Digestive and Liver Disease
Volume 38, Issue 6 , Pages 363-373, June 2006

Hepatotoxicity and antiretroviral therapy with protease inhibitors: A review

Division of Infectious and Tropical Disease, IRCCS S. Matteo Hospital, University of Pavia, 27100 Pavia, Italy

Received 19 July 2005; accepted 25 January 2006.

Article Outline

Abstract 

Highly active antiretroviral therapy including protease inhibitors has led to dramatic decrease in the morbidity and mortality resulting from infection with human immunodeficiency virus-1. However, this combination regimen can be associated with the occurrence of serious toxicities, which may reduce patient compliance. In particular, human immunodeficiency virus-1 protease inhibitors and nevirapine among nonnucleoside reverse transcriptase inhibitors, have the potential for producing hepatotoxicity. We summarise current knowledge of the hepatotoxic effects associated with the commercially available human immunodeficiency virus-1 protease inhibitors based on a literature review of the major retrospective and prospective clinical studies designed to elucidate risk factors for developing hepatotoxicity among human immunodeficiency virus-1-infected patients receiving antiretroviral therapy containing protease inhibitors. Coinfection with chronic hepatitis, a common occurrence in human immunodeficiency virus-1-infected patients, is identified as an independent risk factor for developing hepatotoxicity in antiretroviral-treated human immunodeficiency virus-1-infected patients treated with antiretroviral regimens containing protease inhibitors. The importance of other risk factors for developing protease inhibitor-associated hepatotoxicity and the mechanism underlying the drug-related hepatotoxicity are discussed. The data indicate that the potential for producing hepatotoxicity is variable among the protease inhibitors and suggest that based on differences in drug-related hepatotoxicity, certain protease inhibitors may be preferred for the treatment of human immunodeficiency virus–hepatitis C virus coinfected patients.

Keywords: Antiretroviral therapy, Coinfection, Hepatotoxicity, Protease inhibitor

 

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1. Introduction 

Highly active antiretroviral therapy (HAART) incorporating combinations of reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) has been very successful in reducing morbidity and mortality among individuals infected with human immunodeficiency virus (HIV)-1 and is currently the standard of care for this disease [1], [2], [3]. This combination pharmacotherapy results in dramatic reductions in plasma HIV RNA, increase in CD4 T-cell counts and restoration of pathogen-specific immunity [4], [5]. However, a principal shortcoming of this successful therapeutic approach to limiting HIV replication is the potential toxicity of HAART regimens, which may also lead to reduced patient compliance. Adherence to therapy is of special importance in HIV-1-infected individuals in order to avoid the appearance of protease-resistant viral mutants and to ensure prolonged suppression of viral replication. Elevations in liver enzymes have been documented as a potential side effect of the majority of antiretroviral agents used for the therapy of HIV-1 infection [6], [7]. Severe hepatotoxicity in HAART-treated HIV-infected patients is a common cause of treatment interruption or patients’ discontinuation of therapy [8]. The risk of developing liver toxicity in patients receiving HAART is significant, varying between 2% and 14% of the treated population [9], [10].

Although the inclusion of PIs in therapeutic regimens has had a significant impact on the increase in survival, enhancement of immune function and decrease in opportunistic infections, this class has been associated with liver-related toxicity in some individuals [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]. It is noteworthy that a number of reports suggest that the risk of antiretroviral drug-related hepatotoxicity is enhanced significantly in those HIV-positive individuals who are coinfected with hepatitis viruses, particularly with the use of HAART comprising three-drug combinations that incorporate nevirapine and PIs [10], [11], [12], [13], [25], [26], [27], [28], [29], [30]. The role of hepatitis C virus (HCV) and hepatitis B virus (HBV) coinfection in the development of drug-related hepatotoxicity in HIV-1-infected patients is especially important as patients infected with HIV-1 are very commonly coinfected with HCV and/or HBV [31], [32], [33], [34], [35]. The frequently observed coinfection is consistent with the fact that these viruses have similar ways of transmission [36], [37].

In this review we present a summary and composite analysis of the results from various recent cohorts and both prospective and retrospective clinical trials designed to elucidate the role of PI-containing regimens in the development of antiretroviral therapy-related hepatotoxicity in HIV-infected patients receiving HAART that contained a PI [11], [12], [13], [18], [28], [29]. We compare and contrast the relative risks for hepatotoxicity among the selected PIs used in these major clinical studies. The data provide further evidence that hepatotoxicity is a significant side effect of HAART containing PIs and support the conclusion that the potential for hepatotoxicity differs among the commercially available PIs. However, to date, a long-term data on the use of PIs without nucleoside reverse transcriptase inhibitors (NRTIs) are lacking, and this is probably a confounding factor if we consider that the NRTIs too may play an important role in determining hepatotoxicity. Moreover, we must also consider the possible pitfalls existing in most of the study analysed here, which can make some limitations in assessing the relationship existing between HAART and the development of hepatic abnormalities.

Coinfection with hepatitis viruses as well as intravenous drug use and alcohol abuse is identified as other significant risk factor for hepatotoxicity in the HIV-1-infected population treated with HAART containing PIs. This information will be valuable in establishing appropriate guidelines for treatment algorithms for the clinical management of HIV-1-infected patients.

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2. Study designs 

The study designs of the clinical studies that are reviewed here were both retrospective and prospective and compared the toxic effects of multiple PIs (Table 1). Nine of the eleven studies were European-based and either multicentre [11], [12], [13], [26], [27], [38], [39] or single centre [18], [28], [29], and two studies were conducted in a US university's urban HIV clinic [20]. All of these studies included patients receiving combination regimens containing one PI or a two PI combination at initiation of HAART; moreover, in some studies a nonnucleoside reverse transcriptase inhibitor (NNRTI) was administrated together with PIs, representing an additional risk factor for developing hepatotoxicity (Table 1). In the combined studies cited in Table 1, a total of 9025 patients (range, 120–1325) received PIs as part of the treatment regimen. Among the seven PIs or PI combinations that were studied, indinavir was the most frequently prescribed: 3731 patients received indinavir (range, 36.8–55.5% of total patients), followed by saquinavir (1795 patients), nelfinavir (1496 patients), ritonavir (834 patients), amprenavir (32 patients) and lopinavir/ritonavir(120 patients) (Table 2).

Table 1. Study designs and treatment regimens in major clinical studies on the risk factors for hepatoxicity in HIV-1-infected patients receiving antiretroviral therapy including PIs
StudyDesign (study dates)Regimen
Den Brinker [28]Retrospective observational, single centre (1996–1998)HAART regimen with at least one PI
Sulkowski [18]Prospective cohort, single centre (1996–1998)PIs in combination therapy (211); nucleoside analog regimens (87)a
Monforte [11]Prospective observational, multicentre (1997–2000)First HAART regimen including at least two NRTIs and one PI or one NNRTI
Bonfanti [13]Prospective cohort, multicentre (1997–unspecified)HAART with at least one PI at initiation of therapy
Aceti [12]Retrospective multicentre (1997–1999)HAART with at least one PI for at least 6 mob
Nùňez [29]Retrospective chart review, single centre (1997–2000)HAART with two NRTIs plus PIs, NNRTIs and a PI plus an NNRTI
Savés [26]Prospective cohort in the Bordeaux University Hospital and four general hospitals (1996–1998)Two NRTIs without a PI, or HAART with a PI
Savés [27]Prospective multicentre (1997–1998)PI-containing antiretroviral regimen
Sulkowski [19]Prospective cohort (1996–2003)RTV-boosted or unboosted PI-based ART
Meraviglia [38]Prospective observational study, multicentre (2000–2002)LPV/RTV in HIV antiretroviral-experienced patients (782)
Gonzalez-Requena [39]Prospective observational study, single centreLPV in HIV patients with or without HCV coinfection (120)

HIV=human immunodeficiency virus; HAART=highly active antiretroviral therapy; NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=nonnucleoside reverse transcriptase inhibitor.

aPatient numbers in parentheses.

bNo modification of therapy allowed.

