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Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir
  AIDS: Volume 18(17) 19 November 2004
Sulkowski, Mark Sa; Mehta, Shruti Hb; Chaisson, Richard Ea; Thomas, David La,b; Moore, Richard Da,b
From the aDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, and the bDepartment of Epidemiology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, USA.
Note Presented at the 54th Annual Meeting of the American Association for the Study of Liver Diseases (Poster No. 1125). Boston, MA, October 24-28, 2003.
Objective: To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development.
Design: Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy.
Methods: The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level.
Results: The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity.
Conclusions: Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.
Author Discussion
Based on clinical trials demonstrating efficacy and tolerability, recent guidelines developed by the United States DHHS for the use of antiretroviral agents in HIV-infected adults designate lopinavir/RTV in combination with two NRTIs as the preferred PI-based ART regimen and support the use of other PIs in conjunction with low-dose RTV; however, little data has been published regarding the hepatic safety of these PI-based ART regimens outside of well-circumscribed trials. In our urban cohort, grade 3 or 4 liver enzyme elevations were observed in 12% of patients prescribed their first PI-based ART regimen. Notably, the risk of hepatotoxicity in patients receiving lopinavir/RTV-based ART was similar to that of those taking nelfinavir-based ART. However, in multivariate analysis, the use of PI regimens containing indinavir with or without RTV (200 or 400 mg/day) and saquinavir/RTV (800 mg/day) was associated with an approximately two-fold greater risk of hepatoxicity compared with regimens containing those containing nelfinavir. Interestingly, the addition of low-dose RTV to indinavir was not associated with an increase in the incidence of hepatoxicity compared to that observed with indinavir alone, suggesting that the addition of low-dose RTV did not impact the hepatic safety of indinavir-based ART.
With respect to lopinavir/RTV and nelfinavir, our findings support the hepatic safety data generated from randomized controlled trials of these PIs. In five studies involving ART-naive and experienced patients treated with lopinavir/RTV, elevations in serum ALT or AST levels greater than five-fold above the upper limit of the normal range were observed in 4-10% of subjects randomized to receive lopinavir/RTV in combination with NRTIs. Similarly, grade 3 or 4 elevations in serum ALT or AST were observed in approximately 2% of 751 antiretroviral-naive patients treated with nelfinavir-based ART in two clinical trials. In addition, in a study which directly compared these agents in a randomized fashion, Walmsley and colleagues reported that approximately 4% of subjects receiving nelfinavir and lopinavir/RTV-based ART developed grade 3 or 4 hepatotoxicity. Taken together, these data suggest that the incidence grade 3 or 4 liver enzyme elevations during lopinavir/RTV-based ART is not substantially increased in clinical practice settings and is similar to the incidence of hepatic injury observed with nelfinavir-based ART.
In addition, our data suggest that the risk of liver enzyme elevation associated with the use of lopinavir plus low-dose RTV (200 mg/day) is significantly lower then the rate observed with saquinavir plus higher RTV doses (800 mg/day) and then the rate previously reported with full dose RTV (1200 mg/day). Among patients followed in our cohort, we previously observed grade 3 or 4 hepatotoxicity in 27% of patients prescribed full dose RTV. Similarly, among patients followed in the Swiss HIV Cohort, Wit and coworkers found full-dose RTV was independently associated with grade 4 liver enzyme elevations (hazard ratio, 4.9) whereas no grade 4 hepatic events were observed with the use of low-dose RTV (200 mg/day). Hence, these data suggest that the risk of hepatotoxicity during therapy with PIs boosted by low-dose RTV is largely attributable to the primary PI, which is consistent with the observation that the plasma concentration with RTV (200 mg/day) is approximately 7% of that achieved with full-dose RTV (1200 mg/day).
We also detected an approximately 2.5-fold increased risk of developing grade 3 or 4 hepatotoxicity among HCV-infected patients compared with those without HCV co-infection. For example, we observed hepatotoxicity among approximately 16 and 13% of HCV-infected patients and 6.5 and 6% of HCV-uninfected patients to prescribed nelfinavir and lopinavir/RTV-based ART, respectively. Interestingly, Bernstein and coworkers observed similar incidence rates of hepatotoxicity among HCV-infected subjects randomized to receive nelfinavir (19.2%) or lopinavir/RTV (10.5%)-based ART. Moreover, after adjusting for type of ART received and other baseline covariates, HCV co-infection was independently associated with an approximately 1.7-fold greater risk of hepatotoxicity. Nonetheless, the majority of HCV-co-infected patients treated with PI-based ART did not develop severe hepatotoxicity, supporting current recommendations that HCV-infected patients are candidates for protease inhibitors.
