Abstract Book Vol. 2 [International Conference on AIDS (14th: 2002: Barcelona, Spain)]

378 Abstracts ThOrB1389-ThOrB1438

XIV International AIDS Conference

ThOrB1 3891 Long-term clinical efficacy of resistance testing:
results of the CERT trial
S.A. Wegner1, M. Wallace1, N. Aronson1, D. Blazes', C. Tammingal,
S. Fraser1, M. Dolan1, K. Stephan1, L. Jagodzinski2, M. Vahey2, L. Tracy1,
N. Graham3, K. Hertogs4, D. Birx1. 'US Military HIV Research Program, 1600
East Gude Drive, Rockville, MD, 20850, United States; 2Henry M. Jackson
Foundation, Rockville, MD, United States; 3Tibotec-Virco, Mechelen, Belgium;
4Tibotec-Virco, Mechelen, United States
Background: Previous short-term studies have shown the benefit of HIV resistance testing for antiretroviral(ARV) management. The impact of resistance testing on long-term clinical outcome has not been assessed. We studied the longterm efficacy of either genotype or phenotype to guide therapy changes in a large
cohort of HIV-1 infected US Department of Defense beneficiaries.
Methods: 450 HIV-1-infected subjects on 3 or more ARV drugs, including at least
one NNRTI or PI, were enrolled in a long-term study to assess the efficacy of resistance testing. Subjects were randomized to genotype (G), Phenotype (P) and
viral burden (VB) arms. Resistance results were available in the G and P arms
at time of virologic failure(VF). VF was defined as either a rise in plasma viral
load (VL) to > 3 logs in a subject with previously undetectable viral load, or a failure to suppress VL to < 3 logs by 16 weeks. Study endpoint was reached when
a subject had persistent VF despite a change in therapy. Subjects remained on
study if therapy changes resulted in resolution of VE The primary analysis was
the difference in time to endpoint between the arms.
Results: There were no differences in age, CD4 count, viral burden, number of
previous antiretroviral drugs, or number of previous NNRTI between study arms
at baseline. At baseline, there were 299, 69, and 82 subjects in CDC stages A,
B, and C respectively. Median time of follow-up was 525 days. Median times to
endpoint were 478 days, 521 days and 574 days for the VB, P, and G arms, respectively A Kaplan-Meyer analysis of time to endpoint stratifying by study arm
and CDC stage revealed a delayed time to study endpoint for the G and P arms
compared with the VB arm (Log rank p=.00035) at 600 days of follow-up. There
was no difference between G and P arms.
Conclusion: When employed as part of routine clinical HIV care, resistance testing appears to delay the time to virologic failure compared with empiric selection
of drug regimens.
Presenting author: Scott Wegner, 1600 East Gude Drive, Rockville, MD, 20850,
United States, Tel.: [phone], Fax: [phone], E-mail: swegner
@hivresearch.org
ThOrB13901 Expanded response analyses of tenofovir DF
Therapy by Baseline Resistance Genotype and
Phenotype
N.A. Margot, A.K. Cheng, B. Lu, M.D. Miller. Gilead Sciences, Foster City United
States
Background: Studies 902 and 907 were placebo-controlled studies evaluating
tenofovir DF (TDF) when added to stable regimens in patients (pts) with incomplete HIV RNA suppression. At wk 24, the placebo (PLB) arms crossed over to
TDF 300 mg.
Methods: In virology substudies, baseline (BL) plasma HIV genotypes (n=332)
and phenotypes (n=138, Antivirogram) from pts randomized to PLB or TDF 300
mg were obtained. Analyses were expanded to include wk24 plasma samples as
BL for PLB cross-over (PLB CO) pts (n=103).
Results: TDF therapy resulted in significant mean HIV RNA reductions from BL
to wk24 (-0.59 log) that were notably durable through wk48 (-0.56 log). At wk24,
significant HIV RNA reductions relative to PLB (p<0.001) were observed for pts
without TAMs (-0.80 log, n=97) or with 1-2 TAMs (-0.66 log, n=88). For >3 TAMs
with M41L or L210OW, responses were diminished (-0.21 log, n=86) but superior
to PLB (p=0.013); pts with >3 TAMs without M41L or L210W had -0.67 log responses (n=61, p<0.001). From wk 24-48, the PLB CO pts had an HIV RNA
decrease of -0.65 log. The PLB CO pts confirmed the genotypic response patterns observed from TDF pts. Of note, PLB CO pts with L74V or Q151M had
responses of -0.59 log (n=15) and -0.86 log (n=2). Combined phenotypes from
BL (TDF) or wk24 (PLB CO) showed mean reduced susceptibility of 1.8-fold for
TDF (n=204, range 0.1-11). 24 wk response for pts with <1 (n=79), 1-2 (n=66),
2-3 (n=27) and 3-4 (n=13) fold changes in TDF susceptibility were -0.84, -0.61,
-0.58 and -0.40 logs.
Pts with >4-fold reductions in TDF susceptibility (n=19, 9%) showed diminished
responses of -0.22 log. Recursive partitioning analysis confirmed a 4-fold cut-off
for response to TDF therapy.
Conclusions: Adding tenofovir DF once-daily to an existing regimen showed significant and durable HIV RNA reductions. Reduced responses to TDF treatment
were associated with multiple TAM patterns inclusive of M41L or L210W, or >4 -fold reduced susceptibility to TDF.
Presenting author: Michael Miller, Gilead Sciences, 333 Lakeside Drive, Fos
ter City, CA, 94404, United States, Tel.: [phone], Fax: [phone],
E-mail: [email protected]

