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  • 2002;16:369). Possibly the most important studies of the value of resistance testing with therapeutic failure were TORO-1 and TORO-2 (NEJM 2003;348:2175 and 2293) that showed a strong correlation between the number of active drugs in the background regimen (by genotype or phenotype analysis) and virologic response. Multiple "salvage trials" have confirmed this observation.
  • The currently available tests are standardized for clade B strains; utility for the other clades is not known or is less well established (Scand JID 2003;35[Suppl 106]:75; J Med Virol 2007;80:1).
  • Primary HIV infection: Studies of untreated patients with acute HIV infection have found substantial variation in the frequency of transmitted resistance over time and geographic area. In the US the rates of resistance increased rapidly in the late 1990s and then stabilized. The largest early study is the report by Little and colleagues of 377 patients in the U.S. with acute infection, with samples taken from 1995 to 2000. The rate of resistance by phenotypic analysis (IC50 >10x wild-type) to at least one agent was 3.4% for 1995-98 compared to 12.4% for 1999-2000. Genotypic analysis of these strains found that the most common resistance mutations on the RT gene were at codons 103, 118, 184 and 215; the most common protease mutations were at codons 82 and 90 (NEJM 2002;347:385). The greatest increase in resistance by class during the 5-year study was for NNRTIs, for which resistance increased from 1.9% to 7.1%. A study of patients with acute HIV infection in New York City found that NNRTI resistance at baseline increased from 2.6% in 1995-98 to 13.4% in 2003-06 (JAIDS 2006;41:439). Other reports found resistance to at least one class of drugs in 12% of recently infected persons (AIDS 2007;21:2223; BMJ 2005;331:1368; JID 2005;192:958; JAIDS 2005;40:505). This rate has generally stabilized or decreased in North America and Europe (Table 2-7).
  • Baseline testing in patients with chronic HIV infection. Baseline genotypic resistance testing is now considered the standard of care. Because mutations in transmitted strains tend to persist, testing should be performed at the time of diagnosis, regardless of the duration of infection and regardless of whether therapy will be initiated immediately (JAIDS 2006;41:573; JAIDS 2004;37:1665). It must be remembered that resistance testing may fail to detect mutations present at low levels, which is most likely to be a problem in patients with longstanding untreated infection. Therefore, they are better indicators of what drugs not to use. This more complete baseline data requires testing for resistance in the "minor- ity pool" which is technically possible but not commercially available. A common recommendation is to repeat genotypic testing in patie- nts with unexplained viral failure according to expected responses at 2- 8 weeks after initiating HAART.

 
2007 © John G. Bartlett, M.D. All rights reserved.32

Chapter 2: Laboratory Tests

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