The success of potent antiretroviral treatment regimens has resulted in a shift in the pattern of morbidity and mortality associated with HIV infection, with hepatic safety emerging as a key issue in the management of HIV-infected patients. Hepatic enzymes are frequently elevated in HIV-infected patients, especially in those undergoing HAART . In 2947 patients undergoing HAART in clinical studies, the most common grade 4 events were hepatic-related . Liver-related death has been reported to be the most frequent cause of non-AIDS-related death in HIV-infected patients .
Although hepatic disease in HIV-infected patients may be related to chronic coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV), alcohol consumption, or recreational drug use, combination antiretroviral therapy has been identified as a contributing factor [4,5]. Approximately 1–8% of HIV-infected patients develop severe hepatotoxicity (mostly grade 3 or 4 elevations in aminotransferases) in their first year of HAART, and the incidence increases to more than 15% when one or more predisposing risk factors for drug-related liver injury are present, such as chronic coinfection with HBV and/or HCV [4–7]. Although nearly every agent approved to treat HIV infection is associated with increases in aminotransferase concentrations, some drug classes carry higher risks of aminotransferase abnormalities than others .
Maraviroc is the first approved agent in a new class of oral antiretroviral drugs – the CCR5 antagonists. Maraviroc has a novel extracellular mechanism of action that prevents entry of HIV-1 into CD4+ cells by binding to the CCR5 coreceptor and is the first approved antiretroviral drug to target host cell proteins. Compared with placebo plus optimized background therapy (OBT), maraviroc plus OBT resulted in a significantly greater virologic response and CD4+ cell count increase and had a similar safety profile in treatment-experienced patients with CCR5-tropic (R5) HIV-1 [9–12].
Experiments in knockout mice showed that genetic CCR5 deficiency is associated with increased mortality and hepatic injury after administration of concanavalin A (ConA) – an inducer of experimental T-cell-mediated hepatitis . These data contrast with our in-house results in a ConA-induced hepatitis model (CCR5 knockout mice), in which plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities decreased dramatically 24 h after initial treatment with ConA compared with the response in wild-type mice. Moreover, the development of the CCR5 antagonist aplaviroc was halted because of severe hepatotoxicity in HIV-1-infected patients . This led to concerns that hepatotoxicity may be a class effect for CCR5 antagonists. However, current animal and human data suggest that aplaviroc hepatotoxicity is an idiosyncratic reaction specific to the molecule rather than to its mode of action  – an interpretation supported by a US Food and Drug Administration advisory panel on CCR5 antagonist safety .
The hepatic safety of maraviroc has been closely monitored at all stages of the product's clinical development program. This article presents an analysis of the hepatic safety data of maraviroc recorded throughout this program, including a subanalysis of patients coinfected with HBV and/or HCV participating in phase 2b/3 trials.
This assessment of the hepatic safety of maraviroc was based on safety data from 2350 participants who received maraviroc in the clinical development program. The analysis included a review of the incidence of all hepatic enzyme abnormalities and hepatobiliary adverse events, including hepatotoxicity, recorded throughout the phase 1/2a program and up to the 48-week or 96-week visit in the phase 2b/3 studies for all patients who received at least one dose of study medication.
The phase 1/2a program includes single-dose and multiple-dose studies in healthy volunteers and in HIV-1-infected patients; the phase 2b/3 program involves studies in both treatment-naive (MERIT study) and treatment-experienced (MOTIVATE 1, MOTIVATE 2, and A4001029 studies) patients.
Patients enrolled in the double-blind phase 2b/3 studies of treatment-experienced patients with R5 HIV-1 (MOTIVATE 1 and 2) [11,12] or dual/mixed-tropic (X4) virus (A4001029)  were randomly assigned to receive maraviroc daily (q.d.), maraviroc twice daily (b.i.d.), or placebo in combination with OBT with three to six antiretroviral drugs. Patients with an aminotransferase concentration more than 5 × ULN (upper limit of normal) or a bilirubin concentration more than 2.5 × ULN were excluded, and patients coinfected with HBV or HCV were eligible only if they did not meet these exclusion criteria for liver enzymes.
