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JAC Advance Access originally published online on February 14, 2008
Journal of Antimicrobial Chemotherapy 2008 61(4):925-932; doi:10.1093/jac/dkn045
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Liver toxicity of antiretroviral combinations including atazanavir/ritonavir in patients co-infected with HIV and hepatitis viruses: impact of pre-existing liver fibrosis

J. A. Pineda1,*, J. Santos2, A. Rivero3, L. Abdel-Kader1,4, R. Palacios2, A. Camacho3, F. Lozano1, J. Macías on behalf of the Liverey Study Investigator Team1,{dagger}

1 Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Seville, Spain 2 Unidad de Enfermedades; Infecciosas, Hospital Universitario Virgen de la Victoria, Malaga, Spain 3 Sección de Enfermedades Infecciosas, Hospital Universitario Reina Sofía, Cordoba, Spain 4 Servicio de Farmacia, Hospital Universitario de Valme, Seville, Spain

* Corresponding author. Tel: +34-955015684; Fax: +34-955015787; E-mail: japineda{at}telefonica.net

Received 5 November 2007; returned 13 December 2007; revised 15 January 2008; accepted 18 January 2008


   Abstract
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 Abstract
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 Patients and methods
 Results
 Discussion
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Objectives: To appraise the rate of grade 3–4 transaminase elevations (TEs) and grade 4 total bilirubin elevation (TBE) in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C or hepatitis B virus (HCV or HBV, respectively) who receive atazanavir/ritonavir. Moreover, the relationship between these events and the degree of prior liver fibrosis was evaluated.

Methods: A cohort of 189 HIV-infected patients, 175 co-infected with HCV, 4 with HBV and 10 with both, receiving atazanavir/ritonavir, was analysed. Baseline liver fibrosis was assessed in 113 (60%) patients. Twenty-four patients had cirrhosis, whereas such a diagnosis was ruled out in 58 patients.

Results: Twelve (6%) and 28 (15%) patients developed grade 3–4 TEs and grade 4 TBE, respectively. Eight (10%) of 84 patients with fibrosis ≥F2 versus 1 of 29 (3%) with F0-F1 (P = 0.51) developed grade 3–4 TEs. The frequencies of grade 3–4 TEs in patients with and without cirrhosis were 8% and 5% (P = 0.63), respectively. Grade 4 TBE was more common among patients with cirrhosis (35% versus 13%, P = 0.05) in the univariate analysis. In the multivariate study, the only predictor of grade 3–4 TEs was baseline CD4 cell count <300 cells/mm3 [adjusted OR (AOR) (95% CI) = 8.77 (1.07–71.42), P = 0.04]. The factors independently associated with grade 4 TBE were baseline total bilirubin >1 mg/dL [AOR (95% CI) = 3.2 (1.21–8.45), P = 0.01] and age >40 years [AOR (95% CI) = 2.98 (1.19–7.47), P = 0.02].

Conclusions: Prior significant liver fibrosis or cirrhosis do not increase substantially the risk of severe TE associated with atazanavir/ritonavir in patients co-infected with HIV and hepatitis viruses.

Keywords: liver disease , cirrhosis , hepatitis C , hepatitis B , antiviral therapy


   Introduction
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 Abstract
 Introduction
Patients and methods
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Viral hepatitis co-infection is a common condition in human immunodeficiency virus (HIV)-infected patients, involving 33% of the subjects in United States and over half in Mediterranean countries, such as Italy or Spain.1–3 Co-infection with hepatitis B virus or hepatitis C virus increases the risk of liver toxicity associated with antiretroviral therapy (ART).1 The degree of liver fibrosis at starting therapy is a critical factor for the risk of hepatotoxicity linked to antiretroviral drugs in these patients. Thus, the more severe the liver fibrosis, the higher the likelihood of drug-related liver toxicity.4–6 However, the available data concerning the incidence of hepatotoxicity associated with antiretroviral drugs in patients with cirrhosis are very scarce.7