Although our data suggest the hepatic safety of lopinavir/RTV is comparable with other PI-based HAART regimens (e.g., nelfinavir), we did not directly evaluate the incidence of hepatoxicity associated with the NNRTI-based ART regimens, efavirenz and nevirapine, in the absence of PIs. However, we did not observe an increased risk of hepatoxicity among patients prescribed efavirenz in combination with PI-based ART compared with those not taking NNRTIs. Similarly, among patients followed in the Johns Hopkins HIV cohort, we previously reported that grade 3 or 4 hepatotoxicity developed in 4.1% of 146 patients and 10.9% of 55 patients receiving efavirenz- and nevirapine-based ART, respectively. Likewise, among patients followed in Spain, Martin-Carbonero and colleagues reported that 4% of 136 efavirenz-treated and 12% of 162 nevirapine-treated patients developed severe hepatotoxicity. Thus, although not directly compared in our study, these data suggest the risk of hepatotoxicity associated with recommended PI-based ART regimen, lopinavir/RTV, is similar to that of the recommended NNRTI-based regimen, efavirenz.
Several other potential limitations could affect the results of this study. First, because patients were not randomly assigned to treatment in this cohort, there could be bias if clinical or laboratory parameters associated with the development of liver injury were not equally distributed between the treatment groups. Although there were some differences in baseline parameters among patients receiving lopinavir/RTV, no difference was detected in baseline serum ALT and AST levels or the proportion of patients with elevated liver enzymes. Second, we were unable to assess the risk of hepatotoxicity associated with other PI regimens, such as boosted or unboosted amprenavir, fosamprenavir, and atazanavir, or with alternative boosting strategies, such as saquinavir (1000 mg twice daily)/RTV (100 mg twice daily). Third, because follow-up assessments were not standardized, ascertainment bias could have occurred if one group of patients was monitored more closely or for a longer time leading to increased detection of toxicity in that group. However, the analysis of the incidence rate (cases per person years of exposure) yielded similar findings, and the Cox regression analysis was limited to hepatotoxicity during the first year of PI exposure. Finally, since not all patients with reactive HCV antibody are likely to be viremic, the effect of HCV infection could be underestimated. However, we have previously found that greater than 90% of HIV-infected persons with a reactive HCV antibody have detectable plasma HCV RNA, suggesting that our case definition is acceptable.
In conclusion, the incidence of grade 3 or 4 liver enzyme elevations in patients prescribed the lopinavir/RTV was similar to the incidence observed among those taking nelfinavir, as well as the incidence previously reported among patients receiving efavirenz. In addition, the risk of hepatotoxicity observed with low-dose RTV-boosted PI regimens was substantially lower than the risk seen with higher dose RTV either alone or in combination with saquinavir. Furthermore, although hepatitis C co-infection was independently associated with the development of significant liver enzyme elevations during therapy with PI-based regimens, the majority of co-infected patients taking PI-based HAART did not experience significant hepatotoxicity. Taken together, our data suggest that the risk of hepatotoxicity does not substantially differentiate between lopinavir/RTV-based regimen and alternative PI (e.g, nelfinavir) or NNRTI-based regimens (e.g, efavirenz); accordingly, other medication-related characteristics (e.g, efficacy, resistance and non-hepatic adverse effects) should guide individual treatment decisions. Finally, randomized, controlled studies will be necessary to directly compare the risk of liver injury with PI- and NNRTI-based regimens, including novel PIs and/or dosing regimens, and to further define the mechanism of interaction between drug-induced hepatotoxicity and chronic viral hepatitis.
Although the use of antiretroviral therapy (ART) has dramatically reduced HIV-related morbidity and mortality, 6-30% of patients treated with antiretrovirals develop significant increases in serum liver enzymes, which may require discontinuation of ART. Furthermore, the incidence of ART-related hepatotoxicity is even greater among patients co-infected with hepatitis B (HBV) and/or hepatitis C virus (HCV), and, in most studies, chronic viral hepatitis has been independently associated with the development of hepatotoxicity following initiation of ART. In some studies, high-dose ritonavir (RTV, 1200 mg/day) has been associated with an increased risk of hepatotoxicity compared to other antiretroviral regimens. However, high-dose RTV is no longer recommended as first line treatment and, increasingly, RTV, a potent inhibitor of cytochrome P-450 3A4 metabolism, has been co-administered with other protease inhibitors, such as lopinavir, saquinavir and indinavir, at lower doses to improve bioavailability and prolong the elimination half-life of these drugs, leading to more favorable dosing schedules and, in some studies, enhanced efficacy.
