Full text of DOI:10.1592/phco.22.16.1468.33702

Looking Beyond Highly Active Antiretroviral Therapy:
Drug-Related Hepatotoxicity in Patients with Human
Immunodeficiency Virus Infection
Robert Orenstein, D.O., and Nickolaos Tsogas, M.D.
Management of human immunodeficiency virus (HIV) has become
increasingly complex since the introduction of highly active antiretroviral
therapy (HAART). Patients with HIV have become exposed to an increasing
array of drugs to treat HIV, prevent opportunistic infections and immune
dysfunction, and manage comorbid illnesses and therapeutic complications.
Hepatic complications have become common and may lead to discontinuation
of treatment and significant morbidity. Up to 90% of patients with acquired
immunodeficiency syndrome (AIDS) receive at least one drug that can cause
hepatotoxicity. Clinicians treating patients with HIV frequently face difficulty
distinguishing abnormal liver transaminase levels and toxicities in patients
receiving several drugs. Some potential causes of hepatic dysfunction are viral
infections, alcohol and substance abuse, and hepatotoxic drugs such as
HAART. Recent reports have focused on the hepatotoxicity of HAART and the
role of hepatitis viruses to the exclusion of many other agents prescribed for
patients with HIV. Many of the common antibiotics, antifungals, antivirals,
and ancillary agents prescribed for patients with HIV are independently
associated with hepatotoxicity. Clinicians should be aware of the potential
non–antiretroviral hepatotoxic agents that are frequently administered in HIV
management.
(Pharmacotherapy 2002;22(11):1468–1478)
OUTLINE
The introduction of highly active antiretroviral
therapy (HAART) in the mid-1990s transformed
acquired immunodeficiency syndrome (AIDS)
from a progressively fatal disease complicated by
opportunistic infections to a chronic one that is
now often complicated by drug toxicities,
resistance, and new comorbidities.1 As patients
infected with human immunodeficiency virus
(HIV) live longer, comorbid illnesses such as
Methods
Antifungal Agents
Prevalence
Mechanism
Macrolides
Antituberculosis Agents
Anti-Pneumocystis Agents
Antiherpes and Anticytomegalovirus Agents
Lipid-Lowering Agents
Anabolic Steroids
viral hepatitis,
tuberculosis, diabetes,
hyperlipidemia, metabolic bone disease, and
opportunistic infections have increased their
exposure to a variety of pharmaceuticals beyond
HAART. Many of these agents independently
may cause liver injury, and some toxicities may
be exacerbated by drug-drug interactions or
comorbid liver diseases. Of the patients infected
with HIV, 16% may be coinfected with hepatitis
C, which may increase their risk of treatment-
Conclusion
From the Divisions of General Internal Medicine and
Infectious Diseases, Mayo Clinic, Rochester, Minnesota (Dr.
Orenstein); and the Division of Infectious Diseases, Virginia
Commonwealth University, School of Medicine, Richmond,
Virginia (Dr. Tsogas).
Address reprint requests to Robert Orenstein, D.O., Mayo
Building W17, 200 First Street Southwest, Mayo Clinic,
Rochester, MN 55905; e-mail: orenstein.robert@mayo.edu.

DRUG-RELATED HEPATOTOXICITY IN PATIENTS WITH HIV Orenstein and Tsogas
1469
related complications.2, 3 Several recent articles
have addressed the issue of the hepatotoxicity of
HAART in patients with and without coinfection
with hepatitis C virus.3–13 Clinicians should be
aware of other hepatotoxic drugs commonly
administered to patients with HIV.
megalovirus agents, and statins.
Most reports defined hepatotoxicity as a 3- to
5-fold increase from baseline in serum
aminotransferase levels, with no known other
precipitating cause, and with a return to normal
after drug withdrawal. A few of these articles
reported results of liver biopsy and/or drug
rechallenge with the suspected agent. Ideally,
reports of hepatotoxicity should characterize the
type (hepatocellular, cholestatic, or mixed), the
mechanism (direct cytotoxicity, hypersensitivity,
immunologic, or mitochondrial toxicity), dose
dependency, predictability, severity, and causality;
however, these data frequently were absent from
the reported literature. When they were available,
we attempted to review the relationships of these
variables with respect to drug class and specific
agents.
Transaminase levels 5 times higher than
normal have been noted in 6% of asymptomatic
patients with HIV.3 Drug-related hepatotoxicity
has been estimated to occur in up to 30% of
patients with HIV treated with HAART.4
However, the specific agents, actual frequency,
and causal mechanisms associated with
hepatotoxicity are difficult to assess from the
literature due to a failure to use standardized
definitions and reporting biases. Toxicity data
from clinical trials may overstate asymptomatic,
clinically irrelevant elevations in transaminase
levels, whereas case reports are more biased
toward reporting serious toxicities. With respect
to HIV, newer observations regarding the
mechanisms of HAART-related hepatotoxicity
may negate some of the older reports of liver
injury that predated these observations. With
these caveats in mind, we attempted to review
the hepatotoxicity of drugs other than HAART
that are commonly administered to patients with
HIV.
Antifungal Agents
Fluconazole, ketoconazole, and itraconazole
are azole antifungal agents commonly admin-
istered to patients with HIV to treat vaginal, oral,
and esophageal candidiasis; dermatophyte
infections; and systemic mycoses such as
histoplasmosis, coccidioidomycosis, and
cryptococcosis. The agents are generally well
tolerated; side effects are primarily nausea,
vomiting, and abdominal discomfort.
Methods
Prevalence
We performed a MEDLINE search of the
literature published in English from January
1966–March 2002 on drug-related hepatotoxicity.
Search terms were hepatotoxicity, hepatitis, liver
toxicity, and the individual drugs (or drug
classes) of interest. We narrowed the search to
specific agents commonly administered to
patients with HIV as recommended in clinical
guidelines for management of HIV and
opportunistic infections.14, 15 Many agents we
reviewed have been administered to patients
without HIV, and many predated the admin-
istration of HAART. These reports were reviewed
since they provided supportive data that
associated the drug independently with
hepatotoxicity in the absence of HIV and
antiretroviral therapy. Whenever possible, we
reviewed articles specifically about HIV-positive
patients. Though other hepatotoxic pharma-
cologic agents are administered to patients with
HIV, we limited our review to azole antifungals,
anti-Pneumocystis agents, antituberculous agents,
anti–Mycobacterium avium complex agents,
anabolic steroids, antiherpes agents, anticyto-
All three azoles can cause transient elevations
in liver transaminase levels; ketoconazole is the
most frequent offender.16 One in 10,000–15,000
patients who receive ketoconazole may have a
severe idiosyncratic liver reaction.17 An
estimated 2–10% of patients receiving
ketoconazole experience asymptomatic increases
in alanine aminotransferase and aspartate
aminotransferase levels versus approximately
1–5% of those receiving fluconazole or
itraconazole.18
Mechanism
All the azoles exert their antifungal effect by
interacting with C-14␣-demethylase, an enzyme
dependent on cytochrome P450 (CYP), to inhibit
ergosterol synthesis.19 Similar interactions in
mammalian cells with enzymes dependent on
CYP may mediate some of the major toxic effects
of the azoles (e.g., hepatotoxicity).18 The
observation that imidazoles, like ketoconazole,
appear to be implicated more frequently than the

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PHARMACOTHERAPY Volume 22, Number 11, 2002
triazoles in causing liver damage may be due to
their extensive liver metabolism and lower
affinity for fungal rather than mammalian CYP
enzymes.20 Itraconazole, which also has
extensive liver metabolism, more commonly
causes abnormal transaminase levels than
fluconazole.21
Though generally considered safe across a wide
dosage range, fluconazole has caused significant
hepatotoxicity. This may involve mild transient
elevations in transaminase levels (1–3 times
higher than normal), clinical hepatitis,
cholestasis, fulminant liver failure, and even
death.17, 22–35 Most cases of significant liver injury
related to fluconazole have occurred in severely
immunocompromised patients (e.g., those with
AIDS or a malignancy, or those who underwent
transplantation), who frequently receive this
drug.