The MERIT study is an ongoing, double-blind, randomized phase 3 study comparing 300-mg maraviroc b.i.d. with 600-mg efavirenz q.d., both in combination with Combivir (zidovudine/lamivudine; GlaxoSmithKline, Research Triangle Park, North Carolina, USA) b.i.d., in antiretroviral-naive patients with R5 HIV-1. Patients with aminotransferase concentrations more than 3 × ULN or a bilirubin concentration more than 2 × ULN at screening were excluded. Patients coinfected with HBV or HCV were eligible for enrollment.
Hepatic safety was monitored in all studies, including evaluations of AST, ALT, and total bilirubin. In the phase 2b/3 studies, safety was monitored at screening, randomization, baseline, and the 2-week and 1-month visits and then monthly until 24 weeks. Thereafter, safety was assessed every 8 weeks. Elevations in AST, ALT, or total bilirubin were graded according to the Division of AIDS/AIDS Clinical Trials Group scale ; causality was assessed by the investigator. The data were scrutinized for hepatic-related adverse events by system organ class of ‘hepatobiliary disorders’ in the MedDRA dictionary.
Two subpopulation analyses of hepatic safety were conducted in the phase 2b/3 trials to assess the potential increase in hepatic risk with maraviroc in certain subgroups of patients: patients coinfected with HBV and/or HCV (defined as testing positive for hepatitis B surface antigen and/or HCV RNA at screening) and patients who received tipranavir, which is associated with hepatotoxicity (MOTIVATE and A4001029 studies).
In the phase 1/2a studies, 780 volunteers received maraviroc at doses ranging from 3 mg b.i.d. to 1200 mg q.d. To date, 14 single-dose phase 1 studies (two in HIV-infected men), 18 multiple-dose phase 1 studies in healthy volunteers (including a 28-day safety study), and two phase 2a multiple-dose, placebo-controlled studies in HIV-infected patients  have been conducted.
Few aminotransferase abnormalities, no dose–response relations, and no hyperbilirubinemia were observed during the phase 1 studies (Table 1). No elevations in aminotransferases or bilirubin were noted during the 28-day safety study in healthy volunteers at doses as high as 300 mg b.i.d. – the dose approved by the Food and Drug Administration. Likewise, no unexplained abnormalities in hepatic enzymes or dose effects were observed in a multiple dose-escalation study with a maximum dose of 1200-mg maraviroc.
No hepatic adverse events were reported during the phase 1 single-dose studies. Two volunteers in the phase 1 multiple-dose studies discontinued the study because of aminotransferase abnormalities: one volunteer had abnormal aminotransferase concentrations during the placebo run-in period, and one volunteer who received 300-mg maraviroc b.i.d. had a mildly elevated ALT concentration that resolved later. Jaundice (total bilirubin 17.1 μmol/l) was reported by one volunteer who received maraviroc and atazanavir, but this patient had normal aminotransferases. Atazanavir has been reported to be associated with jaundice and elevated conjugated bilirubin concentrations .
In the phase 2a studies, one male patient had an adverse event – an elevated ALT concentration of 180 U/l on day 5 (baseline concentration 86 U/l), which decreased to baseline by day 45 after treatment with the study drug. He tested IgM-negative but IgG-positive for Epstein–Barr virus.
A potentially drug-related case of elevated ALT, AST, and bilirubin concentrations associated with rash, fever, and eosinophilia was reported in a phase 1 study in a healthy female volunteer with concurrent group A streptococcal infection who received 600-mg maraviroc q.d. This volunteer reported a sore throat, had leukocytosis during the placebo run-in period, and later developed flu-like symptoms with cervical/submaxillary lymphadenopathy and orthostatic hypotension while taking the study drug. All symptoms resolved 3 days after the drug was discontinued. A pharyngeal culture was positive for group A streptococcus, and the antistreptolysin O titer was elevated. The Streptococcus pyogenes isolate was found to produce pyrogenic exotoxins (SpeA, SpeB, SpeC, SpeG, SpeJ, and SmeZ). This patient received more than 4 g paracetamol, and hepatic synthetic function improved (total bilirubin decreased to half the maximum value 3 days after therapy ended) despite detectable plasma maraviroc concentrations. The possibility that maraviroc contributed to the adverse event could not be excluded.
