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

12th World AIDS Conference

Abstracts 12387-12391 91

of the events have been asymptomatic Grade 3 or 4 laboratory abnormalities,
primarily of ALT, AST, or creatine kinase (CK). Approximately 5% of enrolled patients experienced increases in ALT/AST. CK increases were reported in 2.5%
of patients, and were usually exercise-related. Renal abnormalities were reported
in 1.5% of patients. Approximately one-half of these cases were characterized
by evidence of a proximal tubular defect with bicarbonate and phosphate wasting,
proteinuria and glucosuria, but generally without increases in serum creatinine.
Serum creatinine exceeded 2.0 mg/dL in 12 cases (range: 2.1-4.0 mg/dL in 11
cases, and one with 11.2 mg/dL). All cases resolved with discontinuation of study
medication. GI events (nausea, vomiting or diarrhea) were reported in 14 patients.
All other events occurred in -1% of patients enrolled.
Conclusions: Serious and/or Grade 3 or 4 adverse events have been uncommon in clinical trials of adefovir dipivoxil, and most of the episodes have been
asymptomatic laboratory abnormalities. Preveon appears to be safe and well
tolerated for the treatment of HIV-infected patients.
12387 Hyperglycemia associated with protease inhibitor therapy
Montserrat Sala Rodo1, R. Pena C.3, M. Cervantes2, B. Font2, G. Serrate2,
F. Segura2. AIDS Unit Internal Med. D Inf. Dis Program Corp. Sanitaria Parc.
Tavli Sabadell, Barcelona; 2Medical Doctor Internal Medicine; Resident,
Jabadell, Spain
Introduction: New-onset diabetes mellitus and hyperglycemia have occurred
in HIV-infected patients treated with all four FDA-approved protease inhibitors.
The mechanism by which protease inhibitors cause diabetes is unclear, perhaps
as a result of inhibition of the protease that converts proinsulin to insulin. The
occurrence of these event seems to be infrequent and probably patients for whom
these products are indicated should not discontinue therapy. Reports, range from
hyperglycemia, controlled through either diet modification or hypoglycemic agents
to diabetic ketoacidosis. In some patients, hyperglycemia persisted even after the
drug was stopped.
Patients and Methods: 298 HIV-infected patients treated with protease inhibitors from July 96.
Results: 45 patients (15.1%) developed hyperglycemia (>120 mg/dl). The average time to diagnosis was 5 months (range 1-12 months). Most patients could
be controlled with dietetic changes. Two patients (less than 1%), one of them with
previous family history of glucose intolerance, developed severe diabetes.

12389 I Pharmacokinetic drug interactions with amprenavir
Brian Sadler1, C. Gillotin2, G.E. Chittick3, W.T. Symonds3. 1Glaxo Wellcome Inc.
Five Moore Dr. RTR NC; 3Glaxo Wellcome Inc. RTP NC, USA; 2Glaxo Wellcome
Issy-les Moulineaux, France
Background: During the course of its clinical development, a number of concurrently and historically controlled studies were conducted in order to characterized
the likelihood and magnitude of various key drug-drug interactions with the HIV-1
protease inhibitor amprenavir (USAN approved name).
Methods: Six concurrently and two historically controlled clinical trials assessed
the interactions ofamprenavir with zidovudine (ZDV), lamivudine (3TC), ketoconazole (KCZ), rifabutin (RFB), rifampin (RFP), clarithromycin (CLR), efavirenz (EFV),
abacavir (ABV), saquinavir (SQV), nelfinavir (NFV), and indinavir (IDV).
Results: A summary of currently available data is tabulated below:

Cmax
1 16-31%
1 39%
116%
i 67%
5%
T15%

AUC Cmin
N/A
N/A
t 22-64% N/A
1 36% 43%
' 32% N/A
S81% 91%
114% 10%
T 18% t 39%

with
ZDV
3TC
ABV
IDV
EFV
KCZ
RFP?
RFB
CLR

Cmax AUC Cmin
r 40% r 31% N/A
S16% i 9% N/A

9
t 19%
9
1 10%

T 15%
1 44%
7

N/A
N/A
I 3-6x

Table 1
Pt Age Baseline
CD4
1 57 150/mm3
2 47 105/mm3

Baseline Baseline Protease Time
V. Load glucose inhibitor (month)
ND 90 mg/dl Indinavir 12
215.500 146 mg/dl Saquinavir 3
5.33 logs