Azole-associated elevations of transaminase
levels tend to occur early in treatment, are
usually reversible on discontinuation of the drug,
and may recur on rechallenge.26, 27 Acute
hepatitis has developed as early as day 7 and as
late as week 32 of therapy. Three patients with
HIV who received fluconazole for cryptococcosis
experienced early increases in liver enzyme
levels, with a return to normal after discon-
tinuation.28 All three were rechallenged with
fluconazole after 7–15 days without incident.
Fatal hepatic necrosis has been reported with
fluconazole-induced hepatotoxicity in patients
with AIDS.17, 31–35 Furthermore, reversible
subacute hepatitis characterized by a mixed
hepatocellular and cholestatic pattern was
reported in a patient with AIDS who was not
receiving antiretrovirals and required prolonged
fluconazole therapy for cryptococcosis.32
Electron microscopy of the patient’s liver biopsy
revealed giant mitochondria with paracrystalline
inclusions and enlarged smooth endoplasmic
reticulum. These abnormalities resolved within 1
month after discontinuation of fluconazole. The
authors suggested that liver injury during
fluconazole treatment may be associated with
hepatocyte mitochondrial disease in patients with
AIDS. Many such cases were reported before
administration of HAART or even multi-
nucleoside agents for treatment of HIV.
found biochemical evidence of hepatocellular or
mixed liver injury that developed 1.5–24 weeks
after ketoconazole therapy was begun; median
onset of clinical illness was 4 weeks.36 Abnormal
laboratory values persisted up to 7 weeks after
discontinuation of therapy. Commonly reported
manifestations of ketoconazole-induced liver
toxicity are jaundice (up to 50% of patients) and
anorexia, malaise, nausea, and vomiting (one
third of patients).16 Rechallenge usually results
in recurrent hepatitis, with symptoms identical to
those of the initial episode. Ketoconazole also
has been associated with death from acute
hepatic necrosis.36, 39–42
Itraconazole frequently is better tolerated than
ketoconazole; however, it also may cause hepatic
dysfunction. The frequency of reversible
symptomatic acute hepatitis secondary to
itraconazole is increased with higher dosages and
prolonged therapy.43 The pattern of abnormal
laboratory values and clinical symptoms of acute
hepatitis begin within 5–6 weeks after
itraconazole therapy is begun, and is similar to
the pattern that occurs with ketoconazole
hepatotoxicity. Laboratory values return to
normal approximately 8–10 weeks after
discontinuation of the drug.43, 44
The newest azole, voriconazole, is a triazole
with enhanced activity against Candida as well as
Aspergillus organisms. It undergoes extensive
hepatic metabolism. The first of two recent large
studies of voriconazole efficacy and safety
compared voriconazole with liposomal
amphotericin B in patients with neutropenia and
persistent fever.45 In the voriconazole group, 9%
had abnormal transaminase levels, which was
comparable to those in the amphotericin B
group.45
The second study evaluated
voriconazole in 137 patients with acute invasive
aspergillosis (4% of whom were HIV positive).46
Increases in transaminase levels were significant
in 14% of patients, but alterations in therapy
were not required. One third of the patients with
abnormal liver test results had very high blood
levels of voriconazole.
Macrolides
Erythromycin, the most widely prescribed
macrolide, is associated with cholestatic liver
injury in 3.6/100,000 doses and usually occurs
1–3 weeks after administration.16 It is
administered infrequently to patients with HIV.
However, azithromycin and clarithromycin are
expanded-spectrum macrolides frequently given
Most of the initial reports of symptomatic
hepatitis associated with ketoconazole have
involved HIV-negative patients who were
receiving treatment for resistant superficial
dermatophyte infections.36–42 Analysis of 33
patients with ketoconazole-induced liver injury

DRUG-RELATED HEPATOTOXICITY IN PATIENTS WITH HIV Orenstein and Tsogas
1471
for treatment of respiratory tract infections and
for prophylaxis and treatment of M. avium
complex infection and disease in patients with
HIV. In early clinical trials in patients without
HIV, less than 1% of patients treated with
clarithromycin experienced elevations in alanine
aminotransferase, aspartate aminotransferase, ␥-
glutamyl transferase, alkaline phosphatase,
lactate dehydrogenase, and total bilirubin
levels.47 Elevations in transaminase and alkaline
phosphatase levels (more than 5 times the upper
limit of normal) were observed in up to 4% of
patients with HIV who were participating in
manufacturer-sponsored clinical trials.
Postmarketing adverse events with
clarithromycin are hepatic dysfunction with
increased transaminase levels and cholestatic
hepatitis with or without jaundice.48
Hepatotoxicity may be dose related, especially in
elderly patients.49 Hepatic dysfunction, although
rare, may be severe and is usually reversible on
discontinuation of the drug. One case of severe
hepatocellular injury requiring liver trans-
plantation occurred in an otherwise healthy 25-
year-old man who was receiving clarithromycin.50
A study of clarithromycin for treatment of
disseminated M. avium infection in patients with
late-stage HIV reported abnormal transaminase
levels as the most common adverse effect. This
occurred in 26% of patients, of whom 5%
required discontinuation of clarithromycin and
8% required dosage modification.51
Because of simple once-weekly dosing,
azithromycin has become the preferred agent for
M. avium complex prophylaxis for patients with
AIDS. Though the 1200-mg dose administered
for prophylaxis is commonly associated with
nausea, vomiting, and diarrhea, hepatic
dysfunction is rare. The frequency of cholestatic
jaundice was 1% or less in premarketing trials of
azithromycin. The frequency of abnormal
laboratory findings (increased levels of alanine
aminotransferase, aspartate aminotransferase,
and ␥-glutamyl transferase) reported during
clinical trials with azithromycin was 1–2%.52
Postmarketing information contains infrequent
reports of hepatitis and cholestatic jaundice.
development of serious hepatotoxicity during
treatment with antituberculosis agents.54, 55
Isoniazid, rifampin, and pyrazinamide—the first-
line antituberculosis drugs—are effective but are
associated with an increased frequency of adverse
reactions, which limits their administration.
