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

12th World AIDS Conference

Abstracts 12377-12381 89

of birth defects among children whose mothers used zidovudine (ZDV) under
protocol, the population experience of mothers using this drug is also important
in evaluating the safety of ZDV in pregnancy.
Methods: We examined the prevalence of major congenital malformations
(New York State Congenital Malformations Registry definition) in 1,315 liveborn
deliveries during 1993-95 by HIV+ women enrolled in New York State (NYS)
Medicaid. Maternal HIV status was determined using a tested algorithm and Medicaid claims files. ZDV use was based on pharmacy claims. Birth defects were
ascertained from birth certificates, and ICD-9-CM codes on inpatient, clinic, and
physician claims. A standardized morbidity ratio (SMR) was calculated comparing observed to expected case counts based on standard prevalences from the
New York State Congenital Malformations Registry adjusting for race, sex, and
geographic location. Within the study cohort, odds of major malformation were
compared by presence of any maternal ZDV use and trimester of first use, with no
maternal usage as the reference group. Odds ratios (ORs) were adjusted separately for maternal age, race, education, smoking, alcohol consumption, and illicit
drug use as well as low birthweight and preterm delivery using Mantel-Haenszel
methods.
Results: 112 children in our cohort had a major malformation. After adjustment,
the prevalence was 2.5 times that expected (SMR = 2.54, 95% CI 2.07, 3.01). The
unadjusted OR for any ZDV was 1.49 (0.97, 2.29). The crude ORs by trimester
of first use were 1.15 (0.49, 2.57), 1.93 (1.09, 3.41), and 1.29 (0.64, 2.53) for
1st, 2nd, and 3rd, respectively. Adjustment for confounders did not alter the size of
these effect estimates substantively.
Conclusion: Although we found no definitive statistical evidence supporting a
link between maternal ZDV use and birth defects in this cohort, there is a clear
need to assemble larger population-based cohorts of HIV+ parturients and their
offspring, through both administrative data and registries, to explore further the
associations seen here.
12377 Risk factors for diabetes mellitus in HIV positive patients
Stefan Mauss, E. Wolf, R. Pascucci, G. Virg, E. Jaegel-Guedes, H. Jaeger. KIS,
Curatorium for Immunedeficiency Mozartstr. 3, D-80336 Munich, Germany
Rationale: There is preliminary evidence that use of HIV protease inhibitors is
associated with an increased incidence of Diabetes mellitus.
Objective: To assess the incidence of Diabetes mellitus in the patient population
of a private HIV outpatient clinic and to identify possible risk factors.
Methods: The data of all patients attending the clinic in 1997 were reviewed for
blood glucose levels, antiretroviral treatment, gender, age and personal history
of diabetes or impaired glucose tolerance. Impaired glucose tolerance is defined
as a serum glucose level of >140 mg/dl; diabetes is defined as a serum glucose
level of >180 mg/dl.
Results: 84 (10.7%) of 783 patients had a serum glucose level >140 mg/dl.
Of these patients 26 (3.3%) had a level >180 mg/dl. Treatment with PIs was
associated with an impaired glucose tolerance but not with manifest diabetes. An
association with a specific PI could not be shown.

