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New Mutations Found in 43% of People With Low But Detectable Viral Loads
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International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
Only 5% of patients in two ACTG trials had incomplete "near-target viral suppression" after 24 weeks of treatment [1]. But new resistance mutations arose in almost half of these people within about a year of incomplete suppression. The findings add to evidence that maintaining an incompletely suppressive regimen poses a threat of evolving resistance.
This retrospective analysis involved 1234 previously untreated people who took a new antiretroviral regimen in ACTG A5095 or ACTG A5142. ACTG A5095 randomized people to efavirenz plus zidovudine/lamivudine, abacavir plus zidovudine/lamivudine, or efavirenz and abacavir plus zidovudine/lamivudine. ACTG 5142 randomized people to efavirenz plus two nucleosides, lopinavir/ritonavir plus two nucleosides, or efavirenz and lopinavir/ritonavir without nucleosides. The ACTG team defined near-target viral suppression as a viral load between 50 and 1000 copies at least twice during a 6-month period or longer while on randomized therapy . During that time, incomplete suppressors with three or more viral load results could have one viral load below 50 copies or one above 1000 copies.
The investigators identified 65 cases of near-target viral suppression (5% of 1234 trial participants), 39 from A5142 and 26 from A5095. Among incomplete suppressors, 31% were taking efavirenz plus two nucleosides, 31% lopinavir/ritonavir plus two nucleosides, 22% lopinavir/ritonavir plus efavirenz, and 17% efavirenz plus three nucleosides.
Median pretreatment viral load in this group stood just above 100,000 copies, and median pretreatment CD4 count was 121. Median age was 38 years, and 86% of near-target suppressors were men. Only 6% had a history of injecting drugs. The median first week of near-target viral suppression was trial week 39 (10-90 percentile 30 to 97), and the median duration of incomplete suppression was 38 weeks (10-90 percentile 24 to 48).
Pretreatment viral samples for resistance testing were available in 59 of 65 incomplete suppressors, from 59 people during near-target viral suppression, and from 54 people both before treatment and during near-target viral suppression. Thirteen of 59 people with a pretreatment sample (22%) had pretreatment resistance mutations, either a nonnucleoside-related mutation or a reverse transcriptase codon 69 insertion. No one had a pretreatment mutation in protease.
Twenty-three of 54 samples (43%) had detectable new resistance mutations during near-target viral suppression. Again there were no protease mutations. The most frequent mutations in incomplete suppressors were the 184V/I mutations evoked by lamivudine or emtricitabine in 14 people and the nonnucleoside-related 103N/R mutations in 11.Most other mutations were nonnucleoside-related changes.
Several factors favored emergence of mutations during incomplete viral suppression. In the group with new mutations, 57% were black, compared with 26% who were Hispanic and 17% who were white (P = 0.048). During the incomplete suppression period, minimum viral load was higher in people with new mutations (62% versus 25% without new mutations, P = 0.003), as were maximum viral load (368 versus 143 copies, P = 0.008) and viral load area under the curve (137 versus 69 copies, P < 0.001).
Factors that did not influence emergence of resistance mutations were pretreatment viral load and CD4 count, week and viral load at onset of near-complete viral suppression, and duration of near-complete viral suppression.
Babafemi Taiwo (Northwestern University, Chicago) and ACTG colleagues pointed out that although a higher viral load favored emergence of new mutations, some mutations appeared at very low viral loads. Workshop attendees noted that African-Americans may have a higher risk of new mutations during near-target viral suppression both because of adherence difficulties and genetic factors affecting nonnucleoside metabolism. The ACTG team did not have drug plasma levels as a check on adherence.
Reference
1. Taiwo B, Gallien S, Aga E, et al. HIV-1 drug resistance evolution during persistent near target viral suppression. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 30.
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