ABT-378/r 36-Week Phase II Update: experience with 1 PI and NNRTI naive

At ICAAC, Joe Eron presented data on individuals who had failed a single PI but were NNRTI-naïve. ABT-378 is taken twice daily  and the high blod levels achieved may play a role in its effectiveness against HIV resistant to other protease inhibitors. 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 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.

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 patients were on NRTIs 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.

Discontinuations.  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.

Viral Load Results.  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.

Most Common Adverse Events.  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.

Lab Abnormalities.  The participants in the 765 experienced studies entered with higher cholesterol and triglycerides. ULN= upper limit of normal (See Table 13):