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Do Trace Levels of HIV Drug Resistance Transmitted During Infection Affect Virological Response?
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Mark Mascolini
February 27, 2007
14th Conference on Retroviruses and Opportunistic Infections
Los Angeles
Two studies presented at the Retrovirus Conference disagreed on whether covert resistance mutations transmitted during HIV infection raise the risk of virologic failure once treatment begins. Jeffrey Johnson and Centers for Disease Control (CDC) colleagues used ultrasensitive resistance assays to detect 42% more transmitted resistance mutations than conventional tests [1]. These tiny mutant clusters greatly upped the odds of virologic failure in three clinical trials. But French Aquitaine cohort investigators determined that only transmitted mutations spotted by standard assays imperil response to first-line therapy [2].
CDC researchers used supersensitive point mutation assays to delve for hidden resistance mutations in 205 viral samples classified as nonresistant by conventional sequencing in the United States from 2003 through 2005 and in 302 US and Canadian samples in which standard tests found one or more mutations between 1998 and 2004 [1]. The CDC assays can ferret out eight mutations that make up only 0.4% to 2.0% of a person's total viral population. Previous work indicates the assays have a specificity of 100% and sensitivities ranging from 97% to more than 99%. The tests probe for the L90M protease mutation and for M41L, K70R, K103N, Y181C, M184V, T215Y, and T215F in reverse transcriptase--by no means all the mutations that may be transmitted when one person infects another.
In 205 presumably nonresistant viral samples, Johnson found that 30 (15%) had one or more minority-population mutations. M41L, K70R, and K103N proved the most frequent covert mutations, turning up in 4% to 5% of samples tested. Looking at 302 viral isolates already rated resistant by standard assays, the CDC tests found that 21 (7%) had low-frequency mutations conferring resistance to another drug class. The extra mutations flushed out increased resistance prevalence by 5% (for K103N) to 340% (for T215F).
Next Johnson retrospectively analyzed virologic failure in 95 people enrolled in three trials of efavirenz and 3TC plus AZT or abacavir, and in 221 people rated as virologic successes in these trials. Seven of 9 people (78%) with only low-frequency mutations when first infected suffered virologic failure after they started their first antiretrovirals. One person with low-level dual-class resistance (K103N plus M184V) endured virologic failure within 2 months. In 6 people with resistance samples collected at virologic failure, 5 had the same mutations spotted by ultrasensitive tests before treatment began.
Multivariate logistic regression analysis pinpointed low-frequency transmitted mutations as the only risk factor for virologic failure, boosting the odds of failure 11 times (P = 0.04). Neither pretreatment viral load nor pretreatment CD4 count differed significantly between people with low-level mutations and people without virologic failure and without mutations.
Analyzing responses to first-line regimens in 172 people starting treatment from 1996 through 2005, Olivia Peuchant and French coworkers found that large mutant populations detected by standard assays made virologic failure more likely than it was in people without pretreatment mutations [2]. But minority mutant populations smoked out by allele-specific PCR did not raise the risk of virologic failure.
The study involved people who had a resistance test within 18 months of infection. Peuchant and colleagues used an ultrasensitive PCR assay that can spot mutations making up only 0.5% of a viral population to search for covert traces of L90M in protease and K103N and M184V in reverse transcriptase, five fewer mutations than the CDC team tracked. Among people in whom standard resistance tests saw mutations to one or more antiretrovirals before treatment began, pretreatment loads were significantly lower than in those with nonresistant virus (3.76 versus 4.59 log, P = 0.002), perhaps because resistant virus tends to be less fit than nonresistant virus. But pretreatment viral loads did not differ significantly between people with only low-level mutant populations and people with nonresistant HIV.
After treatment began, viral load dropped more steeply in people without resistant virus than in those with mutations seen by standard testing. After 3 to 6 months of treatment, viral clearance ran significantly faster in the nonresistant group (P = 0.02). The ultrasensitive PCR assay spotted K103N in 3 of 15 viral samples (20%), M184V in 19 of 77 (25%), and L90M in none of 41. But infection with low levels of K103N and M184V did not affect virologic or immunologic response to therapy when Peuchant compared people with low-level mutations and those with no mutations.
The ANRS team cautioned that lack of statistical power because of the small patient sample could not be excluded as a reason for failure to detect a response difference. The French researchers noted that M184V, the mutation evoked by 3TC or FTC, makes HIV less fit, and this could balance out the decreased sensitivity of mutant populations to antiretroviral therapy.
References
1. Johnson J, Li JF, Wei X, et al. Low-frequency mutations substantially increase the prevalence of transmitted drug resistance and greatly strengthen the relationship between resistance mutations and virologic failure. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 639.
2. Peuchant O, Thiebaut R, Capdepont S, et al. Transmission of HIV-1 minority resistant variants and response to first-line ART. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 666.
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