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Background:  In patients with HIV multidrug resistance, maintaining a failing full-dose HAART regimen usually results in significant drug toxicity and in continued accumulation of resistance mutations that can preclude future therapeutic options. In contrast, treatment interruption provokes the reemergence of wild type virus with full replicative and pathogenic capacity. We investigated whether a calibrated reduction in drug pressure could stabilize the evolution and the pathogenic potential of resistant virus.

Methods:  This is a prospective pilot study in patients with virological failure of PI-based HAART, a resistance genotype predicting fewer than 2 active drugs (2002 ANRS algorithm), CD4 counts >100/mm³, and plasma HIV RNA <5 log/mL. The treatment was low-dose IDV/RTV (200/100 twice daily) and 3TC 150 mg twice daily. IDV doses were adjusted at week 4 to ensure a C_min of 250±100 ng/mL, which, based on a panel of PI-resistant viruses, was calculated to yield an inhibitory quotient (C_min/IC₅₀) of 0.50. Primary end-points were >25% decrease in CD4 counts (immunological failure), or >0.7 log increase in plasma HIV RNA (virological failure) at 2 consecutive monthly visits during the 24-week study. Inclusions were to stop when the total number of failures (both viral and immunological) reached 7.

Results:  26 patients were included and 21 completed the study. At inclusion, 50% of patients were receiving more than 3 full-dose drugs. Median baseline plasma HIV RNA was 4.49 log/mL (IQR: 4.17; 4.98) and median baseline CD4 count was 290/mm³ (IQR:  226; 425). During the study, 3 patients experienced VF, 6 experienced IF, and 1 patient experienced both VF and IF. At week 24, the median change in plasma HIV RNA was +0.22 log (IQR: 0.00; 0.50, p = 0.003) and the median change in CD4 count was -49 cells/mm³ (IQR:  -93; -14, p <0.001). However, the slope in CD4 counts during the 24 weeks of the study (-9,8±2,3 cells/mm³/month) was not significantly different from that experienced under full-dose HAART during the 6 months that preceded the study (-6,9±2,5 cells/mm³/month, p = 0,41). Genotype changes (available for 16 patients) only involved the addition of M184V in 2 patients and minimal protease fluctuations in 3 patients (one addition of M46L, one addition of I54V, one loss of G73S).

Conclusions:  Adjusting a low drug pressure on HIV protease and RT in patients with multidrug resistance and limited treatment options can stabilize HIV evolution and pathogenicity.

Keywords: HAART failure; resistance; treatment strategies