patients (hazard risk ¼ 6.8 for grade 4 liver tox-
icity).17The presence of underlying liver inflammation
as reflected by elevated ALT at baseline has been also
identified as a risk factor for HAART liver toxicity.16,17
Isolated studies have identified additional host factors
including older age, female sex, thrombocytopenia, re-
nal insufficiency, high HIV RNA levels, increased
body mass index, and non-black ethnicity.15-18
Aside from host factors, several individual antiretrovi-
rals or classes have been independently associated with
HAART hepatotoxicity, such as nevirapine, protease
inhibitors, high doses of ritonavir (?600 mg/day), and
prolonged zidovudine or stavudine exposure.14,17,18
Alcohol use and concurrent hepatotoxic medications are
additional factors identified.15,16,18Lastly, an increase in
viral hepatitishas been consistently
CD4 cell counts of >50 cells/mm3after HAART initia-
tion was associated with almost two-fold increased risk
of severe ALT elevation in one study.14Other risk fac-
tors individual to each pathogenic mechanism are cov-
ered within its corresponding section.
Mechanisms of HAART-Related
A major challenge for mechanistic classifications is
that the pathogenesis of drug hepatotoxicity is poorly
understood in many instances. It involves several
mechanisms, regulatory systems, and risk factors with
complex interactions.19Hepatotoxicity events are more
often idiosyncratic, that is, they are unpredictable and
occur with variable latency and low incidence.10Idio-
syncratic drug-induced liver injury can be further clas-
sified as allergic and nonallergic.20The pathogenesis of
drug hepatotoxicity involves exposure to the toxic
agent (the parent drug or most often a reactive metab-
olite), the amount of which depends on genetically
determined metabolism of the agent by the liver. Fol-
lowing exposure, the toxic moiety induces some type
of stress or functional disturbance, with mitochondrial
injury being one of the most important targets recog-
nized.21,22A number of adaptation mechanisms are
then initiated to counteract the inflicted damage.23,24
In addition, innate and adaptive immune responses are
other factors of interest which determine the progres-
sion and severity of liver injury.25,26Detailed reviews
focusing on pathogenesis and mechanisms of drug-
induced liver injury are available elsewhere.10,19,20,27
Liver toxicity caused by antiretroviral therapy can be
inflicted through several mechanisms. The pathogenesis
often remains enigmatic. Table 1 summarizes the mech-
anisms of HAART-related liver toxicity by antiretroviral
class. Five categories are proposed: hypersensitivity reac-
tions, direct mitochondrial inhibition, disturbances of
lipid/sugar metabolism and steatosis, direct cell stress,
and immune reconstitution in the presence of viral hep-
atitis coinfection. Despite the limitations of the classifi-
cation, which ultimately is merely descriptive, it may be
useful in clinical practice because it describes typical
clinical characteristics of hepatotoxicity for specific anti-
retrovirals or classes and might give hints on the mecha-
nism, ultimately helping the management.
