Summary

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• Specific studies have not been conducted in patients with hepatic insufficiency.¹
• Summaries of a prospective study, retrospective studies, and case reports published in the literature are described below.^2-13

Company core data sheet

• Specific studies have not been conducted in patients with hepatic insufficiency.¹

Clinical data

Prospective Study

Ting et al (2018)² conducted a prospective cohort study to evaluate the risk of hepatitis B virus (HBV) reactivation in patients with moderate to severe psoriasis (PsO) with varying HBV status who received STELARA treatment.

• At baseline, all patients were tested for hepatitis B serology and serum viral deoxyribonucleic acid (DNA).
• HBV status of each patient was classified into one of the following 6 categories:
  • naïve to HBV,
  • vaccinated,
  • inactive HBV carrier,
  • chronic active hepatitis B,
  • resolved HBV infection, or
  • isolated anti-hepatitis B core (HBc) positivity.
• Patients received STELARA 45 mg subcutaneously at weeks 0 and 4, and then every 12 weeks.
• Serum alanine aminotransferase (ALT) levels were measured before each STELARA administration.
• HBV reactivation was defined as:
  • a marked increase in HBV replication (>2 log increase from baseline levels),
  • a new appearance of HBV DNA at a level of >100 IU/mL in a person with previously stable or undetectable levels,
  • or detection of HBV DNA at a level >20,000 IU/mL in a person with no baseline HBV DNA.
• Hepatitis was defined as an ALT level exceeding 2 times the upper limit of normal (40 IU/L).
• A total of 93 patients were included and the average duration of follow-up was 24 ± 12 months.
  • Of these, a total of 39 were naïve to HBV (n=20) or vaccinated (n=19), and none of these patients had HBV reactivation during STELARA treatment.
  • The other 54 patients were classified as resolved HBV infection (n=38), inactive HBV carriers (n=10), or isolated anti-HBc positivity (n=6).
    • Among these, a total of 3 patients, none of whom received antiviral prophylaxis, experienced HBV reactivation (2 in the inactive HBV carrier group, both without hepatitis, and 1 in the resolved HBV infection group with mild hepatitis). None of these patients had liver failure.
    • Of the 2 patients in the inactive HBV carrier group, the first patient experienced 2 episodes of virologic reactivation, 6 and 28 months after STELARA, respectively. The patient received lamivudine for 30 days during the second reactivation, achieving a rapid drop in viral load. The second patient had reactivation 3 months after STELARA with low levels of serum HBV DNA fluctuating between 72 and 600 IU/mL and did not receive any antiviral treatment.
    • One patient in the resolved HBV infection group experienced virologic reactivation with mild hepatitis (peak ALT of 87 IU/L) 12 months after STELARA treatment. The patient received concurrent methotrexate (MTX) during reactivation. The patient’s serum HBV DNA became undetectable without antiviral therapy 6 months after MTX discontinuation.
  • A total of 2 of the 93 patients received antiviral prophylaxis (in the inactive HBV carrier group) and of these none had HBV reactivation.

Retrospective Studies

Liu et al (2024)³ conducted a retrospective, multicenter study to evaluate the incidence of HBV reactivation in patients with Crohn’s disease (CD) treated with STELARA, with or without prophylactic anti-HBV therapy. The safety and efficacy of STELARA in patients with CD with past HBV infection were also assessed. Results specific to HBV are summarized below.

• A total of 52 patients were included in the effectiveness analysis, of whom 17 with CD reported HBV infection.
• The patients were screened for HBV infection before initiating treatment with STELARA.
• Liver function was assessed for all the patients at every STELARA administration, while HBV DNA was monitored for the patients with past HBV infection every 3 to 6 months.
• HBV status was classified according to the European Association for the Study of Liver Disease into the following 4 categories:
  • active chronic HBV infection (hepatitis B surface antigen [HBsAg] positive and HBV DNA positive),
  • inactive chronic HBV infection (HBsAg positive and HBV DNA negative),
  • past HBV infection (HBsAg negative, hepatitis B surface antibody [HBsAb] positive, and hepatitis B core antibody [HBcAb] positive),
  • isolated core antibody positivity (HBsAg negative, HBsAb negative, and HBcAb positive).
• HBV reactivation was defined as an increase in HBV DNA levels in patients with viremia or the reappearance of HBV DNA in patients who previously had no detectable viral DNA.
• Among the 17 patients, 4 (23.5%) were female and 13 (76.5%) were male, with a mean age of 37.7 ± 11.1 years.
• Fourteen patients reported an inactive HBV infection, while 3 had a history of HBV infection.
• All patients had serum HBV DNA levels below 2000 IU/mL.
• Of the 17 patients:
  • Six did not receive antiviral prophylaxis (mean duration of follow-up, 53 weeks).
  • Eleven received antiviral prophylaxis (8 with entecavir, 3 with tenofovir; mean duration of follow-up, 48 weeks).
  • No overt increases in ALT, aspartate aminotransferase (AST), gamma-glutamyl transferase, alkaline phosphatase, or total bilirubin levels were observed. No liver dysfunction was observed during follow-up.
  • No case of active HBV infection was reported in either group.

