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One in 10 Genotyped Britons Started Therapy With Resistant HIV
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
One in 10 genotyped people in a big British cohort study began antiretroviral therapy with at least one major resistance mutation, while almost two thirds of those starting treatment did not get a pretreatment resistance test [1]. Having fewer pretreatment mutations independently raised the chance of reaching a viral load under 50 copies with a first-line regimen. UK Resistance Database and UK CHIC researchers urged clinicians to consider the possibility of transmitted resistant virus when planning a first-line regimen.
The study involved everyone in the Resistance Database who started antiretrovirals from 1999 through 2006. In people with a pretreatment genotype, the investigators searched for mutations experts designated as markers of transmitted resistant virus in a 2007 analysis [2]. They used a Stanford University resistance tool to calculate the genotypic sensitivity score (GSS) for every antiretroviral regimen these patients began. A lower score indicates greater resistance.
Of 3344 people linked to the UK CHIC Resistance Database, only 1244 (37%) got a resistance test before starting therapy. Among 1175 genotyped people with complete records, 84% were men, 73% were men who have sex with men, 69% were white, and 15% were black African. While 13% got their first genotype in 1999-2001, 37% were genotyped in 2002-2003 and 50% in 2004-2006. Median CD4 count and viral load at genotyping measured 265 cells and 4.9 log (80,000 copies). The first regimen included a nonnucleoside in 73% of the cohort and a boosted protease inhibitor (PI) in 22%.
The investigators counted at least one pretreatment resistance mutation in 116 people (9.9%), including 76 nucleoside mutations (6.5%), 65 nonnucleoside mutations (3.8%), and 24 PI mutations (2%). The most common mutations were AZT/d4T mutations, including 8 T215Y/F mutations and 47 T215 revertants. The most frequent nonnucleoside mutation was K103N in 29 people, and the most frequent PI mutation was L90M in 12 people.
Fifty-four people (4.6%) began treatment with a GSS below 3, indicating their starting regimen could be vulnerable to transmitted resistant virus. Multivariate analysis determined that people with a GSS under 3 had more than twice the chance of starting therapy in 1999-2001 than in 2004-2005 (odds ratio [OR] 2.63, 95% confidence interval [CI] 1.19 to 5.82), and these people were twice as likely to start a ritonavir-boosted PI than an NNRTI (OR 1.97, 95% CI 1.06 to 3.64).
In the first few months of therapy, 959 people (82%) reached a viral load below 50 copies. Every 1-unit higher (better) GSS raised the chance of attaining an undetectable load 50% (hazard ratio [HR] 1.50, 95% CI 1.19 to 1.89, P = 0.001). Starting treatment with an unboosted PI (versus a nonnucleoside) lowered the chance of reaching an undetectable load 61% (HR 0.39, 95% CI 0.22 to 0.71, P = 0.002), and starting a triple-nucleoside regimen lowered the chance 49% (HR 0.51, 95% CI 0.35 to 0.76, P = 0.001). Five other factors independently predicted attaining an undetectable load:
· Starting treatment in 1999-2001 versus 2004-2006 lowered the chance 39% (P = 0.0002).
· Starting treatment in 2002-2003 versus 2004-2006 lowered the chance 22% (P = 0.004).
· Every added 10 years of age raised the chance 17% (P = 0.001).
· Every 50 extra CD4 cells before treatment lowered the chance 3% (P = 0.02)
· Every 10-fold higher viral load before treatment lowered the chance 27% (P < 0.0001).
Gender, transmission risk group, ethnicity, and HIV-1 subtype did not affect the chance of reaching a sub-50-copy load.
Sixty-eight people (9.4%) who pushed their viral load under 50 copies had a later rebound. While GSS did not predict viral rebound, four other factors did:
· Every added 10 years of age lowered the rebound chance 30% (HR 0.70, 95% CI 0.50 to 0.98).
· Every 50 extra CD4 cells before treatment raised the rebound chance 14% (HR 1.14, 95% CI 1.05 to 1.23).
· Starting treatment in 1999-2001 versus 2004-2006 more than doubled the rebound chance (HR 2.28, 95% CI 1.06 to 4.89).
· Starting a PI versus a nonnucleoside raised the rebound chance almost 5 times (HR 4.74, 95% CI 1.93 to 4.89).
"Selection of first-line HAART," the UK team counseled, "should take into account the presence of transmitted drug resistance, together with tolerability and other recognized predictors of virological outcomes."
References
1. Geretti AM, Bansi L, Dunn D, Sabin C, UK HIV Drug Resistance Database, UK CHIC. The impact of resistance testing in antiretroviral drug-naive patients: does it guide optimal therapy selection and improve virological outcomes? 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 40.
2. Shafer RW, Rhee SY, Pillay D, et al. HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance. AIDS. 2007;21:215-223.
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