As reflected in Table 1, some antiretrovirals or classes
may be toxic for the liver through different pathways, a
hepatotoxicity in general.19Immune reconstitution in
the setting of viral hepatitis is a mechanism of amino-
transferase elevation shared by all antiretrovirals, just
1144NU´N˜EZHEPATOLOGY, September 2010
because is the result of an effective HAART.28Distur-
bances in lipid and sugar metabolism which seem to be
contributors to a not well-defined steatohepatitis syn-
drome can be caused by all or several members in three
antiretroviral classes: nucleoside reverse transcriptase
inhibitors (NRTIs), non-nucleoside reverse transcriptase
inhibitors (NNRTIs), and protease inhibitors (PIs).29
Mitochondrial liver toxicity leading to steatosis and lac-
tic acidosis, which is secondary to mitochondrial RNA
depletion by NRTI use, is particular to that class.30
Hypersensitivity reactions with liver involvement are
common to NNRTIs but are possible also for specific
drugs in other classes.31-37Direct liver cell stress, which
is dose-dependent, seems to be the underlying mecha-
nism of liver toxicity of ritonavir and tipranavir.8,38,39
Of note, higher boosting doses of ritonavir (400 mg/
day) increase toxicity, whereas liver safety using ?200
mg/day is comparable to that of nonboosted PIs.8,38
Drug-to-drug interactions can increase the potential
for hepatotoxicity as in the case of stavudine and dida-
nosine.40,41In a similar manner, ribavirin, which is
given for the treatment of HCV, should not be given
concomitantly with stavudine because there is risk of
liver decompensation, especially in cases of advanced
Liver Safety Profile of FDA-Approved Antire-
Table 2 summarizes the information provided in the
package inserts of all antiretroviral drugs approved to
date by the U.S. Food and Drug Administration
(FDA).31-37,43-58Unfortunately, the information is het-
erogeneous and often scattered, which makes it diffi-
cult to compare the potential for hepatotoxicity across
antiretrovirals. Most recently marketed drugs tend to
provide separate data for subjects coinfected with viral
hepatitis, whereas prescribing information of older
drugs includes information on liver side effects which
only have been revealed after extensive use. The liver-
related black box warnings (see note at the end of this
article) are based on reports of lactic acidosis with liver
damage in the case of NRTIs, on hypersensitivity reac-
tions secondary to drugs from three different classes,
and on direct toxicity for didanosine (NRTI) and
tipranavir/ritonavir (PI). Mitochondrial liver toxicity
has motivated a mandatory black box warning across
the class, although the potential toxicity is not homo-
geneous for the various NRTIs.
Clinical Syndromes of HAART-Related
The full extent of hepatic damage related to
HAART use has not been fully elucidated. Although
there are acute events which have been clearly recog-
nized, other syndromes are less evident at this time.
The most relevant issues are addressed in this section.
Hypersensitivity Reactions. Hypersensitivity reac-
tions are idiosyncratic reactions of the host, not related
to the dose of the drug, and are immune-mediated.
They involve the generation of neoantigens formed by
the reaction of liver proteins with reactive drug
Table 1. Mechanisms of liver toxicity by antiretroviral class
Mechanisms of HAART-Related Liver Toxicity
Disturbances and Steatosis
in Viral Hepatitis
Possible for all
D-drugs > the
All Possible for allNevirapine
Possible for all
PIs > non-ritonavir-boosted PIs
D-drugs: dideoxinucleosides (didanosine, stavudine, zalcitabine); zalcitabine has been removed from the market.
HEPATOLOGY, Vol. 52, No. 3, 2010NU´N˜EZ 1145
metabolites.59They usually occur within the first 4-6
weeks of treatment. These hypersensitivity reactions
with liver involvement have resulted in black box
warnings for three drugs: nevirapine, abacavir, and
maraviroc. Acute hepatitis leading to liver failure with
fatal outcome in the context of a hypersensitivity drug
reaction has been reported with nevirapine and abaca-
vir, both in HIV-infected patients and in subjects
receiving prophylaxis after HIV exposure.60-64Nevira-
pine discontinuation due to hypersensitivity-related
skin rash occurs in 5%-7% of patients.65-68It is
unknown how many of those allergic reactions are
accompanied by liver involvement; however, statisti-
cally significant association between the two events has
been reported, with skin rash preceding liver toxicity.69
Abacavir discontinuations due to hypersensitivity reac-
tions range between 5% and 8%.70,71With widespread
human leukocyte antigen (HLA)-B*5701 testing, the
incidence is expected to be currently much lower (see
below). There has been one reported case of fatal hep-
atitis with allergic features possibly related to mara-
viroc in an HIV-1–negative volunteer.36Cases of acute
hepatitis and liver failure with characteristics of hyper-
sensitivity reaction have also been reported with efavir-
enz.72,73Severe elevation of aminotransferases along
with skin rash has been reported as well in HIV-nega-
tive individuals receiving ritonavir-boosted fosamprena-
vir as part of a postexposure prophylaxis regimen.74
Aminotransferase elevation in the setting of skin rash
suggesting a hypersensitivity reaction has also been
Table 2. Information on Hepatotoxicity Reported in the Full U.S. Prescribing Information of FDA-Approved Antiretrovirals
Increased Risk in
Other Groups with
High Risk of Hepatotoxicity
Black Box Warning
þDDI 6 D4T, pregnancy
þOther hepatotoxic drugs
Higher CD4counts, F>M
Non-HIV postexposure prophylaxis
2.4%Insufficient data– Yes1
*Grade 3-4 AIDS Clinical Trials Group (ACTG) ALT elevation (>5? ULN) unless stated otherwise.