Antiretroviral combinations including atazanavir boosted with ritonavir have been reported to be associated with a low frequency of transaminase elevations (TEs) in previous clinical trials and cohort studies.8–14 On the other hand, indirect hyperbilirubinaemia was found to be very common in patients taking atazanavir/ritonavir in these studies, although it usually did not lead to therapy discontinuation.8–14 Data on the incidence of liver toxicity due to atazanavir/ritonavir in the specific subset of HIV/hepatitis co-infected individuals are very limited and come from relatively small populations.13–15 In addition, there is no information about the impact of pre-existing liver fibrosis on the risk of TE or hyperbilirubinaemia in that setting. Moreover, as with other ART drugs, the incidence of these adverse reactions in patients with liver cirrhosis taking atazanavir/ritonavir is unknown.

The aim of the present study was to assess the frequency of severe TE and hyperbilirubinaemia in patients co-infected with HIV and hepatitis C virus (HCV) or hepatitis B virus (HBV) undergoing ART including atazanavir/ritonavir. We have also analysed the relationship between the former events and the pre-existing degree of liver fibrosis.


   Patients and methods
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Study design and patients

A cohort of 8783 HIV-infected patients was prospectively followed in 13 hospitals from Andalusia, Southern Spain, between October 2004 and April 2006. In this study, we analysed retrospectively the patients belonging to this cohort who fulfilled the following criteria: (i) they were co-infected with HCV, as proven by detectable HCV-RNA in serum, or with HBV, showing positive hepatitis B surface antigen (HBsAg) in serum; and (ii) they received an antiretroviral drug combination including 300 mg atazanavir once daily plus 100 mg ritonavir once daily, outside a clinical trial. Patients were sequentially evaluated, with visits at least every 12 weeks. In each visit, clinical examinations, as well as liver function tests and blood cell count determinations, were completed.

Diagnosis of liver events

Elevations of the values of plasma aspartate aminotransferase (AST) or alanine aminotransferase (ALT) higher than 5 times above the upper limit of normality, when baseline levels were normal, or more than 3.5 times the baseline values, if they were abnormal, were considered as grade ≥3 TEs. Plasma total bilirubin elevations (TBEs) over 5-fold the upper level of normality were considered as grade 4 hyperbilirubinaemia.

Liver fibrosis assessment

To assess liver fibrosis, we used a stepwise algorithm (Figure 1). According to this algorithm, in patients with an available liver biopsy performed 1 year before or after the enrolment date, the degree of liver fibrosis found in such biopsy was considered as the baseline fibrosis. Fibrosis in the biopsies was scored following the Knodell histological activity index modified by Scheuer.16 In patients without a liver biopsy 1 year before or after the date of starting on atazanavir/ritonavir, but having a liver stiffness measurement by transient elastometry within this period of time, the result of this procedure was used to score liver fibrosis. Patients with stiffness values ≥7.2 kPa were considered to harbour significant (≥2) fibrosis (≥F2).17 A result higher than 14.6 kPa was indicative of the presence of cirrhosis.18 Stiffness measurements were carried out using a commercial elastometer (FibroScanTM, Echosens, Paris, France).


Figure 1
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  		Figure 1. Patients in whom liver fibrosis was assessed, algorithm used and result obtained using each procedure. aBlood markers of liver fibrosis were carried out in all patients. However, their results were considered evaluable only when they were indicative of F ≥ 2. They were considered uninterpretable otherwise, since the negative predictive value of the test is low. bIn patients in whom fibrosis was categorized as F ≥ 2 by blood markers, it was not known if they had cirrhosis or not.

 
When no biopsy or transient elastometry measurement was available, AST to platelet ratio index (APRI) and Forns index were used to calculate liver fibrosis. Forns index is computed on the basis of platelet count, {gamma}-glutamyl-transpeptidase, age and cholesterol. In the algorithm used here, APRI is calculated first. If a result ≥1.5 is obtained, a diagnosis of significant fibrosis is established. If not, the Forns index is computed. Values ≥6.9 are considered indicative of significant fibrosis. Sequential use of these two indexes has a positive predictive value of 89% and a negative predictive value of 64% for liver fibrosis ≥F2 in HIV/HCV co-infected patients.19 Therefore, in patients with results above the mentioned cut-offs, the diagnosis of significant fibrosis was assumed. However, in these patients we were not able to know if cirrhosis was present, as the positive predictive value of these indexes for such a diagnosis is low.19 In individuals with figures lower than the former cut-off values, the degree of fibrosis could not be inferred.