Table 2. Distribution of PI use among the HIV-infected patient populations treated with antiretroviral therapy including PIs
Den Brinker [28] (N=394)Sulkowski [18] (N=211)aMonforte [11] (N=1255)bBonfanti [13] (N=1477)cAceti [12] (N=1325)dNùňez [29] (N=125) [5]Savés [26] (N=1253)Savés [27] (N=1047)Sulkowski [19] (N=1161)Meraviglia [38] (N=782)eGonzalez-Requena [39] (N=120)Data from clinical TRIAL [54], [93], [94]
NFV–51 (24.3%)71 (5.7%)348 (23.6%)88 (6.6%)61 (48.8%)13f (1%)254f (24.3%)6055
IDV145 (36.8)117 (55.5%)644 (51.3%)865 (59.6%)680 (51.3%)57 (45.6%)639f (51%)466f (44.5%)10018
SQV112 (28.4)17 (8.1%)329 (26.2%)380 (25.7%)372 (28.2%)21 (16.8%)426f (34%)117f (11.2%) 21
RTV66 (16.8)22 (10.4%)180 (14.3%)279 (18.9%)120 (9.1%)11 (8.8%)–156f (14.9%)
RTV+SQV71 (18.0)28 (13.3%)–146 (9.9%)60 (4.5%) 13e (1%)–273
IDV+RTV––––5 (0.4%) 94
LPV+RTV 89782120
APV 32
Fos APV
ATV 20–40%
TPV 6%

HIV=human immunodeficiency virus; NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=nonnucleoside reverse transcriptase inhibitor; PI=protease inhibitor.

aNumber of patients receiving a PI-containing regimen.

bTwenty-six patients (2.1%) received two PI-containing regimens.

cSince patients were allowed to change treatment regimens in this observational study, the combined number of patients in the treatment groups exceeds the total number of enrolled patients.

dFour hundred and seventy three patients (35.7%) were therapy-naïve and 852 (64.3%) were therapy-experienced.

eSeventy-six patients (9.7%) were treated with LPV/r associated with another PI.

fPatient numbers were estimated from the percentages provided by Savés et al. [26], [27].

The baseline parameters were generally well matched among the various subgroups of HIV-infected patients, although those with chronic hepatitis had higher baseline aminotransaminase levels, which were indicative of their underlying liver disease. The ranges of the mean and the median ages of these predominantly male populations were 37–40 years and 34–36 years, respectively. All of the studies contained a significant proportion of HIV-infected patients who were coinfected with hepatitis viruses. A total of approximately 3946 patients (43.7% of the 9025 total patients combined for all studies) receiving PI-containing regimens had HCV and/or HBV coinfection.

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3. Incidence of hepatotoxicity 

In all of the studies cited above, hepatotoxicity was evaluated by changes in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT); in the prospective cohort study, gamma-glutamyl transferase was also included [13]. Severe hepatotoxicity, as defined by aminotransaminase levels >5 or >10× upper limit of normal (ULN), was observed in all studies. Severe hepatotoxicity was observed in higher percentages of patients coinfected with hepatitis virus versus those who were not coinfected. For example, 83 patients (53.9%) and 38 patients (4.8%) had severe hepatotoxicity in the coinfected population compared with 56 patients (38.9%) and 6 patients (1.1%) in the non-coinfected population, as described by Sulkowski et al. [18] and Aceti et al. [12], respectively. In a study by Sulkowski et al. [19], 63% of cases of hepatotoxicity were recorded among patients coinfected with HCV. In a retrospective case report study by Nùňez et al. [29], severe hepatotoxicity occurred in 10/96 patients (10%) receiving individual PIs and in 3/96 patients (9%) receiving PIs and NNRTIs. In a study by Gonzalez-Requena et al. [39], the total cumulative incidence of severe liver toxicity linked to LPV/r use at 12 months was 4% (4/99), all cases occurred among patients coinfected with HCV, and all had liver enzyme elevations at baseline. Among HCV-positive patients, the cumulative incidence of LPV associated liver toxicity was 8% (4/51), which was significantly greater (P=0.027) than among HCV-negative individuals. However, in this study there was no association between LPV plasma levels and severe hepatotoxicity.

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4. Risk factors 

Overall, a review of the data across all studies strongly supported an increased risk of developing hepatotoxicity associated with coinfection with HCV and/or HBV (Table 3). Sulkowski et al. [18] reported that severe hepatotoxicity developed in 83/154 coinfected patients (46.6%) versus 56/144 patients (38.9%) without coinfection (P=0.009), and Aceti et al. [12] reported that hepatotoxicity developed in 117/785 coinfected patients (14.9%) versus 30/540 patients (5.6%) without coinfection at 6 months of therapy and 90/604 coinfected patients (14.9%) versus 27/604 patients (4.5%) without coinfection at 12 months of therapy (P<0.0001 at both time points). The retrospective chart review reported by Nùňez et al. [29] identified coinfection with HCV (risk ratio, 3.99; 95% confidence interval (CI), 1.32–12.09; P=0.014) as one of the main predicting factors for hepatic injury. In the multivariate analysis conducted by Savés et al. [26], coinfection with HBV (hazard ratio, 3.0; 95% CI, 1.4–6.2) and HCV (hazard ratio, 3.2; 95% CI, 1.7–6.2) as well as a history of liver cytolysis (hazard ratio, 2.3; 95% CI, 1.2–4.4) and baseline ALT levels (hazard ratio, 2.4; 95% CI, 1.2–4.8 and hazard ratio, 3.3; 95% CI, 1.4–7.4, for 51–100IU/L and 101–200IU/L, respectively) was significantly associated with the occurrence of severe hepatic cytolysis. Rodriguez-Rosado et al. [10] also reported chronic HCV infection as an independent predictor of hepatotoxicity with transaminase levels increased more than twofold in 16/76 patients (21.1%) with chronic HCV versus 4/54 patients (7.4%) with no chronic HCV infection (P=0.03). Similarly, in 560 HIV-1-infected patients receiving HAART, chronic HCV and chronic HBV infections were also identified as independent risk factors for grade 4 liver transaminase elevations (i.e., AST or ALT≥10× ULN and an increase in absolute transaminase level >200IU/mL) (hazard ratios, 9.2 and 5.0, respectively) [40]. In a study by Meraviglia et al. [38], 58 of 71 patients developing a liver enzyme elevation presented HCV and/or HBV coinfection.