**Grades 2-4 ACTG ALT elevation (>2.5? ULN).
***Defined as shifts from grade 0 at baseline to at least grade 3 (>5? ULN) or from grade 1 (1.25?-2.5? ULN) to grade 4 (>10? ULN).
¶Symptomatic events: 1%-11%.
¶¶Ritonavir boosting doses most often 200 mg/day except with atazanavir (100 mg/day) and tipranavir (400 mg/day).
¶¶¶Includes data on 400 mg/day dose of ritonavir.
1Hypersensitivity reactions with liver involvement.
3Increased risk of liver failure with/without fatal outcome in patients with underlying liver disease.
4Risk of liver decompensation in patients treated for HCV with interferon and ribavirin.
5Hepatic failure reported postmarketing.
6Contraindicated in patients with moderate-severe liver impairment.
ALT, alanine aminotransferase; D4T, stavudine; DDI: didanosine; FDA, U.S. Food and Drug Administration; HU, hydroxyurea.
1146NU´N˜EZHEPATOLOGY, September 2010
reported with darunavir, which has prompted a warn-
ing by the FDA.75
The risk of hypersensitivity-related severe hepatic tox-
icity with a nevirapine-based regimen, in some occa-
sions with fatal outcome, is higher among patients naı ¨ve
for antiretroviral therapy with CD4 counts >250 cells/
mm3for women and >400 cells/mm3for men, but can
also occur with any CD4 count.76They occur almost
exclusively within the first 6 weeks of nevirapine treat-
ment. Low body mass index is an independent risk fac-
tor for this type of event.69Individuals with HLA-
DRB1*0101 and >25% CD4 cells have the greatest
risk of developing nevirapine -induced hypersensitivity
reactions.77Other HLA haplotypes have been reported
more recently to be associated with a higher risk of
hypersensitivity reactions to nevirapine.78,79
authors have suggested that these events do not occur in
antiretroviral-experienced patients in whom nevirapine
is initiated, although this seems to be the case only
when HIV load is undetectable.65,80,81Of note, life-
threatening events of hypersensitivity hepatotoxic reac-
tions in non–HIV-infected subjects who took nevira-
pine as part of postexposure prophylaxis regimens led to
contraindicating the drug in that setting.82
A genetic predisposition has been identified for
hypersensitivity reactions to abacavir, which can be
identified through a pharmacogenetic test.83Thus,
HLA-B*5701 screening has been shown to reduce the
risk of hypersensitivity reaction to abacavir, with a
reported negative predictive value for immunologically
confirmed hypersensitivity reaction of 100% in white
and black individuals.70,84The positive predictive
value of a positive HLA-B*5701 result is much lower,
with 55% of those carrying the allele able to tolerate
abacavir; however, it is not recommended to use abaca-
vir in those at risk.70
Lactic Acidosis with Hepatic Steatosis. There is an
infrequent but distinctive type of severe hepatotoxicity
involving mitochondrial damage, clinically defined by
lactic acidosis and hepatic steatosis which evolves to
acute liver failure and carries a high mortality. The
main feature of the hepatic lesion is microvesicular or
macrovesicular steatosis and mitochondrial depletion
in liver cells. Focal necrosis, fibrosis, cholestasis, prolif-
eration of biliary ducts, and Mallory bodies may
appear if the process evolves.30,59,85,86Mitochondrial
abnormalities are seen by electron microscopy.87
NRTIs are implicated as causal agents, which subse-
quently served as motivation for the generalized black
box warning for all NRTIs regardless of each drug’s
potential for mitochondrial toxicity. The pathogenesis
of this syndrome has not yet been completely eluci-
dated. Severe mitochondrial injury of the hepatocytes
secondary to NRTIs has been reported in asymptom-
atic patients with normal lactic acid levels and in the
absence of steatohepatitis.88
The hepatic abnormalities in lactic acidosis second-
ary to NRTI toxicity have been described in a system-
atic review of cases reported in the literature which
included 90 patients with lactic acidosis.85Laboratory
evidence of mild to moderate hepatic dysfunction was
present in 41 of the 63 cases (65%) in whom informa-
tion was given, with median (range) aminotransferase
values between 1.5 and 2.5 (1.4-10.7) times above the
ULN. Of 39 premortem or necropsy liver biopsies, 36
(92%) had hepatic steatosis: macrovesicular steatosis in
12 (31%), microvesicular steatosis in eight (21%), and
with a mixed pattern in 16 (41%). The other three
biopsies showed inflammation and hepatic fibrosis.
