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Everywhere you look these
days there are sound bites for the treatment of HIV: “…Simplify
your HIV regimen” and “Now, one tablet, once daily for simpler
HIV combination therapy.” Some pharmaceutical companies have
been deploying ads, implementing educational programs and
other concentrated marketing efforts to promote QD therapy
(QD, meaning once daily). The once-a-day push is attracting
the attention of people with HIV who are weary of popping
fists full of pills two or three times a day, and some companies
have also responded to these concerns with treatment options
that reduce pill burden. Researchers, who are either employees
or agents of pharmaceutical companies, are reformulating existing
drugs and designing new drugs.
At the recent International
AIDS conference in Barcelona, a lot of buzz was generated
about the pros and cons of QD dosing. Doctors are already
prescribing the QD drugs to their patients. Clearly, there
is a need for simplified HIV regimens, be that fewer pills
or once-a-day dosing. And for some people this is important,
however it should not be the only factor when considering
meds. Few QD drugs have been studied in randomized clinical
trials in combinations—the way HIV drugs must be taken to
be effective at slowing virus replication. Without these trials
the following questions can’t really be addressed. What is
the long-term effectiveness of QD drugs against HIV? Do they
minimize resistance? Are they tolerable in HIV positive individuals?
Is once-a-day really ready
for prime time? Are the QD regimens currently available proven
to be better or equal to BID (twice a day) or TID (three times
a day) in randomized clinical trials? Will once-a-day be an
option for everyone with HIV? Is QD another pharmaceutical
ploy to sell drugs? Will the QD drugs cost more? There are
a lot of unanswered questions. It is clear that people not
sacrifice efficacy for dosing simplicity.
Standard of Care
The Health and Human Services
(HHS) guidelines strongly recommend a combination of antiviral
medications from two drug classes as the standard for HIV
treatment. This may involve taking a combination of several
drugs, two or three times a day. HIV treatment combinations
require sometimes as much as 30 pills a day. Swallowing that
many pills can create many problems for appropriate adherence.
Progress has been made to reduce the numbers of pills, and
there are now regimens that don’t require as many pills. However,
not all QD drugs are reformulated to reduce pill burden. The
reality is that even though a drug may be approved for QD,
it may mean swallowing the same number of pills at once rather
than splitting up the amount in two or three doses. Therefore,
pill burden remains an issue, even with QD dosing.
HAART (highly active antiretroviral
therapy) has been shown to reduce sickness and death, making
HIV a chronic condition for many people. As a result, the
emphasis of treating HIV has been shifted to improving quality
of life. Since HAART has to be taken indefinitely—not necessarily
a rosy prospect for individuals living with HIV—this means
better efficacy with less side effects, fewer pills and less
dosing. This is not an easy task as the virus can mutate easily
to resist the drugs. HIV meds have to be taken 95% of the
time in order to be the most effective. And yet some drugs
are adhered to 95% of the time and still resistance to them
develops. On the one hand, you need a regimen that will continue
to work long-term. On the other hand, you need a regimen that
you can continue taking long-term.
The longer one has to “adhere”
the more chances forgetfulness will occur. We are, after all,
only human. So, the idea of simplified regimens, fewer pills,
lower dosing and less toxicity can ultimately help to achieve
the goals of HIV therapy and the needs of HIV-positive individuals:
keeping people healthy by keeping the amount of HIV in the
body below detectable and CD4 T-cells as high as possible.
Therefore in terms of having a regimen that works and is tolerable,
is QD all that better than BID?
How Drugs are Broken Down
in the Body
According to research on
adherence, the biggest improvement in adherence is noted when
there is no middle of the day dose. There is only a slight
difference in adherence between once a day and twice a day.
Food and Drug Administration (FDA) regulations require approved
drugs to maintain blood levels in the body long enough to
keep working. But that’s assuming you don’t miss a dose. What
happens if you miss a QD dose? Will resistance set in faster
if you miss a QD dose compared to a BID dose? Some drugs,
like Sustiva, remain active in the body for much longer than
24 hours. If people remember to take their dose shortly after
they miss it—at least not 24 hours later—the blood levels
will remain at a safe level. As long as drug levels remain
high enough to control virus replication, drug resistance
is less likely to happen.
One important piece of information
to remember is that what is “high enough” varies, from person
to person and from drug to drug. HIV does not operate the
same from one person to the next. For example, in some people,
the virus is more difficult to treat in resistant form. In
this form, drug levels may need to be consistently higher
to keep the virus from developing additional mutations. With
all of the buzz on increasing rates of resistant HIV, this
is an important consideration for everyone, not just HIV-positive
individuals who have been on therapy for awhile.
Another factor to consider
is the drugs themselves. Some drugs are known for maintaining
higher levels in the body, whereas others have lower levels.
How long after a missed dose before drug levels are dangerously
low depends on, in part, two things. First, how high the drug
levels were in the first place. And secondly, how long it
takes the drug levels to drop.
