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Final Results of CPCRA 064: A Randomized Trial Examining Structured Treatment Interruption for Patients Failing Therapy with Multi-drug Resistant HIV
Jody Lawrence*1, K Huppler Hullsiek2, L Thackeray2, D Abrams1, D Mayers3, L Crane4, M Jones1, J Saldanha5, B Schmetter6, T Dionne7, C Pettinelli8, J Baxter9, and for the 064 Study Team of the Terry Beirn Community Programs for Clinical Research on AIDS
1Univ of California, San Francisco, USA; 2Univ of Minnesota, Minneapolis, USA; 3Henry Ford Hosp, Detroit, MI, USA; 4Wayne State Univ, Detroit, MI, USA; 5Denver Publ Hlth Dept, CO, USA; 6Social & Sci Systems, Inc, Silver Spring, MD, USA; 7VA Med Ctr, Washington, DC, USA; 8DAIDS, NIAID, NIH, DHHS, Bethesda, MD, USA; and 9Cooper Hosp, Robert Wood Johnson Med Sch, Camden, NJ, USA
Background: CPCRA 064 examines the effect of structured
treatment interruption (STI) on progression of disease or death, CD4, and HIV
RNA in treatment-experienced patients with multi-drug resistant HIV. The study
closed in June 2004 with median follow-up of 36 months.
Methods: HIV-infected patients on stable
antiretroviral regimens with virologic failure and multi-drug
resistant virus were randomized 1:1 to a 4-month STI
followed by a new regimen, or to immediate change to a new regimen. Baseline
genotypic (TRUGENE) and phenotypic (Antivirogram)
resistance tests were provided to help optimize new regimens. The primary
endpoint is progression of disease or death. Secondary endpoints include
changes in CD4, HIV RNA, and quality of life. All analyses are intent-to-treat,
using proportional hazard and longitudinal regression models adjusted for
baseline CD4 and HIV RNA.
Results: Baseline measurements for 274 patients were: mean CD4 = 180, log HIV RNA = 5.0, nadir CD4 =
69, prior progression of disease = 58%, prior number of antiretrovirals
= 10.6, number of drug-resistance mutations = 9.7, 3-class drug exposure = 97%,
mean number of drugs in initial new regimen = 3.7. Minimum follow-up is 24
months (maximum 48). During the STI,
55% of the STI arm lost at least
half of the mutations present at randomization; 26% lost all mutations. The
treatment arm differences in log HIV RNA favor the control arm by –1.2 (p < 0.0001) for the follow-up period of
0 to 4 months; there are no differences for follow-up periods 5 to 24 and after
24 months. The treatment arm differences in CD4 for the follow-up periods 0 to 4,
5 to 24, and after 24 months are 84.3 (p
< 0.0001), 47.0 (p = 0.0001), and
42.8 (p = 0.07), favoring the control
arm. In the STI arm, 54 patients
experienced 91 progression of disease or death events; in the control arm 47
patients had 71 events (adjusted hazard ratio for the time to first event = 1.27,
p = 0.27). There were 30 deaths in
the STI arm and 33 in the control
arm, of which 14 and 19 were first events. Considering only progression of
disease, 40 patients in the STI
arm and 28 patients in the control arm experienced at least 1 event (adjusted hazard
ratio = 1.58, p = 0.08). There are no
significant differences between the treatment arms in adherence, symptoms or quality
of life.
Conclusions: Final results of CPCRA 064, with median
follow-up of 36 months, show that STI
prior to changing treatment in patients failing therapy with multi-drug
resistant virus does not confer clinical, immunologic, virologic,
or quality of life benefits. STI is associated with a significantly unfavorable
CD4 response and a strong trend toward increased progression of disease that
persists well after treatment reinitiation.
Keywords: STI (structured treatment interruption); multi-drug resistant (MDR) HIV; treatment strategies (salvage therapy)
