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  International HIV and Hepatitis Drug Resistance Workshop
June 8-12, 2010,
Dubrovnik Croatia
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Transmitted Resistance Imperils First-Line Response in 10,000-Person Study
  International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
Transmitted resistance mutations correlated with a worse 1-year virologic response to first-line therapy if a person began a regimen containing one or more antiretrovirals against which HIV had at least low-level resistance [1]. But transmitted mutations did not predict virologic failure if a patient began a regimen predicted to be fully active--unless that regimen consisted of a nonnucleoside and two nucleosides. Standard genotyping was used in this study.
The study involved over 10,000 people starting combination antiretroviral therapy after January 1, 1998 in a collaboration involving the CASCADE, COHERE, EuroSIDA, and PENTA-EPPICC cohorts and CHAIN, a pan-European project on resistance to antiretrovirals. Cohort members could be any age. All of them had at least one viral sample collected before treatment began and on-treatment viral load measures.
Linda Wittkop (INSERM U897, Bordeaux) and colleagues used the 2009 World Health Organization (WHO) list of transmitted mutations and the Stanford resistance prediction tool to put people into one of three categories: (1) no mutations, (2) one or more mutations but beginning a regimen predicted to be fully active, or (3) one or more mutations and at least low-level resistance to one or more prescribed drugs. Virologic failure meant two consecutive viral loads above 500 copies after 6 months of therapy.
Of 12,481 people with a resistance test performed before therapy began, the investigators included 10,458 in the analysis. They excluded the others because those patients did not have adequate on-treatment viral load data. One or more WHO mutations could be found in 953 people (9.1%), of whom 476 (4.5%) started a regimen predicted to be fully active by the Stanford tool and 477 (4.6%) had virus predicted to be resistant to one or more drugs in the initial regimen.
A year after treatment began, virologic failure rates stood at 6.3% in people starting a predicted fully active regimen and 16.2% in those starting a regimen predicted to be compromised by resistance mutations. Statistical analysis adjusted for other failure risk factors determined that people with one or more pretreatment mutations had a 2.6 times higher risk of virologic failure (95% confidence interval [CI] 2.0 to 3.4, P < 10(-4)) than did people with no transmitted mutations. Overall, risk of failure did not differ between people starting a predicted fully active regimen and those with no transmitted mutations (hazard ratio 1.2, 95% CI 0.8 to 1.8, P = 0.34).
First-line regimens consisted of two nucleosides (NRTIs) plus a nonnucleoside (NNRTI) in 5038 people (48.2%), two NRTIs and a boosted protease inhibitor (PI) in 3250 (31.1%), two NRTIs and an unboosted PI in 1268 (12.1%), and other regimens in 902 (8.6%). Among people starting two NRTIs and one NNRTI, those with 1 or more transmitted mutations and a regimen predicted to be fully active had a 2.3 times higher risk of failure (95% CI 1.2 to 4.6, P = 0.02) than did people with no mutations. Wittkop and colleagues suggested the higher failure risk in this group might be blamed on transmitted mutations undetectable with standard genotyping.
Three factors independently lowered the risk of virologic failure: treatment started in 2006 or later, sex between men as a transmission risk category, and European origin.
The researchers concluded that transmitted resistance "was associated with a poorer virological response when patients received combination antiretroviral therapy containing one or more drugs for which at least low-level resistance was present." Despite the finding of a higher failure risk with transmitted resistance and a nonnucleoside regimen predicted to be active, for the whole study group having pretreatment mutations did not predict virologic failure if a fully active regimen began.
1. Wittkop L on behalf of the EuroCoord-CHAIN project team. Impact of transmitted drug resistance on virological response to initial combination antiretroviral therapy. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 98.