Paper # 150LB
QDMRK, a Phase III Study of the Safety and Efficacy of Once Daily vs Twice Daily RAL in Combination Therapy for Treatment-naïve HIV-infected Patients
Joseph Eron*1, J Rockstroh2, J Reynes3, J Andrade-Villanueva4, J Madruga5, J Zhao6, P Sklar6, B-Y Nguyen6, and QDMRK Study Team
1Univ of North Carolina at Chapel Hill, US; 2Univ of Bonn, Germany; 3Ctr Hosp Univ Montpellier, France; 4Univ of Guadalajara, Mexico; 5Ctr de Referencia e Treinamento DST/AIDS, Sao Paulo, Brazil; and 6Merck Res Labs, North Wales, PA, US
Background: Based on prior pharmacokinetic and in
vitro data suggesting that once-daily dosing of raltegravir (RAL) might be
effective as an alternative to twice-daily RAL in treatment-naive patients,
QDMRK was initiated to evaluate once-daily RAL (800 mg once daily) vs twice-daily
RAL (400 mg twice-daily) regimens.
Methods: QDMRK was a non-inferiority study with
prespecified –10% margin, where treatment-naive patients with HIV RNA levels
>5000 copies/mL and no resistance to tenofovir (TDF) or emtricitabine (FTC)
were randomized to receive once-daily vs twice-daily RAL, each with TDF/FTC.
The primary efficacy endpoint was percentage of patients with HIV RNA <50 copies/mL
at week 48 (non-completer = failure analysis). Enrollment began with a vanguard
cohort of 150 patients followed by the first of 2 completed interim analyses
monitored by an external DMC; a total of 770 patients were randomized and
treated.
Results: Of 382 once-daily and 388 twice-daily
RAL-treated patients, 40% and 39% had baseline HIV RNA >100,000 copies/mL,
respectively. Week 48 results
appear in the table: 88 patients experienced virologic failures (non-response
or rebound) by week 48: 53 of 382 (13.9%) and 35 and 388 (9.0%) in the once-daily
and twice-daily groups, respectively. Of patients with available resistance
data, there were 9 vs 2 patients from the once-daily and twice-daily groups,
respectively, with integrase (and FTC) -resistant virus. Higher Ctrough
and Call (geometric mean of all sparse pharmacokinetics for an
individual) were associated with a greater probability of a successful
treatment outcome. Serious clinical adverse events and discontinuations
occurred at a similar and infrequent rate in both arms.
|
|
Percentage (n/N) of
Patients with HIV RNA <50 copies/mL2
|
Change from Baseline in
CD4 Cell Count (cells/mm3) 11
|
|
|
Overall
|
Baseline viral load
≤100,000 copies/mL
|
Baseline viral load
>100,000 copies/mL
|
Overall
|
|
Once-daily
|
83.2 (318/382)
|
89.1 (205/230)
|
74.3 (113/152)
|
210
|
|
Twice-daily
|
88.9 (343/386)
|
91.9 (215/234)
|
84.2 (128/152)
|
196
|
|
Once-daily to
twice-daily1
|
–5.7*
(–10.7 to –0.83)
|
–2.7
(–8.3 to 2.7)
|
–9.9
(–19.0 to –0.8)
|
14
(–7 to 34)
|
|
1 Difference between once-daily and twice-daily
(95%CI);
*p value for
non-inferiority not significant, p value/hypothesis testing apply only to
the overall primary
endpoint of percentage with <50 copies/mL per protocol
2 Baseline value carried forward for discontinuation
due to lack of efficacy
|
Conclusions: Both once-daily and twice-daily RAL in
combination with TDF/FTC achieved high virologic response rates and similar
immunologic effects. However, once-daily was inferior in virologic efficacy as
compared to twice-daily RAL; with once-daily, higher pharmacokinetic and lower
baseline viral load were associated with treatment success. RAL-based regimens
in treatment-naive patients continue to demonstrate a favorable tolerability
and safety profile.
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