No increase in hepatic enzyme abnormalities or in other adverse events was noted in a phase 1 single-dose (300 mg) study in patients with mild or moderate (Child–Pugh A or B) hepatic impairment, despite increased maraviroc exposure relative to patients with normal hepatic function .
A total of 1049 patients were randomly assigned to receive at least one dose of the study medication in the combined MOTIVATE studies (n = 840 maraviroc, n = 209 placebo + OBT). Pooled safety data to week 96 were analyzed with a total exposure of 522.0, 550.6, and 159.8 patient-years in the maraviroc q.d., maraviroc b.i.d., and placebo arms, respectively. The duration of exposure was significantly shorter in the placebo arm primarily because of the lack of efficacy. Thus, the results of these two studies were adjusted for duration of exposure.
In the combined 96-week analysis of the MOTIVATE studies, although the proportion of patients with liver function test (LFT) abnormalities (grades 1–4) was similar across treatment groups, the exposure-adjusted incidence of these abnormalities per 100 patient-years was lower in the maraviroc groups than in the placebo group (Table 2). For the maraviroc q.d., maraviroc b.i.d., and placebo treatment arms, respectively, the incidences (per 100 patient-years) of grade 3/4 abnormalities were 4.5, 4.7, and 5.1 events for AST; 3.9, 2.6, and 6.5 events for ALT; and 9.1, 5.4, and 8.6 events for total bilirubin. For ALT, the most reliable biomarker of drug-induced hepatic injury, exposure-adjusted and exposure-unadjusted incidence of grade 3/4 changes was lower in the maraviroc b.i.d. group than in the placebo group.
In the patients whose OBT included tipranavir (15% of MOTIVATE patients), the addition of maraviroc did not increase the frequency of observed hepatic enzyme abnormalities compared with the addition of placebo (Table 2); in this subgroup, a greater proportion of patients who received placebo rather than maraviroc experienced grade 3/4 ALT abnormalities.
The proportion of patients reporting grade 3/4 hepatobiliary adverse events (including treatment-related adverse events) over 96 weeks was small and similar in the maraviroc q.d., maraviroc b.i.d., and placebo arms (Table 2). When adjusted for exposure to study treatment, grade 3/4 hepatobiliary adverse events were reported by 1.4, 2.5, and 3.2 patients per 100 patient-years in the maraviroc q.d., maraviroc b.i.d., and placebo arms, respectively. Eleven hepatobiliary serious adverse events (SAEs) were reported by 10 patients in the maraviroc arms. The only event that was considered possibly related to the study drug was hepatic failure in one patient who received maraviroc b.i.d. This patient had a history of chronic HCV infection and hepatic angioma and permanently discontinued study treatment on day 337 because of hepatic failure that was not confirmed clinically or biochemically. This patient's ALT values were normal or grade 1 throughout the study.
No differences in time to onset or duration of adverse events were observed between the maraviroc and placebo arms, and most of the adverse events were reported in the first 3 months of dosing. No difference in the rate of discontinuation due to hepatobiliary adverse events was observed between treatment groups.
In study A4001029, the safety population consisted of 124 patients who received maraviroc plus OBT and 62 who received placebo plus OBT. The median duration of study treatment was longer in the maraviroc b.i.d. group (176 days) than in the maraviroc q.d. (119 days) and placebo (127 days) groups.
As shown in Table 3, the incidence of liver enzyme abnormalities at 48 weeks was low and similar between treatment groups. Of the 14 patients who experienced grade 3/4 elevations in bilirubin with treatment and who had no corresponding abnormality at baseline, one received concomitant indinavir and the remaining 13 received atazanavir as OBT.
Grade 3/4 hepatobiliary adverse events were reported by 3.2% (n = 2), 0% (n = 0), and 1.6% (n = 1) of patients in the maraviroc q.d., maraviroc b.i.d., and placebo arms, respectively, over the 48-week study period (Table 3). One patient (maraviroc q.d. group) reported a hepatobiliary SAE (hepatitis). None of the patients withdrew from the study because of a hepatobiliary adverse event.
A total of 721 antiretroviral-naive patients received at least one dose of 300-mg maraviroc b.i.d. (n = 360) or 600-mg efavirenz q.d. (n = 361) with Combivir in the MERIT study. Safety data were derived over a median treatment duration of 337 days for each arm, with a total exposure of 506.0 and 507.9 patient-years for the maraviroc and efavirenz arms, respectively.