Statistical analysis

Continuous variables are expressed as medians (Q1–Q3) and the categorical ones as numbers (percentages). The Friedman test was used to compare values of continuous variables at different time points. When variables were categorical, the McNemar test was used.

The factors potentially associated with grade ≥3 TEs or grade 4 TBE were analysed. Continuous variables were compared using the Mann–Whitney U-test and the categorical ones by Yate's corrected {chi}2 test or Fisher's test, when applicable. Those variables associated with grade ≥3 TEs with a P value ≤0.2 were entered in stepwise binary logistic regressions analysis, where grade ≥3 TEs was the dependent variable. The same procedure was applied for grade 4 TBE. The goodness of fit of the models was analysed by the Hosmer–Lemeshow test. Analyses of the entire population along with other circumscribed to patients with an available assessment for liver fibrosis or cirrhosis were performed. All the analyses were carried out using the SPSS 14.0 statistical software package (SPSS, Chicago, IL, USA).

Ethics

This study was designed and conducted according to the principles of the declaration of Helsinki. It was approved by the Ethics Committee of the Hospital Universitario de Valme.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
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Characteristics of the study patients

One hundred and eighty-nine patients fulfilled the inclusion criteria. One hundred and eighty-five patients were co-infected with HCV (98%), 14 (7%) with HBV and 2 (1%) with hepatitis D virus (HDV). Three (2%) were ART naive at starting atazanavir/ritonavir and the remainder had been pre-treated. The main reason for starting atazanavir/ritonavir among the latter was prior drug toxicity in 49 (26%) patients, simplification of the former antiretroviral regimen in 27 (14%), virological failure in 88 (47%) and other reasons in the remaining 22 (12%) subjects. The drugs given concomitantly with atazanavir/ritonavir and the combinations used are shown in Table 1. Atazanavir/ritonavir was the only new drug introduced at starting treatment in 69 (37%) patients. One further new drug was given in 55 (29%), two in 64 (34%) and three new drugs, in addition to atazanavir/ritonavir, were prescribed in 1 (1%) subject.


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  		Table 1. Antiretroviral drugs prescribed along with atazanavir/ritonavir in the study patients and combinations used

 
Patients were followed for a median (Q1–Q3) time of 11 (8–13) months. Eighteen (10%) individuals were lost to follow-up. Two patients died during the study, one due to liver decompensation and the other as a consequence of opiate overdose. Atazanavir/ritonavir was discontinued in 17 (9%) patients. The reasons for atazanavir/ritonavir discontinuation are stated in Figure 2. The number of patients who reached the follow-up time points at 12, 24, 36 and 48 weeks were 169, 154, 120 and 97, respectively.


Figure 2
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  		Figure 2. Patient disposition at the end of the study. ATV/R, atazanavir/ritonavir.

 
The main baseline features are shown in Table 2. The median (Q1–Q3) baseline levels of ALT and AST were 48 (32–78) and 44 (31–71) IU/mL, respectively. The median (Q1–Q3) baseline total bilirubin was 0.7 (0.5–1) mg/dL. An assessment of the baseline degree of liver fibrosis was available in 113 (60%) subjects. Eighty-four of these 113 patients had liver fibrosis ≥F2 and 29 showed fibrosis lesser than F2 at enrolling. Twenty-four (13%) patients had documented liver cirrhosis at starting on atazanavir/ritonavir (Figure 1). Four subjects with cirrhosis had developed a hepatic decompensation prior to start on atazanavir/ritonavir.


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  		Table 2. Baseline characteristics of the study patients

 
Changes in CD4 cell counts and plasma HIV-RNA load

The median (Q1–Q3) CD4+ cell counts/mm3 at baseline and at week 48 were 290 (166–476) and 381 (238–544), respectively (P < 0.01). CD4 cell counts had increased >50 cells/mm3 over the baseline level in 68 (36%) patients after 12 weeks of follow-up. The proportion of patients with plasma HIV-RNA load <50 copies/mL increased from 39% at baseline to 71% at week 48 (P < 0.01).

