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

Track B: Clinical Science
exhibited G 190--a E RTs, whereas group B viruses each had developed a number of other
mutations affecting the NNRTI binding pocket, some of them have not been reported todate (i. e.V I106-l, G 190--T).This discrepancy between variants of group A and group B
was statistically significant. Secondary mutations in RT codons 74 and 75 were observed in
some of the mutant strains,.
Conclusions: We conclude that lowering the selective pressure of HBY 097 results in
avoidance of the detrimental G 190-E RT by HIV I in vitro.
Consequently these findings underline the importance of pharmacokinetic parameters for
the type of mutations which appear in HIV-infected patients undergoing therapy
J.-P Kleim, Hoechst AG, H 8 I I, 65926 Frankfurt, Germany
Tel: [phone] --7293 Fax: [phone]
Mo.B.I 124
LONGTERM OUTCOME OF ZDV/DDC TREATMENT IN ZDV-EXPERIENCED PATIENTS.
Binhegyi, Dnes-1, Gerlei Zs I, Szlbvik J]1, Miskovits EI, Ujhelyi E2, D.Tdth F3, Fust Gy2. Saint
Laszlo Hospital, BudapestI, Nat. Inst. for Haematology Budapest2, Univ. of Medicine,
Debrecen3, Hungary
Objective: To evaluate the long term outcome of zidovudine/zalcitabine ZDV/DDC treatment in heavily ZDV-pre-treated patients (pts) in survival, HIV related diseases and surrogate markers.
Methods: 28 ZDV-experienced (mean 19,2 month, 6 - 40) pts were involved into this
study Mean CD4+cell count was 174/mm3 (42 - 320). Pts were treated with 250 mg ZDV
b.i.d. and 0,75 mg DDC t.i.d. HIV-related diseases, Karnofsky score, surrogate markers as
CD4 + cell counts, p24, ICD-p24, neopterin, were monitored. In ten pts neutralising and
enhancing antibodies were determined trimonthly an enhancing/neutralising antibodies titre
index (E/N) was calculated; E/N < 0,5 = HIV-neutralising effect.
Results: Mean duration of ZDV/DDC treatment was 17,5 month (7 - 35), with 3 dropouts. In the responder (R) group: (AUC of CD4+ > 120%) 10 pts fulfilled the criteria, 3 HIVrelated event was detected, values of p24 and ICD-p24 were decreased/negative. In all
three cases E/N < 0,5. In the stabile (S) group: (AUC of CD4+> 90%) were 9 pts, 6 HIVrelated events were recorded, p24 and ICD-p2 values varied (elevated in 2, become positive in I, decreased in 3 cases). E/N <0,5 in I and late elevation in 2 out of the 4 cases. In
the progressor (P) group: (AUC of CD4+ <90%) were 6 pts. I 2 HIV-related events and one
death were recorded. Change in treatment was introduced in 3 pts. p24 values were elevated, E/N > 0,5 in all three cases. Mean CD4+ cell counts were higher in the group R and 5,
than in P: 231, 194 and 67 respectively Data of neopterin values were inconclusive.
Conclusion: ZDV/DDC treatment was effective in ZDV-experienced pts only if CD4+ cell
counts were higher then 100/mm3. Introduced enhancing/neutralising antibodies index
seems to have predictive value.
D. Binhegyi, Saint Laszlo Hospital, Dept. of Immunology, Gyili t 5, Budapest, Hungary
T: (36)-1215-2883 F:(36)- 1217-1422 E-mail:[email protected]
Mo.B. I 125
FROM MONOTHERAPY TO THE MULTIDRUG COMBINATION ERA:A CASE OF
SUSTAINED RESPONSE TO ADDITION OF NEVIRAPINE TO CONTINUED
ZIDOVUDINE
Tumietto F, Costigliola P Moroni Marco*, Colangeli V, Borden M,Venturi C, Spinosa S,
Chiodo F. Dpt of Clinical and Experimental Medicine-Division of Infectious Diseases,
University of Bologna, Bologna, ITALY; *Boehringer Ingelheim Spa, ITALY
Background and introduction: Recently, trials have demonstrated that multidrug treatment
based on concurrent administration of at least two antiretrovirals is more effective than
nionotherapy in the treatment of HIV infection. Nevirapine (NVP), a new antiretroviral drug
of the non-nucleoside reverse transcriptase inhibitor class has been evaluated in phase
II/phase III international trials, in order to assess its efficacy in the treatment of the HIV
infection, administered as monotherapy or in combination with nucleoside analog RT
inhibitors.The case of a patient under long term treatment with zidovudine (ZDV) with the
addition of NVP is reported.
Case Report: HIV infection was diagnosed in June I1988 in the heterosexual partner of an
HIV+ subject. She started treatment with ZDV (500 mg/daily) in April 1991I with low count
of CD4+ lymphocytes (29 I /cmm) and a persistent ICD-p24 antigenemia. Despite maintaining the high level of ICD-p24 antigenemia, the response to ZDV treatment was a sustained
increase in CD4+ count, documented for I16 months (August 1992: 59 I/cmm). NVP at 400
mg/daily was added in December 1993, when ICD-p24 antigenemia had increased to 85.5
pg/ml and CD4+ count had declined (October 1993=345/cmm). A brief reduction of ICDp24 antigenemia followed.The CD4+ count rose to values greater than 600 cells/cmm and
this response has persisted through more than two years of NVP treatment.
Discussion: It is widely accepted that combination treatments are preferable to the
monotherapyThe case of our patient illustrates the potential benefits. Genotypic determination of the RT sequence of the HIV will be identified in order to better characterise the
combined effect of ZDV and NVPThis case supports the pursuit of combined therapy for
HIV infection and encourages the clinical investigations of NVP
Moroni Marco, Boehringer Ingeiheim, Italia Via Lorenzini 8, 20100 Milano Italy
Mo.B. I 126
A MULTICENTRIC, PROSPECTIVE, RANDOMIZED TRIAL OF IFN+ DDI VERSUS DDI
MONOTHERAPY IN HIV PATIENTS.A PRELIMINARY REPORT.
Casari 5. (*), OrQani A. (~), Scalzini A. (^), Donisi A. (*), Gregis, Giampietro (*), Gattuso G. (^),
Carosi C. (*). Clinic of Infectious and Tropical Diseases, Brescia (*); Departments of Infectious
Diseases, Lecco (~), Mantova (^) -ITALY; Financially supported by Istituto Superiore di Saniti.
Objectives: To evaluate tolerability and efficacy of the combined therapy with IFN-DDI versus DDI monotherapy
Methods: Nsive ARC pta with CD4+ <350/cmm were randomized to receive IFNta-2b
MU 3x3/week + 00I mg 200x2/die for 12 months (CR I) versus DDI mg 200x2/die for
I 2 months (CR 2), followed by I 2 months of UDI monotherapy. End-points: progression to

