Most people take their HIV pills twice a day at present, but a choice of once-daily regimes will be with us soon. Gus Cairns investigates
Once-daily
- what are the issues?One recent European study of 500 patients in five countries including the UK (the APPT-1 Study) found that 80 per cent of them would prefer to take their HIV drugs once daily.
Yet only three per cent actually did so. Why aren’t more people taking once-daily? After all, it’s a no-brainer - as one PN reader commented, “Well, it’s one less thing to forget, isn’t it?”
Some doctors (and patients) may be unaware of the options, but there are reasons other than medical conservatism that have made once-daily regimes slow to catch on.
Choice: Until recently there’s been a very limited choice of once-daily drugs (see below) and a once-daily regime of any kind only really became possible two years ago. Now, however, the drug companies are all sponsoring studies to see if their products can be dosed once-daily and there will soon be enough choices to devise first, second and possibly even third once-daily regimes.
‘Forgiveness’: The biggest potential drawback to a once-daily regime is that if you miss a dose, there’s a 48-hour gap. So you have to take drugs that stay in the body long enough to keep your HIV suppressed despite the odd lapse. However, recent studies report that certain once-daily regimes are as potent as twice-daily ones - one, for instance, showed that ddI, 3TC and efavirenz once a day works as well as AZT, 3TC and efavirenz twice a day. (see Q&A for more on adherence).
Lifestyle: People are individuals, and for this reason a regime that looks once-daily may turn out not to be. Take ddI/3TC/efavirenz. Most doctors would recommend taking this once-daily combo last thing at night, because efavirenz can zonk you out during the day, and ddI needs to be taken at least two hours away from food. But what if efavirenz gives you bad dreams? Or you’re a habitual midnight snacker? In that case you might want to take one of the drugs in the morning, and we’re back to twice-daily. One size does not fit all, and a ‘once-a-day’ regime should not be inflexibly so.
Once-daily
choicesUntil 18 months ago the only drugs with once-daily licences were ddI and efavirenz - not enough for a full combo.
In 2001 a Thai study found that both 3TC and abacavir could be dosed once daily without measurable differences in result. They found the same results whether the three-drug AZT/3TC/abacavir combo was given as all three drugs twice a day, or either the 3TC or the abacavir given in one double size dose once a day. Unfortunately they did not investigate if both 3TC and abacavir once-daily would work.
It’s unlikely that abacavir will be prescribed to you once a day as it is not licensed for this, but 3TC is now licensed for once-daily dosing and manufacturers GSK make a double-size 300mg pill for this purpose.
Second
choicesEarly last year Gilead licensed their by now highly-successful new once-daily drug tenofovir, adding a third nucleoside drug to the mix.
So now, you could try 3TC (or FTC, its soon-to-be licenced stronger cousin) /ddI/efavirenz, and still have tenofovir as a further nuke. (Tenofovir may enable you to take ddI with food, but this is as yet an ‘unofficial’ option: Its manufacturers Gilead are planning to combine it in one pill with FTC.)
Bristol Myers-Squibb are also developing a once-daily ‘Prolonged Release Capsule’ version of d4T, but this is not yet available. Some once-daily nucleoside drugs, like d4T or abacavir, may also not work if you’ve already developed resistance to others like AZT.
So you still wouldn’t have completely different once-daily regimes. You either need a second once-daily non-nucleoside drug instead of efavirenz, or you need six different once-daily nucleoside drugs that aren’t cross-resistant - so you can switch all three. Not quite there yet. Complicated, isn’t it?
So are once-daily regimes possible with other drugs? And do they work for drug-experienced patients too?
Efavirenz’s non-nucleoside twice-daily ‘sister’ nevirapine hangs around in the body nearly as long as efavirenz so should in theory work once a day. A trial named ‘2NN’, which compares nevirapine with efavirenz, and includes a once-daily regime of both as one of its ‘arms’, will have had its results announced by the time you read this, at Boston’s Retrovirus Conference from 10-14 February.
Protease
inhibitorsBut what if your first regime already contained one of these NNRTI drugs? Cross-resistance means if you fail one NNRTI, you’ve failed both. Any further once-a-day regime would almost certainly have to contain a protease inhibitor (PI).
Here the new PI atazanavir comes into the picture. This new drug is likely to be licensed if all goes well later this year, and will be available soon for some patients on an ‘expanded access’ basis. This once-a-day pill does not increase blood fat levels in the body. Here at last is a first choice once-daily PI, and if atazanavir does get through its last licensing stage, we really will have two sequential once-daily regimes to choose from.
There are, however, unanswered questions about atazanavir’s potency. The cautious interpretation is that it’s at least as strong as nelfinavir, but it has yet to be established if it will work in people who’ve already taken a PI and have some degree of resistance.
Third
choices for PIsAny other once-a-day PI on the horizon? And one that could work in PI-experienced patients? Well, here you have to go to combined formulas which boost the PI levels up enough in the body to overcome resistance. 908 or fosamprenavir (Telzir) is one option that may work. It is a tweaked version of amprenavir, which is better absorbed by the body. It can be given twice a day by itself or once a day with ritonavir, and one study found it to be more potent than nelfinavir. It’s unlikely to be licensed till early 2004, but is available on a named-patient basis. You can take regular amprenavir plus ritonavir once-daily, but that means a lot of big pills. This in itself, along with side effects, has limited this combo’s effectiveness.
The already-used combined formula Kaletra (lopinavir/ritonavir) could in theory be dosed once a day. But it might not do what Kaletra has so far been a bit of a star at doing - working with highly PI-resistant HIV.
One intriguing possibility is atazanavir/saquinavir. A trial compared once-daily atazanavir/saquinavir (with two once-daily nucleoside drugs) with twice-daily ritonavir/saquinavir, in patients that had already failed a protease inhibitor regime. Success rates were similar, but there were far fewer dropouts in the atazanavir patients (nine per cent instead of 30 per cent) and declines in blood lipids instead of marked rises.
Is
once a day better?So once-a-day can work just as well. But it true that it will lead to better adherence, which will in turn lead to more sustained long-term success?
Anna Poppa, editor of Aids Treatment Update, has written the adherence guidelines of the British HIV Association. She says: “While many people might prefer to take their drugs once a day, there’s actually very little concrete evidence that people adhere better to once-daily rather than twice-daily medicines.”
In the APPT-1 Study quoted above, four out of every 10 patients on once-daily regimes admitted to occasionally forgetting their daily dose, compared with nearly two-thirds of patients on two or three doses. This was a self-reported study, though, and it didn’t establish whether this reported difference in adherence made a difference to clinical outcome.
Chelsea and Westminster’s Dr Graeme Moyle, who presented the APPT-1 findings at the Glasgow Aids Conference, told Positive Nation: “The study is about patients’ preferences, not clinical results: it’s more market research than clinical trial. Patients do say they’d prefer once-daily regimes, but they are much more concerned about avoiding drug toxicity and having a regime that works.”
Even if they are no more potent, though, once-daily regimes may be easier to fit in with your lifestyle. The choices are yours.
