Download Antiretroviral-associated Hepatotoxicity

Antiretroviral-associated Hepatotoxicity
Kendra D. Kress, PharmD
Address Roche Laboratories Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
E-mail: [email protected]
Current Infectious Disease Reports 2005, 7:103-107 Current Science Inc. ISSN 15233847 Copyright © 2005 by Current Science Inc.
The use of highly active antiretroviral therapy has dramatically reduced HIVassociated morbidity and mortality. As a result, patients are often being treated longer
and with more complex medical regimens than ever before, increasing the risk for drug
interactions and toxicities. In particular, hepatotoxicity caused by antiretroviral use has
become an increasingly appreciated potential complication of drug treatment. All
classes of antiretrovirals have been reported to induce liver enzyme abnormalities.
However, certain antiretrovirals appear much more likely to be associated with
druginduced hepatotoxicity. The risk of antiretroviral-related hepatotoxicity may be
associated with patient-specific risk factors, including pre-existing viral hepatitis,
baseline elevated liver function test results, female gender, and substance abuse. In
addition, complex drug-drug interactions may potentate the risk of
antiretroviralassociated hepatotoxicity. Coinfection with hepatitis B or hepatitis C
appears to increase the risk of antiretroviral-related hepatotoxicity.
Introduction
The introduction of highly active antiretroviral therapy (HAART) has significantly
increased the lifespan and improved the quality of life of most HIV-infected individuals
[1]. However, hepatic complications associated with HIV have emerged as increasingly
important adverse events for physicians who manage patients infected with HIV. Druginduced hepatotoxicity is a frequent cause of significant liver enzyme elevations in
patients receiving HAART therapy. Hepatotoxicity is often and most generally de.ned
as an increase in serum transaminase levels three to five times the upper limit of normal.
Also commonly used to report hepatotoxicity are the National Institutes of
Health/National Institute of Allergy and Infectious Diseases definitions of
hepatotoxicity, which are based on a scale of severity ranging from 1 to 4 (Table 1).
Most cases of antiretroviral-associated hepatotoxicity are asymptomatic and resolve
spontaneously or upon discontinuation of the drug. However, antiretrovirals have also
been reported to induce severe, even life-threatening cases of hepatotoxicity [2].
Although all classes of antiretrovirals have been associated with increases in serum
transaminases, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and
protease inhibitors (PIs) appear most commonly associated with inducing liver enzyme
elevations. Nucleoside reverse transcriptase inhibitors (NRTIs) have been associated
with a rare, but potentially life-threatening syndrome that is characterized by lactic
acidosis and hepatic steatosis [3].
Background
Liver disease has become one of the overall leading causes of morbidity and mortality
in HIV-infected patients [4]. The precise etiology of hepatic dysfunction observed in
these patients is often not clearly defined, likely because of the complex sets of
molecular mechanisms involved in the pathogenesis of HIV infection and treatment.
Liver dysfunction in HIV may be idiosyncratic in nature or may re.ect the effects of
chronic viral hepatitis, alcohol-related liver disease, illicit drug use, or medication-
induced liver toxicity. Although less common since the advent of HAART,
opportunistic infections such as cytomegalovirus, mycobacteria, parasitic infection, or
lymphoma are additional causes of liver disease in the HIV-infected individual.
Hepatitis B (HBV) or hepatitis C (HCV) infection each cause signi.cant hepatic injury
alone and may additionally increase the risk of antiretroviral-related hepatotoxicity [5].
Hepatotoxicity in HIV-infected patients is most often multifactorial as related to
complex drug-drug and drug-disease state interactions. The pathophysiologic
mechanisms underlying most forms of antiretroviralrelated hepatotoxicity are not fully
understood. Postulated hepatotoxic mechanisms include alterations in drug metabolism,
underlying liver disease, immune-mediated hypersensitivity, immune reconstitution,
mitochondrial toxicity associated with lactic acidosis or lipodystrophy syndrome, and
steatohepatitis [6]. Because the diagnosis and management of antiretroviral-related
hepatotoxicity may be complex, some experts have proposed algorithms or checklists to
be used for the diagnosis and management of hepatotoxicity in the HIV-infected patient
[7] (Table 2).
