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UNBP0518 04/14

The Body PRO Covers: The 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment

Tipranavir Heralds New Era for Treatment-Experienced Patients

July 27, 2005

Tipranavir (TPV, Aptivus) is the newest protease inhibitor (PI) to become available in the United States (and soon enough in other parts of the world) having been approved June 22, 2005. As previously reported, it's a non-peptidic PI that has a distinct resistance profile and, in clinical trials, has exhibited potency, durability and tolerability in patients exposed to many previous highly active antiretroviral therapy (HAART) regimens.

We are still learning about its optimal use in clinical practice, and a number of presentations at the 3rd IAS Conference on HIV Pathogenesis and Treatment were quite helpful in this regard. These represented new analyses of the extensive data generated in the RESIST studies.

In the RESIST studies (Poster WePe16.7B07 [this abstract cannot be linked to directly, but is available within this listing], Poster WePe6.3C07), 1,159 heavily treatment-experienced patients with significant genotypic resistance to PIs, but with no more than 2 mutations at codons 33, 82, 84 and 90, were randomly assigned to receive optimized background therapy with the addition of tipranavir + ritonavir (RTV, Norvir) at 500 mg/200 mg twice daily (n = 582) or a ritonavir-boosted PI of the investigator's choice (n = 577).

The 2 groups were well matched with respect to baseline HIV plasma viral load (4.83 versus 4.82 log10 copies/mL), CD4+ cell count (155 versus 158/mm3), number of mutations in the protease gene (16 in both groups), prior exposure to antiviral agents/PIs (12/4 each group) and prior enfuvirtide (T-20, Fuzeon) use (69% versus 68%).

In the tipranavir group, 24% of the patients and 9% in the control group experienced full virologic suppression (HIV plasma viral load below 50 copies/mL) at 24 weeks. A 90% (1 log10) decrease in plasma viral load was observed in 41% of the patients in the tipranavir group versus 19% of the participants who were receiving another PI.

When examining the participants who received enfuvirtide, the mean decrease in viral load was 2.06 log10 copies/mL if tipranavir was used, as compared to only 0.40 log10 copies/mL in patients receiving another PI. If 2 other active agents were added to the regimen, tipranavir patients experienced a 1.38 log10 copies/mL decrease, versus only 0.3 log10 copies/mL in the control group. If 3 active drugs were available, these figures increased to 1.82 and 1.0.

If one excludes participants who had a baseline CD4+ cell count below 50 cells/mm3, the response rates (90% decrease in HIV plasma viral load at 24 weeks) increase to 46% and 22%. Even in the group with the most advanced immune disease (CD4+ cell count below 50 cells/mm3), tipranavir still has a distinct advantage over the control group (26% versus 9%). Immunologically, there was a greater median increase in CD4+ cell count in the tipranavir group at 24 weeks (34 versus 4 cells/mm3), a figure that increases to 55 cells/mm3 if patients who are on enfuvirtide are considered separately. Taken together, these data suggest that tipranavir is an important tool in the design of salvage therapy regimens, more so if it can be combined with enfuvirtide.

Ongoing follow-up of patients enrolled in the RESIST studies (with data hopefully presented at scientific meetings over the next year) will help confirm the durability of virologic benefit as well as the safety of tipranavir-based regimens.

Parameters of Tipranavir Efficacy

In another presentation, a random subset of 329 trial participants who were taking tipranavir in the RESIST studies (99 on enfuvirtide, 230 on other drugs) were enrolled in a pharmacokinetic study to establish the parameters of antiviral efficacy and toxicity (Oral WeOa0205).

Trough tipranavir concentrations were measured and then used to calculate a protein-adjusted inhibitory quotient (IQ) (based on measured phenotypic susceptibility of a contemporary clinical isolate). In this group, 66% of the patients had 2 mutations at codons 33, 82, 84 and 90, representing among the most resistant viruses that could be found in study participants.

Modeling experiments clearly showed that if a tipranavir IQ of more than 60 is achieved in trial participants who are taking tipranavir + enfuvirtide, fully 60% of them would achieve a viral load of less than 400 copies/mL at week 24 (37% to less than 50 copies/mL).

Similar figures are achieved in the absence of enfuvirtide with a tipranavir IQ of more than 90, a figure that is readily achievable in the majority of patients. Even at lower IQ levels (say 30-60), a benefit of tipranavir is still present (median 90% decrease in viral load). At the IQ of 60, modeling allows us to establish the relative impact on HIV plasma viral load of each of the elements of the regimen at 24 weeks:

  • tipranavir: 1.25 log10 decrease (penalty of 0.17 log10 for each mutation at codons 33, 82, 84 and 90)

  • enfuvirtide: 0.91 log10

  • each other active drug: 0.25 log10

Taken together, these data help us understand the true impact of tipranavir on our ability to manage treatment-experienced patients in 2005. This is especially true in patients who can be adherent to therapy (and thus can achieve the higher IQ levels) and, in addition, take tipranavir in conjunction with enfuvirtide. This regimen can produce a decrease in HIV plasma viral load that exceeds 99% (2 log10) in the majority of patients. Other active drugs that are available may contribute to the benefit, but the new "salvage backbone" for 2005 becomes tipranavir + enfuvirtide.