Mortality was 48% in this review of cases.
Lactic acidosis has been reported in persons receiving
both single-NRTI and dual-NRTI regimens including
combinations of zidovudine or stavudine with didano-
sine, zalcitabine, or lamivudine.86The role of each spe-
cific NRTI in the development of lactic acidosis is often
difficult to determine because the patients might have
been exposed to several NRTIs and frequent changes in
medications are made. Nevertheless, it is known that
the dideoxynucleosides (d-drugs) have a higher poten-
tial for mitochondrial toxicity with greater ability to
inhibit mitochondrial DNA synthesis in vitro and
in vivo.30,85,86,89Several cohorts suggest that the coad-
ministration of stavudine and didanosine is associated
with the greatest relative risk.40,41Of note, this drug
combination is contraindicated by the guidelines due to
high risk of lactic acidosis.9Hydroxyurea, which was
used in the past as adjuvant treatment with didanosine,
increases its toxic effect due to the rise of intracellular
levels of 50-triphosphate products.90,91Cumulative ex-
posure to NRTI is another factor believed to be impor-
tant for the development of lactic acidosis.85,92In addi-
tion, lactic acidosis appears to be more common in
women and the obese.85,86,93An increased risk of lactic
acidosis among pregnant women being treated with
didanosine and stavudine has been also reported.43,46A
contribution to the pathogenesis of lactic acidosis of
HIV and HCV has been suggested but it has not been
Progressive Liver Damage
Increased Liver Fibrosis in Patients with Chronic
HCV? In a retrospective and cross-sectional study in
which liver biopsies from 152 HIV/HCV-coinfected
HEPATOLOGY, Vol. 52, No. 3, 2010 NU´N˜EZ1147
patients were evaluated, associations between acceler-
ated fibrosis progression and nevirapine, and between
slower fibrosis progression and PI use were found.94As
recognized by the authors, this study has several limita-
tions, including biases in the selection of the study
population and lack of evidence of linear progression
of HCV-related liver fibrosis. The number of patients
in the nevirapine and efavirenz groups was low. In
addition, the effect of NRTIs was not evaluated, and
the variables exploring the effect of antiretroviral drugs
on liver fibrosis were categorical, and therefore did not
take into account the duration of exposure. Three
other retrospective cross-sectional studies do not sup-
port those results.95-97Therefore, based on the avail-
able data, we cannot affirm that nevirapine accelerates
For the effect of antiretroviral therapy to be assessed,
it is necessary to take into account additional factors
which may have opposite effects on fibrosis progression
rate. Thus, adequate control of HIV replication has
been shown to be associated with lower necroinflam-
matory scores, slower liver disease progression, and
decreased mortality, whereas alcohol intake contributes
to more advanced fibrosis.96-99Therefore, in order to
determine a possible negative impact of antiretroviral
drug(s) on the liver disease of HIV/HCV-coinfected
patients, longitudinal studies with pathology informa-
tion and inclusion of multiple factors in the analysis
would be most valuable. The role of transient elastog-
raphy as a noninvasive tool for monitoring of liver dis-
ease progression remains to be elucidated.
