Time Trends in Primary HIV-1 Drug Resistance Among Recently Infected Persons

Transmission of multiclass drug-resistant HIV-1 may increase with wider use of antiretroviral therapy. Researchers analyzed time trends in prevalence of HIV-1 genotypic and phenotypic primary drug resistance among recently infected individuals in San Francisco -- an area with a high density of antiretroviral treatment -- from June 1996 through June 2001.

Consecutive case series of 225 patients with evidence of acute or recent HIV-1 infection were enrolled in the Options Project at San Francisco General Hospital. Patients were recruited through physician referrals, community-based organizations, community health centers and self-referral. There were no significant differences over time in age, sex, risk group, CD4 cell count, CD4 percentage or viral load. Resistance determinations were obtained before any treatment in 215 (95.6 percent) participants and during the first seven days of treatment in ten (4.4 percent) persons.

Genotypic evidence of resistance was detected in 52 (23.1 percent) individuals. Genotypic resistance to NRTIs initially decreased from 25 percent (10/40) in 1996-1997 to 7.4 percent (7/94) in 1998-1999 and then returned to prior levels, 20.9 percent (19/91) in 2001. There was one mutation associated with PI resistance in 1996-1997 (2.5 percent) and there were seven (7.7 percent) in 2000-2001. Mutations associated with resistance to NNRTIs steadily increased from 0 in 1996-1997, to 12 (13.2 percent) in 2000-2001. Genotypic resistance to two or more classes of drugs increased from 2.5 percent (1/40) to 13.2 percent (12/91), but only one infection (.4 percent) in the latter period was resistant to all three classes of antiretroviral therapy.

Phenotypic drug susceptibility testing was attempted in all 225 participants with completed genotypic analysis and was successful in 210 cases (93 percent). The proportion of new infections with NNRTI resistance increased over time from zero cases in 1996-1997 to 8 (9.9 percent). The prevalence of primary phenotypic resistance increased for PIs from 2.6 percent in 1996-1997 to 6.2 percent in 2000-2001. Primary phenotypic resistance to NRTIs decreased throughout the study, from 21 percent in 1996-1997 to 6.2 percent in 2000-2001. The proportion of individuals with decreased susceptibility to two or more classes of antiretroviral agents was 2.6 percent in 1996-1997 and 4.9 percent in 2000-2001. Phenotypic resistance to all three classes of agents occurred in only one person, who enrolled in 2000.

To determine whether primary resistance was associated with delayed virologic response, the researchers analyzed the time to virologic suppression (plasma RNA <500 copies/mL) in a subset of 141 (62.7 percent) participants who initiated antiretroviral therapy. If therapy was stopped for any reason, observations were excluded from the analysis after the last treatment date. Resistance testing was not used to select the initial drug regimen in any participant. Median time to viral load suppression was longer in 30 individuals with genotypic resistance compared with 111 without resistance, 12 weeks vs. 5 weeks, respectively. One of the patients was infected with HIV-1 resistant to NRTIs and PIs and had persistent plasma viral load after six months of combination therapy (see above).

The detection of primary genotypic resistance was more frequent among individuals who were infected for shorter periods. Resistance was detected in 28.8 percent of those in the first quartile of duration of infection, 27.4 percent among the second quartile, 19.2 percent among the third quartile, and 11.5 percent among the quartile infected for the longest period. These indexes of the duration of infection were not associated with year of enrollment. The initial plasma viral RNA load was highly variable, most likely because of rapid changes in viremia that occur during recent HIV-1 infection. There was no difference in initial plasma viral load between individuals with resistant virus and those with sensitive virus. In contrast, baseline CD4 cell counts and CD4 cell percentages were significantly higher among individuals infected with resistant HIV-1. Multivariate logistic regression indicated that a higher CD4 cell count was independently associated with resistant HIV-1 after duration of infection was controlled.

Researchers concluded that the frequency of primary resistance to NNRTIs is increasing, although resistance to all available classes of antiretroviral therapy remains rare.

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