CMEonHIV.com is dedicated to providing online CME presentations (slides with voiceover) on HIV/AIDS for healthcare professionals given by local and international experts to keep you up-to-date on the ongoing developments in the field.
Conference
"Predicting the Future: The role of resistance in selecting a first-line backbone" Dr. Vincent Calvez (biography) English - 2005-11-19 - 24 minutes
(23 slides)
Summary : The importance of the initial regimen to the overall treatment paradigm has supplied much of the impetus towards greater treatment convenience in recent years. The resultant changes in regimen composition have greatly influenced the extent and type of resistance observed at first – line virological failure. The emergence of resistance to non-nucleoside reverse transcriptase inhibitors at first virological failure is common and mutational patterns similar across selecting agents, and virological failure on any retonavir-boosted protease inhibitor (PI) seldom appears to result in protease mutations in viruses that were not previously exposed to PIs.
Given this, the diversity of resistance patterns at first virological failure is driven predominantly by the nucleoside analogues used in the backbone, and the increasing popularity of convenient fixed dose combinations (FDCs) of two nucleoside has further simplified the patter seen. There are 3 current dual nucleoside FDCs: zidovudine/lamivudine (ZDV/3TC) and the more recent once daily combinations of tenofovir/emtricitabine (TDF/FTC) and abacavir/lamivudine (ABC/3TC). All have a deoxycytidine analogue in common (3TC or FTC) that generates M184V as the most common NRTI mutation associated with virological failure. M184V generates high level resistance to both 3TC and FTC but has little impact on the other components of the various FDCs.
Mutations to the non-deoxycytidine analogue FDC components are less common at first-line failure than M184V, and generally only found in combination with it. ZDV has the most complex and variable pattern, being an accumulation whose phenotypic effect on susceptibility to other NRTI drugs depends on the number of mutations present. The K65R mutation along with M184V will be observed in a proportion of failures on TDF with either 3TC or FTC. K65R has relatively low level phenotypic effects on a range of NRTIs, whose clinical impact is still not entirely certain. However, in combination with M184V it significantly reduces susceptibility to subsequent abacavir at a level likely to abrogate response.
Abacavir generates L74V as the second most common mutation after M184V in the minority of failures on ABC/3TC regimens. Like K65R, L74V have typically low level phenotypic effects of uncertain clinical relevance. However, L74V with M184V promotes a substantial improvement in susceptibility to tenofovir. Interestingly, although abacavir can also select for K65R, data from first-line ABC/3TC failures show very uncommon and low level emergence of K65R in viral samples displaying L74V.
USER ACKNOWLEDGES AND AGREES THAT ALL DECISIONS MADE WITH THE ASSISTANCE OR USE OF THE SOFTWARE AND/OR THE WEBSITE AND/OR BASED ON CONTENT FOUND HEREIN WILL BE EXCLUSIVELY THE RESPONSIBILITY OF THE USER.
