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NNRTI Treatment Breaks Boost Risk of
Resistant HIV RNA in Female Genital Tract
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
Interrupting a nonnucleoside (NNRTI)-based antiretroviral regimen more than 48 hours raised the risk of detectable resistant virus in the female genital tract by a factor of 14 [1]. Resistance mutations detectable in plasma arose in 9 of 102 women during 12 months of follow-up and in genital secretions in 5 of 102 women.
Virus resistant to NNRTIs can evolve quickly when viremia is not suppressed. Because NNRTIs have long half-lives, drug remains in the circulation after an NNRTI regimen stops and can allow emergence of resistant virus as the viral load rebounds. Resistant virus in genital secretions poses a risk of transmitted drug resistance.
To identify predictors of drug-resistant HIV RNA in genital secretions after an NNRTI regimen starts, researchers from the University of Washington, the University of Nairobi, and other centers planned this study of 102 antiretroviral-naive Kenyan women starting treatment with nevirapine plus lamivudine and stavudine or zidovudine. The investigators measured plasma and genital HIV RNA at 0, 3, 6, and 12 months and tested viral samples for resistance mutations in any women with a viral load above 1000 copies at month 6 or 12.
The 102 women made 382 study visits. They had a median pretreatment CD4 count of 122 (interquartile range [IQR] 78 to 164) and a median pretreatment viral load of 5.5 log10 copies/mL (about 300,000 copies, IQR 5.2 to 6.0).
Before treatment began, only 1 woman had a detectable resistance mutation, the V108I nevirapine/efavirenz mutation in cervical secretions. At the 6-month follow-up point, 26 of 102 (25%) women had a detectable viral load in plasma, 14 (14%) had a load above 1000 copies, and 5 of those 14 (36%) had detectable resistance mutations. At 12 months 41 women (40%) had a detectable viral load in plasma, 10 (10%) had a load above 1000 copies, and 6 of those 10 (60%) had detectable resistance mutations.
At 6 months 43 of 102 women (42%) had a detectable viral load in genital secretions, 5 (5%) had a load above 1000 copies, and 3 of those 5 (60%) had detectable resistance mutations. At 12 months 41 women (40%) had a detectable load in genital secretions, 7 (7%) had a load above 1000, and 3 of those 7 (43%) had detectable resistance mutations.
Overall, resistance mutations became detectable in plasma in 9 women (for an incidence of 10 per 100 person-years) and in genital secretions in 5 women (for an incidence of 5.5 per 100 person-years). The mutations that evolved in the genital tract were the NNRTI mutations K103N (in 5), G190A (in 3), V106A (in 2), V108I (in 2), and Y181C (in 1), and the lamivudine-related mutations M184V (in 2) and M184I (in 1). Y181C confers resistance to all currently available NNRTIs, and G190A is associated with resistance to nevirapine, efavirenz, and etravirine [2].
Multivariate analysis identified a single predictor of detectable resistance mutations in the genital tract: A treatment interruption longer than 48 hours raised the risk 14 times (adjusted hazard ratio 14.2, 95% confidence interval 1.3 to 158.4, P = 0.03). Adherence by pill count or self-report and pretreatment plasma viral load were associated with detectable genital-secretion mutations in univariate analysis but not multivariate analysis.
The researchers stressed that "genital shedding of HIV-1 isolates with genotypic resistance to antiretroviral agents is an important problem, as it likely reflects the risk of transmitting drug-resistant HIV-1." They called for patient- and program level interventions to reduce the risk of genital shedding during antiretroviral therapy.
References
1. Graham S, Jalalian-Lechak Z, Shafi J, et al. ART interruptions predict female genital shedding of genotypically resistant HIV-1 RNA. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 1053. http://www.retroconference.org/2012b/PDFs/1053.pdf.
2. Johnson VA, Calvez V, Gunthard HF, et al. 2011 update of the drug resistance mutations in HIV-1. Top Antivir Med. 2011;19:156-164. http://www.iasusa.org/pub/topics/2011/issue4/156.pdf.
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