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

12th World AIDS Conference

Abstracts 42254-42282 829

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.
S42277 Methods to measure protease inhibitor (PI) and reverse
transcriptase inhibitor (RTI) concentrations in human
plasma
Thomas Moyer, Lynn Ester, R.J. Enger, J.R. Charlson, Z. Temesgen, L.K. Oliver.
Mayo Clinic, 200 First Street, SW Rochester, MN, USA
Background: Implementation of combination therapy for AIDS using Pl's and
RTI's has resulted in significant treatment success. However, as many as 53% of
patients do not have a sustained response to treatment as indicated by viral load
testing. Among many possibilities, treatment failure may be due to lack of compliance, genetic differences in metabolism, and pharmacokinetic interactions among
the drugs used. Measurement of blood concentration may provide clinically useful
information to clarify these factors.
Methods: Analytical methods to measure blood serum concentrations of indinavir (In), nelfinavir (NI), ritonavir (Rt), saquinavir (Sq), delavirdine (DI), neverapine
(Nv), didanosine (ddl), lamivudine (3TC), stavudine (d4T), zalcitabine (ddC), and
zidovudine (AZT) used to treat HIV-1 infection have been developed. The assays
are sufficiently sensitive to measure concentrations achieved during routine clinical therapy. The drugs In, NI, Rt, Sq, and DI are extracted from plasma using
ethyl acetate and hexane followed by HPLC analysis on reverse phase with UV
detection at 254 nm. The drugs AZT and Nv are extracted from plasma using
chloroform and isopropyl alcohol followed by HPLC analysis on reverse phase
with UV detection at 266 nm. The drugs 3TC, ddl, ddC, and d4T are measured by
subjecting plasma to acetonitrile precipitation followed by HPLC analysis of the
protein-free supernatant on reverse phase with UV detection at 270 nm.
Results: Precision of the assays ranges from 5% at peak levels to 20% at
trough levels, and the drugs are stable in human plasma for at least one hour at
56 C, seven days at ambient temperature, and 30 days at 20 C. No interference
has been noted from the drug combinations or antibiotics commonly used in this
patient group.
Conclusion: Methods to measure blood serum concentrations of currently
licensed antiretroviral drugs are available and may provide additional useful
information to assess efficacy and outcome of treatment.
42278 1 Single-dose plasma profiles of abacavir (1592, ABC) in
renal failure
Melanie Thompson1, T. Enstrom', H. Bohn', J. Savla', W. Weinberg1,
L. Wang2, J. Johnson2. 1AIDS Research Consortium of Atlanta, 131 Ponce de
Leon, S. 130 Atlanta, GA; 2Glaxo-Wellcome, Research Tri Pk., NC, USA
Objective: To determine whether the plasma pharmacokinetics of abacavir are
such that dose modification is necessary in the setting of renal failure.
Background: ABC is primarily metabolized by carboxylation and glucoronidation, with ---3% of the parent drug excreted in the urine in subjects with normal
renal function. These are the first data reported in the setting of renal failure.
Methods: A male patient on peritoneal dialysis for chronic renal failure (glomerular filtration rate -10 ml/min) volunteered to enroll in a pharmacokinetic substudy
of an open-label trial (CNAA3008). A single 300 mg tablet of ABC was administered, with plasma sampling at 2, 3, 4, 5, and 6 hours post dosing. Plasma
concentrations of ABC were determined by an HPLC assay.
Results: The calculated plasma half-life was 1.33 hours. Plasma concentrations were:

42280 | Pharmacokinetic interaction between efavirenz (EFV) and
rifampin (RIF) in healthy volunteers
Irma Benedek, A. Joshi, W.D. Fiske, S.J. White, D. Stevenson, G. Bawerjee,
D.M. Kornhauser. DuPont Merck Pharmaceutical Company, Wilmington and
Newark, Deleware, USA
Objective. The objective of this study was to determine if there is a pharmacokinetic interaction between EFV and RIF.
Methods. Subjects (n = 12) were administered EFV, 600 mg qd, on Days 1-14.
RIF was administered, 600 mg qd, on Days 8-14. Plasma samples were obtained
on Days 7 and 14 for EFV and plasma samples were obtained on Day 14 for
RIF and 25-desacetyl RIF. EFV, RIF and 25-desacetyl RIF were measured using
validated HPLC methods.
Results: There was a significant decrease in mean (n = 12) EFV Cmax on Day
14. However, in two subjects, EFV plasma levels were higher on Day 14 than
on Day 7, while, the other ten subjects (ie, induced) had significantly lower EFV
Cmax and AUC on Day 14 compared to Day 7. Mean RIF and 25-desacetyl RIF
Cmax and AUC values were similar to literature values.