Glucose Therapy
pH
654 mg/dl 7.36 Insulin
319 mg/dl 7.45 oral hypogly

Conclusions: Mild hyperglycemia is relatively frequent in patients using protease inhibitors. Patients rarely need insulin or oral hypoglycemic agents to
control hyperglycemia. None of our patients developed diabetic ketoacidosis but
one of them required hospitalization. In our experience patients don't need discontinuation of therapy with the protease inhibitor, but long term evaluation is
required.
12388 The loin pain/indinavir syndrome and urolithiasis
associated with indinavir therapy
Mark R. Nelson, Brian Gazzard, R.S. Kooner, G. Smith, K. Jordan, M. Dineen,
J. Ramsay. Chelsea and Westminster Hospital, 369 Fulman Rd, London,
England, UK
Aim: Define the incidence, characterize the clinical picture and suggest a management plan for loin pain in patients on indinavir.
Method: Retrospective case review of 573 patients on indinavir from April 1996
to October 1997.
Results: The 42 presentations with loin pain occurred in 38 patients (35 M,
3 F) giving an incidence of 6.63%. Mean duration of therapy was 7.4 months.
The mean hospital stay was 2.0 days (1-11 days). 83% who were admitted
and 10 had previous unreported episodes. All but 3 had microscopic haematuria
and there were significant rises in creatinine in 7. Of the 34 who underwent
renal imagining (31 IVU, 3 US) obstruction was demonstrated in 47% despite
the KUB reported as normal in 81% of these cases. The stones were small and
relatively radiolucent. 18 had a clinical picture of renal colic with negative imaging
suggesting that intrarenal sludging was the cause of the pain. 35 presentations
(83%) were managed conservatively with vigorous hydration and analgesia. 7
underwent surgical intervention (2 ESWL, 3 ureteroscopy and 2 JJ stenting). All
stones fragmented easily. 4 required cessation of indinavir.
Conclusion: Loin pain is common during indinavir therapy. A new syndrome
characterised by loin pain with obvious urolithiasis exists and is likely due to intrarenal sludging. The stones are small, relatively radiolucent, fragment easily and
consist of indinavir crystals. Most patient respond to conservative management
without requiring cessation of indinavir.

Conclusion: Clinically significant interactions have been seen with rifabutin and
rifampin. Rifabutin doses should be reduced when co-administered with amprenavir. Amprenavir should not be administered with rifampin. All other interactions
studied to date have not been sufficient to warrant dosage adjustments.
S123901 Prediction of in vivo impairment of cytochrome
P450-mediated metabolism by HIV protease inhibitors
Pascal Bonnabry1, A.F. Rasca2, T. Leemann3, P. Dayer2. 1Division of
Pharmacology & Pharmacy, University Hospital 1211 Geneva 14; 2Division of
Clinical Pharmacology-University Hospital, Geneva; 3 Pharmacy-University
Hospital, Geneva, Switzerland
Objectives: To evaluate and differentiate the risk of in vivo drug interactions due
to inhibition of specific cytochrome P450 isoforms by HIV protease inhibitors.
Design: Data of CYP2D6 and CYP3A4 in vitro inhibitions by indinavir, nelfinavir,
ritonavir and saquinavir were extrapolated to the clinical situation.
Methods: The in vivo impact of inhibitions was calculated by means of a
computer-based quantitative drug interactions prediction system (Q-DIPS). Enzymatic and pharmacokinetic data were integrated in a simple model assuming
competitive inhibitions. An Inhibition Index (II), expressing the in vivo potential of
each drug to inhibit each isozyme, was then calculated over time. Results were
then compared with clinical data.
Results: Although all drugs display a high in vitro CYP3A4 inhibition potential,
extrapolations suggest a strong inhibition by indinavir and ritonavir, but a low in
vivo risk of nelfinavir and saquinavir. A moderate inhibition of CYP2D6 by indinavir
and ritonavir was also found. These results are mostly coherent with the known
clinical interaction profiles, except for indinavir. For this drug, the predicted risk
for both isozymes seems to be overestimated by the system. Reasons for this
discrepancy are currently investigated (tissue distribution?, protein binding?).
Conclusion: In vitro-in vivo extrapolations confirm strong inhibitions of CYP3A4
by indinavir and ritonavir, leading to major risks of interactions with substrates of
this isozyme (ergotamine, macrolide antibiotics, benzodiazepines e.g.). Ritonavir
and possibly indinavir also inhibit moderately CYP2D6 activity. At the opposite,
the potential of nelfinavir and saquinavir to impair drug metabolism seem very
low. Supported by the National Swiss Research Foundation (32-36600.92)
S123911 Indinavir-associated facial atrophy in HIV positive
patients
Ka Hing Wong, Tin Yee Ho, C.W. Chan, S.S. Lee. AIDS Unit Department of
Health, 5/F Yaumatei JCC, 145 Battery Street, Yaumatei Kowloon, Hong Kong
(China)
Objectives: To study the incidence of facial atrophy and its associated factors in
patients with HIV infection receiving protease inhibitors.
Design: Retrospective study
Methods: During a 2-month period, from August to October 1997, all patients with HIV infection receiving protease inhibitors seen at the Department of
Health's HIV clinic were assessed for facial atrophy. Patients were asked specifically whether they noticed this condition; pre- and post-treatment body weights
and the general physique were also noted.
Results: Among 29 patients who had been receiving indinavir (800 mg every 8
hours) for 3 months or more, 7 (24%) noticed a significant isolated wasting of the
cheeks not associated with weight loss at 13 to 35 weeks after commencement
of indinavir. Five of them were Chinese, 1 was Thai, and 1 Caucasian. All but
one were male. None of these 7 patients had received any protease inhibitor before. Besides indinavir, nucleoside analogue reverse transcriptase inhibitors were
given as part of highly active antiretroviral therapy. All 7 patents showed satisfactory response to treatment as evidenced by viral load and/or CD4 changes. The
development of facial atrophy was not associated with age, sex, ethnicity, route
of HIV transmission, CD4 count, history of AIDS-defining illness and concurrent