Glasgow Day Two - Abbott Symposium: Ritonavir+Indinavir, ABT-378, and Ritonavir+Saquinavir
From Jules Levin
At today's Abbott symposium data was presented on ABT-378, an update on ritonavir+saquinavir, and the new combination of ritonavir+indinavir. Dr Frank Palella of Northwestern University reported preliminary data from a phase II study. He said that ABT-378 is a very potent drug, in vitro it was 10 fold more potent than ritonavir. High plasma concentrations of ABT-378 are achieved and sustained in animals and humans when co-dosed with small concentrations of ritonavir. Studies so far show it to be well tolerated, better tolerated than ritonavir. Trough concentrations of ABT-378 were 25-100 fold above the IC50 of wild-type HIV at steady state. This means that there is a lot of drug still in the blood at the end of the dosing period (12 hours). Therefore, it may be more difficult to develop resistance to the drug. It appears as if food has no effect on the bioavailibility of the drug. Study participants received ABT-378 monotherapy for 3 weeks and then d4T+3TC was added. In order to identify a dose, individuals received either 200mg or 400 mg with 100 mg of ritonavir. Patients were treatment-naïve. The purpose of the study was too look at tolerability, changes in plasma HIV RNA and CD4s, and PK (pharmacokinetics). The baseline median CD4 was 424, 24 individuals had >100 CD4s, 7 had <100 CD4s, and viral load was 100,000 copies/ml. Palella said there was a "dramatic and abrupt" reduction of viral load of 2 logs within the first two weeks. The median reduction at 6 weeks was 2.2 log and this has been sustained out to 24 weeks. The data available is on 11 patients at week 24. At week 24, 10/11 had <400 copies/ml. At week 20, 16/17 had <400 copies/ml. No patients have discontinued from the study due to drug related adverse events. Median CD4 increase was 150 cells.
Adverse events were GI related; moderate Aes possibly or probably drug related-
| Event | No. | % |
| Abnormal stools* | 5 | 15.6% |
| Diarrhea | 5 | 15.6% |
| Asthenia | 3 | 9.4% |
| Headache | 3 | 9.4% |
| Abdominal Pain | 2 | 5.3% |
Ritonavir+Saquinavir
In a Danish study (DAPIS) RTV+SQV was compared to IDV and RTV as part of regimens involving two NRTIs. Participants were PI naïve. The Danish criteria for starting therapy is conservative: HIV related symptoms, or CD4 count <300, or HIV RNA >100,000 copies/ml. Wow! How would you like to live there? Its like living in Mississippi and trying to get ADAPT. As of Jan 98 284 patients were enrolled receiving 400 mg RTV bid+400 mg SQV bid, RTV 600 mg bid, or IDV 800 mg tid. All patients also received 2 NRTIs. It was recommended that people change at least 1 NRTI.
This first data set applies to all patients in study: naïve and experienced together. At week 24 in an intent-to-treat analysis 82% receiving RV+SQV, 67% receiving RTV, and 71% receiving IDV had <200 copies/ml (p=0.06). Using the ultrasensitive assay with a cutoff of 20 copies/ml, 59% receiving RTV+SQV, 45% receiving RTV and 39% receiving IDV were undetectable (p=0.05).
For the treatment-naïve patients in the study, at week 24, 89% receiving RTV+SQV had <200 copies/ml. By visual observation of graph it appeared that 70% using IDV and 60% using RTV had <200 copies/ml (=0.01). With a detection limit of 20 copies/ml 61% were undetectable with RTV+SQV. Significantly better than RTV or IDV (p-0,01). By visual observation it appeared that about 30% were undetectable in both IDV and RTV arms.
In the treatment-experienced group all three arms had about 75% <200 copies/ml and about 50-55% had <20 copies/ml.
Ritonavir+Indinavir
Dr Cassy Workman reported data from two studies of RTV+IDV. A dose of 400 mg IDV bid+400 mg RTV BID was used in both studies. There was no food effect; RTV raises IDV trough levels and lowers its Cmax reducing risk of kidney stones.Three RTV+IDV arms have been explored: 100+800, 200+600, and 400+400. The 400+400 was the only dose which raised Cmin and reduced Cmax of IDV. 21 treatment-naïve patients received RTV+IDV+d4T+3TC. Their median baseline viral load was 54,000 copies/ml, mean baseline VL was 149,000 copies/ml, and mean CD4 count was 400.
Viral load results-
CD4 cell increase of a mean of 143 at week 12 (n=15), 225 at week 20 (n=11), and 425 (n=7) at week 52.
Eight people who had failed a PI, either SQV or IDV received RTV+IDV without any NRTIs because they exhausted them. They also chose to save their NNRTI option. One SQV failure with a baseline VL of about 500,000 copies/ml had a nice VL reduction initially but rebounded within weeks. A second person also with a high VL reduced their VL to about 10,000 and appeared to stabilize there out to about 20 weeks. The other 6 patients appeared to have profound VL reductions going out to from 12 to 52 weeks.
Workmam reported having 57 patients on this regimen with a total exposure of 2,412 weeks. The mean time on theapy was 42 weeks. There was no increase in fluid intake and no cases of kidney stones or flank pain.
Workman reported data from a second study of RTV+IDV conducted by a German research group. 71 treatment-naïve patients received RTV+IDV+2 NRTIs. Median baseline VL was 210,000 copies/ml and CD4 of 229 cells. 51% used AZT+3TC, 38% used d4T+3TC, and 11% used d4T+DDI.
The median VL decrease was 3.6 log in the 17 patients who reached week 24 so far. 100% of patients had <500 copies by week 16 which was sustained at week 24. 80% had <80 copies/ml. The median rise in CD4 cells was 165. Workman said regimen was well-tolerated.
That's it for tonite. Its 11pm and I am going to bed.