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Nevirapine
Versus Efavirenz: The 2NN Study
By
Julio S. G. Montaner, MD, FRCPC, FCCP
Dr.
Montaner is Professor of Medicine and Chair of AIDS Research, St.
Paul’s Hospital and the University of British Columbia, Vancouver,
Canada. He is a Principal Investigator of the 2NN study.
The
2NN Study
CD4 responses between treatment
arms were also equivalent.
Commentary
The role of
the non-nucleoside reverse transcriptase inhibitors (NNRTIs) in
the treatment of HIV infection was originally established by the
results of the INCAS Trial, first presented at the Vancouver International
AIDS Conference in 1996 (1). Equally promising results were presented
at the same time regarding the role of protease inhibitor based
triple drug therapy, particularly indinavir [Crixivan] (2).
A
fair bit of controversy regarding the relative merits of PI versus
NNRTI-based triple drug therapy was generated as a result of these
and later studies. The body of data in support of the effectiveness
of PI-based therapy continued to grow rapidly since then as other
protease inhibitors became available, including saquinavir Invirase),
ritonavir (Norvir) and nelfinavir (Viracept).
In contrast,
the database in support of the effectiveness of NNRTI-based strategy
was off to a slow start. It was not until the late 90’s that new
evidence was presented emerging from the Atlantic trial, which clearly
demonstrated comparable efficacy for nevirapine versus indinavir-based
therapy (3).
Despite these
encouraging results the controversy persisted, particularly in North
America where PI-based HAART was still regarded as the preferred
initial treatment option.
By this time
it had become abundantly clear that highly active antiretroviral
therapy (HAART) could not eradicate HIV infection. The consequent
need for long-term therapy coupled with the complexity of available
PI-based regimens forced to a re-evaluation of the relative merits
of PI versus NNRTI based therapy.
At about the
same time, data from Study-006 (also known as DMP-006), a pivotal
open label study of efavirenz (Sustiva) versus indinavir in combination
with zidovudine (Retrovir) and lamivudine
(Epivir) became available (4). The results of this study
showed that efavirenz was statistically significantly more effective
than indinavir.
Of note, this
difference was largely attributable to a high frequency of early
discontinuations in the indinavir arm of the study, even in the
absence of documented adverse effects. Despite this important limitation
of the study, efavirenz emerged as a new and attractive NNRTI option.
Even in the
absence of head to head comparative trials between the available
NNRTIs some were ready to assume that the newer compound, efavirenz,
was more effective than nevirapine.
Most
notably, the US Department of Health and
Human Services (DHHS) Panel on Clinical Practices for Treatment
of HIV Infection as recently as a year ago continued to place efavirenz
as a “strongly recommended” first-line antiretroviral agent and
nevirapine as an “alternative” (5).
Of note this
position was not shared by 2001 British HIV Association (BHIVA)
Guidelines (6) or the IAS-USA Guidelines (7), which listed efavirenz
and nevirapine as comparable options for initial combination antiretroviral
therapy. The controversy grew further as a result of cohort studies
(9, 10), which despite significant limitations, concluded that efavirenz
was superior to nevirapine-based HAART.
The
2NN Trial presented at the 10th
Conference of Retroviruses and Opportunistic Infections on
February 14, 2003 finally set the record straight.
The
2NN Study
CD4 responses between
treatment arms were also equivalent.
Commentary
The
2NN Study
The 2NN Trial
was an open-label, randomized, comparative trial of nevirapine versus
efavirenz-based HAART regimens. Randomized patients received either
efavirenz, nevirapine once daily or nevirapine twice daily, or both
NNRTIs together in addition to stavudine (d4T) [Zerit] plus lamivudine
(3TC), as shown below:
- Nevirapine, 400
mg once daily (n = 220)
- Nevirapine, 200
mg twice daily (n = 387)
- Efavirenz, 600
mg once daily (n = 400)
- Nevirapine 400
mg once daily plus efavirenz, 800 mg once daily (n
= 209)
Total
daily doses of efavirenz and nevirapine in the single NNRTI arms
of the study were as currently recommended. The nevirapine arms
of the study incorporated a dose escalation from 200 mg daily to
400 mg daily on day 14, as per current standard of practice.
The dose of
efavirenz in the double NNRTI arm was increased to 800 mg once daily
to maintain full exposure to this agent, based on a previous pharmacokinetic
study, which demonstrated that nevirapine co-administration decreases
the bioavailability of efavirenz.
The 2NN study
randomized over 1200 individuals, and a full 84% of the patients
completed the anticipated 48 weeks of follow-up. The patient groups
were well matched at baseline with regard to key prognostic variables,
such as CD4 cell count and plasma viral load. The overall CD4 cell
count at baseline was just below 200 cells/mm3 and the overall median
plasma viral load was slightly in excess of 4.5 log10 copies/mL.
