Higher pill burden is associated with poorer adherence to HIV therapy and reduced chances of achieving an undetectable viral load

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Lower pill burden is associated with higher rates of adherence to HIV treatment and better virological outcomes, according to the results of a meta-analysis published in the online edition of Clinical Infectious Diseases. The research also showed that adherence was better with once-daily regimens compared to twice-daily treatment, but once-daily therapy did not have any advantages in terms of virological suppression.

“Higher pill burden was associated with both lower adherence and worse virologic suppression in both twice-daily and once-daily subgroups,” comment the authors. “Adherence was higher with once-daily ART [antiretroviral therapy] regimens than twice-daily regimens…however, this difference was minimal and did not translate into better treatment outcomes.”

The past decade has witnessed important improvements in antiretroviral treatment. Overall, drugs are now less toxic and better tolerated than in the past. Pill burden has also been reduced and dosing schedules simplified. Two fixed-dose pills (Atripla and Stribild) are now available, providing potent HIV therapy in a single tablet.  


pill burden

The number of tablets, capsules, or other dosage forms that a person takes on a regular basis. A high pill burden can make it difficult to adhere to an HIV treatment regimen.


In HIV, an individual who is ‘treatment naive’ has never taken anti-HIV treatment before.


A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.


A person who has never taken treatment for a condition.


When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.

A meta-analysis of randomised trials published in 2009 showed that once-daily treatment was associated with higher rates of adherence compared to twice-daily therapy, but that rates of virologic suppression did not differ greatly between the treatment strategies.

More randomised trials have been published since then. An international team of investigators therefore re-visited the questions of whether pill burden and dosing schedule have an impact on adherence and virologic suppression.

Randomised-controlled trials comparing once- and twice-daily therapy published or presented before 31 March 2013 were eligible for inclusion in the analysis. The study populations could include people who had not taken treatment before (treatment naive); treatment-experienced people switching treatment with an undetectable viral load; or treatment-experienced people switching treatment with detectable viraemia.

A total of 19 studies including 6312 people met the inclusion criteria. The studies were conducted between 2004 and 2011. Most (18/19, 95%) were published in peer-reviewed journals. Seven studies (37%) included treatment-naive patients, nine (47%) monitored patients who switched treatment with an undetectable viral load and three (16%) evaluated treatment-experienced individuals who changed treatment when their viral load was detectable.

The median duration of follow-up was 48 weeks, and 17 studies (89%) reported on both adherence and virologic suppression. The majority of studies (eleven, 58%) used MEMS (Medication Event Monitoring System) to assess adherence. The remaining eight studies used pill count.

However, the authors note that none of the studies included fixed-dose single pill therapies.

Higher pill burden was associated with lower rates of adherence (p = 0.004). But when the results were stratified by treatment strategy, the association between adherence and pill burden was only significant for twice-daily combinations (p = 0.001).

There was also a significant association between higher pill burden and reduced chances of achieving virologic suppression (p < 0.0001). This was the case for both once-daily (p = 0.005) and twice-daily (p = 0.0003) regimens.

Turning to dosing schedule, adherence was higher with once-daily regimens compared to twice-daily therapy (weighted mean difference [WMD] = 2.51%; 95% CI, 1.20%-3.83%, p = 0.0002). The adherence advantage of once-daily treatment was apparent in treatment-naive individuals (WMD = 3.94%; 95% CI, 1.42%-6.47%, p = 0.0002), as well as people switching therapy with detectable viraemia (WMD = 5.28%; 95% CI, 0.60%-9.96%, p = 0.03) and also people who changed treatment with an undetectable viral load (WMD = 0.95%; 95% CI, 0.36%-1.54%, p = 0.002). The difference between these sub-groups was significant (p = 0.02).

Virologic outcomes did not differ significantly between once- and twice-daily regimens. The investigators believe there are several possible explanations for this finding. These include the relatively small difference in adherence rates between once-and twice-daily regimens; the short period of follow-up in many studies; and the high levels of adherence support provided in clinical trials. “For all these reasons,” write the investigators, “the difference in virologic suppression that we found between once- and twice-daily ART regimens may be understated.”

They conclude that once-daily treatment is associated with better adherence, and that higher pill burden is associated with poor virologic outcomes.

The authors believe their findings are of significance to health systems which are looking at ways of reducing costs. Single tablet HIV therapy and fixed-dose combinations are marketed at a premium, but the investigators believe “separating out the single-tablet regimens and or/fixed-dose combinations into their constituents is not likely to have a major detrimental impact on virological outcomes (provided that the overall pill burden does not increase dramatically).”


Nachega JB et al. Lower pill burden and once-daily dosing antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials. Clin Infect Dis, published online ahead of print, 22 January 2014.

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