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What a Difference a Day Makes

Is Once-a-Day Dosing of d4T Better?

November/December 2001

At the 8th European Conference on Clinical Aspects and Treatment of HIV Infection in Athens this Fall, results were reported from a 48-week randomized trial comparing the standard twice-daily form of d4T (stavudine, Zerit) with a new once-daily extended release form of d4T.

One hundred fifty treatment naive patients were enrolled into the double-blinded study and received efavirenz, 3TC plus d4T in either the once-a-day or standard twice-a-day doses. Patients assigned to receive once-daily d4T also took a twice-daily placebo, while those randomized to receive the standard form also took a once-daily placebo.

While the mean viral loads for each group were similar (around 45,000 copies/mL), the mean CD4 count for the once-daily group was higher than that for the twice-daily group (354 vs. 261 cell/mm3). All but one of the 75 patients assigned to receive the extended release d4T began treatment while 4 of the 80 assigned to the standard form dropped out without receiving the drugs. Of the individuals who started treatment, 91% of those on once-daily d4T completed the 48-week study compared to 82% of those on twice-daily d4T. Non-adherence and adverse events were responsible for most discontinuations before the end of the trial. The incidence of peripheral neuropathy was higher in the standard d4T group while those on extended release d4T reported more headaches.

The primary endpoint of the trial was the proportion of patients achieving viral load below 400 copies/mL by the end of 48 weeks. Among all patients who started the trial (including those who dropped out), 78% of those on extended release d4T compared to 67% on twice-daily dosing successfully suppressed viral load below 400 copies. But if the bar was raised to suppression below 50 copies/mL, the proportion of those who were successful dropped to about 49%, with no difference between the groups.

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The Bristol Myers press release on these data was content to claim that the new extended release form of d4T is safe and effective. This was wrapped by a larger context suggesting that once-daily d4T can be part of simpler HAART drug regimens for treating HIV. In presenting this data at the conference, the investigator stressed the association between ease of adherence to one's treatment regimen and the likelihood of that regimen successfully suppressing viral load. The implication (and hope) is that once-daily pills are going to be easier to remember to take and will make life easier for the person taking them without letting up pressure on the virus.

It should be noted that this trial was not designed to uncover the benefits of simpler dosing, only to establish equivalent safety and efficacy with the existing twice-daily formulation. As a blinded study, all patients took pills (either placebo or the real thing) twice a day -- even more pills than normally taken for the standard dose. Therefore ease of adherence should not have been a factor in the results from this trial. Yet the company presents, without comment, data that shows apparent improvements in efficacy between the two forms of d4T. If there is equivalency between the two formulations, then what explains the differences in response and frequency of toxicity in the results?

To understand this we need to see results from pharmacokinetic studies that track the levels of drug in the blood over time. In particular we would like to compare the difference in peak concentrations and in the area under the curve (AUC) which charts the available blood concentration of the drug during an entire day.

Another open question about once-daily dosing is the impact a skipped dose will have upon blood levels. With a twice-a-day regimen the catch-up dose enters the blood twelve hours late; with daily dosing a full day will pass before drug levels are brought to recommended concentrations. Longer term studies of daily regimens are needed to determine if there is a greater risk of drug resistance developing when doses of these less burdensome regimens are missed.




  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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