Also, of note, over one third of study participants were women.
The overall
efficacy analysis of the study was based on the percent of patients
with treatment failure at week 48 based on a composite pre-defined
end point, which included virological failure, as well as disease
progression events or change in randomized treatment.
Based on this
analysis, the dual NNRTI arm was statistically significantly less
effective than the other study arms (ie: the two nevirapine containing
arms (once daily and twice daily) and the efavirenz arm). Of note,
this was largely attributable to a greater rate of adverse effects
related discontinuations in the dual NNRTI arm of the study.
With regard
to antiviral potency, as measured by the fraction of patients achieving
a plasma viral load <50 copies/mL at 48 weeks, the 2NN Study
showed that the two nevirapine arms and the efavirenz arm of the
study were equivalent, both in an intent-to-treat and on-treatment
analysis.
Specifically,
a full 70% of patients in the nevirapine once daily and the efavirenz
once daily arms of the study achieved <50 copies/mL at 48 weeks
in an intent-to-treat analysis. Similarly, a full 87% and 89% of
patients treated with efavirenz once daily and nevirapine once daily,
respectively achieved <50 copies/mL at 48 weeks in the on-treatment
analysis.
CD4
responses between treatment arms were also equivalent.
Safety analyses
demonstrated, a trend towards more hepatobiliary and rash events
in the nevirapine treated patients and more CNS and psychiatric
events in the efavirenz treated patients. A total of 25 patients
died during the study. Two deaths were attributed to nevirapine
use. There were no statistically significant differences with regard
to mortality endpoints between study arms.
In a lipid
sub-study (11) conducted in a sub-set of patients within the 2NN
Study, differing trends were observed between treatment arms. In
particular, HDL increases were more pronounced for patients receiving
nevirapine as part of the treatment. Similarly, the total cholesterol
to HDL ratio was more favorably affected among patients receiving
nevirapine as part of their treatment.
Dr.
Joep Lange, the principal investigator of the 2NN Study, concluded
that nevirapine and efavirenz have comparable efficacy. Furthermore,
nevirapine whether given once daily or twice daily has equivalent
antiviral potency to efavirenz. Finally, co-administration of nevirapine
and efavirenz should not be recommended as it resulted in higher
treatment failure due to increased toxicity.
Commentary
The 2NN Study
represented a tremendous effort organized by a group of independent
investigators through the International AIDS Treatment Evaluation
Centre in the Netherlands under the leadership of Dr. Joep Lange.
A total of 65 centres from 17 countries participated in this trial.
Boehringer Ingelheim, the manufacturer of nevirapine (Viramune®)
provided funding for the study.
The results
of the 2NN Study should have a significant impact on current antiretroviral
therapy practices. This study demonstrates that nevirapine has
comparable potency to efavirenz in the context of NNRTI-based highly
active antiretroviral therapy. In addition, nevirapine is associated
with substantial improvements in lipid profiles that one would expect
would translate in decreased long-term cardiovascular morbidity.
The latter is an important emerging concern, particularly as data
continues to accumulate regarding increasing rates of cardiovascular
morbidity in cohorts of HIV-infected individuals on long term antiretroviral
therapy.
Finally, given
the substantial price differential in favor of nevirapine, it is
anticipated that third party payers and HIV treatment programs around
the world would welcome these results as an opportunity to help
to deal with the sustainability of antiretroviral therapy, a problem
that currently affects not only the developing but also the developed
world.
In
summary, the results of the 2NN Study finally set the record straight
regarding the relative efficacy and safety of nevirapine and efavirenz.
In
brief, both agents have comparable clinical efficacy. Also, both
agents have equivalent antiviral potency and identical effects on
CD4 cell counts. Furthermore, both agents lend themselves well
to the development of simplified, compact, and once daily regimens.
Some
differences between these compounds are readily apparent. Among
them, there are subtle differences regarding their safety profile,
with more hepatobiliary and rash events among nevirapine treated
patients and more CNS events among efavirenz treated patients.
Also,
nevirapine has a rather intriguing effect on lipids.
Finally,
nevirapine has a definitive advantage in terms of price. Based
on the results of the 2NN Study, the choice between nevirapine and
efavirenz in the clinic will most likely be driven by a combination
of factors, primarily including the individual patients characteristics
(i.e., co-morbidities, and cardiovascular risk), as well as cost.
02/24/03
References
1.
Montaner JSG, Reiss P, Cooper D, Vella S, Harris M, Conway B, Wainberg
MA, Robinson P, Hall D, Myers M, Lange JMA. A randomized, double-blinded
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279(12):930-937.
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