Moreover, current guidelines for the treatment of HIV infection developed by the United States Department of Health and Human Services (DHHS) designate lopinavir/RTV (100 mg twice daily) in combination with two nucleoside (or nucleotide) analogues as the preferred protease inhibitor (PI)-based antiretroviral regimen and identify other RTV-boosted and unboosted PIs as alternative regimens. Yet, the hepatic safety of lopinavir/RTV and other RTV-boosted PI regimens has not been extensively evaluated in patient populations outside well-defined clinical trials, such as in urban settings where relatively high prevalence rates of liver disease due to hepatitis B and C are frequently observed. Accordingly, hepatic safety data derived from trials may not be generalizable to such patients, and may substantially under-estimate the incidence of liver injury. Given the relatively high prevalence of liver-related comorbidities among HIV-infected patients, clinicians need accurate real-world information regarding the risk of hepatotoxicity associated with the use of RTV-boosted PI regimens.
The objective of this study was to determine the incidence of severe hepatotoxicity following the initiation of PI-based antiretroviral therapy with or without co-administration of RTV in an urban HIV clinic, and to define the role of chronic viral hepatitis in its development.

Between January 1996 and March 2003, 1161 patients were prescribed their first PI-containing antiretroviral drug regimen (nelfinavir, 605 patients; lopinavir/RTV, 89 patients; indinavir, 100 patients; indinavir/RTV, 94 patients; saquinavir/RTV, 273 patients) and met inclusion criteria. Prior to initiation of HAART, patients prescribed lopinavir/RTV and saquinavir/RTV were less likely to have an undetectable HIV RNA level and had lower CD4 cell counts than subjects prescribed other regimens whereas those taking saquinavir/RTV had a lower prevalence of HCV infection. However, no significant differences were detected between groups with respect to age, sex, race, HBsAg status, and pretreatment ALT and AST levels.
The median time from the pretreatment serum AST and ALT to initiation of treatment was: nelfinavir, 30 days [interquartile range (IQR), 13-83 days]; indinavir, 41 days (IQR, 14-93); lopinavir/RTV, 30 days (IQR, 15-68 days); indinavir/RTV, 45 days (IQR, 21-91 days); and saquinavir/RTV group, 29 days (IQR, 14-64 days). The median duration of follow up was: nelfinavir, 365 days (IQR, 156-820); indinavir, 211 days (IQR, 71-469); lopinavir/RTV, 223 days (IQR, 131-354); indinavir/RTV, 237 days (IQR, 91-363); and saquinavir/RTV, 224 days (IQR, 91-703) (P < 0.001 for comparison of nelfinavir with other PIs). However, the median number of serum ALT and/or AST measurements was similar for each PI-based regimen: nelfinavir, 5 measurements (IQR, 2-11); indinavir, 4 (IQR, 2-9); lopinavir/RTV, 5 (IQR, 3-8); indinavir/RTV, 4 (IQR, 2-8); and saquinavir/RTV, 4 (IQR, 2-12).
Development of hepatotoxicity
Prior to initiation of therapy, the median AST and ALT levels were 44.5 U/l (IQR, 32-68) and 37 U/l (IQR, 24-61) for HCV-infected patients and 28 U/l (IQR, 21-41) and 25 U/l (IQR, 16-40) for HCV-uninfected patients (P < 0.0001). During follow up, serum AST and ALT levels increased significantly in all treatment groups (data not shown); however, the magnitude of increase in serum ALT and AST levels was greater among saquinavir/RTV users in comparison with those using other PIs (P < 0.001) and among HCV-infected in comparison with HCV-uninfected persons (P < 0.0001).
Serum ALT levels remained less than 1.25 times ULN or their pretreatment level (grade 0) in 54% of lopinavir/RTV users, 62% of indinavir/RTV users, 48% of indinavir users and 54% of nelfinavir users in comparison with only 42% of saquinavir/RTV users (P < 0.0001 for the comparison of saquinavir/RTV with other PI regimens). Severe (grade 3 or 4) hepatotoxicity was observed in 148 of 1161 [12.7%; 95% confidence interval (CI), 10.9-14.8%] of patients prescribed PI-based HAART (incidence per 100 person-years, 9.94%; 95% CI, 8.47-11.6%). The incidence of severe hepatotoxicity varied significantly according to the specific PI prescribed: nelfinavir, 67 of 605 patients (11.1%; 95% CI, 8.7-13.9%); indinavir, 113 of 100 patients (13.0%; 95% CI, 7.1-21.2%); lopinavir/RTV, eight of 89 patients (9.0%, 95% CI, 4.0-16.9%); indinavir/RTV, 12 of 94 patients (12.8%, 95% CI, 6.8-21.2%); and saquinavir/RTV, 47 of 273 patients (17.2%, 95% CI 12.9-22.2%) [Relative risk (RR), 1.55; 95% CI, 1.12-2.16 for the comparison of saquinavir/RTV to other PI regimens]. Incidence per 100-person years of exposure for each PI-based regimen is shown in Table 2. The median duration of treatment before the detection of severe hepatotoxicity was: nelfinavir, 253 days (IQR, 77-669 days); lopinavir/RTV, 122 days (IQR, 58-158 days); indinavir/RTV, 228 days (IQR, 55-318 days); and saquinavir/RTV, 105 days (IQR, 63-224 days) (P < 0.001 for comparison of nelfinavir with other PIs).
