Liver enzyme elevation (LEE) was reported as a relatively common side effect of treatment since the introduction of highly active antiretroviral therapy (HAART), in particular among patients coinfected with HIV and hepatitis C virus (HCV).1 Few studies have demonstrated an association between hepatotoxicity and a specific drug or drug class and the highest rates of significant LEE were reported during treatment with antiretroviral drugs that are no longer commonly used in clinical practice, such as stavudine, didanosine, nevirapine, full-dose ritonavir, or tipranavir.2–5 Nonetheless, HAART-related drug-induced liver injury continues to be a clinically relevant problem and asymptomatic LEE is the most common form of drug-associated liver injury.
Early studies conducted after the introduction of ritonavir-boosted protease inhibitors (PI/r) suggested that their use was not associated with a significantly increased risk of LEE compared with unboosted protease inhibitors, either among HCV-infected or uninfected patients.6,7 Since then, several novel PI/r have been approved for HIV treatment. However, information about their hepatic safety profile is scarce, because they are either based on registration studies, which excluded patients with significant liver impairment at baseline, or derived from observational studies conducted on limited cohorts and/or with low prevalence of HCV coinfection. Despite the fact that the overall rate of LEE with novel PI/r has been reported to be low,8 reports of severe to fatal cases of hepatotoxicity in hepatitis-coinfected patients receiving darunavir/ritonavir have led several governmental agencies to release a warning.9,10 Actual differences between different PI/r, therefore, cannot be ruled out but, to date, the risk of LEE associated with different modern PI/r-based regimens has never been comparatively assessed.
The aim of this study was to assess the risk of LEE associated with different PI/r in a large real-life cohort of HIV-infected subjects, with high rates of HCV coinfection.
Patients were included from the observational Italian MASTER database cohort, which is an ongoing prospective multicentre cohort that includes all patients in care for HIV infection in selected major Italian clinical centers.11 Data are collected using a common electronic database (HealthNotes or NetCare, Healthware Technology SpA, Salerno, Italy), which is used to manage the everyday activity of the outpatient HIV clinic in each center. The study is conducted in 8 sites: Bari, Bergamo, Brescia, Cremona, Ferrara, Firenze, Monza, and Rome, in agreement with human experimentation guidelines of the declaration of Helsinki and after approval of the Ethic Committee in each participating center.
All sequential patients initiating HAART including a PI/r plus at least 2 antiretroviral drugs between 1998 and 2012 were enrolled, provided that aspartate aminotransferase (AST) and alanine aminotransferase (ALT) measured within 90 days before treatment and HCV antibody (HCV-Ab) status had been assessed. Patients treated with tipranavir or full-dose ritonavir were excluded.
Any grade ≥3 LEE as by ACTG classification (ALT or AST ≥5 times the upper limit of normality, ULN) during the course of PI/r-containing regimen was considered as the primary end point. Grade 4 LEE (any increase of ALT or AST level ≥10 × ULN) was the secondary study end point.
In addition to absolute transaminase elevation, the following classification of LEE, based on changes relative to the baseline value, was used in a secondary analysis: grade 3, >3.5 to 5 times baseline; grade 4, greater than 5 times baseline.12
Follow-up accrued from the date of PI/r initiation up to its discontinuation. Multiple observations per patient (treatment episodes) were considered for patients treated with different PI/r during their treatment history. All covariates were updated at the time of the introduction of a new PI/r. To ascribe hepatotoxicity to the current study regimen only, follow-up was right censored in case of discontinuation of PI/r (ie, only events occurring during PI/r treatment were considered) or occurrence of the first LEE during PI/r treatment. Treatment episodes occurring after the first LEE event were censored.
