Our meta-analysis found that the rate of adherence to once-daily antiretroviral regimens was better (+2.9%) than the rate of adherence to twice-daily regimens. To our knowledge, this is the first attempt to quantify, in a meta-analysis, the effect of dosing schedule on adherence to anti-retroviral therapy. This effect was greater for patients who were initiating treatment than for those receiving stable therapy who were observed in “switch” studies. The smaller effect among recipients of stable treatment may be related to selection bias toward more-highly adherent patients in these studies, because all studies required an undetectable viral load before enrollment. Publication bias (i.e., the tendency for negative or inconclusive results to remain hidden and unpublished) was not likely for the primary end point, because the reporting of similar adherence rates between arms increases the internal validity of efficacy results. Random allocation of the dosing schedule and the use of objective measurements further support the internal validity of the adherence effect size estimate.
Although it was statistically significant, the 2.9% difference in adherence between once-daily and twice-daily regimens was modest. This difference in adherence did not correspond to an overall difference in rates of viral suppression among all studies. However, similar to the primary analysis of adherence, there was a difference in the rates of viral suppression that favored studies involving antiretroviral-naive patients over switch studies. Antiretroviral-naive patients may be more sensitive to differences in adherence because of lower rates of preexisting drug resistance. Furthermore, the association between adherence and viral suppression is likely to be more critical when rates of viral replication are high, such as at the time of initiation of a first antiretroviral regimen. There was also a difference in the rates of viral suppression that favored studies in which all medications were administered as a once-daily regimen. Administration of the entire regimen once per day may have led to better regimen adherence (and not just to the monitored medicine), leading to better virologic outcomes, than in regimens with more complicated dosing schedules.
Improvements in treatment adherence for once-daily versus twice-daily regimens in switch studies were marginal and statistically nonsignificant. However, because the switch studies reviewed here required subjects to have an undetectable viral load, it is unclear whether simplification from twice-daily to once-daily regimens would improve adherence to a greater extent in less-adherent patients. Among individuals with viral suppression, switches in the reverse direction (from once-daily to twice-daily regimens) are sometimes necessary for management of toxicities. These data suggest that a switch from once-daily to twice-daily treatment regimens may not result in adherence problems or loss of virologic efficacy.
There are several limitations to our study. The differences we observed could have been due to the drugs themselves, rather than how often they were taken each day. Most studies had relatively short follow-up periods and recruited patients who were highly adherent to treatment in clinical trial settings. The impact of dosing frequency on adherence and virologic outcome may differ in less-adherent populations found in routine clinical practice. The effect of dosing frequency may also be different with longer follow-up periods, because adherence wanes over time [19
]. Finally, because only the adherence rate for the once-daily or twice-daily regimen component was measured, the potential for differential drug exposure, which increases the risk of resistance [21
], was not evaluated.
The availability of once-daily combination antiretroviral regimens represents a considerable advancement, which has been welcomed by patients [23
]. On the basis of our findings, we conclude that once-daily dosing improved adherence, particularly at treatment initiation and if all of the medications were administered once per day. Furthermore, these effects were compatible with better virologic outcome in selected subgroups. However, physicians should be aware that the objective impact of once-daily versus twice-daily dosing on adherence rates is modest. Because adherence to medication regimens is a complex behavior with multiple factors at play, efforts to improve adherence should not be restricted to prescription of once-daily medications [24
]. Other factors, including tolerability, potency, and potential risk of resistance, given the patient's individual adherence pattern, are important considerations in selecting the optimal regimen for each patient.