World AIDS Conference Data Supports Dual Protease Inhibitor
Therapy With Norvir as First-Line Treatment For HIV And AIDS
Growing Experience Shows Norvir Regimen Highly Potent, Durable, Tolerable
Tuesday June 30, 10:45 am Eastern Time
Company Press Release
GENEVA, June 30 /PRNewswire/ -- Leading experts at the XII World AIDS Conference in Geneva presented data that
support the use of a treatment regimen that includes two protease inhibitors as first-line therapy for HIV and AIDS. The
growing importance of dual protease therapy has emerged as a major treatment trend.
The researchers, led by Dr. J Court Pedersen (Odense University Hospital, Denmark), Professor Sven Danner (NATEC,
University of Amsterdam), Dr. Cassy Workman (Fitzroy Street Centre, Sydney, Australia), and Dr. Charles Flexner (Johns
Hopkins University Medical School, USA), presented data from four different studies showing therapy with Norvir(R)
(ritonavir) in combination with a second protease inhibitor offers potent therapy, twice-daily dosing, lower doses, and good
tolerability.
''Intervention with a combination therapy including two protease inhibitors is equal to, or more effective than, other current
first-line treatment regimens in achieving viral suppression,'' said Professor Danner. ''Not only is dual protease therapy at
least as potent as other first-line therapies, but its greater convenience enhances the likelihood of long-term success for
patients.''
Since the introduction of protease inhibitors two years ago, standard antiretroviral therapy has been a three-drug regimen
including two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor. However, the difficulty in
complying with current three-drug combinations has resulted in a significant rate of treatment failures.
More recently, scientists have studied the potential of two protease inhibitors and one or two NRTIs as a new standard.
These recent data suggest that the most widely studied regimen, ritonavir and Invirase(R) (saquinavir), appears to be a
potent and durable therapy in suppressing viral load below detectable levels, has convenient twice-daily dosing, and is well
tolerated.
The protease inhibitor ritonavir, when used in combination therapy, increases the serum levels of co-administered protease
inhibitors by slowing their metabolism. This leads to greater reductions of viral load, a key measurement in the management
of HIV/AIDS, and reduces the amount of medication required.
Dual protease plus nucleoside analogues vs. standard triple therapy Data presented by Dr. Pedersen demonstrated that
treatment with ritonavir/saquinavir, both 400mg twice daily, in conjunction with two NRTIs is well tolerated and may have
superior short-term anti-viral activity compared with other single protease-inhibitor regimens.
''The use of ritonavir with saquinavir results in a combination regimen that achieves high levels of anti-viral activity while
using lower doses of both drugs. The regimen is also well tolerated,'' said Dr. Pedersen.
The study looked at 284 protease-inhibitor naive patients, of whom 119 patients were naive to antiretroviral agents. All
patients were randomly assigned to one of three regimens containing either ritonavir, indinavir or ritonavir/saquinavir. All
patients received nucleoside analogues during the study. At six months, in the antiretroviral naive group, 92 per cent of
patients in the ritonavir/saquinavir group achieved an HIV-RNA of less than 200 copies per microlitre compared to 74 per
cent in the indinavir-only (p=0.05) group and 64 per cent in the ritonavir-only group (p=0.01). At one year, the proportion
of patients in the antiretroviral naive group achieving an HIV-RNA of less than 20 copies per microlitre was 77 per cent in
the ritonavir/saquinavir group compared to 58 per cent in the indinavir group and 39 per cent in the ritonavir-only groups.
There were no differences in the discontinuation rate between patients on indinavir and patients on ritonavir/saquinavir.
''Dual protease inhibitors provide potent antiretroviral therapy and are well tolerated,'' said Dr. Pedersen.
Other ritonavir/saquinavir studies
Professor Danner, reviewing the data from a 72-week long-term study of a protease inhibitor regimen in protease
inhibitor-naive patients, concluded that a ritonavir/saquinavir combination demonstrated a sustainable viral load suppression,
was well tolerated, and highly durable.
