Abstracts Vol. 1 [International Conference on AIDS (11th: 1996: Vancouver, Canada)]

Monday, July 8, 1996

Mo.B.I 18 - Mo.B.174

Mo.B.I 18
GASTRIC HYPOCHLORHYDRIA IS ASSOCIATED WITH MYCOBACTERIUM AVIUM
COMPLEX (MAC) INFECTION IN PATIENTS WITH HIV/AIDS
ohannesi Koch, Scott MK, Morgan D, Steuerwald M, Lor E, Cello JP. Department of
Medicine, UC(SF, Division of Gastroenterology, San Francisco General Hospital
Purpose: To determine the association between gastric hypochlorhydria and MAC infection
in patients with HIV/AIDS.
Methods: Evaluation of gastric fluid aspirate in patients with HIV/AIDS (study group) and
patients not HIV infected (control group) undergoing elective endoscopy (off all proton
pump inhibitors and histamine receptor blockers). In 62 patients with HIV/AIDS and 25
control patients, at least 3 ml of fluid were recovered.Two pH measurements were performed usingry the Fisher Scientific pH analyzer model 15. MAC blood culture results
obtained as part of the patients' standard clinical care were reviewed within 12 months of
the endoscopy Logistic regression was used to examine the association between gastric pH.
age, CD4 count and serum albumin level.
Results: In the study group (60 men and 2 women), the mean age was 38.3 years and the
mean CD4 count was 133 cells/mm3 (range 2-395).The gastric pH in the study demonstrated a bimodal distribution, 50 patients (81%) had a pH <4 (mean 2.12 ~ 0.8) and 12
(I 9%) had a pH > 4 (mean 7.04 ~ 1.02). In the control group the mean pH was 1.92 (~
I.26), only I patient had a pH > 4. In the final study group logistic regression model, pH,
CD4 count and albumin were retained.The adjusted Odds Ratios (95% CI) were: gastric
pH 1 3.5 (2.4 77.2), CD4 count 0.97 (0.95-1.00) and albumin 0.33 (0.12-0.90).The standardized CD4 count OR was 0.20 (95% Cl 0.46-0.88).The conditional effect plot expresses the
probability of MAC infection versus gastric pH for CD4 contours.
Conclusion: Gastric hypochlorhydria
(pH >4) is a distinct clinical entity noted CD4=1o
in nearly 20% of patients undergoing,,CD4=50
endoscopy Gastric hypochlorhydria is CD4=10o
associated with a significantly higher
probability of systemic MAC infection,
independent of CD4 count. Of note, n
the absorption of rifampin and rifabutin
are impaired in an alkaline environment, -. T
potentially limiting their efficacy
Johiines Koch, MD, Div. of GI, NH 3D-5, San Francisco General Hospital, 1001 Potrero
Avenue, San F rancisco, CA 94110 Telephone: [phone] Fax: [phone]
email: hinnes(sitsa.ucsf.edu
Mo.B. 170
MAINTENANCE OF LONG-TERM VIRUS SUPPRESSION IN PATIENTS TREATED
WITH THE HIV- I PROTEASE INHIBITOR CRIXIVAN~ (INDINAVIR)
Emini, Emilio A, Condra JH, Schleif WA, Massari FE, Leavitt RY Deutsch PJ, Chodakewitz JA.
Merck Research Laboratories, West Point, PA, USA.
Objective: Loss of Indinavir mediated virus suppression seen in some patients during treatment with the inhibitor has been shown to be associated with the selection of viral variants
expressing reduced Indinavir susceptibility However, the apparent probability and timing of
resistant virus selection varies widely among patients.We, therefore, used our understanding
of the genetic basis of resistance to design a general strategy of clinical use for Indinavir that
would forestall resistance selection and that would increase the probability of longterm
virus suppression in patients.
Methods: Virus isolates were obtained at intervals from patients treated with sub-optimal
doses of Indinavir during early dose-ranging studies of the inhibitor. For each isolate, the
cell culture susceptibility to indinavir was determined. An association was established
between the degree of resistance expression and the accumulation of specific amino acid
substitutions in the viral protease.
Results: Resistance was associated with multiple and variable amino acid substitutions at
eleven protease residue positions. However, measurable resistance required the co-expression of at least several amino acid changes and higher levels of resistance generally required
the co-expression of greater numbers of substitutions.The sequential accumulation of substitutions needed for high-level resistance was driven by continued virus replication in the
presence of sub-optimal indinavir doses. As a result, patients who initiated therapy at optimal doses (800mg q8hr) of the inhibitor were less likely to select for resistant viral variants
duinng the observation period of the studies.Additional restriction of virus replication
imposed by the use of Indinavir in combination with other antiretroviral agents appeared to
further restrict resistance selection.
