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

12th World AIDS Conference

Abstracts 12338-12342 81

12338_ Virological and immunological effectiveness of protease
inhibitor therapy in protease inhibitor-experienced
patients
Ma Jesus Perez-Elias, J.L. Casado, A. Antella, F. Dronda, J. Blazquez,
V. Muhoz, P. Marti-Belda. Hospital Ramon & Cajal, Carretera de Colmenar SN
KM 9, Madrid 28029, Spain
Background: Limited effectiveness has been reported with the use of protease
inhibitor (PI) therapy in PI-experienced patients. The aim of this study was to
assess the virological effectiveness and factors associated to response in patients
receiving a second PI.
Methods: We prospectively studied 190 HIV-infected patients in whom PI therapy was switched due to toxicity/intolerance in 48.4%, and to treatment failure in
43%, from March '96 to March '97. Virological and immunological responses were
defined as HIV RNA decrease of 1 log or below undetectable limits and a CD4+
count increase greater than 100 cell/t L, after 3 months on second PI therapy.
Results: Mean age was 35 years, and 58% were IDUs as risk factor for HIV
infection. PI received as second option was saquinavir in 13% of cases, ritonavir
in 5%, indinavir in 65%, and ritonavir plus saquinavir in 17% of patients. Prior
mean time of PI therapy was 178 days. Median CD4+ count was 121//1, and HIV
RNA level was 4.5 loglo, at the time of change. At the 3rd month, 39% and 70%
of patients reached virological and immunological response, respectively. In a
logistic regression analysis, a higher baseline HIV RNA level (RR 2.17, p = 0.002),
and use of saquinavir (RR 8.86; p = 0.001) were statistically associated with lack
of maximum response to treatment. Also there was a trend to poorer response
in patients with a longer exposure to previous PI. (RR: 1.004 per each day of
therapy; p = 0.07). By contrast, immunological response was more frequently
achieved in patients with higher CD4+ cell count at entry.
Conclusions: In PI-experienced patients, optimal response to a new PI therapy
is achieved when switching is made as soon as possible, with the lowest viral
load, and using the most potent agents.
12339 In vitro antiviral activity and pharmacokinetic (PK)
profiles of KNI 272 when combined with other protease
inhibitors (PIs)
Hideharu Sato1, M.S. Shintani2, T.M. Mimoto2, K.T. Terashima2, H.H. Hayashi2,
H.M. Mitsuya3. 1 10-1 Toranomon 2-Chome, Minato-Ku, Tokyo 105-8407; 2Japan
Energy Corporation, Tokyo; 3Kumamoto Univ. Kumamoto, Japan
Background: To examine the potential of an HIV protease inhibitor (PI), KNI-272,
for therapy of HIV-1 infection when combined with other PIs.
Method: Cross resistance between PIs was examined using various drug resistant HIV-1 strains generated in vitro. Antiviral activity of KNI 272 combined other
Pis was analyzed in vitro using the method of Prichard and Shipman (Antiretroviral
Research 14:181, 1990). For PK studies, Pis combined were orally administered
to male rats and plasma concentrations of each PI were determined to evaluate
drug interactions.
Results: 1) Cross resistance: KNI-272-resistant virus induced in vitro (with
47-fold higher IC50 to KNI-272 compared to wild type HIV-1) was sensitive to
saquinavir, indinavir, and nelfinavir (<5-fold) but resistant to ritonavir (7-fold).
KNI-272 remained active against indinavir-resistant clinical isolates (<3-fold). 2)
Combination effects: synergism was observed when KNI-272 was combined with
saquinavir, ritonavir, indinavir, nelfinavir or 141W94. 3) Improved PK profiles:
combination of KNI-272 with ritonavir and indinavir remarkably improved the PK
of KNI-272 (fold-increases of AUC: 11 and 22, respectively). Co-administration
of KNI-272 + nelfinavir or KNI-272 + delavirdine also improved PK profiles of
KNI-272 (e.g., more than 0.1 /M KNI-272 was sustained for >12 hr).
Conclusions: These results suggest possible advantages of combination of
KNI-272 + indinavir and KNI-272 + nelfinavir, i.e., low levels of cross resistance
and PK improvements. The combination of KNI-272 and delavirdine may also
have advantage.
12340 Experiences in protease inhibitor use in patients heavily
pretreated with reverse transcriptase inhibitors
Heinz-August Horst1.2, C.H. Hoffman2. I Chemnitzstr. 33 2nd Dept. Int. Medicine,
Univ. of Kiel, D-24116 Kiel; 2Privatdozent Dr. Med. D-24116 Kiel, Germany
Objective: To evaluate the efficacy of a three drug antiretroviral therapy (ART)
including saquinavir and the efficacy of subsequent protease inhibitor (PI) containing regimens in reverse transcriptase inhibitor (RTI) experienced patients.
Design/Methods: Retrospective analysis of 29 (28 males) HIV-1-infected and
RTI experienced patients who were treated with three- and four-drug combination
regimens including saquinavir, nelfinavir or indinavir. Antiviral efficacy was determined by measuring viral load (PCR; Roche Amplicor). Response was defined
as a drop from base line levels by at least 2 log10 and/or a drop below detection
(400 RNA copies/ml).
12342: Table

