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

70 Abstracts 12287-12290

12th World AIDS Conference

indinavir were collected and analyzed with a validated HPLC assay at 8 hours
post ingestion and 120 minutes thereafter. Viral load (VL) was routinely measured
by Nuclisens (Organon). Twenty eight patients were protease inhibitor naive prior
to receiving indinavir (mean: 8.6 months; range: 6-14 months).
Results: Eleven out of 31 patients (35%) had undetectable VL (<80 copies/ml),
whereas the remaining 20 patients (65%) had variable plasma HIV-1 RNA levels
(mean: 4.3 log 10; range: 2.5-5). There were no differences in terms of CD4 cell
counts among patients with detectable and undetectable plasma VL (mean: 276
cells/itl; range: 60-697; p = 0.3). Mean plasmatic levels for indinavir among both
groups were as follows:
Undetectable VL (range) Detectable VL (range)
8 h after ingestion (mg/L) 1.542 mg/L (0.061-11.931) 1.524 mg/L (0.016-16.590)
120 minutes post-ingestion (mg/L) 16.133 mg/L (1.473-30.414) 13.712 mg/L (1.272-52.153)
Ten out of 11 patients (91%) with undetectable VL as well as 17 out of 20
patients (85%) with detectable plasma HIV-1 RNA (OR: 1.76; p = 0.9) had plasma
levels of indinavir above the IC95 (0.075 mg/L) during the whole dosing interval
of 8 hrs. The intersubject variability was homogeneously distributed among both
groups.
Conclusions: Detectable VL does not appear to be related to low plasma
concentrations of indinavir. Only one third of our HIV infected patients maintained
undetectable plasma VL after a mean of 8 months of indinavir therapy. Nonetheless, the majority of them (27/31; 87%) had plasma levels of indinavir above the
IC95 during the entire dosing interval. Therefore, the role of other factors such as
resistance to indinavir -currently in progress-, should be sought.
12287 Reversal of hyperlipidaemia and lipodystrophy in
patients switching therapy to nelfinavir
Chris Duncombe1, M. Bloch2, D. Austin2, D. Quan2. Oxford Street,
Darlinghurst, Sydney; 2Holdsworth Clinic, Sydney, Australia
Background: Dislipidaemia and a syndrome of peripheral lipodystrophy (loss of
fat in the arms, legs, and face and concomitant weight loss) have been observed
in patients treated with protease inhibitors (PIs).
Objectives: To evaluate changes in serum lipids and weight in patients with
established lipodystrophy switching from existing PI therapy to nelfinavir.
Methods: This observational study enrolled 21 patients with hyperlipidaemia
and visual evidence of lipodystrophy. All were taking combination therapy
which included indinavir or saquinavir plus ritonavir, in addition to two nucleoside/non-nucleoside analogues. Patients were switched to nelfinavir as the only
PI and at least one other antiretroviral was also changed at baseline. Serum lipids
and weight were measured at 1-3 monthly intervals. Visual assessment for the
presence of lipodystrophy was made at each clinic visit.
Results: Median serum triglyceride level prior to commencing nelfinavir was
3.7 (2.3-43.2) nmol/l. This was 2.8 (1.2-4.5) nmol/l after 3 months. Median serum
cholesterol level prior to commencing nelfinavir was 6.6 (4.3-17.5) nmol/l. There
was no change at three months.
Average weight increased from 72.2kg to 74.6kg. At three months, the treating physician assessed the visual appearance of lipodystrophy as stabilised/no
change in 12 (57%) of patients, partially reversed in 7 (33%) patients, and
progressive in 2 (10%) patients.
Conclusion: Switching PI therapy to nelfinavir in addition to changing at least
one other drug in a combination regimen reduces serum triglycerides, increases
weight, does not alter serum cholesterol and may have a favourable impact on
the visual signs of established peripheral lipodistrophy syndrome.
112288 Hepatotoxicity after introduction of highly active
antiretroviral therapy (HAART)
Rafael Rodriguez-Rosado', J. Garcia-Samaniego2, V. Soriano2, F. Muhoz2,
J. Gonzalez-Lahoz2. 1Service Infectious Diseases, Carlos III, Calle Sinesio
Delgado 10, 28029 Madrid; 2/nstituto Salud Carlos III, Madrid, Spain
Background: the life expectancy of HIV+ patients has dramatically changed in
the last two years after the introduction of triple drug combinations, mainly those
including protease inhibitors. However, issues on compliance and adverse effects
has now became evident as a limiting cause of benefit in a substantial proportion
of individuals. Among others, liver toxicity is now one of the leading causes of
treatment withdrawn.
Patients and Methods: We have analyzed the first 187 patients who began
HAART in our center. The exam of liver function was made at baseline and after
one month of beginning treatment. Criteria for liver injury were established when:
i) both ALT and AST increased at least twice in respect to baseline values; ii)
bilirrubin levels raised above 2.5 g/L; and iii) development of clinical hepatic failure
(ascites, encephalopathy, jaundice).
Results: Transaminases increased >2-fold in 26 (13.9%) patients, & bilirrubin
raised above 2.5 g/L in 7 (3.7%). 11 (5.9%) subjects needed to stop the medication
for either hepatic cytolisis (9), hiperbilirrubinemia (1), or both (1). Four (2.1%)