Time to grade ≥3 and 4 LEE were assessed using conditional Cox regression models, which took into account within patients variability. The following covariates were tested: age, gender, country of birth, HIV risk factor, previous exposure to antiretroviral treatment, hepatitis B coinfection, HCV-RNA status (only among those testing positive for HCV-Ab), baseline AST, ALT, and CD4+ T-cell count, body mass index, type of PI/r administered, calendar year at PI/r initiation, and nonnucleoside reverse transcriptase inhibitors coadministration. Body mass index was categorized as underweight (<18.5), normal (18.5–24.9), overweight (25–30), or obese (>30) plus a separate category for missing data. Among HIV/HCV-coinfected patients, liver fibrosis, as estimated using FIB-4 formula, was considered as an additional covariate and ranked in 3 categories as follows: <1.45 (F0–F1), 1.45–3.25 (undetermined), and >3.25 (F3–F4).13 Multivariable regression analyses, including all tested variables adjusted for each other, were performed. The analyses were separately conducted in HCV-Ab negative and HCV-Ab positive patients. A sensitivity analysis, restricted to patients with a positive HCV-RNA measured before PI/r initiation, was also conducted. All statistical analyses were performed using SAS 9.2 statistical software (SAS Institute Inc., Cary, NC, 2008). All P values presented are 2 sided and a P value <0.05 indicated conventional statistical significance.
During the study time frame, 17,273 new HAART regimens including a PI/r were initiated. Among these, 5960 and 283 treatment episodes were excluded because pretreatment HCV-Ab or AST/ALT levels were not available, respectively. Moreover, 891 treatment episodes occurring in patients who had already experienced a grade ≥3 LEE during PI/r treatment were censored. The remaining 10,129 treatment episodes, corresponding to 6193 patients (3242 HCV-Ab negative and 2951 HCV-Ab–positive patients), were finally selected. The characteristics of the patients at the time of administration of the first PI/r are depicted in Table 1.
Patients with positive HCV-Ab were more likely to be male, Italian-born, former intravenous drug users, previously exposed to antiretroviral therapy, and to have abnormal ALT and AST levels at baseline, than those with negative HCV-Ab. Use of darunavir/ritonavir was less common among HCV-Ab–positive than among HCV-Ab–negative subjects.
Overall, the available follow-up for each PI/r was 7070, 6487, 414, 881, 1758, and 1709 patient-years of follow-up (PYFU) for lopinavir/ritonavir, atazanavir/ritonavir, darunavir/ritonavir 800/100 mg once daily, darunavir/ritonavir 600/100 mg twice daily, fosamprenavir/ritonavir, and other PI/r, respectively.
Among the 4927 treatment episodes in HCV-Ab–positive patients, 2571 were from patients whose latest HCV-RNA before treatment-episode initiation was positive and 525 from HCV-RNA–negative patients, whereas in 1831, there was no available HCV-RNA measurement before the initiation of treatment with that particular PI/r.
Risk of LEE
A total of 761 cases of grade ≥3 and 199 of grade 4 LEE were observed over 18,433 and 20,376 PYFU, respectively. Incidence of grade 3 LEE was 1.05 and 7.66 per 100 PYFU in HCV-Ab–negative and HCV-Ab–positive patients, respectively (P < 0.001). Among HCV-Ab–positive patients, the incidence of grade 3 LEE was significantly lower in those with negative rather than positive HCV-RNA (3.76 versus 8.27 per 100 PYFU, P < 0.001), but still higher than that reported among HCV-Ab–negative patients. Incidence of grade 4 LEE was 0.37, 1.57, and 1.74 per 100 PYFU among HCV-Ab–negative, HCV-Ab–positive, and HCV-RNA–positive patients, respectively.
Hepatitis B virus coinfection was associated with a higher rate of grade ≥3 LEE among HCV-Ab–negative patients (4.3% versus 1.8% among those testing positive and negative for hepatitis B surface antigen, respectively), whereas comparable rates were observed among patients with positive HCV-Ab, with or without hepatitis B (14.3% versus 15.7%, respectively).