The incidence of LFT abnormalities with treatment is summarized in Table 4. A similar proportion of patients in both groups reported grade 3/4 ALT abnormalities; 88/353 (24.9%) patients in the maraviroc arm and 81/350 (23.1%) patients in the efavirenz arm experienced an increase in ALT of at least one grade from baseline. Similar results were seen for AST. Three patients in the maraviroc arm experienced a grade 3 elevation in indirect bilirubin, none of which were associated with an elevation in aminotransferases. In two of the three patients, the bilirubin elevation was confirmed as being secondary to underlying Gilbert's syndrome. Although higher rates of grade 1 and 2 bilirubin abnormalities were reported in the maraviroc group, most of these patients had abnormal baseline values.
Two patients (0.6%) in the maraviroc arm and five patients (1.4%) in the efavirenz arm reported grade 3/4 hepatic adverse events. No hepatobiliary SAEs were reported in the maraviroc arm, but one hepatobiliary SAE (hepatitis) was reported in the efavirenz arm.
One patient (0.3%) in the maraviroc arm (hypertransaminasemia) and two patients (0.6%) in the efavirenz arm (hypertransaminasemia and hepatitis) discontinued treatment because of hepatobiliary adverse events; in all cases, causality was due to the study drug.
A single case of life-threatening hepatotoxicity, which resulted in a liver transplant, was reported in the discontinued maraviroc q.d. arm in a female patient who received 300 mg q.d. (administered dose 150 mg q.d.). The patient began treatment with trimethoprim-sulphamethoxazole and isoniazid at the screening visit and experienced an increase in aminotransferase concentrations in the 7 weeks between screening and baseline (before receiving maraviroc). Pyrexia, rash, and abnormal LFT results were noted on day 5 of maraviroc treatment. Although maraviroc was discontinued, she continued to receive other drugs with known hepatotoxicity for several more days (including intravenous paracetamol/acetaminophen, lopinavir/ritonavir, zidovudine/lamivudine, and trimethoprim-sulphamethoxazole). Her condition deteriorated and she received a liver transplant on day 16. The patient's hepatic function abnormalities were most likely due to isoniazid or co-trimoxazole toxicity, but maraviroc toxicity may have been a contributing factor.
An increase in ALT and/or AST (to >3 × ULN) and a simultaneous increase in total bilirubin, without evidence of biliary obstruction or other possible causes, may be an indicator of drug-induced hepatotoxicity – ‘Hy's Law’ . Few patients met the biochemical criteria for Hy's Law (AST and/or ALT >3 × ULN and total bilirubin >3 × ULN) while taking the study drug: eight (2.0%) in the maraviroc q.d. arm, seven (1.6%) in the maraviroc b.i.d. arm, and two (1.0%) in the placebo arm of the MOTIVATE studies. One patient (0.3%) who received maraviroc and one patient (0.3%) who received efavirenz met the biochemical criteria for Hy's Law in the MERIT study. On the basis of pathology results that were available for all of these cases, none fully met the criteria for Hy's law.
Although HCV-infected and/or HBV-infected patients were allowed full access to the phase 3 maraviroc trials, the number of such patients enrolled was relatively small. Coinfection rates for the maraviroc q.d., maraviroc b.i.d., and placebo groups in the three treatment-experienced patient trials were low (Table 5).
The number of adverse outcomes in patients coinfected with HCV and/or HBV was similar in the maraviroc and placebo arms: One of 20 HCV-coinfected patients and two of 22 HBV-coinfected patients in the placebo arm had grade 3/4 ALT abnormalities compared with five of 50 and one of 57 patients, respectively, in the combined maraviroc arms (Table 5; data unadjusted for duration of therapy). Higher rates of abnormalities at baseline were observed in HCV-coinfected patients who received maraviroc [three of 15 (all grade 2) and five of 29 (three with grade 2 and two with grade 3) patients in the maraviroc q.d. and b.i.d. groups, respectively, had an ALT value of grade 2 or higher] than in patients who received placebo (one of 19 patients). Coinfection did not influence the maximum or last on-treatment liver enzyme values, nor did it affect the incidence of hepatobiliary adverse events in this small population.