Tipranavir Side Effects

In another presentation about tipranavir (Poster WePe6.2C05 [this abstract cannot be linked to directly, but is available within this listing]), investigators led by Gerald Pierone looked at the adverse effects of tipranavir. In the RESIST pharmacokinetic substudy, significant elevations of transaminases were observed in 45% of individuals with tipranavir trough levels of more than 120, and were seen much less frequently at lower drug levels. Since more than 80% of patients in the substudy had levels of 13-80 µM, hepatotoxicity may not be a significant concern in patients now receiving tipranavir at its clinically-approved dose.

If one looks at the overall long-term toxicity of tipranavir (a drug which, in clinical trials, has now been given to more than 1,100 individuals, with more than 300 participants taking it for 18 months or more), the incidence of 5x elevation of transaminases is 8.9%, but only 5.9% if we consider patients who have been treated with the current formulation at the licensed dose. There were no cases of fatal or fulminant hepatitis. The only other significant laboratory abnormality is elevated triglyceride levels, which has been seen in 16% of patients overall, but only in 4.5% during the most recent era. Diarrhea and nausea (at 11% and 9%, respectively) are much less frequent than they were in earlier tipranavir studies. But no new events were reported after 24 weeks of therapy.

Another point made by Curtis Cooper at the Ottawa Hospital and his group is that in single-dose studies in 3 patients, the pharmacokinetics of tipranavir do not appear to be altered in patients who have moderate hepatic disease (Poster TuPe3.1B07 [this abstract cannot be linked to directly, but is available within this listing]).

Conclusions

In conclusion, tipranavir is a major addition to our therapeutic armamentarium for treatment-experienced HIV-infected patients at all levels of HIV plasma viral load and immune disease. This is particularly true when it can be used in conjunction with enfuvirtide.

In addition, given what we now know about the relationship between trough levels and therapeutic success, there may be a role for therapeutic drug monitoring and dose adjustment, particularly if enfuvirtide is not being used.

Tipranavir also has a favorable toxicity profile, especially as its dose and formulation have been modified in recent clinical trials and in the final commercial product. It will be important to continue to collect information on efficacy and toxicity in this post-launch era so that we can optimize the use of tipranavir in clinical practice.

References

Abstract: Tipranavir/ritonavir (TPV/r) demonstrates superior immunologic response to comparator protease inhibitors (CPIs) in a PI-experienced population with advanced disease (Poster WePe16.7B07)
Authored by: B Grinsztejn, C Hicks, P Cahn, J Villacian, S McCallister

Affiliations: Fiocruz, Rio de Janeiro, Brazil; Duke University Medical Center, Durham, United States of America; Foundacion Huesped, Buenos Aires, United States of America; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, United States of America
View poster: Download PDF
This abstract cannot be linked to directly, but is available within this listing.

Abstract: Tipranavir/ritonavir (TPV/r) demonstrates superior treatment response to lopinavir/r (LPV/r), amprenavir/r (APV/r) or saquinavir/r (SQV/r) in PI-experienced patients from the TPV RESIST-1 and RESIST-2 trials (Poster WePe6.3C07)
Authored by: A Lazzarin, G Mukwaya, N Clumeck, C Workman, J Gathe, B Trottier, J Villacian, D Neubacher, S McCallister
Affiliations: Fondazione Centro San Raffaele Del Monte Tabor, Milan, Italy; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, United States of America; Hopital Universitaire St. Pierre, Brussels, United States of America; AIDS Research Initiative, Darlinghurst, Australia; Therapeutics Concepts, Houston, United States of America; Clinique Medicale l'Actuel, Montreal, Canada
View poster: Download PDF

Abstract: Tipranavir/ritonavir (TPV/r) 500 mg/200 mg BID drives week 24 viral load (VL) below 400 copies/mL when combined with a second active drug (T-20) in protease inhibitor experienced HIV+ patients (Oral WeOa0205)
Authored by: H Valdez, S McCallister, V Kohlbrenner, D Mayers
Affiliations: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, United States of America

Abstract: 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 (Poster WePe6.2C05)
Authored by: G Pierone, M Drulak, K Arasteh, S Walmsley, C Katlama, A Lazzarin, J Miki, D Mayers
Affiliations: Treasuer Coast Infectious Disease Consultants, Vero Beach, United States of America; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, United States of America; Epimed GmbH, Berlin, Germany; Toronto General Hospital, Toronto, Canada; Hopital Pitie-Salpetriere, Paris, France; Mexican Institute of Social Security, Mexico City, Mexico
View poster: Download PDF
This abstract cannot be linked to directly, but is available within this listing.

Abstract: The pharmacokinetics (PK) of single-dose and steady-state tipranavir/ritonavir (TPV/r) 500 mg/200 mg in subjects with mild or moderate hepatic impairment (Poster TuPe3.1B07)
Authored by: C Cooper, R van Heeswijk, M Bilodeau, B Kovacs, J Sabo, T MacGregor, J Wruck, M Elgadi, D Neubacher, S McCallister
Affiliations: The Ottawa Hospital, Ottawa, Canada; Université de Montréal, Montreal, Canada; Boehringer Ingelheim Pharmaceuticals, Ridgefield, United States of America; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, United States of America; Boehringer Ingelheim Canada, Ltd, Burlington, United States of America
View poster: Download PDF
This abstract cannot be linked to directly, but is available within this listing.


It is a part of the publication The 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment.
 



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