In order to evaluate how
once or twice dosing works one needs to understand how drugs
are “metabolized” in the body. Drugs are swallowed, then broken
down by saliva, stomach acid and liver or kidney enzymes so
that the active chemical can get into the blood stream to
do its work. Over time the amount of chemical is used up,
then excreted. Then, more drug needs to be taken to keep up
the level of the drug in the blood. In HIV it is critical
to keep drug levels constant and well above the amount needed
to control the virus. If the rate of HIV production can’t
be slowed down enough then the virus can change and go on
multiplying, spreading a mutant virus. This is HIV’s strategy
for survival—clever yet dangerous, even more reason to adhere
to drugs and more corroboration for QD therapies.
There is speculation by some
physicians that the effectiveness of a once-a-day dose schedule
may depend on how each person metabolizes the drug individually,
and that different cellular levels absorbed in a QD regimen
may be quite different than in a twice a day regimen, therefore
raising concerns regarding toxicity. In a new move to monitor
this phenomenon, therapuetic drug monitoring assays are being
developed to look at how each individual processes different
drugs, but the science is clearly lagging behind the realities
of treatment.
The bottom line is that many
QD meds are not as forgiving as certain BID meds, when a dose
is missed. Therefore, taking a dose at or near the appropriate
time is still the optimal choice and efforts should always
be made to teach physicians and patients to adhere to a regular
dosing schedule.
QD HIV Drugs
There are currently five
drugs available in once-a-day formulations today: Sustiva
(efavirenz), Videx EC (didanosine enteric coated), Viread
(tenofovir), boosted Agenerase (amprenavir), and Epivir (3TC).
(See Newsbriefs on page 17.) New QD agents such as Zrivada
(atazanavir), Coviracil (emtricitibine), and T-1249, a fusion
inhibitor, may be available soon. New formulations of existing
antivirals such as Viramune (nevirapine), Ziagen (abacavir)
and Zerit XR (extended release stavudine) are in development.
And Kaletra (lopinavir/ritonavir) is being studied as a QD
option. One can see the interest and results of simplified
drug development in our market-driven society.
Pricing
Will drug companies pursue
a price increase for the new QD therapies? Their contention
is that in order to develop the drugs they need to pay for
the research. According to past history, new drugs, especially
new classes, have always resulted in an increase in price.
Any price increases in new therapies will place ADAPs (AIDS
Drug Assistance Programs), already teetering on the verge
of collaspe, in jeopardy. Pricing is a complex issue. When
a drug is reformulated to reduce pill burden or dosing in
half, it does not mean that manufacturing costs associated
with the drug are also cut in half. It will be up to the community
to hold the companies accountable as far as pricing is concerned.
What HAART Regimens are
Effective in QD?
Up to this point only individual
drugs have been discussed for once daily dosing, however,
remember that HIV meds must be used in combination. Drug companies
are promoting QD drugs individually, but they have not necessarily
been studied together. Several different companies may produce
the drugs within any one given combination, but the question
remains: Is QD a viable option available to those who need
therapy?
The QD regimen with the most
data demonstrating effectiveness is Videx, Epivir and Sustiva.
An open label prospective study (people knew what they were
taking and were followed from the time they were put on treatment)
looked at the feasibility of using this QD regimen. Though
the study was not compared with other drugs, everyone ended
with a lower viral load and higher CD4 T-cells at the end
of 48 weeks, showing the combination was effective. Another
study looking at a new drug, Coviracil, in combination with
Videx and Sustiva in treatment naïve patients (patients initiating
therapy for the first time) has been reported. This combination
has demonstrated an ability to suppress viral load for up
to two years, showing another potential effective QD regimen.
However, Coviracil has not yet been approved.
Doctors are prescribing combinations
besides Videx EC, Epivir and Sustiva. Viramune is being looked
at in combination with Videx and Epivir. Crixivan is being
studied in combination with the same QD background. The studies
are not complete. And therein lies the problem of combining
drugs that have not been studied together in controlled clinical
settings. Unknown cross reactions have been reported, as was
found with Viread and Videx EC after the drugs were being
combined in community practice. People using the new Videx
EC capsule must not take it with any food, and Epivir and
Sustiva should be taken with food, so the regimen is not a
QD regimen as is thought.
From a Consumer’s Perspective
How does switching to a QD
regimen affect people in the real world? Paul Dalton, a PWA
(person with AIDS) from San Francisco, switched to a once
daily regimen of Epivir, Viread and Viramune. Previously,
he was on the same drugs, but used Viramune twice a day until
studies showed that it was effective once daily. So, he made
a relatively safe change based on what we know about these
drugs. The outcome has been good in terms of viral control.
However, he did have a 50% reduction in CD4 T-cells, but feels
that the “disconnect” between his success in switching and
his CD4 count was more related to stress in his life than
to the therapy having failed (Does this constitue a failure?).
