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  XVII International HIV Drug Resistance Workshop
June 10-14, 2008
Sitges, Spain
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Impact of Raltegravir on HIV DNA--and Fitness of Raltegravir-Resistant Virus
  XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
French investigators found that raltegravir modestly lowers HIV DNA levels in peripheral blood mononuclear cells (PBMCs), and they marshaled evidence they believe shows this integrase inhibitor may protect newly minted cells from viral encroachment [1]. Lower cellular DNA loads have long been a grail of HIV medicine because integrated DNA is an obvious yet so far unassailable obstacle to clearing the virus. Another French group found that raltegravir-induced resistance mutations inhibit both integrase activity and viral replication capacity--but those apparent benefits do not help people with raltegravir-resistant virus [2].
Since drug developers first envisioned making agents that inhibit integration of viral DNA into an infected cell's nucleus, experts have speculated that integrase inhibitor therapy could eventually deplete the horde of HIV DNA that lies dormant in resting CD4 cells as those cells slowly turn over and dump their contents. Now that raltegravir has entered the clinical arena, Charlotte Charpentier and Paris coworkers tested the foundations of that hypothesis in 18 highly pretreated people who started a raltegravir-based rescue regimen [1]. These people had advanced HIV infection with CD4 counts ranging from 3 to 109 (median 29), though the group's median HIV RNA stood around only 10,000 copies. Median HIV DNA load before raltegravir measured 3.5 log (under 4000 copies per 1 million PBMCs).
Raltegravir salvage failed in 3 people, in whom integrase mutations arose. Charpentier eliminated these 3 from the following analysis. After 12 weeks of treatment, 8 people had a plasma RNA load under 40 copies, while median RNA load fell to 2.12 log (close to 100 copies) in the others. At that point median HIV DNA dropped to 2.95 log (just under 1000 copies per 1 million PBMCs).
In 14 people with 24 weeks of follow-up, median DNA load stood at 2.77 log copies per 1 million PBMCs. Median DNA loads measured 2.91 log in 11 people at week 36 and 2.90 log in 7 people at week 48. So it appeared that DNA load in PBMCs fell slightly then stabilized after a few months, at least in this small study group.
A median DNA decline of 0.35 log at 12 weeks did not correlate with pretreatment HIV RNA load or CD4 count. But the DNA drop did correlate with HIV DNA before raltegravir--the higher the pretreatment DNA load, the greater the decline (r = 0.28, P = 0.03). Also, the week 0 to 12 decrease in the ratio of HIV DNA to CD4 count correlated with the HIV RNA decline--the greater the DNA/CD4 ratio decrease, the greater the HIV RNA decrease (r = 0.35, P = 0.01).
Charpentier and colleagues believe these correlations suggest that raltegravir may protect CD4 cells generated during treatment from infection. Whether this potential benefit has any clinical impact remains unknown. And they stress that raltegravir does not profoundly lower DNA quotients in PBMCs during the first months of therapy.
Vincent Calvez and Paris coworkers analyzed the impact of two raltegravir mutation patterns (N155H and G140S/Q148H) on replicative capacity and integrase activity of virus in lab cells [2]. Emergence of the mutations correlated with loss of virologic control in 2 people taking raltegravir in salvage regimens. Measuring viral production by HIV p24 antigen levels after infecting lab cells with recombinant mutant virus, Calvez charted marked deficits in p24 production for mutant versus nonmutant virus:
· Day 5: 6.10(2) vs 7.10(3) vs pg/mL for mutant vs nonmutant virus
· Day 10: 2.10(5) vs 10(3) pg/mL for mutant vs nonmutant virus
The G140S/Q148H mutations altered both 3'-end processing and strand transfer--two critical integrase functions--while N155H impaired only strand transfer. Despite these effects on integrase function and replicative capacity, the mutant viruses replicated well in the 2 patients, both of whom had viral rebounds when the mutations emerged. Calvez suggested this discrepancy may be explained by a compensatory mechanism involving a viral factor outside integrase or a cellular factor absent in the lab cells he used.
A separate study by US investigators documented a stable though detectable viral load when a person stopped raltegravir with only the N155H mutation [3]. Viral load climbed only when the mutation faded from the viral population.
1. Charpentier C, Piketty C, Laureillard D, et al. HIV DNA viral load evolution under a raltegravir-based therapy. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 19.
2. Marcelin AG, Malet I, Delelis O, et al. Raltegravir mutations affect strongly the integrase activities and the replicative capacity of viruses harboring such mutations. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 17.
3. Hatano H, Lampiris H, Huang W, et al. Virological and immunological outcomes in a cohort of patients failing integrase inhibitors. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 10.