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Extensive Three-Class Resistance May No Longer Predict Progression or Death
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Tenth International Congress on Drug Therapy in HIV Infection, November 7-11, 2010, Glasgow
Mark Mascolini
Extensive resistance to drugs in the first three antiretroviral classes no longer predicted a new AIDS disease or death in people treated from 2004 through 2008, whereas extensive resistance did independently predict progression or death in people in the same cohort treated from 1999 through 2003 [1]. This analysis of more than 1500 people in Italy found that infection by drug injection, high viral load, and low CD4 count still did adversely affect chances of AIDS-free survival in 2004-2008.
Researchers at the National Institute for Infectious Diseases Lazzaro Spallanzani and the University of Tor Vergata in Rome studied 1522 people, 782 treated from 1999 to 2003 and 740 treated from 2004 to 2008. All study participants had genotypic resistance testing after virologic failure. The investigators used the Rega interpretation system to determine when a mutation pattern indicated that no fully active drugs were left in the "historical" first three antiretroviral classes--nucleosides, nonnucleosides, and protease inhibitors. For purposes of this analysis, the researchers did not consider the protease inhibitors tipranavir and darunavir or the nonnucleoside etravirine as belonging to the "historical" antiretroviral classes because they were not available in the first study period.
During 3583 person-years of follow-up, 171 people in the 1999-2003 group had a new AIDS diagnosis or died. During 1934 person-years of follow-up from 2004 through 2008, 59 people had a new AIDS illness or died. Comparing people who had no active drugs in the first three classes, the investigators recorded the following 1-, 3-, and 5-year survival rates in the two study groups:
-- Survival at 1 year: 88% in 1999-2003 versus 93% in 2004-2008
-- Survival at 3 years: 65% in 1999-2003 versus 84% in 2004-2008
-- Survival at 5 years: 59% in 1999-2003 versus 75% in 2004-2008
For people with only one active class, survival rates were more similar in the two groups:
-- Survival at 1 year: 94% in 1999-2003 versus 98% in 2004-2008
-- Survival at 3 years: 88% in 1999-2003 versus 93% in 2004-2008
-- Survival at 5 years: 81% in 1999-2003 versus 84% in 2004-2008
Cox regression analysis determined that having no active drugs in the first three classes independently doubled the risk of progression in 1999-2003: hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.18 to 3.38, P = 0.01). The same kind of analysis in the 2004-2008 group suggested a higher risk of progression with extensive three-class resistance, but the association was not statistically significant (HR 1.79, 95% CI 0.61 to 5.23, P = 0.29).
In the 1999-2003 group, injection drug use, an AIDS diagnosis at genotyping, and each 10-fold higher viral load independently raised the risk of progression, while each 50-cell higher CD4 count independently lowered the risk of progression more than 10% (HR 0.87, 95% CI 0.83 to 0.91, P < 0.0001). In the 2004-2008 group, each 50-cell higher CD4 count also independently lowered the risk of progression (HR 0.93, 95% CI 0.87 to 1.00, P = 0.044). In this more contemporary group, injection drug use almost tripled the risk of progression (HR 2.80, 95% CI 1.63 to 4.81, P < 0.0001), and each 10-fold higher viral load raised the risk almost 50% (HR 1.49, 95% CI 1.12 to 1.99, P = 0.007).
Antiretrovirals that became available in the second period clearly had a big impact on lowering progression risk, even in people with extensive resistance to the first three antiretroviral classes. Two thirds of the 2004-2008 group with triple-class resistance took one of more of these new drugs: enfuvirtide, darunavir, tipranavir, maraviroc, etravirine, and raltegravir. More than half of these people with triple-class resistance used darunavir or tipranavir.
Reference
1. Zaccarelli M, Lorenzini P, Marconi P, et al. Is extended resistance to the historical antiretroviral drugs and drug classes still a risk factor for HIV progression? Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Abstract P138.
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