Paul said he has been 100% adherent with the new QD regimen
and believes it can be beneficial for others if they stick
to the simpler strategy. “QD can make sense if people can
construct a viable regimen based on their history.” Still,
the disconnect in Paul’s case (viral load decline, T-cell
decline) should be carefully monitored by a physician. Adherence
is not the lone factor in determining whether or not a regimen
is effective.
Jeff Gustavson, also from
San Francsico, had trouble with his regimen, which was Viread
(QD) in combination with twice daily drugs. He mistakenly
took the Viread twice daily with his other drugs, doubling
the dosage, which is one of Cafaro’s concerns. This anecdote
highlights the fact that QD dosing is individual and must
be geared for each person. It remains a treatment model in
transition until all the bugs can be worked out.
A Matter of Choice… How to
Decide?
Many factors, including lifestyle,
emotional readiness and ability to adhere, come into play
when you decide to initiate HIV therapy. However, other factors
that are just as important are drug efficacy, tolerability
and minimizing resistance. Someone who has never taken HIV
treatment may have more treatment options than the more treatment
experienced individuals. Individuals who have taken antivirals
in the past may have fewer therapeutic options. However, as
previously stated, HIV therapy must be individualized. A treatment
naïve patient may have acquired a resistant strain of HIV,
and therefore have more drug resistance than a treatment experienced
patient. So the question becomes, are pharmaceuticals doing
what is really in the best interest of the patient? Should
they develop more resistance minimizing meds, as well as those
that are more tolerable and convenient? Or are they merely
responding to market opportunities when promoting drugs as
QD?
A hospital cohort study presented
in Barcelona looked at 1,313 patients and their consecutive
regimens. The rate of treatment change was high in the study
due to adverse events. So, after five consecutive regimens,
most patients had been exposed to almost every available antiretroviral
drug. Therefore, in this heavily treated group, QD would likely
be impossible.
For people who have previously
used anti-HIV drugs, it is critical that resistance tests
be performed and medical histories looked at before switching
or constructing any regimen. The tests can help determine
which drugs are still viable options for each individual.
Individuality must be considered in deciding upon any regimen.
Howard Grossman, a physician
from New York City, has been prescribing once daily regimens
for years. According to Grossman’s cohort data presented in
Barcelona, his patients are benefiting from once daily dosing.
Whereas many physicians would not offer QD to patients who
can’t adhere due to the risk of resistance, Grossman offers
patients with the worst adherence problems once-a-day regimens
and looks at toxicity issues and effectiveness. His cohort
was a retrospective analysis looking at 40 people from his
clinic who either started on a QD regimen or switched from
one QD regimen to another, or from BID to QD. At the completion
of the study, viral load values were stable at less that 4,000
in all groups, not undetectable by any clinical standard.
However, he states that those who began on a QD regimen did
the best. But again research demonstrates that individuals
have the best results on their initial regimen.
Virginia Cafaro, a long-term
HIV doctor in San Francisco, presents an opposing point of
view, “A lot of my patients are on BID and think it’s fine,
they have the rhythm and figure ‘if it ain’t broke, don’t
fix it.’ They have been stable for years.” Some motivated
people are satisfied if they are doing well with their regimen.
However, people who are having adherence problems, or who
are dealing with pill fatigue, who can afford to switch may
want to consider QD. But they should talk over their options
with a doctor. According to Cafaro, a major concern is that
people with HIV simply want to switch, whether QD is geared
for them or not. Cafaro muses, “I think it’s [QD] a lot of
hype and marketing from drug companies all saying their drugs
are, or will be able to go QD. Is QD really all meds at one
time? We have to worry about drug interations [such as] with
tenofovir and ddI-EC. Patients hear ‘once-a-day’ and may drop
half of their present regimen or pile them all up into one
dose.”
Grossman believes that many
progressive doctors are reluctant to switch their patients
to QD. He states, “there are so many treatment options and
they want to wait until more proof is in. No one wants to
do harm [to the patient].” However, it begs the question,
how are less experienced doctors who have fewer HIV-positive
patients going to react to the new QD paradigm? In the land
of HIV treatment and care, treatment trends always take time
to take hold.
Experienced doctors such
as Cafaro and Grossman, who understand the complexities, drug
interactions and other restrictions of HIV treatments, are
more in tune to their patient’s needs, but care needs to be
taken with those prescribing without a specialist’s knowledge.
We are upon an era of a major
treatment shift in HIV disease, where efficacy, tolerability,
avoiding resistance and dosing convenience are all key factors.
Adherence to mega-dosing of the older drugs has been a systematic
and complex problem for people with HIV and their providers.
However, progress has been made in this area. Treating a virus
that is capable of a multitude of changes still has to be
sorted out, so we must not put the cart before the horse in
pushing ahead with simpler regimens that might fail for multiple
reasons.
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