Liver events

Twelve (6%) patients developed a grade 3–4 TE during follow-up. The incidence of grade ≥3 TEs was 8% (95% CI: 4–14) per 100 person-years. Grade 3–4 TEs were detected in nine patients within the first 12 weeks of follow-up, in two at week 24 and in the remaining patient at week 36.

Six patients (3%), all of them having cirrhosis at baseline, developed hepatic decompensation during follow-up. All these patients showed ascites, in two cases along with hepatic encephalopathy. Two of these patients had developed a prior episode of ascites, whereas the remaining subjects showed the first episode of decompensation while receiving atazanavir/ritonavir. There was no relationship between the drug background given with atazanavir/ritonavir and the emergence of decompensations in patients with cirrhosis. Specifically, didanosine was used only in one cirrhotic patient, who did not developed decompensations during the follow-up.

Twenty-eight (15%) patients developed grade 4 TBE. The incidence of grade 4 TBE was 19 (95% CI: 13–26) per 100 person-years. The proportion of patients with grade 4 TBE were 8%, 8%, 6% and 5% at weeks 12, 24, 36 and 48, respectively. These changes were not statistically significant. The median (Q1–Q3) maximum peak of total bilirubin was 6.90 (5.50–8.10) mg/dL in patients who developed TBE. Indirect bilirubin level was measured in patients in whom total bilirubin value was ≥2 mg/dL. Thus, indirect bilirubin was available in all patients with grade 4 TBE, when TBE was detected. The median (Q1–Q3) value of indirect bilirubin during the peak of hyperbilirubinaemia in patients with grade 4 TBE was 5.70 (4.52–7.50) mg/dL. Thus, the median (Q1–Q3) proportion of indirect bilirubin over total bilirubin was 85% (81% to 92%). The ratio of indirect bilirubin to total bilirubin during the peak was less than 0.65 only in one patient. This was a patient with liver cirrhosis, who developed mixed hyperbilirubinaemia after 12 weeks and ascites thereafter, which led to treatment discontinuation. One more patient developed ascites and hepatic encephalopathy at week 12, along with TBE, reaching a level of 6 mg/dL of total bilirubin, with 5 mg/dL indirect bilirubin. In this case, atazanavir/ritonavir was continued, ascites controlled and total bilirubin decreased to 3.86 mg/dL, with 3.27 mg/dL indirect bilirubin at week 36. No other patient with TBE showed further signs of liver decompensation.

There was no relationship between the degree of pre-existing liver fibrosis and the emergence of grade 3–4 TEs (Table 3). Eight (9%) of 84 patients with documented significant fibrosis versus 1 of 29 (3%) of those who had fibrosis lesser than F2 (P = 0.51) showed grade 3–4 TEs. TEs were observed in two (8%) cirrhotic patients and in three (5%) of 58 patients in whom lack of cirrhosis was proven by histology or transient elastometry (P = 0.63).


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  		Table 3. Predictors of grade 3–4 TEs and grade 4 hyperbilirubinaemia

 
Grade 4 TBEs were more common among patients with proven cirrhosis than in remaining participants (Table 3). When the analysis was restricted to patients in whom the presence of cirrhosis could be assessed by biopsy or transient elastometry, an association between cirrhosis and a higher risk of hyperbilirubinaemia was also observed. Thus, eight (35%) patients with proven cirrhosis versus seven (13%) without cirrhosis developed grade 4 TBE (P = 0.05).