Among patients who received an non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with PI-based HAART, severe hepatotoxicity was observed in 38 of 190 patients prescribed nevirapine (20.0%; 95% CI, 14.5-26.5%) and in 18 of 148 of those prescribed efavirenz (12.2%; 95% CI, 7.4-18.5%) (RR, 1.6; 95% CI, 1.0-2.8 for the comparison of nevirapine to efavirenz) whereas severe hepatotoxicity developed in 91 of 823 (11.1%; 95% CI, 9.0-13.4%) patients not prescribed NNRTIs (RR, 1.8; 95% CI, 1.3-2.6 for the comparison of nevirapine to no NNRTI; and RR, 1.1; 95% CI, 0.7-1.8 for the comparison of efavirenz to no NNRTI).
Hepatotoxicity (any grade) was observed in 65% of HCV-infected persons compared with 35% of HCV-uninfected persons (P < 0.0001), and 61% (90 of 148) of severe hepatotoxicity events were observed in HCV-infected patients. Overall, the incidence rate of grade 3 or 4 hepatotoxicity was significantly higher in patients with HCV infection (13.5 cases per 100 person-years) in comparison with those without HCV infection (7.0 per 100 person-years) (incidence rate ratio, 1.9; 95% CI, 1.36-2.72) (P < 0.0001). Among patients receiving nelfinavir and saquinavir/RTV, the incidence of grade 3 or 4 liver enzyme elevations was significantly greater among HCV-infected patients in comparison with those HCV-uninfected; whereas among patients prescribed indinavir/RTV a significantly increased risk among HCV-infected patients was not detected. The prevalence of NNRTI use (nevirapine and efavirenz) was similar among HCV-infected (nevirapine, 14.9%; efavirenz, 11.2%) and HCV-uninfected (nevirapine, 17.5%; efavirenz, 14.0) patients (nevirapine, P = 0.25; efavirenz, P = 0.15). Interestingly, among nevirapine users, the incidence of grade 3 or 4 liver enzyme elevations was similar in HCV-infected (25.3%) and HCV-uninfected (16.2%) patients (RR, 1.56; 95% CI, 0.9-2.7); conversely, among efavirenz users, the incidence of grade 3 or 4 liver enzyme elevation was significantly greater in HCV-infected (23.7%) compared with HCV-uninfected patients (4.4%) (RR, 5.27; 95% CI, 1.8-15.3). In addition, the detection severe hepatotoxicity was more rapid among HCV-infected than HCV-uninfected patients (Fig. 2). Nonetheless, while patients with HCV accounted for 61% of hepatotoxicity cases, the majority of HCV-co-infected patients treated with nelfinavir (84%), indinavir (85%), saquinavir/RTV (74%), indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop severe hepatotoxicity. In addition, the majority (90%) of patients chronically infected with HBV did not experience grade 3 or 4 hepatotoxicity, and the incidence of hepatotoxicity in HBV-infected patients (10.1%) was not significantly greater than that observed in HBV-uninfected patients (9.4%) (P = 0.79).
