Hepatotoxicity (liver toxicity), often indicated by elevation of the liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST), is a possible side effect of several antiretroviral drugs. Researchers at the recent 11th European AIDS Conference (EACS) in Madrid (October 24-27, 2007) presented the results of a study looking at the liver profile in patients who received the protease inhibitor (PI) tipranavir (Aptivus) boosted with ritonavir.

Background

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As background, the investigators noted that tipranavir is effective in treatment-experienced patients with HIV that is resistant to ≥1 PI [1–3]. Elevations in serum transaminases are common in patients treated with antiretrovirals; some patients are at risk of severe hepatotoxicity [4–6].

Chronic viral hepatitis coinfection may increase the risk of drug-related hepatotoxicity [7,8,9]. A study by Mark Sulkowski and colleagues evaluated patients receiving PI-based antiretroviral therapy, with or without co-administration of a booster dose of ritonavir [10]. The risk of developing hepatotoxicity was similar with all of the PIs evaluated, and a booster dose of ritonavir was associated with a much lower risk of hepatotoxicity than a full therapeutic dose.

The study concluded that, when making treatment decisions, the efficacy, resistance profile, and overall safety of an antiretroviral regimen are more important factors than the risk of elevations in liver enzymes [10].

Cases of elevated serum transaminase levels and serious hepatic adverse events associated with tipranavir/ritonavir in the RESIST studies through 48 weeks of therapy were evaluated by Sulkowski and colleagues [11].

The majority (89.9%) of patients treated with tipranavir/ritonavir did not develop Grade 3/4 ALT/AST elevations, and serious hepatic adverse events (SAEs) associated with Grade 3/4 ALT/AST elevations were infrequent (0.9%) through the first 48 weeks of treatment.

The frequencies of Grade 3/4 ALT/AST elevations, adjusted for exposure to study medication, were compared for tipranavir/ritonavir and comparator boosted PIs (CPI/ritonavir) arms. The Kaplan-Meier probability of a Grade 3/4 ALT elevation occurring at Week 48 was 9.9% and 2.8% for the tipranavir/ritonavir and CPI/ritonavir arms, respectively; and 6.1% and 2.1% for Grade 3/4 AST levels in the tipranavir/ritonavir and CPI/ritonavir arms, respectively. Multivariate analysis demonstrated the most significant risk factors for Grade 3 or higher ALT/AST elevations in RESIST participants who took tipranavir/ritonavir were elevated baseline ALT/AST levels and chronic viral hepatitis coinfection.

The aim of the present hepatic safety analysis was to evaluate the risk and natural history of transaminase elevations and hepatic SAEs among patients receiving 500/200 mg twice-daily tipranavir/ritonavir in Phase IIb/III trials through 96 weeks.

Methods

Transaminase elevations and hepatic SAEs through 96 weeks were characterized using pooled data from 5 tipranavir/ritonavir Phase II and III trials. The 5 trials were 2 Phase II trials (1182.51 [n=67] and 1182.52 [n=72]), 2 pivotal Phase III trials (RESIST-1 [n=311] and RESIST-2 [n=436]), and 1 “roll-over” trial (1182.17 [n=413]) that allowed patients from completed Phase II trials to continue to receive tipranavir/ritonavir at the approved dose of 500/200 mg twice daily as well as provide tipranavir/ritonavir to those in RESIST who failed CPI/ritonavir therapy.

All participants included in these trials were HIV infected male or female adults (aged ≥18 years) with > 3 months of prior treatment with 3 classes of antiretrovirals (nucleoside reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptase inhibitors (NNRTIs), and PIs), including at least 2 prior PI-based regimens (1 being the regimen at screening) and had a viral load of > 1000 copies/mL at baseline.

Patients with chronic viral hepatitis coinfection (hepatitis B virus [HBV] or hepatitis C virus [HCV] were eligible for inclusion if transaminase levels were less than DAIDS Grade 2.

Kaplan-Meier probability estimates for time to first Grade 3 or 4 transaminase elevation, first clinical hepatic SAE, and clinical outcomes after Grade ≥ 3 transaminase elevations were analyzed.

Hepatic SAEs were defined as any SAE with a MedDRA (version 8.1) preferred term falling into hepatobiliary system organ class. In addition, symptomatic hepatic adverse events were determined by review of all patients who had hepatobiliary system organ class adverse events.

