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  50th ICAAC
Boston, MA
September 12-15, 2010
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Raltegravir Re-Use Response After Failure Depends on Mutation Pattern
  50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
People in whom a raltegravir regimen failed without a signature raltegravir mutation had a better chance of responding to continued raltegravir (with a new background regimen) than did people with a signature mutation, with one exception [1]: People who had the N155H mutation upon raltegravir failure were more likely to respond to continued raltegravir than people with other signature mutation patterns. But fewer than 25% of patients with no signature mutations or with N155H had a viral load below 50 copies/mL after 48 weeks in an intention-to-treat analysis, and CD4 counts did not improve in anyone who continued raltegravir with signature mutations.
The study involved 126 people who continued raltegravir with a retuned background regimen after raltegravir failure in three placebo-controlled trials that enrolled antiretroviral-experienced people: BENCHMRK 1 and 2 (phase 3 studies) and P005 (a phase 2 study). People with virologic failure at 16 weeks in these trials could continue open-label raltegravir with a reoptimized background regimen. People randomized to placebo in these trials could start raltegravir if their placebo regimen failed.
Merck investigators divided people whose raltegravir regimen failed into four groups based on their raltegravir mutation pattern at failure: 36 people with no raltegravir-related mutations, 90 with at least one signature raltegravir mutation, 27 with only a Q148 mutation (and no mutations at positions 143 or 155), and 40 with only N155H (and no mutations at positions 143 and 148). These groups were not mutually exclusive. The analysis did not include 4 people with only a Y143 mutation because the sample size was too small. Most people had secondary integrase mutations, but secondary mutations were not considered in this analysis.
Median CD4 counts upon entry into the original trials were low in all of these groups--76.5 in those with no raltegravir mutations, 120 in those with at least one mutation, 146 in those with a Q148 mutation only, 114 in those with N155H only, and 111.5 in the placebo group. Median baseline viral loads were 100,000 copies or higher in all four raltegravir groups and 80,000 copies in the placebo group.
At the time of this analysis, 13 people (36%) had stopped raltegravir in the no-mutation group, 46 (51%) had stopped in the group with at least one mutation, 15 (56%) had stopped in the group with a Q148 mutation only, 15 (37.5%) had stopped in the group with N155H only, and 57 (34%) had stopped treatment in the placebo group.
To evaluate virologic response on continued raltegravir plus a new optimized background regimen, the investigators used an observed-failure approach in which discontinuation for lack of efficacy is considered virologic failure. By those criteria, 50-copy response rates at week 48 of open-label raltegravir were just over 20% in people with no signature raltegravir mutations and in people with N155H only, but response rates were much lower in the other resistance groups:
Below 50 copies at week 48
--No raltegravir mutations: 5 of 23 (22%)
--At least one raltegravir mutation: 9 of 80 (11%)
--Q148 mutation only: 1 of 24 (4%)
--N155H only: 8 of 35 (23%)
Below 400 copies at week 48
--No raltegravir mutations: 9 of 23 (39%)
--At least one raltegravir mutation: 13 of 80 (16%)
--Q148 mutation only: 1 of 24 (4%)
--N155H only: 8 of 35 (23%)
About 50% of people in the original placebo groups had a week-48 viral load below 50 copies in this analysis, and about 60% had a week-48 load below 400 copies.
Average CD4 counts through 48 weeks of the open-label phase fell moderately in the three groups who continued raltegravir with mutations (-5.9 in the any-mutation group, -13.0 in the Q148-only group, -4.5 in the N155H group). People with no signature raltegravir mutations when they continued open-label raltegravir gained an average of 43.8 CD4 cells through week 48. People in the original placebo group gained more than 50 CD4 cells, on average, through 48 weeks of raltegravir therapy.
The Merck researchers noted that the better virologic response in the group with no primary raltegravir mutations could reflect better prognostic factors when the open-label phase began: better phenotypic and genotypic sensitivity scores for the new background regimen and a lower viral load. Earlier work by Monogram Biosciences and Merck investigators determined that virus harboring the Q148 mutation "generally displayed larger reductions in raltegravir susceptibility than viruses with an N155H mutation" [2]. Work by French researchers found that the N155H mutation may be replaced by Y143 mutations if raltegravir continues after virologic failure [3].
1. Zhao J, Teppler H, Nguyen B, Hazuda D, Miller M. Raltegravir (RAL) resistance mutations observed after virologic failure differentially affect subsequent response to a RAL-containing regimen. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-914.
2. Fransen S, Gupta S, Danovich R, et al. Loss of raltegravir susceptibility by human immunodeficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J Virol. 2009;83:11440-11446.
3. da Silva D, Van Wesenbeeck L, Breilh D, et al. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemother. 2010;65:1262-1269.