| HIGHLIGHTS FROM HAMBURG Latebreaker Abstracts
Approximately 25 abstracts were accepted for latebreaker
presentation at the conference. A selection are discussed below
Saquinavir
Soft gelatin formulation
A new soft gel capsule formulation of saquinavir (SQV-SGC; FortovaseTM) has
been developed which, at the recommeded dosage, achieves plasma exposures 8-10 fold
greater than those attained with the current recommended dose of the existing hard gel
capsule (SQV-HGC), Invirase.
Data presented today at the conference support its role as
a potent antiretroviral. Dr Brian Conway (USA) reported data from a study of 171
HIV-infected subjects na�ve to antiretorviral treatment and with HIV RNA >5000
copies/mL, who were randomised to 2 RTIs of choice plus either SQV-SGC 1200mg tid or
SQV-HGC 600mg tid. In an intent-to-treat analysis conducted after 16 weeks�
treatment, 80% of patients in the SQV-SGC arm achieved plasma viral loads below the level
of quantification of the Amplicor assay (<400 copies/mL) compared to 43% in the SQV-HGC
arm (p<0.001).
The activity of SQV-SGC is also being investigated in
children old enough to swallow the capsule. To date, 14 children aged 3-13 years (median
of 4 years of prior NRTI therapy) have been recruited into the study. Preliminary data
presented by Dr. C. Fletcher (USA) showed that at weeks 4 and 8, plasma HIV RNA was below
the limit of quantification (<400 copies/mL) in 5 of 12 and 7 of 7 children,
respectively. The regimen has been well tolerated, with no serious adverse events or
discontinuations reported to date.
Hard gelatin formulation
As well as the development of a new formulation, attempts are being made to maximise
plasma SQV exposure by exploiting pharmacokinetic synergy with other agents. In a study of
25 heavily pretreated patients with advanced HIV infection (mean CD4 count
80�cells/mm3 and HIV RNA 4.5 log10copies/mL) a bid regimen of
SQV 1000�mg, nelfinavir (NFV) 1250�mg + 2 NRTIs achieved a mean HIV RNA decrease
of 1.8 log10 copies/mL at 8 weeks (Lohmeyer et al.). This was accompanied by an
increase in CD4 count of 113 cells/mm3. In 10 of 17 patients, HIV RNA levels
were below quantification (<500�copies/mL) at week 8. The regimen was generally
well tolerated, with only one discontinuation due to intolerance (diarrhoea).
Dr C. Workman (Australia) reported on 12 heavily pretreated
patients who had failed all previous treatment regimens (including all 3 licensed protease
inhibitors) who then received salvage therapy with a 6-drug regimen comprising SQV, NFV
and nevirapine (NVP) plus 3 NRTIs. Despite a mean baseline viral load of 170,000
copies/mL, all 9 patients who remained on the regimen for 12 weeks had no detectable
plasma HIV RNA. Drug failure was not associated with adherence but with tolerance.
Particularly encouraging was the fact that recycling of previously failed drugs appeared
effective in this multi-drug regimen.
Nelfinvair
The use of nelfinavir plus 2NRTIs in RTI-, PI-experienced
patients was discussed by Dr U Hengge (Germany). A total of 43 patients with mean baseline
HIV RNA of 5.15�log10copies/mL and CD4 cells counts of 132 cells/mm3
were treated with NFV 750mg tid + d4T 40mg bid + ddI 400mg. After 12�weeks, HIV RNA
had dropped by a median of 2.23 log10, falling to below the limit of detection
in 9/29 (31%) patients. Adverse events included one death due to pancreatitis (a known
toxicity of ddI), lipase elevation (n=3), hypertriglyceridaemia (n=2), loose stools (n=9),
depression (n=1) and allergic reaction to NFV (n=1). Dr Hengge concluded that this triple
NFV-containing regimen appears to provide potent antiretroviral activity in patients
pretreated with other PIs and RTIs, although individuals need to be carefully followed for
adverse events.
Preliminary data presented by Dr M Sension (USA) suggest
that NFV may be able to be administered in a bid regimen. NFV 1250mg + d4T 30 or 40mg +
3TC 150mg were given twice daily to 10 asymptomatic HIV-infected individuals (median
baseline HIV RNA and CD4 count 191,976 copies/mL and 399 cells/mm3,
respectively), one of whom was lost to follow up. In all remaining individuals, plasma HIV
RNA had fallen to below the limit of quantification (<400 copies/mL) by week 16, with a
mean change from baseline of -2.73 log10copies/mL. The regimen was generally
well tolerated, the most frequently reported adverse event being diarrhoea/loose stools.
Pharmacokinetic and preliminary activity data on the
combination of NFV and indinavir (IDV) were reported by Dr K Squires (USA). NFV 750mg +
IDV 1000mg was given every 12 hours to PI-na�ve individuals with HIV RNA � 30,000
copies/mL and CD4 counts � 100 cellls/mm3. Pharmacokinetic data are available
for 11 patients. The mean AUC12, trough C12h and Cmax for IDV were
similar to those reported for historical controls treated with IDV in the standard 800mg
tid regimen without NFV. Although average NFV Cmax and C12h were similar to
historical data for NFV 750mg tid without IDV, average NFV trough were lower in this study
than those reported historically for the tid regimen (0.7�mg/L vs 1.5mg/L). The
combination had potent antiviral activity reducing HIV RNA to <500 copies/mL at week 8
in 7 of 10 patients. One patient discontinued because of rash. Other adverse events
included diarrhoea/loose stools (n=6), bloating (n=2), and nephrolithiasis (n=1). Based on
the PK data, higher NFV concentrations may be required when the drug is coadministered
with IDV.