ThOrB1437 Structured Treatment Interruptions (STI) in patients
receiving HAART within 90 days after onset of
Primary HIV-1 Infection (PHI) symptoms:
spontaneous control of viremia in only one third of
cases after four cycles off therapy
J.M. Mirol, M. Plana1, F Garcia', G.M. Ortiz2, M.J. Maleno1, M. Arnedo1,
A. Del Rio1, X. Claramonte1, A. Garcia1, J. Joseph', T Pumarola1, D. Nixon2,
T Gallart1, J.M. Gatell1. 'H. Clinic - Idibaps, Infectious Diseases Service,
Hospital Clinic - Idibaps, Villarroel, 170, 08036-Barcelona, Spain; 2Gladstone
Institute for Virology and Immunology, UCSF, San Francisco, United States
Bakground: To analyze if four cycles of STI can restore HIV-1 specific T-cell responses (CD4+ and CTL) and control HIV-1 replication in patients who started
HAART within 90 days after onset of PHI symptoms.
Methods: 12 consecutive patients with sustained viral suppression (<20
copies/mL) and a CD4+/CD8+ ratio >1 after d4T, 3TC& indinavir for at least 1
year since PHI were included in an STI program (4 cycles of 2 months off therapy
and 2-4 months on HAART).
Results: 8 patients were homosexual men. Median age was 34 years.
Median (range) plasma viral load (PVL) at PHI was 134,500 copies/mL
(3,215-+ 1,000,000). After a median (range) of 23 months (12-45) of HAART, all
but one patient had plasma and tonsil tissue VL <5 copies/mL or <40 copies/mg
respectively. Median (range) CD4+T cell count = 927 (613-1,648) cells/mm3. Median (range) TREC CD4+/10(6) T cells = 978 (249-2880). None of 12 patients
had HIV-1-specific CD4+ (LPR) T-cell responses before first stop. The number of
patients who completed the 1st, 2nd, 3rd and 4th cycles = 12, 12, 12 and 6 cases,
respectively. During the 1st, 2nd, 3rd and 4th period off therapy, mean (SD) PVL
rebound = 4.89 (0.7), 3.89 (1), 4.04 (1.6) & 3.48 (1.8) logl0/mL and PVL rebound
remained <3,000 copies/mL in 0/12, 4/12, 4/12 & 2/6 cases, respectively. There
was no correlation between the level of TRECs and the type of virological response. HIV-1 specific CD4+ LPR responses were detected in 5/12, 6/12, 7/12
and 2/6 cases during each period off therapy, respectively. A weak CTL response
(ELISPOT) was detected at baseline in 6 out of 12 patients. The magnitude of the
CTL response increased after each cycle off therapy. No genotypic resistance to
antiretrovirals was found.
Conclusions: HIV-1 specific T-cell responses can be restored using STI in patients receiving HAART within 90 days after PHI. However, a spontaneous control
of viremia (<3,000 copies/mL) was found in only one third of cases.
Presenting author: Jose M. Miro, Infectious Diseases Service, Hospital Clinic
- Idibaps, Villarroel, 170, 08036-Barcelona, Spain, Tel.: [phone], Fax:
[phone], E-mail: [email protected]
ThOrB14381 Immunologic and virologic factors at baseline may
predict response to structured therapy interruption
in early stage chronic HIV-1 infection
F. Garcia1, M. Plana2, G. Mestre3, C. Gil3, A. Cruceta3, J.1. Arostegui3,
M. Arnedo3, J.M. Miro3, J. Joseph3, T. Pumarola3, T. Gallart3, J.M. Gatell3.
Infectious Diseases Unit HospitalClinic, Infectious Diseases Unit, Villarroel,
170, Spain; 21mmunology laboratory Hospital Clinic, Barcelona, Spain; 3Hospital
Clinic, Barcelona, Spain
Background: To analyze immunologic and virologic predictors of response to STI
in 3 Spanish pilots studies in CHI patients in early stage.
Methods: 44 chronic HIV-1-infected patients were treated with diverse regimens
of STI. Plasma and tonsillar tissue VL, lymphocyte immunophenotyping and LPR
to mitogens, and specific antigens and HIV-1 specific CTL responses were assessed at baseline. Response was defined as a VL set-point after 6 months off
ART after the last interruption < 5,000 copies/ml and 0.5 log10 < BVL before any
ART and presence of specific CTL and helper response against HIV-1 antigens.
Results: After STI, patients (n=44) were classified as follow: 18 (41%) had a
response, and 26 (59%) no response. In the univariate analysis patients who responded had a significantly lower level of CD4+CD38+ and CD4+ naive T cells
and a higher level of memory CD4+ T cells and proliferative response to tetanus
toxoid (TT) and p24 HIV-1 Ag than non-responder patients. A model incorporating
5 qualitative variables transformed according to the median value (CD4+CD38+,
CD4+ naive and memory T cells and stimulation index to TT and to p24 HIV-1 Ag)
at baseline can classify correctly a 97% of patients (p= 0.0001). Tonsillar tissue
VL, CD8+ T cell subsets, proliferative response to mitogens or CTL responses at
baseline were not predictors of progression.
Conclusions: A high baseline level of memory CD4+ T cells and the presence of
a proliferative response to recall antigens above the median may predict a good
response to STI, suggesting that preserved memory response in CD4+ could be
the most important factor to obtain response after STI.
Presenting author: Felipe Garcia, Infectious Diseases Unit, Villarroel, 170,
Spain, Tel.: [phone], Fax: [phone], E-mail: fgarcia@medicina.
ub.es