Context.—
Current guidelines recommend that individuals infected with the human
immunodeficiency virus type 1 (HIV-1) be treated using combinations of antiretroviral
agents to achieve sustained suppression of viral replication as measured by
the plasma HIV-1 RNA assay, in the hopes of achieving prolonged remission
of the disease. However, until recently, many drug combinations have not led
to sustained suppression of HIV-1 RNA.Objective.—
To compare the virologic effects of various combinations of nevirapine,
didanosine, and zidovudine.Design.—
Double-blind, controlled, randomized trial.Setting.—
University-affiliated ambulatory research clinics in Italy, the Netherlands,
Canada, and Australia (INCAS).Patients.—
Antiretroviral therapy–naive adults free of the acquired immunodeficiency
syndrome with CD4 cell counts between 0.20 and 0.60×109/L
(200-600/µL).Intervention.—
Patients received zidovudine plus nevirapine (plus didanosine placebo),
zidovudine plus didanosine (plus nevirapine placebo), or zidovudine plus didanosine
plus nevirapine.Main Outcome Measure.—
Plasma HIV-1 RNA.Results.—
Of the 153 enrolled patients, 151 were evaluable. At week 8, plasma
HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the triple drug
therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups,
respectively (P<.05). The proportions of patients
with plasma HIV-1 RNA levels below 20 copies per milliliter at week 52 were
51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and
zidovudine plus nevirapine groups, respectively (P<.001).
Viral amplification was attempted in 59 patients at 6 months. Viral isolation
was unsuccessful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients
in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus
nevirapine groups, respectively. Among patients from whom virus could be amplified,
resistance to nevirapine was found in all 11 patients receiving zidovudine
plus nevirapine and in all 5 patients receiving triple drug therapy. Rates
of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51)
for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple
drug therapy groups, respectively (P=.08).Conclusions.—
Triple drug therapy with zidovudine, didanosine, and nevirapine led
to a substantially greater and sustained decrease in plasma viral load than
the 2-drug regimens studied. Our results also suggest that suppression of
viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load
below the level of quantitation of the most sensitive test available, may
at least forestall the development of resistance.
Figures in this Article
NEVIRAPINE, a potent and selective noncompetitive inhibitor of the reverse
transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1), belongs
to the class of antiretroviral compounds referred to as nonnucleoside reverse
transcriptase inhibitors.1- 2 Nevirapine
has a wide distribution throughout body tissues, including the central nervous
system.3- 5 Nevirapine
has at least an additive in vitro antiviral effect with zidovudine, didanosine,
and lamivudine, regardless of prior zidovudine exposure.6
Early clinical experience with nevirapine monotherapy demonstrated a
substantial but transient decline of serum p24 antigen levels.7- 8
The loss of nevirapine activity was temporally associated with the emergence
of drug resistance.9 Similar transient benefits
were demonstrated when zidovudine and nevirapine were used in an alternating
schedule.10 Administration of nevirapine in
combination with zidovudine alone or zidovudine plus didanosine in previously
treated patients led to a substantial improvement in the magnitude and durability
of the antiviral response.11- 12
Nevertheless, the responses waned over time. Of note, the response seen with
the triple drug therapy regimen was more durable, remaining beyond 1 year,
particularly among patients with limited prior drug exposure.12
We hypothesized that a more vigorous suppression of viral replication
could prevent or delay the emergence of nevirapine resistance and ultimately
prolong the effect of treatment. We therefore undertook the present study
to compare the virologic and immunologic effects of various combinations of
nevirapine, didanosine, and zidovudine among antiretroviral therapy–naive,
HIV-1–infected patients free of the acquired immunodeficiency syndrome
(AIDS).