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Resistance Emergence With Raltegravir Versus Efavirenz in Treatment Naive
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International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik. Croatia
Mark Mascolini
Among previously untreated people with virologic failure while taking raltegravir or efavirenz with tenofovir (TDF) plus lamivudine (3TC) or emtricitabine (FTC), resistance to efavirenz usually emerged at the same time as resistance to 3TC or FTC [1]. In contrast, resistance to raltegravir usually emerged later than resistance to 3TC or FTC--sometimes much later.
With collaborators from two randomized trials of raltegravir versus efavirenz, Michael Miller of Merck tracked emergence of resistance-conferring mutations in people with virologic failure during protocol 004 [2], a phase 2 trial, or STARTMRK [3], a phase 3 trial. The integrase inhibitor raltegravir proved virologically equivalent to efavirenz in both trials. Among 441 antiretroviral-naive people randomized to raltegravir in these studies, 10 (2%) had virologic failure with resistance, as did 11 of 320 (3%) randomized to efavirenz. Miller observed that the resulting sample size for this analysis is small and represents a tiny proportion of the trial population.
Among the 11 people in whom efavirenz failed virologically, mutations conferring resistance to efavirenz emerged in 5 at the same time as mutations that make HIV resistant to 3TC or FTC. Efavirenz mutations emerged in all 6 of the remaining patients, but resistance to 3TC or FTC never developed in 4 of them. Follow-up in 3 of these 4 lasted for 13, 20, and 30 weeks after resistance to efavirenz emerged, while the fourth person stopped treatment after the efavirenz-induced K103N mutation emerged.
Among 10 people in whom a raltegravir regimen failed virologically, 3TC/FTC mutations emerged in 8 before raltegravir mutations could be detected. Time to emergence of raltegravir-related mutations ranged from 4 weeks to more than 1 year after resistance to 3TC or FTC developed. In the remaining 2 people, resistance to raltegravir and to 3TC or FTC emerged at the same time or within 1 week. Raltegravir-related mutations never emerged before 3TC/FTC mutations during virologic failure in these trials.
One patient in whom FTC resistance emerged at study week 24 never had detectable raltegravir resistance mutations through 96 weeks of follow-up, even though that patient continued the same regimen. Another person had resistance to 3TC in the first 8 weeks of treatment, but raltegravir mutations evolved only after more than 1 year with the same regimen.
The findings suggest raltegravir has a higher barrier to resistance than efavirenz in previously untreated people. After Miller's presentation at the Resistance Workshop, Swiss researcher Huldrych Gunthard observed that many people in these two trials continued taking a failing regimen much longer than knowledgeable HIV clinicians would now allow. He suggested the results underline the importance of quickly stopping a failing regimen.
The SWITCHMRK trials found that raltegravir is more vulnerable to resistance than virologically suppressed patients continuing lopinavir/ritonavir if those people have a history of nucleoside failure [4].
References
1. Miller M, Fransen S, Huang W, et al. Temporal order of resistance emergence for lamivudine/emtricitabine, efavirenz and raltegravir in treatment-naive patients. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik. Croatia. Abstract 3.
2. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007;46:125-133.
3. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374:796-806. Erratum in: Lancet. 2009;374:786. Lancet. 2009;374:2054.
4. Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomized controlled clinical trials. Lancet. 2010;375:396-407.
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