Report 6: ABT-378/r

Report 6

ABT-378/r

Connie Benson reported data from this study of ABT-378 in individuals who had experience with one PI and were NNRTI naīve. ABT-378's in vitro anitiviral activity is 10 fold higher than that for ritonavir in vitro. The addition of small amounts of ritonavir insufficient for antiviral activity enhanced the trough concentrations of ABT-378 to levels >30-fold above the EC50 and >2-3 fold for the EC90 of wild type virus at steady state. It is the ability of ABT-378 with small amounts of ritonavir to reach high blood levels that are the predominant reason for the drug's potency and potential ability to suppress PI resistant virus. While tipranavir's potential for suppressing PI resistant virus is based on a different resistance profile.

In study M97-720 in treatment-naīve individuals viral load was <400 copies/ml in 93-95% of patients on treatment at week 24. There were no discontinuations related to study drug due to adverse events. For this study (# 765) patients had a viral load between 1000 and 100,000 copies/ml. Median was 10,000 copies/ml. They had to be currently on treatment with 1 PI and 2 NRTIs for >3 months, naīve to at least one NRTI, naīve to NNRTIs, not had dual PI therapy and no prior treatment with other PI for >6 weeks.

Individuals were blindly randomized to 400mg ABT-378 with either 100 or 200 mg of ritonavir, with BID dosing. For the first two weeks of therapy only the PI was changed to ABT-378 in order to evaluate the contribution of the drug. After day 14 individuals added nevirapine and changed their nucleoside backbone. At least one had to be a new NRTI.

70 patients were enrolled. The median CD4 count at entry was 349 (range 72-800). The median viral load was 10,000 copies/ml (range (2.9 log to 5.8 log). Of the patients entering the study 44% (31) were on indinavir, 36% (25) were on NFV, 13% (9) were on SQV, 6% (4) were on RTV, and 1 person was on amprenavir. 89% (62) were on 3TC, 58% (39) on d4T, 46% (32) on AZT, and 10% (7) on ddI.

At baseline 64% of 57 patients in this analysis had 4 fold or greater loss in susceptibilty to their previous PI. 33% had a 4 fold or greater loss in susceptibility to 3 or more PIs. They used the Virco Antivirogram phenotypic assay. For those entering the study who were using indinavir the mean fold change in EC50 compared to wild type was 7.7 (that is, they had 7.7 fold resistance to IDV); those entering having failed NFV had 19 fold resistance (19 fold increase in EC50) to NFV, 9.5 fold for SQV and 23 fold for RTV. There was a broad range of genotypic mutations seen in these patients at baseline, prior to receiving ABT-378/r.

Again using the Virco phenotypic assay, 65% of individuals had 4 fold or greater resistance or loss of susceptibility to 1 baseline NRTI. 22% had 4 fold or greater resistance or loss of susceptibility to both baseline NRTIs. More than 90% of 57 patients had 3TC resistance and about 45% had AZT resistance. There was little resistance detected to d4T, ddI and ddC. One person had NVP resistance but several people had some loss of phenotypic susceptibility to NVP.

Of the 70 patients enrolled 64, remained on study and 6 discontinued: 1- adverse event related to ABT-378 (nausea and vomiting in the first few days of therapy), 1- adverse event related to ABT-378+NVP (rash attributed to NVP), 1- adverse event unrelated to study drug, 1 for personal reason, 1 lost to follow-up and I death unrelated to study drug.

Results-

During the initial two-week period when only the PI was switched, 66/70 or 94% of individuals had 0.5 log decrease in HIV-RNA or a viral load <400 copies/ml (n=24). Response during first two weeks appeared to be independent of what PI they used previously, and independent of baseline phenotypic susceptibility to ABT-378. On treatment analysis 54/64 (84%) had a decline in viral load to <400 copies/ml, while using an Intent-To-Treat analysis 77% were <400 copies/ml. A <50 copy analysis has not been completed yet. The mean viral load reduction during the first two week period was 1.2 log but since many individuals were <400 copies/ml you cannot measure their full viral load reduction. The mean increase in CD4s was 93 at week 24 for those on treatment.

Patients with >4 fold phenotypic resistance at baseline to 2 or more drugs in their new regimen were more likely to rebound 4/12 (33%) than those who had >4 fold phenotypic resistance at baseline to 0 or 1 drug (4/42, 10%). Viral rebound was observed in 8 patients, and was defined as HIV-RNA increases from nadir to >1000 copies/ml without documented therapy interruption.

Most severe adverse events seen were GI related: 3 or fewer loose stools per day (4%), diarrhea (16%), nausea (4%). Events included here were of at least moderate severity and probable, possible or unknown relationship to ABT-378. Diarrhea were seen early in therapy, ameliorated as therapy moved on, and only 1 person discontinued due to GI side effects.

Three individuals experienced elevation in glucose (>250 mg/dL). Two of these 3 had diabetes at baseline. 16 (23%) had triglycerides >750 mg/dL. The mean baseline triglyceride value for these patients was 500 mg/dL vs 190 mg/dL for patients who never experienced triglycerides levels >750 mg/dL on study. Mean baseline triglycerides levels for all patients was 268 mg/dL with a mean change of 109 mg/dL at week 24. 17 (24%) had cholesterol >300 mg/dL. The mean baseline value for these patients was 227 mg/dL vs 169 mg/dL for patients who never experienced a cholesterol value >300 mg/dL on study. Mean baseline cholesterol for all patients was 184 mg/dL with a mean change of 31 mg/dL at week 24. 13% had AST/ALT >5 times above the upper limit of normal. Triglycerides and cholesterol samples were all drawn non-fasting.