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Order and Combination
of Anti-HIV Drugs Imporant to First Time Users(onlinedatingmagazine.com -
December 10, 2003) How anti-HIV drugs are combined
and the order in which they are given are important
factors to consider when designing treatment strategies
for patients new to antiretroviral therapy, says a
new study funded by the National Institute of Allergy
and Infectious Diseases (NIAID), one of the National
Institutes of Health. When HIV-infected individuals
begin treatment with a combination of the drugs zidovudine,
better known as AZT, lamivudine and efavirenz, the
drugs retain their effectiveness for a longer period
of time than when individuals begin treatment with
one of several other three-drug regimens.
The study, which involved researchers and participants
from the United States and Italy, was one of the largest
and most complex of its kind to help in determining
the optimal drug treatment strategy for first-time
recipients of antiretroviral drugs. The findings are
reported in two papers published in the Dec. 11 issue
of The New England Journal of Medicine, and have been
incorporated into the U.S. Department of Health and
Human Services HIV/AIDS Treatment Guidelines.
"These findings offer new insight into the most
effective approach for treating previously untreated
HIV-infected individuals," said Anthony S. Fauci,
M.D., director of the NIAID. "Through well-conceived,
collaborative clinical studies such as this one, researchers
are learning how to use the many anti-HIV drugs now
on the market to provide the maximum benefit for the
longest period of time."
Highly active antiretroviral therapy (HAART) employs
combinations of anti-HIV drugs to help suppress the
virus in people with HIV/AIDS. The goal of HAART is
to combine three or more drugs from one or more different
classes of anti-HIV drugs to suppress HIV replication
and prevent progression to AIDS and death. Two key
classes include those that prevent the virus from copying
itself, called reverse transcriptase (RT) inhibitors,
and those that prevent the virus from becoming infectious,
called protease inhibitors. RT inhibitors can be further
broken down into nucleoside RT inhibitors, which halt
HIV replication by making faulty DNA building blocks,
and non-nucleoside inhibitors, which bind to the enzyme
reverse transcriptase to prevent the virus from copying
itself. The effectiveness of different drug combinations
may diminish over time, however, and physicians often
must implement new ones over the course of a person's
treatment.
"Until now, it has been unclear which sequences
of antiretroviral regimens provide the greatest benefit
to patients previously untreated," said Gregory
K. Robbins, M.D., clinical researcher at Massachusetts
General Hospital and instructor in medicine at Harvard
Medical School, and lead author of one of the papers. "Findings
from this and similar studies can help reduce some
of the guesswork involved, enabling physicians to develop
the most effective treatment plan for their HIV-positive
patients."
Study Description
In the first part of the study, Robbins
and a team of researchers compared the effectiveness
of four three-drug
sequencing strategies over roughly a two-year period
in 620 HIV-positive individuals who had never before
received antiretroviral therapy. Two groups began treatment
with didanosine (ddI) and stavudine (d4T), two nucleoside
RT inhibitors, with one group also receiving efavirenz
(EFV), a non-nucleoside RT inhibitor, and the other
receiving nelfinavir (NFV), a protease inhibitor. Two
other groups began treatment with zidovudine (ZDV)
and lamivudine (3TC), two other nucleoside RT inhibitors,
combined, again, with either EFV or NFV.
If the initial regimens failed, patients were given
all new HIV medications. For example, the patients
failing ddI, d4T and EFV switched to ZDV, 3TC and NFV,
while the group that began with ZDV, 3TC and EFV followed
up with ddI, d4T and NFV, and so on. The primary measure
of a sequence's success was the amount of time before
the second regimen failed: the greater the delay, the
more successful the sequence. Secondary measures included
amount of time before the first regimen failed, as
well as ability to suppress viral replication, development
of resistance to anti-HIV drugs and drug toxicity.
In the second part of the study, Robert W. Shafer,
M.D., assistant professor of medicine at Stanford University
Medical Center, and colleagues sought to determine
how two four-drug regimens compared in effectiveness
with the three-drug sequential regimens. Three-hundred
sixty HIV-positive individuals who had never before
received antiretroviral treatment were given one of
two four-drug treatments: ddI, d4T, EFV and NFV or
ZDV, 3TC, EFV and NFV. A key question in this comparison
was whether incorporating three anti-HIV drug classes
instead of two increases the potency of a drug combination
at the expense of increasing the risk of toxicity or
drug resistance. Because participants were exposed
to three drug classes in the initial regimen, there
was no second regimen. Therefore, the primary measure
of success was the amount of time before the initial
treatment failed (compared with two failures of the
sequential three-drug regimens), with secondary measures
remaining the same as before.
Major Findings
All six regimens successfully controlled
HIV infection. Patients who received ZDV, 3TC and EFV
as the first
or second regimen delayed failure of the second regimen
compared to those who took other three-drug regimens,
and patients who started with ZDV, 3TC and EFV delayed
first regimen failure compared to the other three-drug
treatments. These findings indicate that the combination
of ZDV, 3TC and EFV is the best choice for initiating
antiretroviral therapy among the drugs studied. In
addition, researchers found that after 48 weeks on
the initial regimen, approximately 10 percent of individuals
taking ZDV, 3TC and EFV experienced failure, as opposed
to the other three-drug regimens, in which approximately
30 to 40 percent of individuals experienced failure.
The researchers also found that in regard to the primary
measure of success, the four-drug treatments were no
more potent than sequential three-drug regimens. In
several secondary measures however, such as time to
first regimen failure and development of drug resistance,
they outperformed all three-drug regimens except one--ZDV,
3TC and EFV. Finally, although the risk of drug toxicity
was no different between four-drug regimens and three-drug
sequential treatments, drug toxicity was found to occur
more frequently in individuals who began treatment
with ddI and d4T than in those who began treatment
with ZDV and 3TC. Such individuals experienced more
health-related problems such as peripheral neuropathy,
a neurological disorder resulting from damage to the
peripheral nerves, or inflammation to the pancreas,
among other problems. Based in part on the results
of this study, leading researchers now recommend that
anti-HIV treatment should not begin with regimens that
contain both ddI and d4T.
Background
The study was conducted by the Adult AIDS
Clinical Trials Group (AACTG), an NIAID-sponsored program
that
consists of a network of more than 30 clinical research
institutions in the United States, with international
collaborations. AACTG conducts all phases of clinical
trials designed to assess the safety and efficacy of
new and improved therapies for HIV/AIDS and its associated
illnesses, including those in which combination drugs
from different manufacturers are evaluated. AACTG sites
are funded through cooperative agreements. This study
was conducted in collaboration with the Istituto Superiore
di Sanità, the Italian National Institute of
Health, and enrolled both U.S. and Italian subjects.
Pharmaceutical sponsors contributed medications and
financial support for the study.
The drugs ZDV and 3TC are manufactured by GlaxoSmithKline;
ddI, d4T and EFV are manufactured by Bristol-Myers
Squibb Company; and NFV is manufactured by Pfizer.
References
Gregory K. Robbins et al. Comparison of
Sequential Three-Drug Regimens as Initial Therapy for
HIV-1 Infection. The New England Journal of Medicine
349(24): 2293-2303 (2003).
Robert W. Shafer et al. Comparison of Four-Drug Regimens
and Pairs of Sequential Three-Drug Regimens as Initial
Therapy for HIV-1 Infection. The New England Journal
of Medicine 349(24): 2304-15 (2003).
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