Isoniazid may cause hepatocellular injury. Liver
toxicity was reported in 3% of patients treated
with rifampin and isoniazid in the United States56
and in 4% of patients treated with rifampin and
isoniazid with or without pyrazinamide in the
United Kingdom in the pre-HIV era.57
In most cases, elevations in liver enzyme levels
due to antituberculosis drugs are mild and
resolve without treatment modification.
However, the frequency of all adverse reactions to
antituberculosis agents prescribed for patients
with HIV in the United States and the United
Kingdom is much higher and varies from
4–18%.58, 59 The relative risk of drug-induced
hepatotoxicity in patients infected with the
hepatitis C virus or HIV is increased 5 and 4
times, respectively, and 14 times in those
coinfected with both viruses.55 Frequent
monitoring is recommended for all patients with
HIV who are receiving antituberculosis therapy,
especially when several risk factors for
development of hepatotoxicity are present (age >
35 yrs, concomitant alcohol consumption, and
chronic liver disease).60, 61
Direct cytotoxicity (by the drug or its
metabolites) is the most likely mechanism of
drug-induced hepatotoxicity from antituber-
culosis drugs. An immune-related component is
believed to coexist, as both isoniazid and
rifampin have documented immunologic
effects.55 Histopathologic findings may range
from spotty to diffuse necrosis with partial to
complete cholestasis. Chronic active hepatitis
may develop in up to 10% of patients with
isoniazid-induced hepatotoxicity who show
degenerative changes of the periportal space as
well as inflammation and fibrosis.62 Rifampin is
the only antituberculosis agent that can inhibit
both the uptake and excretion of bilirubin in a
dose-related manner. As a result, patients may
experience jaundice from elevated plasma levels
of both conjugated and unconjugated bilirubin.
Rifampin alone seldom causes hepatitis. The
mechanism of this liver injury is unknown but is
unpredictable and not dose related.62 Pyrazinamide
is a synthetic analog of nicotinamide, which is
bactericidal against intracellular mycobacteria.
At one time pyrazinamide was given at a dosage
of 40–50 mg/kg/day and was responsible for
Antituberculosis Agents
During the 1980s and 1990s, a resurgence of
tuberculosis occurred in the United States,
affecting primarily patients with HIV.53 In
addition to increasing the risk of developing
active tuberculosis, AIDS may predispose to the

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PHARMACOTHERAPY Volume 22, Number 11, 2002
many cases of acute hepatitis, some of which
were fatal.63 Since the recommended dosage has
been decreased, hepatotoxicity has been reduced
substantially and is generally mild.63 In a large
series of cases, the addition of pyrazinamide
25–40 mg/kg/day to regimens containing
rifampin and isoniazid did not increase the
frequency of hepatitis.57
HIV status; rifampin administered daily for 4
months is an acceptable alternative. Rifampin-
pyrazinamide should be administered daily for 2
months only with caution and only when the
patient can be monitored closely throughout the
course of treatment.
Rifabutin, a derivative of rifamycin S, is as
effective against M. tuberculosis as rifampin.71
Furthermore, rifabutin has lower minimum
inhibitory concentrations than those of rifampin
against M. avium complex isolates,72 and it is a
less potent inducer of the CYP enzyme system.73
Therefore, rifabutin could be administered for
treatment of tuberculosis or for prophylaxis or
treatment of M. avium complex in patients with
HIV who are receiving HAART.
Rifabutin appears to be well tolerated at a
dosage of 300 mg/day in patients with HIV73 and
up to 450 mg/day in HIV-negative patients.74 No
significant liver toxicity was reported with
rifabutin administration in these patients.73, 74
However, the combination of rifabutin and
clarithromycin seems to increase the possibility
of clinically significant hepatotoxicity.75 In one
small study, abnormal liver enzyme levels
developed in 12% of patients with HIV who were
receiving both drugs; one third of these patients
required adjustment of therapy.75 Dosage
adjustment or drug level monitoring may be
necessary for patients receiving concomitant
rifabutin and HAART.
In an effort to control the resurgence of
tuberculosis in the United States, the Centers for
Disease Control and Prevention (CDC)
recommended prophylaxis in purified protein
derivative skin test converters of all ages who are
at risk for activation of tuberculosis.64 The
preferred regimens for isoniazid-susceptible
strains of tuberculosis are isoniazid (either 300
mg/day or 900 mg twice/wk) for 9 months, or
rifampin 600 mg/day plus pyrazinamide 20
mg/kg/day for 2 months. The risk of isoniazid-
induced hepatotoxicity during treatment of latent
tuberculosis infection is thought to be 5–20
cases/1000 patients treated, with a case-fatality
rate of 1–10%.65 These estimates are based on
studies conducted more than 20 years ago, when
the diagnosis of isoniazid-induced hepatotoxicity
was made on the basis of only mild elevations in
transaminase levels.65 More recent studies have
shown that administration of isoniazid for
treatment of latent tuberculosis infection is
generally safe and well tolerated, regardless of
age, when symptoms and liver enzymes are
monitored monthly.66 A large prospective cohort
study found that although the rate of hepatotoxic
reactions during isoniazid preventive therapy
increased with age, the overall risk was much
lower than previously recorded (0.10–0.15% vs
2–3%).65
The regimen of rifampin plus pyrazinamide for
2 months is a valuable alternative for isoniazid-
resistant strains of tuberculosis for patients who
experienced previous adverse reactions to
isoniazid, or when patient adherence to a longer
regimen could be unreliable. The efficacy and
safety of this regimen has been demonstrated in
patients with HIV.67–69 However, 23 cases of
severe and fatal liver injuries associated with the
rifampin-pyrazinamide regimen among patients
not infected with HIV were reported to the CDC
from February–August 2001. As a consequence,
the American Thoracic Society and the CDC,
with the endorsement of the Infectious Diseases
Society of America, revised their recommen-
dations.70 They propose that for treatment of
latent tuberculosis infection, the 9-month
isoniazid regimen is still preferred, regardless of
Anti-Pneumocystis Agents
Four agents commonly administered for
prevention and treatment of Pneumocystis jiroveci
pneumonia in patients with AIDS are
trimethoprim-sulfamethoxazole (TMP-SMX),
pentamidine, dapsone, and atovaquone.
Trimethoprim-sulfamethoxazole is commonly
prescribed for a wide variety of infections. In
patients with HIV, this combination antibiotic
often is given to treat acute episodes of P. jiroveci
pneumonia, or as prophylaxis in patients whose
CD4+ cell count is less than 200/mm3 (or < 14%
of the lymphocytes) or who have thrush or
unexplained fevers.