Table 3. Occurrence of hepatotoxicity in HIV-infected patients receiving antiretroviral therapy containing PIs
Incidence of hepatotoxicity
Den Brinker [28]Sulkowski [18]Monforte [11]Bonfanti [13]Aceti [12]Savés [26]Sulkowski [19]
Total hepatotoxicity70 (17.8%)139 (46.6%)a,b61 (4.9%)(5.8 [5.7–5.9])c147 (11.1%)N/AN/A
With coinfectiond13 (44.8%)e83 (53.9%)a46 (8.6%)e 117 (14.9%)f,g, P<0.0001f,h 65%
19 (33.3%)i 5 (11.1%)i 90 (14.9%)j, P<0.0001h
47 (4.5%)k 54 (18.7%)f,l, P<0.0001h

Without coinfection38 (12.4)56 (38.9%)a, P=0.009h3 (6.5%) 30 (5.6%)f,g 35%
24 (6.2%)f,j
5 (3.0%)f,l

Severe HepatotoxicityN/A139 (46.6%)a,b61 (4.9%)(2.7 [2.6–2.8])c44 (3.2%)23 (2.2)148 (12.7%)
With coinfectiond 83 (53.9%)a46 (8.6%)e 38 (4.8%)g, P<0.0001h21 (91.3%)
5 (11.1%)i 27 (4.5%)j, P<0.0001h
47 (4.5%)k 17 (5.9%)l, P<0.0001h

Without coinfection 56 (38.9%)a3 (6.5%) 6 (1.1%)g2 (8.7%)
1 (0.2%)j
0 (0%)l

Mild HepatotoxicityN/A 103 (7.8%)N/AN/A
With coinfectiond 79 (10.1%), P<0.0001h
63 (10.4%), P=0.01h
37 (12.8%), P<0.0002h

Without coinfection 24 (4.5%)
23 (5.7%)
5 (3.0%)

Incidences are expressed as patient numbers (percentage). Total hepatotoxicity refers to all cases regardless of severity. Percentages of patients calculated for total hepatotoxicity were based on the total number of patients in the study, whereas the percentages for those patients coinfected or not coinfected with hepatitis viruses were based on the numbers of patients in each of these categories. Hepatotoxicity was classified as follows: AST and/or ALT=3.5–5× baseline and >5× baseline (grades 3 and 4, respectively) for patients with pretreatment serum baseline aminotransferase levels above ULN, and 5.1–10.0× ULN and >10× ULN (grades 3 and 4, respectively) for patients with baseline aminotransferase levels within the normal range [18]; 1.25–2.5× baseline (grade 1), 2.6–3.5× baseline (grade 2), 3.6–5× baseline (grade 3), and >5× baseline (grade 4) for patients with pretreatment serum baseline aminotransferase levels above ULN; and 1.25–2.5× ULN (grade 1), 2.6–5× ULN (grade 2), 5.1–10× ULN (grade 3), and >10× ULN (grade 4) for patients with baseline aminotransferase levels within the normal range [29]; ALT≥200IU/mL (severe hepatotoxicity) [11]; ALT≤5× ULN (mild toxicity) or ALT>5× ULN (severe hepatotoxicity) [12], [13], [28]. ALT=alanine aminotransferase; AST=aspartate aminotransferase; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; N/A=data not available; PI=protease inhibitor; ULN=upper limit of normal.

aOnly patients on a PI regimen (N=211) are included.

bIncludes regimens containing PIs and dual nucleoside analogs.

cExpressed as incidence rate per 100 patient-years (95% CI).

dHBV+/HCV−.

eThe numbers of coinfected and non-coinfected patients were 785 and 540, respectively, at 6 months; 605 and 405, respectively, at 12 months; and 289 and 165, respectively, at 24 months.

fSix months after initiation of therapy.

gCompared with the comparable number of patients without coinfection in the study of Aceti et al. [12].

hCoinfected with HCV and/or HBV. In the data derived from the studies by Den Brinker and Sulkowski only patients coinfected with HBV and HCV, respectively, are included.

iHBV−/HCV+.

jTwelve months after initiation of therapy.

kHBV+/HCV+.

lTwenty-four months after initiation of therapy.

By contrast, Bonfanti et al. [13] did not find the correlation of hepatotoxicity with HBV positivity as measured by hepatitis B surface antigen to be statistically significant (P=0.06), and there appeared to be no further effect of coinfection with HBV/HCV on hepatotoxicity. However, these investigators reported that the presence of increased cytolysis at the initiation of the study, as measured by increased baseline transaminase levels, was significantly correlated with hepatotoxicity development (multivariate rate ratio, 2.6; P<0.001) and with HCV antibody positivity (multivariate rate ratio, 2.5; P<0.001). Coinfection with HBV was also not identified as a statistically significant risk factor for developing severe transaminase elevations in the univariate analysis conducted by Nùňez et al. [29]. The authors speculate that this negative result may have resulted from the use of lamivudine as part of the HAART regimens in almost all of the patients included in this study in light of the anti-HBV activity of lamivudine [41]. In the study by Gonzalez-Requena [39], none of HBsAg-positive carriers developed severe liver toxicity undergoing LPV/rtv.

Elevated baseline transaminase was predictive of developing liver enzyme elevations (relative risk, 1.05 and 95% CI, 1.01–1.08, per 10IU/L increase; P=0.01; hazard ratio, 7.41 and 95% CI, 4.88–11.22, per 10IU/L increase; P<0.01), as reported for Den Brinker et al.'s [28] and Monforte et al.'s [11] studies, respectively, according to the Cox proportional univariate models [42]. In the multivariate analysis conducted by Monforte et al. [11], baseline ALT levels continued to be associated independently with severe hepatic damage, as evidenced by an increase of 5.27 in the hazard ratio for every 10IU/L increase in ALT levels. The multivariate analysis conducted in the Swiss HIV Cohort Study also supported the conclusion that elevation in baseline ALT levels is an independent risk factor for grade 4 liver transaminase elevations (as defined above) in 560 HIV-1-infected patients receiving HAART (hazard ratio, 1.05 per 10IU/mL increase in ALT) [40].

It is noteworthy that the results of the prospective university-based study by Sulkowski et al. [18] did not provide evidence for a relationship between chronic hepatitis coinfection and the development of liver toxicity. Of HIV-1-infected patients with chronic HBV or HCV infection in this study, 88% did not have significant hepatotoxic effects. A potential explanation for the discrepancy with the data from the other studies is the smaller patient population in the study of Sulkowski et al. [18]. A statistical analysis indicated that the hepatotoxicity observed in this study was related to toxicity of the PI component, especially ritonavir (adjusted odds ratio, 8.6; 95% CI, 3.0–24.6) (see Section 4.1).

Sulkowski et al. [18] also reported in their single-centre study that an increase in CD4 cell recovery >0.05×109/L was associated with severe hepatotoxicity; patients exhibiting this increase had a higher rate of liver enzyme elevations than patients with smaller increases or decreasing CD4 cell counts (odds ratio, 3.0; 95% CI, 0.9–10.3).