Klujszo et al (2022)⁴ presented observations on the safety of STELARA treatment in patients with moderate to severe PsO and serologically proven past HBV infection.

• One-hundred and six patients were included in the retrospective analyses and of these patients 5 reported having a past HBV infection.
• The 5 patients having reported past HBV infection were tested for the presence of HBsAg, HBcAb, HBsAb, and HBV DNA at baseline and at the end of follow-up period.
• HBV reactivation was defined as a changing of “undetectable” to “detectable” viremia.
• The cut-off for HBsAb positive status was >10 IU/mL HBV DNA.
• Patients who were negative for HBsAg, positive for HBcAb, and negative for HBV DNA were classified as past HBV infection regardless of HBsAb status.
• Baseline liver function tests (LFTs) were within normal range for each of the patients.
• No patients experienced an increase in LFTs and no signs of hepatitis or HBV reactivation were observed.
• Serological HBV evaluation for each patient is described in Table: HBV Infection Serological Markers

• The average treatment time was 82.4 (28, 96) weeks and the average follow-up time was 75.2 (31, 176) weeks.

Siegel et al (2019)⁵ retrospectively reviewed a cohort of patients treated with STELARA who were infected with HBV and/or hepatitis C virus (HCV).

• A total of 18 adult patients (13 men, 5 women; age 23-60 years) who had received at least 2 doses of STELARA for PsO (17 with plaque-type PsO and 1 with palmar/plantar type PsO; 9 with concurrent psoriatic arthritis [PsA]) were included in this review (see Table: Features of Patients with HBV, HCV, or HBV/HCV Coinfection During STELARA Treatment).
• Of these 18 patients, 7 had HBV infection alone (3 received concurrent antiviral therapy), 3 were coinfected with HBV and HCV (2 received concurrent antiviral therapy for HBV), and 8 were infected with HCV alone.
  • Four of the HCV⁺ patients had biopsy-proven cirrhosis at the start of therapy.
  • Of the 11 patients with HCV or HBV/HCV, 3 were treated for HCV before and during STELARA use.
• There was no evidence of viral reactivation or significant elevations in liver enzymes (defined by 10-fold increase in viral load and/or threefold increase in serum ALT, between baseline and the maximum recorded value) based on serial monitoring of serum transaminases and viral DNA/ribonucleic acid (RNA) levels.
  • The exception was patient 10, who was diagnosed with a relapse of HCV 6 months post-antiviral therapy; it is unknown if this reactivation was related to STELARA.
• At the time of the report, 11 patients remained on STELARA treatment while 7 patients discontinued therapy due to unsatisfactory skin clearance results.

Chiu et al (2013)⁶ retrospectively evaluated STELARA in the treatment of patients with PsO with concurrent HBV or HCV infection.

• A total of 18 patients (n=14, HBV; n=4, HCV) who received ≥2 STELARA injections were included in the study.
• Patients received STELARA 45 mg subcutaneously at weeks 0 and 4, and then once every 2-3 months for maintenance treatment.
• At baseline and at least each time before each STELARA injection, HBV DNA/HCV RNA levels were assessed.
• ALT/AST was evaluated in patients with viral reactivation.
• Out of the 11 patients positive for HBsAg, there were 7 patients who did not receive prophylactic antiviral treatment and 4 patients who did receive antiviral prophylaxis.
  • Two of the 7 patients without antiviral prophylaxis had HBV reactivation while receiving STELARA.
  • As AST/ALT elevation did not occur in these 2 cases, they were classified as a very mild reactivation.
  • One of the 2 patients with reactivation subsequently received entecavir 0.5 mg daily and the viral load decreased rapidly within 3 months of therapy (after preemptive therapy was deferred until the detection of virological reactivation).
  • The other patient with HBV reactivation received follow-up with a hepatologist without antiviral therapy.
  • None of the 4 patients with antiviral prophylaxis (entecavir 0.5 mg daily) had HBV reactivation during STELARA treatment and their serum viral loads decreased significantly.
• No HBV reactivation was reported in the 3 occult HBV infected patients (HBsAg-negative/HBcAb-positive). None of these patients received antiviral prophylaxis.
• Of the 4 patients with concurrent HCV, 1 case of HCV reactivation during STELARA treatment was reported.
  • In this case, the patient developed HCV reactivation after 1 month and recurrence of hepatocellular carcinoma (HCC) after 4 months of STELARA treatment.
  • The patient had liver cirrhosis 5 years prior to STELARA treatment.
  • There was no elevation in the patient’s liver function tests.
  • STELARA was discontinued after the patient’s HCC recurrence and the patient underwent transarterial chemoembolization.
• Psoriasis Area and Severity Index (PASI) 75 (a 75% improvement from the baseline PASI) was achieved in 5 of the 14 PsO patients with HBV and 0 of the 4 PsO patients with HCV during STELARA treatment.

