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HIV Regimens with Fewer Pills Promote Adherence and Viral Suppression

Antiretroviral regimens that contain fewer pills are associated with improvement in treatment adherence and higher likelihood of achieving undetectable viral load, according to a meta-analysis published in the January 22, 2014, advance edition of Clinical Infectious Diseases. Once-daily dosing however, had only a modest effect on adherence and did not significant impact viral suppression.

Over the past 2 decades, antiretroviral therapy (ART) has evolved from handfuls of pills taken multiple times per day to once-daily all-in-1 single tablet regimens. People with HIV often prefer to take fewer pills less often, but studies looking at the effects of pill burden and dosing schedule have produced mixed results.

Jean Nachega from Pittsburgh University and colleagues performed a meta-analysis of randomized controlled trials to investigate the impact of pill burden and once-daily versus twice-daily dosing on ART adherence and virological outcomes.

The researchers conducted a literature search of 4 electronic databases (Cochrane Central, PubMed, Google Scholar, and Web of Science) and abstracts from relevant scientific conferences through the end of March 2013.

They included open-label randomized controlled trials that compared once- versus twice-daily regimens and reported on adherence and viral load suppression. (They did not include blinded placebo-controlled trials, because in such studies participants in different arms often receive the same number of pills so neither patients nor researchers know who is taking what.) Included studies used objective measures of adherence (pill counts or MEMS) rather than patient self-reports. Viral suppression was defined as <50 or <200 copies/mL in an intent-to-treat analysis.

The literature search turned up more than 400 potentially relevant articles, of which 46 were analyzed more thoroughly. Of these, 19 studies with a total of 6312 participants met the inclusion criteria and were included in the meta-analysis. 7 studies enrolled treatment-naive participants, 9 looked at treatment-experienced patients who switched regimens with undetectable viral load, and 3 looked at people who switched while experiencing virological failure. The median duration of follow-up was 48 weeks.

The included studies were published between 2004 and 2011. Importantly, they did not look at single-tablet regimens, which offer the lowest pill burden plus once-daily dosing. Atripla (efavirenz/tenofovir/emtricitabine) has been available since 2006, followed by Complera (rilpivirine/tenofovir/emtricitabine) in 2011 and Stribild (elvitegravir/cobicistat/tenofovir/emtricitabine) in 2012.

Results

• Higher pill burden -- or more pills taken per day -- was significantly associated with lower adherence (p=0.004).
• Taking more pills was also associated with lower rates of virological suppression overall (p<0.0001).
• Looking only at people taking once-daily regimens, however, the association between pill count and adherence was no longer statistically significant.
• Average adherence was modestly higher among people taking once-daily compared with twice-daily regimens (p=0.0002).
• People taking once-daily regimens did not achieve virological suppression significantly more often than those using twice-daily regimens (relative risk 1.01; p=0.57).
• Both adherence and viral load suppression decreased over time, but adherence decreased less among people taking once-daily regimens.

"Lower pill burden was associated with both better adherence and virologic suppression," the study authors concluded. "Adherence, but not virologic suppression, was slightly better with once- vs twice-daily regimens."

More in-depth analysis showed that greater adherence was only significantly associated with better adherence among treatment-naive participants and people switching from twice- to once-daily regimens when they were experiencing virological failure. Those who had undetectable viral load when they switched -- a group that evidently was already achieving good adherence -- did not see significant improvement.

Considering explanations for the apparent lack of effect of once- versus twice-daily dosing, the authors noted that the impact of once-daily dosing on adherence was small (2.5% increase), and suggesting that it was "possibly too small to result in a clinically meaningful difference in virologic suppression."

"Nowadays, as all recommended regimens are highly potent, ART combinations should be selected based on factors such as tolerability, potential drug interactions, patient preference for dosing frequency and pill burden, as well as structural factors (e.g., cost, drug availability, access to care, insurance coverage)," they recommended. "Efforts to improve and sustain adherence should not be limited to regimen simplification, but consideration should be given to proven evidence-based interventions to improve adherence such as social support, adherence support toolkits (e.g., pillbox organizers), use of cell phone and/or text messages, treatment supporters, and other targeted interventions when necessary."

Given that single-tablet regimens are more expensive that their components taken separately, the authors researchers said that for health systems looking to reduce costs, "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."

2/11/14

Reference

JB Nachega, JJ Parienti, OA Uthman, et al. Lower Pill Burden and Once-daily Dosing Antiretroviral Treatment Regimens for HIV Infection: A Meta-Analysis of Randomized Controlled Trials. Clinical Infectious Diseases. January 22, 2014 (Epub ahead of print).