Why is adherence such a big deal?

The word ‘adherence’ has been a part of our treatments vocabulary for many years – it emerged as after an energetic discussion seeking to find a more user-friendly term than ‘compliance’, which was seen as overly authoritarian. ‘Compliance’ still pops up in the literature, but the other candidate, ‘concordance’, never really garnered much support.

Whatever term you use, they all mean the same thing: taking your pills, taking them on time, and missing as few doses as possible.

Adherence is important because regular antiretroviral doses are needed to maintain sufficient levels of the drugs in the bloodstream to adequately suppress HIV replication.

HIV drugs start to be eliminated from the body relatively quickly after being taken, and if another dose isn’t taken before the drug level falls too low, the virus can start to re-emerge. Drug levels are never constant – they rise to their maximum shortly after the pills are taken, then start to fall again. Drug doses and dosing requirements have to take account of this without giving too high a dose (which would worsen side effects) and while keeping the number of doses per day to a minimum.

When only partially suppressed by treatments where too many doses have been missed, the virus that is able to break through the weakened treatment barrier tends to have a slight level of resistance to the treatments you’re taking. Over time, these tiny improvements in HIV’s ability to beat the treatments build up, and eventually can become strong enough to lead to treatment failure.

Added to that, for many HIV drugs, the development of resistance to one drug can also make HIV resistant to other drugs in the same class or even to the whole class.

Adherence is important for non-HIV medications too – all medications only work well when taken as designed. But the level of adherence required to prevent viral rebound is much higher than for most other drugs (at least 95 percent of antiretroviral doses must be taken on time) and HIV treatments must be taken for very long periods of time.

It’s a high-stakes game: our continued wellbeing depends on treatments working for many years, and the treatments depend on our success in integrating daily HIV therapy into our lives.

Nonetheless, we know that a substantial proportion of people living with HIV/AIDS have problems sticking to their medication schedule and risk treatments failure as a result. A recent American study¹ found that 15 percent of people didn’t adhere to all the components of the antiretroviral regimen all the time.

People in this study were more likely to miss doses if they had to deal with side effects, if they had more frequent dosing or more complex treatment regimes, if they were taking protease inhibitors (versus non-nucleosides) or if they were on their second (versus first or third) antiretroviral drug combination.

Different people have different experiences taking medications, of course, and lead different lives. Different HIV medications, too, have different dosing requirements and some are more forgiving than others of fluctuating adherence levels. Finding a good fit between your life and your medications may involve taking into account your living and working circumstances, dietary habits and ability to get into and stick to a routine.

For people starting treatments for the first time, this is likely to be their first experience of taking medication on a regular, long-term basis. The impact treatments have on your life can be more pronounced during this transitional period, and the risks of treatment failure are that much greater – we know that the more treatments a person has failed, the less chance there is of successfully controlling the virus.

Your attitude towards your treatments – whether you believe they are doing you good or harm – and the side effects you experience as a consequence of taking your pills can also have a big impact on adherence. It’s tough to swallow a handful of tablets you know are going to make you feel sick.

These factors call for a complex process of weighing up your own attitudes and level of commitment, examining your lifestyle, possibly changing your diet and daily habits, and considering which medications are likely to deliver the greatest medical benefit for your particular circumstances. For people just starting treatment, these considerations typically occur at a time when you’re trying to assimilate a lot of new information about living with HIV.

Given all of that, it’s not just understandable that some people have problems with adherence – it’s a miracle that some people don’t!

Cut to the chase – how many doses can I miss safely?

If you ask your doctor this question, the answer he or she will most likely give you is ‘none’. It’s a fair enough response, given the importance of getting the patient (that’s you) to quickly achieve the best possible adherence.

A more forgiving answer might be ‘as few as possible’ – at least this acknowledges the reality that pretty much everyone misses at least one dose of HIV medications from time to time. But if your idea of ‘as few as possible’ is three or four doses a week, it’s of little comfort when treatments fail.

Surely there’s hard data out there that can provide us with a yardstick?

