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Randomized Comparison in Treatment-naïve Patients of Once-daily vs Twice-daily Lopinavir/ritonavir-based ART and Comparison of Once-daily Self-administered vs Directly Observed Therapy
D Mildvan1, C Tierney2, Robert Gross*3, A Andrade4, C Lalama2, S Eshleman4, T Flanigan5, J Santana6, M Dehlinger7, C Flexner4, and the ACTG A5073 Study Team
1Beth Israel Med Ctr, New York, NY, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Univ of Pennsylvania Sch of Med, Philadephia, US; 4Johns Hopkins Univ Med Inst, Baltimore, MD, US; 5The Miriam Hosp, Providence, RI, US; 6Univ of Puerto Rico Sch of Med, San Juan; and 7Div of AIDS, NIAID, NIH, Bethesda, MD, US
Background: Potential advantages of directly observed
therapy (DOT) in non-HIV settings and of simplified ART dosing in HIV justify
studying these approaches in patients initiating ART.
Methods: A5073 was a multicenter 3-arm open-label 48-week
trial that randomized ART-naïve patients with HIV-1 RNA ≥2000 copie/mL
and stratified by screening RNA </≥100,000 copies/mL to receive in a
2:2:1 ratio lopinavir/ritonavir (LPV/r) soft gel capsule 400/100 mg, self-administered
twice daily; LPV/r 800/200 mg, self-administered once daily; or LPV/r 800/200 DOT
once daily (protocol-defined, Monday through Friday, weeks 0 to 24, self-administered
once daily weeks 24 to 48). Patients also received emtricitabine (FTC) 200 mg once
daily with extended-release stavudine (d4T XR) 100 mg once daily, or tenofovir (TDF)
300 mg once daily. The primary efficacy endpoint was sustained virologic
response (<200 copies/mL, intent-to-treat) through week 48 for twice daily
vs once daily self-administered, estimating the probability of sustained
virologic response by Kaplan-Meier method, and through week 24 for DOT vs once
daily self-administered, using a one-sided test of DOT having ≥0.075
higher probability of sustained virologic response.
Results: We enrolled 402 patients at 24 sites who were
78% male, 34% Hispanic, 33% black non-Hispanic; 62% initiated d4T XR; median baseline
CD4 count was 197 cells/mm3 and HIV-1 RNA was 4.8 log10 copies/mL.
Of the total, 82% of patients completed the study, and 71% remained on initial
LPV/r dose schedule. Overall, the probability of sustained virologic response
through week 48 did not differ significantly between twice daily and once daily
self-administered (difference
0.03; 95%CI –0.07, 0.12); however, the difference depended on the HIV RNA
stratum (p = 0.038, pre-specified
analysis). In the higher HIV RNA stratum, the probability (95% CI) of sustained
virologic response through week 48 was significantly higher in the twice daily arm
with 0.89 (0.79, 0.94) vs 0.76 (0.64, 0.84) in the once daily self-administered arm for a
difference of 0.13 (0.01, 0.25). In
the lower stratum, the probabilities were 0.72 (0.59, 0.81) and 0.80 (0.69,
0.88) for twice daily and once daily self-administered
for a difference of –0.08 (–0.23, 0.06). Median DOT
visit compliance was 86%. The
probability of sustained virologic response through week 24 was higher
for DOT (0.91: 0.81, 0.95) than once
daily self-administered (0.84: 0.77, 0.89), but the difference of 0.07
(lower 95%CI: –0.01) was not
significantly larger than 0.075 (p = 0.56).
The probability of sustained virologic response through week 48 was not
significantly different between DOT (0.72:
0.61, 0.81) and once daily self-administered (0.78: 0.70, 0.84) for a difference of –0.06 (–0.18,
0.07), 2-sided p = 0.19.
Conclusions:
Although overall
there was no difference in sustained virologic response between twice daily and
once daily LPV/r, twice daily may have an advantage for ART-naive patients with
high viral loads. DOT may have a treatment role while maintained, but there is
no evidence of sustained virologic benefit once stopped.
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