CROSS RESISTANCE DATA
PRESENTED AT ICAAC SUPPORT FIRST-LINE USE OF VIRACEPT
LONG TERM DATA SUPPORTS
TWICE DAILY ADMINISTRATION
Studies continue to expand the VIRACEPT« (nelfinavir mesylate) knowledge
base, supporting its role as an optimal first PI to preserve other treatment options, as
well as its use in convenient twice-daily (or BID) dosing regimens. These new data were
among those presented at the 39th Interscience Conference on Antimicrobial
Agents and Chemotherapy in San Francisco.
VIRACEPT As The "First" Protease Inhibitor
A new study presented by Dr. Haubrich1 has found that patients treated with
VIRACEPT before using other protease inhibitors (PIs) are less likely to develop
cross-resistance to other PIs even if HIV resistance to VIRACEPT develops. The multicenter
California Collaborative Treatment Group study examined differences in protease inhibitor
phenotypic susceptibility after failure of a patient's first PI-containing regimen.
The trial studied 116 patients with a median HIV RNA of 4.1 log10 copies/ml
and a median CD4 cell count of 295 cells/mm3; 96 patients had received prior PI
therapy. In patients previously treated with VIRACEPT, viral isolates remained susceptible
to FORTOVASE« (saquinavir) and amprenavir in the majority of cases. Only 29%
of patients who had received VIRACEPT had reduced susceptibility to 2 or more PIs; 70% of
patients with prior indinavir experience had reduced susceptibility and 43% with other
prior PIs had reduced susceptibility (p=0.001).
Conversely, 84% of patients had viral isolates that remained susceptible to FORTOVASE,
and 83% responded to amprenavir.
The varying degrees of cross-resistance reported suggest that prior use of indinavir is
associated with greater cross-resistance than prior use of the other PIs studied. These
data lead the researchers to suggest that when VIRACEPT is used as the first PI, it is
associated with less cross-resistance than the other available PIs, thereby preserving
patient treatment options.
VIRACEPT Twice-A-Day: the Women First Study
Data presented by Dr. Clark2 from a 48-week prospective study, known as the
Women First Study, evaluated two combination regimens in women na´ve to PIs, d4T and 3TC:
VIRACEPT 1250-mg BID (or two times a day) + FORTOVASE 1000-mg BID + standard
doses of d4T and 3TC or VIRACEPT 750-mg TID (or three times a day) + FORTOVASE 600-mg
TID + standard doses of d4T and 3TC.
An intent-to-treat analysis of the data found that the BID arm was more effective than
the TID arm in reducing viral load (HIV RNA <50 copies/ml = 67% vs. 50%, respectively)
and demonstrated similar increases in CD4 cell counts (182 cells/mm3 and 170
cells/mm3, respectively). The study also assessed the effect of these two
regimens on several markers of metabolic function: cholesterol, triglycerides, and
glucose. There were no significant differences between the two arms, but both arms caused
small elevations of these markers.
VIRACEPT Helps Patient Adhere Better to Treatment, Study Shows
Data from a prospective study examining drug efficacy and patient convenience --
believed to be a strong factor in patient adherence -- were presented by Dr. Roca3.
One hundred twelve treatment-experienced patients were randomized to one of two arms:
VIRACEPT + d4T + 3TC or indinavir + d4T + 3TC. Most significant was the difference between
the groups in their actual drug adherence levels. At 6 months, 70% of subjects taking
VIRACEPT were adequately adherent, while only 48% of the indinavir group demonstrated
adequate adherence (p = 0.0311). Side effects also proved to be a factor in adherence,
with 12% of those on VIRACEPT discontinuing their participation by
6 months while 34% of patients on indinavir discontinued their drug regimen due to side
effects during the same period.
The researchers conclude that while the efficacy of both regimens was similar, those on
the VIRACEPT-containing regimen displayed a stronger level of adherence, which may
translate into longer lasting virological benefit when compared to those receiving
Protease Inhibitors Suppress Viral Load Longer Vs. Protease-Sparing Regimen
Julio Montaner, M.D., St. Paul's Hospital, Vancouver, presented retrospective data from
a study comparing the durability of three drug regimens, two of which used protease
inhibitors and one of which was protease-sparing4.
Data on 151 patients on triple therapy from the INCAS (AZT + ddI + NVP), AVANTI 2
(indinavir + AZT + 3TC), and AVANTI 3 (VIRACEPT + AZT + 3TC) trials with an HIV-RNA nadir
between 20 and 400 copies were combined into a single database. After controlling for
baseline differences in viral load, CD4 count, and adherence among the three trials, there
were statistically significant differences in the times viral load remained below 500
copies/ml, below 1,000 copies/ml, and 1 log10 below baseline levels.
Among the patients who were between the limit of quantification and 400 copies/ml,
those assigned to either protease inhibitor-containing regimen had longer virologic
suppression than those assigned to AZT + ddI + NVP, the NNRTI-containing regimen.
