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ICAAC 2005; Washington, D.C.; December 16-19, 2005

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The Body PRO Covers: The 45th Interscience Conference on Antimicrobial Agents and Chemotherapy

Ritonavir-Boosted Tipranavir Increases ALT and AST Levels in HIV/Hepatitis-Coinfected Patients

December 16, 2005

Tipranavir (TPV, Aptivus) is a non-peptidic protease inhibitor (PI) with a resistance profile distinct from that of other currently available PIs. Studies have found ritonavir (RTV, Norvir)-boosted tipranavir to be superior to standard-of-care ritonavir-boosted PI therapy in treatment-experienced patients.1,2 Tipranavir therapy has been shown to be potent, durable and generally well tolerated -- but not perfect.

For instance, we know from past studies that elevated levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) may be an issue for patients who use tipranavir.1,2 Whether tipranavir itself or the 200 mg of ritonavir needed twice a day to boost it is the real culprit here is still unclear. Sulkowski et al found high hepatotoxicity rates with PIs, especially high-dose ritonavir -- 400 mg twice a day -- in HIV/hepatitis coinfected patients.3 Hepatotoxicity with this lower level of ritonavir as a booster is not well studied.

The potential impact of tipranavir on ALT and AST levels resonates even more in the context of today's HIV epidemic in the United States, where liver complications are a growing concern. The improved life expectancy provided by highly active antiretroviral therapy (HAART) means that many HIV-infected patients now live long enough to develop hepatic complications related to underlying liver disease from chronic active hepatitis B (HBV) or hepatitis C (HCV) infections. HAART use can often exacerbate these hepatic conditions.

But to what extent should clinicians be concerned that tipranavir use may be dangerous for HIV-infected patients coinfected with HBV or HCV? In July 2005 at the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, Gerald Pierone et al presented a four-year follow-up study on tipranavir-treated patients.4 They found an overall grade 3/4 AST elevation rate of 3.1% in early tipranavir studies, versus 0.6% to 0.7% in more recent studies, including the RESIST trial.

While the early study patients were treated with tipranavir doses that are different from the currently prescribed dose, the fact that they had a higher rate of adverse events and had been followed for the longest time period (over four years) makes clarifying the risk factors for hepatotoxicity crucial.

The ritonavir-boosted tipranavir package insert notes that healthy volunteers in phase 1 studies, as well as HIV-infected patients in phase 3 trials, had a 6% risk of developing grade 3/4 liver enzyme elevations. The insert also notes that the risk of subsequent hepatotoxicity is 2.5-fold higher in patients who have underlying HBV or HCV coinfection or elevated transaminases. It further notes that the drug is contraindicated in those with Child-Pugh class B or C liver disease and that deaths from hepatotoxicity have been reported.5 These facts only further support the need for additional research into the efficacy and safety of tipranavir use in HIV/HBV- and HIV/HCV-coinfected patients.

Current Study: Tipranavir and Coinfection in the RESIST Trials

At this conference, Jürgen Rockstroh from the University of Bonn in Germany presented a poster on behalf of his colleagues at Johns Hopkins University and Boehringer Ingelheim, the company that developed tipranavir. Their analysis focuses on a subgroup of HIV/HBV- and HIV/HCV-coinfected patients from the RESIST 1 and 2 studies.

The RESIST 1 and 2 studies are phase 3, multicenter, open-label, randomized companion trials examining the efficacy and safety of tipranavir. The two studies were constructed identically, but took place in different geographical regions: RESIST 1 enrolled in the United States, Canada and Australia, while RESIST 2 enrolled in Europe and South America.

In both RESIST studies, patients were randomized into one of two arms:

  • 500-mg tipranavir boosted with 200-mg ritonavir, along with an optimized background regimen
  • a ritonavir-boosted, PI-based comparator regimen chosen using baseline genotypic data (the selected PIs included amprenavir [APV, Agenerase], indinavir [IDV, Crixivan], lopinavir [LPV] and saquinavir [SQV, Invirase])

At randomization, patients were stratified by the pre-selected PI and enfuvirtide (T-20, Fuzeon) use. Patients had to have at least three consecutive months of experience with all three major antiretroviral classes (nucleoside/tide reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptase inhibitors [NNRTIs] and PIs) and have been on at least two PI-based regimens (including their regimen at study entry) for a minimum of three months. There were no restrictions regarding CD4+ cell count, but HIV viral load had to be at least 1,000 copies/mL. Total cholesterol and triglycerides had to be Division of AIDS (DAIDS) grade 2 or lower, and ALT/AST levels could be no higher than 2.5 times the upper limit of normal (DAIDS grade 1).

The majority of trial participants were Caucasian males; mean age was 43 years. Median baseline HIV-1 RNA levels were similar between treatment arms.

24-Week Study Results in Coinfected Patients

In total, 582 patients on the ritonavir-boosted tipranavir arm were compared to 577 patients on the comparator arm. On the ritonavir-boosted tipranavir arm, 9.8% of the patients were coinfected with hepatitis (defined as being HBV surface antigen positive or HCV RNA positive), versus 14.6% of the patients on the comparator arm.

The chart below stratifies treatment response (TR) by hepatitis status; "treatment response" in this case is defined as an HIV viral load reduction of 1 log or greater. As you can see, ritonavir-boosted tipranavir patients had a greater level of treatment response at week 24, regardless of whether they were coinfected or not.