Univariate proportional analysis identified intravenous drug use as an independent risk factor for the occurrence of liver toxicity [11], [12]. In the study by Monforte et al. [11], intravenous drug users had a higher risk of severe hepatic cytolysis than heterosexuals (hazard ratio, 5.27; 95% CI, 2.57–10.80). Aceti et al. [12] reported that intravenous drug use is an independent risk factor for hepatotoxicity when the entire population of HIV-1-infected patients is analysed (odds ratio, 1.95; 95% CI, 1.17–3.27; P=0.0108), but reported no significant differences in the occurrence of hepatotoxicity with and without intravenous drug use when the coinfected population of HIV-1-infected patients was considered. In the prospective observational study by Meraviglia et al. [38], the use of intravenous drugs in the past is considered a risk factor related to a liver enzyme elevation (P=0.0006; RR 2.22; 95% CI, 1.405–3.510). Alcohol abuse has also been recognised as an independent risk factor for hepatotoxicity by univariate analysis. These investigators also noted that alcohol abuse was an independent risk factor associated with hepatotoxicity development after 6 months of treatment (odds ratio, 1.7; 95% CI, 1.13–2.54; P=0.010). In this study there was a significant difference in the incidence of total hepatotoxicity in alcohol abusers both with and without coinfection (21/133 versus 1/33; P=0.04) although the occurrence of hepatotoxicity was the same in cases of mild or moderate hepatotoxicity [12]. Similarly, in the retrospective chart analysis conducted by Nùňez et al. [29], alcohol abuse was identified in the multivariate analysis as the greatest risk factor (risk ratio, 5.87; 95% CI, 1.49–23.15; P=0.011), followed by HCV infection (risk ratio, 3.99; 95% CI, 1.32–12.09; P=0.014) and older age (risk ratio, 1.11; 95% CI, 1.04–1.18; P=0.001).

4.1. PIs as risk factors 

The rates of occurrence of liver enzyme elevations in HIV-1-infected patients as a function of the PI that were reported for six major clinical studies are summarised in Table 4.

Table 4. Occurrence of liver enzyme elevations in HIV-1-infected patients as a function of the PIa
Incidence of liver enzyme elevations (cases per 100 patients exposed)
Sulkowski [18] (N=211)bNùňez (N=135)Monforte [11] (N=1255)Bonfanti [13] (N=1477)Aceti [12] (N=1325)Savés [25] (N=1253)
Hep−cHep+dAll patients
Nelfinavir5.9 (1.2–16.2)9.81.33.5000e0.7
Indinavir6.8 (3.0–13.1)8.84.14.70.71.91.3e0.8b
Saquinavir5.9 (0.15–28.7)14.36.16.31.64.83.7e0.2b
Ritonavir27.3 (10.7–50.2)18.26.19.71.720.011.7e0.5b
Ritonavir+saquinavir32.1 (15.9–5.4) 8.2 11.6–
Indinavir+ritonavir– – 0–

AST=aspartate aminotransaminase; ALT=alanine aminotransaminase; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; ULN=upper limit of normal.

aLive toxicity was defined as AST or ALT>3–5 or 5× ULN (grades 3 and 4, respectively) for patients with elevated baseline aminotransferase levels above ULN, or 5.1–10.0 and >10× ULN (grades 3 and 4, respectively) for patients with baseline aminotransferase levels within the normal range [18]; ALT≥200IU/mL; AST or ALT>5× ULN [12], [13]; 3.6–5× baseline (grade 3), and >5× baseline (grade 4) for patients with pretreatment serum baseline aminotransferase levels above ULN, and 5.1–10× ULN (grade 3), and >10× ULN (grade 4) for patients with baseline aminotransferase levels within the normal range [29].

bOnly cases of severe cytolysis were reported. Patient numbers were estimated from the percentages provided by Savés et al. [26].

cHepatitis virus negative.

dHepatitis virus positive (HBV and/or HCV).

eDifferences between nelfinavir, indinavir, saquinavir and ritonavir are highly significant (P=0.0001).

Ritonavir full-dose was generally associated with a high risk for cytolysis and associated liver enzyme elevations. The incidence (cases per 100 patients) of liver enzyme elevations for all patients ranged from 11.7 to 27.3 for ritonavir and from 11.6 to 32.1 for ritonavir/saquinavir compared with 0–9.8, 1.3–8.8 and 3.7–14.3 for nelfinavir, indinavir and saquinavir, respectively (excluding the data of Savés et al. [26] which were based on severe hepatotoxicity only) (Table 4). In the study by Bonfanti et al. [13], the relative risk was 2.2 (1.4–2.5; P<0.001) for ritonavir and 1.6 (0.9–3.0; P=0.13) for the ritonavir/saquinavir combination PI therapy compared with 0.7 (0.4–1.3; P=0.25), 0.7 (0.4–1.3; P=0.07) and 0.9 (0.6–1.6; P=0.97) for nelfinavir, indinavir and saquinavir, respectively (Table 4). In the retrospective cohort study by Wit et al. [40], a multivariate model also identified recent use of ritonavir as an independent risk factor (hazard ratio, 4.9; CI, 2.0–12.1; P=0.0007). It is also relevant that among phase III trials utilising antiretroviral therapy containing PIs, a rate of 9% hepatotoxicity was seen with ritonavir [43] compared with 2–3% for indinavir [44], [45]. In the study by Aceti et al. [46], hepatotoxicity developed in a low number of subjects in patients without coinfection, but was significantly higher in coinfected patients; moreover, ritonavir full-dose was associated with higher rates of severe liver toxicity in the coinfected group. The severe ritonavir-associated hepatotoxicity in the coinfected group may be due, in part, to the fact that the plasma levels of ritonavir may increase in HCV coinfected patients. However, we must underline that all the previously cited papers are talking about full (high)-dose ritonavir, which is no longer used in clinical practice from many years.

Hepatotoxicity has been reported as an adverse effect in the prescribing information for the US FDA-approved PIs nelfinavir [47], indinavir [48], atazanavir [49], ritonavir [50], lopinavir/ritonavir [51], saquinavir [52], amprenavir, fosamprenavir [53] and tipranavir [54]. The incidence values have ranged from 1 to 2 cases per 100 patients for nelfinavir, which was the lowest range among this group, and from 2.2 to 9.5 for lopinavir/ritonavir. Among the studies described here, Sulkowski et al. [18] observed that the relative risk of severe hepatotoxicity in patients receiving a PI-containing regimen was more than twice that seen in patients who were prescribed regimens with dual nucleoside analogs (adjusted odds ratio, 8.6; 95% CI, 3.0–24.6).

The hepatotoxicity associated with ritonavir may be reduced by lowering the dose. Low-dose ritonavir (≤200mg b.i.d.) has been increasingly used to change the pharmacokinetics of other PIs like lopinavir and indinavir to permit less frequent dosage as well as to increase efficacy [55], [56], [57], [58]. Sulkowski et al. [22], [23] have recently reported the incidence of severe hepatotoxicity (i.e., grade 3 or 4 change in serum ALT/AST) in HIV-infected patients receiving antiretroviral regimens containing PIs with or without ritonavir. It is notable that the highest risk was observed in patients receiving combinations of saquinavir/ritonavir (800mg/day) and indinavir/ritonavir (200–400mg/day). No increased risk was reported for patients receiving either nelfinavir or the lopinavir/ritonavir combination. In addition, this study showed that the incidence of grades 3–4 hepatotoxicity was higher in HCV-positive patients (4%) than in HCV-negative patients (8.7%) (relative risk 2.0; 95% CI, 1.44–2.78). Of HCV/HIV-coinfected patients, 83% did not exhibit hepatotoxicity, although the risk of developing it in this patient population was twofold greater than in HIV-monoinfected patients. The authors concluded that the use of PIs should not be restricted in this coinfected population. In a study of 19 consecutive HIV-1 patients coinfected with HCV or HBV treated for at least 6 months with indinavir and at least two nucleoside analogues, low-dose ritonavir did not appear to impair liver function tests [59].