This review included all serious and non-serious adverse events regardless of severity. All events that were not specifically due to biliary disease alone, or only elevations of liver laboratory tests (without reported clinical hepatic events), were categorized as symptomatic hepatic events. Clinical actions and outcomes following the development of Grade ≥ 3 transaminase elevation were analyzed with regards to treatment continuation, interruption or discontinuation of tipranavir/ritonavir.

Low-risk patients were defined retrospectively as those not coinfected with HBV or HCV and who had baseline transaminase elevations of Grade 1 or less. High-risk patients were characterized retrospectively by the presence of either chronic viral hepatitis or elevated serum transaminases Grade >1 at baseline. HCV coinfection was determined by the presence of both a positive serological test for HCV antibody and a positive HCV RNA. HBV coinfection was assessed at baseline by the presence of hepatitis B surface antigen.

Study protocols excluded patients with screening ALT and/or AST elevation of ≥ Grade 2; however a significant number of patients (n=48) who met the screening criteria were found to have Grade 2 elevations at baseline on the first study visit and were included in the trials.

Results

• In the 5 trials, 1299 treatment-experienced patients took 500/200 mg twice-daily tipranavir/ritonavir. A total of 1088 patients were classified as low-risk, 179 as high-risk, and 32 were unclassified (due to incomplete baseline data).

• Most of the patients were male (86.5%) and there were similar proportions of each sex in the 2 risk groups. 

• The median baseline HIV RNA and CD4 cell count were similar between the 2 risk groups.

• Low-risk patients had a median HIV RNA of 4.8 log₁₀ copies/mL and a median CD4 cell count of 158 cells/mm³ at baseline. High-risk patients had a median CD4 cell count of 151 cells/mm³ at baseline.

• 21 patients (1.6%) who took 500/200 mg twice-daily tipranavir/ritonavir over a period of 96 weeks developed Grade 3 or 4 ALT/AST elevations accompanied by non-serious or serious symptomatic hepatic AEs; only 4 of these patients (0.3%) experienced a hepatic SAE.

• 85% (123/144) of these cases were asymptomatic, i.e. not associated with any clinical adverse events such as fever, malaise, or abdominal pain.

• The Kaplan-Meier risk of developing a Grade 3 or 4 ALT and/or AST level was greatest in the first 24 weeks (6.1%) versus the subsequent 24 week periods (Week 48: 9.5%; Week 96: 13.7%).

• By Week 96, the cumulative risk for Grade 3 or 4 ALT/AST elevations was approximately 2-fold lower in low-risk (12.5%; 110/1088) patients versus high-risk (20.6%; 30/179).

• Investigators decided to continue or temporarily interrupt tipranavir/ritonavir in 121 of 144 patients with ALT/AST Grade 3/4 elevations. The majority (105/144; 72.9%) were successfully treated with tipranavir/ritonavir with a subsequent decrease in transaminase elevations to Grade ≤ 2.

• After developing Grade 3 or 4 ALT/AST levels, 93 of 144 patients (65%) continued tipranavir/ritonavir. Of these, 88 (94.6%) experienced a return to Grade ≤ 2 ALT/AST levels in a median of 32 days (IQR 14-84 days) while taking tipranavir/ritonavir.

• 28 of 144 patients (19.4%) interrupted therapy at least once. In 17 of the 28 patients (60.7%) who interrupted therapy, elevated transaminase levels returned to Grade ≤ 2 after a median of 46 days (IQR 20-58 days).

• However, 11 of 28 patients (39.3%) who had a treatment interruption developed subsequent recurrence(s) of Grade 3 or 4 transaminases that led to therapy discontinuation.

• The course of action taken among low-risk and high-risk tipranavir/ritonavir patients was similar, with the majority (81/110 or 74% of low risk patients; 22/30 or 73% of high risk patients) able to continue, or interrupt and re-introduce, tipranavir/ritonavir treatment.

• All low-risk patients that continued with tipranavir/ritonavir treatment had transaminase levels return to Grade ≤ 2 after a median of 29 days.

• Similarly, among high-risk patients who continued with tipranavir/ritonavir treatment, all patients except 1 had transaminase levels decrease to Grade ≤ 2 although the recovery median time was longer than in low-risk patients (43 days).