 Ritonavir-Boosted Tipranavir ArmComparator Arm
 Hepatitis +Hepatitis -Hepatitis +Hepatitis -
% with TR at 24 weeks42.1%41.3%19.0%19.2%

Ritonavir-boosted tipranavir patients also had a greater mean viral load reduction at week 24 than patients on the comparator arm, regardless of hepatitis status:

 Ritonavir-Boosted Tipranavir ArmComparator Arm
 Hepatitis +Hepatitis -Hepatitis +Hepatitis -
Median log10 viral load change at 24 weeks-0.70-0.81-0.33-0.25

Among coinfected patients in both study arms, the most commonly reported adverse events were diarrhea, nausea, pyrexia, fatigue and headache. In the ritonavir-boosted tipranavir arm, both the types and frequencies of adverse events, including hepatobiliary events, were comparable between coinfected and hepatitis-uninfected patients. No hepatic events occurred in more than 5% of patients.

Coinfected patients experienced a higher rate of grade 3/4 ALT or AST elevations in both arms; however, these elevations did not lead to any symptomatic hepatic events.

As the chart below shows, patients in the ritonavir-boosted tipranavir arm experienced higher rates of lipid and liver enzyme elevations. However, most elevations were asymptomatic, with no jaundice or other signs of liver problems, and most patients remained on treatment without permanent discontinuation. There were no data for the number of patients with symptomatic elevations, or on the number of patients who discontinued due to liver-related events.

 Ritonavir-Boosted Tipranavir ArmComparator Arm
 Hepatitis -HBV +HCV +Hepatitis -HBV +HCV +
ALT Grade 3/48.4%17.4%14.3%1.5%5.0%7.4%
AST Grade 3/45.2%17.4%10.2%1.3%5.0%5.9%

Baseline evidence of chronic, active HBV or HCV infection was an independent risk factor for the development of elevated liver enzymes in both treatment arms.

The Bottom Line: Cause for Concern, but Not Avoidance

The results of the RESIST studies reassure us that ritonavir-boosted tipranavir is generally well-tolerated, and exhibits superior antiviral activity at 24 weeks in treatment-experienced patients regardless of their hepatitis status. However, we do see increased incidence of transaminitis in hepatitis-coinfected patients on ritonavir-boosted tipranavir, which raises some concerns.

One unresolved question is how much of these ALT/AST elevations can be attributed to tipranavir itself, and how much is caused by the ritonavir that must be used to boost it. A higher-than-normal dose of ritonavir (200-mg twice daily, versus 100-mg twice daily for most boosted PIs) is required to adequately boost tipranavir levels.

We know from past studies -- such as Sulkowski's now-classic JAMA article -- that hepatotoxicity risks increase with high-dose ritonavir (although the Sulkowski study examined ritonavir at doses of 400 to 600 mg twice daily).3 Whether this is from direct drug toxicity, the effects of immune reconstitution on the liver or some other mechanism remains unclear.6

What is clear, though, is that this issue requires much more research, particularly into the long-term effects of ritonavir-boosted tipranavir on liver and lipid toxicity results. In the meantime, both practitioners and coinfected patients who are taking ritonavir-boosted tipranavir need to be ever vigilant; frequent laboratory monitoring of ALT and AST levels are essential, especially for patients with underlying, chronic, active HBV or HCV infection. As this study shows, even if a patient is asymptomatic, ALT and AST values may be quietly on the rise. Further research may delineate who really is at risk -- women, certain ethnic groups, etc.

Footnotes

  1. Hicks C. RESIST-1: a phase 3, randomized, controlled, open-label, multicenter trial comparing tipranavir/ritonavir (TPV/r) to an optimized comparator protease inhibitor/r (CPI/r) regimen in antiretroviral (ARV) experienced patients: 24-week data. In: Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, D.C. Abstract H-1137a.
  2. Cahn P. 24-week data from RESIST 2: phase 3 study of the efficacy and safety of either tipranavir/ritonavir (TPV/r) or an optimized ritonavir (RTV)-boosted standard-of-care (SOC) comparator PI (CPI) in a large randomized multicenter trial in treatment-experienced HIV+ patients. In: Program and abstracts of the 7th International Congress on Drug Therapy in HIV Infection; November 14-18, 2004; Glasgow, Scotland. Abstract PL 14.3.
  3. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. January 5, 2000;283(1):74-80.
  4. Pierone G, Drulak M, Arasteh K, et al. A long-term open-label rollover trial assessing the safety and tolerability of combination tipranavir and ritonavir (TPV/r) use in HIV-1-infected patients. In: Program and abstracts of the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Poster WePe6.2C05.

    This abstract cannot be linked to directly, but is available within this listing.
  5. Aptivus (tipranavir) capsules, 250 mg [package insert]. Ridgefield, CT: Boehringer Ingelheim; June 23, 2005.
  6. Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clinical Infectious Diseases. March 1, 2004;38(suppl 2):S90-S97.
Reference

Abstract: 24-week efficacy of tipranavir boosted with ritonavir (TPV/r) in hepatitis B (HBV) or hepatitis C (HCV) co-infected patients (Poster H-525)
Authored by: J Rockstroh, M Sulkowski, D Neubacher, D Mayers, J Stern

Affiliations: Univ. Bonn, Bonn, Germany, John Hopkins Univ., Baltimore, MD, Boehringer Ingelheim, Ridgefield, CT
View poster: Download PDF


It is a part of the publication The 45th Interscience Conference on Antimicrobial Agents and Chemotherapy.
 



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