Liver injury induced by TMP-SMX is rare and
is characterized by a mixed hepatocellular-
cholestatic pattern. Symptoms of hepatocellular
necrosis can develop quickly after the start of
TMP-SMX therapy (a few hrs–10 days) and are
considered a hypersensitivity reaction.76 Cases of
severe hepatocellular injury resulting in death
have been reported.77 A less severe, primarily

DRUG-RELATED HEPATOTOXICITY IN PATIENTS WITH HIV Orenstein and Tsogas
1473
cholestatic reaction appears reversible on
discontinuation of the antibiotic. Symptoms
develop an average of 2.5 weeks after onset of
TMP-SMX therapy (ranging a few days to 1 mo).
Although the symptoms usually resolve within 6
months, pruritus and abnormal liver function
tests can persist for up to 2 years after
discontinuation of the agent.78 Liver biopsy
reveals a centrilobular pattern with minimal
inflammation. Inadvertent rechallenge has
resulted in repeated episodes of acute cholestatic
hepatitis.79
Given the high frequency with which TMP-
SMX is prescribed worldwide, the rarity of well-
documented cases of liver damage suspected to
be induced by this compound is surprising. A
large population-based study in the United
Kingdom revealed that 5.2/100,000 patients risk
developing clinically important liver disease after
receiving a course of TMP-SMX.80 Furthermore,
in a 10-year span in Denmark, only 23 cases of
liver disease induced by TMP-SMX were
reported.81 However, early in the AIDS epidemic
it became clear that frequency of hepatic damage
is substantially higher due to TMP-SMX,82–86 with
hepatotoxicity observed in approximately 20% of
patients taking the compound. The cause of this
increase in toxicity is unclear but has been
postulated to be associated with inability to clear
a hepatotoxic metabolite, sulfamethoxazole
hydroxylamine.87
Intravenous pentamidine is given as an
alternative treatment of moderate-to-severe P.
jiroveci. Prospective studies have reported
treatment-limiting toxicity with pentamidine in
13–80% of patients.86 Liver toxicity seems to be
less common and less severe than with TMP-SMX
but developed in 15% of patients in one study.88
None of the patients required discontinuation or
reduced dosage of pentamidine. The drug’s most
common side effects are nephrotoxicity and
hypoglycemia, but liver function abnormalities,
though frequent, usually are of little consequence.
Few data are available regarding risk of inhaled
pentamidine for treatment of P. jiroveci
prophylaxis. In one trial, incidence of elevated
transaminase levels was 1.7% for pentamidine in
aerosol form versus 12.2% for oral TMP-SMX.89
Dapsone is a sulfone antiinfective administered
for both treatment and prophylaxis of P. jiroveci
in patients with HIV who cannot tolerate TMP-
SMX. Some adverse reactions are dose-related
hemolytic anemia and methemoglobinemia,
which are most severe in patients with glucose-6-
phosphate dehydrogenase deficiency. The
frequency of dapsone-induced adverse events is
increased in patients treated with dapsone and
trimethoprim in combination, probably due to
higher dapsone serum concentrations.90
Transient elevations in transaminase levels
typically occur within the first 2 months of
dapsone therapy. Reversible hepatic injury has
been reported with dapsone and can be either
hepatocellular or cholestatic.91, 92
Dapsone-induced hepatotoxicity usually is
considered a hypersensitivity reaction (referred to
as sulfone syndrome); symptoms include fever,
malaise, jaundice, exfoliative dermatitis,
lymphadenopathy, methemoglobinemia, and
hemolytic anemia. This syndrome is rare, and
hepatic involvement ranges from mild increases
in transaminase levels to fatal fulminant
hepatitis.91 Dapsone-induced hepatitis without
the classic features of sulfone syndrome also has
been described.92
Trimetrexate, an antimetabolite, is a potent
inhibitor of the P. jiroveci dihydrofolate
reductase.93 Addition of leucovorin protects
mammalian cells from the cytotoxic effects of the
drug without affecting the anti–P. jiroveci effect.
Despite its potent enzymatic inhibition,
trimetrexate is less effective than TMP-SMX or
pentamidine in treating severe P. jiroveci.93 It is
administered infrequently to patients with
moderate-to-severe hypoxia who cannot tolerate
initial treatment with TMP-SMX or pentamidine
or for whom treatment failed. Abnormal liver
transaminase levels have been reported in 6–15%
of patients treated with trimetrexate-
leucovorin.94, 95
Atovaquone, an alternative agent for prophylaxis
and treatment of mild-to-moderate P. jiroveci,
does not appear to cause hepatotoxicity.
Antiherpes and Anticytomegalovirus Agents
Acyclovir is a synthetic purine nucleoside
analog with in vitro and in vivo inhibitory
activity against herpes viruses (herpes simplex
and varicella zoster). It is well tolerated even
during long-term administration; its most
common side effects are nausea, diarrhea,
headache, and malaise. Rare cases of elevated
transaminase levels, clinical hepatitis, and
jaundice have been reported.96, 97 Valacyclovir, a
valine-esterified form of acyclovir with an
extended half-life, is rapidly converted to
acyclovir in vivo, and during clinical trials,
elevations in transaminase levels were no more
frequent than with placebo, according to the

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PHARMACOTHERAPY Volume 22, Number 11, 2002
label information. Rare cases of hepatitis due to
this agent have been observed during clinical
practice.98 Famciclovir, the oral prodrug of
penciclovir, has caused only mild elevations of
transaminase and bilirubin levels in less than 3%
of patients, according to the label information.
Ganciclovir, an acyclic synthetic guanine
derivative related to acyclovir, is used primarily
for the treatment of cytomegalovirus disease and
may cause mild abnormalities in liver
function.99–101 Significant hepatotoxicity has
been reported only rarely in patients with HIV
being treated for cytomegalovirus retinitis with
ganciclovir.102, 103 The onset of ganciclovir
hepatotoxicity occurs within the first 2 weeks of
treatment and tends to resolve within 2 weeks
after withdrawal of the agent.102, 103 Whether this
is a dose-related phenomenon and what the
mechanism is that causes the hepatotoxicity are
both unknown.
The most recent addition to this drug class is
valganciclovir, another valine-esterified
compound, which is rapidly converted to
ganciclovir and has equivalent bioavailability to
the parenteral formulation of ganciclovir. Thus
far, no serious hepatotoxicity has been reported
with this agent.
Foscarnet, a pyrophosphate analog available
only intravenously, is another agent active against
herpes viruses. Liver toxicity has been reported
rarely in patients without HIV treated with this
agent.104
competitively inhibit the HMG-CoA reductase
enzyme. Clinical trials in patients without HIV
have shown that statins are well tolerated and are
associated with a low rate of treatment with-
drawal due to adverse effects.107 Hepatotoxicity
during therapy with statins is rare and is
manifested primarily as asymptomatic
transaminase elevations in 1–2% of patients.
These elevations are transient and often dose
related, and usually revert to normal while
therapy is continued. Hepatocellular injury
usually reverses with discontinuation. Cases of
documented liver failure due to statins are rare.108
The lack of large-scale studies on the safety of
statins in patients with HIV warrants close
monitoring of these patients during treatment.