Portal Hypertension and Nodular Regenerative
Hyperplasia. Of more concern is the report by Span-
ish authors of nine cases of portal hypertension com-
plicated by variceal bleeding, ascites, or hepatic ence-
phalopathy without known
disease.100,101Five patients were thought likely to have
fibrosis, either through liver biopsy or transient elas-
tography. Of note, portal thrombosis occurred in six
cases. All patients had maintained prolonged viral sup-
pression under HAART. Through a case-control study,
the researchers identified prolonged didanosine use as
the only factor associated with these cases of crypto-
genic liver disease.
In a separate report, French authors described eight
HIV-infected patients who developed portal hyperten-
sion, and liver biopsy revealed nodular regenerative
hyperplasia.102As a result, three of the patients were
included in a liver transplant list. Like in the Spanish
cases, all patients had well-controlled HIV replication
and had been exposed to didanosine. The authors dis-
cuss that nodular regenerative hyperplasia appears to
have a vascular etiology, with occlusion of terminal
branches of the hepatic arterioles and portal venules.
They speculate that HIV infection and antiretroviral
drugs, in particular didanosine, could contribute to the
production of thrombotic intrahepatic phenomena
leading to liver damage and portal hypertension.
The reports prompted other groups to communicate
23 additional cases of symptomatic liver disease which
have been subsequently published.103-107Common pa-
thology findings for those cases included compressed
liver cells, sinusoidal dilation (with or without nodular
regenerative hyperplasia), and in some cases also fibro-
sis. In several cases, there was also portal thrombosis.
More recently, focal fibrous obliteration of small portal
veins has been recognized in some of these cases.108
Most of those cases had a history of didanosine use,
often over 2 years. The growing cumulative data is of
concern for a possible new form of liver toxicity of the
drug. In a recent nested case-control study, the associa-
tion of noncirrhotic portal hypertension with pro-
longed didanosine use was very robust.109Interestingly,
a report of ’’fatal portal hypertension’’ had already
been reported in 2001 by Australian investigators.110
The patient had been exposed to didanosine and sta-
vudine for 14 months. Of concern, the subject had
been off therapy for more than 2 years when he died
due to variceal hemorrhage, suggesting that the
changes in the liver leading to portal hypertension are
irreversible. Further research is needed to sort out the
link of didanosine (or dideoxynucleosides) with this
complication, in particular, the question of which are
the additional required predisposing factors. In this
regard, several individuals in one of the case series of
nodular regenerative hyperplasia had thrombophilic
Nonalcoholic Steatohepatitis. Nonalcoholic steato-
hepatitis (NASH) is the result of complex metabolic
disturbances in which lipid and carbohydrate metabol-
ysis pathways are altered.111HAART has been shown
to alter both metabolic systems.29Although HAART-
related NASH has thus far not been defined as a spe-
cific entity, there are data supporting the contribution
of HAART to the development of liver steatosis which
as a result can lead to inflammation and fibrosis.112
Steatosis in HIV-infected patients has been reported
to be independently associated with the use of dideox-
ynucleosides and occasionally of other NRTIs.113-118
However, other studies have not found such an associ-
ation.119,120NRTIs can cause mitochondrial toxicity
and steatohepatitis in a condition reflective of dimin-
ished mitochondrial beta-oxidation of fatty acids.121,122
1148 NU´N˜EZHEPATOLOGY, September 2010
In an in vitro study, incubation with high concentra-
tions of stavudine can rapidly induce accumulation of
authors have found no correlation between mitochon-
drial function or DNA and the presence of NASH.112
Steatosis may be part of a metabolic syndrome asso-
ciated with HAART. Thus, hyperglycemia, overweight,
and insulin resistance have been associated with
liver steatosis in treatment-experienced HIV-infected
patients.112,114Several studies assessing liver histopa-
thology have found NASH in more than half the
HAART-treated HIV-infected patients who underwent
liver biopsy due to chronic unexplained aminotransfer-
ase elevation, some of them also with lipodystro-
phy.112,124,125Significant liver fibrosis, and even cir-
rhosis,has been recognized
patients.111NASH can also worsen HCV-related liver
disease.126-129Thus, liver steatosis was reported to be
present in 40%-61% of patients and associated
with higher degrees of liver fibrosis in two HIV/HCV-
in someof those
Clinical Consequences of HAART-Related
The clinical consequences of HAART-related hepa-
totoxicity are summarized in Table 3. Even if we were
to assume that asymptomatic aminotransferase eleva-
tion is not clinically relevant for the patient, it at least
increases costs due to additional tests and clinic visits,
and medication changes. It also alters the prescription
patterns and has an impact on the recommendations
of antiretroviral treatment issued in official guidelines.