Other predictors of grade ≥3 TEs and grade 4 TBE are shown in Table 3. There was no relationship between the emergence of grade 3–4 TEs or grade 4 TBE and the antiretroviral drugs used along with atazanavir/ritonavir. In the multivariate analysis, grade 3–4 TEs were independently associated only with baseline CD4 cell counts <300 mm3 [adjusted OR (AOR) (95% CI) = 8.77 (1.07–71.42), P = 0.04]. An analysis restricted to 113 patients in whom liver fibrosis was assessed yielded similar results. Grade 4 TBE was independently associated with baseline total bilirubin level >1 mg/dL [AOR (95% CI) = 3.2 (1.21–8.45), P = 0.01] and with age older than 40 years [AOR (95% CI) = 2.98 (1.19–7.47), P = 0.02] in the logistic regression analysis. Cirrhosis did not remain independently associated with grade 4 TBE in this analysis (P = 0.31). When the analysis was circumscribed to the 82 patients in whom a cirrhosis assessment had been carried out, the only parameter associated with grade 4 TBE was baseline total bilirubin level >1 mg/dL [AOR (95% CI) = 5.25 (1.40–19.69), P = 0.01].


   Discussion
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This study shows that the incidence of severe TE associated with atazanavir/ritonavir-containing regimens is low in HIV-infected patients with chronic viral hepatitis, including those with higher degrees of liver fibrosis. Remarkably, the frequency of toxic hepatitis in patients with viral liver cirrhosis receiving such combinations is similar to that observed in subjects without cirrhosis.

The presence of severe liver fibrosis markedly increases the risk of liver toxicity associated with some antiretroviral drugs.4–6 In studies where the definition of grade ≥3 TEs and the fibrosis scoring system used here were also applied, the frequencies of grade ≥3 TEs associated with nevirapine, efavirenz and nelfinavir including combinations were 25%, 18%4 and 18%,5 respectively, in patients with fibrosis F3 or F4. These figures are higher than those found in this study, both in patients with F ≥ 2 and in subjects with cirrhosis. Conversely, a frequency of 8% has been reported in patients with F ≥ 3 taking lopinavir/ritonavir.20 These and the findings of the present study are in agreement with the results of a meta-analysis, where the frequency of grade ≥2 TEs in patients on boosted protease inhibitors (PIs) was lower than in those receiving non-nucleoside analogues or unboosted PIs.21

The frequency of grade 4 TBE found in our study was expected, according to the results previously reported, and it does not seem to be substantially different from that observed in patients without viral hepatitis co-infection.11,12,14 TBEs were due to indirect bilirubin elevation in all but one patient in this study. In addition, TBE appeared without other signs of decompensated liver disease in most patients. These facts suggest that atazanavir/ritonavir treatment, rather than liver disease progression, was the cause of TBE. The only factors independently associated with grade 4 TBE were age older than 40 years and a level of baseline total bilirubin >1 mg/dL. In the univariate analysis, grade 4 TBE was more common among patients with cirrhosis. Plasma levels of atazanavir are increased in patients with moderate to severe hepatic insufficiency.22 Likewise, atazanavir and total bilirubin concentrations in plasma correlate.23 Because of this, it is conceivable that cirrhosis is a risk factor for TBE secondary to atazanavir/ritonavir. However, cirrhosis did not remain independently associated with TBE in the multivariate analysis in this study. This suggests that cirrhosis was a confounder and that the baseline level of bilirubin is actually the main determinant of hyperbilirubinaemia in patients on treatment with atazanavir/ritonavir. The presence of some polymorphisms of the gene of uridine-glucuronosyl transferase (UGT) 1A1, the enzyme responsible for the conjugation of indirect bilirubin, increases the risk of hyperbilirubinaemia associated with atazanavir therapy.24 Baseline total bilirubin level could reflect the activity of UGT1A1, which explains that it is a predictor of subsequent development of TBE in patients who start atazanavir/ritonavir. In addition, in patients with cirrhosis, total bilirubin plasma level is a marker of liver function. Because of this, the risk of TBE would be more strongly associated with this functional parameter than with the diagnosis of cirrhosis, a histological finding. Older age has also been reported to be a predictor of hyperbilirubinaemia associated with atazanavir therapy.24 A reduction in the activity of UGT1A1 with ageing could explain this finding. In any case, grade 4 TBE, despite being common, led to atazanavir/ritonavir discontinuation only in 2% of patients. The same low proportion of patients had to stop atazanavir/ritonavir due to TE. Both data demonstrate that the liver tolerance of atazanavir/ritonavir including combinations is good in patients with viral hepatitis co-infection, even though they have advanced liver fibrosis.

