Being Alive 1997 Jul 5: 5
In the media and in the hiv community vernacular, "protease
inhibitors," "triple-drug cocktails" and "highly active
antiretroviral therapy (HAART)" are used interchangeably. This
is inaccurate and potentially misleading. It could lead
positive people and less hiv-specialized physicians to assume
that any drug regimen not including a protease inhibitor is
inferior and inappropriate.
Effective suppression of hiv (as measured by reducing viral
loads to undetectable levels) has been achieved with various
other two- and three-drug regimens in at least some groups of
people. Increasingly popular, especially for people who have
not yet taken any antiviral drugs, are combinations containing
What Are NNRTIs?
NNRTIs are a class of drugs that have been under investigation
for a long while but have just recently come into general use.
The term is an acronym for a real mouthful: "non-nucleoside
reverse transcriptase inhibitors." This means that its
antiviral action comes by blocking the enzyme (reverse
transcriptase) that allows hiv to translate its genetic
material into a form that can merge into the core of a T-cell,
to quietly lurk and one day turn the "host" T-cell into an hiv
factory. This is the same target as the "nukes" (the nucleoside
reverse transcriptase inhibitors like AZT, 3TC and the "d"
drugs), but the NNRTIs work through a different mechanism.
The most widely used NNRTI is nevirapine (brand name Viramune).
The FDA recently approved a second drug of the class,
delavirdine (Rescriptor). Dupont Merck is currently conducting
widespread clinical trials (with several sites in Los Angeles)
of a third NNRTI, known for now as DMP266. DMP266, on the basis
of preliminary studies, is thought to be considerably more
active in blocking hiv than either of the first two.
How Good Are They?
First thing to remember is that NNRTIs must only be used in
combinations! Used alone, or with another drug to which your
body has already become resistant, NNRTIs very rapidly lead to
Viramune, in combinations with two nukes (say AZT plus 3TC, AZT
plus ddI or ddI plus d4T) in people with intermediate or high
T-cell counts (more than 200), has shown an antiviral effect
comparable to that of combinations including a protease
inhibitor. In one such study of 151 people, 70% of those taking
AZT plus ddI plus Viramune achieved and maintained undetectable
viral loads as of six months of treatment, compared to 40% of
those on AZT plus ddI alone. In a larger study of people with
more damaged immune systems (average T-cell count of 138) and
with previous experience with nuke drugs alone or in
combinations, the benefit was much slighter for combos with
Viramune. There was a sustained T-cell rise averaging 140 above
baseline in the Viramune group after one year compared to the
AZT plus ddI alone group (40), but there was not significantly
better reduction in viral load or survival.
Later trials of combination therapy including nevirapine have
failed to substantiate the duration of viral suppression found
in the smaller trial mentioned above. In other words, viral
load dropped as far as with proteases, but didn't last. For
this reason, the new federal guidelines list
Viramune-containing combinations as an alternative starting
regimen to those containing protease, but an alternative with
less evidence for its effectiveness over time.
Rescriptor (delavirdine) has shown less evidence of a
significant effect in clinical trials so far, and its approval
was somewhat controversial. The hiv treatment advocacy
community's attitude is typified by the April/May 1997 issue of
Treatment Issues; its cover story on Rescriptor's approval is
entitled "Now There Are Eleven [FDA-approved antiretroviral
drugs], But So What?" One study in people with no prior drug
treatment (or less than six months of it), found that AZT plus
ddI is virtually equal to AZT plus ddI plus delavirdine and ddI
plus delavirdine. However, empirical data collected carefully
by some physicians, Dr. Paul Bellman of New York in particular,
found that a number of patients who were being failed by
protease combinations started responding and improving again
when delavirdine was added to their existing regimen. This may
be due to a side effect of NNRTIs, increasing the bloodstream
concentration of Crixivan. So approval came largely on the
basis of providing one more alternative that may work for some
people whom other combos are failing.
Side Effects And Interactions
The most common side effect of NNRTIs is a rash, usually
temporary and starting fairly soon after one begins the drug,
but which may become quite severe and even life-threatening.
The rash has occurred in about 22% of the people taking
Viramune, and about 7% have had to stop taking their drug
because of it. In unusual cases, this can escalate to a
life-threatening allergic reaction known as Stevens-Johnson
syndrome for which emergency treatment is necessary. If you or
any one close to you ever starts having breathing problems or
any other rapid-onset changes with a Viramune or Rescriptor
rash, stop taking the drug immediately and get thee to an
emergency room! Unlike say Bactrim, it is not recommended to
re-start Viramune or Rescriptor after once stopping it because
of the rash. What is now becoming standard practice is to start
Viramune, at least, with a half dose for several days to two
weeks before ramping up to full dose. Other side effects can
include liver function abnormalities, fever and muscle
Drug interactions can be a big problem, at least if you need to
take any of the other long list of drugs that are metabolized
along the same liver-enzyme pathway as the NNRTIs. The pattern
is similar to Norvir, but the list is constantly changing as
more information accumulates from expanding use. Sometimes the
interactions can be used to good effect, as was apparently done
by Dr. Bellman in increasing Crixivan concentration to help
those who can't absorb that drug well enough, but this should
only be done under careful and expert medical monitoring. For
the latest updates, call the Project Inform hotline
(800.822.7422) or the manufacturer's special interaction
information numbers (available on the package inserts or from
your pharmacist or physician).
The new draft federal guidelines rank Viramune plus two nukes
as an inferior-grade alternative to proteases, but one which
may be better or preferable for some people. The niche that the
studies seem to indicate for NNRTIs is as a part of the
starting combination for people with relatively high (over 200
anyway, some would say higher) T-cell counts who have not taken
antiviral drugs previously. The virus is somewhat more
forgiving of missed doses and other compliance problems with
NNRTIs compared to protease inhibitors. This is another reason
that many doctors and patients prefer to start with two nukes
and an NNRTI, saving the protease inhibitors for later. You can
learn how to be the "Compleat Compliant Pill Taker" and save a
powerful backup for later, both at the same time! However,
because of the lack of consistent evidence that the viral
suppression benefits of NNRTIs are prolonged, many experts
would recommend starting out directly with a
protease-containing regimen, under the assumption that one
wants optimal therapy from the beginning. This is an issue
worth careful discussion with your provider.
The other usage is as a backup or "try-anything" drug for those
who have run out of other choices. In the main, as with
proteases, when changing therapies one should change as many as
you can at the same time to give your body the best shot at
knocking out virus resistant to your former drugs.
Both NNRTIs are on the MediCal and ADAP formularies.
Manufacturers also have patient assistance programs to help
people get drugs, even for free on a limited basis, if you have
no other way to get them paid for. For Viramune, the number is
800.274.8651 and for Rescriptor it is 800.711.0807.