HAART hepatotoxicity may have devastating conse-
quences. Although infrequent, symptomatic acute hep-
atitis can evolve into liver failure and result in death.
As elaborated in previous sections, some ’’chronic hep-
atotoxicity syndromes’’ are also of concern and can
lead to severe liver complications and death.
Prevention and Management of HAART
General rules for the management of severe HAART
hepatotoxicity (grades 3 and 4) are summarized in Fig.
1. The prevention and management strategies address-
ing specific HAART hepatotoxicity syndromes are out-
lined in the following sections.
Hypersensitivity Reactions with Liver Involve-
ment. HLA-B*5701 screening is an effective way to
prevent exposure to abacavir in susceptible sub-
jects.70,84A close follow-up and selection of patients
with lower CD4 counts in antiretroviral-naı ¨ve patients
can minimize the risk of nevirapine-related idiosyn-
cratic reactions with liver involvement. It is unclear if
this also applies to treatment-experienced subjects,
although it seems prudent to take the same precaution
when there is not complete viral suppression.65,80,81
For other drugs able to cause liver hypersensitivity
reactions, close follow-up is recommended during the
first weeks of treatment, with liver enzymes tested if
the patient develops an allergic rash.
Should a hypersensitivity reaction develop, the sus-
pected drug and all the other components of HAART
should be discontinued (Fig. 1). A new regimen can
be restarted when symptoms resolve. If the patient
develops hepatic failure, supportive treatment is rec-
ommended along with discontinuation of HAART
and, if possible, other hepatotoxic drugs.9
Lactic Acidosis with Hepatic Steatosis. Cases of
lactic acidosis with acute hepatitis and hepatic steatosis
are likely in decline because d-drugs have been dis-
placed by NRTIs that are less toxic for the mitochon-
dria. Thus, the preferred NRTI combination currently
includes tenofovir, which does not affect mitochondrial
DNA content or level of mitochondrial enzymes in
liver cells, and emtricitabine, which has a low potential
for mitochondrial toxicity.9,30,89,130Guidelines contra-
indicate the combination of two d-drugs.9Individual
use of those drugs should also be discouraged, consid-
ering the availability of many other compounds.
If severe lactic acidosis occurs in a clinical setting in
which this syndrome is highly suspected, all antiretroviral
drugs should be discontinued.9However, it is important
to note that the diagnosis is established by clinical corre-
lations, drug history, and lactate level, and interpretation
of high lactate level should be done only in the context
of clinical findings. Management includes symptomatic
support with fluid hydration, intravenous bicarbonate
infusion, hemodialysis or hemofiltration, parenteral nutri-
tion, or mechanical ventilation depending on the severity
of the syndrome.30,85,86,90,92,93Intravenous administration
Table 3. Negative Clinical Implications of HAART-Related
Clinical PracticeClinical Outcomes
Additional visits and tests for work-up
Acute liver failure with
or without death
Package inserts increase patient anxiety
Changes of HAART regimens
Changes in prescription patterns
Impact on treatment guidelines
HEPATOLOGY, Vol. 52, No. 3, 2010 NU´N˜EZ 1149
of thiamine and/or riboflavin has been reported to rap-
idly resolve hyperlactatemia in isolated cases.131After the
acute phase, HAART can be resumed using NRTIs with
less propensity for mitochondrial toxicity (e.g., tenofovir,
lamivudine, emtricitabine, abacavir) or NRTI-sparing reg-
imens.9Close monitoring of serum lactate after restarting
NRTIs has been recommended, although its interpreta-
tion has to be done in accordance with clinical status,
because the meaning of elevated lactate levels in asymp-
tomatic patients is unknown at this time.
