Abacavir, efavirenz, didanosine, with or without hydroxyurea, in HIV-infected adults failing initial nucleoside/protease inhibitor-containing regimens

Abstract

Background: Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy.

Methods: A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA < or = 400 copies/mL after > or = 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24).

Results: Baseline mean HIV-1 RNA was 3.86 log10 copies/mL and CD4+ cell count was 345 cells/mm3. A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (< 400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; < 50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm3 and -63 cells/mm3 (P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed.

Conclusion: ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events.

Figure 1

Proportion of subjects in the non-HU and HU arms who achieved plasma HIV-1 RNA <400 copies/mL and <50 copies/mL in the intent-to-treat: missing = failure analyses. HU = hydroxyurea.

Figure 2

Proportion of subjects in the non-HU and HU arms who achieved plasma HIV-1 RNA <400 copies/mL and <50 copies/mL in the intent-to-treat: observed (B) analyses. HU = hydroxyurea.

Figure 3

Time to virologic failure. ABC = abacavir; ddI = didanosine; EFV = efavirenz; HU = hydroxyurea. Virologic failure was defined by any of the following: HIV-1 RNA >400 copies/mL by week 24, repeated detection (>400 copies/mL) after initial suppression to undetectable levels (<400 copies/mL) or a 3-fold or greater increase in plasma HIV-1 RNA level from the nadir at week 8 or later.

Figure 4

Time to treatment failure. ABC = abacavir; ddI = didanosine; EFV = efavirenz; HU = hydroxyurea. Virologic failure was defined by any of the following: HIV-1 RNA >400 copies/mL by week 24, repeated detection (>400 copies/mL) after initial suppression to undetectable levels (<400 copies/mL) or a 3-fold or greater increase in plasma HIV-1 RNA level from the nadir at week 8 or later.

Figure 5

Median change from baseline in CD4+ cell counts in non-HU arm, total HU arm, and HU arm that began HU at baseline and at week 8. BL = baseline; HU = hydroxyurea.