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Conference Poster

5th International Congress on Drug Therapy in HIV Infection
Glasgow, Scotland, October 22-26, 2000

Treatment of HIV+ Subjects Co-infected with Hepatitis B or C Safety and Efficacy Comparison of Kaletra™ (ABT-378/ritonavir) vs. Nelfinavir from a Phase III Blinded Randomized Clinical Trial. J Arribas ,C Barros², J Gonzalez-Lahoz, W Cameron⁴, R Rubio⁵, F Altice, B. Clotet⁷ M King⁸ P Cernohous⁸, J Moseley⁸, MSattle⁸, E Baue , B Bernstein⁸, and E. Sun⁸ for the M98-863 Study Team. [P369]

1 Hosp. Universitario "LaPaz", Madrid, 2 Hosp. De Mostoles, Madrid, 3 Hosp. "Carlos III", Madrid, 4 Ottawa Gen. Hosp., Ottawa, Canada, 5 Hosp. Doce de Octubre, Madrid, 6 Yale University School of Medicine, New Haven, CT, 7 Hosp. Universitari Germans Trias I Pujol, Madrid, 8 Abbott Laboratories, Abbott Park, IL

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ABT-378/r is a novel HIV protease inhibitor (PI) that has shown significant antiviral activity and tolerability in clinical trials to date. ABT-378 is co-formulated with ritonavir, an inhibitor of cytochrome P450 3A. It is uniquely sensitive to pharmacokinetic enhancement by ritonavir, resulting in substantially increased ABT-378 drug exposure, even at low ritonavir doses. The mean ABT-378 C _trough /EC ₅₀ ratio (Inhibitory Quotient or IQ) for wild-type HIV is >75 when dosed at 400/100 mg BID, contributing to durability and potentially providing a pharmacologic barrier to the emergence of viral resistance.¹ The efficacy and safety of ABT-378/r are currently being studied in both antiretroviral-naïve and PI-experienced subjects. Study M98-863 further examines the antiviral activity of ABT-378/r in a large, blinded, randomized, prospective study comparing the activity and safety to that of nelfinavir. (Figure 1). Results for all study subjects through Week 40 are shown in Table 1, Figure 2 and Figure 3. ²

Figure 1. Study Design

80% of enrolling subjects were male, 56% were Caucasian, and the mean age was 38 years.

Table 1. M98-863 Subject Disposition at Week 40 for All Subjects

At week 40, 84% and 70% of subjects on ABT-378/r and nelfinavir respectively had HIV RNA levels <50 copies/mL (p<0.001) by the Roche Amplicor assay (OT); 70% and 54% respectively (ITT).

This study examines the safety, tolerability and antiviral activity of ABT-378/r and nelfinavir in the subset of M98-863 subjects who were hepatitis B/C+ at baseline.

METHODS

Subjects who were hepatitis B/C+ at baseline were allowed to enter the study. Any subject, regardless of hepatitis status, was excluded from the study if their SGOT/SGPT level was >3 times ULN at baseline. Of the 653 subjects, 125 were hepatitis surface antigen positive (HepB+) and/or hepatitis C antibody positive (Hep C+). In these subjects, study drug was interrupted if the subject developed signs or symptoms of clinical hepatitis associated with LFT elevation > 5 x ULN (Grade 3) or if the SGOT/AST or SGPT/ALT values elevated to > 10 x ULN (Grade 4). The safety and efficacy of anti-retroviral therapy in subjects who were Hep B/C+ at baseline was compared with that of subjects who were Hep B/C- at baseline.

RESULTS

Table 2. Demographic Characteristics for Hepatitis B/C+ Subjects

Within each treatment group, the response rate for subjects who were Hep B/C+ at baseline were similar to those subjects who were Hep B/C- at baseline.

Within each treatment group, the proportion of subjects who achieved HIV RNA levels <50 copies/mL was also similar regardless of hepatitis status.

Figure 5. M98-863 Mean CD4 Cell Count from Baseline in Treatment Groups

Within each treatment group, the mean change in CD4 cell counts for subjects who were Hep B/C+ at baseline were similar to those subjects Hep B/C- at baseline.

SAFETY / TOLERABILITY

Table 5. Most Common Adverse Events within Treatment Groups for Subjects Hep B/C+ and Hep B/C-

Table 6. Incidence of Grade 3/4 Lab Abnormalities within Treatment Groups for Subjects Hep B/C+ and Hep B/C-

Hep B/C+ subjects had a significantly greater risk of Grade 3/4 SGOT/SGPT elevation when compared to Hep B/C- subjects in each treatment group.

CONCLUSIONS

Both regimens were well tolerated with low study drug-related discontinuation rates. There were no discontinuations due to elevated liver enzymes or clinical hepatitis among the Hep B/C+ patients through Week 40 in either treatment arm.

The proportion of subjects achieving HIV RNA level <LOQ, and the mean change in CD4 count was similar in Hep B/C+ subjects compared to Hep B/C- subjects within each treatment group.

Presence of HbsAg or HCV antibody at baseline significantly increased risk of Grade 3/4 SGOT/SGPT elevations.

Grade 4 SGOT/SGPT elevations were uncommon occurrences in Hep B/C+ subjects. None of the ABT-378/r and 3 of the nelfinavir subjects were noted to have Grade 4 elevations.

REFERENCES

Bertz R, Lam W, Brun S, et al. Multiple-dose pharmacokinetics (PK) of ABT-378/ritonavir (ABT-378/r) in HIV+ subjects. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 1999 (abstract 0327).
Walmsley S, Badley A, Beall G, et al. Superior efficacy of ABT-378/r vs. nelfinavir (NFV) in antiretroviral (ARV) -naive subjects: Results of a phase III blinded randomized clinical trial. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 2000 (abstact 693).

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Treatment of HIV+ Subjects Co-infected with Hepatitis B or C Safety and Efficacy Comparison of Kaletra(ABT-378/ritonavir) vs. Nelfinavir from a Phase III Blinded Randomized Clinical Trial s

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