Direct Liver Toxicity. Antiretrovirals able to inflict
direct liver cell stress can cause symptomatic hepatitis.
HAART discontinuation is warranted (Fig. 1). How-
ever, other causes should be ruled out such as alcohol
use, other hepatotoxic drugs, acute viral hepatitis, and
in the presence of HBV coinfection, withdrawal of an
active anti-HBV agent (i.e., lamivudine, emtricitabine
or tenofovir) or development of HBV resistance. After
symptoms subside and serum aminotransferases return
to normal, a new antiretroviral regimen without the
potential offending agent(s) can be constructed.
Whether asymptomatic patients with elevated amino-
transferases in the presence of an agent with potential
for direct hepatotoxicity should discontinue current
HAART and start a new antiretroviral regimen without
the offending agent is an undecided matter. Amino-
transferase elevation >10? ULN even in the absence of
symptoms is considered enough reason to stop the
agent. However, although some physicians may consider
discontinuing antiretrovirals if ALT level is >5?10?
ULN, others may continue therapy with close monitor-
ing unless direct bilirubin is also elevated.9In selected
cases, such as in the absence of other options due to
extensive antiretroviral exposure and intolerance or
resistance to other drugs, the latter option might be
justified. In this era of availability of multiple antiretro-
virals, maintaining a patient with chronic aminotrans-
ferase elevationon an
antiretroviral is becoming less and less justified.
Patients with Concurrent Chronic Viral Hepatitis
Infection(s). Patients with concurrent HCV infection
have higher risk of HAART-related aminotransferase
Fig. 1. Algorithm for the management of severe HAART-related toxicity.
1150NU´N˜EZ HEPATOLOGY, September 2010
elevation.1,2,5-7,12Although caution is recommended
with NNRTIs in HCV-coinfected patients, the class
should not be used in patients with cirrhosis, especially
if Child-Pugh stage is B or C. Tipranavir, which is
used with high doses of ritonavir for boosting, is con-
traindicated in patients with cirrhosis.9Several other
drugs should be used with caution in patients with
underlying liver disease (Table 2). On the contrary, ral-
tegravir has been shown to have an excellent liver
safety profile in HCV/HIV-coinfected subjects.132
With HBV/HIV coinfection, a regimen which con-
tains anti-HBV active drugs (tenofovir, emtricitabine,
lamivudine) is recommended with the purpose of also
controlling HBV replication.9As long as that is
achieved, patients should not have higher risk of
HAART hepatotoxicity than those with HIV monoin-
fection. However, if cirrhosis is present, the same
restrictions for tipranavir and the NNRTI class apply.
In like manner, other drugs better suit HIV-infected
subjects on concurrent treatment with drugs with high
potential for hepatotoxicity (e.g., isoniazide).
Immune reconstitution that causes aminotransferase
elevation in the presence of HBV-coinfection is a
known phenomenon which results from increased T
cell activation against viral particles.28Elevated amino-
transferases and high levels of HBV DNA at baseline
seem to be predisposing factors.28At present, there are
no recommendations for the prevention of this type of
event. However, because HBV DNA levels at week 4
of HAART treatment are higher in patients with he-
patic flare-ups,105achieving prompt and complete
HBV suppression might be the best way to minimize
these HAART-related hepatic flare-ups. That is more
likely to be achievable with a regimen including teno-
fovir in patients with high HBV DNA levels. Should a
hepatic flare occur in a HBV-coinfected patient, it is
expected to spontaneously resolve while continuing on
HAART, as long as control of HBV replication is
Steatohepatitis. To prevent steatohepatitis, control
of hyperglycemia, hyperinsulinemia, and hyperlipid-
emia should be pursued in patients with the metabolic
syndrome. Certain antiretrovirals may help that pur-
pose. At present, raltegravir is the HAART ’’third
agent’’ with the most benign lipid safety profile and
should be strongly considered in patients with underly-
ing obesity, insulin resistance, or lipid abnormalities.