Predisposing factors for hepatotoxicity, such as
chronic liver disease (e.g., hepatitis C virus) and
polypharmacy, are more common among these
patients. Drug-drug interactions may play a
significant role. In patients with HIV, inhibition
of CYP3A4 by commonly prescribed drugs (e.g.,
clarithromycin, azoles, and protease inhibitors)
can increase serum levels of all statins (except
pravastatin) several-fold. In a small study of
patients with HIV and hyperlipidemia who were
treated with statins (most received lovastatin and
simvastatin), transaminase elevations occurred in
approximately 7%, a much higher number than
reported in similar studies with HIV-negative
patients.109 Larger studies are needed to confirm
this observation.
Lipid-Lowering Agents
Anabolic Steroids
Hyperlipidemia has become a significant
comorbid problem for patients with HIV. The
risk of developing lipid abnormalities increases
with duration of HIV treatment and exceeds 50%
of patients after 2 years.105 Though most
commonly associated with HAART, specific
agents as well as HIV may contribute to these
abnormalities. Most clinicians believe it is
appropriate to manage these disorders according
to current guidelines from the AIDS Clinical
Trials Group.106 Although optimal treatment
strategies for hyperlipidemia associated with HIV
remain undefined, many patients receiving
HAART are taking one or more lipid-lowering
agents.
Another frequent manifestation of prolonged
survival with HIV is the wasting syndrome.
Anabolic steroids (e.g., nandrolone, oxandrolone,
and oxymetholone) are synthetic analogs of
testosterone that have been administered for HIV-
associated wasting. In both men and women
with HIV, they are well tolerated but may be
associated with serious hepatotoxicity.110–112
Transaminase elevations may occur in 10–20% of
patients receiving anabolic steroids.110–112
Cholestatic jaundice, occurring within 1–10
months after onset of treatment, is the major
hepatic side effect of this drug class and is
dependent on both the dosage and duration of
therapy. Prolonged administration of high
dosages of anabolic steroids has been associated
with peliosis hepatis, an otherwise uncommon
vascular lesion of the liver, and may result in
liver failure and neoplasms.112, 113 Benign and
malignant hepatic tumor formation also has been
Among the most widely prescribed agents for
lowering total and low-density lipoprotein
cholesterol are the analogs of 3-hydroxy-3-
methylglutaryl coenzyme A (HMG-CoA)
reductase (statins). These are prodrugs, which

DRUG-RELATED HEPATOTOXICITY IN PATIENTS WITH HIV Orenstein and Tsogas
1475
7. Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in
HIV-1-infected patients receiving nevirapine-containing
antiretroviral therapy. AIDS 2001;15:1261–8.
associated with anabolic steroids, and tumor
regression has been reported after cessation of
treatment.114, 115
8. Ormseth EJ, Holtzmuller KC, Goodman ZD, Colonna JO,
Batty DS, Sjogren MH. Hepatic decompensation associated
with lamivudine: a case report and review of lamivudine-
induced hepatotoxicity. Am J Gastroenterol 2001;96:1619–22.
9. Centers for Disease Control and Prevention. Serious adverse
events attributed to nevirapine regimens for postexposure
prophylaxis after HIV exposures worldwide, 1997–2000.
MMWR Morb Mortal Wkly Rep 2001;49:1153–6.
10. Gisolf EH, Dreezen C, Danner SA, Weel JL, Weverling GJ.
Risk factors for hepatotoxicity in HIV-1-infected patients
receiving ritonavir and saquinavir with or without stavudine:
prometheus study group. Clin Infect Dis 2000;31:1234–9.
11. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD.
Hepatotoxicity associated with antiretroviral therapy in adults
infected with the human immunodeficiency virus and the role
of hepatitis C or B infection. JAMA 2000; 283:74–80.
12. den Brinker M, Wit FW, Wertheim-van Dillen PM, et al.
Hepatitis B and C virus co-infection and the risk for
hepatotoxicity of highly active antiretroviral therapy in HIV-1
infection. AIDS 2000;14:2895–902.
13. Spengler U, Litchfield M, Rockstroh JK. Antiretroviral drug
toxicity: a challenge for the hepatologist? J Hepat
2002;36:283–94.
14. Centers for Disease Control and Prevention. Guidelines for
using antiretroviral agents among HIV-infected adults and
adolescents: recommendations of the panel on clinical
practices for treatment of HIV. MMWR Morb Mortal Wkly
Rep (no. RR-7) 2002;51:1–55.
15. Anonymous. USPHS/IDSA guidelines for the prevention of
opportunistic infections in persons infected with human
immunodeficiency virus. Clin Infect Dis 2000;30(suppl
1):S529–65.
16. Reddy KR, Schiff ER. Hepatotoxicity of antimicrobial,
antifungal, and antiparasitic agents. Gastroenterol Clin North
Am 1995;24:923–36.
17. Gearhart MO. Worsening of liver function with fluconazole
and review of azole antifungal hepatotoxicity. Ann
Pharmacother 1994;28:1177–81.
18. Como JA, Dismukes WE. Oral azole drugs as systemic
antifungal therapy. N Engl J Med 1994;330:263–72.
19. Joly V, Bolard J, Yeni P. In vitro models for studying toxicity
of antifungal agents. Antimicrob Agents Chemother
1992;36:1799–804.
20. Vanden Bossche H, Bellens D, Cools W. Cytochrome P-450:
target for itraconazole. Drug Dev Res 1986;8:287–98.
21. Rodriguez Garcia LA, Duque A, Castellsague J, Gutthann-
Perez S, Stricker BHC. A cohort study on the risk of acute
liver injury among users of ketoconazole and other antifungal
drugs. Br J Clin Pharmacol 1999;48:847–52.
22. Powderly WG, Saag MS, Cloud GA, et al. A controlled trial
of fluconazole or amphotericin B to prevent relapse of
cryptococcal meningitis in patients with acquired
immunodeficiency syndrome. N Engl J Med 1992;326:793–8.
23. Saag MS, Powderly WG, Cloud GA, et al. Comparison of
amphotericin B with fluconazole in the treatment of acute
AIDS-associated cryptococcal meningitis. N Engl J Med
1992;326:83–9.
24. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled
trial of fluconazole to prevent fungal infections in patients
undergoing bone marrow transplantation. N Engl J Med
1992;326:845–51.
25. Abramowicz M, ed. Fluconazole. Med Lett Drugs Ther
1990;32:50–2.
26. Munoz P, Moreno S, Berenguer J, Bernaldo de Quiros JC,
Bouza E. Fluconazole-related hepatotoxicity in patients with
acquired immunodeficiency syndrome. Arch Intern Med
1991;151:1020–1.
27. Stern JJ, Hartman BJ, Sharkey P, et al. Oral fluconazole
therapy for patients with acquired immunodeficiency
syndrome and cryptococcosis: experience with 22 patients.
