In order to suppress HIV, it is necessary to have high levels of anti-HIV drugs in the blood. To accomplish this, doctors sometimes prescribe two protease inhibitors (PIs) together as part of a combination drug regimen. One of the issues involved in taking two drugs simultaneously is that they can interact — raising or lowering levels of each other in the blood. For example, the PI ritonavir (Norvir) can usually boost levels of another PI when the two drugs are taken together. Taking ritonavir together with another PI also helps to maintain high levels of the other PI in the blood. Ritonavir can be used to boost levels of the following PIs:
Using ritonavir with these other PIs sometimes results in people with HIV/AIDS (PHAs) having to take fewer pills, thus allowing them to use a twice-daily regimen rather than a three-times-a-day schedule. An example of this is with the PI indinavir. Ordinarily indinavir has to be taken every 8 hours and according to dietary restrictions. But when used with ritonavir, the combination can be taken every 12 hours without dietary restrictions.
A major issue about this ritonavir-indinavir combination is what is the best dose of both drugs that could be used in combination. Some PHAs use a "400-400" dose: 400 mg of ritonavir and 400 mg of indinavir, taken twice daily. However, tolerating this dose of ritonavir isn't easy, so researchers are testing reduced doses of ritonavir in this PI combination.
A research team working at Merck, the drug company that manufactures indinavir, recently published results from its studies of various combinations of ritonavir-indinavir. Although these experiments were done using HIV negative volunteers, the results may be useful for doctors who prescribe ritonavir-indinavir for their PHA patients.
Researchers enrolled 73 healthy, HIV negative subjects (44 female, 29 male). Combinations of ritonavir-indinavir that were tested included the following, which were taken every 12 hours:
Data collected from this study were compared to those from previous studies in which indinavir was taken at a dose of 800 mg every eight hours (without ritonavir). All subjects in the current study were required to drink 1.5 litres of water daily. Subjects took their assigned drugs for 15 days.
As expected, researchers found that ritonavir boosted levels of indinavir. There were no significant differences with regard to indinavir levels when the following combinations were taken:
The levels of indinavir in the blood with the combination of twice-daily ritonavir 100 mg and indinavir 800 mg, although high, were not as high as those seen with the two doses listed above.
In order to suppress production of HIV, PI levels have to be high and remain high for prolonged periods, particularly between doses. When ritonavir-indinavir is taken either at the 200-800 dose or the 400-800 dose, the level of indinavir in the blood 12 hours later (near the time for the next dose) is between 10 to 25 times greater than it would be if indinavir 800 mg without the ritonavir boost was used. Taking ritonavir with indinavir therefore helps keep indinavir levels in the blood within a stable range, making it harder for HIV to develop resistance.
Researchers also tested the effect of high- and low-fat meals, which they defined as follows:
The researchers found that absorption of indinavir was not affected when indinavir was taken with high- or low-fat meals — as long as subjects also took ritonavir at the same time.
It is important to remember that in the combinations ritonavir is used as a "booster" and not for its anti-HIV activity. Nonetheless, researchers measured ritonavir levels during the study and found that indinavir raised ritonavir levels when low doses of ritonavir (100 mg or 200 mg) were used. This is not clinically significant. Ritonavir and indinavir levels were not affected by a person's gender.
Although 73 subjects enrolled in the study, only 53 were able to complete the two-week clinical trial. Ten subjects left the study because of side effects and 10 others left for unknown reasons.
In general, the researchers described side effects seen during the study as being "mild to moderate in severity." Side effects commonly noted during this study included nausea and vomiting. One subject developed kidney stones and two had blood in their urine. Side effects were most common among subjects using the ritonavir-indinavir 400-800 dose. This is likely due to the high level of ritonavir.
Results from this study suggest that a combination of ritonavir 200 mg and indinavir 800 mg, taken twice daily, may be the most useful of the doses tested. Doctors who prescribe this combination need to remind their patients about the importance of drinking at least 1.5 litres of water daily, in addition to all the fluid they usually drink.
REFERENCE
1. Saah AJ, Winchell GA, Nessly ML, et al. Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers. Antimicrobial Agents and Chemotherapy 2001;45(10):2710-2715.
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Copyright © 2001 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284 http://www.catie.ca.
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