Unboosted atazanavir also has a good lipid safety pro-
file, but its use without ritonavir places it in the cate-
gory of ’’acceptable regimen’’, meaning that it may be
selected for some patients but is a less satisfactory regi-
men.9Alternatively, ritonavir-boosted atazanavir and
ritonavir-boosted darunavir have the most favorable
lipid safety profile among the boosted PIs.
The same recommendation applies to patients who
already have developed NASH, in an attempt to mini-
mize the hyperlipidemia. To date, NASH has proven
to be a difficult disease to treat. Lifestyle modifications
resulting in weight loss through decreased caloric
intake and moderate exercise is generally believed to
be beneficial in patients with NASH, but is often diffi-
cult to maintain in the long term.133Given that insu-
lin resistance plays a dominant role in the pathogenesis
of NASH, many studies have examined the use of in-
sulin sensitizers. Results with metformin (a biguanide)
have been heterogeneous, most studies have been small
and have flaws in the design, and its effect may be
largely related to its ability to induce weight loss.134-
138Data with thiazolidinediones (pioglitazone, troglita-
zone, and rosiglitazone) for the treatment of NASH
are more robust.139-142However, it is unclear whether
a thiazolidinedione-associated increase in adiposity and
weight gain would ultimately limit its benefits.133In
addition, long-term toxicities of these agents include a
potential for cardiovascular events and fracture risk.
Therefore, we need more information regarding the ef-
ficacy and safety of these agents before recommenda-
tions for safe use can be made.
Portal Hypertension and Nodular Regenerative
Hyperplasia. Available information
didanosine as the antiretroviral agent linked to cases of
noncirrhotic portal hypertension, which should dis-
courage use of this agent.100,109With the continued
decrease in its use, this complication should fade away
and disappear over time. A conclusion which may be
drawn from these cases of nodular regenerative hyper-
plasia is the need to obtain image studies, and in
selected cases, also liver biopsy for diagnosis when
HIV-infected patients have persistent and unexplained
liver enzyme elevation while on HAART. Strategies for
the management of noncirrhotic portal hypertension
include placement of transjugular intrahepatic porto-
systemic shunt (TIPS) and liver transplant.143,144Anti-
coagulant therapy with low-molecular-weight heparin
is a more specific treatment for this entity which has
been recently reported.145
HAART hepatotoxicity complicates the management
of HIV-infected patients, increases medical costs, alters
the prescription patterns, and has an impact on official
treatment recommendations. Several mechanisms of
liver toxicity in patients receiving HAART have been
HEPATOLOGY, Vol. 52, No. 3, 2010 NU´N˜EZ1151
recognized. Although infrequent, HAART-related liver
damage may have devastating consequences. Among
clinical syndromes of HAART liver toxicity, hypersen-
sitivity reactions and lactic acidosis are recognized as
acute events with potential to evolve into fatal cases,
whereas there are other syndromes not as well charac-
terized but of equal concern as possible long-term liver
NASH, liver fibrosis, portal hypertension, and nodular
regenerative hyperplasia are discussed. Prevention is
the best strategy to minimize the cases of hepatotoxic-
ity and includes recognition of antiretrovirals’ liver
safety profile and of susceptible hosts. Management of
hepatotoxic events includes discontinuation of sus-
pected culprits and changes in HAART regimens as
well as identification of mechanisms involved and
treatment of specific disorders.
NOTE: Definition of boxed warning as it is found in
the Code of Federal Regulations Title 21, Volume 4
(chapter 1, subchapter c): (1) Boxed warning. Certain con-
traindications or serious warnings, particularly those that
may lead to death or serious injury, may be required by
the FDA to be presented in a box. The boxed warning or-
dinarily must be based on clinical data, but serious animal
toxicity may also be the basis of a boxed warning in the
absence of clinical data. The box must contain, in upper-
case letters, a heading inside the box that includes the
word ’’WARNING’’ and conveys the general focus of the
information in the box. The box must briefly explain the
risk and refer to more detailed information in the ’’Con-
traindications’’ or ’’Warnings and Precautions’’ section,
accompanied by the identifying number for the section or
subsection containing the detailed information.
Pharm.D., for kindly providing the ’’black box warn-
I thankJamesW. Johnson,
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