Results: All patients had been pretreated with RTI two-drug combinations. The
median duration of pretreatment was 17 months. Patients were switched to the
first three-drug combinations containing two RTIs + saquinavir according to the
recommendations by Carpenter et al. (JAMA 1996; 276: 146-154). The median
viral load before switch of ART was 94 000 RNA copies/ml. Viral load dropped by
more than 2 log10 in 8/29 patients, and below detection in 7/29 patients.Those
patients who showed a significant increase in viral load (>0.5 log) or a sustained
high viral load (>10 000 copies/ml) while being treated with a saquinavir based
regimen were switched to a four-drug regimen (2 RTI + saquinavir and nelfinavir)
or to a second three-drug regimen (2 RTI + nelfinavir or indinavir). One of 4
patients receiving 4 drugs had a reduction of the viral load by more than 2 log10
and reached a viral load below detection. None of 6 patients receiving 2 RTI +
nelfinavir but 3 of 4 patients receiving 2 RTI + indinavir had a reduction of the
viral load by more than 2 log10 and the viral load dropped below detection.
Conclusion: The data of this cohort indicate that saquinavir containing ART in
heavily pretreated HIV-patients is accompanied by a high failure rate. The switch
to a second PI containing regimen is worthwhile in patients who failed to respond
to the first three-drug therapy. The data further suggest that the antiretroviral efficacy of nelfinavir-, nelfinavir/saquinavir, and indinavir containing regimens may
be different although no major overlapping genotypic resistance with saquinavir
should be expected if ART is switched immediately after drug failure becomes
obvious.
S12341 Follow-up of antigen-specific CD4 cell function in HAART
patients
Valerio Del Bono1, D. Fenoglio2, E. Pontali1, M.P. Terranova2, E. Donelli1,
F. Manca2, D. Bassetti1. 1Dept. INF DIS. S. Martino Hosp, Univ Genoa, Largo
R. Benzi, 10-16132 Genoa; 2Dept. IMMUNOL. S. Martino Hosp, Univ. Genoa.
Genoa, IT Italy
Objective: to determine changes of in vitro antigen specific CD4 cell function in
HAART patients
Design: 6 months follow-up of patients
Methods: 14 patients, 11 males and 3 females (mean age 38 ~ 5 years), were
randomly selected for this study based on their informed consent. Blood samples
were obtained at time 0 (pre-HAART) and after 1, 3, 6 months of treatment. 10
pts could be evaluated after 6 months. 6 pts were CDC stage B3, 1 A3, 1 C3, 1
A2, 1 B2. CD4 counts were performed by standard flow-cytometry.
VL was determined with the Organon method. Proliferative responses were
measured on Ficoll separated peripheral blood lymphocytes from heparinized
blood. Cultures in microtiter plates (2 x 104 cells per well in RPMI 1640 containing 5% AB serum) were incubated for four days, pulsed and harvested 24 hrs
later. The recall antigens were PPD and C.albicans. Increased or decreased CD4
counts >30% of basal level and VL changes of 1 log were considered significant.
Proliferation assays with a stimulation index >2 were considered positive.
Results: increased CD4 counts were observed in 7 pts, and no changes in
3. VL decreased in 6 pts, while it increased in 4. After 6 months proliferative
responses were higher to PPD in 8 pts and to C. albicans in 6 pts. The recovery
in proliferative response was not yet evident after 1 and 3 months.
Conclusion: these data confirm that HAART is effective in recovery of CD4
counts. Nevertheless, the functional recovery is evident only in a fraction of pts
after 6 months of therapy. This also suggests that a quantitative CD4 restoration
does not imply a full functional restoration.
12342 Viral load reduction after changing from nelfinavir- to
indinavir-containing regimens and associated resistance
mutations
John T. Brooks, Martha Vander Vliet, Paul E. Sax. Brigham and Women's
Hospital, Harvard Medical School, 75 Francis St., Boston MA, 02115, USA
Objective: To describe the effect of changing from nelfinavir (NFV)- to indinavir
(IDV)-containing regimens and the associated mutations in HIV protease and
reverse transcriptase.
Method: Cases were selected from trials of NFV combined with reverse transcriptase inhibitors (RTI's) in protease inhibitor (PI) naive patients; selection
occurred after study completion and unblinding. Inclusion required demonstrating
a reduced vital load (VL) while taking NFV-containing regimens, followed by loss
of viral suppression and change to IDV-containing regimens. Exclusion criteria
included noncompliance, intercurrent illness, or use of concomitant medications
known or expected to alter PI metabolism. HIV protease and reverse transcriptase
mutations were determined using standard methods.
Results (table): Four patients met enrollment criteria. Prior to NFV treatment
CD4 counts ranged 89-364 cells/mm3 (7-21%) and VL's ranged 9,874-205,400
copies/mI. Length of NFV treatment averaged 7.7 months and was associated
with a mean -1.47 log A in VL. After loss of viral suppression, switching to
regimens containing IDV was associated with a mean -1.80 log A in VL. Three

Case Prior RTIs used NFV + RTI CD4 count before NFV Mos. on NFV Max. log A Max. log A vload IDV + RTI Mos. on IDV Max. log A CD4 count currently Current vload
@ IDV start

1
2
3
4
Mean

AZT, ddl
AZT, 3TC, ddl
AZT, d4T, 3TC, ddl
AZT, 3TC

d4T
d4T
AZT, ddl
AZT, 3TC

364 (21%)
167 (7%)
89 (7%)
134 (7%)
188 (10%)

7.2
16.3
2.3
5.0
7.7

-1.80
-2.30
0.92
0.85
-1.47

16.140
26.010
104,800
21,840
42,198

d4T, 3TC
AZT, 3TC, NVP
d4T, 3TC
d4T, 3TC

6.9 -1.51
4.4 -1.72
14.1 -2.32
9.0 -1.64
8.7 -1.80

443 (25%)
417(23%)
309 (11%)
227 (11%)
349 (18%)

- 500
S500
500
827