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Viramune
vs. Sustiva
Speaking of guidelines, the
updated adult treatment version reviews the latest head-to-head
data regarding Viramune vs. Sustiva (see “Does
Viramune = Sustiva?” in the May/June Positively
Aware). The updated guidelines clearly state that Sustiva
is preferred over Viramune, except in pregnant women or those
who desire to have a child.
Counterfeit
Kaletra
The U.S. Food and Drug Administration
(FDA) in October warned that bottles of Kaletra may actually
contain a different drug, the wrong expiration date or a counterfeit
lot number. The warning came after 58 bottles of Kaletra had
to be recalled because they contained a different HIV drug
or had the other problems. The take-home message: if your
drugs look funny to you, check with your pharmacist!
For
women
The Well Project, an initiative
designed by and for women living with HIV and AIDS, in September
launched a comprehensive, woman-specific HIV website. The
site offers the latest information on living with and managing
HIV for HIV positive women, health care providers, and advocates.
The mission of The Well Project is to improve the lives of
all women living with HIV disease and the lives of those who
care for them. Founder and CEO Dawn Averitt has provided woman-specific
HIV information and advocacy for more than 10 years, and has
been a source of inspiration for many. More recently, she
was featured with her newborn daughter on the cover of POZ
magazine (December 2002) as part of her story of finally overcoming
HIV to have the child she always wanted.
TheWellProject.com
includes fact sheets, data sets, summary slides, a searchable
clinical trials database, a resource directory and a physician
network for expert discussion on treatment. It is divided
into five targeted sections—HIV: The Basics, Treatment
and Trials, Diseases and Conditions, Living Well and a Women’s
Center. Each section contains articles, links and related
topics. Additionally, members will be able to participate
in confidential and secure discussion boards, read about real
people living with and successfully managing HIV, download
advocacy tools, and receive a regular e-mail newsletter highlighting
the most up-to-date information about women and HIV.
New
name for PCP
PCP stands for “Pneumocystis
carinii pneumonia,” an opportunistic infection that
can flare up in people with a weakened immune system. It was
for a long time a top killer of people with AIDS. However,
“carinii” is a parasite, and it was more
recently found that PCP is actually caused by an atypical
fungus. PCP has now been renamed “Pneumocystis jiroveci”
(or “P. jiroveci” for short). In the September
issue of AIDS Clinical Care, Dr. A. Albrecht notes that the
name change can cause problems with patients, such as explaining
that prevention and treatment remain the same, and with recordkeeping.
Dr. Albrecht says there’s reason to keep the acronym
PCP, which is very well-known among people with HIV/AIDS,
in that it can stand for “PneumoCystis pneumonia.”
The change is helpful to patients, writes Dr. Albrecht, in
that they no longer fear getting PCP from rat droppings or
from pets.
Heart
woes
A survey taken by the International
Association of Physicians in AIDS Care (IAPAC) shows that
nearly 80% of physicians believe that HIV patients taking
antiretroviral drugs are at an increased risk for cardiovascular
complications. They cited smoking, antiretroviral use and
family history as the top three risk factors for heart problems.
Results of the survey of 600 physicians and patients were
presented in a September 16 supplement to the Chicago-based
association’s peer-reviewed publication, JIAPAC.
News
from the 43rd Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC), held in Chicago in September
The Viread/Ziagen problem
Just because a drug combination
seems like a good idea doesn’t mean it will work. That’s
perhaps the most important conclusion from ESS30009, a trial
comparing once-daily Sustiva and Viread, both combined with
the once-daily, fixed-dose co-formulated Ziagen/Epivir. The
study had to be stopped early because of poor results with
the combination of Viread plus Ziagen/Epivir, a combination
of three potent drugs that was expected to work well, but
which failed miserably.
Researchers are investigating
possible reasons for the failure of this triple nucleoside
combination. One possibility is the similar resistance profiles
of the three medications. Unless they’re completely suppressing
viral load, HIV drugs put pressure on the virus that cause
it to mutate and become resistant. In most cases, the different
drugs in a regimen cause different mutations, which means
that it takes several mutations to become resistant to the
combination. However, in the case of the Ziagen/Epivir + Viread
combination, one mutation (K65R) can cause resistance to all
three of the drugs.
Study presenter Dr. Joel
Gallant, an HIV specialist at Johns Hopkins University, said
that the low barrier to resistance may have been responsible
for the failure of this combination. “On the other hand,
we have drug regimens requiring only two mutations for resistance,
such as Viread + Epivir + Sustiva, that are extremely potent
and durable.” Also, a third of the patients who failed
on the Viread + Ziagen/Epivir combination did not have the
K65R mutation, so it’s not clear whether the resistance
explanation is the answer.