Predictors of LEE Among HCV-Ab–Negative Patients
Using univariate analysis, the choice of PI/r did not influence the risk of liver toxicity. In particular, use of darunavir/ritonavir was not significantly associated with the risk of grade 3 LEE compared with other PI/r, either when used as 600/100 mg twice daily [hazard ratio (HR): 1; 95% confidence interval (CI): 0.35 to 2.86] or as 800/100 mg once daily (HR: 1.76; 95% CI: 0.85 to 3.66) (Fig. 1).
When a multivariable model was conducted (see full results in Table 2), hepatitis B coinfection and higher baseline transaminase levels were associated with a significantly higher risk of grade 3 LEE among HCV-Ab–negative patients. Conversely, patients who had acquired HIV through heterosexual intercourses had lower risk of grade 3 LEE, compared with intravenous drug users. Despite adjustment for possible confounders, no statistically significant differences were detected in terms of risk of grade 3 LEE among different PI/r (Fig. 1).
Similar results were obtained when grade 4 LEE was used as outcome measure. Using univariate analysis, HBsAg positivity (HR: 2.82; 95% CI: 1.16 to 6.81) and higher baseline AST (per IU/mL increase, HR: 1.13; 95% CI: 1.01 to 1.26) were the only covariate significantly associated with the risk of hepatotoxicity. When a multivariable model was run, only AST level remained marginally associated with LEE (per IU/mL increase, HR: 1.13; 95% CI: 1.00 to 1.28). No statistically significant association was found between type of PI/r and risk of grade 4 LEE, either using univariable or multivariable analysis.
Predictors of LEE Among HIV/HCV-Coinfected Patients
The same analyses were run among patients with a positive HCV-Ab test before baseline. Using univariate proportional hazards regression model, no significant association between the choice of PI/r and the risk of hepatotoxicity was found. In particular, use of darunavir/ritonavir was not statistically associated with the risk of grade 3 LEE compared with other PI/r, either when used as 600/100 mg twice daily (HR: 0.79; 95% CI: 0.48 to 1.3) or as 800/100 mg once daily (HR: 0.68; 95% CI: 0.37 to 1.25).
Table 2 presents the results of the multivariable Cox regression analysis, after adjustment of all covariates for each other. In this model, the following variables were significantly associated with a higher risk of grade 3 LEE: older age, male gender, being naive to antiretroviral therapy, increased AST at baseline, being overweight, nonnucleoside reverse transcriptase inhibitor (NNRTI) coadministration, and advanced estimated liver fibrosis, which was tested in a separate model not including AST level due to collinearity. Conversely, negative HCV-RNA was associated with a significantly lower risk of LEE. In addition, after adjusting for other covariates, a statistically significant association was found between type of PI/r and LEE. In particular, using lopinavir/ritonavir as comparator, atazanavir/ritonavir was associated with a significantly higher risk of grade 3 LEE. This association was mainly driven by a higher rate of grade 3 LEE observed among patients previously experienced to antiretrovirals. Adjustment for liver fibrosis did not significantly modify the association between use of atazanavir/ritonavir and grade 3 LEE (HR: 1.35; 95% CI: 1.07 to 1.69; P = 0.01). Notably, DRV/r was not associated with hepatotoxicity, either when used twice daily or when used once a day.
As shown in Table 3, when the analyses were restricted only to patients who had positive HCV-RNA before treatment, type of PI/r was no longer associated with grade 3 LEE. Age, male gender, NNRTI coadministration, being naive to antiretrovirals, baseline AST levels and, in a separate multivariable model, FIB-4 score >3.25 were confirmed as independent predictors.
In a secondary analysis using transaminase changes relative to the baseline value as outcome measure, neither use of DRV/r nor ATV/r were associated with grade ≥3 LEE. Full results of this secondary analysis are shown in (see Supplemental Digital Content, https://links.lww.com/QAI/A652).
Eventually, when grade 4 LEE was used as outcome measure, no differences in terms of hepatotoxicity risk were found between different PI/r, among HCV-Ab–positive patients (in multivariable analysis, HR: 0.51; 95% CI: 0.15 to 1.8 and HR: 1.38; 95% CI: 0.88 to 2.17 for darunavir/ritonavir and atazanavir/ritonavir, both compared with lopinavir/ritonavir, respectively) or among HCV-RNA–positive patients (Table 3).
