Bridging the Gap: Conference Record [Abstract book, International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

52 Abstracts 12203-12207

12th World AIDS Conference

125*/112203 ACTG 364: Virologic efficacy of nelfinavir (NFV)
and/or efavirenz (EFV) in combination with new
nucleoside analogs in nucleoside experienced
subjects
Mary Albrecht', D. Katzenstein2, R.J. Bosch3, S.H. Liou3, S.M. Hammer1. 'Beth
Israel Deaconess Medical Center One Deaconess Rd. Boston, MA; 2Stanford
University Medical Center, Stanford, CA; 3SDAC Harvard School of Public
Health, Boston, MA; ACTG 364 Study Team National Inst. Allergy Infectious
Disease, Bethesda, MD, US
Background: ACTG 302/303 subjects derived from the initial rollover trials of the
ACTG 175 study group represent a well-defined population with long-term nucleoside analog experience in which the effect of adding NNRTIs and/or protease
inhibitors to new RTIs in combination can be evaluated.
Objectives: To determine proportion of subjects who achieve a plasma HIV
RNA concentration below the limit of detection (HIV RNA <500 copies/mL) at 16
weeks.
Design: Randomized, Phase II, partially double-blind trial for ACTG 302/303
subjects originally randomized to d4T monotherapy or new combination nucleoside regimens featuring selected RTI agents ddl, d4T, ddC, ZDV, and 3TC, who
remain on their assigned treatment at enrollment into ACTG 364.
Methods: A total of 196 subjects with screening HIV RNA >500 copies/mL
were randomized to 1 of 3 treatment arms. ARM I: NFV, EFV placebo, plus RTIs*;
ARM II: NFV placebo, EFV, plus RTIs'; ARM III: NFV, EFV, plus RTIs*. Subjects
were assigned open label RTI therapy featuring at least 1, and if possible, 2 new
RTIs: ddl + d4T, 3TC + d4T, or ddl + 3TC. Plasma viral load (Roche Amplicor
assay) and CD4 cell counts were obtained at baseline, weeks 2, 4, 8, 12 and 16.
Results: 195 subjects were evaluable. The study remains blinded and grouped
preliminary data are shown. Baseline characteristics: mean CD4 count and
median baseline plasma HIV RNA were 389 cells/mm3 and 5,386 copies/mL,
respectively. 181 subjects at week 16 demonstrated a mean CD4 increase of
80 cells/mm3. To date, 72% (125/173) subjects at week 16 achieved virologic
suppression below 500 copies/mL HIV RNA and 20% (35/173) subjects at week
16 experienced virologic failure defined as plasma HIV RNA > 2,000 copies/mL.
AIDS defining events: 1 subject diagnosed with lymphoma at week 3. The 3
treatment arms were well tolerated.
Conclusions: The addition of EFV and/or NFV to a regimen with 1 or 2 new
RTIs provided effective viral suppression at week 16 in the majority of subjects.
Longer term CD4 and HIV RNA responses and results by treatment arm will be
presented.
286*/12204 Combination abacavir (1592, ABC)/amprenavir
(141W94) therapy in HIV-1 infected antiretroviral
naive subjects with CD4+ counts >400 cells/plI
and viral load >5000 copies/ml
Pierre-Alexandre Bart1, G.P. Rizzardi2, S. Gallant2, P. Meylan3, W. Spreen4,
H. McDade5, U.K. Pantaleo2. 1Chuv-Lab AIDS Immunopathogenesis, Hopital
De Beaumont Lausanne; 2Chuv-Lab AIDS Immunopathogenesis Lausanne;
3Chuv-Microbiology Institute Lausanne, Switzerland; 4Glaxowellcome RTP,
USA; 5Glaxowellcome London, UK
Objectives: Abacavir (NRTI) and amprenavir (USAN - approved) (PI) are two
antiretroviral drugs with proven antiviral effect against HIV-1. This study investigates the activity (viral load and lymphocyte changes in peripheral blood and
lymph nodes) and safety of abacavir and amprenavir in combination.
Design: Open-labeled prospective trial.
Method: Forty HIV-1 infected subjects (viral load >5000 copies/ml, CD4+
>400 cells//l, antiretroviral naive) are being treated with abacavir (300 mg po
bid) and amprenavir (1200 mg po bid) for 72 weeks. Virological and immunological
measures are assessed in both blood and lymph nodes (LN).
Results:
Table 1. Cumulative results out to 24 weeks of therapy
Week 0 2 4 8 12 16 20 24
No. subjects evaluated 35 35 28 21 18 15 14 11
% HIV-1-RNA <500 c/ml 0 57 79 90 89 93 93 100
Mean HIV-1 RNA logio c/ml 4.43 2.84 2.8 2.93 2.79 2.8 2.8 <2.7
Mean CD4+ cells//ll 747 732 712 709 801 863 847 934
Mean CD8+ cells/dl 1258 1216 1133 1126 1078 981 991 870
Mean LN %CD4+ T cells 36.75 - - - - - - 57.84
Mean LN %CD8+ T cells 29.56 - - - - - - 15.26
Week 20 and 24 plasma viremia detected with a boosted Amplicor Roche
assay (limit of detection: 5 copies/ml) was negative in 3 of 11 patients, < 5
copies/ml in 6 of 11, and < 50 copies/mi in 9 of 11 patients. Comparing the
percentages of LN CD4~ and CD8+ T cells of HIV-infected subjects to those
found in 8 HIV-negative individuals (56.1% and 12.5%, respectively), differences
were observed at baseline, whereas comparable values were measured after 24
weeks of therapy, indicating a normalization of the LN CD4/CD8 ratio. Adverse

experiences have included nausea, diarrhea, epigastric pain, and headache and
five subjects experienced a rash. Two subjects discontinued therapy due to rash.
Conclusion: Abacavir/amprenavir therapy is well tolerated, effectively suppresses HIV-1 replication, induce a normalization of the CD4/CD8 ratio in the
peripheral blood, and restores CD4' T cells in LN.