RIT), respectively. In patients without chronic liver disease the mean SQV plasma
level was 99 ~ 136 ng/ml (SQV) and 1002 ~ 1216 ng/ml (SQV + RIT). HIV-RNA
levels decreased from 15216 ~ 30333 copies/ml to 5085 ~ 11882 copies/ml
(SQV monotherapy) and from 52485 ~ 127245 to 22503 ~ 40821 (SQV + RIT).
ALT was significantly elevated in the hepatitis group (49 ~ 40 U/I vs. 16 ~ 11 U/I)
with no significant change during therapy.
Conclusions: During monotherapy with SQV plasma concentrations are low
with a wide with and without chronic liver disease as well. The combination of
SQV (0.6 g/bid) with RIT (0.6 g/d) n leads to about 10-fold higher SQV plasma
concentrations in both patient groups. Chronic viral hepatitis without impaired liver
function does not seem to influence SQV plasma concentrations. Drug monitoring
might be helpful in management of PI therapy.
S12379 Sterile leucocyturia and reversible impairment of renal
function in indinavir treated patients
Volker Rickerts', H. Hanel2, T. Leder2, S. Stazzewski2, W. Stille2.
1 Theodor-Stern-KAI 7/Uni-Klinikum/HS68, 60590, Frankfurt, AM Main,
Germany; 2JWG-Uni-Klinik/HS 68/lnfektionsambulanz, Frankfurt/Main, Germany
Objectives: Indinavir is a virologic active and clinically important inhibitor of
HIV-protease. Nephrolithiasis without impairment of renal function is a well known
side effect which occurred in 3% of patients in clinical trials.
Design and Methods: We prospectively monitored urine sediment and serum
creatinine in 256 HIV-infected patients without renal disease in medical history,
receiving antiretroviral drug combinations including indinavir.
Results: Crystalluria with typical indinavir crystals was present in 160 urine
samples (35%) of 124 patients (48%). 21 pts. (17%) with crystalluria developed
a sterile leucocyturia in more than 3 consecutive urine samples, monthly taken. 9
patients (7%) had elevations of serum creatinine after 12 months (mean) of treatment (Range 6-25). Serum creatinine levels reached 1.5 - 2.1 mg/dl (Mean 1.7
mg/dl) (Norm 0.8-1.4 mg/dl). Seven out of these 9 patients received concomitantly
with indinavir at least one nephrotoxic drug [cotrimoxazol (5), ciprofloxacine (2),
aciclovir (1)]. In six patients indinavir-therapy was discontinued and replaced by
nelfinavir. Serum creatinine levels declined to normal values with disappearance
of crystalluria and sterile leucocyturia.
Conclusion: Reversible impairment of renal function is a possible side effect
in long term treatment of HIV infected patients with drug combinations including
indinavir. Careful monitoring of urine and serum-creatinine is required in long term
indinavir treatment.
12380 1 A pharmacokinetic interaction evaluation of MKC-442 and
nelfinavir (NFV) in healthy male and female volunteers
M. Robert Blum, C.P. Moxham, D.J. Kargl, J.B. Quinn, D.W. Barry,
F.S. Rousseau. Triangle Pharmaceuticals Inc., 4611 University Drive, Durham,
NC, USA
Background: MKC-442 is a non-nucleoside reverse transcriptase inhibitor that
has demonstrated potent antiviral activity in a Phase 1/Il trial. MKC-442 is metabolized in vitro by CYP3A4/5. Prior to initiation of efficacy trials with other antiviral
agents, pharmacokinetic interaction studies have been conducted.
Objectives: To evaluate the safety and potential pharmacokinetic interaction
between MKC-442 and NFV.
Design: Thirty healthy volunteers were initially randomized into 2 cohorts.
Cohort 1 received single-dose (SD) MKC-442, 250 and 100 mg on Days 1 and 9,
respectively, and NFV 750 mg tid, Days 2-9. Cohort 2 received SD NFV 750 mg
on Days 1 and 9, and MKC-442 250 mg bid, Day 2-9. Steady-state evaluation
consisted of subjects from Cohort 1 (n = 5) and 2, (n = 10) who received MKC-442
100 mg bid and NFV 750 mg tid, Days 10-16. Pharmacokinetic evaluations were
conducted on Days 1, 9 and 16.
Results: Mean (CV%) steady-state peak concentration (Cmax, /lg/mL), area
under the curve (AUC, hr.~-g/mL) and clearance (CI/F, ml/min) are shown below
(Day 16 MKC-442 Cmax and AUC are normalized to 250 mg):
MKC-442 (n = 10) Cmax AUC CI/F NFV (n = 5) Cmax AUC CI/F
D9 0.73 (35) 3.07 (45) 1776 (67) D9 2.95 (33) 17.2 (31) 783 (30)
D16 (+NFV) 0.74 (76) 3.13 (58) 1921 (74) D 16 (+MKC) 2.21 (15) 11.7 (19) 1112 (24)
AUC for MKC-442 and NFV decreased by 2 and 28%, respectively, when given
together for 7 days. The drugs were well tolerated when administrated at the
doses used in this study.
Conclusions: In healthy volunteers when administered concurrently, NFV
does not effect the pharmacokinetics of MKC-442. However, MKC-442 increases
the oral clearance of NFV. Concomitant administration use may require a dose
adjustment for NFV. Because MKC-442 is an inducer and NFV is an inhibitor
of cytochrome P450, single-dose interaction evaluation of these drugs was not
predictive of chronic dosing.