Lopinavir is a recently developed PI that is well tolerated and demonstrates potent antiviral activity against HIV-1 when formulated with ritonavir [60], [61], [62]. In a recent retrospective evaluation of the effects on HIV viral load and liver transaminase flares in HIV/HCV coinfected patients receiving HAART containing either lopinavir/ritonavir or nelfinavir [63], 8/41 patients (19.5%) in the nelfinavir arm and 2/29 patients (6.9%) in the lopinavir/ritonavir arm experienced grade 3+ ALT elevations. However, the increase in ALT from baseline was not statistically different for the two groups at 48 weeks. The percentage of patients in the nelfinavir group showing hepatotoxicity in this study was significantly higher than in previous studies (Table 4), which may reflect the significantly lower total number of patients in this subset analysis.

Atazanavir (Reyataz®) is a recently licensed PI that has a favourable lipid profile compared to current commercially available PIs and hence is used in patients with dyslipidemia [64], [65]. It can cause hyperbilirubinaemia by inhibiting glucoronisation pathway. The incidence of hepatotoxicity in registrative trial is 2–7/100 patient exposed [24].

Fosamprenavir (Telzir®) is another recently licensed PI used for the treatment of both antiretroviral naïve and experienced patients. The previous formulation (Amprenavir) required an intake of high number of pills per day, but its dosage could be adjusted according to Child Pough score. Fosamprenavir should be administered with and without ritonavir boosting. Incidence of ALT increase ranges from 6% to 8%, both in naïve and experienced patients. [53].

Tipranavir (Aptivus®) is another promising investigational PI that is of special interest because it demonstrates broad activity against various PI-resistant strains [66], [67]. As TPV is rapidly metabolised, combination with other PIs like ritonavir has been evaluated in clinical trials in order to increase exposure. In a multicentre, double-blinded study of 3 TPV/ritonavir doses (500mg/100mg, 500mg/200mg and 750mg/200mg; all administered twice daily), grade 3/4 ALT and triglycerides elevations were seen in 11% and 27%, respectively, of patients [68]. Further clinical studies are needed to evaluate more fully the hepatotoxicity potential of both atazanavir and TPV.

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5. Mechanisms for hepatotoxicity 

The mechanism for the relationship between antiretroviral therapy and the development of hepatotoxicity remains speculative. Moreover, the way in which hepatotoxicity is defined, the type of patients included in the study, the previous treatment history, the concomitant treatment, the alcohol use, the past intravenous drug use and the duration of follow-up are fundamental to make a real analysis of the incidence of hepatotoxicity in each study analysed; in the same way, the type of study which assesses the relationship between antiretroviral drugs and hepatotoxicity is important. Both types of study, randomised clinical trial and observational database studies, have in fact some limitation [69].

The enhanced hepatotoxicity may simply reflect direct drug-related hepatotoxicity that is enhanced in the presence of hepatitis viral coinfection [25], [70], [71] or, alternatively, an immune-mediated activation of latent or chronic hepatitis viral replication that is associated with reconstitution of the immune system following HAART. Although the mechanism for the enhanced hepatotoxicity under these conditions was not elucidated, potential explanations include an increase in HCV replication and/or enhanced cytotoxic T-cell activity. This elevated level of CD4 and CD8 T-cell responses could result in enhanced HBV- and HCV-specific lysis of infected liver cells with consequent elevation of serum transaminase activity and increase in hepatitis viral load and replication [72], [73], [74], [75], [76], [77]. In cases of acute symptomatic hepatitis associated with the use of PIs, HCV infection was recognised only after HCV antibody seroconversion [74]. This generation of a specific humoral response was considered indicative of functional restoration of T-cell activity and provided evidence that the hepatitis seen in patients coinfected with HCV and HIV was actually an “immune restoration disease”. Patients with low CD4 levels also had an increased incidence of severe hepatotoxicity.

However, the immune restoration theory of hepatotoxicity is not uniformly supported by the clinical results. Aceti et al. [12] have observed that hepatotoxicity occurred more often in those patients who were unresponsive to HAART and, conversely, that responders to therapy demonstrated a decrease in serum transaminase activity. This result challenges the theory that there is an enhanced lysis of hepatitis-virus-infected cells in those patients who have a restoration of their immune systems in response to therapy. The improvement in chronic liver disease in these patients appeared to parallel the increase in CD4 cell counts, and hence it appears that the immune restoration actually reduced HCV replication. Interference with the progression of hepatic fibrosis has also been seen with HAART containing PIs [78]. HIV infection in fact may have a direct cytopatic effect on liver cells or modify the pattern of cytokine production, leading to the production of fibrogenic factors or to a decrease in antifibrogenic factors [79], [80]. The risk of direct viral cytotoxicity can be controlled, for example, in HBV infection by the use of some NRTIs that can inhibit the HBV-DNA polymerase, such as lamivudine, adefovir dipivoxyl and tenofovir. Unfortunately this is not true for the HCV infection, even if an anedoctal case of disappearance of detectable HCV-RNA level have been described in patients receiving HAART (especially ritonavir) [81].

The Prometheus Study reported by Gisolf et al. [17] was designed to investigate potential risk factors for liver enzyme elevations after treatment with ritonavir and saquinavir with or without stavudine. This study was an open-label, multicentre trial conducted in 208 HIV-1-infected patients randomised to receive oral ritonavir and saquinavir (400mg each b.i.d.) with or without stavudine (40mg b.i.d.; 30mg b.i.d. if body weight <60kg). Although the Prometheus Study did not find that baseline HCV levels are predictive of this severe liver toxicity, the results did provide further support for baseline HBV positivity as a risk factor for elevated liver enzyme levels. Hepatitis B surface antigen positivity (relative risk, 8.8; 95% CI, 3.3–23.1) and the use of stavudine (relative risk, 4.9; 95% CI, 1.5–16.0) were identified as significant risk factors for developing liver enzyme elevations.

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6. Therapeutic drug monitoring 

PIs show large variations in interpatient and intrapatient serum levels, principally because of differences in the metabolism of this class through the cytochrome P450 system, specifically the 3A4 isozyme. Other drugs that are also metabolised by this system may therefore interact with PIs, leading to elevations or depressions of circulating PI levels. A number of clinical studies support a relationship between suboptimal drug levels and lack of efficacy, or elevated levels and enhanced toxicity, of antiviral regimens incorporating PIs [82], [83], [84], [85], [86], [87], [88]. Thus, at least in theory, it is reasonable to propose therapeutic drug monitoring of serum levels of PIs in order to achieve maximal suppression of viral load and to prevent the emergence of resistant mutations, as well as to minimise side effects such as hepatotoxicity, especially among the HIV/HCV coinfected population. Such monitoring may be of special importance for PI combinations such as ritonavir with other PIs that have as the goal an increase in concentration of the paired drug.

