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

76 Abstracts 12314-12318

12th World AIDS Conference

from peripheral blood mononuclear cells (PBMC), quantitative DNA PCR (using an in house, competitive PCR assay) and SI/NSI-phenotyping from the
culture supernatant were performed at baseline, week 9 and week 57 of treatment.
Results: Sixty-four patients were included in this protocol. At baseline, the
median CD4 count was 80/i1, HIV-RNA was 5.2 loglo and HIV-DNA load was
3.3 logio copies/106 PBMC. All patients had positive HIV-cultures at baseline
and an SI phenotype was found in 36 of 64 patients. Fifty-six patients were
followed for more than 9 weeks. At week 9, HIV-cultures were negative in 29
percent of patients and no significant changes of SI/NSI-phenotypes occurred.
The HIV-DNA load dropped by 0.35 loglo copies per ml (p < 0.001 in a pairwise
analysis). The treatment response both in RNA and DNA was not affected by the
SI/NSI-phenotype of the circulating virus.
Conclusion: These data indicate that this potent antiretroviral treatment with
saquinavir plus ritonavir plus d4T in protease naive patients has a significant
effect on the cellular proviral load in PBMC. The presence of SI phenotype at
baseline does not influence the therapeutic result in this study. Follow-up data up
to one year will be presented.
S12314 Potent and convenient FortovaseTM (SQV) SGC BID
regimens in combination with 2 nucleosides or nelfinavir
(NFV) plus 1 nucleoside in HIV-1 infected patients
Calvin Cohen', P. Siemon-Hryczk2, R. Pilson2, B. Holzknecht2, K. Phillips2,
C. Karol2, S. Palleja2. 'Community Research Initiative 320 Washington ST
Brookline MA 02146; 2Roche Laboratories Inc., Nutley NJ, USA
Background: Fortovase'" (Saquinavir) Soft Gel Capsules has been shown to be
a potent protease inhibitor in single and double PI combination regimens. This
study compares the antiviral activity and safety of Fortovase"T (FTV) TID + 2
nucleoside analogs (NAs) to that of FTV BID + 2 NAs or FTV BID+NFV BID + 1
NA in NA naive and experienced HIV-1 infected patients.
Methods: 825 HIV-1 infected patients (antiretroviral nalve and NA experienced)
with >5000 copies/mL HIV-RNA will be randomized to receive FTV 1200 mg TID
(Group A), or FTV 1600 mg BID (Group B), each in combination with 2 new NAs
of choice or FTV 1200 mg BID+NFV 1250 mg BID (Group C) + 1 new NA of
choice. Study duration is 48 weeks with the option to intensify treatment at week
16.
Results: 231 patients have been enrolled to date. At baseline, mean viral load
was 4.7 loglo copies/mL for each of the Groups A (n = 79), B (n = 77) and C (n
= 80), and mean CD4 cell count was 302, 357 and 325 cells/mm3, respectively.
120 patients completed week 8 and are ongoing. The preliminary results are as
follows:
Group n % Patients below Mean Change from Baseline at Week 8
400 copies/mL HIV-RVA loglo c/mL CD4 cell/mm3
A- FTV TID 41 62 -2.2 +114
B - FTV BID 38 65 -2.2 +89
C - FTV + NFV BID 41 51 -1.9 +117
Treatments have been generally well tolerated, the most frequently reported
adverse events in all three arms associated with study drug have been gastrointestinal.
Conclusions: The BID regimens containing FTV or FTV+NFV provide potent
HIV suppression, tolerability and convenient dosing. Patients are continuing to
enroll and will be followed for 48 weeks on study therapy. Week 16 data, including
a subanalysis of the antiretroviral naive and NA experienced patient populations
will be presented.
12315 Synergistic anti-HIV activity of ritonavir and other
protease inhibitors in the presence of human serum
Akhteruzzaman Molla, T. Chernyavskiy, S. Vasavanonda, J. Praestgaard, T. Lin,
E. Sun, W. Kohlbrenner, D. Kempf. 200 Abbott Park Road Dept. 47D Bldg. AP
52-N Abbott Park IL 60064, USA
The use of combinations of protease inhibitors for the treatment of HIV infection
is under wide investigation as a means of devising highly suppressive/potent
therapeutic regimens that are also convenient and well tolerated. In particular,
the ability of ritonavir to enhance and sustain the plasma levels of other protease
inhibitors produces combinations of high in vivo potency as determined by the
durable antiviral effect in patients receiving ritonavir plus saquinavir. A recent
report has suggested, however, that the in vitro combination of two protease
inhibitors, indinavir and saquinavir, is antagonistic. In order to examine the in
vitro relationship of protease inhibitors under conditions that closely mimic human plasma, we studied the activity of ritonavir in combination with saquinavir,
indinavir, nelfinavir and amprenavir against wild-type HIV in the presence of 50%
human serum, which extensively binds many protease inhibitors. Data were analyzed for combination indices by the method of Chou. For each combination, the
combination index was less than one for nearly the entire spectrum of inhibition,

indicating an additive or synergistic interaction. Further statistical analysis of the
interaction of ritonavir and saquinavir using a parametric bootstrap percentile
confidence interval approach for the combination index confirmed a statistically
significant synergistic relationship between the two drugs.
Our results suggest that the in vivo combination of ritonavir with other protease
inhibitors is virologically synergistic. Combined with the pronounced pharmacokinetic enhancement produced by ritonavir in combination, these results provide

