Current antiretroviral treatment guidelines recommend modifying therapy as soon as virologic failure is confirmed, particularly following first and second HAART failure. This recommendation is based primarily on well-accepted theoretical principles, but has not been rigorously addressed in either observational studies or large randomized clinical trials. Here, we applied a robust analytic technique that accounts for time-dependent confounding to two large prospective clinic-based cohorts, and found that among patients failing a reverse transcriptase inhibitor-based regimen (the vast majority of which were receiving a NNRTI and two nucleoside analogues), delay until treatment modification following virologic failure increased the hazard of both long-term mortality and immunologic failure. There was no clear harm associated with a delayed modification after failure of a protease inhibitor-based regimen. These observations were stable when we limited our analysis to those who were treatment naïve prior to their first HAART regimen and when we limited our analysis to those whose protease inhibitor regimen included ritonavir boosting.
Data-adaptive regression was used to explore how the hazard of mortality changed over time under various switch times. Following first HAART failure on a reverse transcriptase inhibitor regimen, the hazard of mortality increased sharply while the patient remained on his or her original failing therapy. The hazard of mortality plateaued following regimen modification, but remained elevated for up to 4 years among subjects who delayed switching. This finding is consistent with the two hypothesized mechanisms by which delayed modification increases mortality: 1) ongoing viral replication contributes to immune depletion and increased mortality risk while subjects remain on their non-suppressive therapy; and, 2) delay of modification results in accumulation of additional resistance mutations, with long term consequences for treatment options.
In contrast, we observed no harm from delaying modification of a regimen containing a protease inhibitor drug following first and second HAART failures. Data-adaptive regression supported a distinct pattern in the hazard of mortality over time in this group (as compared to subjects failing a reverse transcriptase inhibitor regimen). Following first HAART failure on a protease inhibitor regimen, the hazard of mortality increased over time, with very little short-term difference between subjects who modified therapy immediately and those who delayed modification. To the extent that the hazard of mortality differed among subjects with immediate versus delayed modification times, a protective effect of delayed modification emerged only several years following failure.
Several mechanisms may account for the lack of harm in delaying modification after failure of a protease inhibitor regimen. First, earlier work has shown that resistance emerges rapidly during failure of an NNRTI-based regimen but is uncommon after failure of most protease inhibitor-based regimens.[9
] Second, during first and second HAART failure, cross-resistance among the protease inhibitors is less common than it is among the NNRTI class. Hence, patients who develop resistance to the protease inhibitor component of their regimen may still be able to respond to other drugs in this class. A third and more speculative mechanism pertains to the virulence of protease inhibitor resistant viruses. Failure of a protease inhibitor regimen has been associated with less rapid immunologic progression than failure of an NNRTI regimen.[17
] This effect may be due both to reduced HIV RNA levels and to a reduced capacity of the protease inhibitor-resistant HIV variant to cause CD4+ T cell decline in vivo
] Our observations suggesting differential long-term outcomes based on regimen type (NNRTI versus protease inhibitor) are supported by research showing that NNRTI resistance is a more consistent predictor of mortality than resistance to other therapeutic drug classes.[25
] Collectively, these observations indicate that protease inhibitor-based regimens will be associated with lower rates of disease progression than NNRTI-based regimens in situations where modification is delayed because virologic failure cannot be identified (due to lack of plasma HIV RNA monitoring) or because subsequent regimens are not available.
Given the observational nature of the data, unmeasured confounders may have biased results in an unpredictable direction. Importantly, however, both the JHHCC and UNCHCC included laboratory data collected at the discretion of the clinician, providing access to important factors that affect treatment decisions. Additional bias could have resulted from misspecification of the models used to estimate the weights. In order to minimize this concern, we used flexible data-adaptive approaches in modeling the weights, and performed sensitivity analyses considering alternative weight models. These additional analyses yielded consistent results, supporting the robustness of our findings.
Several factors should be taken into account when considering the extent to which our results can be generalized. First, detection of virologic failure, which determined time of eligibility for our sample, depended on the measurement of consecutive HIV RNA levels. Thus, virologic failure could be identified more rapidly among subjects who had HIV RNA levels assessed more frequently. Similarly, detection of immunologic failure depended on the timing of CD4+ T cell count measurements. In addition, a substantial proportion of our sample consisted of subjects treated with non-boosted protease inhibitor regimens and of subjects with exposure to antiretroviral drugs prior to initiating HAART, potentially limiting the applicability of our results to inform expanded access to HAART in treatment-naïve settings. To investigate the latter issue, we performed sensitivity analyses in which we excluded, in turn, subjects treated with non-boosted protease inhibitors and subjects with antiretroviral experience prior to initiating HAART. While the reduced sample sizes meant that the variability of our estimates increased such that the results were no longer significant, the consistency of the point estimates across these subpopulations suggests that the findings reported here are not solely the result of historical treatment patterns experienced by these observational cohorts.
Although we report here no clear harm to delaying a switch in therapy among protease inhibitor-treated patients, it should be emphasized that the optimal long-term clinical outcome was observed among those who were treated with reverse transcriptase inhibitor regimens (most of whom were on standard NNRTI/nucleoside analog regimens) and who were managed aggressively during virologic failure. In other words, there was a hierarchy of efficacy in the context of first HAART failure: subjects failing a reverse transcriptase inhibitor regimen who modified immediately had the lowest mortality, followed by subjects failing a protease inhibitor regimen at a range of switch times, and finally, subjects failing a reverse transcriptase inhibitor regimen who delayed modification had the highest mortality.
In summary, our findings support the recommendation that treatment be modified immediately following first HAART failure. This is particularly true for individuals receiving a standard first HAART regimen containing nucleoside analogues and a NNRTI. Access to HAART is being expanded rapidly worldwide, and, at least in the short term, first HAART regimens are likely to be NNRTI-based. Given the elevated risk of mortality that is associated with delayed treatment modification in patients receiving these regimens, our data support making viral load testing more available. Our data also suggest that the prolonged treatment benefits that have been repeatedly observed during virologic failure—all of which have been based largely on protease inhibitor regimens—may not be realized in regions where access to these regimens is limited.[17
] These considerations should be taken into account when planning HAART delivery systems, and within the context of resource constraints and the urgent need to scale-up therapy as rapidly as possible, efforts should be made to minimize delay until modification.