Table 1. NIH-NIAID grading of liver toxicity
Alt
Alk Phos
Bilirubin
Grade 1
1.25-2.5 X ULN
1.25-2.5 X ULN
1-1.5 X ULN
Grade 2
> 2.5 X ULN
> 2.5 X ULN
> 1.5-2.5 X ULN
Grade 3
> 5-10 X ULN
> 5-10 X ULN
> 2.5-5 X ULN
Grade 4
> 10 X ULN
> 10 X ULN
> 5 X ULN
Alk Phos-alkaline phosphate; ALT-alanine aminotransferase; NIAID-National
Institute of Allergy and Infectious Diseases; NIH-National Institutes of Health;
ULN-upper limit of normal.
Table 2. Did this drug cause hepatitis?
1. Has this reaction been observed before?
2. Was the timing appropriate for toxicity?
3. Did toxicity improve when the drug was stopped?
4. Did toxicity reoccur when the drug was restarted?
5. Were other causes of increased ALT ruled out?
ALT-alanine aminotransferase.
Epidemiology
The actual incidence of antiretroviral-associated hepatotoxicity is difficult to assess, and
the reported values vary widely in most clinical trials and cohort studies. Controlled
clinical trials have offered some data concerning antiretroviral-induced hepatotoxicity in
certain patient populations; however, these studies are limited by patient
inclusion/exclusion criteria, short durationof follow-up, and generally small numbers of
patients [8]. More information on the incidence of antiretroviral-induced hepatotoxicity
in larger and more diverse patient populations has emerged from several cohort studies
and database analysis of patients treated with HAART over the past several years [9o].
Overall, severe antiretroviral-associated hepatotoxicity, defined as liver enzyme
increases more than .ve times the upper limit of normal, has been reported to occur in
4.5% to 10% of HIV-infected study populations [9o,10o]. However, differences in study
populations and de.nitions used for hepatotoxicity make comparisons across studies
dif.cult. Hepatotoxicity Associated with Nonnucleoside Reverse Transcriptase
Inhibitors The NNRTI class of antiretrovirals includes nevirapine, efavirenz, and
delavirdine. Most studies reporting NNRTIrelated hepatotoxicity have found an
increased incidence of hepatotoxicity with nevirapine compared with the other most
commonly used NNRTI, efavirenz. Most cases of nevirapine-associated hepatotoxicity
have been reported to occur within the first 6 to 12 weeks of therapy. Nevirapineinduced hepatotoxicity may often present as part of a systemic hypersensitivity-type
reaction characterized by rash, fever, and eosinophilia [10o,11,12]. However, other
patients develop a more nonspecific fluu-like or gastrointestinal syndrome occurring
with or without elevations in liver enzymes. In some individuals, nevirapine-associated
toxicity may progress rapidly to hepatomegaly with jaundice. In the most severe cases,
hepatic failure develops several days later. A 2-week lead-in dosing schedule of 200 mg
once daily for nevirapine is recommended by the manufacturer to reduce the incidence
of the hypersensitivity reaction and hepatotoxicity.
Boehringer Ingelheim (Ridgefield, CT), the manufacturer of nevirapine, conducted an
extensive review of patients on nevirapine-based antiretroviral regimens, using database
information from their own studies and database sets derived from other sources. In this
review, most cases of nevirapine-related hepatotoxicity occurred within the first 6
weeks of therapy and were often accompanied by fever, rash, and eosinophilia [13]. No
difference in hepatotoxicity was found between nevirapine and placebo after the first 6
weeks of therapy. The authors identified several independent risk factors for the
development of hepatotoxicity while on nevirapine, including female gender with a
CD4 count more than 250 cells per mm3, pregnancy, and male gender with a CD4 count
more than 400 cells per mm3 [13]. Boehringer Ingelheim issued a letter informing
health care providers of these .findings [14].
Although originally considered for this use, nevirapine is not currently recommended
for HIV postexposure prophylaxis because of increased risk of hepatotoxicity and rash
observed in HIV-negative persons. Patel et al. [15] con.rmed earlier reports that HIVnegative persons appear to be at higher risk for nevirapine-related adverse effects. The
authors further suggested that autoimmunity may be at the root of severe toxicities
associated with nevirapine because severe reactions have been found in other studies to
occur most often in HIV-infected persons with high CD4 counts. Nevirapine has been
widely used in pregnancy to prevent mother-to-child transmission of HIV. However,
results from the PACTG1022 study demonstrated that nevirapine is associated with an
increase in liver toxicity in HIV-positive pregnant women with a CD4 count more than
250 cells per mm3 or [16]. Five of 17 women stopped treatment during this study
because of nevirapine-associated hepatotoxicity. Among these women, one developed
Stevens-Johnson syndrome, three had increased liver enzymes (two with symptoms
suggestive of hepatitis), and one experienced fulminate liver failure and died. These
studies have supported the .ndings and recommendations by Boehringer Ingelheim,
concluding that nevirapine should not be used in HIVinfected women with a CD4 count
more than 250 cells per mm3 or in HIV-infected men with a CD4 count more than 400
cells per mm3.
