More News from ICAAC
by Charles E. Clifton and
Enid Vázquez
Switching
studies
In the SWATCH study
(Netherlands), 69% of participants who switched between two
different regimens every three months attained viral loads
under 400, as compared to 57% of individuals who remained
on the same regimen for 48 weeks. One group of 52 participants
took Zerit, Videx and Sustiva. A second group of 54 took Epivir,
Retrovir and Viracept. The third group of 55, the switching
group, alternated between the two regimens. T-cells were not
statistically different among the three groups, however, cholesterol
increased significantly among all three groups, when compared
to baseline. Participants on Sustiva had an increase in HDL
cholesterol levels, and Viracept treated individuals had an
increase in LDL cholesterol.
At 48 weeks, the 106 participants
who switched to Trizivir (Ziagen, Epivir, and Retrovir) from
HAART (highly active antiretroviral therapy) regimens, continued
to have the same rate of success (78%) of maintaining a viral
load less than 400 as the 103 participants who remained on
the same HAART regimen. In order to enter the study, participants
had to have a viral load less than 50 and to have been on
their current regimen for more than six months. The study
also reported a sharper decline in fasting cholesterol and
triglyceride levels in the participants who took Trizivir.
PI
mutations
In a study designed to observe
protease mutation patterns associated with lopinavir, data
at 96 weeks shows no drug resistance in treatment naïve participants
who were given a Kaletra-based regimen. Of the 326 individuals
taking Kaletra in combination with Zerit and Epivir, 40 experienced
a viral load rebound (greater than 400), but none had a protease
inhibitor resistant HIV by genotypic testing.
Resistance
rampant?
Data from the HIV Cost
and Services Utilization Study (HCSUS) indicated that 78%
of HIV-positive adults, treated in early 1996, who had detectable
viral load showed some form of drug resistance. A total of
1906 samples were collected from participants using ViroLogic’s
PhenoSense test. The HCSUS is a longitudinal study representing
some 209,000 HIV-positive adults in the U.S. who were in treatment
in 1996. The levels of resistance differed by drug class,
with 42% for protease inhibitors (PIs), 70% for nucleoside
reverse transcriptase inhibitors (NRTIs), and 31% for non-nucleoside
reverse transcriptase inhibitors (NNRTIs). Male sex, lower
CD4 T-cell count, and higher viral load were identified as
key indicators of higher risk of drug resistance.
The report got treatment
advocates to raise charges of media and research hype. As
stated here before, the issue of resistance—when the virus
learns to resist the drugs thrown at it—is very complicated.
Sometimes the virus mutates before people go on meds, which
means that their HIV may develop resistance to one or more
of the HIV meds. One study found that even with a near-perfect
adherence level of 95%, one out of five people will develop
detectable viral load (one indication of drug resistance).
And generally, if you go on HIV drugs, you develop HIV drug
resistance. Maybe only a very little and maybe not even detectable
by drug resistance tests. On top of that, it’s not very clear
what all the mutation patterns of the virus mean for clinical
care.
Longtime activist and advocate
Matt Sharp said the results of the survey are not surprising,
and only indicate that HIV medications are too “mediocre”
to control the virus. Another advocate pointed out that you
can often still do well and be healthy with resistant virus—absolutely
true. Another important point: the majority of the people
looked at in this analysis started out with suboptimal therapy,
which contributes to the development of resistance. People
taking HIV medications today start out with stronger therapy.
In his longtime, highly respected
newsletter, AIDS Treatment News, John James concludes
that, “…generally it is best to have HIV fully suppressed
whenever antiretrovirals are used, so that there is little
or no viral replication, and resistant virus cannot evolve.
But for many patients this goal is not feasible. For these
patients and for everyone else with HIV, we need new drugs
that are more effective, less toxic, and less susceptible
to viral resistance. We especially need new classes of treatments,
including new targets for antiretrovirals, and immune-based
therapies to help the body itself control HIV.”
New
drug on the block: Viread
Viread (tenofovir disoproxil
fumarate, TDF) is a nucleotide reverse transcriptase inhibitor
that was approved by the FDA last fall (see 2002
Positively Aware HIV Drug Guide). It is taken as
a single 300 mg tablet once a day with food. Data was presented
on Gilead 907 study, a phase III trial with 552 participants
(viral load between 400-10,000 copies/mL) on a stable antiretroviral
regimen. TDF was added to the regimen of 368 participants,
and 184 were given a placebo (sugar tablet). At 24 weeks,
the viral load of participants who added TDF had dropped 0.61
log; the viral load of 42% of the TDF recipients was less
than 400 copies/mL; and less than 50 copies/mL in 22%.