Treatment Study
Day
EFV 7
EFV + RIF 14

All Subjects (n = 12)
EFV Cmax (/M) EFV AUC (/tMh)
17.6 [7.0] 269 [128]
15.1 [9.5] 233 [215]

Induced Subjects (n = 10)
EFV Cmax (IM) EFV AUC (IM.h)
15.1 [3.2] 224 [61]
11.7 [3.4] 151 [53]

Significant differences (p 0.05) between EFV + RIF and EFV; mean [standard deviation] are
reported.
Conclusion: RIF appeared to induce EFV metabolism in 10 of 12 subjects.
However, there were two individuals in whom the metabolism of EFV appeared
to not be induced by RIF. EFV metabolism was affected by RIF to a lesser extent
than with other HIV drugs (ie, protease inhibitors). Concomitant use of EFV and
RIF may require an increase in EFV dose to offset RIF enzyme induction. The
rifampin data suggest that RIF metabolism is not appreciably affected by EFV.
42281 Nelfinavir, didanosine and stavudine in HIV-infected drug
users enrolled in opiate substitution programs at four
outpatient clinics - The Zurich Prometheus study
Markus Flepp', C. Nigg', F. Kuhn2, M. Schaub3, D. Meili3, B. Somaini2,
P. Grob'. 'University Hospital Zurich, Ramistr 100 UPOL41, CH 8091 Zurich;
2Institute F Social & Preventive Medicine, Zurich; 3Zokl 1, Methadone
Substitution Clinic, Zurich, Switzerland
Objectives: Open label study to evaluate the feasibility, efficacy, safety and impact on the quality of life of a combination therapy consisting of nelfinavir (NFV)
+ didanosine (ddl) + stavudine (d4T) in HIV-1 infected participants of opiate
substitution programs at four outpatient clinics in the city of Zurich, Switzerland.
Methods: Eligible patients had to be antiretroviral-naive or received <2 months
of antiretroviral drugs not used in the study, to have a CD4 count <750 cells/1I or
a HIV-1 RNA load -5,000 copies/ml and to be enrolled in an opiate substitution
program. Treatment was initiated with NFV 750 mg tid, ddl 300-400 mg qd (pediatric powder) and d4T 30-40 mg bid. Drugs were supplied at the same frequency
than the opoid drug. ddl (for some clients mixed together with methadone) and at
least one dose of d4T were intended to be taken under observation for patients
with daily opiate supply. Changes in CD4 cell count and plasma HIV-1 RNA load
(Roche Amplicor HIV monitor) were measured, as well as signs of clinical and
laboratory toxicity.
Results: As of 17 December 1997 sixteen (10 m/6 f, median age 32 years,
range 20-42) HIV infected patients met the inclusion criteria (13/16 antiretroviral
drug naive) and received study medication. At baseline, patients had a median
CD4 cell count of 133 cells//ii (range 9-765) and a median HIV-1 RNA load of
4.6 loglo copies/ml (3.5-6.4). Eight- and 12 week data are available for 9 and 4
patients, respectively. On an intention to treat analysis 6/9 and 3/4 patients had
either a viral load decrease of -2 log10 and/or to -200 HIV-1 RNA copies/mi.
CD4 cell counts had increased by >100 cells// I in 3/9 and 2/4 patients, respectively. 8/16 patients had a median of 2.5 (range 1-13) emergency room visits or
hospitalizations. Except for one hospitalization, this adverse events are believed
to be unrelated to antiretroviral drug toxicities.
Conclusion: Partly observed therapy with NFV, ddl and d4T achieves a potent viral load response and a remarkable increase of CD4 cell counts, at least
on a short term, among a drug-using population normally associated with little
access to HIV/AIDS-related therapy. Follow-up data of all patients will be presented including findings concerning compliance and health-related quality of life
compared to matched HIV-negative and untreated/elsewhere treated HIV-positive
participants of the opiate substitution programs.
413*/42282 Predictors for not currently receiving protease
inhibitor therapy: Results from a multisite
interview project
Allyn K. Nakashima, Jeffrey L. Jones, D.A. Burgess, J.W. Ward. Centers for
Disease Control and Prevention, 1600 Clifton Rd., Mailstop E-47, Atlanta, GA
30333, USA
Objective: To describe risk factors for not receiving protease inhibitor therapy.
Methods: We interviewed persons -18 years of age reported to health departments with HIV or AIDS in 6 population-based and 6 facility-based locations in

Post-Dose Time Interval
2 hours
3 hours
4 hours
5 hours
6 hours

Concentration (//g/ml)
1.27
0.71
0.38
0.24
0.16

Discussion: Plasma half-life in volunteers with normal renal function was 1.18
hours (mean) following a single 300 mg dose in study 131-001, with the dose
range of 100-1200 mg. The calculated haft-life in renal failure falls within this
range and does not support dose modification in the setting of renal failure.
Additional patients are being studied.
Conclusions: Preliminary data suggest that renal impairment does not affect
the plasma profiles of ABC, and thus, no dose modification is recommended in
patients with renal dysfunction.