Several groups have tried to identify a relationship between nevirapine-induced
hepatotoxicity and plasma levels of the drug, but the published results have been
con.icting. Gonzalez et al. [17] reported a relationship between increased nevirapine
trough levels and transaminase elevations after 12 weeks of therapy. In addition, Geel et
al. [18] found that fluconazole, when coadministered with nevirapine, results in
increased plasma levels of nevirapine and a subsequent increased risk for developing
hepatotoxicity. In contrast, other investigators found no signi.cant correlation between
plasma concentrations of nevirapine and the risk for hepatotoxicity in HIV-infected
patients [19,20]. To better understand this possible correlation, work is underway
analyzing potential genetic markers that could accurately predict the risk of nevirapineinduced adverse reactions. Mallal et al. [21] have reported that human leukocyte antigen
type DRB1*0101 appears to be associated with development of nevirapine
hypersensitivity. Clearly, more studies are needed to evaluate the relationship of
nevirapine plasma levels and pharmacogenomics in the development of drug-related
hepatotoxicity in de.ned populations. Other areas needing clari.cation include
mechanisms of NNRTI-induced hepatotoxicity and the in.uence of immune status,
gender, age, and coinfection with hepatitis B or C on the risk of adverse drug effects.
Hepatotoxicity Associated with Protease Inhibitors
Drug-related hepatotoxicity associated with PI use has been observed in 1% to 9.5% of
treated patients in randomized clinical trials that were conducted before US Food and
Drug Administration approval [22o]. In these studies, most cases of liver dysfunction
were asymptomatic and resolved upon discontinuation of the PI. However, severe
hepatotoxicity associated with PI use has been occasionally reported. Cohort studies
have provided more information regarding the incidence of PIrelated hepatotoxicity in
larger and more diverse patient populations, compared with controlled clinical trials,
which have generally included only healthy patients without signi.cant comorbidities. In
several retrospective and prospective cohort studies, the overall incidence of
hepatotoxicity with PI use was 5% to 23%, although the de.nition of hepatotoxicity
varied widely among the studies [23]. Potential risk factors for development of
PIassociated hepatotoxicity have been identi.ed in several of these cohort studies. Such
risk factors include infection with HBV or HCV, increased baseline alanine
aminotransferase, high-dose ritonavir use, increased CD4 count, d4T use, alcohol abuse,
increased age, nevirapine use, female gender, and stopping lamivudine. The only PI
routinely identified as an independent risk factor for developing hepatotoxicity was
high-dose ritonavir (defined as > 400 mg of ritonavir daily). There was no evidence that
lowdose ritonavir use (100-200 mg/day) to boost the levels of other PIs was a risk factor
for hepatotoxicity.
The hepatotoxic risk of ritonavir-"boosted" PI-based regimens has not been well
evaluated outside of clinical trials. However, Sulkowski et al. [24] recently evaluated
PIbased antiretroviral regimens with or without ritonavir in an urban HIV clinic with a
high incidence of HBV and HCV infection. Severe hepatotoxicity was observed in
12.7% (148/1161) of patients prescribed a PI-containing HAART regimen. Risk factors
for developing hepatotoxicity in this study were identi.ed as detectable HCV antibody,
baseline CD4 count more than 50 cells per mm3, baseline HIV RNA more than 10,000
copies per mL, baseline aspartate aminotransferase more than 35 U per L, and use of
indinavir or saquinavir/ritonavir (800 mg ritonavir/day). Race, gender, age, HBV status,
concurrent NNRTI use, change in CD4 count, or viral load during treatment were not
identified as risk factors for hepatotoxicity. No difference in the incidence of
hepatotoxicity was found between lopinavir/ritonavir-based regimens and nel.navirbased regimens in patients with or without HCV infection. However, the researchers did
find a 2.5-fold increased risk of hepatotoxicity overall, among patients with HCV
infection. In this study, the authors were unable to determine the rate of hepatotoxicity
with PI-based regimens including atazanavir, amprenavir, fosamprenavir, or
saquinavir/ritonavir (1000 mg/100 mg twice daily). Clearly, more studies are needed to
evaluate PI-associated hepatotoxicity, especially with newer PI-based antiretrovirals
including atazanavir, fosamprenavir, and saquinavir plus low-dose ritonavir.
