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Total Mutation Number--and Specific Mutations--Predict Death
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5th European HIV Drug Resistance Workshop
Cascais, Portugal
March 30, 2007
Mark Mascolini
Having 9 or more resistance mutations after virologic failure or one of three individual mutations raised the risk of death in an analysis of multidrug-resistant people in the HIV Danish Cohort Study [1].
The study involved 133 cohort members in whom the first three antiretroviral classes failed from January 1995 through November 2004. The Danish researchers defined class failure as a viral load above 1000 copies for 120 (not necessarily consecutive) days while taking a drug from that class. Triple-class failure meant meeting this definition for nucleosides, nonnucleosides, and protease inhibitors (PIs).
Of the 133 people with triple-class failure, 81 (61%) had genotypic evidence of mutations conferring resistance to all three classes. The most frequent nucleoside mutations were at positions 215 (60%), 184 (50%), and 41 (49%). Among nonnucleoside mutations, position 103 changes appeared in 53% and position 181 changes in 25%. The most frequent PI mutations arose at positions 90 (41%), 82 (33%), and 48 (30%).
Over a median follow-up of 4.3 years, mortality measured 70 per 1000 person-years in people with triple-class failure versus 29 per 1000 person-years in the whole Danish HIV Cohort after potent antiretroviral regimens arrived. A statistical model factoring in CD4 count at triple-class failure, viral load, year of triple-class failure, age, gender, and previous suboptimal antiretroviral therapy figured that 9 or more resistance mutations independently inflated the risk of death from any cause 2.3 times (95% confidence interval [CI] 1.1 to 4.8). Three individual mutations also independently raised the death risk at the following mortality rate ratios (MRR) and 95% CIs:
- T215Y: MRR 3.4 (1.6 to 7.0)
- G190A/S: MRR 3.2 (1.6 to 6.6)
- V82F/A/T/S: MRR 2.5 (1.2 to 5.3)
T215Y is a key thymidine analog mutation that typically reflects a failed AZT regimen, possibly AZT monotherapy or AZT plus only one other nucleoside. Mutations at position 190 confer resistance to both nevirapine and efavirenz. Position 82 mutations figure in resistance to most protease inhibitors.
When these three mutations and total number of mutations were factored into the statistical model, only T215Y and G190A/S still predicted death. And when the model changed to include most recent CD4 count instead of CD4 count at triple-class failure, only T215Y still independently raised the risk of death--tripling that risk (MRR 3.0, 95% CI 1.7 to 7.0). In this analysis a latest CD4 count between 50 and 200 versus more than 200 also tripled the risk of death (MRR 3.0, 95% CI 1.1 to 7.9), and a latest CD4 count under 50 versus over 200 inflated the death risk nearly 10 times (MRR 9.6, 95% CI 3.7 to 25.1).
A higher death rate in people with more resistance mutations, the Danish team proposed, may simply reflect lower susceptibility of resistant virus to antiretrovirals and consequently faster HIV disease progression. The link between T215Y and death may signal early treatment with AZT and thus longer immunosuppression. (The researchers suggested that most mutations they recorded "appear to have accumulated during suboptimal therapy in the 1990s.") Or the mutation-death correlation may point to an unmeasured variable, such as worse antiretroviral adherence by people in whom resistant virus evolves.
Reference
1. Jorgensen LB, Lohse N, Kronborg G, et al. Genotypic drug resistance and long-term mortality in patients with triple-class antiretroviral drug failure. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 92.
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