Navarro et al (2013)⁷ conducted a retrospective, multicenter study evaluating the safety and efficacy of STELARA and anti-tumor necrosis factor (TNF) therapy in 25 adult patients with PsO and chronic HBV or HCV.

• Twenty patients with HCV and 5 patients with HBV were included. Of these, 3 HCV patients and 1 HBV patient received treatment with STELARA.
• The 3 HCV patients treated with STELARA all had plaque-type PsO (baseline PASI scores ranged from 18.6-34) with disease duration of 3-10 years and a history of HCV of 7-14 years.
  • None had received treatment for HCV.
  • Two of the patients were also receiving isoniazid and antiretrovirals concomitantly.
  • The duration of STELARA treatment ranged from 12-17 months.
  • One patient experienced a slight increase in viral load, and AST and ALT were increased in another patient. There were no serious adverse events (AEs) reported.
  • A 75% or greater reduction in PASI score (PASI 75) was achieved at the end of therapy in 2 of the 3 patients; no data were available for the third patient.
• Only 1 HBV patient with plaque PsO received STELARA. That patient had a 10-year history of PsO (baseline PASI was 17.6) and a 2-year history of HBV.
  • The patient had hepatic steatosis and was an alcoholic and obese.
  • He received antiviral treatment with entecavir and received STELARA for 7 months.
  • Viral load decreased from 2000 at baseline to 0 at the end of evaluation.
  • AST and ALT remained stable and there were no serious AEs reported.
  • PASI 75 was achieved at the end of therapy.

Case Reports

Song EJ et al (2021)⁸ described the case of a 13-year-old female from Guatemala with no known medical or family history who presented with widespread plaque PsO (body surface area [BSA] involvement of 12% and static investigator global assessment [IGA] score of 3).

• No sufficient plaque PsO improvement was reported with prior ultrapotent topical steroids and MTX treatment.
• The patient tested positive for HBsAg, HBcAb, and hepatitis B envelope antibodies, but negative for hepatitis B envelope antigen (HBeAg) and HBsAb. HBV DNA load was 3.4 IU/mL.
• LFTs (AST, 24; ALT, 23) were in normal ranges.
• STELARA 45 mg was initiated based on patient body weight of 160 lbs along with entecavir 0.5 mg daily.
• Six weeks after initiation of STELARA, a slight increase in liver enzymes (AST, 51; ALT, 77) and decrease in viral load (2.4 IU/mL) were seen with no reported or observed abdominal pain, jaundice, itching or flu-like symptoms.
• At the 28-week follow-up with treatment of STELARA, the patient presented to dermatologist with a 7% BSA involvement and an IGA 3 and was then switched to guselkumab 100 mg.
• Following one dose of guselkumab (4-week follow-up), the patient had 3% BSA and an IGA 3. At 12-week with treatment of guselkumab, the patient had 1% BSA with an IGA 2. Her liver enzymes remained stable (AST, 26; ALT, 42) and viral load was undetectable.

Abuchar et al (2013)⁹ reported the case of a 62-year-old Hispanic male with HCV and a long-term history of PsO and PsA who received STELARA.