Protease inhibitors boosted with low-dose ritonavir have now been used as components of HIV treatment for more than a decade. Early concerns regarding the potential for drug-induced liver toxicity have been addressed in previous studies, suggesting that PI/r are not associated with a higher risk of liver toxicity than single PI or NNRTI, among HCV-infected and uninfected patients.6,7 In these studies, lopinavir/ritonavir was used in most of the patients treated with PI/r. Since then, other PI/r have been released on the market but few studies have assessed their profile of liver safety, comparing the drugs with each other. In this respect, most of data come from drug registration trials, which could not demonstrate any significant difference in terms of LEE between PI/r.14–19 However, clinical trials often underrepresented patients with pre-existing liver disease and, therefore, their findings may not reflect the actual clinical practice in settings with high rates of HCV coinfection. Of note, despite the fact that a warning on the risk of hepatotoxicity associated with the use of darunavir/ritonavir has been released by governmental authorities, it is still unclear whether this drug is associated with a higher risk of LEE than other PI/r.9,10
In our cohort, occurrence of hepatotoxicity during treatment with PI/r was a rare finding among patients not coinfected with HCV and rates of grade 3 and 4 LEEs among HCV-Ab–negative subjects were lower than those reported in the “early” boosted-PI era.6 Not surprisingly, the risk of LEE was markedly higher among HCV-coinfected than among HIV-monoinfected individuals, but still comparable or even lower than that reported in previous cohorts of HIV/HCV-coinfected patients treated with PI/r.6–8,20,21 Among HCV-Ab–positive patients, negative HCV-RNA was associated with lower risk of LEE, in line with previous demonstrations that sustained viral response to HCV therapy can reduce the risk of severe transaminitis during antiretroviral therapy.22,23
These findings are consistent with the report of a low risk of liver toxicity using the most recent antiretroviral regimes and may reflect a lower drug toxicity as well as an improved management of patients with liver disease.8 Although patients with hepatitis C coinfection were as much as 8 times more likely to develop grade 3 LEE during treatment, >90% of them did not experience significant LEE, thus confirming that HCV coinfection should not be considered per se a contraindication to treatment with PI/r. Nonetheless, given the availability of highly effective drugs, early treatment for HCV should be considered, also to reduce the risk of drug-induced liver toxicity.
The use of darunavir/ritonavir, which has been previously linked with severe cases of hepatotoxicity, was not associated, in our setting, with a higher risk of LEE than other PI/r, irrespectively of drug dosing, neither among HIV-monoinfected nor among HIV/HCV-coinfected patients. Darunavir/ritonavir was not associated with grade 3 and 4 LEE also in multivariable models adjusted for other risk factors of liver toxicity (including liver fibrosis). This suggests that the lack of association with hepatotoxicity cannot be explained by major prognostic differences between patients who were prescribed darunavir/ritonavir and those who were not. Our findings are in agreement with other very small observational studies and with a subanalysis of POWER 1 and 3 trials and indicate that the presence of HCV coinfection should not limit the use of darunavir/ritonavir.19,24,25
Although atazanavir/ritonavir was found to be associated with risk of grade 3 LEE among HCV-Ab–positive patients, this finding could not be confirmed in a sensitivity analysis restricted to HCV-RNA–positive patients or when grade 4 LEE was used as outcome measure, partially due to the lower power of these analyses. Moreover, previous uncontrolled studies suggested that the risk of severe liver toxicity during atazanavir/ritonavir is low, even among HIV/HCV-coinfected subjects with advanced liver disease.26,27 Also, an analysis of a large cohort of Italian patients suggested that liver tolerability of atazanavir was good and not influenced by bilirubin increases.28 A possible explanation for our findings is that, in our cohort, patients switching to atazanavir/ritonavir could be more likely to suffer from conditions, such as diabetes, insulin resistance, dyslipidemia, and other metabolic disorders (including fatty liver disease), which, in their turn, may have increased the risk of LEE. As a matter of fact, the association between atazanavir/ritonavir and grade 3 LEE emerged only in multivariable analyses, after adjustment for previous antiretroviral exposure and was mainly driven by a higher event rate observed in experienced patients. A direct effect of atazanavir/ritonavir in causing transaminase elevation, especially in heavy experienced patients, however, cannot be ruled out. In a previous case report, severe acute cytolytic hepatitis due to atazanavir, in a patient previously treated with lopinavir/ritonavir, was demonstrated.29 Continuing surveillance for hepatotoxicity is warranted, especially because experience to antiretroviral drugs is increasing in populations of patients with HIV coinfected by HCV.
