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  53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO
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Tricky Pharmacokinetics May Not Matter in Switch From Efavirenz to Stribild
  53rd ICAAC, September 10-13, 2013, Denver
Mark Mascolini
Elvitegravir concentrations were lower than normal after a switch from Atripla (efavirenz plus tenofovir/emtricitabine) to Stribild (elvitegravir/cobicistat plus tenofovir/emtricitabine), probably because of CYP3A and UGT induction by efavirenz [1]. But elvitegravir levels remained several-fold above the range associated with good antiviral activity, and virologic suppression in 14 switch patients in study 104 was good.
Stribild proved noninferior to Atripla in antiretroviral-naive people [2,3], but pharmacokinetic properties of elvitegravir, cobicistat, and efavirenz suggest that elvitegravir concentrations may be lower than normal immediately after a switch from an efavirenz regimen to elvitegravir-containing Stribild. Efavirenz is an inducer of CYP3A and UGT and has a half-life of 40 to 55 hours, so its pharmacokinetic impact persists after the drug stops. Elvitegravir depends mainly on CYP3A and partly on UGT1A1/3 for its metabolism. Cobicistat, the agent that boosts elvitegravir in Stribild, is an inhibitor and substrate of CYP3A.
To assess the possibility of a harmful drug-drug interaction between efavirenz and Stribild, study 104 investigators planned two analyses. The first involved 14 people originally randomized to Atripla who switched to Stribild after 48 weeks. The second involved 32 healthy volunteers who took Stribild after Atripla.
Study 104 involved 71 antiretroviral-naive people randomized 2-to-1 to Stribild or Atripla. In an open-label extension after 48 weeks, 14 people assigned to Atripla switched to Stribild. This group averaged 37 years in age (range 22 to 55), 12 of them were men, and 3 were black. All of them had a viral load below 50 copies at study week 48, though one had a load of 97 copies at the switch to Stribild.
Twenty-four weeks after the switch from Atripla to Stribild, 12 of these 14 people (86%) had a viral load below 50 copies. Of the two people who did not, one had a sub-50 load 4 weeks after the switch but then stopped returning for study visits. The other had a viral load of 54 copies 24 weeks after the switch but had a sub-50 load before and after that.
In the pharmacokinetic study, 32 healthy volunteers took Stribild for 1 week to establish reference drug concentrations then took no drugs for 7 days. Next they took Atripla for 2 weeks then switched immediately to Stribild for 5 weeks. The study group averaged 38 years in age (range 22 to 45), half were men, and 10 (31%) were black. Weight averaged 74 kg (range 53 and 103). On the basis of genetics known to affect efavirenz metabolism, the researchers rated 8 people (25%) as poor efavirenz metabolizers.
One and 2 weeks after the switch from Atripla to Stribild, elvitegravir area under the concentration time curve (AUC) was 37% and 29% lower than reference AUCs, and trough concentrations were 67% and 55% lower. But average elvitegravir trough remained 3- to 5-fold above the protein binding-adjusted 95% inhibitory concentration (45 ng/mL) 1 and 2 weeks after the switch from Atripla. Elvitegravir troughs were 7- to 8-fold above the IC95 at 5 weeks after the switch.
AUC of GS-9200, a metabolite of elvitegravir, was 47% higher than reference levels 1 week after the switch and 37% higher 2 weeks after the switch. GS-9200 trough concentrations did not differ from reference values 1 and 2 weeks after the switch. Cobicistat AUCs were 20% and 11% lower than the reference level 1 and 2 weeks after the switch from Atripla, and cobicistat troughs were 48% and 35% lower 1 and 2 weeks after the switch.
Efavirenz AUC was twice higher in poor efavirenz metabolizers than in other volunteers. Efavirenz troughs remained above the 90% inhibitory concentration for about 4 weeks after poor metabolizers stopped taking efavirenz and for about 3 weeks after other volunteers stopped taking efavirenz. Overall efavirenz concentrations were comparable to historical data. Switching from Atripla did not affect concentrations of tenofovir or emtricitabine.
The researchers conclude that after a switch from Atripla to Stribild, elvitegravir and/or efavirenz concentrations remain high enough to control HIV, as indicated in the 14-patient study. They proposed that elvitegravir concentrations are lower than normal immediately after the switch from efavirenz because of CYP3A and UGT induction by efavirenz, and they noted that this effect is more pronounced in poor efavirenz metabolizers.
A phase 3b trial is now evaluating Stribild in HIV-positive people switching from Atripla.
1. Cohen C, Elion R, Ruane P, et al. Switch from efavirenz/emtricitabine/tenofovir DF to elvitegravir/cobicistat/emtricitabine/tenofovir DF: efficacy and pharmacokinetics. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-658.
2. Zolopa A, Sax PE, DeJesus E, et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013;63:96-100.
3. Wohl D, Cohen C, Gallant J, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir DF has durable efficacy and differentiated long-term safety and tolerability versus efavirenz/emtricitabine/tenofovir DF at week 144 in treatment-naive HIV patients. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-672a.