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CD4-guided Scheduled Treatments Interruptions Compared to Continuous Therapy: Results of the Staccato Trial
Jintanat Ananworanich*1, A Gayet-Ageron2, M Le Braz2, W Prasithsirikul3, P Chetchotisakd4, S Kiertiburanakul5, P Phanuphak1, D Cooper6, K Ruxrungtham1, B Hirschel2, and the Staccato Study Group
1HIV Netherlands Australia Thailand Res Collaboration, Bangkok; 2Geneva Univ Hosp, Switzerland; 3Bamrasnaradura Inst, Nonthaburi, Thailand; 4Khon Kaen Univ, Thailand; 5Mahidol Univ, Bangkok, Thailand; and 6Natl Ctr in HIV Epidemiology and Clin Res, Univ of New South Wales, Sydney, Australia
Background: Stopping HIV
therapy may reduce costs and side effects, but carries the risk of increased
immune suppression and of emergence of resistance.
Methods: We randomized 430 patients with CD4 counts >350, and viral load
<50 1:2 to either continuous therapy (n
= 146) or scheduled treatment interruption (STI) (n = 284), with treatment stops as long as CD4 counts exceeded 350. The
median time on randomized treatment was 21.9 months. At the end of the study,
both groups were again treated continuously for 12 to 24 weeks. In Thailand, 352 patients
received 1600 mg of saquinavir (SQV) with 100 mg of ritonavir (RTV) once daily with 2 nucleoside reverse
transcription inhibitors (NRTI): didanosine/stavudine (ddI/d4T) from 2002 until March 2003,
and tenofovir/lamivudine (TDF/3TC) after that. In
Swiss and Australian patients, the type of HAART used was defined by the
treating physician.
Results: The probability of restarting treatment in STI
was 53% at 6 months, 64% at 12 months, and 74% at 24 months. Drug savings in
STI, compared to continuous therapy, amounted to 61.2% during randomized
treatment. In an intent-to-treat analysis, the percentage with viral <50
copies was 91.8 % in continuous therapy, compared to 90.3% in STI after
re-treatment at the end of the trial (delta 1.6%, 95%CI –4.0 to 7.3%). At the
end of randomized treatment, median CD4 counts were 374 in STI (60.5% >350),
and 601 in continuous therapy (96.2% >350, p <0.002). After re-treatment, median CD4 counts rose in STI
from 374 to 459 after 12 weeks, with 85.9% >350, compared with 96.9% in continuous
therapy (p <0.01). During STI, 17
patients (5.8%) had symptoms of acute retroviral syndrome. Diarrhoea (p = 0.04) and neuropathy (p = 0.03) were more frequent in continuous
therapy, whereas oral and vulvo-vaginal candidiasis (p = 0.03)
and thrombocytopenia (p = 0.06) were
more frequent in STI. Sequencing was attempted in 125 patients where resistance
was most likely because of numerous stop-start cycles, problems with compliance,
and/or viral breakthrough. We observed no resistance mutations in the RT and P genes in 115. Resistance mutations occurred in 7 patients in the RT gene, and 3 in the P gene.
Conclusions: During 484 patient-years of STI, little evidence of
treatment resistance emerged. Treatment-related adverse effects were more
frequent in continuous therapy, but minor manifestations of HIV infection were
more frequent in STI.
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