Consistent with several previous studies, average percent adherence to boosted PIs was closely associated with viral suppression [11
]. Greater than 95% adherence conferred 100% sensitivity to predict HIV RNA suppression <50 copies/mL. However, viral suppression was also common among patients with >70% average adherence: all except 1 (98%) had an HIV RNA level <400 copies/mL, and all except 4 (92%) had an HIV RNA level <50 copies/mL. Consequently, this implies that <95% adherence to boosted PIs, as opposed to unboosted PIs, can lead to viral suppression [13
]. When the analysis was restricted to patients with low-to-moderate adherence (ie, <80%), average percent adherence remained statistically associated with HIV RNA replication <400 copies/mL. In contrast to Shuter et al [14
], our data suggest that the level of adherence is closely associated with HIV replication, even at an adherence rate of <80%. Treatment interruptions also predicted virologic replication in a univariate logistic regression model; however, treatment interruptions were no longer statistically significantly associated with virologic replication in the multivariate logistic regression analysis, adjusting for average adherence, or among patients with low-to-moderate adherence.
As adherence rates decrease, different patterns of missed doses are possible, as shown in . Missed doses can either occur as sustained interruptions or as more regularly interspersed missed doses. Unlike NNRTI-based regimens (, adapted from Parienti et al [10
]), the characteristics of treatment interruption did not emerge as major risk factors explaining virologic outcome with ritonavir-boosted PI-based regimens.
Figure 3 Relationship between average percent adherence to nonnucleoside reverse-transcriptase inhibitor (NNRTI) and longer treatment interruption among subjects with (red) and without (green and blue) HIV replication. The red lines on the X-axis and the Y-axis (more ...)
Although the assessment of MEMS-defined adherence patterns was precise, both the sample size and the number of events were small. In addition, we did not measure drug resistance, and the risk of resistance after the initial virologic failure of ritonavir-boosted PI-based therapy is predictably low [11
]. Finally, differences in study design may limit the comparison between current and previous work [10
]. We believe that the biological plausibility of our observational findings compensates for these limitations. Boosted PIs have a short half-life. For this reason, regularly interspersed missed doses may pose more problems for ritonavir-boosted PIs than for NNRTI-based regimens [10
]. On the other hand, the emergence of drug resistance in the presence of suboptimal plasma drug levels is unlikely given the short-half life of the drug [9
], the poor viral fitness [17
] of the mutants, and the high genetic barrier of boosted PIs. These results may not extrapolate to darunavir-ritonavir–based regimens, because of the unique pharmacodynamics conferred by a very long fixation to the protease enzyme [18
]. Lopinavir-ritonavir was more sensitive than darunavir-ritonavir to a suboptimal average adherence of <95% in term of HIV RNA replication [12
]. Finally, patterns of adherence for all the components of combination antiretroviral therapy, including the boost, need to be considered [19
]. Because only 1 medication was monitored, we were unable to assess the impact of differential adherence, which is impossible with regimens composed of a single fixed-dose combination dosage form.
Our results, combined with previous studies [10
], may have implications for the choice of antiretroviral therapy among patients at risk of treatment interruptions [21
]. Of note, drug supply shortage or difficulties in transportation are the most frequent reasons for treatment failure in developing countries [20
]. NNRTI-based regimens are the most commonly used regimen class in resource-limited settings. We know that treatment failure, as a consequence of NNRTI interruptions, is associated with HIV RNA rebound and drug resistance [4
]. Because, HIV RNA monitoring and genotyping are not routinely available, pharmacy refill monitoring has been proposed as a substitute for viral load monitoring [24
]. Such monitoring may be more effective for PI regimens than NNRTI regimens because it does not capture interruption patterns. The use of boosted PIs may confer several advantages in this setting, including improved performance of pharmacy refill monitoring for virologic suppression and a reduction in the impact of interrupted therapy, which is a common form of missing doses in resource-limited settings.
In summary, maximal average percent adherence confers the highest probability of sustained viral suppression in HIV-infected patients treated with boosted PI-based regimens. In contrast to NNRTI-regimens [10
], ritonavir-boosted PI regimens do not appear to be specifically vulnerable to treatment interruptions.