Hepatotoxicity Associated with Nucleoside Reverse Transcriptase Inhibitors
The use of two drugs from the NRTI class of antiretrovirals is considered to be the
backbone of most HAART regimens. This class has been associated with a rare but
serious syndrome characterized by lactic acidosis and hepatic steatosis [25]. Lactic
acidosis syndrome and other adverse effects of NRTIs are thought to be mediated by
inhibition of human DNA polymerase ð¨, resulting in mitochondrial dysfunction [26].
Symptoms of NRTI-related lactic acidosis may include fatigue, exercise intolerance,
dif.culty breathing, nausea, vomiting, abdominal pain, and weight loss. Diagnosis is
con.rmed by a serum lactate level more than 3 mmol per L. Upon diagnosis, all
antiretrovirals should be stopped. Treatment for lactic acidosis remains mostly
supportive; however, studies are currently being conducted on the prevention and
treatment of lactic acidosis, with essential cofactors including thiamin and riboflavin.
The risk factors for developing lactic acidosis in HIV infected patients receiving
HAART are currently unknown. Certain NRTIs, such as d4T and ddI, appear to be more
likely to cause mitochondrial toxicity; however, data on the incidence of lactic acidosis
with specific NRTIs and in combination with other antiretrovirals are limited.
It is unknown if HCV infection is a risk factor for development of lactic acidosis in
patients on NRTIs. In patients treated for HCV infection, concomitant use of ribavirin
and didanosine or stavudine increases the risk of lactic acidosis and is not recommended
[27].
HIV/Hepatitis C Virus Coinfection
In the United States, up to 30% of HIV-infected persons are coinfected with HCV.
Preliminary data suggested that coinfected patients are more likely to develop HAARTrelated hepatotoxicity than are HIV-infected individuals. However, attributing
incidences of hepatotoxicity to antiretroviral use is dif.cult because of the presence of
HCV-mediated liver damage, frequent comorbid risk factors (eg, alcohol ingestion and
illicit drug use). In addition, the phenomenon of immune reconstitution occurring after
the initiation of HAART may also indirectly contribute to elevation of serum
transaminase levels commonly observed in coinfected treatment [27].
HIV infection appears to have a deleterious effect on progression of HCV, infection
resulting in higher rates of .brosis and cirrhosis in patients with coinfection, although
this effect remains to be completely characterized [28]. Additional preliminary data
indicate that the transaminase levels decrease or even normalize in coinfected women
undergoing HAART, possibly because of the later, more bene.cial, effects of immune
reconstitution on hepatic function in this population [29]. Conversely, Uberti-Foppa et
al. [30] recently showed that 6 months of HCV treatment before initiation of HAART
reduced the risk of antiretroviral-related toxicity in patients able to defer HAART based
on their immune status. In a study published in early 2004, nevirapine-containing
HAART regimens were associated with faster progression of liver fibrosis in coinfected
patients, compared with PI-based HAART [31]. More evidence linking nevirapine and
hepatotoxicity in HIV/HCV-coinfected patients was presented at the Seventh
International Congress on Drug Therapy in HIV Infection in November, 2004.
Aranzabal et al. [32] reported that among coinfected patients receiving HAART, the risk
of a fivefold increase in liver transaminases was greater in patients with grade 3 to 4
liver fibrosis, compared with those with grade 1 to 2 liver fibrosis. Nevirapinecontaining regimens had a higher incidence of transaminitis than efavirenz or non-
NNRTI-based regimens.
