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5th International Workshop on HIV Drug Resistance & Treatment Strategies4-8 June 2001, Scottsdale, Arizona |
BACKGROUND: Structured treatment interruption (STI) has been demonstrated useful in a low proportion of chronic HIV-1 infection (CHI) patients (about 20%). It is necessary to investigate if new approaches could improve the effectiveness of STI.
OBJECTIVES: To analyse if the association of hydroxyurea (HU) with STI could help to control viral load (VL) replication after cyclic interruption of antiretroviral therapy (ART) without deleterious effect in HIV-1-specific immune responses.
METHODS: Twenty CHI patients with a baseline CD4+ T lymphocytes >500/mm3 and baseline viral load (BVL) >5000 copies/ml treated with stavudine plus lamivudine plus indinavir for 52 weeks and VL <20 copies/ml >32 weeks were randomized to stavudine plus didanosine plus indinavir plus HU (HU group; n=10) versus stavudine plus didanosine plus indinavir (ART group; n=10) during 6 months. Thereafter, five cycles of STI were performed separated by periods of 2 months with same highly active antiretroviral therapy (HAART; reintroduced if VL increased >200 copies/ml in the first stop, after 2 weeks in the second, third and fourth stop, and after VL reached a set-point after the fifth stop). HU was discontinued during the periods off ART in the first, second and third stops, and maintained in the fourth and fifth (and last) stops. Plasma VL (PVL), CD4+ lymphocyte proliferative responses (LPR) to HIV-1 antigens and HIV-1-specific cytotoxic T lymphocyte (CTL) responses were assessed.
RESULTS: Sixteen patients (n=7 HU group; n=9 ART group) have reached at least 6 months off therapy after the fifth stop (median of follow-up off therapy 40 weeks). A rebound in VL was detected in all cases in all the stops, even when HU was maintained. The mean doubling time (DT) of VL rebound increased from the first to the last stop [from 2.08 (0.38) days to 6.2 (2.8) days (P=0.05) in the HU group and from 3.3 (0.65) days to 5.6 (1.6) days in the ART group (P=0.05)] without differences between the two groups. Peak of VL rebound was lower when HU was maintained in the periods off ART, reaching a level >5000 copies/ml in only 2/7 versus 1/9 patients in the HU and ART groups, respectively (P=0.035). VL remained <5000 copies/ml in 5/7 patients in HU group and in 3/9 patients in ART group after a median of 40 weeks of follow-up after the last interruption of therapy (P=0.054). HIV-1-specific CD4+ LPR increases from the first to last interruption of therapy from 0/10 patients at first stop to 2/9 patients at last stop in ART group and from 0/10 patients at first stop to 6/7 patients at last stop in HU group. HIV-1-specific CTL responses increases from the first to last interruption of therapy from 1/9 patients with strong response at first stop to 5/8 patients at last stop in ART group and from 1/8 patients with strong response at first stop to 5/6 patients at last stop in HU group. CD4+ T lymphocytes did not drop below 500/mm3 in any patient.
CONCLUSIONS: Immunosuppressive therapy can increase the percentage of patients able to achieve a reasonable control of viral replication (PVL<5000 copies/ml) after cycles of STI and a long period off therapy.
PRESENTING AUTHOR: JM Gatell
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