Saquinavir: Combination Shows Survival Benefit; New Formulation Trial Recruiting

While three protease inhibitors are now approved for treatment of HIV infection, until now only one (Abbott's ritonavir, brand-name Norvir(TM)) had demonstrated in a clinical trial that it can reduce disease progression and increase survival of patients. On May 7, as this newsletter went to press, Hoffmann-La Roche released survival analysis of a major clinical trial comparing its protease inhibitor saquinavir (INVIRASE(TM)) plus ddC (Hivid(R)) vs. saquinavir alone vs. ddC alone. The combination showed a substantial survival benefit, with 28 deaths on ddC alone and 34 on saquinavir alone, but only 9 on the combination treatment -- a two-thirds reduction in deaths.

The two groups were also compared on disease progression -- defined as the number of persons who either died or had their first AIDS-defining event. There were 85 such progressions on ddC, 77 on saquinavir, and 46 on the combination. An analysis of time to event (not just number of events) showed a reduction of disease progression risk of slightly over one half with the combination, compared to ddC alone.

In both cases, the improvement of the combination vs. ddC alone was highly statistically significant, in this intent-to-treat analysis.

The trial volunteers had baseline CD4 counts between 50 and 300, and had at least 16 weeks of prior treatment with AZT. The treatment arms were balanced with respect to sex, age, race, baseline viral load, baseline CD4 count, and reason for discontinuing AZT; however, there had been less prior AZT therapy (68 weeks) in the combination group than in the other groups (74-75 weeks).

Discontinuation for toxicity was highest in the ddC arm. The combination did not seem to increase ddC toxicity.

Comment

It is encouraging that a second protease inhibitor has now proven that it can increase survival (when used in combination). The data above indicate that saquinavir did not work well alone. Probably this is because the approved dose is too low; but even with a better dose, or with any other protease inhibitor, use in combination with other antiretrovirals will probably be strongly preferred.

The reason ddC was chosen for use in this saquinavir trial is that the two drugs are marketed by the same company -- and also because this trial began recruiting in February 1994, when ddC was a reasonable choice. ddC need not be chosen today for combination use with saquinavir.

Our impression is that saquinavir (in its new formulation, which delivers a higher blood level -- or possibly in combination with ritonavir, if it is found possible to combine these drugs safely) will work much better than the currently approved dose and formulation, and become an important drug; but the research is not yet available on how to use it optimally. ddC, however, will be much less important in the future, because of its relatively small benefit vs. relatively high toxicity, although it can still be useful for some patients in some combinations.

New Saquinavir Trial

A trial of the new formulation of saquinavir (the soft gelatin capsule, which is more bioavailable than the currently approved drug) is now enrolling in 40 sites across the U.S. Although 400 volunteers were needed, about half enrolled in the first 10 days.

Volunteers must be at least 13 years old, and at least three quarters of those enrolled must not have used any protease inhibitor before. Any CD4 count may be allowed, but only 100 of the 400 volunteers can have counts of 100 or less.

All volunteers will receive the same dose of the new formulation of saquinavir for at least one year. Volunteers are allowed to use other antivirals during this trial, but not other protease inhibitors until safety information is available.

For more information, or to contact a site near you, call the AIDS Clinical Trials Information Service, 800/TRIALS-A.