August 8, 2002
Time to viral suppression was defined by the first of two consecutive plasma values of less than 500 HIV RNA copies/ml in plasma samples collected at least 14 days apart. Treatment interruption for more than 14 days was considered a discontinuation of therapy. The time to virologic failure was defined as the time from the first achievement of viral suppression to the first value for plasma RNA > 500 copies/ml while the subject received potent antiretroviral therapy (ART).
Baseline plasma samples were analyzed for susceptibility, measured by determining the ratio of the concentration required for 50 percent inhibition [IC50] of the subject's virus to the IC50 for a drug-sensitive control virus (NL4-3) for each antiretroviral drug tested.
Over the five-year period, the frequency of transmitted drug resistance increased significantly between the two groups of patients divided according to date of diagnosis (1995-1998 and 1999-2000). The frequency of high-level resistance to one or more drugs increased from 3.4 percent during 1995-1998 to 12.4 percent during 1999-2000, and the frequency of multidrug resistance increased from 1.1 percent to 6.2 percent. Among subjects with multidrug resistance, none identified before 1999 had an IC50 ratio of more than ten for one or more drugs in all three antiretroviral classes, whereas 75 percent of subjects with multidrug resistance identified in 1999 or 2000 had high-level resistance to all three classes. A total of 74 subjects (20 percent) were identified who had an IC50 ratio between 2.5 and 10 for one or more drugs, possibly indicating transmitted drug resistance, but they were below the stringent criterion of an IC50 ratio of more than ten.
Among subjects infected with drug-resistant virus, the time to viral suppression after initiating antiretroviral therapy was longer, and the time to virologic failure was shorter. According to a comparison between subjects receiving two or fewer active drugs (drugs with an IC50 for the subject's virus no more than 10 times that for the control virus) and those receiving three or more active drugs, the number of active drugs in the treatment regimen did not significantly affect time to viral suppression.
Researchers concluded that 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, they write, is now indicated even for recently infected patients.
New England Journal of Medicine
08.08.02; Vol. 347; No. 6:385-394; Susan J. Little, M.D.; Sarah Holte, Ph.D.; Jean-Pierre Routy, M.D.; Eric S. Daar, M.D.; Marty Markowitz, M.D.; Ann C. Collier, M.D.; Richard A. Koup, M.D.; John W. Mellors, M.D.; Elizabeth Connick, M.D.; Brian Conway, M.D.; Michael Kilby, M.D.; Lei Wang, Ph.D.; Jeannette M. Whitcomb, Ph.D.; Nicholas S. Hellmann, M.D.; Douglas D. Richman, M.D.