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48-Week Results of Study Comparing New Version of Amprenavir Once-A-Day to
Nelfinavir Twice-A-Day Presented at Glasgow International HIV Meeting
Reported by Jules Levin
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Clearly we are entering the age of once-a-day therapy for HIV. An increasing
number of drugs are approved for once daily use, and these include d4T, ddI,
efavirenz (Sustiva), tenofovir (Viread) and 3TC. Nevirapine is being studied
once daily but has not yet been approved in the USA for once daily use.
Saquinavir also boosted by low dose ritonavir is being studied once per day.
As well, Kaletra is being studied once per day. For some drugs once-a-day use
may or may not be appropriate for some patients and so the pros and cons of
once daily dosing should be discussed between doctor and patient.
Here are excerpts from press release from GlaxoSmithKline reporting the
results of a study comparing the new formulation of their protease inhibitor
amprenavir (called "908) administered in this study once a day and boosted
with loe dose of ritonavir to nelfinavir administered twice a day. Brief
Summary: In what appears to be patients with more advanced HIV, 68% receiving
908/r regimen and 65% of patients receiving nelfinavir regimen had <400
copies/ml after 48 weeks of study; patients achieving <50 copies/ml was 56%
in 908 regimen and 52% in nelfinavir regimen. Patients with >500,000
copies/ml before therapy had a higher percent undetectable when receiving 908
compared to nelfinavir. Although the discontinuation rates for the two drugs
were about the same, more patients withdrew due to lack of viral response in
the nelfinavir group and more patients withdrew due to adverse events in the
908 group. More details are reported below.
Results of the SOLO trial, an open-label, multi-center study evaluating the
safety and efficacy of once-a-day (QD) dosing of the investigational protease
inhibitor (PI) GW433908 (908) boosted with ritonavir (908/r) QD in
antiretroviral therapy-naive patients versus twice-a-day (BID) nelfinavir
(NFV, Viracept), were presented today at a late breaker session at the 6th
International Congress on Drug Therapy in HIV Infection. SOLO is one of the
first pivotal studies to investigate the potential of QD (once-a-day) dosing
of an HIV protease inhibitor. Both drug arms were administered as part of
combination therapy that included abacavir (ABC) and lamivudine (3TC). 1400
mg of 908 is 2 pills and 200 mg of ritonavir 200 mg is 2 pills for a total
pill burden of 4 pills once a day. In the CONTEXT study described at the end
of this report Glaxo is studying 908 in treatment-experienced patients
boosted by low doses of ritonavir compared to Kaletra.
A large proportion of patients with advanced HIV disease. The patients
enrolled in the SOLO trial generally had advanced HIV disease at
baseline (median viral load: 4.8 log; 63,000 copies/ml), with 43 percent
having a viral load greater than 100,000 copies/ml. In addition, 20 percent
had CD4
counts <50 cells/mm3 at baseline. Although patients with active or
acute Class C events were excluded, 22 percent of subjects in the SOLO
trial had a history of Class C events, designated by the U.S. Centers
for Disease Control and Prevention as signs of advanced infection.
Gender diversity. Females represented 30 percent of the patients in the
908/r QD arm and 24 percent in the NFV BID arm.
Ethnic Diversity. In the 908/RTV QD arm, 38 percent of patients were of
African descent and 7 percent were Hispanic. In the NFV BID arm, 33
percent were African and 8 percent Hispanic.
Age range of patients was 18-69 (median 36) years.
Sexual orientation. 48 percent of 908/RTV QD recipients were
heterosexuals, versus 44 percent in the NFV BID arm.
The CONTEXT study is an open-label trial in PI-experienced subjects assessing
908 dosed at 700 mg BID in combination with 100 mg RTV, or 908 at 1400 mg QD
in combination with 200 mg RTV, compared to a third treatment arm of 400 mg
lopinavir/100 mg RTV BID. Participants also receive two active reverse
transcriptase inhibitors. The trial is fully enrolled with more than 300
patients and is being conducted at more than 80 research centers worldwide.
The study is assessing the safety and efficacy of each regimen at 24 and 48
weeks. Results from the CONTEXT trial are expected to be presented in 2003.
649 patients were randomized to receive either 1400 mg of 908 QD combined
with low dose ritonavir (200 mg QD), or 1250 mg of NFV BID. Both groups took
the medications in combination with 300 mg BID of ABC and 150 mg BID of 3TC.
In the 908/r QD arm, 68 percent of 322 patients achieved viral suppression
(<400 copies/ml) compared to 65 percent of 327 patients in the NFV arm.
Virologic failure at 48 weeks was seen in 4 percent of patients taking 908/r
QD compared to 15 percent of those taking NFV BID. Further, a viral load
below 50 copies/ml was achieved in 56 percent of patients taking 908/r QD
compared to 52 percent of patients taking NFV BID.
Seventy-one percent (71%) of patients in the 908/r arm with high viral load
(>500,000 copies/ml) at baseline (n=51) achieved undetectable viral load
compared to 53 percent of patients with high viral load at baseline (n=47) in
the NFV arm.
73 percent of patients in the 908/r arm with low CD4 count (<50) at baseline
(n=62) achieved undetectable viral load compared to 51 percent of patients
with low CD4 counts at baseline (n=69) in the nelfinavir arm. Quantitative
plasma HIV-1 RNA measures in the SOLO study were made using the Amplicor
HIV-1 MONITOR Test, Version 1.5, with the UltraSensitive sample preparation
method (limit of detection=50 copies/ml).
SAFETY
Study researchers report the incidence of dose limiting adverse events (AEs)
and severe laboratory abnormalities was low in both groups. The only drug
related AE that was significantly different between the two groups was
diarrhea, which was significantly (p=0.008) more prevalent in patients on NFV
(16 percent) than patients on 908 (9 percent). Most common other AEs with
908/r were allergy (7 percent), nausea (7 percent), and vomiting (6 percent).
The incidence of Grade 3-4 lipid abnormalities was <1 percent with the
exception of triglycerides which were 6 percent in patients taking 908/r QD
versus 2 percent in the NFV BID arm, but this report does not contain
percentages of patients with grade 2-3 lipid abnormalities. All mean fasting
cholesterol levels remained below the recommended National Cholesterol
Education Program (NCEP) intervention guidelines. In addition, normalization
of HDL-C was achieved in a substantial proportion of subjects.
Study investigator Joseph Gathe, MD reports "the overall rates of
discontinuations were similar in both study groups, more subjects withdrew
due to insufficient viral response in the NFV BID group - 8 percent, or 27
patients - compared to only 1 patient in the 908/r QD group. At the same
time, 9 percent, or 28 subjects, withdrew due to AEs in the 908/r QD group
compared to 5 percent, or 16 subjects, in the NFV BID group".
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