It is notable that liver impairment through hepatitis infection or the drug-induced hepatotoxicity itself may affect the pharmacokinetics of the antiretroviral drug and achievable serum levels. Thus, results of a well-designed study by Arribas et al. [89] in patients with chronic hepatitis and cirrhosis point to the detrimental effects of hepatotoxicity on the pharmacokinetic parameters of lopinavir. The lopinavir Cmin obtained from pooled data from the mildly and moderately liver-impaired population was significantly different when compared with that of the control group (P<0.05). In addition, a French group reported that indinavir Cmin exceeding the desired value of 675ng/mL appeared at a higher frequency in coinfected patients (HCV and/or HBV coinfection) than in a non-coinfected control population (83% and 18%, respectively) [90]. This result may explain why patients with chronic hepatitis show an increased rate of nephrolithiasis when compared with a non-coinfected population.

In the study by Regazzi et al. [91] about the PK of Nelfinavir and its metabolite M8, the NFV CL/F was significantly lower in HIV/HCV coinfected patients with and without cirrhosis than in HIV+/HCV− individuals (28% and 58% lower, respectevly; P<0.05), which translated into higher levels of systemic drug exposure in cirrhotic and noncirrhotic patients. However, it is not yet firmly established that elevated serum levels of PIs contribute significantly to the development of hepatotoxicity.

One report suggests that plasma nelfinavir and saquinavir concentrations may not predict hepatotoxicity [92]. However, this conclusion was not based on parallel measurements of serum drug levels and liver enzyme elevations. Thus, controlled clinical studies are yet required to definitively establish the role of therapeutic drug monitoring in HIV-1 patients receiving HAART containing PIs as well as the serum concentrations of PIs and other components of the antiretroviral regimens that must be achieved for optimal therapeutic effect with minimal toxicity.

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7. Conclusions 

Hepatotoxicity is now recognised as a significant potential toxicity associated with multidrug antiretroviral therapy involving PIs, even if the PI related hepatotoxicity is still less than that one observed for nevirapine. The clinical data reviewed here show that risk factors for developing hepatotoxicity in HIV-1-infected patients treated with HAART containing PIs include coinfection with hepatitis virus prior to treatment, high baseline liver enzyme levels, intravenous drug use and alcohol abuse. This is way in coinfected patients or in HIV+ individuals with underlying liver disease, the diagnosis and the management of liver-related biochemical abnormalities are more difficult. We recommend that antiviral therapy should not be withheld from patients coinfected with HIV and hepatitis virus but rather that the PI to be incorporated into the combination regimen be selected judiciously. To date nelfinavir and lopinavir/ritonavir come across as being the less hepatotoxic PIs in coinfected patients. Regular monitoring of transaminases levels in HIV-1-infected patients is advisable. The risk of hepatotoxicity can be reduced through avoidance of excess alcohol intake and prior therapy for hepatitis virus infections. Continued monitoring of adverse events in HIV-1-infected patients treated with antiretroviral therapy incorporating PIs is recommended in order to extend the database on potential risk factors and the incidence of hepatotoxicity. Further controlled clinical trials are required to understand the mechanism for the interaction between antiretroviral therapy containing PIs and the emergence of hepatotoxicity in coinfected patients.

Conflict of interest statement

None declared.

