+ zidovudine + lamivudine)
Therapy Is Not Responsible for Unexplained Liver
Disease in HIV Patients without Viral Hepatitis
Launches New Patient Assistance Program for 7 Antiretroviral
Drugs or Coformulations
Approves Updated Prescribing Information for
Abacavir (Ziagen, Epzicom,
Trizivir is an anti-HIV
medication. It is in a category of HIV medicines
reverse transcriptase inhibitors (NRTIs).
Trizivir prevents HIV from entering the nucleus
of healthy T-cells. This prevents the cells
from producing new virus and decreases the amount
of virus in the body.
Trizivir is marketed by
GlaxoSmithKline. It was approved by the U.S.
Food and Drug Administration (FDA) for use by
people living with HIV in 2000.
Trizivir is a combination
of three previously approved drugs: 300mg of
(AZT), 150mg of Epivir
(3TC), and 300mg of Ziagen
(abacavir). Trizivir should be prescribed
by a healthcare provider for patients who need
to take all three drugs. For patients only taking
AZT and 3TC, a combination tablet called Combivir
is available. Also, any of these three drugs
can be purchased individually for use in combination
with other anti-HIV drugs.
Does It Work?
As with all the NRTI drugs,
the combination of Ziagen,
works by terminating the growing DNA (gene)
chain of HIV as it is tries to reproduce itself.
This results in an inability of the viral RNA
to replicate and stops HIV from incorporating
its genetic material into the genetic material
of the human cell. This stops HIV infection
at a very early stage of infection.
taking regularly as prescribed, Trizivir combination
therapy usually leads to a decrease in HIV viral
load (RNA) in the blood and an increase in the
CD4+ T cell count. The use of Trizivir or its
individual component drugs has been associated
with decreased rates of AIDS opportunistic infections,
improved quality of life and increased survival.
contains abacavir sulfate, which has been associated
with serious and sometimes fatal hypersensitivity
reactions. Hypersensitivity to abacavir is a
multi-organ clinical syndrome usually characterized
by a sign or symptom in 2 or more of the following
vomiting, diarrhea, or abdominal (stomach
ill feeling, extreme tiredness, or achiness
of breath, cough, or sore throat
TRIZIVIR as soon as a hypersensitivity reaction
is suspected. Permanently discontinue TRIZIVIR
if hypersensitivity cannot be ruled out, even
when other diagnoses are possible
a hypersensitivity reaction to abacavir, NEVER
restart TRIZIVIR or any other abacavir-containing
product because more severe symptoms can occur
within hours and may include life-threatening
hypotension and death
of TRIZIVIR or any other abacavir-containing
product, even in patients who have no identified
history or unrecognized symptoms of hypersensitivity
to abacavir therapy, can result in serious
or fatal hypersensitivity reactions. Such
reactions can occur within hours
Is Clinically Characterized and Recognizable
a median onset of 9 days, symptoms typically
appear in the first 6 weeks,* but may occur
by symptoms indicating multi-organ/body system
worsen with continued therapy, but often resolve
upon discontinuation of abacavir; when HSR
is suspected, discontinue therapy with abacavir
was reported in approximately 8% of patients
receiving abacavir BID in 9 recent clinical
trials (range 2% to 9%)
GlaxoSmithKline's series of 37 clinical trials
with abacavir, the frequency of hypersensitivity
reaction was 5.4%
Zidovudine has been
associated with hematologic toxicity including
neutropenia and severe anemia, particularly
in patients with advanced HIV disease. Prolonged
use of zidovudine has been associated with symptomatic
acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with
the use of nucleoside analogues alone or in
combination, including abacavir, lamivudine,
zidovudine, and other antiretrovirals.
Tablets are contraindicated in patients
with hepatic impairment.
acute exacerbations of hepatitis B have
been reported in patients who are co-infected
with hepatitis B virus (HBV) and HIV and
have discontinued lamivudine, which is
one component of TRIZIVIR. Hepatic function
should be monitored closely with both
clinical and laboratory follow-up for
at least several months in patients who
discontinue TRIZIVIR and are co-infected
with HIV and HBV. If appropriate, initiation
of anti-hepatitis B therapy may be warranted.
decompensation (some fatal) has occurred
in HIV/HCV co-infected patients receiving
combination antiretroviral therapy for
HIV and interferon with or without ribavirin.
Patients receiving interferon with or
without ribavirin and TRIZIVIR should
be closely monitored for treatment-associated
toxicities, especially hepatic decompensation,
neutropenia, and anemia. Discontinuation
of TRIZIVIR should be considered as medically
reconstitution syndrome has been reported
in patients treated with combination antiretroviral
therapy, including TRIZIVIR. During the
initial phase of combination antiretroviral
treatment, patients whose immune system
responds may develop an inflammatory response
to indolent or residual opportunistic
infections (such as Mycobacterium avium
infection, cytomegalovirus, Pneumocystis
jirovecii pneumonia [PCP], or tuberculosis),
which may necessitate further evaluation
of body fat including central obesity,
dorsocervical fat enlargement (buffalo
hump), peripheral wasting, facial wasting,
breast enlargement, and "cushingoid appearance"
have been observed in patients receiving
antiretroviral therapy. The mechanism
and long-term consequences of these events
are currently unknown. A causal relationship
has not been established.
most common adverse events (≥5%
Grades 2-4) were nausea (19%), headache
(13%), malaise and fatigue (12%), nausea
and vomiting (10%), hypersensitivity reaction
(8%), diarrhea (7%), fever and/or chills
(6%), depressive disorders (6%), musculoskeletal
pain (5%), skin rashes (5%), ear/nose/throat
infections (5%), viral respiratory infections
(5%), and anxiety (5%).
drug resistance means that HIV is still
able to reproduce in a person who is taking
the drug. Since Trizivir consists of Ziagen,
this usually implies multi-drug resistant
HIV. However, understanding resistance to
Trizivir means first to understand resistance
to each drug.
resistance to Ziagen increases
with an increasing number of mutations.