patients developed clinical hepatic decompensation, and one of them died. He
was receiving d4T, 3TC plus indinavir, and he had multiple viral hepatitis (B+C+D),
although this was the first episode of clinical liver failure. In IDUs, baseline AST
& ALT were higher (p < 0.001) than in other groups. This could reflect the
high prevalence of chronic hepatitis C among IDUs. After HAART, transaminases
raised >2-fold in 17 (19.8%) of 86 IDUs, but only in 8 (8.6%) of the remaining
93 subjects (p = 0.08). Chronic hepatitis C was an independent predictor of hep
atotoxicity (p = 0.03). Patients receiving indinavir developed hiperbilirrubinemia
more frequently (56/138; 40.6%) than subjects receiving other PIs (3/49; 6.1%)
(p < 0.001). None of the nucleoside analogues was particularly more hepatotoxic
than the others.
Conclusion: hepatotoxicity is frequently seen in patients under HAART, and
can force to withdraw antiviral treatment in a significant proportion of patients;
occasionally it can result in fatal outcome. The development of cytolitic injury is
particularly common in subjects with chronic hepatitis C, meanwhile cholestasis
seems to be more frequent under indinavir containing regimens. Since most
HIV+ IDUs carry chronic HCV infection, clinicians must be alert on the hepatic
complications which can follow the introduction of HAART in them.
12289 Peptidic "tongs" constrained by a rigid spacer: A novel
series of dimerization HIV-1 protease inhibitors
Nicole Boggetto1, A. Bouras2, E. De Rosny', Z. Benatalah2,
M. Reboud-Ravaux', S. Sicsic2. 'Istitut Jacques Monod Univ. Paris 6 & 7 Tour
43, 2 Place Jussieu 75251 Paris Cedex 05; 2Biocis-CNRS FAC. Pharm. 2Rue
J.B. Clement, 92296 Chatenay-Malabry, France
Objectives: Design, synthesis and biological evaluation of novel constrained
dimerization inhibitors of HIV-1 protease
Design: To target the antiparallel /1-sheet formed by the interdigitation of N- and
C-terminal strands of each enzymic monomer, molecules based on a conformationnally-constrained spacer Ar attached to two peptidic strands were designed
(Figure). These compounds are susceptible to interact with the C-terminal end of
each HIV-1 protease monomer preventing the formation of the active dimer.

M
0 0
N_
p.pold. OM. o V ENZYME
Ar C-lrmmus M 0IMER
l ylObptplld.aOMa, a p \
Inactive Inhibitor-monomer complex

o
o, K~0
H$'H o

Results: To discriminate between active-site or dimerization inhibition, kinetic
analyses according to Zhang et al. (1991) were performed. It was found that
when it occurred, the inhibition was due strictly to an antidimer effect. The inhibition potency was influenced by the nature of the spacer (2,7-naphtalenediol
> 2,6-pyridinediol > resorcinol), the length of the peptidic chains (tripeptide
> tetrapeptide > dipeptide) and their sequence. For example, hairpin with the
spacer 2,7-naphtalenediol and peptide sequence V-L-V displayed an inhibitory
constant Kid of 0.56 iM which was among the best values described for inhibitors
of dimerization.
Conclusion: Structurally simple inhibitors of dimerization have been obtained
characterized by their efficiency and the simplicity of their synthesis.
112290 Sixteen week follow-up of indinavir sulfate (IDV)
administered q 8 hours (q8H) versus q12H in
combination with efavirenz (EFV)
Robin Isaacs', Diane Havlirl, J. Pottage2, J. Kahn3, C. Shikuma4, D. Mehrotra5.
SUCSD Treatment Center San Diego CA; 2Rush Presbyterian St. Lukes Med.
Ctr. Chicago IL; 3San Francisco General Hospital San Francisco CA; 4HARC
Honolulu; 5Merck Research Laboratories West Point PA, USA
Background: Simplified dosing regimens with potent antiretroviral therapy may
improve adherence and outcome of HIV therapy. We compared the antiviral
activity and safety of a twice daily regimen (BID group: IDV 1200 mg q12H in
combination with EFV 300 mg q12H) to that of a thrice daily regimen (TID group:
IDV 1000 mg q8H in combination with EFV 600 mg qhs).
Methods: 71 HIV-1 infected patients who were protease inhibitor- and nonnucleoside reverse transcriptase inhibitor-naive, with baseline CD4 counts > 100
cells/mm3 and serum vRNA > 10,000 copies/mL were randomized to one of the
two regimens in an open-label, multicenter study (Merck Protocol 067).
Results: After up to 16 weeks of therapy, preliminary results are:

Week 8
Week 12
Week 16

Proportion (%) <400 HIV RNA copies/mL
BID Group TID Group
11/19 (58%) 7/18 (39%)
11/14 (79%) 7/12 (58%)
6/7 (86%) 6/8 (75%)

The median changes in CD4 cell count after 8 and 16 weeks of therapy were
160 cells/mm3 (n = 15), respectively, in the BID group, and were 120 cells/mm3
(n = 21) and 141 cells/mm3 (n = 14), respectively, in the TID group. Study drugs
were generally well tolerated; two patients in the BID group and one in the TID
group required discontinuation of study medications attributed to drug toxicity.
Conclusions: Preliminary results suggested that the antiviral activity and safety
profile of the twice daily regimen (IDV/EFV q12H) appeared to be comparable
to that of the thrice daily regimen (IDV q8H/EFV qhs). Updated data will be
presented.