Risk factors for the development of severe hepatotoxicity
Cox proportional hazards regression was used to determine factors associated with the development severe hepatotoxicity during PI-based antiretroviral therapy during the initial 365 days of therapy. In univariate analysis, the presence of HCV antibody (RR, 1.61; 95% CI, 1.09-2.38), baseline CD4 cell count > 50 × 106 cells/l (RR, 0.55; 95% CI, 0.43-0.70), baseline HIV RNA level > 10 000 copies/ml (RR, 2.98; 95% CI, 1.30-6.85), baseline AST level > 35 U/l (RR, 1.67; 95% CI, 1.12-2.49), indinavir use (RR, 2.01; 95% CI, 1.0-4.05); indinavir/RTV use (RR, 2.02; 95% CI, 1.0-4.06) and saquinavir/RTV use (RR, 2.63; 95% CI, 1.67-4.15) were associated with the development of severe hepatotoxicity toxicity. No significant associations were detected between the development of severe hepatotoxicity and race, gender, age, HBsAg status, concurrent NNRTI use or change in HIV RNA level or CD4 cell count during treatment. In multivariate analysis, HCV infection (RR, 1.73; 95% CI, 1.14-2.63), baseline CD4 cell count > 50 × 106 cells/l (RR, 0.51; 95% CI, 0.33-0.79), baseline HIV RNA level > 10 000 copies/ml (RR, 2.59; 95% CI, 1.08-6.18), indinavir use (RR, 2.30; 95% CI, 1.06-4.98), indinavir/RTV use (RR, 2.73; 95% CI, 1.33-5.63), and saquinavir/RTV use (RR, 2.39; 95% CI, 1.47-3.89) were independently associated with the development of severe hepatotoxicity.
The outcome of PI-based HAART was analyzed in a heterogeneous cohort of patients receiving medical care from January 1996 to March 2003 in the Johns Hopkins Hospital HIV Clinic. In this urban setting, all patients undergo a comprehensive enrollment evaluation as previously described. HCV and HBV serologies are routinely performed by a licensed, commercial laboratory. Patients with a reactive serum HCV antibody by immunoassay and those with a positive HBV surface antigen (HBsAg) by immunoassay with neutralization (two or more occasions) were considered to have chronic infection.
Trained personnel abstracted data regarding demographics, social practices, clinical and laboratory variables from patient charts and the laboratory database at enrollment and every 6 months. Medication prescriptions are recorded by name, dose, and number dispensed in the patient chart, which is updated at each clinical encounter including telephone and mailed prescriptions. Validity checks of medication prescriptions and adverse events were performed through chart review on a sample (10%) of the collected data.
Hepatotoxicity was examined for all PI-naive patients receiving an initial PI-containing antiretroviral regimen. Patients were classified based on which PI medication (RTV, lopinavir, indinavir, saquinavir or nelfinavir) was prescribed. The PI-based regimens were classified as pharmacologically boosted if a protease inhibitor was given in combination with low-dose RTV (<= 400 mg/day). Low-dose RTV-boosted ART regimens studied included lopinavir plus RTV 100 mg twice daily and indinavir plus RTV 100 or 200 mg twice daily. Amprenavir use with or without RTV boosting was uncommon (< 1%). Regimens which included saquinavir 400 mg plus RTV 400 mg twice daily were not considered pharmacologically boosted since RTV represents a pharmacologically active agent in this combination. No patients received the antiretroviral regimen for less than 45 days, and all patients had records of pretreatment liver enzyme levels within 6 months of the initiation of HAART. According to practice guidelines, all patients had laboratory testing prior to therapy and at regular intervals during antiretroviral treatment, typically 4 weeks after initiation of therapy and then every 12 weeks. At each visit, standard laboratory assessment, performed by a licensed laboratory, included a complete blood count, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBR), CD4 cell count and plasma HIV RNA level (reverse transcriptase-polymerase chain reaction).
The change in serum ALT and AST from pretreatment levels to the highest level during treatment was categorized according to modified, standardized toxicity grade scale. Patients with pretreatment serum AST and ALT levels within the normal range (AST < 35 IU/l and ALT < 31 IU/l) were classified based on changes relative to the upper limit of normal (ULN): grade 0, (< 1.25 × ULN); grade 1, (1.25-2.5 × ULN); grade 2, (2.6-5 × ULN); grade 3, (5.1-10 × ULN); grade 4, (> 10 × ULN). To avoid selection bias favoring the inclusion of persons with chronic viral hepatitis, patients with elevated pretreatment serum AST and ALT levels (> ULN) were classified based on changes relative to the baseline value rather than to the upper limit of normal: grade 0, (< 1.25 × baseline); grade 1, (1.25-2.5 × baseline); grade 2, (2.6-3.5 × baseline); grade 3, (3.6-5 × baseline); grade 4, (> 5 × baseline).
Severe hepatotoxicity was defined as grade 3 or 4 change in either serum AST or ALT levels during antiretroviral treatment. If the AST and ALT grades were discordant, the higher of the two grades was used for classification. The medical records were reviewed on all cases of severe hepatotoxicity to exclude other causes of hepatic disease (e.g., acute viral hepatitis, acute cholecystitis, other infectious processes, non-antiretroviral medication toxicity and alcoholic hepatitis); toxicity was determined to be causally related to the antiretrovirals if no likely alternative explanation was identified.
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