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HIV at ICAAC Dolutegravir 2013
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(Sept 10-13, Denver, CO)
Report written for NATAP by David H. Shepp, MD Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine North Shore University Hospital - Manhasset, NY
Dolutegravir. The newest addition to the antiretroviral (ARV) armamentarium is dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI). It shares with the other members of this therapeutic class a favorable safety and tolerability profile, potency, and rapid suppression of HIV replication. It also has the advantages of once-daily dosing without a pharmacokinetic enhancer and a higher genetic barrier to resistance. At ICAAC 2103, Feinberg et al reported the 48 week results of the FLAMINGO trial [1], a randomized, open-label comparison of DTG 50 mg daily and ritonavir-boosted darunavir (DRV/r) 800/100 mg daily. To complete the regimen, investigators chose tenofovir/emtricitabine in 67% of patients. The rest received abacavir/lamivudine (ABC/3TC). The study included 242 treatment-naive patients in each arm. Using the FDA snapshot analysis, 90% in the DTG arm and 83% in the DRV/r arm had an HIV RNA <50 copies/mL, which established statistical non-inferiority between regimens and also the statistical superiority of DTG (p=0.025). Virologic failure and discontinuations for adverse events accounted for only slightly more than half of the difference in treatment success between arms. There was a disproportionate number discontinuations for other reasons in the DRV/r arm. DTG appeared to outperform DRV/r in those with baseline viral load >100,000, although the difference was not due to virologic failure. Choice of NRTI backbone did not affect the response rate. CD4 lymphocyte counts increased 210/mm3 in both arms. Diarrhea was somewhat more common with DRV/r. Grade 3/4 laboratory abnormalities did not differ between groups. Small increases in creatinine were seen in the DTG groups due to inhibition of creatinine secretion. The mean increase from baseline in LDL was significantly less with DTG (3.1 vs. 14.1 mg/dL, p<0.001).
Only 2 patients with viral failure in each arm qualified for resistance testing. No relevant resistance mutations were found. This study provides support for DTG-based ART as a good choice for first line therapy. The finding of superiority, however, is not compelling because this was an open-label study, there was an excess of discontinuations for reasons other than efficacy or safety in the DRV/r and the magnitude of the difference was small (7%, with the lower bound of the 95% CI below 1%).
Another presentation examined DTG's efficacy in demographic subsets of participants in two previously published trials [2]. The SAILING study was a randomized, double-blind comparison of DTG and raltegravir (RAL) in treatment-experienced, INSTI-naive subjects, while VIKING-3 was a single arm open-label study of high dose DTG (50 mg twice daily) in INSTI-experienced patients. Both studies employed optimized background ARVs. In SAILING, the overall superiority of the DTG arm was found to be preserved when analyzed by race and gender, but DTG did not appear to be superior to RAL in patients 50 years of age or older. In the VIKING study, responses to DTG-based ART appeared to be equivalent when analyzed by race, gender and age above and below 50. This analysis should help clinician feel confident that the benefits of DTG-based treatment accrue similarly to a variety of patient groups.
New data on the pharmacokinetics (PK) of DTG were also presented. DTG is hepatically metabolized, primarily by UGT1A1 to DTG-glucuronide, and to a lesser extent by CYP3A. DTG-glucuronide is renally excreted. Single dose DTG PK studies were conducted in patients with creatinine clearance <30 mL/min and in healthy volunteers [3]. Exposure (AUC) to DTG was 40% lower and DTG-glucuronide 4.3-fold higher in renally-impaired subjects, but these changes were deemed not clinically significant. The authors concluded no DTG dose modification is needed in renal failure. This conclusion was supported by a pharmacodynamic analysis presented in another abstract [4] which showed these lower plasma levels of DTG were still associated with optimal responses in integrase inhibitor-naive patients. The authors cautioned that the reductions in DTG exposure seen in renal failure may be clinically significant in patients with integrase resistance mutations who require high dose DTG. It should also be noted that the safety of chronic exposure to the much higher levels of DTG-glucuronide seen in renal insufficiency was not established by this study.
DTG is being developed in co-formulation with ABC and 3TC to be used as a once daily single tablet regimen (STR) for treatment-naive patients. A PK study conducted in 66 healthy volunteers [5] demonstrated an investigational fixed-dose combination of DTG 50 mg/ABC 600 mg/3TC 300 mg produced similar component plasma levels to the approved formation of DTG alone and the fixed-dose combination of ABC/3TC, fulfilling the standard criteria for bioequivalence. Administration of a high fat meal increased DTG AUC 48%, but administration with food was not judged to be necessary for the optimal activity of DTG or the STR.
1. Feinberg J, Clotet B, Khuong M-A, et al. Once-Daily Dolutegravir (DTG) is Superior to Darunavir/Ritonavir (DRV/r) in Antiretroviral-Naive Adults: 48 Week Results from FLAMINGO (ING114915). 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1464a.
2. Hagins D, Lazzarin DA, Kumar P, et al. Dolutegravir in Key Demographic Subgroups of Treatment-Experienced HIV-infected Populations. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1460
3. Weller S, Borland J, Chen S, et al. Pharmacokinetics (PK) and Safety of Dolutegravir (DTG) in Subjects with Severe Renal Impairment and Healthy Controls. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract-A1571.
4. Song I, Chen S, Piscitelli S, Min S. Pharmacokinetics (PK) and PI-Pharmacodynamic (PD) Relationship of Dolutegravir (DTG) in Integrase Inhibitor (INI)-Naive Subjects. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract A-1573.
5. Weller S, Chen S, Borland, et al. Bioequivalence of a Dolutegravir, Abacavir and Lamivudine Fixed-Dose Combination Tablet and the Effect of Food. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract A-1572.
ICAAC: Dolutegravir Superior to Darunavir at 48 Weeks in Open-Label ART-Naive Trial (The FLAMINGO Study, slides in report) - Written by Mark Mascolini - (09/14/13)
ICAAC: 48 Week Bone Marker Changes in Dolutegravir (DTG; GSK1349572) Plus Abacavir/Lamivudine (ABC/3TC) vs Tenofovir/Emtricitabine/Efavirenz (EFV/TDF/FTC): The SINGLE Trial - (09/13/13)
ICAAC: Meta-analysis of Safety Data From 8 Clinical Studies With GSK1265744, an HIV Integrase Inhibitor, Dosed Orally or as Injection of Long-Acting Parenteral Nanosuspension (LAP) - (09/12/13)
ICAAC: Dolutegravir in Key Demographic Subgroups of Treatment-Experienced HIV-Infected Populations - (09/16/13)
ICAAC: Bioequivalence of a Dolutegravir, Abacavir and Lamivudine Fixed-Dose Combination Tablet and the Effect of Food - (09/16/13)
ICAAC: Pharmacokinetics (PK) and Safety of Dolutegravir (DTG) in Subjects With Severe Renal Impairment and Healthy Controls - (09/16/13)
ICAAC: Pharmacokinetics (PK) and PK-Pharmacodynamic (PD) Relationship of Dolutegravir (DTG) in Integrase Inhibitor (INI)-Naive Subjects - (09/16/13)
53rd ICAAC Interscience Conference on Antimicrobial Agents and Chemotherapy
September 10-13
2013, Denver CO
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