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References 

  1. The EuroSIDA Study Group . Changing patterns of morbidity and mortality across Europe in patients infected with HIV-1. Lancet. 1998;352:1725–1730
  2. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853–860
  3. Saag M, Gersten M, Chang Y. Long term virological and immunological effect of the HIV protease inhibitor viracept (nelfinavir mesylate) in combination with zidovudine (AZT) and lamivudine (3TC). Program and Abstracts of the Infectious Disease Society of America 35th Annual Meeting [abstract].
  4. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic centimeter or less. N Engl J Med. 1997;337:725–733
  5. Jocobson MA, French M. Altered natural history of AIDS-related opportunistic infections in the era of potent combination antiretroviral therapy. Acquir Immune Defic Syndr. 1997;12(Suppl. A):5157–5163
  6. Notermans DW, van Leeuwen R, Lange JM. Treatment of HIV infection: tolerability of commonly used antiretroviral agents. Drugs Exp. 1996;15:176–187
  7. Lee BL, Safrin S. Interactions and toxicities of drugs used in patients with AIDS. Clin Infect Dis. 1992;14:773–779
  8. Piroth L, Grappin M, Waldner A, Sgro C, Duong M, Buisson M, et al. Discontinuing protease inhibitor therapy for intolerance. Longitudinal study of 309 patients. Presse Med. 1999;28:381–387
  9. Flexner C. HIV-protease inhibitors. N Engl J Med. 1998;338:1281–1292
  10. Rodriguez-Rosado R, Garcia-Samaniego J, Soriano V. Hepatotoxicity after introduction of highly active antiretroviral therapy. Acquir Immune Defic Syndr. 1998;12:1256
  11. d’Arminio Monforte A, Bugarini R, Pezzotti P, De Luca A, Antinori A, Mussini C, et al. Cohort of Naive for Antiretrovirals) Study Group Low frequency of severe hepatotoxicity and association with HCV coinfection in HIV-positive patients treated with HAART. J Acquir Immune Defic Syndr. 2001;28:114–123
  12. Aceti A, Pasquazzi C, Zechini B, De Bac C LIVERHAART Group. Hepatotoxicity development during antiretroviral therapy containing protease inhibitors in patients with HIV: the role of hepatitis B and C virus infection. J Acquir Immune Defic Syndr. 2002;29:41–48
  13. Bonfanti P, Landonio S, Ricci E, Martinelli C, Fortuna P, Faggion , et al. Risk factors for hepatotoxicity in patients treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;27:316–318
  14. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000;356:1423–1430
  15. Fellay J, Boubaker K, Ledergerber B, Bernasconi E, Furrer H, Battegay , et al. Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study. Lancet. 2001;358:1322–1327
  16. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Elevated liver enzymes following initiation of antiretroviral therapy. J Am Med Assoc. 2000;283:2526–2527[letter]
  17. Gisolf EH, Dreezen C, Danner SA, Weel JL, Weverling GJ Prometheus Study Group. Risk factors for hepatotoxicity in HIV-1-infected patients receiving ritonavir and saquinavir with or without stavudine. Clin Infect Dis. 2000;31:1234–1239
  18. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. J Am Med Assoc. 2000;283:74–80
  19. Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitors-based antiretroviral regimens with or without concurrent ritonavir. Acquir Immune Defic Syndr. 2004;18:2277–2284
  20. Arribas JR, Ibanez C, Ruiz-Antoran B, Pena JM, Esteban-Calvo C, Frias J, et al. Acute hepatitis in HIV-infected patients during ritonavir treatment. Acquir Immune Defic Syndr. 1998;12:1722–1724
  21. Picard O, Rosmorduc O, Cabane J. Hepatotoxicity associated with ritonavir. Ann Intern Med. 1998;129:670–671[letter]
  22. Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated with the antiretroviral therapy (ART) containing protease inhibitors with and without pharmacokinetic boosting by low-dose ritonavir (RTV). Hepatology. 2003;38(Suppl. 1):698a;[Abstract 1125]
  23. Sulkowski MS. Hepatotoxicity associated with antiretroviral therapy containing HIV-1 protease inhibitors. Semin Liver Dis. 2003;23:183–194
  24. 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
  25. Matsuda J, Gohchi K. Severe hepatitis in patients with AIDS and hemophilia B treated with indinavir. Lancet. 1997;349:924–925
  26. Savés M, Vandentorren S, Daucourt V, Marimoutou C, Dupon M, Couzigou P, et al. Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations, Aquitane cohort, France, 1996–1998. Acquir Immune Defic Syndr. 1999;13:115–121
  27. Savés M, Raffi F, Clevenbergh P, Marchou B, Waldner-Combernoux A, Morlat P, et al. Hepatitis B or hepatitis C virus infection co-infection and the risk for hepatotoxicity of highly active antiretroviral regimen in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2000;44:3451–3455
  28. den Brinker M, Wit FW, Wertheim-van Dillen PM, Jurriaans S, Weel J, van Leeuwen R, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. Acquir Immune Defic Syndr. 2000;14:2895–2902
  29. Nùňez 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;27:426–431
  30. Martinez E, Blanco JL, Arnaiz JA, Perez-Cuevas JB, Mocroft A, Cruceta A, et al. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. Acquir Immune Defic Syndr. 2001;15:1261–1268
  31. Dieterich DT. Hepatitis C virus and human immunodeficiency virus: clinical issues in coinfection. Am J Med. 1999;107:S79–S84
  32. Ockenga J, Tillmann HL, Trautwein C, Stoll M, Manns MP, Schmidt RE. Hepatitis B and C in HIV-infected patients. Prevalence and prognostic value. J Hepatol. 1997;27:18–24
  33. Zylberberg H, Pol S. Reciprocal interactions between human immunodeficiency virus and hepatitis C virus infections. Clin Infect Dis. 1996;23:1117–1125
  34. Diamondstone LS, Blakley SA, Rice JC, Clark RA, Goedert JJ. Prognostic factors for all-cause mortality among hemophiliacs infected with human immunodeficiency virus. Am J Epidemiol. 1995;142:304–313
  35. Perrillo RP, Regenstein FG, Roodman ST. Chronic hepatitis B in asymptomatic homosexual men with antibody to the human immunodeficiency virus. Ann Intern Med. 1986;105:3382–3383
  36. McNair AN, Main J, Thomas HC. Interactions of the human immunodeficiency virus and the hepatotropic viruses. Semin Liver Dis. 1992;12:188–196
  37. Horvath J, Raffanti SP. Clinical aspects of the interactions between human immunodeficiency virus and the hepatotropic viruses. Clin Infect Dis. 1994;18:339–347
  38. Meraviglia P, Schiavini M, Castagna A, Vigano P, Bini T, Landonio S, et al. Lopinavir/ritonavir treatment in HIV antiretroviral-experienced patients: evaluation of risk factors for liver enzyme elevation. HIV Medicine. 2004;5:334–343
  39. Gonzalez-Requena D, Nunez M, Jimenez-Nacher I. Liver toxicity of lopinavir-containing regimens in HIV-infected patients with or without hepatitis C coinfection. Acquir Immune Defic Syndr Res Hum Retroviruses. 2004;7:698–700
  40. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis. 2002;186:23–31
  41. Benhamou Y, Katlama C, Lunel F, Coutellier A, Dohin E, Hamm N, et al. Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. Ann Intern Med. 1996;125:705–712
  42. Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187–220
  43. Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet. 1998;351:543–549
  44. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997;337:734–739
  45. Pialoux G, Raffi F, Brun-Vezinet F, Meiffredy V, Flandre P, Gastaut JA, et al. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. N Engl J Med. 1998;339:1269–1278
  46. Aceti A, Pasquazzi C, Zechini B, De Bac C, the LIVERHAART Group . Development of hepatotoxicity in HIV patients switching at least one protease inhibitor. Int J Sex Transm Dis Acquir Immune Defic Syndr. 2005;16:148–152
  47. Viracept® (nelfinavir). Prescribing information—USA. San Diego, CA: Agouron Laboratories; 1999.
  48. Crixivan® (indinavir sulfate). Prescribing information—USA. Whitehouse Station, NJ: Merck and Co.; 2001.
  49. Reyataz® (atazanavir sulfate). Prescribing information (USA). Princeton, NJ: Bristol Myers Squibb; 2003.
  50. Norvir® (ritonavir). Prescribing information (USA). North Chicago, IL: Abbott Laboratories; 1999.
  51. Kaletra® (lopinavir/ritonavir) capsules and oral solution. Prescribing information (USA). North Chicago, IL: Abbott Laboratories; 2000.
  52. Fortovase® (saquinavir). Prescribing information (USA). Nultey, NJ: Roche Laboratories; 1998.
