Combining Indinavir with Ritonavir

The combination of indinavir and ritonavir (also known as Crixivan and Norvir, respectively) has been attracting attention as a potentially potent and 'user-friendly' combination.

Poster Session 22361: Indinavir Can Be Taken with Regular Meals When Administered with Ritonavir

Dr. Hsu's pharmacokinetic study of the combination of indinavir and ritonavir (400 mg of each every 12 hours) enrolled 13 men and 3 women who were HIV-negative; this is frequently done to get a preliminary look at the way drugs work in the body. The study goal was to determine whether lower -- and in the case of indinavir less frequent -- doses could be given without lowering blood levels. Lower blood levels generally mean less antiretroviral effect. 9 men and 1 woman actually completed the 17-day study; three discontinued because of side effects, while three others withdrew consent.

Because ritonavir inhibits metabolism of indinavir, the study found that the lower dose of indinavir remained in the blood stream longer, even when given with a regular meal. Currently, indinavir can only be taken with low-fat foods. It also showed that twice-daily rather than 3-times daily dosing may be effective in combination with ritonavir. Key results showed:

  • Indinavir could be given without regard to food
  • Indinavir half-life was extended from 2 hours to 4 hours
  • Ritonavir half-life was extended from 3-5 hours to 8 hours
  • Blood levels of indinavir in this combination where similar to the standard 800 mg every 8 hour dose regimen

Given these promising but very preliminary results, studies of this combination will now move forward in HIV-positive people to determine efficacy.

Poster Session 22372: Novel Double Protease Combinations: Combining Indinavir with Ritonavir

Dr. Workman's study went a bit further than Dr. Hsu's, and examined the indinavir (IDV) and ritonavir (RTV) combination, 400 mg of each every 12 hours, given in combination with d4T and 3TC, in HIV-positive patients receiving clinical care.

38 patients were enrolled in the following three groups:

  • Group A: 12 patients who had received d4T+3TC+RTV+saquinavir (SQV), with stable CD4 counts and viral loads below 400 copies, for more than six months

  • Group B: 18 treatment-naïve patients. This group had a mean baseline viral load of 138,118 copies, and a mean CD4 cell count of 369

  • Group C: 8 patients who had previously failed protease inhibitor therapy (four had failed on SQV, four on IDV)

Results were:

  • Group A: All ten patients who reached the 36-week mark were undetectable (<400). Seven of 9 patients who reached week 52 were undetectable on the sensitive viral load test (below 40 copies), with the remaining two having viral loads of 42 and 72 copies. Nine of 12 achieved CD4 cell increases of over 100 cells, which was somewhat surprising given a) that these are experienced patients and b) their viral loads are already undetectable. Studies have shown indinavir's ability to increase CD4 cell counts over time, so the addition of IDV may account for this increase. Results in this arm suggest that the immune system may still derive benefit from treatment changes even when viral loads are already below the limits of detection. This is not in itself a reason to switch from one suppressive regimen to another, but it does warrant further investigation.

  • Group B: All patients reached levels <400 by Week 12, with 8 of 9 patients who completed Week 32 going below 40 copies of HIV per mL. Six of these 18 patients did experience mild diarrhea, which went away with out changing the RTV dose.

  • Group C: All patients experienced a viral load drop, but the researcher did not say what proportion reached undetectable. Two of the patients who had previously failed on indinavir maintained viral loads below 800 copies out to Week 32.

These studies help confirm the findings of earlier studies presented at this and previous conferences. One major theme of the conference in Geneva has been the search for easier dosing regimens, because of their obvious advantages in terms of adherence.