Conclusions: Treatment with indinavir (and likely with other protease inhibitors) should be
itiate d and maintained at the highest tolerated and effective dose.Viral variants expressing
the multiple protease amino acid substitutions required for resistance to optimal Indinavir
doses requires ongoing viral replication and the restriction of this replication by high
Indinavir doses and by the use of effective combination therapies forestalls resistance selection and helps maintain long term virus suppression.
Emilio A. Emin, Merck Research Laboratories, Bldg. 16-225, Sumneytown Pike, West Point, PA
19486 USA telephone: [phone] Fax: 2 I5-652-0994 email: [email protected]
Mo.B. 17 I
CONCURRENT RITONAVIR AND RIFABUTIN INCREASES RISK OF
RIFABUTIN-ASSOCIATED ADVERSE EVENTS
Snie eath Chiozzi M, Cameron DWi, Hsu A, Granneman RG, Maurath CJ,
Leonard JM. Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL, USA;
*Unersity of Ottawa, Ottawa. Canada
Rifabutin is used for the prophylaxis and treatment of MAC infection in AIDS patients.
Dose related side effects include uveitis, skin discoloration, and arthralgia/arthritis. Ritonavir
(ABT 538) is a potent inhibitor of the HIV protease, and has demonstrated clinical and virologic efficacy in a placebo controlled Phase Ill trial of patients with advanced HIV disease. In
this study, the re are higher incidences of arthralgia (4.8% vs. 1.7%), joint stiffness (I.7% vs.
0%), and uveitis (5.7% vs. 04%), in the ritonavir group compared with placebo (p<0.05 for
each event). Since these events have been described in conjunction with high-dose rifabutin,
and pharmacokinetic data demonstrate significant elevation in levels of rifabutin and its 25 -
O-deacetyl metabolite in the presence of ritonavir; we examined the association of these
events with concurrent drug regimens. Rifabutin was used concurrently in I 68 of 54 I ritonavir treated patients and 171 of 545 placebo patients. In patients not receiving concurrent
rifabutin, the incidences of these events were comparable between the two treatment
groups.The patients receiving concurrent rifabutin largely accounted for the excess risk of
these events between treatment groups (9.4% vs. 0.6% for arthralgia, 4. I% vs. 0% for joint
stiffness, and 4.6% vs. 0.6% for uveitis). Furthermore, ritonavir treated patients receiving
rifabutin had twice the incidence of leukopenia as those not receiving rifabutin (38% vs.
19%). Coadministration of ritonavir and rifabutin therefore appears to increase the risk of
arthralgia, joint stiffness, uveitis and leukopenia that is probably attributable to elevation of
rifabutin levels, and warrants consideration of therapeutic alternatives to rifabutin.
I Siegal FP; Elbott D; Burger H; Gehan K; Davidson B; Kaell AT;Weiser B Dose limiting toxicity
of rifabutin in AIDS-related complex: syndrome of arthralgia/arthritis. AIDS 1990, 4:433-44I.
Eugene Sun, 100 Abbott Park Road, D-48U AP9A -LL, Abbott Park, IL 60064-3500 USA
Telephone: [phone] Fax: [phone] I email: [email protected]
Mo.B. 172
EFFICACY AND SAFETY OF TRIPLE COMBINATION THERAPY WITH INVIRASE
(SAQUINAVIR/SQV/HIV PROTEASE INHIBITOR), EPIVIR (3TC/LAMIVUDINE) AND
RETROVIR~ (ZDV/ZIDOVUDINE) IN HIV-INFECTED PATIENTS.
Baruch, Alice, Mastrodonato-Delora, P. Schnipper E., Salgo,M., Hoffmann-La Roche, Inc.,
Nutley New Jersey 07 f10.
Objective:To provide activity and safety data for SQV in combination with ZDV and 3TC
Methods: A total of 33 HIV + patients, naive to antiretroviral therapy and with CD4 counts
I50-500 cells/mm3 were enrolled in an exploratory single arm open-label study of combination treatment with SQV 600 mg tid, 3TC 150 mg bid and ZDV 200 mg tid at three
centers. Efficacy was being measured as change friom baseline of both CD4 cell count and
viral load, indicated by the change in log l0 HIV RNA PCR titer (copies/ml). Safety data were
also collected. Patients were on study from 8 to 14 weeks, with efficacy data collected at
baseline, week 2 (HIV RNA only), week 4 (CD4 and HIV RNA) and a common closing date.
