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New Drugs Reported at 9th Retrovirus Conference
Reported by Jules Levin
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Two new, second generation NNRTIs showed effectiveness in studies for
patients with resistance to nevirapine or efavirenz. TMC-125, from
Tibotec-Virco, showed a 0.9 log reduction in a 7-day study of 16 patients
with extensive NNRTI resistance. Patients stayed on the same nukes for the
7-day study. In a second 7-day study of TMC-125 monotherapy in 12
treatment-naive patients, the viral load decline was a potent 2 log and the
initial viral load decline was as rapid as seen with a 5-drug triple-class
regimen. Both study authors commented on the potency of this drug, in early
studies.
Another second generation NNRTI called DPC-083 from Bristol Myers also showed
potency for patients with resistance to efavirenz or nevirapine, and for
patients naive to treatment. 4/10 patients (on-treatment analysis) who did
not add new NRTIs but simply switched their NNRTI to DPC-083 had <400
copies/ml after 8 weeks; 72% of patients who added 1 new NRTI had <400
copies/ml. The viral load reduction was more than 1 log. In a second study of
DPC-083 in treatment-naive patients, this drug appeared to be as potent as
efavirenz. Although patients experienced rash and CNS side effects, the rate
appeared to be less than that seen with efavirenz in the lower DPC-083 dose
groups. When using the higher DPC-083 dose rash frequency was higher than for
efavirenz. So the dose for treatment-naive patients has been identified , but
not yet for NNRTI resistant patients. More study is needed.
10 treatment-naive patients received Tenofovir once daily monotherapy. They
were hospitalized for the first 72 hours to monitor their viral load
reductions closely. Their viral load was 20,000 and CD4s were 600+. 6 were
African-American and 9 men. The median viral load reduction was 1.6 log at
day 21. And the initial decline in viral load was as rapid as with Norvir
monotherapy. The study authors concluded Tenofovir is as potent as a potent
PI. And that further studies are warranted in treatment-naive patients. The
implications from this study are that Tenofovir may be useful as a first-line
therapy. Doctors recommend following kidney related lab tests every 2 months
while on therapy. Tenofovir appears to be easy to tolerate and the once per
day dosing is convenient.
Initial information was presented on the first integrase inhibitor (S-1360)
from Shionogi-Glaxo Smith Kline to reach this far in development. It showed
potent antiviral activity against viruses from patients in the test tube. It
was synergistic in the test tube with other HIV ART medications. The
preclinical safety data is so far good. And the drug appears to be active
against the integrase target.
There were two interesting presentations on entry inhibitors in development.
Bristol Myers announced for the first time at a conference their development
program for entry inhibitors. They presented on an entry inhibitor it appears
they will try to develop.
Schering Plough presented data in HIV+ humans on their entry inhibitor. SCH-C
has a 24 hour half-life, which suggests it can be dosed once daily. Schering
reported data from a study in 12 HIV+ patients who received 25 mg twice a day
of SCH-C monotherapy. CD4 counts were >250; viral load was 5000-200,000, and
it was a 10-day study. Higher dosing, 50 and 100 mg bid was given in this
study but results weren't presented. CD4s were 377 and viral load was 38,000
on average. There were no discontinuations due to adverse events. 7/12
reported at least 1 AE: headache, bad taste. There was 1 severe AE. The
concern about this drug is that it prolongs QT. This relates to heart beats.
It is not known if this is a significant & prohibitive problem yet. 10/12
patients had at least a 0.50 log reduction. The viral load rebound after
stopping drug was slow. And the viral load decline was steep after a couple
of days. Some patients had 1.0 or 1.4 log reductions. The presenter said the
drug was well tolerated, and the QT effect was small. Schering also has SCH-D
as a backup to this drug.
These studies presented very encouraging information saying the drug pipeline
for patients with drug resistance is promising. as well, the new drugs--2 new
entry inhibitors, and an integrase inhibitor offer new treatment options and
strategies. More detailed reports on these drugs and the conference will
follow.
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