Many factors must be carefully considered when initiating treatment of HIV in
coinfected patients. In addition to such standard parameters as CD4 count and HIV viral
load, liver function tests, HCV viral load and genotype, hepatic imaging, and, in most
patients, a liver biopsy should also be obtained [33]. Antiretrovirals shown be
associated with an increased risk of hepatotoxicity coinfected patients, such as
nevirapine, should be used with extreme caution, or not at all, in most coinfected
patients. It is important to weigh the risks and benefits HAART therapy in patients with
hepatitis. Unfortunately, research is lacking concerning the relative risk of
hepatotoxicity with speci.c drugs and antiretroviral regimens this patient population
[34o]. Many studies are underway to address the optimal timing and modulation of
HCV therapy in coinfected patients.
Conclusions
Antiretroviral-associated hepatotoxicity is an important consideration in the
management of HIV-infected patients, especially those with comorbidities that may add
additional risk for liver injury. All classes of antiretrovirals have been associated with
liver enzyme abnormalities; however, the incidence of speci.c antiretroviral-related
hepatotoxicity has not been well de.ned in clinical studies. Nevirapine and high-dose
ritonavir are the only antiretrovirals found to be a signi.cant risk factor development of
drug-related hepatotoxicity. Although con.icting data exist, HBV and HCV coinfection
appear to be signi.cant risk factors for hepatotoxicity in patients receiving HAART.
References and Recommended Reading Papers of particular interest, published recently,
have been highlighted as: o Of importance oo Of major importance
1. Palella FJ Jr, Delaney KM, Moorman AC, et al.: Declining morbidity and mortality
among patients with advanced human immunode.ciency virus infection. HIV Outpatient
Study Investigators. N Engl J Med 1998, 338:853-860.
2. Puoti M, Torti C, Ripamonti D, et al.: HIV-HCV Co-Infection Study Group. Severe
hepatotoxicity during combination antiretroviral treatment: incidence, liver histology,
and outcome. J Acquir Immune De.c Syndr 2003, 32:259-267.
3. Ogedegbe AO, Sulkowski MS: Antiretroviral-associated liver injury. Clin Liver Dis
2003, 7:475-499.
4. Bica I, McGovern B, Dhar R, et al.: Increasing mortality due to end-stage liver
disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001,
32:492-497.
5. Dieterich D: Managing antiretroviral-associated liver disease. J Acquir Immune De.c
Syndr 2003, 34(Suppl 1):S34-S39.
6. Pol S, Lebray P, Vallet-Pichard A: HIV infection and hepatic enzyme abnormalities:
intricacies of the pathogenic mechanisms. Clin Infect Dis 2004, 38(Suppl 2):S65-S72.
7. Nierenberg DW: "Did this drug cause my patient s hepatitis?" and related questions.
Ann Intern Med 2002, 136:480-483.
8. Sabin CA: Pitfalls of assessing hepatotoxicity in trials and observational cohorts. Clin
Infect Dis 2004, 38(Suppl 2):S56-S64. 9.o Becker S: Liver toxicity in epidemiological
cohorts. Clin Infect Dis 2004, 38(Suppl 2):S49-S55. This is a nice review of important
cohort studies that have reported risk factors associated with increased risk of
hepatotoxicity.
10.o Dieterich DT, Robinson PA, Love J, et al.: Drug-induced liver injury associated
with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis 2004,
38(Suppl 2):S80-S89. This is an excellent discussion of NNRTI-associated
hepatotoxicity and supporting evidence.
11. Kontorinis N, Dieterich DT: Toxicity of non-nucleoside analogue reverse
transcriptase inhibitors. Semin Liver Dis 2003, 23:173-182. 12. Manfredi R, Calza L,
Chiodo F: Efavirenz versus nevirapine in current clinical practice: a prospective, openlabel observational study. J Acquir Immune De.c Syndr 2004, 35:492-502.
13. Stern JO, Robinson PA, Love J, et al.: Nevirapine hepatic safety project. Paper
presented at the XIV International AIDS Conference. Barcelona, Spain, July 7-12,
2002.
14. Shepard K: Clari.cation of risk factors for severe, life threatening and fatal
hepatotoxicity with Viramune (nevirapine) [letter]. Rigde.eld, CT: Boehringer
Ingelheim Pharmaceuticals; 2004.
15. Patel SM, Johnson S, Belknap SM: Serious adverse cutaneous and hepatic toxicities
associated with nevirapine use by non-HIV-infected individuals. J Aquir Immune De.c
Syndr 2004, 35:120-125. 16. For the PACTG 1022 Study Team: Maternal toxicity with
continuous nevirapine in pregnancy: results from PACTG1022. J Acquir Immune De.c
Syndr 2004, 36:772-776.