• The patient was started on etanercept 50 mg twice a week in September 2004 with good control of his PsO and PsA.
• Over time, the patient had a loss of responsiveness to etanercept.
• In October 2007, patient was switched to adalimumab 40 mg every other week and exhibited a good response for his PsO and PsA.
• HCV diagnosis occurred in October 2008, revealing positive antibody but not showing any symptoms of the disease, with normal liver function (ALT: 19 U/L [9-60 U/L] and AST: 22 U/L [10-35 U/L]).
• Treatment with adalimumab was continued until March 2009 when he developed pancreatitis leading to discontinuation of adalimumab.
• Treatment was changed to narrowband ultraviolet B (UVB) and topical steroids for several months, but PsO became erythrodermic.
• In March 2010, the patient was started on STELARA 45 mg at weeks 0, 4, then every 12 weeks after being cleared by a hepatology specialist.
• Patient had a very good response relative to PsO after second dose (May 2010); HCV remained asymptomatic with a low positive antibody of 5.70, with normal liver function (ALT: 18 U/L [9-60 U/L] and AST: 22 U/L [10-35 U/L]), and an undetectable viral load.

Koskinas et al (2013)¹⁰ reported a case of HBV reactivation in a 59-year-old male patient after 16 months of treatment with STELARA for PsO.

• The patient had received 4 months of treatment with cyclosporine 3 mg/kg/day prior to starting STELARA, which was initiated due to a "serious relapse."
• Prior to initiation of STELARA, the patient was HBsAg negative, anti-HBc positive, and anti-HBs positive (17 mIU/mL).
• The patient received STELARA 45 mg subcutaneous every 3 months.
• Approximately 16 months after starting STELARA, the patient exhibited an elevated ALT level of 65 IU/mL.
• The patient’s HBV status was rechecked, and he was found to be HBsAg positive, HBeAg positive, and his anti-HBs titer had dropped to 15 mIU/mL, and then to <10 mIU/mL 1 month later. HBV DNA load was 140,000 IU/mL.
• The patient remained asymptomatic throughout this period with normal routine blood tests with the exception of the moderately elevated ALT levels.
• The patient continued STELARA therapy while receiving antiviral treatment with tenofovir.

Malara et al (2012)¹¹ described the case of a middle-aged woman with a 15-year history of untreated chronic HCV and a more recent history of pustular PsO.

• Her pustular PsO was treated with phototherapy and, for a short period, with cyclosporine with no significant improvement.
• After appropriate screening, she was started on anti-TNF-alpha treatment with etanercept resulting in mild improvement of her skin lesions but marked reduction of LFTs. Her viral load remained stable.
• Due to the lack of efficacy after 1 year of etanercept, her treatment was switched to STELARA.
• Liver enzymes and viral load (measured using the quantitative HCV RNA in real time polymerase chain reaction [PCR]) were measured before and every 8 months after initiation of STELARA treatment. Additionally, HCV genotyping was performed using immunoblotting method (Genotype 2a). Fibroscan technique was used to quantify and monitor liver fibrosis which was unchanged during STELARA therapy. PASI and BSA were used to evaluate the PsO.
• Before starting STELARA, her PASI score and BSA were 16.4 and 36%, respectively.
• The patient received >1 year of STELARA treatment with notable improvement of her psoriatic lesions (PASI was 3.6 and BSA was 8% after 4 weeks of treatment) and no significant variations in her liver function and viral load (6,020,000 IU/mL before and unchanged during STELARA treatment).

Opel et al (2012)¹² reported 2 cases of acute HBV infection in STELARA-treated patients with plaque PsO from a phase 3 (PHOENIX [A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial Evaluating the Efficacy and Safety of CNTO 1275 in the Treatment of Subjects with Moderate to Severe Plaque-type Psoriasis Followed by Long-term Extension] 1) and a phase 4 (TRANSIT [Trial to Assess Naturalistic Safety and Efficacy Outcomes In Patients with Moderate to Severe Plaque Psoriasis Transitioned to Ustekinumab from Previous Methotrexate Therapy]) study.

Patient #1 was a 33-year-old white male from the PHOENIX 1 study with a 12-year history of moderate to severe plaque PsO and an otherwise uncomplicated medical history.

