Durban World AIDS Conference
Tuesday, July 11
Durban, South Africa
Reported by Jules Levin

Report 14

ABT-378 in Mutiple PI-Experienced: Viral Load Data at week 24 Potential Changes May Be Needed in HHS Treatment Guidelines

I just came from what may turn out to be a key presentation by T. Sterling from Johns Hopkins University. He reported findings from a study suggesting that the viral load used by the HHS Treatment Guidelines may be too low for men and for women. But they may have to be raised more for men than for women. He has spoken to the head of the HHS Treatment guidelines Committee and the committee will be discussing this. In addition, I just ran into Julio Montaner and he told me he is reporting data that will be in a late breaker poster on Thursday saying that therapy may not have to be started until a person's CD4 is 200. He suggests viral load should not be used in the decision as to when to begin therapy, only the CD4 count. The HHS Treatment Guidelines have always been just to be used as guidelines for practicing physicians, but they have taken on a sort of mandate for some doctors as to when to begin therapy. Stay tuned on this for further information.

Imediately below is a report on the use of ABT-378 in individuals with experience with 2 or more protease inhibitors and multiple NRTIs. This drug appears to be effective for individuals with PI resistance. The question is how much PI resistance reduces it's effectiveness. It's discussed below in the first paragraph. One concern is the use of resistance tests to detect resistance to ABT-378. The 2 widely used phenotypic resistance tests use cut-offs of 2.5, 4.0, and 10.0 fold changes in drug needed to suppress HIV (or as more commonly called resistance) to report resistance. Studies reported on ABT-378 at the Resistance Workshop show that much higher resistance is needed to have resistance to ABT-378. The exact cut-offs for ABT-378 have not been exactly identified but the studies reported estimates that should be helpful. It's incumbant on the resistance test manufacturers to re-assess their cut-offs and establish more accurate criteria to judge susceptibility to ABT-378. It's my understanding Abbot is in discussions with both manufacturers--Virologic & Virco. Hopefully, this will be resolved when the drug is approved by the FDA for commercial access.

ABT-378 (Kaletra) and Efavirenz: 24 Week safety/Efficacy Evaluation in Multiple PI-Experienced Patients

This study reports the percent <400 copies/ml for ABT-378 at week 24. In Sitges, at the Resistance Workshop, data was broken down by response according to baseline genotypic and phenotypis resistance. Individuals with 0-5 mutations responded best. Individuals with >7 mutations may not respond as well to ABT-378. Individuals with phenotypic resistance <20 fold responded best. Those with phenotypic resistance >40 fold may not respond well to ABT-378. For more details, an extensive report is available on the NATAP web site in the section listing reports from the Workshop (4th International Workshop on HIV Drug Resistance & Treatment Strategies).

This is a study of 57 patients receiving ABT-378/r 400/100 mg (3 coformulated capsules) twice daily (BID) in place of their current PI, in combination with efavirenz (Sustiva) once daily (QD) and NRTIs chosen by the doctor/study investigatot, for the first 13 days of the study. On day 14, some patients (n=28) randomly had their ABT-378/r dose increased to 533/133 (ABT/378/ritonavir)--4 coformulated capsules. The remaining (n=29) continued on the 400/100 dose. ABT/378 trough levels wwere drawn at week 2l full PK (drug levels) was performed at week 5; efavirenz levels were drawn at weeks 2 and 5. Viral load in plasma was measured with the Roche Amplicor Monitor assay with a lower limit of quantification of 400 copies/ml. To qualify for this study patients had to be NNRTI-naÔve and had multiple PI-experience (history of sequential or concurrent treatment with at least 2 protease inhibitors for at least 3 months each.

The baseline viral load was 4.6 log (39,000 copies/ml) in the group remaining on 400/100 dose; viral load was about 25,000 copies/ml (about the same) in the 533/133 arm. Cd4s in the 400/100 group were 230 and in the 533/133 arm they were 325.

Prior to this study the mean number of HIV drugs were 7 (range 3-10); mean number of prior protease inhibitors was 3 (range1-4); and the mean number of NRTIs was 2 (range 1-4). The types of drugs previously used in both arms were pretty evenly distributed, but all protease inhibitors and NRTIs were used. For example, 83% in the 400/100 arm had used indinavir, and 89% had used indinavir in the 533/133 arm. 68% (38/56) of patients had baseline viral isolates demonstrating  4 fold resistance (increased EC50 relative to wild-type) to at least 3 approved protease inhibitors. 43% of these viral isolates (24/56) showed  10 fold resistance (increased EC50 of ABT-378 relative to wild-type virus).

BASELINE PHENOTYPIC SUSCEPTIBILITY:

PHARMACOKINETIC DATA

ABT-378 levels achieved with 400/100 dose are reduced when taken with efavirenz (C-trough reduced -33%; AUC reduced -25%). Abbott reported that increasing ABT-378 dose produced similar levels as taking 400/100 without efavirenz. They also reported efavirenz levels are similar for both ABT-378/r dose levels studied, so ABT-378 don't appear to affect levels.

PATIENT DISCONTINUATION AT WEEK 24

In the 400/100 group (n=29), 4 (13.8%) patients discontinued at or before week 24--2 due to virologic failure, and 2  due to CNS side effects, GI/CNE side effects, lactic acidosis. In the 533/133 arm, there were 3 patients discontinued (10.7%)--1 due to virologic failure, and 2 due to drug related side effects described just above (both discontinuations occurred prior to study day 145 and initiation of the 533/133 dose).

VIRAL LOAD SUPPRESSION at 24 WEEKS

On Treatment Analysis
--92% (23/25) in the 533/133 arm had <400 copies/ml
--80% in the 40/100 arm (20/25) had <400 copies/ml

ITT Analysis
--82% in the 533/133 arm had <400 copies/ml
--69% in the 400/100 arm had <400 copies/ml

In both dose groups CD4s increased about 45 at week 24.

SAFETY and TOLERABILITY

The most common study drug side effects of at least moderate severity were diarrhea and asthenia, while the most common lab abnormality was lipid elevations.  Of the 7 patients who discontinued through week 24 4 were due to adverse events/lab abnormalities related to study drug.

MOST COMMON ADVERSE EVENTS OF AT LEAST MODERATE SEVERITY and PROBABLE<POSSIBLE or UNKOWN RELATIONSHIP TO ABT-378 and GRADE 3/4 LAB ABNORMALITIES

Total cholesterol/HDL cholesterol ratios were not significantly changed from
baseline at week 24 at either dose level of ABT-378.