• Among the 1299 treatment-experienced, 14 (1.1%) experienced hepatic (non-biliary and non-laboratory) SAEs.

• The cumulative risk of clinical hepatic SAEs remained low through 96 weeks (0.5% at Week 24, 0.9% at Week 48, and 1.4% at Week 96).

• Among low-risk and high-risk patients, the cumulative risks of hepatic SAEs were similar during the first 24 weeks (0.5% and 0.6%, respectively).

• However after Week 24 the risks of clinical hepatic SAEs increased disproportionately among high-risk patients compared with low-risk patients.

• In high-risk patients, Kaplan-Meier rates increased to 2.1% at Week 48 (an accumulation of 1.5% additional risk from Week 24 to 48), to 3.0% at Week 72 (accumulated additional risk of 0.9% from Week 48 to 72), and to 4.3% at Week 96 (accumulated additional risk of 1.3% from Week 72 to 96).

• For low-risk patients, the corresponding accumulation of additional risk was 0.2% from Week 24 to 48, 0.1% from Week 48 to 72, and by 0.2% from Week 72 to 96.

• For all grades of maximal on-treatment ALT/AST, i.e. Grades 0-4, among the high-risk patients, there were 5 of 179 patients (2.8%) with hepatic SAEs:

o        1 with hepatic failure;

o        1 with hepatic steatosis;

o        1 with cirrhosis and liver damage;

o        1 with hyperbilirubinemia;

o        1 with hepatic insufficiency and portal hypertension.

• All 5 were coinfected with HBV or HCV.

• There were 9 of 1088 low-risk patients (0.8%) with hepatic SAEs: 

o        4 with hepatic failure;

o        2 with steatosis or cirrhosis;

o        2 with hepatotoxicity or toxic hepatitis;

o        1 with hepatosplenomegaly.

• Overall, there were 6 patients who had a hepatic SAE denoting hepatic failure; 5e had fatal outcomes.

• These events occurred in advanced patients with intercurrent end-stage AIDS events, including disseminated Mycobacterium avium-intracellulare, visceral leshmaniasis, Burkitt’s lymphoma, squamous carcinoma, sepsis, and multi-organ failure. 

• The sixth patient recovered rapidly and was discharged from the hospital after 5 days.

Conclusions

• In tipranavir/ritonavir Phase IIb/III trials in highly treatment-experienced patients (n=1299), the majority of patients (88.9%) did not develop Grade 3 or 4 ALT/AST elevations through 96 weeks of treatment.

• Most cases of Grade 3 or 4 transaminase elevations were asymptomatic (85%). The majority of patients (105/144; 72.9%) were able to continue and/or interrupt tipranavir/ritonavir without permanent discontinuation with subsequent decrease in transaminase elevation to Grade ≤ 2.

• After developing Grade 3/4 ALT/AST levels, 93 of 144 patients (65%) continued tipranavir/ritonavir. Of these, 88 (94.6%) experienced a return to Grade ≤ 2 ALT/AST levels in a median of 32 days while taking tipranavir/ritonavir.

• Among the 144 patients developing Grade 3/4 ALT/AST, only 21.7% (31/144) required discontinuation of therapy (20 with immediate discontinuations and 11 with interruptions followed by subsequent discontinuation).

• Clinical hepatic SAEs were infrequent (1.1%) in the 5 tipranavir/ritonavir trials included in this analysis.

• Asymptomatic laboratory Grade 3/4 ALT/AST elevations were a poor predictor of serious clinical hepatic events.

For more details on this study, please see the full poster that includes Tables and Figures presented at the 11th EACS in Madrid.

Hôpital Cochin, APHP, Unite d'Hepatologie, Paris, France; Service d'Hepato-Gastroenterologie, Hopital Pitie-Salpetriere, Paris, France; Department of Medicine I, University of Bonn, Germany; Division of Infectious Diseases, John Hopkins University School of Medicine, Baltimore, MD; Mount Sinai School of Medicine, New York, NY; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT.

10/30/07

Source
S Pol, Y Benhamou, J Rockstroh, and others. Hepatic profile of tipranavir in treatment experienced HIV-1 infected individuals. 11th European AIDS Conference. Madrid, Spain. October 24-27, 2007. Abstract (poster) P4.5/03.

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