• At baseline, the patient’s disease was severe with 77% BSA involvement and a PASI score of 46. Prior treatments included topical steroids, UVB, psoralen plus ultraviolet A, and acitretin.
• The patient had an HBV risk factor of a same-sex relationship. Blood samples collected at baseline were retrospectively analyzed and were negative for HBV viral DNA.
• The patient received STELARA 90 mg at weeks 0 and 4, followed by maintenance every 12 weeks starting in March 2006.
• By week 8, total clearance of PsO was achieved, with 100% improvement from baseline in PASI score (PASI 100). No AEs were reported, and liver enzyme levels were within normal limits through week 16.
• At week 20 (36 days following the last dose), significant, transient elevations in ALT and AST were reported. Alkaline phosphatase and total bilirubin levels were also elevated 1-2 weeks later.
  • Liver synthetic function, as assessed by serum albumin, was normal.
  • The patient experienced jaundice and fatigue.
  • No history of alcohol or medication use was reported.
  • Serologies for hepatitis A and C were negative; however, HBsAg, immunoglobulin M antibody to HBcAb (anti-HBc IgM), HBeAg, and HBV DNA were positive.
  • The patient was diagnosed with acute HBV infection.
• STELARA treatment was temporarily interrupted.
• Patient remained asymptomatic, with liver synthetic function remaining normal and hepatic laboratory abnormalities resolving over 8 weeks.
• Transaminase and bilirubin levels returned to baseline by week 28, when seroconversion of HBeAg to the antibody to HBeAg (anti-HBe) was observed. Serum HBV DNA decreased to below the detection limit by week 36, and HBsAg was undetectable at week 40.
• Protective immunity toward HBV was confirmed at week 41 (seroconversion to HBsAg to the antibody to HBsAg [anti-HBs]), and the patient was considered to have recovered.
• The patient reinitiated STELARA treatment, recaptured his original clinical response, and completed study treatment through 5 years. At the final dosing visit (week 244), PASI 100 was achieved and LFT results remained within normal limits.
• There were no further reports of liver-related AEs through the end of the 5-year study.

Patient #2 was a 40-year-old white male with a 14-year history of moderate to severe plaque PsO from the TRANSIT study.

• He had a 25-year history of smoking and currently smoked about 40 cigarettes per day.
• The patient was otherwise healthy, had no known risk factors for HBV, and was HBsAg negative 6 months before receiving STELARA (in January 2010).
• Prior treatments included topical therapies, acitretin, cyclosporine, and MTX.
• He did not respond to MTX (20 mg/day for 6 months), as indicated by a baseline PASI score of 31.6; liver enzymes were normal.
• The patient received STELARA 90 mg on June 25, 2010 (week 0), while terminating MTX, without tapering.
• At week 2, significant elevations of AST, ALT, γ-glutamyltransferase, and lactate dehydrogenase were reported. Tests were repeated 4 days later, and levels remained elevated.
• He did not present with any symptoms but was hospitalized and treated by a hepatologist for closer monitoring. Jaundice developed during hospitalization.
• He was evaluated and screened for alcohol use, concomitant medications, hepatitis serologies, and an abdominal ultrasound.
• Hepatitis A and C serologies were negative, and ultrasound imaging revealed heterogeneous echogenicity without focal lesions.
• Acute HBV infection was diagnosed based on detectable serum HBV DNA and the presence of serologic markers (HBsAg, total antibody to hepatitis B core antibody [anti-HBc], anti-HBc IgM, and HBeAg).
• Antiviral therapy (entecavir 0.5 mg/day) was initiated, STELARA was discontinued, and topical PsO treatment was continued.
• Assessments between weeks 5 and 16 showed normalization of liver enzyme levels.
• Liver synthetic function, as assessed by serum albumin, remained normal.
• Seroconversion of HBsAg to anti-HBs had not occurred; the hepatologist concluded the hepatitis had likely resolved (based on the final serological profile at week 24 which showed undetectable HBsAg and anti-HBc IgM, and HBeAg seroconversion to anti-HBe).
• At the final follow-up at week 28, the patient did not experience further hepatic abnormalities and treatment with entecavir was ongoing.
• PsO topical therapy was continued, and a final PASI score of 30.3 was reported.
• The patient terminated medical care at the site, and no further information regarding his condition was obtained.

Steglich et al (2014)¹³ reported the case of a 53-year-old male who presented with a 27-year history of recalcitrant severe PsO and positive HBV serology who was treated with STELARA.

• The patient had a baseline PASI of 61.2, BSA of 81%, a poor quality of life, and a history of inefficacy, intolerance, or toxicity with standard systemic treatment for psoriasis.
• Pretest HBV serology revealed anti-HBc positivity, low titer anti-HBs (2 mIU/mL), and negativity for anti-HBc IgM, HBsAg, HBeAg, and anti-HBe.
• Before starting biologic therapy, patient was vaccinated against HBV, achieving anti-HBs positivity.
• Lamivudine 75 mg per day was started on the same day as STELARA.
• STELARA treatment significantly improved the lesions. At 1 year of follow-up, a PASI of 3.8 was maintained, BSA of 13%, normal liver test results, and no adverse effects.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 15 May 2024.