Another possible reason for
the failure of this regimen would be a drug interaction between
Ziagen and Viread. So far, no one has found any evidence of
such an interaction, but it’s still possible that there
might be some interaction taking place within the cell that
hasn’t been discovered. Intracellular pharmacokinetic
interactions are now being studied.
Dr. Gallant said that other
explanations for the failure of this combination were unlikely.
For example, dosing Ziagen/Epivir once a day doesn’t
seem to have been the problem, since once-daily Ziagen and
Epivir have worked well in other studies, including in the
Sustiva-arm of ESS30009. And while the criteria for treatment
failure in this trial were admittedly stringent, Dr. Gallant
noted in the question and answer period that even with less
strict criteria, the results would have been the same.
Dr. Gallant said the study
“emphasizes the importance of basing practice on clinical
trials rather than assumptions about what will work.”
Other doctors concurred. They noted that with all the HIV
drugs on the market today and the number of combinations that
can be put together, doctors and patients no longer need to
try experimental concoctions the way they did in previous
years. Today there are more options, and more knowledge to
go with them.
Once-a-day
Ziagen, Epivir and Sustiva
Epivir and Sustiva are once-a-day
drugs. Ziagen is on the market at a twice-daily dose, but
there is data (mostly from the laboratory) showing efficacy
with just a once-daily dose. An international team of researchers
reported that all three medications taken together only once
a day was highly effective out to one year (a significant
amount of time). As the researchers noted, other combinations
of once-daily drugs can be problematic because the medications
cannot actually be taken together due to problems such as
different food requirements.
The 770 participants in the
ZODIAC study (Ziagen Once Daily in Antiretroviral Combination)
took Ziagen either once-a-day or twice-a-day. At week 48,
both combinations had similar efficacy. The majority of people
had less than 50 viral load (66% once-a-day vs. 68% twice-a-day).
In as-treated analysis the figure was 86%. Participants also
had an increase of around 200 T-cells. Half of the group had
started out with less than 262 T-cells and 44% had more than
100,000 viral load at baseline.
Of the “few” participants
with virologic, or viral load, failure (10%), half had a rebound
to less than 500 viral load (almost undetectable). Although
9% of participants experienced Ziagen hypersensitivity, doctors
noted that there was a very strict definition of this, so
that even rash that might be due to Sustiva would be listed
as the infamous Ziagen allergic reaction.
Kaletra
monotherapy
Every once in a while startling
information is presented at a conference. So it was that Dr.
Joseph C. Gathe, Jr., an African American doctor from an inner-city
clinic in Houston, presented a pilot study of 30 patients
on Kaletra monotherapy. He noted that he received no funding
(such as free drug from the manufacturer of Kaletra), and
could not devote clinical staff time to “cajole”
patients the way most studies do. Yet, the study participants
had success with the treatment out to 24 weeks (still early
results for a clinical trial). None of them had taken HIV
therapy before, which makes them an ideal group for treatment.
He explained the rationale
behind his tiny pilot proof-of-concept study: Kaletra has
short-term activity similar to triple therapy (three week
data). If the drug fails to work, there’s a lack of resistance
to other medications in people who are naïve to therapy.
And it has a long half-life, that is, it stays in the body
a long time. He called this “single-drug HAART”
(highly active antiretroviral therapy).
At 24 weeks, using a strict
intent-to-treat (ITT) analysis, 70% of the study’s participants
had less than 400 viral load (undetectable). ITT counts all
patients, even those who dropped out of the trial (considered
failure). Using an on-treatment analysis (OT), which looks
at only those people still in the trial at the 24-week mark,
95% were below 400 (21 of 22). Half of the participants started
out with less than 204 T-cells and more than 200,000 viral
load. The clinic gave a higher dose to people weighing more
than 154 pounds (70 kg), four capsules twice a day rather
than the standard dose of three capsules twice a day.
Two people in the study were
lost to follow-up (they stopped coming to the clinic), two
people discontinued due to gastrointestinal upset, one person
was non-adherent, one person had virological failure (viral
load above 400) despite adequate blood levels of Kaletra,
one person developed hepatitis B and one person was deported,
but had been undetectable with a greater than two log drop
in his viral load (highly successful treatment). One HIV specialist
pointed out that this was a high drop-out rate (27%). In some
studies out to a year, a drop-out rate of 30% is not acceptable,
and this trial is still early.
All in all, these are really
small numbers, almost meaningless to the real world of medicine.
Nevertheless, in this proof-of-concept trial, the concept
has been proven.
