Imagine popping two tiny pills in the morning -- and going on with your day, your chemical shield against HIV intact for the next 24 hours. Sounds like a fantasy, but with the ballooning number of once-a-day HIV meds, this dream is fast coming true. But some skeptics are wondering about this so-called emperor's new clothes.

One-a-day is already the standard for efavirenz (Sustiva), ddI (in its Videx EC form) and tenofovir (Viread). And some researchers argue that the typically twice-daily 3TC (Epivir) and nevirapine (Viramune) are safe and effective "qd" (or quaque die, Latin lingo for once a day). Then there's the trend toward boosting protease inhibitor (PI) levels with ritonavir (Norvir), which allows almost any PI to become a qd, and the number of potential once-daily regimens doubles.

While this brave new world of a single pill has yet to dawn, there are now several qd regimens consisting of a mere three or four pills -- all easy to tolerate and low on toxicity. Once Bristol-Myers Squibb's once-daily d4T (Zerit XR) and its once-a-day protease atazanavir (Zrivada) get to market -- likely in the next year -- the potential for qd combos swells (see "Once-Daily Doses," below).

Now, about that naked emperor: Adherence troubles sparked the quest for once-daily regimens. But it's not entirely clear that compliance actually improves when a twice-a-day regimen is replaced with a qd.

In a giant cross-study analysis of pill-poppers with chronic diseases such as diabetes, there was only a tiny difference in adherence rates between twice-a-day and once-daily regimens -- although the difference between three times vs. once daily was huge.

ONCE-DAILY DOSES

FDA-Approved
Agenerase with Norvir (PI)
Sustiva (NNRTI)
Videx EC (NRTI)
Viread (NtRTI)

Pending Research/Approval
Epivir (NRTI)
Fortovase with Norvir (PI)
Viramune (NNRTI)
Zerit XR (NRTI)
Zrivada (PI)

Skeptics also point to a treatment-simplification study by GlaxoSmithKline. After their viral loads went below 50 on a PI/two nuke combo, half of the volunteers were switched to Glaxo's Trizivir (abacavir/AZT/3TC). "With a single tablet morning and night, what could be easier?" Glaxo asked rhetorically -- and then got an answer it didn't much like. Only 60 percent of those on the protease combo reported perfect adherence, but the Trizivir-takers did only slightly better: Fewer than three-quarters reported complete compliance.

Then there's the "forgiveness" factor: the tricky question of whether HIVers risk sacrificing reliable drug levels for the convenience of simple dosing. ddI, Viread, Sustiva? No problem. Miss a dose and the stuff's still floating around in your blood a few days later. But the other qd drugs are far less generous with their time.

In a recent Treatment Issues, the GMHC newsletter, editor Bob Huff lampooned BMS' efforts to reassure queasy qd wannabes, recalling how at last February's Retrovirus confab, BMS researchers showed that twice- and once-daily pills were equally effective for 24 hours -- but were conveniently silent about what happens after that. After all, with once-daily meds, a skipped dose could leave 48 hours between pills -- and that would dump you in a data no-man's-land.

We're all eager for simpler pill-popping schedules, but the moral of this story is, HIVers should keep one eyebrow raised as the new crop of once-a-day therapies springs up this fall, and after.