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Raltegravir Did Not Lower HIV DNA Levels in Cell Reservoirs in Salvage Patients in 24 Weeks
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
During development of the integrase inhibitor raltegravir, some authorities speculated that treatment with this novel agent would lower HIV DNA levels in cell reservoirs because the drug blocks integration of virus into the host cell genome. As cells with integrated DNA became activated and died, the DNA load would in theory fall, because no new DNA would be integrated. But that didn't happen in the first 24 weeks of the French EASIER trial, in which raltegravir replaced enfuvirtide in some patients taking an effective salvage regimen [1].
Constance Delaugerre and ANRS 138 trial colleagues measured circularized DNA (cDNA) and total viral DNA in the first 30 study participants randomized to continue enfuvirtide and the first 30 who switched to raltegravir. cDNA represents viral DNA that has not yet stitched itself into the infected cell's genetic material. Some experts proposed cDNA may be a marker of raltegravir's antiviral activity in people with well-controlled viremia. Total DNA consists of cDNA, linear DNA, and integrated DNA.
A 24-week analysis of the complete study established that raltegravir is not inferior to continued enfuvirtide in people with heavy antiretroviral experience [2]. Defining virologic failure as a confirmed viral load above 399 copies, the ANRS team saw no failures at 24 weeks in the 82 people continuing enfuvirtide and 1 failure in 82 people who switched to raltegravir.
Of the 60 people enrolled in the DNA substudy, 36 (60%) had CDC stage C disease. They had taken antiretrovirals for a median of 14 years and enfuvirtide for a median of 2.5 years. Median lowest-ever CD4 count stood at 37, and median CD4 count at study entry was 400. Eight people (13%) had a viral load above 50 copies when the EASIER trial began. At that point median total DNA stood at 3.61 log per 1 million peripheral blood mononuclear cells (PBMCs). cDNA forms (2-LTR circles) at a level above 20 copies per 1 million PBMCs could be detected in 6 people (10%) with a median DNA load of 89 copies per 1 million PBMCs.
After 24 weeks of treatment, CD4 count remained essentially unchanged in the 60-person subgroup. Fifty-three people (88%) had an HIV RNA plasma load below 50 copies, and the remaining 7 had 50 to 400 copies.
Total DNA at week 24 measured 3.68 log per 1 million PBMCs, a level essentially unchanged from baseline. After 24 weeks 3 people (5%, 2 on enfuvirtide and 1 on raltegravir) had 2-LTR circle levels above 20 copies per 1 million PBMCs, but none of them were among the 6 who had 2-LTR circles at that level when the study began. Five people (8%, 4 on enfuvirtide and 2 on raltegravir) had 2-LTR circle levels above 1 copy per 1 million PBMCs at week 24. Only 1 of those 5 was among the 10 people who had 2-LTR circles above that level when the study began.
Randomization to raltegravir versus continued enfuvirtide had no impact on total DNA. And total DNA change did not differ between people who started the study with a plasma load below 50 copies and those who started with 50 to 400 copies.
Delaugerre and coworkers proposed their findings suggest that "the majority of viral DNA is non-dynamic in patients with [HIV RNA in] plasma controlled below 400 copies/mL." They also suggested that 2-LTR circles are a poor signal of raltegravir activity in people with a low HIV RNA load in plasma.
References
1. Delaugerre C, Charreau I, Braun J, et al. No evolution of HIV-1 total DNA and 2-LTR circles after 24 weeks of raltegravir-containing regimen: a substudy of randomized EASIER-ANRS 138 trial. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 9.
2. De Castro N, Braun J, Charreau I, et al. Switch from enfuvirtide to raltegravir in highly treatment-experienced HIV-1-infected patients: a randomized open-label non-inferiority trial, Easier--ANRS 138. 16th Conference on Retroviruses and Opportunistic Infections. 8-11 February 2009. Montreal. Abstract 572.
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