Antiretroviral resistance in clinical practice.
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Biomedical subjects
Publications and source records attributed to Eric S Daar.
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We isolated a subtype B infectious DNA clone of human immunodeficiency virus type 1 (HIV-1) from a seronegative patient with acute infection and determined the entire nucleotide sequence. All the reading frames encoding the structural proteins (Gag, Pol, and Env) and nonstructural proteins (Tat, Rev, Vpr, Vif, and Nef) were found. Although moat functional domains in these proteins were conserved, we identified a duplication of the T cell factor lei (TCF-1alpha) element in the long terminal repeat and many variations in the N-linked glycosylation sites in the V4-V5 region but not in the V1-V3 loop of Env, compared with prototype subtype B clones. Furthermore, phylogenetic analysis of the entire nucleotide sequence indicated that this HIV-1 was distinct from the prototype subtype B clones, suggesting that transmitted viruses can be variants. This HIV-1 DNA done will be a useful prototype for investigating the mechanism of HIV-1 transmission.
BACKGROUND: Among persons in North America who are newly infected with the human immunodeficiency virus (HIV), the prevalence of transmitted resistance to antiretroviral drugs has been estimated at 1 to 11 percent. METHODS: We performed a retrospective analysis of susceptibility to antiretroviral drugs before treatment and drug-resistance mutations in HIV in plasma samples from 377 subjects with primary HIV infection who had not yet received treatment and who were identified between May 1995 and June 2000 in 10 North American cities. Responses to treatment could be evaluated in 202 subjects. RESULTS: Over the five-year period, the frequency of transmitted drug resistance increased significantly. The frequency of high-level resistance to one or more drugs (indicated by a value of more than 10 for the ratio of the 50 percent inhibitory concentration [IC50] for the subject's virus to the IC50 for a drug-sensitive reference virus) increased from 3.4 percent during the period from 1995 to 1998 to 12.4 percent during the period from 1999 to 2000 (P=0.002), and the frequency of multidrug resistance increased from 1.1 percent to 6.2 percent (P=0.01). The frequency of resistance mutations detected by sequence analysis increased from 8.0 percent to 22.7 percent (P<0.001), and the frequency of multidrug resistance detected by sequence analysis increased from 3.8 percent to 10.2 percent (P=0.05). Among subjects infected with drug-resistant virus, the time to viral suppression after the initiation of antiretroviral therapy was longer (P=0.05), and the time to virologic failure was shorter (P=0.05). CONCLUSIONS: The proportion of new HIV infections that involve drug-resistant virus is increasing in North America. Initial antiretroviral therapy is more likely to fail in patients who are infected with drug-resistant virus. Testing for resistance to drugs before therapy begins is now indicated even for recently infected patients.