Starting
above 350 T-cells
After years of a downward
trend in when to start HIV therapy (below 500 T-cells, now
below 350 or, according to British guidelines, 200), along
come Italian researchers setting the clock back. The BASTA
study looked at treatment interruptions. It found that people
with lower T-cell nadir (lowest point ever) did less well
than people with a higher nadir. Nothing new there. What was
new was the Italian group’s suggestion that perhaps people
with HIV should begin therapy at a higher T-cell level in
order to preserve their options for treatment interruption
in the future. Many conference goers found the idea fascinating.
One doctor pointed out that the data for waiting is based
on the toxicity of older drugs.
The study found that people
with a nadir of less than 200 T-cells had an average of 14
months off therapy before having to go back on (when T-cells
went below 400) vs. 22 months for people with a nadir above
200. However, only one person with a nadir above 400 had to
re-start therapy. The people with less than 200 nadir rapidly
lost T-cells and the researchers said they would not recommend
a treatment interruption for anyone in this group.
BASTA looked at people with
less than 50 viral load and more than 800 T-cells. It compared
38 people being continued on therapy against 78 people whose
therapy was stopped. The researchers said the option for prolonged
structured treatment interruption in people with such good
immune response to therapy should be preserved. They noted
that there was also a great cost savings despite the intense
laboratory monitoring of the study.
They concluded that “to
preserve the option of longterm prolonged structured treatment
interruption, the optimal time to start HAART should be re-considered
and probably placed between 350–450 T-cells. Patients
with a nadir above 500 can safely and steadily interrupt therapy.”
Sustiva
resistance
As if resistance wasn’t
difficult enough, now researchers are talking rare mutation
patterns. One group looked at how a person’s HIV gets
resistant to Sustiva even though it doesn’t have the
standard mutations associated with Sustiva resistance. How
does it do that? With rare mutations, of course. Mutations
so rare they’re not listed on the resistance tests your
doctor can order. These resistance tests already come with
difficult-to-read results information. Nevertheless, regardless
of how difficult it is to analyze resistance tests, the research
must go forward to find HIV mutations and try to understand
how they develop. This in turn helps drug development.
ViroLogic, the maker of both
genotypic and phenotypic resistance tests, looked at 18,034
samples. Of these, 8,673 did not have the Sustiva mutations.
In analyzing these, ViroLogic came up with new mutation points
that made HIV highly resistant to Sustiva, rendering it impotent
against the virus. They concluded that, “Although rare,
NNRTI [the drug class Sustiva is from] resistance in the absence
of known mutations can be dramatic and is currently not reported
by standard genotype [test].” The company recommended
adding the following mutation points to NNRTI resistance results
because of their strong negative influence on treatment: K101P
and the combination of K103R and V179D.
Diabetes
and hepatitis C
The U.S. Veterans Administration
found an increased risk of diabetes in people with hepatitis
C, but the risk was greater for those who are HIV positive
than in those who are negative. The Veterans Aging Cohort
study compared 33,280 positive vets with 38,232 negative vets.
The report said that, “In the post HAART era, HIV infection
appears to increase the risk of [diabetes] associated with
established risk factors including [hepatitis C] infection,
age and minority race. The degree to which this association
can be attributed to the effects of HIV itself or the effects
of long term HAART therapy remains to be determined.”
They recommended that doctors screen for diabetes and avoid
drugs associated with diabetes risk in the initial regimen
of someone with high risk.
Another
test for your HIV
From what tropic is your
virus? Is it CCR-5 tropic or X4 tropic? You’ll probably
know one day, and it could affect your therapy. An experimental
test is looking at this in clinical trials.
Of the new drugs in development
for HIV, there are five different types of HIV entry inhibitors.
These are five different known ways to prevent HIV from entering
a cell. One of these five drug types, the fusion inhibitors,
is already on the market in the form of Fuzeon (T-20).
One of the other five entry
inhibitors is the chemokine receptor inhibitor. Chemokine
receptors sit on your CD4 T-cells and help HIV enter. Two
chemokine receptors have been found: CCR5 and CXCR4. The cells
are then called CCR5-positive or CXCR4-positive, depending
on which receptor they have.
In turn—ta da!—there
are CCR5 antagonists and CXCR4 inhibitors in drug development.
People who have mostly CCR5-positive cells (called CCR5 tropic)
do better than those who have mostly CXCR4 (X4 for short)
virus. At some point, that balance can shift. Having a shift
to mostly X4 seems to increase disease progression. “Tropic”
comes from “tropism,” the process of attachment
to a co-receptor.
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