AIDS (F I), C04+ decrease >30% from baseline (E2), pancreatic, liver or bone marrow toxicity > grade 2 WHO (E3), death (E4). Other parameters: 132-microglobulin, p24 Ag.
Statistical analysis: ANOVA, Kruskall-Wallis, Chi-2 M-H. A total number of 50 enrolled subjects are expected.

Mo.B.l 124 - Mo.B.1 128
Results: From 0 1/94 to I 2/95 43 pts enrolled: 24 pts were randomized to GR I (55.8%)
and 19 (44.2%) to GR 2. On enrolment the 2 groups had similar mean values of the considered parameters. Mean observation period = 12. I months; 21 drop-outs (48.8%) were
observed, after a mean period of 5.2 months from the enrollement; the reasons for dropout were: EI=2 (9.5%) (both oesophageal candidiasis), E2=7 (33.3%), E3=2 (9.6%) (I pancreatitis, I neutropenia), I pt (4.8%) of gastric cancer and 6 pts (28.6%) for personal reasons.Three pts (14.3%) failed to enter the study after randomization.Two pts (4.7%) died, I
non-treated pt and I (I16~ months) drop-out EI patient. An overall increase in amylasemia
was observed: time 0= 137.7, 6th month= 158.7 (p=0.045), 12th month= 161.3 (p=0.045);
this trend was statistically significant in GR I at the 6th month (time 0= I 47; 6th
month= 181.5; p=0.024) and between GRs I and 2 at the 6th month (GR I I 8 1.5; GR
2=131.3; p=0.006).The mean CD4+ increased in all cases at the 6th month (time 0=210.3;
6th month=295. I; p=0.052); this difference was shown to be within the significance limits in
GR I (time 0=20 1.6; 6th month=298.4; p=0.07); in CGR 2 a decrease in CD4+ below the
baseline was observed at the 24th month (mean=89.8; p=0.030). No differences were
observed in the other parameters, including p24 Ag and (32-microglobulin.
Conclusions: In the present study both treatments were well tolerated.The observed amylasis trend may suggest IFN increase of DDI pancreatic toxicity DDI was confirmed to be
effective in increasing CD4+ cell counts.The association with IFN seems to increase and to
prolong this effect.
G. Gregis, Clinica di Malattie Infettive eTropicali, Spedali Civili, 25 100 Brescia, Italy
Tel:.[phone]I Fax:.[phone]I
Mo.B.I 127
ANITI-HIV ACTIVITY AND MECHANISM OF NICKED AND CIRCULAR DUMBBELL
RNA/DNA CHIMERIC OLIGONUCLEOTIDES
Yamakawa H, Hosono K, InagawaT, Singh R,Takai K, Takaku H. Chiba Institute of Technology
Tsudanuma, Narashino, Chiba 275, Japan
Objective: We have studied a new type of antisense oligonucleotide, with RNA-DNA base
pairs (sense (RNA) and antisense (DNA)) in the double helical stem (nicked and circular
dumbbell DNA/RNA chimera oligonucleotides).
Methods: The circularization of the 40 mer DNA/RNA chimeric oligonucleotide was carried out by enzymatic ligation with T4 ligase. RNase H activity was carried out in the presence of the 45 mer HIV- I rev RNA and circular or nicked dumbbell RNA/DNA chimeric
oligonucleotide (NDRD) with E. coli RNase H within 4 h. Stability of oligonucleotides to
exsonuclease digestion were obtained by treatment with nuclease S I and SVPD.The antiHIV assay of the activities of test compounds in fresh, cell-free HIV infection was determined by protection against HIV-induced CPE.
