Factors associated with time to regimen modification
The initial ART regimen was modified in 2285 patients (43%). Table 1 compares the baseline clinical and sociodemographic characteristics (obtained prior to ART initiation) of those who modified versus continued their initial regimen. Of those who modified their regimen, 55% (n = 1257) had a detectable viral load at the time of modification. According to ART class ‘backbone,’ the percentage who modified their regimen with a viral load at least 200 copies/ml was 51, 35, 10 and 3% for NNRTI, protease inhibitor, InSTI and InSTI/protease inhibitor-based regimens, respectively. The percentage who modified their regimen in the setting of a viral load at least 200 copies/ml (i.e. virologic failure) was less than 10% for all regimens except the atazanavir/ritonavir/emtricitabine/tenofovir (15%), efavirenz/emtricitabine/tenofovir (43%), and regimens classified as other (21%). The percentage who modified with a detectable viral load also decreased each year from 56% (2007) to 12% (2015).
In univariate analysis (Table 3), the following factors were significantly associated with regimen modification: ART backbone class (NNRTI, protease inhibitor, InSTI, InSTI/PI), black race, female sex, public and unknown insurance, IVDU, heterosexual HIV transmission, lower CD4+ cell count and initiation in more recent years (2010–2012 and 2013–2015). In a multivariable model, patients aged 30–45 were less likely to modify their initial ART regimen (aHR = 0.8, 95% CI 0.7–0.9, Table 3) relative to those less than 30 years old. Those with black race (aHR = 1.1; 95% CI 1.0–1.2) relative to white race, female sex (aHR = 1.4, 95% CI 1.2–1.6), IVDU (aHR = 1.6, 95% CI 1.3–1.9) relative to homosexual HIV transmission risks, and CD4+ cell count less than 200 cells/μl (aHR = 1.2, 95% CI 1.1–1.3) relative to CD4+ cell count at least 200 cells/μl were more likely to have regimen modification. Compared with patients initiating ART during 2007–2009, those initiating ART during 2010–2012 (aHR = 1.2, 95% CI 1.1–1.3) and 2013–2015 (aHR = 1.5, 95% CI 1.3–1.8) era were more likely to modify ART. Relative to InSTI-based regimens, those regimens that were InSTI/PI (aHR = 2.7, 95% CI 2.0–3.7) or protease inhibitor-based (aHR = 1.9, 95% CI 1.6–2.2) were significantly more likely to be modified. NNRTI-based regimens were not significantly more likely to be modified relative to InSTI -based regimens.
Next, evaluation of individual regimen durability according to three or four-drug composition rather than drug class of the anchor drug were evaluated (Table 2). The results of multivariable analysis were similar to the anchor drug class analyses with regards to socio-demographic and clinical characteristics. Relative to elvitegravir/cobicistat/emtricitabine/tenofovir, the most commonly prescribed regimen in recent years, all regimens were significantly more likely to be modified with the exception of dolutegravir/abacavir/lamivudine, which was statistically insignificant.
In this diverse, multisite cohort of treatment-naïve PLWH in the United States, the overall durability of initial ART regimens in our cohort was over 4 years. A majority of treatment-naive PLWH (57%) remained on their initial regimen at the study end date. The dynamic treatment landscape in which an increased number of co-formulated and single tablet ART regimens became available over the study period (2007–2015) is evident in the changing prescribing trends, the increasing number of ART modifications, and the apparent reduction in ART durability (Fig. 1c) in more recent years. Although efavirenz/emtricitabine/tenofovir previously was the most prevalent initial regimen, elvitegravir/cobicistat/emtricitabine/tenofovir has eclipsed it as the most commonly prescribed first-line ART in this real-world cohort . Of all drug classes, InSTI and NNRTI-based regimens were the most durable and least likely to be modified. Consistent with our hypothesis, new regimens dolutegravir/abacavir/lamivudine and elvitegravir/cobicistat/emtricitabine/tenofovir were highly durable and least likely to be modified over the study period. Notably, dramatic shifts were observed in virologic failure (>200 copies/ml) at the time of ART modification over the study period. Whereas over 50% of modifications were associated with virologic failure in the earlier period, fewer than 10% of ART changes were in the setting of virologic failure in more recent years. Taken together, these findings suggest that the contemporary ART era affording numerous simple, well tolerated regimens has resulted in treatment changes for convenience and side effects, rather than virologic failure, paradoxically resulting in less durable regimens in more recent years.
Despite current dogma and treatment guideline recommendations, results demonstrate that NNRTI-based regimens are highly durable, even surpassing the InSTI-based regimens, and unlikely to be modified. The relative NNRTI durability is likely because of longer time on the market: most NNRTI-based regimens have been available for more than 7 years, unlike many InSTI-based ART. Moreover, for a long period, the only approved single tablet ART regimen available was NNRTI-based, hence, side effects with this regimen may have been more acceptable to patients and providers in the absence of other simple regimens. Nonetheless, it is noteworthy that NNRTI-based regimens are extremely durable with a median time to modification of 61 months. Whenever comparing ART regimens according to composition, all but one (i.e. dolutegravir/abacavir/lamivudine) are more likely to be modified relative to elvitegravir/cobicistat/emtricitabine/tenofovir. This likely reflects changing prescribing practices: InSTI -based regimens, especially single tablet formulations, are more popular, and appear to be usurping older NNRTI and protease inhibitor-based regimens, leading to more regimen modifications (Supplemental Figure, http://links.lww.com/QAD/B196) [13,21].