Patients with liver cirrhosis account for 10% to 20% of HIV/HCV co-infected subjects,25,26 and up to 50% out of individuals triply infected with HIV, HCV and HBV.26 Therefore, liver cirrhosis is a common challenge for healthcarers who attend HIV-infected patients in areas with high prevalence of viral hepatitis co-infection. However, little is known about the optimum management of ART in this subset of patients and the therapy options are limited. The levels of some antiretroviral drugs, such as efavirenz27 or lopinavir/ritonavir,28 have been reported to increase in patients with cirrhosis, although the clinical relevance of such elevations is uncertain. Data on this issue concerning boosted and unboosted atazanavir are very limited.22 Panels of experts recommend dose reduction of atazanavir in patients with a Child–Pugh–Turcotte (CPT) score 7–9 and avoiding this drug in patients with a CPT score >9,29,30 and in all patients with a CPT score ≥7, in the case of boosted atazanavir.30 An assessment of CPT score was not performed in all patients with cirrhosis in this study on starting atazanavir/ritonavir. However, subjects with severe hepatic insufficiency, with prior and subsequent liver decompensations, were included among these patients. Moreover, atazanavir/ritonavir was continued in three patients who developed hepatic decompensations, with resolution of the episode. In addition, the frequency of grade ≥3 TEs in patients with cirrhosis in this study was lower than that reported in very small groups of HIV/HCV-infected patients with cirrhosis who received efavirenz, nevirapine or lopinavir/ritonavir.7 These data suggest that the recommendations of avoiding atazanavir/ritonavir in patients with cirrhosis and moderate to severe hepatic insufficiency should be reconsidered. The results of a case series of patients with cirrhosis who were treated with atazanavir recently reported also support this statement.31

This study has a few limitations. First, not all patients underwent a liver fibrosis assessment. However, the analysis of the entire population and that restricted to patients with a fibrosis evaluation yielded similar results. This suggests that no significant bias has influenced the results. The second limitation is that different procedures have been used for fibrosis assessment. Nevertheless, the correlation of transient elastometry and liver biopsy results is high.17,18,32 Likewise, APRI and Forns indexes have shown a high positive predictive value for F ≥ 2 when compared with biopsy.19 A further limitation is the retrospective analysis of the data. However, transaminase and total bilirubin determinations in this cohort were scheduled and carried out at pre-determined time points, which partly counterbalance this drawback. In contrast, this study has included a larger number of HIV/hepatitis co-infected patients than all the clinical trials15 and cohort studies on atazanavir/ritonavir reported so far.13,14 Moreover, the data presented here probably reflect more accurately what happens in daily patient care than those provided by clinical trials. Both issues are strengths of this study.

The impact that PIs-based antiretroviral combinations may have on the progression of liver fibrosis is a matter of controversy.33–35 Some studies have found that they are associated with a slower progression than no HAART.33,34 On the other hand, atazanavir/ritonavir seems to increase the insulin resistance to a lesser extent than other PIs.36 Insulin resistance has been associated both with a faster fibrosis progression37 and with a lower rate of response to pegylated interferon plus ribavirin in HCV mono-infected patients.38 Both associations have not been proven in HIV/HCV co-infected subjects yet.39 However, if confirmed in studies currently ongoing, atazanavir/ritonavir may provide additional benefits to patients with HIV and hepatitis C co-infection.

In summary, the hepatic tolerance of atazanavir/ritonavir-based combinations is good in HIV-infected patients with chronic viral hepatitis, even in those with significant liver fibrosis or cirrhosis. Because of this and its unique metabolic profile, atazanavir/ritonavir may be an appropriate drug to be used in this subset. Specific clinical trials comparing this drug with other alternative options in such patients are warranted.


   Funding
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Funding
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 References
 
This study has been supported in part by grants from Bristol–Myers Squibb, the Fondo de Investigaciones Sanitarias of the Spanish Health Ministry (Reference EC07/90104) and the ISCIII-RETIC RD06/006.