As mentioned above, clinical trials have shown that adherence above 95 percent is needed to maintain suppression of HIV, and this does provide a handy benchmark. Expressed another way, that means a maximum of about one missed dose every three weeks if you’re on once-daily treatment, every two weeks for twice-daily, or once a week for three-times-a-day.

The 95 percent figure has been established through clinical trials which follow large numbers of people taking treatments for long periods, measuring their level of adherence during the trial in various ways. Adherence can be measured using self-reporting (keeping a diary to record when doses are taken), by counting the number of pills left over at the end of a period of time, or by using special electronic bottle caps (so-called ‘MEMScaps’) which record the time that pill bottles are opened and closed.

One large study published in 2000² followed 99 people taking protease inhibitor-based HAART for around six months. Adherence was measured using MEMScaps. Treatments failure (emergence of detectable viral load) occurred in 22 percent of people with adherence above 95 percent; in 61 percent of those whose adherence was between 80 and 94.9 percent; and in 80 percent of those with adherence levels below 80 percent.

The difference between the more- and less-adherent groups could hardly be more striking. Although this was a fairly small study, it provides a compelling demonstration of the critical importance of adherence in HIV medicine.

A much larger study published in 2002³ found a similar correlation. This study involved 1100 people, some treatment-naive and some treatment-experienced, who enrolled in two large randomised clinical trials. Their adherence was measured by a self-report questionnaire at four regular follow-up visits over a 12-month period. At the end of the trial, the likelihood of having undetectable viral load (below 50 copies/ml) was strongly correlated with the level of adherence reported: 72 percent of those who reported 100 percent adherence at all four visits were undetectable, compared with 66, 41, 35 and 13 percent of those who reported perfect adherence at three, two, one or none of their visits respectively.

Of course, clinical trials tell us a lot about medications and how they work, but people are notoriously variable. The extent to which a single missed dose reduces the level of the drug in the bloodstream depends on a number of factors, including the speed at which the person metabolises the drugs and the drug’s own properties.

Blood levels of indinavir fall relatively quickly, for example, while efavirenz can stay in the body for days or even weeks. That’s why indinavir needs to be taken three times a day while efavirenz is dosed once-daily. Whichever drug you’re taking, the dosing has been worked out to ensure drug levels always remain high enough to suppress the virus – as long as you take the pills correctly.

There are many reasons why people may have difficulty adhering to medications, and many of these have been the subject of research. Social isolation, language problems, poor doctor-patient relationships, mental health and drug and alcohol use have all been linked to poorer adherence in some studies. People who are struggling with side effects, are depressed or who lead unstable lives with inadequate housing and income support may be at increased risk and may need extra support.

A recent study⁴ demonstrated the importance of diagnosing and treating depression in people with HIV/AIDS. An analysis of the medical records of 1713 positive people found that antiretroviral adherence improved significantly if people with symptoms of depression were prescribed antidepressant medication.

The good news is that, in people with poor adherence, even a small increase in the number of doses taken on time can make a difference. A study presented in 2001⁵ found that a 10 percent increase in adherence reduced the risk of disease progression by up to 28 percent.

So reach for the sky and, if you possibly can, try to never miss a dose. But if you do occasionally miss a dose, as long as you’re taking at least 95 percent of your pills on time, you should be OK. If you’re missing more doses than that on a regular basis, the tips below may be able to swing the pendulum in the other direction.

• For some handy hints, tips and suggestions on improving adherence, see our handy checklist of adherence success strategies in this issue.

References

¹ Gardner EM et al. Selective drug taking during combination antiretroviral therapy in an unselected clinic population. J Acquir Immune Defic Syndr 40: 294 – 300, 2005.

² Paterson et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Annals of Internal Medicine 133(1): 21-30, 2000.

³ Mannheimer S et al. The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials. Clinical Infectious Diseases 34(8): 1115-21, 2002.

⁴ Yun LWH et al. Antidepressant treatment improves adherence to antiretroviral therapy among depressed HIV-infected patients. J Acquir Immune Defic Syndr 38: 432-438, 2005.

⁵ Bangsberg DR et al. Adherence to HAART predicts progression to AIDS. 8th Annual Retroviruses Conference, Chicago, abstract 483, 2001.