Increased regimen durability in the era of once-daily fixed-dose combination antiretroviral therapy

Abstract

Introduction: Data on initial antiretroviral regimen longevity predates the arrival of newer nucleoside reverse transcriptase inhibitor backbones and once-daily regimens. Modern regimens are thought to possess greater tolerability and convenience. We hypothesized this would translate into greater durability.

Methods: Retrospective study of antiretroviral-naive patients starting treatment at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic 1 January 2000-31 July 2007. Two periods of antiretroviral initiation were identified, prior and after August 2004 (arrival of once-daily fixed-dose regimens). Kaplan-Meier survival analyses of regimen durability by time period and regimen characteristics were performed. Staged Cox proportional hazards models evaluated the roles of dosing complexity and composition in explaining differences in regimen durability between study periods.

Results: Overall 542 patients started antiretroviral drugs (n = 309, January 2000-July 2004; n = 233, August 2004-July 2007). Median durability was 263 days longer in after August 2004 regimens. Regimens started before August 2004 had increased hazards for discontinuation relative to after August 2004 regimens [hazard ratio (HR) = 1.44; 95% confidence interval (CI) = 1.03-2.02]. Time period of initiation lost statistical significance when the model included dosing frequency (HR = 1.92 for at least twice daily vs. daily; 95% CI = 1.29-2.88). As regimen composition variables were added, time period and dosing frequency lost significance. Increased hazards of discontinuation were observed with didanosine or stavudine relative to abacavir or tenofovir use (HR = 1.92; 95% CI = 1.29-2.88) and all third drugs compared with non-nucleoside reverse transcriptase inhibitor-based regimens (triple-nucleoside reverse transcriptase inhibitor HR = 1.76; 95% CI = 1.14-2.73; unboosted-protease inhibitor HR = 1.58; 95% CI = 1.02-2.46; boosted-protease inhibitor HR = 1.57; 95% CI = 1.02-2.41). Affective mental health disorders increased the hazard of discontinuation in all models.

Conclusion: Durability of contemporary once-daily fixed-dose antiretroviral regimens has significantly eclipsed the duration of earlier antiretroviral drug options. Our results indicate this is due to both more convenient dosing and improved tolerability of modern antiretroviral regimens.

Figure 1

Legend: Regimens started after 8/1/04 (n=233) achieved a median durability of 1043 days (95%CI = 735-NA) vs. 780 days (95%CI = 593-992) for regimens started between 1 January 2000 - 31 July 2004 (n=309). The final curve represents regimens started during the time period 1 January 1996-31 December 1999 (n=293), which is included for comparative purposes and not evaluated in statistical analyses for this manuscript. Strikingly, the median regimen durability of 595 days (95%CI = 453-707) seen during this early time period is almost half of that seen post August 2004 when new once-daily, more tolerable, fixed-dosed combination NRTIs became widely available.

Figure 2

Legend: Duration of initial ARV regimens as a function of regimen dosing complexity. 2a) Pill burden: Regimens ≤ 3 pills per day (n=358) achieved a median durability of 1,218 days (95%CI = 961-1,724) as compared to a median durability of 766 days (95%CI = 468-1,263) for 4-5 pills per day (n=117) and 340 days if the regimen was ≥ 6 pills (n=67) per day (95%CI = 274-640). Overall, as regimens increase in total daily pill count duration is truncated. 2b) Dosing frequency: Once daily regimens (n=228) achieved a median durability of 1,253 days (95%CI = 1,055-NA), outlasting ≥ twice a day (n=314) alternatives whose median durability was 712 days (95% CI 597-905). This variable demonstrates the aggregate effect of newer more tolerable medications as well as the effect of a more convenient dosing scheme.

Figure 2

Legend: Duration of initial ARV regimens as a function of regimen dosing complexity. 2a) Pill burden: Regimens ≤ 3 pills per day (n=358) achieved a median durability of 1,218 days (95%CI = 961-1,724) as compared to a median durability of 766 days (95%CI = 468-1,263) for 4-5 pills per day (n=117) and 340 days if the regimen was ≥ 6 pills (n=67) per day (95%CI = 274-640). Overall, as regimens increase in total daily pill count duration is truncated. 2b) Dosing frequency: Once daily regimens (n=228) achieved a median durability of 1,253 days (95%CI = 1,055-NA), outlasting ≥ twice a day (n=314) alternatives whose median durability was 712 days (95% CI 597-905). This variable demonstrates the aggregate effect of newer more tolerable medications as well as the effect of a more convenient dosing scheme.

Figure 3

Legend: Duration of initial ARV regimens per regimen composition. 3a) NRTI: regimens containing stavudine (D4T) and/or didanosine (DDI) (n=54) have the shortest median duration 405 days, while those utilizing zidovudine (n=271) achieved a median duration of 791 days. Regimens including the NRTIs abacavir (ABC) or tenofovir (TDF) (n=217) have the most prolonged median duration at 1253 days. These NRTIs were combined with either lamivudine or emtricitabine in 98% of regimens. 3b) Third drug class: NNRTI based regimens (median 1,132 days) had the most prolonged duration whereas un-boosted PI regimens (median 382 days) had the shortest durability.

Figure 3

Legend: Duration of initial ARV regimens per regimen composition. 3a) NRTI: regimens containing stavudine (D4T) and/or didanosine (DDI) (n=54) have the shortest median duration 405 days, while those utilizing zidovudine (n=271) achieved a median duration of 791 days. Regimens including the NRTIs abacavir (ABC) or tenofovir (TDF) (n=217) have the most prolonged median duration at 1253 days. These NRTIs were combined with either lamivudine or emtricitabine in 98% of regimens. 3b) Third drug class: NNRTI based regimens (median 1,132 days) had the most prolonged duration whereas un-boosted PI regimens (median 382 days) had the shortest durability.