17. Gonzalez D, Jiménez-Nácher I, Romero M, et al.: Changes in nevirapine plasma
concentrations along 48 weeks and relationship with transaminase elevations [abstract
856]. Antivir Ther 2003, (Suppl 1):S425.
18. Geel J, Pitt J, Orrell CJ, et al.: The effect of fluconazole on nevirapine
pharmacokinetics [abstract WeOr1239]. Program and abstracts of the XV International
AIDS Conference. Bangkok, Thailand, July 11-16, 2004.
19. Almond LM, Bof.to M, Hoggard PG, et al.: The relationship between nevirapine
plasma concentrations and abnormal liver function tests. AIDS Res Hum Retroviruses
2004, 20:716-722.
20. Dailly E, Billaud E, Reliquet V, et al.: No relationship between high nevirapine
plasma concentration and hepatotoxicity in HIV-1-infected patients naive of
antiretroviral treatment or switched from protease inhibitors. Eur J Clin Pharmacol
2004, 60:343-348.
21. Mallal S, Martin A, Cameron P, et al.: Predisposition to nevirapine hypersensitivity
associated with HLA-DRB1 *0101 abrogated by low CD4+ T cell counts. Program and
abstracts of the XV International AIDS Conference. Bangkok, Thailand, July 11-16,
2004.
22.o Sulkowski MS: Drug-induced liver injury associated with antiretroviral therapy
that includes HIV-1 protease inhibitors. Clin Infect Dis 2004, 38(Suppl 2):S90-S97.
This is a recent and comprehensive review of PI-related hepatotoxicity.
23. Sulkowski MS: Hepatotoxicity associated with antiretroviral therapy containing
HIV-1 protease inhibitors. Semin Liver Dis 2003, 23:183-194.
24. Sulkowski MS, Mehta SH, Chaisson RE, et al.: Hepatotoxicity associated with
protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir.
AIDS 2004, 18:2277-2284.
25. Montessori V, Harris M, Montaner JS: Hepatotoxicity of nucleoside reverse
transcriptase inhibitors. Semin Liver Dis 2003, 23:167-172.
26. Montaner JS, Cote HC, Harris M, et al.: Nucleoside-related mitochondrial toxicity
among HIV-infected patients receiving antiretroviral therapy: insights from the
evaluation of venous lactic acid and peripheral blood mitochondrial DNA. Clin Infect
Dis 2004, 38(Suppl 2):S73-S79.
27. Braitstein P, Palepu A, Dieterich D, et al.: Special considerations in the initiation
and management of antiretroviral therapy in individuals coinfected with HIV and
hepatitis C. AIDS 2004, 18:2221-2234.
28. Bonacini M: Liver injury during highly active antiretroviral therapy: the effect of
hepatitis C co-infection. Clin Infect Dis 2004, 38(Suppl 2):S104-S108.
29. French AL, Benning L, Anastos K, et al.: Longitudinal effect of antiretroviral
therapy on markers of hepatic toxicity: impact of hepatitis coinfection. Clin Infect Dis
2004, 39:402-410.
30. Uberti-Foppa C, De Bona A, Morsica G, et al.: Pretreatment of chronic active
hepatitis C in patients coinfected with HIV and hepatitis C virus reduces the
hepatotoxicity associated with subsequent antiretroviral therapy. J Acquir Immune De.c
Syndr 2003, 33:146-152.
31. Macias J, Castellano V, Merchante N, et al.: Effect of antiretroviral drugs on liver
.brosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine.
AIDS 2004, 18:767-774.
32. Aranzabal L, Casado JL, Moya J, et al.: HAART-associated hepatotoxicity in
HIV/HCV co-infected patients: the role of liver histologic damage and drug levels
[abstract PL14.1]. Program and abstracts from the 7th International Congress on Drug
Therapy in HIV Infection. Glasgow, Scotland, November 14-18, 2004.
33. Soriano V, Massimo P, Sulkowski, et al.: Care of patients with hepatitis C and HIV
co-infection. AIDS 2004, 18:1-12.
34.o Powderly WG: Antiretroviral therapy in patients with hepatitis and HIV: weighing
risks and benefits. Clin Infect Dis 2004, 38(Suppl 2):S109-S113. This is a very useful
discussion that brings to light important therapeutic considerations when treating HIV in
coinfected patients.