VIRACEPT + Delavirdine Boosts VIRACEPT Blood Concentrations
Another prospective, 48-week study (the first of two parts) presented by Dr. Slater5
examined the ability of delavirdine (DLV), an NNRTI, to increase blood concentrations of
VIRACEPT. Twenty-two HIV-infected individuals were randomized in the study to receive
either delavirdine 400-mg TID or 600-mg TID in conjunction with VIRACEPT 750-mg BID + d4T
40-mg BID + ddI 200-mg BID for 48 weeks. Mean baseline values were viral load of 4.85 log10
copies/ml and CD4 count of 372 cells/mm3. Mean VIRACEPT trough concentrations
with DLV were roughly twice those seen from historical data with a VIRACEPT 750-mg TID
regimen without DLV.
Mean reduction of viral load was greater in the DLV 600-mg arm at both weeks 24 and 48.
Of the 13 patients who were available to be evaluated at week 48, 69% had viral loads
below 50 copies/ml for the entire 48-week period. The researchers suggest that the
durability and efficacy demonstrated in this trial support the potential use of DLV 600-mg
with VIRACEPT in a BID regimen.
Dr. Gatell6 presented results from part two of this prospective study of the
effect of delavirdine in increasing VIRACEPT concentrations in the blood. The study tested
the safety, efficacy, and tolerability of DLV BID in one of four treatment arms:
- VIRACEPT 1250 mg BID + d4T 40 mg BID + ddI 200 mg BID;
- VIRACEPT 1250 mg BID + DLV 600 mg BID + d4T 40 mg BID + ddI 200 mg BID;
- VIRACEPT 1250 mg BID + DLV 600 mg BID + d4T 40 mg BID; or
- VIRACEPT 1250 mg BID + DLV 600 mg BID + ddI 200 mg BID.
While more than 175 HIV-infected, NNRTI- and PI-na´ve, minimally ddI-experienced
(< 1 month) individuals have enrolled in the trial, week 24 data are currently
available on only 45 patients. Baseline laboratories for all enrolled patients showed a
mean viral load of 4.9 log10 copies/ml and a mean CD4 count of 306 cells/mm3
at week 24.
All four arms reported a mean reduction of 2.6-2.7 log10 in viral load with
81% achieving <400 copies/ml and 67% achieving <50 copies/ml. There was also a mean
increase in CD4 count of 183 cells/mm3. The researchers suggest that these data
show the efficacy and potential durability of a BID regimen combining DLV and VIRACEPT
plus d4T and/or ddI.
Saquinavir + Ritonavir: Effective Following VIRACEPT Therapy
Dr. Zolopa7 presented the results of this retrospective multi-center study
that systematically screened medical records, pharmacy records, and electronic databases
to identify patients who had taken VIRACEPT as their first PI, had a documented 1 log10
decline in HIV viral load; had a rebound of more than 0.6 log10, and were
placed on a salvage regimen of RTV + SQV with or without NAs. Data available on 79
patients show baseline (the point of the change to SQV + RTV) values of a median CD4 of
219 cells/mm3 and a viral load of 4.52 log10.
Data from 3 months and 6 months on salvage therapy show:
The researchers suggest that these data support previous pilot clinical trials that
demonstrate the potential for using SQV/RTV after VIRACEPT with substantial and durable
Dr. Perez-Rodriguez8 presented data from this open-label, prospective study
that enrolled 15 patients with a history of diarrhea induced by VIRACEPT and treated with
at least one prior anti-diarrheal medication with unsatisfactory results. At baseline, all
but three patients had viral loads below 400 copies/ml and a mean CD4 cell count of 565
cells/mm3. Patients were given a short battery of questions to assess their
symptoms and then given 500-mg calcium tablets BID to take with their VIRACEPT. After 48
hours of treatment, they were asked an additional series of questions to determine any
changes in their bowel movements. Prior to calcium treatment, 40% classified their
symptoms as mild, 47% as moderate, and 13% as severe.
After a minimum of 48 hours of calcium supplementation, 87% reported normal stools and
the remaining 13% reported only mild diarrhea symptoms. No side effects were associated
with calcium use. The researchers suggest that calcium supplementation might be an
effective, low-cost intervention to address this type of diarrhea.
In similar study, Dr. Ronagh9 presented data from a short prospective study
that enrolled 16 patients with symptoms of PI-associated diarrhea refractory to treatment
with anti-diarrhea medications to assess the effect of psyllium husk fiber bars on their
symptoms. Fourteen patients completed the study. At baseline, mean HIV viral load was 4.84
log10 copies/ml and mean CD4 count was 275 cells/mm3. Questionnaires
were used before and after the study to assess the state of the patients' symptoms and the
taste of the bars. Patients were provided with dietary counseling and two weeks' worth of
psyllium husk fiber bars. Prior to treatment, 29% classified their symptoms as mild (grade
1), 64% as moderate (grade 2), and 7% as severe (grade 3), with a mean overall grade of
After two weeks of using the bars, 93% of patients reported that their symptoms
improved: 50% reported normal stools, 29% reported grade 1, and 21% grade 2, for a mean
overall grade of 0.93. All of the patients reported liking the taste of the bars and 86%
continued to use the bars after the end of the study. The researchers suggest that
psyllium husk fiber bars might be an effective, low-cost intervention to address one of
the main side effects of PI-induced diarrhea.
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