S12381 The effects of antiretroviral protease inhibitors (PIs) on
serum lipids and glucose in HIV-infected patients
Edmond Chang, M. Deleo, Y.T. Liu, D. Tetreault, G. Beall. Harbor-UCLA Medical
Center, 1000 W Carson St, Box 449, Torrance, CA, USA
Objective: To compare the effects of PIs on serum triglycerides (TG), cholesterol
(CHOL), and glucose (G).

Serum glucose level PI (n = 33):140 mg/ml 56(17%)
180 mg/ml 13 (4%)

RTI (n = 268)
20 (7%).
8 (3%)

no ART (n = 182)
8 (4%)
5 (3%)

PI vs. RTI/no ART: p - 0.001; PI = protease inhibitors, RTI = reverse transcriptase inhibitors,
ART = antiretroviral treatment
Incidence of impaired glucose tolerance was significantly higher in men (p =
0.001). Median age of pts with impaired glucose tolerance (45.5 years) or diabetes
(48 years) was higher than the median age of the whole HIV+ population (37
years, p < 0.05). 3 of 13 pts with PI and diabetes had a personal history before
HIV diagnosis.
Conclusion: Treatment with PIs, male gender and a higher age are risk factors
for impaired glucose tolerance in HIV positive patients. Only age was identified
as risk factor for Diabetes mellitus.
S12378 1 Drug monitoring of saquinavir during monotherapy or in
combination with ritonavir in patients with chronic liver
disease
H. Klinker, Peter Langmann, A. Schubert, C. Writh, E. Richter. Medizinische
Poliklinik, Dept. Infectious Diseases, Josef-Schneider-Str. Wuerzburg, Germany
Background: Saquinavir (SQV) is widely used in first line combination therapies
including protease inhibitors (PI). SQV has a limited bioavailability and is intensively metabolized by the cytochrome p 450 system of the liver. Especially RIT
is known as a potent inhibitor of cytochrome p 450. We have measured SQV
plasma concentrations during antiretroviral therapy in patients with chronic liver
disease.
Methods: 15 patients with HIV infection and chronic viral hepatitis (Hepatitis
C n = 8, Hepatitis B n = 5, Hepatitis B + C n = 2) were treated with SQV (1.34
~ 0.74 g/d), 6 patients with hepatitis were treated with SQV (0.94 ~ 0.4 g/d) in
combination with RIT (0.8 g/d). 25 patients without liver disease received SQV
(1.3 ~ 0.45 g/d) or a combination of SQV (1.1 ~ 0.3 g/d) + RIT (0.6 g/d) (n = 15).
SQV plasma concentrations were measured as trough levels by a HPLC method.
Changes of HI-viral load and liver function tests were investigated before and 6
weeks after the initiation of PI therapy.
Results: During PI - therapy in patients with chronic hepatitis the mean SQV
plasma concentration was 53 ~ 55 ng/ml (SQV) and 762 ~ 1172 ng/ml (SQV +