The study of a ritonavir/saquinavir regimen, the most extensively studied dual-protease combination, looked at
protease-inhibitor naive patients with CD4 cell counts of between 100 and 500 per microlitre. After 72 weeks of treatment,
90 per cent of patients (87 of 97) had a plasma RNA of less than 200 copies per microlitre. The median increase in CD4
cell counts was 185 per microlitre after 72 weeks.
''Ritonavir/saquinavir should be used earlier in the treatment of HIV-1 infected patients, and not only as 'salvage' therapy
after failure of a prior protease-inhibitor-containing regimen. Given its power and tolerability, this combination should be
used more frequently as part of a first-line therapy,'' said Professor Danner.
Ritonavir/indinavir provides potent therapy
Dr. Workman presented results from a study evaluating the safety, efficacy and tolerability of ritonavir and Crixivan(R)
(indinavir), plus two nucleoside analogues (d4T and Epivir(R) 3TC).
The study assessed 30 patients who were assigned to one of two treatment arms. Group A consisted of 12 patients who
received six months of prior treatment with ritonavir, saquinavir, d4T and 3TC, who had viral RNA levels less than 400
copies per microlitre (undetectable), and who had stable CD4 cell counts. Group B consisted of 18 patients who were all
treatment naive. All patients received 400mg each of ritonavir and indinavir twice daily with food, plus the two nucleoside
analogues. Patients were instructed not to increase fluid consumption.
All patients in group A maintained undetectable viral RNA at 36 weeks, with 75 per cent (nine of 12 patients) experiencing
a mean increase of 340 in CD4 cell count. In group B at the time of data analysis, eight patients had completed 36 weeks of
treatment and all had viral load below 400 copies per microlitre. A significant finding of the study was that there were no
reports of kidney stones or flank pain despite instructions not to increase fluid intake.
''The combination of ritonavir and indinavir plus two nucleoside analogues provides potent viral suppression and an
additional strong effect on CD4 counts,'' said Dr. Workman. ''The convenience of twice-daily dosing without the meal
restrictions and increased fluid requirements currently associated with indinavir therapy offers clear advantages for patients,
as compliance is tied to easier dosing.''
Early results from ritonavir/nelfinavir studies
A study presented by Dr. Flexner evaluated 20 protease-inhibitor naive patients who were evenly randomised in a
dose-comparison trial of ritonavir 400mg/nelfinavir 500mg vs. ritonavir 400mg/nelfinavir 750mg. All medications were
administered twice daily.
At 32 weeks in the low-dose nelfinavir group, six patients had viral load suppressed to less than 400 copies per microlitre
while eight patients in the high-dose nelfinavir group had viral suppression of less than 400 copies per microlitre.
''The combination of ritonavir and nelfinavir is a potent and promising regimen in the management of patients with HIV,''
said Dr. Flexner.
Professor Danner concluded, ''The main benefits of dual-protease therapy are strong viral suppression, more convenient
dosing, and the need for patients to take less medication, which may improve patient adherence and therapeutic outcomes.
For these reasons, dual-protease therapy should be considered one of the promising options for first-line treatment for both
protease-experienced and naive patients.''
NOTES:
Norvir is a protease inhibitor that is indicated for the treatment of HIV-1 infected patients.
Protease inhibitors block the action of HIV protease rendering the enzyme incapable of processing the polyprotein required
for production of mature HIV particles. As a result, disease progression is delayed.
The most frequently reported clinical adverse events other than asthenia among patients receiving ritonavir were
gastrointestinal and neurological disturbances including nausea, diarrhoea, vomiting, anorexia, abdominal pain, taste
perversion, and circumoral and peripheral paresthesias. Use of a dose titration schedule may help to reduce
treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Patients should be aware that
frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paresthesias, may diminish
as therapy is continued.
Abbott Laboratories is a global, diversified health care company devoted to the discovery, development, manufacture and
marketing of pharmaceutical, diagnostic, nutritional and hospital products. The company employs 54,000 people and
markets its products in more than 130 countries.
SOURCE: Abbott Laboratories
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