As in the MOTIVATE studies, the number of patients coinfected with HBV and/or HCV at screening was low in the MERIT study (Table 5). No clinically relevant effect of coinfection on hepatic enzymes was observed, and patients coinfected with HBV and/or HCV were not at higher risk of elevated liver enzyme concentrations due to maraviroc. Overall, a smaller proportion of HCV-coinfected patients than of patients with no evidence of HCV RNA at baseline experienced adverse events; however, a higher proportion of HCV-coinfected patients discontinued treatment because of adverse events. Compared with patients who tested negative for HBV surface antigen at baseline, HBV-coinfected patients experienced a higher proportion of adverse events and a higher proportion discontinued treatment because of adverse events. However, this subgroup analysis of adverse event incidence was complicated by the small numbers in each group.
This comprehensive analysis of hepatic safety data from the maraviroc clinical development program indicates a low incidence of hepatic toxicity at therapeutic doses in HIV-infected patients, even after exposures as long as 96 weeks. Maraviroc was not associated with clinically relevant increases in hepatobiliary adverse events or aminotransferase abnormalities (including grades 3 and 4) in either treatment-naive (MERIT study) or treatment-experienced (MOTIVATE 1 and 2 studies and study A4001029) patients relative to comparator groups and in similar patient populations [22–27]. This finding is supported by data from ongoing clinical trials of vicriviroc, an investigational CCR5 antagonist, which have shown no evidence of hepatotoxicity through 48 weeks of therapy [28,29]. Moreover, a comparative secondary pharmacologic analysis of maraviroc, vicriviroc, and aplaviroc strongly suggests no hepatotoxicity associated with CCR5 antagonists [unpublished observation].
The 96-week data from the maraviroc clinical development program in treatment-experienced patients showed no increase in the rate or severity of hepatobiliary adverse events or LFT abnormalities [9,10,30]. In addition, an analysis of the effect of maraviroc dose on changes in ALT and AST from baseline identified no dose-related relations at week 24. Higher maraviroc exposure was associated with a small reduction in ALT and AST from baseline.
One treatment-experienced patient in the maraviroc b.i.d. group experienced hepatic failure (unconfirmed clinically or biochemically) after 337 days of study treatment, which the investigator determined was related to the study drug. Throughout the study, aminotransferase concentrations were within normal ranges or were elevated only as high as grade 1. A case of severe hepatotoxicity in the q.d. arm of the MERIT study, which was considered to possibly be related to maraviroc, was more likely due to isoniazid and/or to co-trimoxazole toxicity. More recently, a case of severe hepatotoxicity in a phase 1 study was complicated by rash, fever, and lymphadenopathy and was considered by independent expert reviewers to be confounded by concurrent streptococcal infection with evidence of pyrogenic exotoxins. However, the contribution of maraviroc to these two cases of hepatotoxicity could not be excluded.
Those few patients who potentially met the biochemical criteria for Hy's Law, on the basis of ALT, AST, and bilirubin concentrations, were evenly distributed between the maraviroc and comparator treatment groups and did not fully meet the criteria on the basis of available pathology results.
Although patients were allowed full access to the maraviroc phase 3 trials, only a small number of participating patients had active HBV infection and/or tested positive for HCV. No evidence of an increase in hepatotoxic effects in patients who received maraviroc was found in this subgroup. The lack of an increase in hepatotoxicity or HCV viremia was also reported in patients with HCV coinfection in a study of another CCR5 antagonist, vicriviroc. The safety of maraviroc in hepatitis-coinfected patients will be further assessed in a future study.
In summary, the current clinical data indicate that maraviroc does not cause clinically relevant abnormalities in hepatic function relative to comparators and published data in similar patient populations. However, given the current size of the safety database, the need for longer term follow-up, the known hepatic morbidity of the target population, and data for aplaviroc, pharmacovigilance activities are ongoing to further assess the hepatic safety of maraviroc.
The authors acknowledge the participants in the MERIT and MOTIVATE studies. This study was sponsored by Pfizer Global Research and Development. Editorial support was provided by Health Interactions and was funded by Pfizer Inc.
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