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AIDS Treatment Data Network
(ATDN) Simpler Dosing: Once-Daily Drugs

January 10, 1999
Treatment Review, Issue #29 * Winter 1999

Recent studies have looked at ways to make HAART easier to take. Some of the available anti-HIV drugs are being studied with new dosing schedules, and several new drugs offer the promise of once or twice daily dosing.

Glossary NRTI: Nucleoside analog reverse transcriptase inhibitor. Approved NRTIs are AZT (Retrovir), ddI (Videx), ddC (HIVID), d4T (Zerit), 3TC (Epivir) and abacavir (Ziagen).

NNRTI: Non-nucleoside analog reverse transcriptase inhibitor. Approved NNRTIs are Sustiva (efavirenz), Viramune (nevirapine) and Rescriptor (delavirdine).

Protease inhibitors (PIs): Approved protease inhibitors are indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir) and saquinavir (Fortovase).

Once-Daily Dosing Sustiva (efavirenz) is a newly approved NNRTI anti-HIV drug that is given just once a day. For a fact sheet on Sustiva, see page 7.

ddI (Videx) is a NRTI drug that's been available for several years. Several small studies have investigated once daily dosing of ddI, usually at 300 or 400mg a day, dependent on body weight. The results suggest that ddI works as well taken once a day as it does when taken twice a day. Based on these results, some doctors are already prescribing ddI once daily, although this has not yet been officially approved by the US Food and Drug Administration (FDA). The company that makes the drug, Bristol Myers-Squibb, is waiting for results of a large study of once daily ddI before asking the FDA if they can change the currently recommended dosing.

Viramune (nevirapine) is an approved NNRTI drug that may work when given once a day. The standard dose is 200mg taken once a day for two weeks followed by 200mg taken twice a day. A study presented at the 1998 International AIDS Conference in Geneva looked at 123 people that took Viramune at a dose of 400mg once a day. The blood levels of Viramune in these people stayed 250 times higher than the amount needed to block 90% of HIV production in the test tube. This study suggests fairly strongly that nevirapine could be given once daily. Like with ddI, the FDA has not yet approved once-daily dosing of nevirapine.

3TC (Epivir) is a twice daily NRTI drug that may have the potential for simpler once daily dosing. This suggestion is based upon the length of time the drug stays inside cells in the body after each dose, as opposed to how much you can measure floating free in the blood. Two recently presented studies have used 300mg of 3TC dosed once daily instead of splitting it into two 150mg doses over the course of the day.

All-in-all, once daily dosing of ddI, 3TC and nevirapine looks very promising. It's important to realize that these studies were based on what's already known about these individual drugs. Not all drugs can simply be switched from three times a day dosing to twice a day, or from twice day to once a day. The anti-HIV drugs AZT, d4T, and abacavir, for example cannot be dosed once a day because they don't stay in the body long enough.

Simpler Dosing: Twice-Daily Drugs Viracept is a protease inhibitor that's already approved for treating HIV. The approved dose is 3 pills (750mg) taken three times a day. Several studies have now compared the approved dose to a simpler dosing schedule of 5 pills (1250mg) taken twice a day. After up to 48 weeks of treatment, the studies have found that Viracept can work just as well given twice-daily. It's likely that the company that makes Viracept will soon ask the Food and Drug Administration to approve this easier dosing schedule, but at the moment twice daily dosing of Viracept is still considered experimental.

Fortovase is the new version of the protease inhibitor saquinavir. The approved dosing of Fortovase is 6 pills (1,200mg) three times a day. Early results of a study comparing the approved dose to a new dose of 8 pills (1,600mg) twice daily were recently presented. Both doses were given along with two NRTI anti-HIV drugs. After eight months of treatment, there is not a big difference between the doses in terms of increases in T4 counts and reduction in viral load. However, eight months may be too soon to tell if the twice daily dosing will work as well as three times a day over the long term.

Norvir + Fortovase is the most commonly used combination of protease inhibitors. Norvir boosts Fortovase levels and allows both drugs to be taken twice-daily, at lower than normal doses. When combined, Norvir and Fortovase are usually both given at a dose of 400mg twice daily. The Public Health Service HIV Treatment Guidelines include Norvir + Fortovase as a reasonable first-line treatment combination. The guidelines recommend that Norvir + Fortovase be used in combination with one or two NRTI drugs.

Other combinations of protease inhibitors that allow twice-daily dosing are also under investigation. Studies of Norvir + Crixivan, Viracept + Fortovase, Crixivan + Viracept and Norvir + Viracept are ongoing.

Not all studies of simpler dosing have been successful. A study of the protease inhibitor Crixivan (indinavir) given twice-daily was recently stopped. The twice daily dose did not work as well as the standard dose of Crixivan, which is 800 mg every 8 hours. After six months, 91% of people in the standard Crixivan dose group had viral loads below 400 copies ("undetectable" on the standard test), compared to 64% of people taking the experimental twice-daily Crixivan dose. The first study of standard dose Crixivan combined with AZT and 3TC has now been going on for three years. A recent update found that 20 of the 30 people taking this triple combination have viral loads less than 50 copies after three years of treatment. The average increase in T-cells so far is 198. This study shows that Crixivan works best at the standard dose of 800 mg every 8 hours.