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None to declare.


   Footnotes
 
{dagger} Members are listed in the Acknowledgements section. Back


   Acknowledgements
 
The Liverey Study Investigator Team also included the following members: J. A. Mira, S. Vergara and J. del Valle, Hospital Universitario de Valme, Seville, Spain; L. López-Cortés, Hospitales Universitarios Virgen del Rocío, Seville, Spain; M. J. Ríos-Villegas, Hospital Universitario Virgen Macarena, Seville, Spain; D. Merino, Hospital Juan Ramón Jiménez, Huelva, Spain; J. A. Girón, Hospital Universitario Puerta del Mar, Cadiz, Spain; F. Brun and A. Terrón, Hospital de Jerez, Jerez, Cadiz, Spain; L. Muñoz, Hospital Universitario San Cecilio, Granada, Spain; M. López and J. Pasquau, Hospital Universitario Virgen de las Nieves, Granada, Spain; V. Gutiérrez-Ravé, Hospital de Motril, Motril, Granada, Spain; A. Del Arco, Hospital Costa del Sol, Marbella, Malaga, Spain; and M. C. Gálvez, Hospital Torrecárdenas, Almería, Spain.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
1 Bonacini M. Liver injury during highly active antiretroviral therapy: the effect of hepatitis C coinfection. Clin Infect Dis (2004) 38(Suppl_2):S104–8.[CrossRef][Web of Science][Medline]

2 Becker S. Liver toxicity in epidemiological cohorts. Clin Infect Dis (2004) 38(Suppl 2):S49–55.[CrossRef][Web of Science][Medline]

3 Roca B, Suarez I, Gonzalez J, et al. Hepatitis C virus and human immunodeficiency virus coinfection in Spain. J Infect (2003) 47:117–24.[CrossRef][Web of Science][Medline]

4 Aranzabal L, Casado JL, Moya J, et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis (2005) 40:588–93.[CrossRef][Web of Science][Medline]

5 Mira JA, Macías J, Girón-González JA, et al. Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C. J Antimicrob Chemother (2006) 58:140–6.[Abstract/Free Full Text]

6 Labarga P, Soriano V, Vispo ME, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis (2007) 196:670–6.[CrossRef][Web of Science][Medline]

7 Casado J, Aranzábal L, Moya J, et al. HAART-associated hepatotoxicity in HIV/HCV-co-infected patients with cirrhosis. In: Abstracts of the Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, USA, 2006. Alexandria, VA, USA: Foundation for Retrovirology and Human Health. Abstract 889.

8 Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clin Infect Dis (2004) 38(Suppl 2):S90–7.[CrossRef][Web of Science][Medline]

9 Murphy RL, Sanne I, Cahn P, et al. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naïve subjects: 48-week results. AIDS (2003) 17:2603–14.[CrossRef][Web of Science][Medline]

10 Wood R, Phanuphak P, Cahn P, et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr (2004) 36:684–92.[Web of Science][Medline]

11 Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr (2004) 36:1011–9.[Web of Science][Medline]

12 Johnson M, Grinsztejn B, Rodríguez C, et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS (2006) 20:711–8.[Web of Science][Medline]

13 Pérez-Elías MJ, Gatell JM, Flores J, et al. Effect of ritonavir-boosted atazanavir (ATV/R) in experienced HIV-infected patients regarding hepatitis B/C status. Abstracts of the Third IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil, 2005. Abstract TuPe1.1C25.

14 Pineda JA, Palacios R, Rivero A, et al. Low incidence of severe liver toxicity in patients receiving antiretroviral combinations including atazanavir. J Antimicrob Chemother (2006) 57:1016–7.[Free Full Text]

15 Witek J, Mc Callister S, Odeshoo L, et al. Safety of atazanavir (ATV) and atazanavir/ritonavir (ATV/R) in subjects co-infected with HIV and hepatitis B and/or C: 1100 subject-years of treatment exposure. Abstracts of the Sixteenth International AIDS Conference, Toronto, Canada, 2006. Poster WEPE0054.

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