additional rationale for the clinical investigations of dual protease inhibitor therapy
with ritonavir.
12316 Efficacy and drug levels of ritonavir/saquinavir
combination salvage therapy
Gerd Fitkenheuer', N. Hunn1, A. JOtte', R. Hoetelmans2, C. Franzen',
B. Sallberger1. 'Klinik Fur Innere Medizin Univ Kiln, Kiln, Germany; 2Dept. of
Pharmacy Slotervhart Hospital, Amsterdam, Netherlands
Objectives: To examine the virological and clinical outcome of ritonavir (RTV)
and saquinavir (SQV) combination therapy in extensively pretreated HIV infected
patients; to correlate plasma levels of RTV and SQV with outcome.
Methods: HIV positive patients were included in this prospective study if they
had experienced virological treatment failure with standard triple therapy and
gave their informed consent. In addition to RTV (400 mg bid) and SQV (600 mg
bid), at least one inhibitor of reverse transcriptase (RTI) was prescribed. Plasma
levels of RTV and SQV were assessed in monthy intervals 4 hours post-dosing.
Virological efficacy was defined as a decline of HIV-RNA of 11log10 copies/mL or
more from baseline.
Results: Thirty patients pretreated with 4 to 9 antiretroviral drugs (11 CDC stage
B, 19 stage C) were included. Baseline characteristics were (median (range)): age
42y (25-60); CD4 180/tLL (16-510), HIV-RNA 4.99 log10 copies/mL (2.56-6.27).
Twelve patients received 1 RTI, 16pts. 2 RTI, 1 pt 3RTI, and 1 pt. 4RTI in addition
to RTV/SQV. Virological efficacy was demonstrated in 9 out of 23 evaluable patients (39%), and 5/23 (22%) pts. had HIV-RNA <200 copies/mL at week 8. CD4
cells (mean (~ SD)) were increased by 43 ~ 41/pL in patients with virological
success versus 19 ~ 26/p/L in patients without success (p = 0.2). No patient had
clinical progression. Plasma levels at week 8 were 2127 ~ 2186 ng/mL for SQV
and 6.55 ~ 4.73 /ig/mL for RTV and did not differ in patients with or without
virological efficacy at week 8 (x2-test). Hyperlipidemia (n = 18; 60%), gastrointestinal disturbances (n = 15; 50%), increase of liver enzymes (n = 18; 60%), and
paraesthesia (n = 6; 20%) were major side effects. Four patients discontinued
therapy at w8 due to side effects.
Conclusion: Therapy with RTV/SQV in heavily pretreated patients showed
favourable virological outcome in 39%. Although side effects of this combination
were common, only 4pts. (13%) discontinued therapy at week 8. Plasma levels
of RTV and SQV were not correlated with virological response.
| 123177 Disease progression and survival on triple therapy:
Indinavir, ritonavir or saquinavir combined with 3TC and
AZT
Matthias Egger', A. Telenti2, M. Wirz3, M. Battegay4. Department of Social
Medicine, University of Bristol, Bristol BS8 2PR, UK; 2University of Lausanne,
Lausanne; 3University of Berne, Berne; 4University of Basle, Basle, Switzerland
Objective: To compare progression to AIDS and death among patients treated
with indinavir (IDR), ritonavir (RIT) or saquinavir (SQR, hard capsules) in combination with the same two nucleoside analogues.
Patients and Methods: 674 Swiss HIV Cohort Study participants who started
treatment with IDR, RIT or SQR combined with zidovudine (AZT) and lamivudine
(3TC) in 1996 and 1997. Cox proportional hazards regression was used to examine the rate of new AIDS events and death. Time zero (baseline) was defined as
the date of starting triple therapy. The analysis was according to intention to treat
and adjusted for baseline log viral load, log CD4 cell count and clinical stage.
Results: 399 (59%) patients received IDR, 221 (33%) RIT and 54 (8%) SQR.
There were no statistically significant baseline differences. In IDR, RIT and SQR
groups 107 (27%), 55 (25%) and 20 (37%) were in clinical stage C (p = 0.20).
Mean log viral load was 4.42, 4.49 and 4.33 copies/ml (p = 0.51), respectively.
Median CD4 count was 201, 159 and 112 cells/tl (p = 0.11). Adjusted hazard
ratios (95% confidence interval)
Events IDR + AZT + 3TC RIT + AZT + 3TC SQR + AZT + 3TC
AIDS 29 1.0 (reference) 0.87 (0.37-2.06) 2.82 (1.08-7.37)
Death 12 1.0 (reference) 0.48 (0.10-2.38) +3.54 (1.00-12.6)
p = 0.035; +p = 0.051
Conclusions: At present cohort studies provide the only source of comparative
information about the effects of frequently used triple combination regimens on
clinical endpoints. Compared to indinavir and ritonavir, patients treated with hard
capsule saquinavir had faster disease progression and increased mortality. This
analysis is unconfounded by disease severity and type of nucleoside analogue
used. However, more follow up is needed to confirm or refute these findings.
S12318 Factors associated with successful ritonavir salvage
therapy in an open trial of antiretroviral (ARV) therapy
Richard Haubrich', J.S. Currier2, D. Forthal3, G. Beall4, C. Kemper5, M. Dube2,
J.A. McCutchan6. 1UCSD Treatment Center, 2760 Fifth Avenue Suite 300, San

Diego California 92103-6325; 2University Of So. Calif., Los Angeles, CA;
3 University Of California Irvine, Orange, CA; 4 University Of California Harbor,
Torrance, CA; 5Santa Clara Valley Medical Center, San Jose, CA; 6University Of
California San Diego, San Diego, CA, USA
Objectives: To evaluate the factors associated with improved virologic response
in patients receiving ritonavir (RTV) therapy in a clinical practice setting.