Our study is unique in that it includes novel ART, like raltegravir, elvitegravir, and dolutegravir which were introduced over the study period in 2007, 2012, and 2013, respectively. It is likely that the increased ART modification and decreased ART durability in more recent years (2010–2012, 2013–2015 versus 2007–2009) results from a preference for newer, convenient single tablet regimens including those containing novel ART anchor drugs, dolutegravir and elvitegravir [13,16]. As older regimens are replaced by newer, once daily regimens, their measured durability is subsequently abbreviated. These findings need further study to analyze if the apparent reduced durability of InSTI -based regimens relative to NNRTIs is because of switching within the class (i.e. raltegravir to dolutegravir; dolutegravir multitablet to FDC). Furthermore, the reduced number of PLWH who modified their initial regimen because of elevated viral load levels (i.e. viral load ≥200 copies/ml) supports the notion that people are switching their regimens for reasons other than virologic failure. Regimen simplification and convenience or convenience only is a leading cause of regimen modification, and virologic failure, resistance and/or treatment-limiting side effects are less likely in the current treatment landscape [16,21].
Although there are inherent challenges in measuring durability (e.g. ART availability, provider preferences), whenever adjusting for ART regimen, year of initiation, and other sociodemographic characteristics, we observed notable differences in vulnerable populations. Youth, women, blacks, and IVDU experienced reduced ART durability. It is likely that those with comorbid IVDU experience reduced adherence, resistance, and virologic failure contributing to this trend [22,23]. Poor durability in women, youth and blacks is more complex. In our study and others, women are more likely to modify their regimen and have significantly shorter time to regimen modification [13,23]. This data suggests there may be ART differences related to pregnancy, pharmacokinetics, and/or health disparities in women with HIV [22,23]. Black experience slightly reduced ART durability relative to white PLWH whenever adjusting for clinical and ART-related differences. ART outcomes experienced by racial and sexual minorities in the contemporary ART treatment era should be further investigated in observational settings to identify and eliminate disparities. Finally, evaluating and optimizing poor ART outcomes in those less than 30 years of age is crucial as this population is disproportionately affected by HIV in the modern era [24,25].
This study is limited by a lack of data on patient-reported reasons for regimen modification, which could include side effects, toxicity, and desire or just desire for more convenient dosing (i.e. single tablet regimen). Likewise, reasons for regimen selection (e.g. opportunistic infection, renal insufficiency) were not available but would shed additional light on prescribing patterns.
In addition, because of a small number and short follow-up time of PLWH receiving some of the most novel regimens (i.e. dolutegravir/abacavir/lamivudine), it is difficult to interpret durability at the regimen level. Results that categorize by class, on the other hand, are sufficiently powered and have a greater cumulative follow-up time to allow interpretation.
In conclusion, this study evaluates the durability of novel ART agents and regimens, including InSTI and FDC single tablet ART, in treatment-naïve PLWH in a real world, multisite cohort initiating therapy from 2007 to 2015. We found that new classes and antiretroviral agents are highly durable relative to older, multitablet regimens. In addition, the adoption of these novel regimens has contributed to an overall reduction in durability and increase in regimen modifications over time. Simultaneously, a dramatic temporal reduction in virologic failure at the time of regimen modification was observed. Taken together, these findings suggest that the contemporary ART era affording numerous simple, well tolerated regimens has resulted in treatment changes for convenience and side effects, rather than virologic failure, paradoxically resulting in less durable regimens in more recent years. Finally, minorities, youth, women and IVDU have disparate ART durability outcomes, which suggest ongoing ART challenges in vulnerable populations and deserves further evaluation.
We wish to acknowledge the CFAR Network of Integrated Systems (CNICS) for their assistance with data collection.
Authorship: E.F.E. was primarily responsible for study design, acquisition of data, interpretation of data, drafting and revising manuscript and approving final version. T.D.-M. assisted with data interpretation and manuscript revision. A.T. conducted data analysis and assisted in data interpretation, reviewing, and revising the manuscript. Dr W.C.M., R.D.M., M.S.S. and M.J.M. assisted with study conception, data interpretation, and revising the original manuscript.
Conflicts of interest
Source of funding: E.F.E. has received support (to UAB) for this project from the Bristol Myers Squibb Virology Fellows Grant. She has also received support from Merck (to UAB) and the Agency for Healthcare Research and Quality (K12HS023009). This study is also supported by the CNICS cohort (R24A1067039) and the UAB Center for AIDS Research (CFAR; P30-A1027767). A.T. and T.D.-M. have nothing to disclose. W.C.M. has nothing to disclose. R.D.M. has received grant funding (to JHU) from the NIH and from Medscape to develop educational content. M.S.S. has received research grants and support (to UAB) from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Merck, Proteus, and ViiV Healthcare. He has also served as a consultant for Bristol-Myers Squibb, Gilead Sciences, Inc, Merck, and ViiV Healthcare. M.J.M. has received grant support (to UAB) from Bristol Myers Squibb Virology Fellows Research Training Program and consulting fees from Gilead Sciences.
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antiretroviral therapy; discontinuation; durability; HIV; persistency
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