Jules Levin, NATAP

Joe Eron presented data from two studies of ABT-378. One in treatment-naïve individuals and a second in individuals who had failed a single PI but were NNRTI-naïve. ABT-378 is taken twice daily and is co-formulated with low dose ritonavir because it enhances its pharmacokinetics or blood levels. Trough concentrations of ABT-378 are 30-fold above the EC50 of wild-type HIV at steady state. This means that ABT-378/r achieves high levels in the blood. It is these high levels that allow it to be taken twice daily and make it potent. As well, these high blood levels of drug may play a role in its effectiveness against HIV resistant to other protease inhibitors. The high drug levels may be high enough to prevent replication of resistant HIV. However, this may vary by individual as some may respond well to ABT-378 but others may not. Additional studies will hopefully delineate who is more or less likely to be responsive.

The experienced study described below offers preliminary data that is encouraging in this aspect but follow-up studies will have to be conducted because the study had limitations: individuals actually failed only 1 PI, their median baseline viral load was only 10,000 copies/ml, and participants were NNRTI-naïve. Additional studies are needed in individuals who have failed more than 1 PI to better characterize how effective ABT-378 can be for individuals who’ve failed multiple protease inhibitors. Such a study is planned. A small 300-person compassionate access program is now available for individuals who have few treatments options remaining and would like to try ABT-378. Early next year a larger and more broad traditional expanded access program is expected.

Study 720 was done in treatment-naïve and there were two groups. In group 1 participants (n=32) received ABT-378/r alone for 3 weeks to evaluate the drug and then participants received either 200/100 ABT-378/r or 400/100 mg bid with d4T+3TC. In group 2 (n=68), patients received immediately ABT-378/r 400/100 or 400/200 mg bid with d4T+3TC. Patients had >5,000 HIV-RNA with any CD4 count. The median baseline viral load was about 100,000 copies/ml in both groups 1 and 2. The median CD4 was 412 in group 1 and 301 in group 2, with a wide range from 2 to over 900. There were 5 discontinuations over 36 weeks (1 in group 1 and 4 in group 2) but none were related to drug: drug addiction (1), lymphoma (1), non-compliance (2), moved outside US (1).

Viral Load Results – Naïve Study

CD4 counts increased about 200 in both groups.

In the Treatment-experienced study (# 765), participants were required to be naïve to NNRTIs and at least 1 NRTI. They had to be on a stable PI regimen for at least 3 months. Patients were enrolled if their viral load was between 1000 and 100,000 copies/ml. ABT-378/r was substituted for their PI for the first two weeks to observe activity of the drug (400/100 or 400/200 mg bid ABT-378). At day 15 nevirapine was added and NRTIs were changed (1 new NRTI must be used). The median baseline viral load was low at 10,000 copies/ml and the CD4 was 349.

Prior PI use: 44% indinavir, 36% nelfinavir, 13% saquinavir, 6% ritonavir, 1% amprenavir. These are NRTis patients were on at enrollment but they may have had other NRTIs previously: 87% 3TC, 56% d4T, 47% AZT, 10% ddI.

Phenotypic PI susceptibility data was available at baseline for 55 of 70 patients. 64% of the participants had > 4 fold resistance to their previous PI. 33% had > 4 fold resistance to 3 or more protease inhibitors. The participants had a good deal of phenotypic resistance to the protease inhibitor they had just been taking: IDV 7.7-fold resistance, NFV 19.1-fold, SQV 9.5-fold, RTV 23-fold.

There were 8 of 70 patients enrolled who discontinued. Two discontinued probably due to an adverse event associated with ABT-378. There were two deaths: 1 from lung cancer and 1 from pneumonia. One was due to an adverse event unrelated to ABT-378. Two for personal reasons. And 1 was lost to follow-up.

After week 36, 78% had <400 copies/ml using on treatment analysis and 67% had <400 using ITT. The ultra-sensitive (<50 copies/ml) results are pending. Cd4 increased about 100.

19% experienced diarrhea in all 3 study groups (groups 1 & 2 in naïve study and the 1 group in the treatment-experienced group). In the naïve group 2, there was a higher rate reported of nausea (19% vs 3-4% in other 2 groups). This could be because they were treatment naïve and some were receiving the higher ritonavir dose (200 mg). Otherwise other adverse events were reported at low rates across all 3 groups: 1-4% for asthenia, headache, vomiting.

The participants in the 765 experienced studies entered with higher cholesterol and triglycerides. ULN= upper limit of normal.

* HbsAg+ or HCV Ab+ at baseline: 4/8 in 720 group 2 and 2/10 in 765

** 4/6 patients had pre-existing diabetes