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More Major Mutations in Newly Diagnosed, Untreated Italian Patients
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
People in central Italy newly diagnosed with HIV in recent years had more complex resistance patterns--and more major mutations--than people diagnosed earlier [1]. This trend to more major mutations in antiretroviral-naive people runs counter to some larger reports at this European HIV Resistance Workshop, which found flat or declining rates.
Researchers from the University of Rome "Tor Vergata" compared transmitted resistance patterns in 152 antiretroviral-naive people diagnosed from 1997 through 2000 and 211 people diagnosed from 2004 through 2006. Transmission risks differed dramatically in the two periods: In the earlier years 68 of 152 people (45%) got infected during sex and 80 (53%) while injecting drugs. In the later period 191 of 211 people (90.5%) got infected during sex and only 15 (7%) while injecting drugs.
Using the IAS-USA and Stanford University database of resistance mutations--plus a list of novel mutationsÑthe investigators gauged a resistance prevalence around 14% in 1997-2000 versus about 9% in 2004-2006, but that difference fell short of statistical significance (P = 0.13). Nucleoside-related mutations appeared marginally more often in the earlier period (about 10% versus 5%, P = 0.06). Although overall rates of nonnucleoside resistance did not differ between the two eras, the nonnucleoside K103N change was the only mutation detected significantly more often in 2004-2006 than in 1997-2000, but its overall prevalence in the later period remained low (3.3% versus 0%, P = 0.04).
Significantly more people in more recent years got infected with virus resistant to two antiretroviral classes (4% versus 0%, P = 0.02). Also, among people with any pretreatment mutation, more recently diagnosed people had two or more primary mutations to any class significantly more often than people diagnosed earlier--6 (32%) versus 1 (4.5%) (P = 0.03).
More recently diagnosed people had complex mutation clusters including the thymidine analog mutations M41L and L210W, T215D revertant virus (indicating infection with AZT/d4T-resistant T215Y/F), the nonnucleoside K103N mutation, and compensatory PI mutations A71V, I72T, V77I, and I93L. Tangled recent resistance patterns also featured jumps in rates of novel mutations, such as the PI mutation R57K (from 8.5% to 18.5%, P = 0.009) and the reverse transcriptase mutations K20R (from 8.5% to 21.3%, P < 0.001) and I135R (from 1.3% to 6.2%, P = 0.03).
On the other hand, prevalence of mutations linked to more susceptible virus declined in recent years, including the PI mutation H69N (from 10.5% to 3.3%, P = 0.008) and the reverse transcriptase I50V mutation (from 7.9% to 2.8%, P = 0.04). (The reverse transcriptase I50V substitution should not be confused with I50V in protease, a primary darunavir and fosamprenavir mutation. IAS-USA does not rank any of the novel mutations explored in this study [2].)
The investigators argued that their findings suggest "transmission of drug-resistant strains is a complex phenomenon that continues to be an alarming problem for public health." They called for "the extension of wide genotyping to all patients who start an antiretroviral regimen."
Meanwhile, a WATCH study update of 6244 untreated people in Europe, North and South America, Asia, and Africa found prevalence of transmitted resistance remaining steady at 10.1% [3]. Rates were higher in North America (14%) and Europe (10%) than in South America (7%), Africa (7%), or Asia (5%).
A SPREAD study focusing on transmitted resistance in Europe from September 2002 through December 2005 charted a jump in incidence of nonnucleoside-related mutations from 2003 through 2004 (from about 1% to 5%, P < 0.05), than a mirror-image decline through the end of 2005 (P < 0.05) [4]. Over this same period incidence of PI-related mutations fell significantly from around 7% to about 2% (P = 0.01). The SPREAD team offered evidence suggesting the overall drop in transmitted resistance reflects declining trends in resistance of treated patients.
From 1998 through 2005 incidence of transmitted resistance fell in Denmark from 13.04% to 4.79% (P = 0.004) for nonnucleosides, from 9.75% to 1.95% for nucleosides (P = 0.018), and from 5.45% to 0% for PIs (not significant) [5]. But a London study traced a trend toward a higher resistance transmission prevalence in 2007 (10.5%) than in 2004 (7.1%) [6].
References
1. Alteri C, Svicher V, Gori C, et al. Complex patterns of drug resistance mutations in newly-diagnosed HIV-infected patients: implications with the transmission of resistant strains. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 13.
2. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2007. Topics HIV Med. 2007;15:119-125.
3. Frentz D, Van de Vijver DAMC, Wensing AMJ, et al. Worldwide comparison of mutational patterns in studies on transmission of drug resistant HIV-1 across the world: update on the results of the WATCH study. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 4.
4. Vercauteren J, Van de Vijver D, Wensing AMJ, et al. Trends in transmitted drug-resistant HIV-1 in Europe (Sept 2002 Ð Dec 2005). 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 5.
5. Audelin A, Lohse N, Obel N, et al. Incidence of antiretroviral drug resistance in HIV-1 infected patients in Denmark 1998-2005. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 6.
6. Booth CL, Garcia-Diaz AM, Smith C, et al. Trends in transmitted antiretroviral resistance in London. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 7.
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