Results: The 45 mer HIV- I rev RNA with anti-ODN was completely cleaved by E. coli
RNase H within 4 h. On the other hand, the reaction of the NDRD chimeric oligonucleotide with RNase H gave the corresponding anti-DNA together with the RNA cleavage
product.The 45 mer HIV- I rev RNA was then added to the above reaction, which produced the characteristically shortened RNA fragments. Furthermore, when the circular
dumbbell RNA/DNA chimeric oligonucleotide (CDRD) was used, in place of NDRD, under
the same conditions as described above, RNA template cleavage was observed. Two
enzymes, SVPD and nuclease S I, were used in comparative digestion studies of NDRD and
CDRD chimeric oligonucleotides.The anti-DNA was digested extensively by SVPD within
10 min, whereas NDRD and CDRD were more resistant.The S I endonuclease activity
digested the anti-DNA to mononucleotides in 30 min, whereas the NDRD and CDRD
were very slowly digested.
Conclusions:The new type antisense oligonucleotide described here has increased nuclease
resistance. Of particular interest, antisense DNA is liberated from the RNase H treatment
of dumbbell RNA/ DNA chimera oligonucleotides in cellular.
H.Takaku, Chiba Institute ofTechnology, 2-17- I,Tsudanuma, Narashino, Chiba 275, Japan
Telephone: +8 I1-474-78-0407 Fax +8 I -474-7 1-8764
Mo.B.I 128
PLASMA VIRAL LOAD (VL) AND CD4 CELL COUNT CHANGES IN NAIVE PATIENTS
AT 3 MONTHS AFTER INITIATION OF COMBINED THERAPY WITH ZIDOVUDINE
(ZDV) AND ZALCITABINE (DDC)
Ibanez Angela*, Ruiz L*, PuigT*, Gutierrez C**, SAnchez I***, Clotet B*, and the Group for
the Study ofVL in patients undergoing combination therapy *Retrovirology Lab. IRSI-Caixa
and AIDS Unit. Hospital Universitari GermansTrias i Pujol, Badalona;** Hospital Joan XXIII,
Tarragona; *** Hospital Arnau deVilanova, Lleida. Spain
Objective:To examine the plasma viral load (RNA HIV- I copies) at baseline, 4 and 12
weeks and to compare these values with CD4 cell counts in naive patients that initiated
antiretroviral therapy with ZDV+ddC.
Methods: We studied 31 HIV seropositive patients not previously exposed to antiretroviral
therapy ("naive patients"). Forty percent were drug addicts and 60% homosexuals.The
range of CD4 cell count at baseline was 200-500/mm3. Dosage of ZDV was 200mg/8h and
ddC 0.75mg/8h. In all patients plasma was collected and frozen at -80C at baseline, weeks
4 and 12. Plasma viral load was determined by RT-PCR (Roche Diagnostic System, Alameda,
inc.). All VL determinations were performed at the same time to avoid interassay variability
Results: The following table summarizes the mean results.

ot
0
U
C
c0
C
0
U
C
0
U
(d
C
0
c
C
-)
C
7
76

N~ patients studied
VL (RNA copies/ml)
VL (log1l0
CD4/mm
CD4%

BASELINE
31
72779
4.86
344
23.20

WK4
25
6267
3.80
360
21.24

WK 12
30
15646
4.20
434
25.22

In 24 out of 31 patients (77%) we observed a mean reduction of viral load of 1.3 log 10
and I. I log 10 at weeks 4 and 12 respectively.The VL decreased > 1.4 Iog 0 at 12 week in
37.5%. Mean CD4 cell count increased from 344/mm3 at baseline to 434 after 12 weeks of
combined treatment.