Results: Efficacy and safety information up to week 4 show the following: Among the current group of 19 patients with baseline and week 4 CD4 data, mean baseline cell count
was 336 cells/mm3 (range 1 4-549). Data from I5 patients with baseline and week 2 HIV
RNA PCR measurements show a mean baseline og I0 tit er of 4.98 (range 3.69-5.77). Mean
week 4 CD4 change from baseline (19 patients) was 125 cells/mm3. HIV RNA PCR titer
decreased by at least 2 log 10 at week 4 in half the patients reaching this milestone (n 14).
Of 33 patients currently enrolled, none has had a serious clinical adverse event or laborato
ry toxicity attributed to trial medication.
Alice Baruch, M.D., Ph.D., Hoffmann La Roche, 340 Kingsland Street, Building 719/3rd Floor,
Nutley New Jersey 07 10. Phone (201) 8 I 2-3606 Fax (201) 8 I 2-3629
Mo.B. 173
EXTENDED FOLLOW-UP OF SAFETY AND ACTIVITY OF AGOURON'S HIV
PROTEINASE INHIBITOR AG 1343 (VIRACEPT~) IN VIROLOGICAL RESPONDERS
FROM THE UK PHASE I/II DOSE FINDING STUDY.
Moyle GJYoule M, Higgs C, Monaghan J, Peterkin J", Chapman S*, Nelson M. Kobler
Centre, Chelsea and Westminster Hospital, London, UK; and * Agouron Pharmaceuticals Inc,
La Jolla, California, USA.
Introduction: In the first 28 day open-label phase /11 dose escalation trial with AG 1343,
HIV positive therapy naive persons, with baseline CD4 200-500 cells/mm3 and viral loads
>20000 copies/ml (by bDNA) were treated with doses of 771I (N- 10) and 1026mg (base
equivalent)/day (N- 10) of AG 1343 [I]. Patients with a _1 log reduction in viral load at day
28 were offered continued AG 1343.
Objective.To assess the extended (>28 days) safety virologic and immunologic activity
of AG1343 in initial virological responders and safety of AG1343 when given with
nucleoside analogues.
Methodology: Virologic responders were offered continued AG 1343 at their initial dose
until safety was established at higher doses.The current dose being 1200mg/day Patients
were assessed monthly for clinical events, CD4 cell count and viral load by bDNA. Patients
were offered the opportunity to receive additional nucleoside analogue therapy at the
physicians' discretion.
Results. Six patients entered the extension phase. Patients have been followed for 5-8
months.To date (Jan 1996) 3 patients have added additional nucleoside analogue therapy
(all with zidovudine 5-600mg/day and zalcitabine 2.25mg/day) due to virological failure as
evidenced by return of viral load to baseline or worse. Nucleosides were added at month 3
or 4 in these patients, prompting falls in viral load of 0.5, 1.2, and 1.8 Iog.The 3 patients
remaining on AG 1343 monotherapy have viral loads at 2.3, 0.67, 0. I 6 below baseline at
months 7, 8, and 6, respectively. CD4 cell counts remain at or above baseline in all patients.
No serious adverse events or disease progressions have occurred. Adverse events reported
include loose stools, poor concentration, intermittent headaches, and moderate hyperten
sion. No unexpected adverse events have been reported in patients receiving concomitant
nurleosida analogues.
Conclusions. AGu 343 may be safely administered for prolonged periods and with nucleo
side analogues. Patients with large initial virological reductions may have prolonged responses to AG I343.
Dr Graeme Moyle, Kobter Centre, Chelsea And Westminister Hospital. London SW I0 9
NH UK.TeI.:0181 746 8000 Fax.: UK 171 938 3460
Mo.B. 174
INDINAVIR (MK 639) DRUG INTERACTION STUDIES
The Indinavir (MK 639) Pharmacokinetic Study Group, Merck Research Labs, Jefferson Med
Coil (US), SUNY Stony Brook (US), Robert Wood Johnson Med School (US), St. Pierre
Univ Hospital (BEL)
Objective: To evaluate potential pharmacokinetic interactions between indinavir (MK 639;
IDV) with drugs that are P-450 3A substrates and/or with drugs that are fiequently pre
scribed to HIV infected patients.

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