  53. Lexiva® (fosamprenavir) product information: Lexiva™, fosamprenavir tablets. GlaxoSmithKline, Research Triangle Park, NC.
  54. Croom KF, Keam SJ. Tipranavir. A ritonavir-boosted protease inhibitor. Drugs. 2005;65:1669–1677
  55. Bergshoeff AS, Fraaij PL, van Rossum AM, Verweel G, Wynne LH, Winchell GA, et al. Pharmacokinetics of indinavir combined with low-dose ritonavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. 2004;48:1904–1907
  56. Acosta EP, Bardeguez A, Zorrilla CD, Van Dyke R, Hughes MD, Huang S, et al. Pharmacokinetics of saquinavir plus low-dose ritonavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother. 2004;48:430–436
  57. Hendrix CW, Fiske WD, Fuchs EJ. Pharmacokinetics of the triple combination of saquinavir, ritonavir, and efavirenz in HIV-positive patients. Presented at the 7th Conference on Retroviruses and Opportunistic Infections [abstract 79].
  58. Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A. Virologic responses to a ritonavir–saquinavir-containing regimen in patients who had previously failed nelfinavir. Acquir Immune Defic Syndr. 1999;13:F23–F28
  59. Vora S, Michon C, Junet C, Balavoine JF, Renold-Moynier C, Yerly S, et al. Switch from indinavir to ritonavir–indinavir regimen in patients treated with highly active antiretroviral therapy co-infected with hepatitis C is not associated with alteration of liver function tests. Acquir Immune Defic Syndr. 2000;14:2795–2797
  60. Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346:2039–2046
  61. Bongiovanni M, Bini T, Chiesa E, Cicconi P, Adorni F, Monforte d’Arminio A. Lopinavir/ritonavir vs. indinavir/ritonavir in antiretroviral naive HIV-infected patients: immunovirological outcome and side effects. Antiviral Res. 2004;62:53–56
  62. Cooper CL, van Heeswijk RP, Gallicano K, Cameron DW. A review of low-dose ritonavir in protease inhibitor combination therapy. Clin Infect Dis. 2003;36:1585–1589
  63. Sherman KE, Shire NJ, Cernohous P. Evaluation of HCV RNA and liver injury in HCV/HIV coinfected patients initiating lopinavir or nelfinavir-based therapy. Presented at the 11th Conference on Retrovirus and Opportunistic Infections [poster 811].
  64. Wood R, Phanuphak P, Cahn P, Pokrovskiy V, Rozenbaum W, Pantaleo G. 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;36:684–692
  65. Eholie SP, Lacombe K, Serfaty L, Wendum D, Girard PM. Acute hepatic cytolysis in an HIV-infected patient taking atazanavir. Acquir Immune Defic Syndr. 2004;18:1610–1611
  66. Turner SR, Strohbach JW, Tommasi RA, Aristoff PA, Johnson PD, Skulnick HI, et al. Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. J Med Chem. 1998;41:3467–3476
  67. Back NK, van Wijk A, Remmerswaal D, van Monfort M, Nijhuis M, Schuurman R, et al. In-vitro tipranavir susceptibility of HIV-1 isolates with reduced susceptibility to other protease inhibitors. Acquir Immune Defic Syndr. 2000;14:101–102[letter]
  68. Kohlbrenner V, Gathe J, Pierone G. Tipranavir/ritonavir (TPV/R) demonstrates potent efficacy in multiple protease inhibitor (PI) experienced patients at 24 weeks: BI 1182.52. Program and abstracts of the 9th European AIDS Conference (EACS), 1st EACS Resistance & Pharmacology Workshop. Warsaw, Poland; 25–29 October; 2003 [abstract 7.2/2].
  69. Sabin CA. Pitfalls of assessing hepatotoxicity in trials and observational cohorts. CID. 2004;38(Suppl. 2):56–64
  70. Brau N, Leaf HL, Wieczorek RL, Margolis DM. Severe hepatitis in three AIDS patients treated with indinavir. Lancet. 1997;349:924–925
  71. Vergis E, Patterson D, Singh N. Indinavir-associated hepatitis in patients with advanced HIV infection. Int J Sex Transm Dis Acquir Immune Defic Syndr. 1998;9:53
  72. Vento S, Garofano T, Renzini C, Casali F, Ferraro T, Concia E. Enhancement of hepatitis C virus replication and liver damage in HIV coinfected patients on antiretroviral combination therapy. Acquir Immune Defic Syndr. 1998;12:116–117
  73. Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor. Lancet. 1997;349:995–996
  74. John M, Flanagan J, French MAH. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with protease inhibitors: an immune restoration disease?. Acquir Immune Defic Syndr. 1998;12:2289–2293
  75. Sepkowitz KA. Effects of HAART on natural history of AIDS-related opportunistic disorders. Lancet. 1998;351:228–230
  76. Gavazzi G, Bouchard O, Leclercq P, et al. Enhancement of hepatitis C virus replication and liver damage in HIV coinfected patients on antiretroviral combination therapy: differences between complete and partial virologic responders. Acquir Immune Defic Syndr Res Hum Retroviruses. 2000;16:1021–1023
  77. Rutschmann OT, Negro F, Hirschel B, Hadengue A, Anwar D, Perrin LH. Impact of antiretroviral treatment with HIV protease inhibitors in hepatitis C viremia in patients coinfected with HIV. J Infect Dis. 1998;177:783–785
  78. Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology. 1999;30:1054–1058
  79. Ghany MG, Leissinger C, Lagier R, Sanchez-Pescador R, Lok AS. Effect of human immunodeficiency virus infection on hepatitis C virus infection in hemophilisac. Dig Dis Sci. 1996;41:1265–1272
  80. Cribier B, Schmitt C, Rey D, Lang JM, Kirn A, Stoll-Keller F. Role of endogenous interferon in hepatits C virus (HCV) infection and in coinfection by HIV and HCV. Res Virol. 1996;147:263–266
  81. Michelet C, Chapplain JM, Petsaris O, Arvieux C, Ruffault A, Lotteau V, et al. Differential effect of ritonavir and indinavir on immune response to hepatitis C virus in HIV-1 infected patients. Acquir Immune Defic Syndr. 1999;13:1995–1996
  82. Lorenzi P, Yerly S, Abderrakim K, Fathi M, Rutschmann OT, von Overbeck J, et al. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir. Acquir Immune Defic Syndr. 1997;11:95–99
  83. Schapiro JM, Winters MA, Stewart F, Efron B, Norris J, Kozal MJ. The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med. 1996;124:1039–1050
  84. Hoetelmans RM, Reijers MH, Weverling GJ, ten Kate RW, Wit FW, Mulder JW, et al. The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy. Acquir Immune Defic Syndr. 1998;12:F111–F115
  85. Acosta EP, Havlir DH, Richman DD. Pharmacodynamics (PD) of indinavir (IDV) in protease-naïve HIV-infected patients receiving ZDV and 3TC. 7th Conference on Retroviruses and Opportunistic Infections [abstract 455].
  86. Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. Indinavir concentrations and antiviral effect. Pharmacotherapy. 1999;19:708–712
  87. Gatti G, Di Biagio A, Casazza R, De Pascalis C, Bassetti M, Cruciani M, et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. Acquir Immune Defic Syndr. 1999;13:2083–2089
  88. Regazzi MB, Villani P, Maserati R, Cocchi L, Giacchino R, Burroni D, et al. Pharmacokinetic variability and strategy for therapeutic drug monitoring of saquinavir (SQV) in HIV infected individuals. Br J Clin Pharmacol. 1999;47:379–382
  89. Arribas J, Pulido F, Peng JZ. Evaluation of the multiple-dose pharmacokinetics of lopinavir/ritonavir (LPV/R) in HIV and HCV coinfected subjects with mild or moderate hepatic insufficiency. 9th European AIDS Conference (EACS). Warsaw, Poland; 2003 [abstract F2/6].
  90. Bossi P, Peytavin G, Lamotte C. High indinavir plasma concentartion in HIV-1 patients co-infecetd with hepatitis B or C virus receiving indinavir and ritonavir low dosages: a GENOPHAR substudy. 10th Congress on Retroviruses and Opportunistic Infections [abstract 546].
  91. Regazzi M, Maserati R, Villani P, Cusato M, Zucchi P, Briganti E, et al. Clinical pharmacokinetics of nelfinavir and its metabolite M8 in human immunodeficiency virus (HIV)-positive and HIV-Hepatitis C virus-coinfected subjects. Antimicrob Agents Chemother. Feb 2005;643–649
  92. Reijers MH, Weigel HM, Hart AA, Ten Kate RW, Mulder JW, Reiss P, et al. Toxicity and drug exposure in a quadruple drug regimen in HIV-1 infected patients participating in the ADAM study. Acquir Immune Defic Syndr. 2000;14:59–67
  93. Swainston Harrison T, Scott LJ. Atazanavir. A review of its use in the management of HIV infection. Drugs. 2005;65:2309–2336
  94. Arvieux C, Tribut O. Amprenavir or fosamprenavir plus ritonavir in HIV Infection. Pharmacology, efficacy and tolerability profile. Drugs. 2005;65:633–659

PII: S1590-8658(06)00021-1

doi:10.1016/j.dld.2006.01.020

Digestive and Liver Disease
Volume 38, Issue 6 , Pages 363-373, June 2006

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