Are we doing all we can to boost adherence to antiretroviral treatment? Can packaging help people take their drugs more consistently?
By Bob Huff
My doctor recently gave me a starter pack for a new medication. The pills were packaged individually in pop-out blisters and numbered 1 through 30. Every day I popped out a new pill and looked at the pack to see how many I had taken so far and how many remained to be taken. It was simple, easy, and kind of fun to interact with the pack and track my progress. I remembered my experience of a year ago when I had to take daily eye drops following surgery. I had the bottles lined up on a shelf so I could remember to use them, but I still would forget to take my doses sometimes—or I would forget if I had taken them earlier, or would lose track of which one I had taken and which I hadn’t. I remember thinking at the time, “Even though I could go blind if I don’t get this right, I can’t get this right.” I don’t think they can put eye drops in a blister pack, but I didn’t have any problem at all taking my preprogrammed course of pills a year later. Meanwhile my daily vitamin D supplement dispensed from a bottle is hitor- miss at best.
Putting pills into blister packs is called unit-dose packaging. Packaging designed to help the consumer remember to take the pills is called adherence-prompting packaging. A blister pack that prompts for the day or time a dose is to be taken is called a calendar blister pack. Studies have shown that this kind of packaging can improve adherence and improve outcomes from medications; yet in the United States, they are rarely used.
Adherence means understanding why, how, and when to take a medication and sticking to it once you have begun. Studies of medication adherence have shown that, in general, people have a hard time taking their pills. Depending on the drug and the purpose, adherence rates range from 20% to 100%, with good adherence for chronic disease treatment estimated at 80% or better. But that’s not good enough for HIV.
The virus replicates so fast, and the mutation rate is so high, that if drug levels drop there is a chance that a drugresistant mutant will spin off and take over the viral population despite the drugs. With some antiretroviral (ARV) regimens for HIV, this could happen after missing just two or three days’ doses. The best chance of keeping HIV fully suppressed comes from maintaining adherence that is 95% or better.
The problem is that adherence is difficult, and some drug regimens make it even more difficult. There are many reasons for nonadherence to HIV drugs. Some people may want to avoid a wave of nausea or diarrhea that follows a dose. Others get tired after years of pill taking and opt for a break. Some forget, and go to bed without taking their pills. Weekend schedules, partying, or travel may upset a routine and cause missed doses. Complicated regimens with food restrictions are harder to take consistently than all-in-one pills. Once resistance to a first regimen has developed, subsequent regimens are usually more complicated and have more restrictions. Some doctors would prefer a patient not begin taking HIV drugs until they are certain that the individual can develop the adherence habits that will make the treatment a success. But in general, studies have shown, doctors assume that patients do what they are told once they leave the office. Unfortunately, they do not.
In the United States, pharmaceuticals are typically distributed in bulk packaging, such as in plastic bottles that contain 500 or 1,000 tablets. The U.S. Food and Drug Administration requires stability testing for drugs in the packaging they are distributed in. This means the drugs have been shown to be stable in their unopened bulk pack bottles for six months or more. But once the bulk pack gets to the pharmacy, it is opened and the pills for an individual’s prescription are counted out and repacked in an amber, child-resistant pill container. ARVs, however, are typically shipped in smaller bottles containing a 30-day supply that can be labeled and given to the patient unopened, though some pharmacists may repackage the pills in an amber container. The containers must be childproof, but in effect that often means that they are difficult to open, especially for seniors. Labeling on pill bottles can also be difficult to read, which can lead to dangerous dosing errors.
To help keep track of their complex regimens (and people with HIV often take many other pills a day on top of their ARVs) some people put a week’s worth of pills into a special seven-day container with individual compartments for each day of the week. This is a do-it-yourself form of unit-dose packaging, and it is a great way to boost adherence and avoid skipping or inadvertently doubling up on doses. But it still requires time and organizational skills on the part of the patient. Having the pills come in a bottle makes more sense for people who use pill organizers and take multiple medications. But for people on simple, once-daily medications, a calendared blister pack might be an adherence booster. One packaging maker is researching custom multiple medication packs that would be created at the pharmacy for people with more complicated daily regimens.
How Packaging Can Help Improve Outcomes of ARV Therapy
With unit-dose packaging, each dose stays in its own protected container until it is used. In the United States, only a few medications, like short courses of antibiotics, are blister packed. Birth control pills have long been supplied in unit-dose packs with a dial calendar feature that prompts adherence. One study found that compliance with birth control pills reached 92% while compliance with organ rejection drugs following transplant surgery was only 82%.1 Calendar blister packs were also reported to improve adherence at a sexually transmitted disease clinic in South Africa.2 A systematic review of eight randomized trials concluded that reminder packaging “may represent a simple method for improving adherence.”3
The most advanced type of packaging is a leaflet pack that opens up and displays all of the pills on one card. There is educational information printed on the card, and there is a sleeve to hold the package insert; labeling is clear and easy to read. The pills push through the blister backing without effort or spilling. These packs get high marks for child resistance, yet are easy for seniors to use. It is simple to tell at a glance where you are in the month and how long before you need to refill the prescription. A downside for HIV is that the packs are not discreet and some patients may not wish to carry a product that prominently displays the name of the drug.
As a report from the Institute of Medicine concluded in its review of studies of unit-dose packaging, “The strategy of using calendar blister packs could help large numbers of patients (including seniors, children, and those challenged by cognitive, physical, and functional impairment) take their medication more reliably and safely, and enhance their treatment outcomes.”4
The current generation of HIV treatment options is fairly good, and forthcoming drugs promise to be even more tolerable and convenient as more complete regimens are formulated into single, daily pills. Yet a small percentage of patients develop drug resistance due to inadequate adherence within a year after starting HIV therapy. Since it is difficult to predict who will and won’t be adherent, it makes sense to give all patients a better shot at treatment success by offering packaging that helps make adherence more likely.
References
1. National Council on Patient Information and Education. Enhancing prescription medicine adherence: A national action plan, August 2007, p. 11.
2. Wright JM, Htun Y, Leong MG, Forman P, Ballard RC. Evaluation of the use of calendar blister packaging on patient compliance with STD syndromic treatment regimens. Sex Transm Dis. 1999 Nov 26;(10):556-63.
3. Heneghan CJ, Glasziou P, Perera R. Reminder packaging for improving adherence to selfadministered long-term medications. Cochrane Database Syst Rev. 2006 Jan 25;(1).
4. Institute of Medicine. National Academy of Sciences, Preventing Medication Errors, August 2006, p. 250.