288* 12205 1 Salvage of multi-drug resistant HIV infection with
D4T/3TC/hydroxyurea
Steven Miles1, R.E. Winters2, P. Ruane3. 1 UCLA Care Center, Rm BH12C CHS
Los Angeles, CA 90095-1793; 2BI-Deaconess Hospital, Boston MA; 2Santa
Monica CA; 3Towerid, Los Angeles CA, USA
Objectives: To determine the safety, tolerance and efficacy of D4T/3TC/hydroxyurea in patients with multi-drug resistant HIV infection.
Design: Open label study in patients with no other treatment options.
Methods: Seventeen patients with advanced HIV, clinical and genotypic resistance to D4T/3TC received at least 4 weeks of D4T (0.5 mg/kg BID), 3TC (150
mg BID), and Hydroxyurea (500 mg BID). No protease inhibitors or NNRTIs were
used. CBC, CD4 counts, HIV RNA, adverse events, and weight were analyzed
for safety/tolerance.
Results: An interim analysis of 17 of 20 treated patients who received at least 8
weeks of therapy was performed. All had received numerous previous treatment
regimens, had >20,000 copies/ml of HIV RNA while on a prior D4T/3TC regimen,
and 184V mutations. Most had mutations at 75 as well as multiple mutations in
the protease gene. The median number of prior regimens was 6, CD4 was 43/p I,
and HIV RNA was 397081 (5.6 logio). The median peak decline in viral RNA
was 1.7 loglo 4 wks. The median weight gain was 4.3 kg. Durable responses
of >6 months, severe cytopenias and epistaxis (n = 3) were observed. Mean
duration on drugs with >0.7 log drop is 13 weeks One patient, who had previously
received hydroxyurea for >3 months, failed to respond initially. Two patients have
subsequently failed at 24 and 44 weeks.
Conclusion: D4T/3TC/Hydroxyurea is a surprisingly potent antiretroviral regimen even in patients resistant to other D4T/3TC containing regimens. The
mechanism of response is unknown. D4T/3TC/Hydroxyurea provides an option
for patients with multi-drug resistant HIV infection
1 12206 Relationship between delavirdine (DLV) plasma levels,
HIV RNA responses and DLV resistance during
combination therapy with zidovudine (ZDV), and
didanosine (ddl)
Brigette Griffit', G. Morse2, L. Demeter3, R. Bassett4, M. Hughes4,
G. Friedland'. ACTG 261 Protocol Team; 1 Yale University School of Medicine
New Haven CT 06510; 2State University of New York Buffalo NY; 3University of
Rochester Rochester NY; 4SDAC Harvard School of Public Health Boston MA,
USA
Objectives: To define the relationship between DLV plasma levels and HIV RNA
responses and DLV resistance in patients enrolled in AIDS Clinical Trials Group
(ACTG) 261, a phase II randomized, double-blinded trial of DLV in combination
with ZDV and/or ddl versus ZDV and ddl.
Design: A substudy was conducted to examine DLV trough concentrations at
weeks 2, 4 and 8 of therapy, HIV RNA changes from baseline at weeks 4, 12, 24
and 48 and the development of DLV resistance by week 8 of therapy.
Methods: DLV trough concentrations were measured by high-performance liquid chromatography. HIV RNA levels were determined using the Amplicor Monitor
Test. Phenotypic susceptibilities were evaluated using the ACTG/DoD consensus
assay. Resistance to DLV was defined as an IC50 >1 / M.
Results: A summary of DLV levels and short term (weeks 4-12) HIV RNA
changes is listed below:

Treatment group N HIV RNA mean change
from baseline (log 10)

Median DLV trough (p M) at week

DLV/ZDV/ddl 43 -1.27 9.3 11.2 10.6
DLV/ZDV 34 -0.71 6.5 8.6 6.4
DLV/ddl 43 -0.85 7.2 7.8 7.9
In addition, there was no significant difference in DLV levels between HIV RNA
responders (with HIV RNA decrease >0.5 log 10) and non-responders. By week
8, 21/63 patients showed DLV phenotypic resistance. Mean DLV levels were
similar in patients with and without DLV resistance.
Conclusions: In this preliminary analysis, DLV levels early during the course
of DLV therapy predicted neither HIV RNA load reductions nor the development
of DLV resistance.
S12207 1 Phase II study of ritonavir-nelfinavir combination
therapy: An update
Joel Gallant', M. Health - Chiozzi2, R. Anderson3, C. Fields2, C. Flexner'.
'Johns Hopkins Univ. School Of Medicine 600 N. Wolfe St. Cam. 292 Baltimore
MD. 21287; 2Abbott Laboratories Chicago IL; 3Agouron Pharmaceuticals LA
Jolla CA, USA
Objectives: To evaluate safety, tolerability, and anti-HIV activity of ritonavir/nelfinavir (RTV/NFV).
Design: Single-site, open-label, multiple-dose, dose-comparison trial of
RTV/NFV in protease-inhibitor (PI) naive, HIV-infected patients.
Methods: Median baseline viral load was 32,459 (range 4,118->750,000);
median baseline CD4 count 325 cells/mm3 (range 23-941). All received RTV at
a dose of 400 mg q12h. Cohorts I (N = 10) and II (N = 10) received NFV at a
dose of 500 mg and 750 mg q12h, respectively.
Results: RTV/NFV was well-tolerated except for moderate or severe diarrhea
(4 in Cohort I, 5 in Cohort II) and moderate to severe nausea (3 in Cohort I, 1 in