In an analysis of the hepatotoxicity of
oxymetholone in 30 patients with advanced HIV
disease, the most common laboratory
abnormalities were mild elevations in ␥-glutamyl
transferase in 17% of treated patients and
significant elevations of total bilirubin in 10%.116
One patient in this study developed a liver lesion
consistent with peliosis hepatis.
Conclusion
Hepatotoxicity is reported increasingly in
patients with HIV. The most recent focus has
been the toxicity of the nucleoside and
nonnucleoside reverse transcriptase inhibitors
and HIV-1 protease inhibitors. However, the
etiology for elevated transaminase levels in these
patients is often multifactorial, confounded by
chronic hepatitis B or C, alcohol consumption,
concurrent drugs and herbal therapies, and a
multitude of drug-drug interactions. The
challenge for clinicians is to recognize the
potential contributors and drug interactions, and
thus prevent serious adverse consequences. The
challenge for investigators is to define drug-
induced hepatotoxicity prospectively using clear
biochemical, pharmacologic, and histologic
markers, to elucidate the mechanisms of hepatic
injury, to determine the specific causative agents,
and to control for multiple confounding biases.
With this further understanding, we then can
proceed to determine whether preventive
measures may help reduce the risk.
References
1. Palella FJ, Delaney KM, Moorman AC, et al. Declining
morbidity and mortality among patients with advanced
human immunodeficiency virus infection: HIV outpatient
study investigators. N Engl J Med 1998;338:853–60.
2. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C
virus prevalence among patients infected with human
immunodeficiency virus: a cross-sectional analysis of the
adult AIDS clinical trials group. Clin Infect Dis
2002;34:831–7.
3. Wit FW, Weverling GJ, Weel J, Jurrianns S, Lange JM.
Incidence of and risk factors for severe hepatotoxicity
associated with antiretroviral combination therapy. J Infect
Dis 2002;186:23–31.
4. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore
RD. Hepatotoxicity associated with nevirapine or efavirenz-
containing antiretroviral therapy: role of hepatitis C and B
infections. Hepatology 2002;35:182–9.
5. Reisler K. High hepatotoxicity rate seen among HAART
patients. Aids Alert 2001;16:118–19.
6. Nunez M, Lana R, Mendoza JL, Martin-Carbonero L,
Soriano V. Risk factors for severe hepatic injury after
introduction of highly active antiretroviral therapy. J Acquir
Immune Defic Syndr 2001;27:426–31.

1476
PHARMACOTHERAPY Volume 22, Number 11, 2002
Am J Med 1988;85:477–80.
patients with acquired immunodeficiency syndrome. Arch
28. Sugar AM, Saunders C. Oral fluconazole as suppressive
Intern Med 1993;153:368–72.
therapy of disseminated cryptococcosis in patients with
52. Hopkins S. Clinical toleration and safety of azithromycin. Am
J Med 1991;91(suppl 3A):40S–45.
53. Cantwell MF, Snider DE, Cauthen GM, Onorato I.
Epidemiology of tuberculosis in the United States,
1985–1992. JAMA 1994;272:535–9.
54. Ozick LA, Jacob L, Comer GM, et al. Hepatotoxicity from
isoniazid and rifampin in inner-city AIDS patients. Am J
Gastroenterol 1995;90:1978–80.
acquired immunodeficiency syndrome. Am
1988;85:481–9.
J Med
29. Trujillo MA, Galgiani JN, Sampliner RE. Evaluation of
hepatic injury arising during fluconazole therapy. Arch Intern
Med 1994;154:102–4.
30. Holmes J, Clements D. Jaundice in HIV positive
heamophiliac [letter]. Lancet 1989;1(8645):1027.
31. Jacobson MA, Hanks DK, Ferrell LD. Fatal acute hepatic
necrosis due to fluconazole. Am J Med 1994;96:188–90.
32. Guillaume MP, De Prez C, Cogan E. Subacute mitochondrial
liver disease in a patient with AIDS: possible relationship to
prolonged fluconazole administration. Am J Gastroenterol
1996;91:165–8.
55. Ungo JR, Jones D, Ashkin D, et al. Antituberculosis drug-
induced hepatotoxicity: the role of hepatitis C and the human
immunodeficiency virus. Am J Respir Crit Care Med
1998;157:1871–6.
56. Snider DE, Long MW, Cross FS, Farer LS. Six-months
isoniazid-rifampin therapy for pulmonary tuberculosis: report
of a U.S. Public Health Service cooperative trial. Am Rev
Respir Dis 1984;129:573–9.
33. Franklin JM, Ellas E, Hirsch C. Fluconazole induced
jaundice [letter]. Lancet 1990;336:565.
34. Wells C, Lever AM. Dose-dependent fluconazole
hepatotoxicity proven on biopsy and rechallenge. J Infect
1992;24:111–12.
35. Bronstein J-A, Gros P, Hernandez E, Larroque P, Moline C.
Fatal acute hepatic necrosis due to dose-dependent
fluconazole hepatotoxicity. Clin Infect Dis 1997;25:1266–7.
36. Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. Hepatic
injury associated with ketoconazole therapy: analysis of 33
cases. Gastroenterology 1984;86:503–13.
37. Lake-Bakaar G, Scheuer PJ, Sherlock S. Hepatic reactions
associated with ketoconazole in the United Kingdom. Br Med
J 1987;294:419–22.
38. Janssen P, Symoens JE. Hepatic reactions during
ketoconazole treatment. Am J Med 1983;74:80–5.
39. Stricker BHC, Block APR, Bronkhorst FB, Van Parys GE,
Desmet VJ. Ketoconazole-associated hepatic injury: a
clinopathological study of 55 cases. J Hepatol 1986;3:
399–406.
40. Bercoff E, Bernuau J, Degott C. Ketoconazole-induced
fulminant hepatitis. Gut 1985;26:636–8.
41. Duarte PA, Chow CC, Simmons F, Ruskin J. Fatal hepatitis
associated with ketoconazole therapy. Arch Intern Med
1984;144:1069–70.
42. Knight TE, Shikuma CY, Knight J. Ketoconazole-induced
fulminant hepatitis necessitating liver transplantation. J Am
Acad Dermatol 1991;25(2 pt 2):398–400.
43. Lavrijsen AP, Balmus KJ, Nugteren-Huying WM, Roldaan
AC, van’t Wout JW, Stricker BHC. Hepatic injury associated
with itraconazole. Lancet 1992;340:251–2.
44. Hecht FM, Wheat J, Korzun AH, et al. Itraconazole
maintenance treatment for histoplasmosis in AIDS: a
prospective, multicenter trial. J Acquir Immune Defic Syndr
Hum Retrovirol 1997;16:100–7.
45. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole
compared with liposomal amphotericin B for empirical
antifungal therapy in patients with neutropenia and persistent
fever. N Engl J Med 2002;346:225–34.
57. British Thoracic Association. A controlled trial of 6-months
chemotherapy in pulmonary tuberculosis: first report: results
during chemotherapy. Br J Dis Chest 1981;75:141–53.
