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Mutation Rate in Antiretroviral-Naive Falling in One US Patient
Population (GSK studies in USA)
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International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
Prevalence of major mutations conferring resistance to the first three antiretroviral classes appeared to peak in 2005 and to fall through 2009 among people enrolling in clinical trials across the United States [1]. Double- and triple-class resistance and nonnucleoside mutations also appeared to be waning sharply in untreated people.
Lisa Ross and GlaxoSmithKline colleagues used both the 2009 IAS-USA list of mutations and the World Health Organization (WHO) surveillance list to categorize major mutations conferring resistance to nucleosides (NRTIs), nonnucleosides (NNRTIs), and protease inhibitors (PIs) in 3829 antiretroviral-naive people enrolling in GSK clinical trials in 36 states and Washington, DC. The investigators used standard genotyping to chart resistance rates yearly from 2000 through 2009. The minor mutations V90I, A98G, V106I, E138A, V179D/F/T, and M230L were excluded from the analysis.
The study group had a median age of 37 years, a median CD4 count of 231, and a median viral load of 4.875 log (about 75,000 copies). Most study participants (83%) were men. For each year, study samples exceeded 200 people, except 2008 (97) and 2009 (190).
Overall prevalence of IAS-USA mutations stood at 12%, rising from 5% in 2000, peaking around 13% in 2005, and falling to about 11% in 2009. According to the IAS-USA list, the overall rate, 2000 rate, and 2009 rate were 4%, 3%, and 4% for NRTIs, 7%, 2%, and 4% for NNRTIs, and 3%, 3% (in 2001), and 4% for PIs.
By the WHO surveillance definition, overall resistance prevalence stood at 13%, rising 6% in 2000 to peak around 15% in 2005, and falling to about 13% in 2009. According to the WHO list, for each antiretroviral class the overall rate, 2000 rate, and 2009 rate were 6%, 5%, and 6% for NRTIs, 6%, 2%, and 4% for NNRTIs, and 3%, 2% (in 2001), and 3% for PIs.
Using either resistance classification, the GlaxoSmithKline team charted an overall 2% prevalence of dual- or triple-class resistance, but a prevalence below 1% in 2009. According to the IAS-USA list, dual- or triple class resistance peaked at 3% in 2002. The WHO list indicated that dual- or triple-class resistance peaked at 4% in 2008 before plummeting in 2009. No triple-class resistance could be detected by either system in 2009.
Because NNRTI-induced mutations were most prevalent in earlier studies of resistance in untreated people, the researchers gauged rates of two specific NNRTI mutations, K103N and Y181I/C/V. K103N prevalence rose from under 1% in 2000 to 6% in 2008, but then fell to 3% in 2009. Prevalence of mutations at position Y181 stood below 1% in 2000, climbed to 2% in 2002, and could no longer be detected after 2007. No other major NNRTI mutations had a prevalence above 2% over the study period. Among IAS-USA-defined NNRTI mutations, only three could be detected in samples collected in 2008 and 2009: K103N, V108I, and P225H.
More sensitive assays may have detected minority populations of mutant virus not detected by the standard sequencing used in this study. Because everyone studied here enrolled in a clinical trial, the results do not reflect resistance in people with undiagnosed HIV infection or perhaps people with poor access to care.
Reference
1. Ross LL, Wine B, Horton JH, et al. Prevalence of HIV-1 drug resistance-associated mutations in a large cohort of antiretroviral-naive HIV-infected individuals in the USA from 2000-2009. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 42.
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