The potential of cross-resistance
between TDF and nucleoside analogs suggests that this is not
a salvage drug. However, it has shown promise as a nucleoside
alternative in the NRTI-experienced or for intensification
in individuals with low-level viral load. Gilead’s ongoing
study 903 will provide much needed data on the effectiveness
of this drug for treatment naïve individuals.
Drugs
on the horizon
TMC 125 is a second
generation NNRTI in the same class of drug as Sustiva and
Viramune, that is being tested by Tibotec-Virco. It has shown
promise in vitro against highly NNRTI-resistant virus. The
results of a small phase II trial were presented. Twelve treatment
naïve participants received seven days of direct-observation
monotherapy with TMC 125, at a dose of 900 mg twice a day,
and were compared with six participants who received a placebo.
Those who took TMC 125 experienced a very impressive 2 log
drop (1.13-3.30 log) in viral load over the one-week treatment
period. “As far as we know, no drug has shown this large of
a viral load drop in this short of a time,” said presenter
Dr. G. Van ‘T Klooster, who works for Tibotec-Virco. “This
spells hope.” Eight participants achieved viral loads less
than 400 copies/mL and two achieved viral loads less than
50 copies/mL in seven days. However, participants taking TMC
125 in this trial had to swallow 18 pills twice a day! This
means that some serious formulation issues will have to be
resolved before TMC 125 can be expanded to larger clinical
trials. Afterwards, they received standard of care therapy.
The primary side effect was mild somnolence (sleepiness).
Study participants were taking HIV medication for the first
time. Doctors at the conference expressed enthusiasm for the
drug’s potential.
Tipranavir (TPV) is a non-peptidic
protease inhibitor that has demonstrated potential against
a wide range of PI-resistant strains, is being developed by
Boehringer-Ingelheim. Data was presented from 16-weeks of
an open-label trial comparing two doses of TPV/Norvir (ritonavir)
[500/100 mg twice a day and 1250/100 mg twice a day] with
Fortovase (saquinavir soft-gel)/Norvir [400/400 mg twice a
day] in participants who had failed a single PI (viral load
greater than 1000 c/mL) and who still had at least two NRTIs
available. The data indicates that participants who received
a higher dose of TPV/Norvir (55%) achieved viral loads less
than 400 c/mL than those who received the lower dose TPV/Norvir
or the Fortovase/Norvir based regimen. Nearly 42% of the participants
in this study did not demonstrate PI resistance, despite failing
a PI-based regimen. This would seem to indicate that more
testing is called for with more PI-resistance participants.
If all goes well atazanvir
(Zrivada), the once a day protease inhibitor, being developed
by Bristol-Myers Squibb, will most likely be the next PI approved
by the FDA. Results from BMS 008 were presented, in which
treatment naïve participants were randomized to receive either:
atazanavir (400 or 600 mg once a day) or Viracept (nelfinavir,
1250 mg twice-a-day) plus d4T/3TC (Zerit/Epivir). The observed
reduction in viral load was similar in all three arms of the
study. Most notable was the increased cholesterol level in
5-7% of those receiving atazanavir, compared to 20-25% receiving
Viracept, and diarrhea was less common in participants taking
atazanavir. Like Norvir, atazanavir increases the level of
other PIs. However, atazanavir seems less likely to cause
hyperlipidemia (heart disease) than Norvir. Atazanavir or
“Taz” (as some doctors call it) also appears to have little
if any adverse effect on lipid profiles. An expanded access
program is expected to start soon; call toll-free 1-877-726-7327.
T-1249, the “Son of T-20”
(as doctors call it), showed a good drop in viral load after
two weeks, despite baseline resistance in the people using
it. You would expect this fusion inhibitor to work for people
with HIV drug resistance, since it’s in a new class of anti-virals.
Nevertheless, the influence of resistance patterns needed
to be examined. Half of the people in this tiny, early trial
had relevant mutations to all three HIV drug classes now on
the market. Like the people in T-20 trials (expected to be
on the market this year), these participants had taken many
other HIV drug combinations. Viral load drop varied according
to the dose of the injections: an insignificant drop for people
on the 6.25 mg dose per day vs. an excellent result in people
taking 50 mg per day (–1.40 log).
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