58. Jones BE, Otaya M, Antoniskis D, et al. A prospective
evaluation of antituberculosis therapy in patients with human
immunodeficiency virus infection. Am J Respir Crit Care Med
1994;150:1499–502.
59. Dean GL, Edwards SG, Ives NJ, et al. Treatment of
tuberculosis in HIV-infected persons in the era of highly
active antiretroviral therapy. AIDS 2002;16:75–83.
60. Kopanoff DE, Snider DE, Caras GJ. Isoniazid-related
hepatitis: a U.S. Public Health Service cooperative
surveillance study. Am Rev Respir Dis 1978;117:991–1001.
61. Gronhagen-Riska C, Hellstrom PE, Froseth B. Predisposing
factors in hepatitis induced by isoniazid-rifampin treatment
of tuberculosis. Am Rev Respir Dis 1978;118:461–6.
62. Westphal JF, Vetter D, Brogard JM. Hepatic side effects of
antibiotics. J Antimicrob Chemother 1994;33:387–400.
63. Danan G, Pessayre D, Larrey D, Benhamou JP. Pyrazinamide
fulminant hepatitis: an old hepatotoxin strikes again. Lancet
1981;7:1056–7.
64. National Center for Prevention Services Division of
Tuberculosis Elimination. Core curriculum on tuberculosis,
3rd ed. Atlanta: U.S. Department of Health and Human
Services, Centers for Disease Control and Prevention, 1994.
65. Nolan CM, Golberg SV, Buskin SF. Hepatotoxicity associated
with isoniazid preventive therapy. JAMA 1999;281:1014–18.
66. Gilroy SA, Rogers MAM, Blair DC. Treatment of latent
tuberculosis infection in patients aged ≥ 35 years. Clin Infect
Dis 2000;31:826–9.
67. Gordin F, Chaisson RE, Matts JP, et al. Rifampin and
pyrazinamide versus isoniazid for prevention of tuberculosis
in HIV infected persons: an international randomized trial.
JAMA 2000;283:1445–50.
68. Mwinga A, Hosp M, Godfrey-Faussett P, et al. Twice weekly
tuberculosis preventive therapy in HIV infection in Zambia.
AIDS 1998;12:2447–57.
46. Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety
of voriconazole in the treatment of acute invasive
aspergillosis. Clin Infect Dis 2002;34:563–71.
47. Guay DR, Patterson DR, Seipman N, Craft JC. Overview of
the tolerability profile of clarithromycin in preclinical and
clinical trials. Drug Saf 1993;8:350–64.
48. Baylor P, Williams K. Interstitial nephritis, thrombo-
cytopenia, hepatitis, and elevated serum amylase levels in a
patient receiving clarithromycin therapy. Clin Infect Dis
1999;29:1350–1.
49. Brown BA, Wallace RJ Jr, Griffith DE, Girard W.
Clarithromycin-induced hepatotoxicity. Clin Infect Dis
1995;20:1073–4.
69. Halsey NA, Coberly JS, Desor meaux J, Chaisson R.
Randomized trial of isoniazid versus rifampin and
pyrazinamide for the prevention of tuberculosis in HIV-1
infection. Lancet 1998;351:786–92.
70. Centers for Disease Control and Prevention. Update: fatal
and severe liver injuries associated with rifampin and
pyrazinamide for latent tuberculosis infection, and revisions
in American Thoracic Society/CDC recommendations: United
States 2001. MMWR Morb Mortal Wkly Rep 2001;50:733–5.
71. Narita M, Stabaugh JJ, Hollender ES, Jones D, Pitchenik AE,
Ashkin D. Use of rifabutin with protease inhibitors for
human immunodeficiency virus-infected patients with
tuberculosis. Clin Infect Dis 2000;30:779–83.
50. Shaheen N, Grimm IS. Fulminant hepatic failure associated
with clarithromycin. Am J Gastroenterol 1996;91:394–5.
51. Dautzenberg B, Marc TS, Meyohas MC, et al.
Clarithromycin and other antimicrobial agents in the
treatment of disseminated Mycobacterium avium infections in
72. Woodley CL, Kilbur n JO. In vitro susceptibility of
Mycobacterium avium complex and Mycobacterium tuberculosis
strains to a spiro-piperidyl rifamycin. Am Rev Respir Dis
1982;126:586–7.
73. Nightingale SD, Cameron DW, Gordin FM, et al. Two

DRUG-RELATED HEPATOTOXICITY IN PATIENTS WITH HIV Orenstein and Tsogas
1477
controlled trials of rifabutin prophylaxis against
Mycobacterium avium complex infection in AIDS. N Engl J
Med 1993;329:828–33.
leucovorin versus trimethoprim-sulfamethoxazole for
moderate to severe episodes of Pneumocystis carinii
pneumonia in patients with AIDS: a prospective controlled
multicenter investigation of the AIDS clinical trials group
protocol 029/031. J Infect Dis 1994;170:165–72.
74. O’Brien RJ, Geiter LJ, Lyle MA. Rifabutin (ansamycin
LM427) for the treatment of pulmonary Mycobacterium avium
complex. Am Rev Respir Dis 1990;141:821–6.
94. Allegra CJ, Chabner BA, Tuazon CU, et al. Trimetrexate for
the treatment of Pneumocystis carinii pneumonia in patients
with the acquired immunodeficiency syndrome. N Engl J Med
1987;317:978–85.
95. Sattler FR, Allegra CJ, Verdegem TD, et al. Trimetrexate-
leucovorin dosage evaluation study for treatment of
Pneumocystis carinii pneumonia. J Infect Dis 1990;161:91–6.
96. Keeney RE, Kirk LE, Bridgen D. Acyclovir tolerance in
humans. Am J Med 1982;73(suppl 1A):176–81.
75. Griffith DE, Brown BA, Girard WM, Wallace RJ Jr. Adverse
events associated with high-dose rifabutin in macrolide-
containing regimens for the treatment of Mycobacterium
avium complex lung disease. Clin Infect Dis 1995;21:594–8.
76. Munoz SJ, Martinez-Her nandez A, Maddrey WC.
Intrahepatic cholestasis and phospholipidosis associated with
use of trimethoprim-sulfamethoxazole. Hepatology
1990;12:342–7.
77. Ransohoff DF, Jacobs G. Terminal hepatic failure following a
small dose of trimethoprim-sulfamethoxazole. Gastro-
enterology 1981;80:816–19.
78. Kowdley KV, Keeffe EB, Fawaz KA. Prolonged cholestasis
due to trimethoprim sulfamethoxazole. Gastroenterology
1992;102:2148–50.
97. Straus SE, Takiff HE, Seidlin M, et al. Suppression of
frequently recurring genital herpes: a placebo-controlled
double-blind trial of oral acyclovir. N Engl J Med
1984;310:1545–50.
98. Renkes P, Trechot P, Blain H. Valaciclovir-induced hepatitis.
Acta Clin Belg 1999;54:17–18.