In abacavir monotherapy trials, point mutations
in the reverse transcriptase (RT) developed
at positions K65R, L74V, Y115F, and M184V.
The M184V and L74V mutations were the most
frequently observed in these trials. High-grade
Ziagen resistance may result from moderate
to high resistance to both Retrovir ("TAMS")
and Epivir (M184V), the gene mutations associated
with multi-drug resistance ("Q151M"
and the 69 insertion) or from a unique mutation
such as K65R. Physicians and patients should
note that in clinical trials, many patients
with prolonged nucleoside analogue exposure
or who had HIV-1 isolates with multiple
NRTI mutations had a limited response to
Ziagen. Some strains of HIV with resistance
to Ziagen may also show resistance to Epivir,
Videx (didanosine) and Hivid (zalcitabine).
to Retrovir increases with an
increasing number of HIV gene mutations.
They generally occur in a stepwise accumulation
of the mutations. There are five or six
more-common ones (occurring at gene codon
location numbers 41, 67, 70, 210, 215 and
219) and these are referred to as "thymidine
associated mutations" ("TAMS")
or "nucleoside associated mutations"
("NAMS"). If two or more are present,
a higher level of resistance occurs and
this may affect other NRTI drugs, including
Zerit. A very high level of resistance occurs
when there are four or five of these mutations.
Interestingly, low level Retrovir resistance
(two mutations) can be reversed by the most
common resistance pattern with Epivir ("M184V,"
see below). Other gene mutations ("Q151M"
and the 69 insertion) not only cause high
level resistance to Retrovir, but to all
the other five marketed NRTI drugs ("multi-drug
resistance" also to Epivir,
resistance to Epivir
commonly results from the development
of the "M184V" mutation (sometimes
preceded by a "M184I" mutation)
in the gene that codes for ("blueprint
of") HIV's "reverse transcriptase"
enzyme. This mutation has been shown to
reverse low level resistance to Retrovir
(i.e., only one or two Retrovir mutations
as noted above). There is also some evidence
that the HIV strain with the "M184V"
mutation is weaker, or less "fit",
in its ability to grow or replicate. In
fact, when the mutation developed in patients
who took Epivir monotherapy years ago,
many of them still had a partial suppression
of viral load, when compared to baseline.
These findings are supported by what happens
with patients more recently. In a meta-analysis
(combining results) of five different
clinical trials with 477 patients taking
triple combination therapy that included
Epivir, the M184V mutation was present
in 92% after 12-48 weeks. Yet, the
majority maintained viral load suppression,
even with the M184V mutation. Moreover,
in another study among patients taking
Epivir plus Retrovir for one year and
who had the M184V mutation, there was
a significantly greater reduction in HIV
viral load than among those patients without
the mutation. The M184V mutation is not
the only one that occurs with Epivir.
Other mutations that are also associated
with Epivir resistance are the K65R, the
69 insertion, Q151M, and the combination
of E44D/A and V118I. However, this information
represents newer data, and the significance
of these findings needs confirmation in
larger studies. Cross-resistance between
Epivir and Retrovir usually does not occur
(unless the "Q151M" or "69S"
mutation is present). The M184V mutation
does, however, lead to some cross-resistance
with Videx, Hivid, and even Zerit in some
patients, although this resistance may
not be clinically relevant.
Trizivir already contains Ziagen, Retrovir
it should not be combined with any of
the following medications: Ziagen, Combivir,
Retrovir, Epivir or Epivir-HBV. Beyond
this issue, the drug interaction considerations
are the same as for the individual drugs
Ziagen, Retrovir and Epivir.
(ribavirin, anti-hepatitis C drug, also
and Retrovir may have an adverse reaction
that cancels the effects of each other
in the laboratory. The same occurs when
ribavirin is combined with Zerit (stavudine,
d4T). Before combining any of these medications
for HIV (Retrovir, Combivir, Trizivir,
Zerit) with any of these medications for
chronic hepatitis C (Rebetol, Rebetron),
you should discuss this interaction with
your doctor. The Retrovir Rebetol interaction
is unlikely to be significant in most
patients, but the data are not definitive
at this point. Thus, if you are using
these medications in combination your
physician should monitor you very carefully.
(Intron A, Roferon A, Wellferon, Infergen,
also in Rebetron) increases the risk
of bone marrow (blood cell) toxicities
when used with Retrovir or Trizivir If
this occurs, a dose reduction, or even
stopping, one or both drugs may be necessary.
(stavudine, anti-HIV NRTI drug)
should not be combined with Retrovir or
Trizivir, since the benefits are canceled.