ABT-378 vs Nelfinavir (+d4T/3TC)

There isn't much new compelling information reported here in Glasgow, but there is updated efficacy data on ABT-378 for the treatment naÔve and experienced studies. The updated data hasn't changed much but its further out now. Perhaps more interesting is new information related to ABT-378 resistance, lipids and hepatitis from the 863 study, which compares nelfinavir TID to ABT-378 bid. Margaret Johnson from Royal Free Hospital in London reported on this study at Glasgow and reported 48 weeks efficacy updated from 40 weeks at ICAAC. Here is the link to the NATAP ICAAC report on study 863:
http://www.natap.org/sept2000/ICAAC/ICAAC_Rpt_2_abt_92000.htm

This study is a double-blind, randomized trial comparing safety and efficacy between these two protease inhibitors in over 600 treatment-naÔve individuals. The study started with NFV dosed at 750 mg three times daily but patients could switch to 1250 twice daily after the FDA approved the dose change. Patients also received d4T+3TC. Patients also received ABT-378 or NFV placebo. About 27% in each arm were Black, 14% Hispanic, and about 20% were female.

RESISTANCE

Abbott is reporting that so far they do not see resistance in patients on ABT-378 with detectable viral load, but they can detect resistance in patients failing nelfinavir.

Abbott reported that 42 of 326 patients in the ABT-378 (+d4T/3TC) arm had viral load >400 copies/ml at week 24 and week 48, while 78 of 327 patients in the nelfinavir (+d4T/3TC) arm had >400 copies/ml at week 24 and 48. In the ABT-378 arm, they had genotypic samples on 31 of the 42 patients, and 64 samples of 78 from the nelfinavir arm. Abbott reported finding no key protease mutations (primary or within the binding pocket) for any of the 31 patients with detectable viral load, but 20 of the 64 nelfinavir genotypes available had protease resistance. In other words, for treatment naÔve ABT-378 treated patients they do not see protease resistance. Some of these patients were non-compliant. Abbott reported in their poster that at week 24 18 of 25 patients (with >400 copies/ml) had genotypes available. 23 in the ABT-378 arm had VL >400, 17/23 (74%) resuppressed their VL at least once, and 17/23 remained on study through week 48. In 14/17, viral load was <400 copies/ml at week 48. At week 24, 8/18 (44%) had 3TC resistance, and 4/8 resuppressed viral load in the presence of the 3TC resistance mutation.

At week 24 in the nelfinavir arm, 40/54 patients had VL >400 copies/ml but 15/40 (38%) had protease resistance. And, 36/40 had 3TC resistance. Abbott reported 11/51 (22%) resuppressed at least once after week 24, 29/51 stayed on study through week 48, and 7/29 had VL <400 at week 48. None of the nelfinavir treated subjects with protease mutations (D30N or L90M) at week 24 experienced viral suppression any time after week 24. And, 3/21 who had 3TC resistance mutation without protease mutation resuppressed viral load.

HEPATITIS

Subjects who were hepatitis B/C+ at baseline were allowed to enter the study. Any patient, regardless of hepatitis status, was excluded from the study if their LFTs (SGOT/SGPT) were >3 times ULN (upper limit of normal) at baseline. Of the 633 patients in the study, 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). They didn't report how many interrupted therapy due to elevated LFTs. No Hep B/C+ subjects discontinued due to elevated liver enzymes or clinical hepatitis.

Abbott reported that of those with Hep B/C receiving ABT-378 2% had >5 x ULN AST, and 10% had >5 x ULN ALT. While, of those Hep B/C+ receiving nelfinavir 11% had >5 x ULN AST, and 17% had ALT >5 x ULN. Abbott did not report that these differences were statistically significant. The mean change in AST/ALT labs from baseline to week 40 were similar regardless of hepatitis status. They reported that none of the ABT-378 and 3 of the nelfinavir patients were noted to have Grade 4 SGOT/SGPT elevations.

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

LIPIDS

As was reported at ICAAC, the same trend was reported here: 9% on ABT-378 and 5% on nelfinavir had cholesterol >300 mg/dL (not significant); 9% on ABT-378 and 1% on NFV had >750 mg/dL triglycerides (<0.001). In Glasgow, Abbott reported that mean triglycerides increased from about 175 at baseline to 185 at week 48 (visual observation of graph). In people receiving NFV mean triglycerides increased from about 175 to 200 at week 48. Cholesterol increased the same in both arms from about 170 to 200.

Mean CD4 increased about the same in both arms at week 48 (about 200).

ADHERENCE THROUGH WEEK 48

Adherence was measured by pill count (% of pills taken overall and between visits). Adherence rates were reported similar between the two arms: 14% in ABT-378 and 17% in NFV arms had overall adherence rates <90%; 5% and 7% had overall adherence rates <80%, respectively.

DISCONTINUATION RATES

17% taking ABT-378 and 24% taking NFV discontinued at or before week 48:  

MOST COMMON ADVERSE EVENTS