Once-a-day pills and other sticky problems

This article originally appeared in HIV Treatment Update, a newsletter published by NAM between 1992 and 2013.
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Less-than-perfect adherence to a once-a-day HIV treatment carries five times more risk of treatment failure than imperfect adherence to a twice-a-day regimen. That’s one of the surprising things that came out of an adherence conference in Miami at the end of May.

We assume once-a-day regimens for HIV are a boon. The appearance of Atripla, the first one-pill, once-a-day treatment for HIV was hailed as a landmark when it was licensed in Europe in 2007. A decade earlier people were taking handfuls of pills two or three times a day.

A study 18 months ago showed that adherence was 4.5% better in once-daily than in twice-daily drug regimens.1 In the NAM treatment survey in 2008, one in twelve people spontaneously mentioned Atripla or once-a-day dosing as the thing that most helped with their adherence.


statistical significance

Statistical tests are used to judge whether the results of a study could be due to chance and would not be confirmed if the study was repeated. If result is probably not due to chance, the results are ‘statistically significant’. 

treatment failure

Inability of a medical therapy to achieve the desired results. 

viral rebound

When a person on antiretroviral therapy (ART) has persistent, detectable levels of HIV in the blood after a period of undetectable levels. Causes of viral rebound can include drug resistance, poor adherence to an HIV treatment regimen or interrupting treatment.

If you miss a dose of a once-a-day regimen, however, there is a longer gap before the next one is taken, and researchers at the Miami conference warned that the consequences of poor adherence may be more serious.2

They looked at 2410 people who started HIV treatment for the first time between 2003 and 2009 and followed them for an average of 2.5 years, conducting regular interviews about their adherence with them.

Poor adherence, defined as missing at least one dose of treatment during the past month, was reported by patients in one-third of interviews. 

More than one in twelve patients (8%) experienced their viral load ‘rebounding’. The researchers stratified their patients into whether they missed zero, one, two or more than two doses; there was no separate analysis of patients who missed very high numbers of doses. For patients taking a once-daily treatment, missing any dose increased their risk of viral rebound and this risk increased with the number of doses missed in the past month. 

Not too surprising: but what was surprising was how much difference missing just one dose made. In comparison with people who didn’t miss any doses, people who missed just one dose had five times the risk of their viral load rising. People who missed two doses had seven times the risk, and people who missed three or more doses had nine times the risk. This mattered: people who missed several doses also had a greater risk of dying in the study period than other people.

Unexpectedly, the same kind of effects weren’t seen in people taking their treatment twice a day. In fact, no statistically significant relationships were found between missed doses and either an increased risk of viral rebound or of death.

So 100% adherence may be easier on a once-a-day regimen but if you do miss doses the consequences are more serious than on a twice-a-day regimen. For someone who’s not confident of near-perfect adherence, once-a-day treatment may be more risky.

Just the fact that a conference is organised where every single presentation is about adherence tells you how important it is to successful HIV treatment.

Another way to get a sense of this is to take a look at some of the ways in which doctors, researchers and drug companies would like to track people’s adherence to medication.3

Currently, methods include just asking patients how many doses they’ve missed, counting how many pills are left in their container and keeping an eye on how often people come back to the pharmacy for a new supply. The trouble is, none of these are foolproof: people almost invariably overestimate their adherence and can also confound the system by building up pill stockpiles or giving them away.

There are devices which record the date and time that a pill container is opened and show both the total number of doses taken and whether they have been taken on time. These don’t work if you stock up a weekly pillbox.

Researchers are now developing devices that use wireless technology to send the information about when the pill container was opened over a mobile phone network to the person’s doctor. Speaking at the conference in Miami, one researcher showed data downloaded to her laptop that morning showing the exact times that a woman in Uganda had taken her medication over the past few days. We could see that she had missed a dose on Saturday morning.

Is this a step too far? What about privacy and personal autonomy? Advocates say that such systems have important advantages. Because they collect information in real time, they can warn doctors of a problem before it’s too late. It’s no good knowing that a person had a treatment break a month ago. If doctors knew immediately that a patient was having problems with adherence they could intervene and offer support in good time. Seeing a couple of missed doses could, for example, be the trigger for a nurse to phone and see what the problem is.

Some people don’t think even such a system goes far enough. Hitherto, no method of monitoring adherence shows whether someone has actually swallowed the drug. So even more high-tech methods are being developed, embedding a supposedly harmless antenna, mini-magnet or microchip inside the pill, which sends a signal when swallowed. It might give accurate data - but would you swallow it?

  1. Parienti J-J et al. Better adherence with once-daily antiretroviral regimens: a meta-analysis. Clin Infec Dis 48, 484-88, 2009.

  2. Glass T et al. Are once daily regimens really the magic bullet? 5th International Conference on HIV Treatment Adherence, abstract 62223, Miami, 2010.

  3. Haberer J et al. Emerging methods and technologies for adherence measurement. 5th International Conference on HIV Treatment Adherence, Miami, 2010.

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