79. Thies PW, Dull WL. Trimethoprim-sulfamethoxazole-
induced cholestatic hepatitis. Arch Intern Med 1984;144:
1691–2.
80. Jick H, Derby LE. A large population-based follow-up study
of trimethoprim-sulfamethoxazole, trimethoprim, and
cephalexin for uncommon serious drug toxicity.
Pharmacotherapy 1995;15:428–32.
99. Collaborative DHPG Treatment Study Group. Treatment of
serious cytomegalovirus infections with 9-(1,3-di-hydroxy-2-
propoxymethyl) guanine in patients with AIDS and other
immunodeficiencies. N Engl J Med 1986;314:801–5.
100. Heinemann MH. Long-term intravitreal ganciclovir therapy
for cytomegalovirus retinopathy. Arch Ophthalmol
1989;107:1767–72.
81. Dossing M, Andreasen PA. Drug-induced liver disease in
Denmark. Scand J Gastroenterol 1982;17:205–11.
101. Orellana J, Teich SA, Friedman AJ, Lerebours F, Winterkorn
JD. Combined short- and long-term therapy for the treatment
of cytomegalovirus retinitis using ganciclovir (BW B759U).
Ophthalmology 1987;94:831–8.
102. Shea BF, Hoffman S, Sesin GP, Hammer SM. Ganciclovir
hepatotoxicity. Pharmacotherapy 1987;7:223–6.
103. Figge H, Bailie GR, Briceland LL, Kowalsky SF. Possible
ganciclovir-induced hepatotoxicity in patients with AIDS.
Clin Pharm 1992;11:432–4.
104. Aschan J, Ringden O, Ljungman P, Lonnqvist B, Ohlman S.
Foscarnet for treatment of cytomegalovirus infections in bone
marrow transplant recipients. Scand J Infect Dis 1992;24:
143–50.
82. Kovacs JA, Hiemenz JW, Macher AM, et al. Pneumocystis
carinii pneumonia: a comparison between patients with the
acquired immunodeficiency syndrome and patients with
other immunodeficiencies. Ann Intern Med 1984;100:663–71.
83. Gordin FM, Simon GL, Wofsy CB, Mills J. Adverse reactions
to trimethoprim-sulfamethoxazole in patients with the
acquired immunodeficiency syndrome. Ann Intern Med
1984;100:495–9.
84. Wharton JM, Coleman DL, Wofsy CB, et al. Trimethoprim-
sulfamethoxazole or pentamidine for Pneumocystis carinii
pneumonia in the acquired immunodeficiency syndrome.
Ann Intern Med 1986;105:37–44.
105. Romeu J, Sirena G, Rego MJ. Cumulative risk for developing
hyperlipidemia in HIV-infected patients treated with protease
inhibitors [abstr]. Presented at the 39th interscience
conference on antimicrobial agents and chemotherapy, San
Francisco, CA, September 26–29, 1999.
85. Wofsy CB. Use of trimethoprim-sulfamethoxazole in the
treatment of Pneumocystis carinii pneumonitis in patients
with acquired immunodeficiency syndrome. Rev Infect Dis
1987;9(suppl 2):S184–91.
86. Sattler FR, Cowan R, Nielsen DM, Ruskin J. Trimethoprim-
sulfamethoxazole compared with pentamidine for treatment
of Pneumocystis carinii pneumonia in the acquired
immunodeficiency syndrome: a prospective, noncrossover
study. Ann Intern Med 1988;109:280–7.
87. Lee BL, Delahunty T, Safrin S. The hydroxylamine of
sulfamethoxazole and adverse reactions in patients with
acquired immunodeficiency syndrome. Clin Pharmacol Ther
1994;56:184–9.
106. Dube MP, Sprecher D, Henry WK, et al. Preliminary
guidelines for the evaluation and management of
dyslipidemia in adults infected with human immuno-
deficiency virus and receiving antiretroviral therapy:
recommendations of the adult AIDS clinical trial group
cardiovascular disease focus group. Clin Infect Dis
2001;31:1216–24.
107. Davidson MH. Safety profiles for the HMG-CoA reductase
inhibitors. Drugs 2001;61:197–206.
88. O’Brien JG, Dong BJ, Coleman RL, Gee L, Balano KB. A 5-
year retrospective review of adverse drug reactions and their
risk factors in human immunodeficiency virus-infected
patients who were receiving intravenous pentamidine therapy
for Pneumocystis carinii pneumonia. Clin Infect Dis
1997;24:854–9.
108. Tolman KG. Defining patient risks from expanded preventive
therapies. Am J Cardiol 2000;85:15E–19.
109. Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of
HMG-CoA reductase inhibitors for treatment of
hyperlipidemia in patients with HIV infection.
Pharmacotherapy 2000;20:1066–71.
89. Montgomery AB, Feigal DW Jr, Sattler F, et al. Am J Respir
Crit Care Med 1995;151:1068–74.
110. Gold J, High HA, Li Y, et al. Safety and efficacy of nandrolone
decanoate for treatment of wasting in patients with HIV
infection. AIDS 1996;10:745–52.
111. Grinspoon S, Corcoran C, Askari H, et al. Effects of
androgen administration in men with the AIDS wasting
syndrome: a randomized, double-blind, placebo-controlled
trial. Ann Intern Med 1998;129:18–26.
90. Lee BL, Medina I, Benowitz NL, Jacob P III, Wofsy CB,
Mills JV. Dapsone, trimethoprim, and sulfamethoxazole
plasma levels during treatment of Pneumocystis pneumonia in
patients with AIDS: evidence of drug interactions. Ann Intern
Med 1989;110:606–11.
91. Chalasani P, Baffoe-Bonnie H, Jurado RL. Dapsone therapy
causing sulfone syndrome and lethal hepatic failure in an
HIV-infected patient. South Med J 1994;87:1145–6.
92. Lawrence WA, Olsen HW, Nickles DJ. Dapsone hepatitis
[letter]. Arch Intern Med 1987;147:175.
112. Zimmerman H, Flockhart D. Hepatic effects associated with
the clinical use of 17-alkylated anabolic-androgenic steroids.
Arlington Heights, IL: Access Medical Group LTD,
1999:1–15.
113. Newshan G, Leon W. The use of anabolic agents in HIV
disease. Int J STD AIDS 2001;12:141–4.
93. Sattler FR, Frame P, Davis R, et al. Trimetrexate with

1478
PHARMACOTHERAPY Volume 22, Number 11, 2002
114. Ishak KG, Zimmerman HJ. Hepatotoxic effects of anabolic-
androgenic steroids. Semin Liver Dis 1987;7:230–6.
115. Hickson RC, Ball KL, Falduto MT. Adverse effects of
anabolic steroids. Med Toxicol Adverse Drug Exp
1989;4:254–71.
116. Pavlatos AM, Fultz O, Monberg MJ, Vootkur A. Review of
oxymetholone: a 17␣-alkylated anabolic-androgenic steroid.
Clin Ther 2001;23:789–801.