Ritonavir and Saquinavir Combination: 12-Week Data at ICAAC

A multi-center study of combination treatment with two protease inhibitors is continuing to produce encouraging results(!). This ongoing clinical trial had earlier reported six-week data from two of its four dosage arms (in July 1996 at the International Conference on AIDS in Vancouver); now it reported 12-week data from those arms, plus 6-week data from two higher dosage arms, on September 16 at the ICAAC conference in New Orleans. At this time median viral load reductions or CD4 count increases from the different doses cannot be distinguished statistically; however, one of the higher doses seems to be causing most of the dropouts.

The side effects seen so far have been those which would be expected from ritonavir alone. But the viral load reductions have been greater than would be expected from either drug by itself.

The two are being studied in combination because ritonavir increases blood levels of saquinavir, which are believed to be too low with the standard dose of that drug -- and also because these protease inhibitors have somewhat different patterns of development of viral resistance, suggesting that it may be more difficult for HIV to become resistant to both of them simultaneously than to one of the drugs alone. Also, each drug alone has shown benefit in clinical trials.

The 12-week data reported here were presented by Cal Cohen, M.D., of the Community Research Initiative of New England, one of the sites running the trial, which is funded jointly by Abbott Laboratories and Hoffmann-La Roche.

The Study Design

Volunteers had to have a CD4 count between 100 and 500, and no previous exposure to protease inhibitors. For this study, they had to discontinue other antiretrovirals two weeks before beginning the protease inhibitor combination.

For safety, lower doses were tested first. A total of 71 volunteers were randomly assigned 400 mg of ritonavir (Norvir(TM)) plus 400 mg of saquinavir (Invirase(TM)) twice daily (dosage arm 1A), or 600 mg of ritonavir plus 400 mg of saquinavir twice daily (dosage arm 1B).

Later, when no safety problems were found, the higher dosage arms were started. Both these arms gave the same total daily dose; the difference was whether it was given twice a day or three times a day. 65 volunteers were randomly assigned to receive either 400 mg of ritonavir plus 400 mg of saquinavir three times a day (dosage arm 2A), vs. 600 mg of ritonavir plus 600 mg of saquinavir twice a day (dosage arm 2B). To reduce side effects, there was a dosage ramp-up period.

Note: Due to a typographical error, the published abstract lists the 400 mg three times daily dose as 400 mg bid (twice daily).

Results

Most of the discontinuations were in arm 2A, the high-dose group receiving 400 mg of both drugs three times a day. The numbers who discontinued were 1 in arm 1A, 3 in arm 1B, 8 in arm 2A, and 0 in arm 2B.

The 12-week viral load reduction for groups 1A and 1B together was a median of 2.97 logs (99.9%), and the median CD4 increase was 95; the two groups were similar. A total of 53 volunteers had completed 12 weeks of treatment. This compares to a viral load reduction of 2.4 logs (99.6%) for the same treatment groups at six weeks.

The high-dose groups had 39 volunteers completing six weeks; their median viral load decrease was 2.14 logs (99.3%), and the median CD4 increase was 75. Remember that this is six-week data, compared to 12-week data from the low-dose groups above.

Another way of looking at the viral load is to ask what percentage of volunteers have viral loads which go below the limit of detection of the test (200 copies, in this trial). The proportion who reached this definition of successful treatment continued to increase during the first 12 weeks of the trial, and was about 75% at week 12. With the high-dose groups, the proportions reaching undetectable viral load were smaller -- but here only six-week results were available, and also those who had to discontinue the treatment (highest in the 2A dosage arm) were counted, and of course they failed to reach undetectable viral load.

Comment

It is possible that this combination might work even better if combined with one or two nucleoside analogs (e.g. AZT plus 3TC) -- provided that the regimen is tolerable. The main reason for combining different classes of drugs is to reduce viral replication as much as possible, to minimize the opportunity for the virus to develop mutants which are resistant to the drug.

During the question period after the ICAAC talk, Dr. Cohen suggested that for some patients who are resistant to all the available nucleosides, this protease inhibitor combination may be the best treatment option.

The most important question now is how long this combination will be successful. We will learn more as the trial continues.

References

1. Cohen C, Sun E, Cameron W, McMahon D, Farthing C, Poretz D, Markowitz M, Follansbee S, Mellors J, Ho D, Hsu A, Maki R, Salgo M, and Leonard J. Ritonavir-Saquinavir Combination Treatment in HIV-Infected Patients. 36 Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, September 15-18, 1996 [abstract #LB7B].