Further data on the resistance profile of NFV were
presented by Dr Hertogs (Belgium). Samples were derived from patients in Phase I/II
dose-ranging studies who had received NFV 1500 to 3000 mg/day for 2-52 weeks. Complete
concordance of phenotypic PI-resistance levels determined by recombinant virus and PBMC
assay were obtained in 11/12 patients. Phenotypic NFV resistance was detected in 8 of the
12 patients. In all 8 cases, the D30N mutation was present. Phenotypic resistance to SQV
and RTV was detected in one isolate. However, the patient had been pre-treated with SQV.
141W94
Professor N. Clumeck (Belgium) presented 12-week data from
PRO2002, a placebo controlled dose ranging study of 141W94, the new protease inhibitor.
141W94 was given at doses of 900mg, 1050mg, 1200mg or placebo in combination with ZDV+3TC,
all drugs given bid. 80 HIV-infected individuals na�ve to protease inhibitors and 3TC and
with a CD4 count � 150 cells/mm3 were included. In the 12-week
intention-to-treat analysis, the 1050mg arm contained the greatest proportion of patients
with HIV RNA below either 400 copies/mL (14/20) or <40 copies/mL (7/20). In contrast,
in the per protocol analysis, the 1200mg arm fared better with regard to this parameter
which can be explained by the higher number of discontinuations due to adverse events in
this arm compared with the 1050 arm (6 vs 0). Paraesthesia (6/20) and skin rashes (9/20)
tended to occur more frequently in the 1200mg group.
DMP 266 (Efavirenz)
Three of the latebreaker abstracts discussed the antiviral
activity of DMP 266 in a variety of combination regimens. In the first, Dr Hicks (USA)
reported the results from a Phase II study in which 137 previously untreated asymptomatic
or mildly symptomatic individuals patients were randomised to ZDV + 3TC + either placebo
or DMP 266 200mg qd, 400mg qd or 600mg qd. Median baseline HIV RNA and CD4 counts ranged
from 4.64-4.79 log10copies/mL and 337-394 cells/mm3, respectively.
Eight patients in the 600mg and 7 patients in the 400mg arms discontinued prematurely
compared to 4 patients in the placebo and 200mg arms. All 3 DMP 266 arms were
significantly superior to placebo in terms of percentage of patients with HIV RNA <40
copies/mL at week 16 (74% vs 63% vs 64% vs 15% in the 200mg, 400mg, 600mg and placebo
arms, respectively). Interestingly, the HIV RNA response was comparable between the 3 DMP
266 dosage arms. Compared with placebo, DMP 266 was associated with a significantly higher
incidence of headache [53% (400mg) vs 24%] and dizziness [44% (600mg) vs 18%].
The combination of DMP 266 and IDV vs IDV monotherapy in
NNRTI-na�ve individuals was reported by Dr N Ruiz (USA). Patients in the monotherapy arm
were allowed to add DMP 266 and d4T after 12 weeks. DMP 266 + IDV supressed HIV RNA to
undetectable (<1 copy/mL by Amplicor) in a significantly higher percentage of patients
than IDV monotherapy at week 12 (64% vs 32%) and week 24 (88% vs 62%).
In a separate presentation, Dr Ruiz evaluated predictors of
virological failures (defined as reappearance of plasma HIV RNA >400 copies/mL) in the
above study. Patients with residual detectable viral load were found to have a higher
relative risk of virological failure and a shorter time to virological failure. Increased
age also seemed to increase risk of failure.
Adverse Events
A poster discussion on Monday evening focused on the
adverse event profile of antiretrovirals, in particular the incidence of crystaluria and
nephrolithiasis with IDV. The incidence of nephrolithiasis in IDV-treated patients varied
between presentations, with one presenter reporting an incidence of 9% (Valencia et al.).
Dr G. Michl (Germany) analysed urine samples from 121 IDV-pretreated patients. In 29
patients, samples were taken continuously. The data suggests that the incidence of
crystalluria is considerably underestimated by random sampling, being reported in 19.6% of
patients evaluated by this method compared to 62.1% in the continuous sampling group.
Interestingly, there appeared to be no difference between those patients who had
crystaluria and those that did not with respect to body weight, urinary pH and fluid
intake. Patients with lower urinary weight over 8 hours appeared to have a higher
incidence of crystalluria.
The tolerability of currently available protease inhibitors
was reviewed by Dr I Santos (Spain). SQV appeared to be the best tolerated agent. RTV
resulted in discontinuation of therapy in approximately 50% of patients, primarily because
of digestive symptoms. Kidney stones was one of the most frequent complications in
IDV-treated patients, with 15/104 patients discontinuing therapy for adverse events.
Two cases of diabetes mellitus under IDV therapy were
reported by Dr R. Walli (Germany). Patient 1 developed diabetes mellitus 4 weeks after
starting IDV+3TC+d4T. IDV was stopped and the patient began treatment with glibenclamide.
In the second patient, acute pancreatitis and diabetes mellitus was diagnosed 2 months
after starting IDV+ZDV+3TC. The patient continued on IDV but was also treated with insulin
for 6 months and glibenclamide.
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