Being naive to antiretroviral therapy was a strong predictor of transaminase elevations among HCV-coinfected patients, but not among those with negative HCV-Ab. Although we cannot exclude that being naive is a possible surrogate marker of exposure to other treatments with possible hepatotoxic effect in HIV newly diagnosed patients, we would have expected a similar effect among HCV-Ab–negative patients. Therefore, we think our findings suggests that reconstitution of HCV-specific response induced by antiretroviral treatment is an important player in the genesis of liver toxicity. Whenever possible, treatment of HCV infection before HIV-treatment initiation, which is now more feasible thanks to the availability of highly effective, all-oral, short-course regimens, could improve the tolerability of antiretrovirals. In addition, early HCV treatment is mandatory for the prevention of advanced liver fibrosis, another independent predictor of LEE in our study. Among patients with already established advanced liver fibrosis or cirrhosis, alternatives to PI/r, such as integrase inhibitors, are promising alternatives and merit to be evaluated further.30,31
Among HCV-Ab–negative patients, the choice of PI/r did not influence the risk of hepatotoxicity. Other risk factors, such as higher transaminases before treatment, hepatitis B coinfection or having acquired HIV through intravenous drug use, predicted a higher risk of LEE. These findings suggest that, among patients not coinfected with HCV, drug-induced liver toxicity is unlikely, unless other causes of liver damage (such as viral, metabolic, or exotoxic) are present.
Our study has some limitations that merit to be acknowledged. First, the lack of a non-PI/r arm as comparator, particularly integrase inhibitors, limited our ability to assess whether newer treatment options may be safer than PI/r, in terms of liver toxicity. Second, data on alcohol consumption were not prospectively collected in the database and, therefore, we were not able to adjust for it. Third, among HCV-coinfected patients liver fibrosis was not directly measured using liver biopsy or transient elastometry. Nonetheless, we adjusted the analysis for estimated liver fibrosis calculated using FIB-4 score, which has been validated as a reliable marker of significant fibrosis among HIV/HCV-coinfected patients.13 Fourth, medical records were not reviewed to exclude other causes of LEE, such as acute viral hepatitis, acute cholecystitis, other noninfectious processes, or non-antiretroviral medication–induced hepatitis.
In conclusion, in our cohort, LEE was a relatively rare finding among HCV-Ab–negative patients and was not influenced by the type of PI/r administered. In particular, among the less studied drugs, darunavir/ritonavir was not associated with a risk of hepatotoxicity higher than the other PI/r, irrespectively of drug dosing and of HCV-Ab serostatus. Being naive to antiretrovirals is an important risk factor among HCV-coinfected patients, thus suggesting a possible role of immune reconstitution in the genesis of hepatotoxicity. Continuing surveillance of hepatotoxicity is important especially in HIV-infected patients with HCV coinfection.
The authors thank Prof. Giampiero Carosi for his thoughtful review of the article. They also thank ANLAIDS (National Association against AIDS), Sezione Lombardia for its continuous support of our work. The Master Study is sponsored by M.I.S.I. Foundation (http://www.fondazionemisi.it).
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