Balasegaram

Brun

F. Chappuis

Priotto

P  pin

Van Nieuwenhove

English

Crossref

Melarsoprol-Free Drug Combinations for Second-Stage Gambian Sleeping Sickness: The Way to Go

Chappuis, F

MSF Field Research

CSE THEME ARTICLE • CID 2007:45 (1 December) • 1443
CSE THEME ARTICLE EDITORIAL COMMENTARY
CSE Global Theme Issue on Poverty and Human Development
Melarsoprol-Free Drug Combinations for Second-
Stage Gambian Sleeping Sickness: The Way to Go
Franc ¸ois Chappuis
Travel and Migration Medicine Unit, Geneva University Hospital, and Me ´decins Sans Frontie `res, Swiss Section, 1202 Geneva, Switzerland
(See the article by Priotto et al. on pages 1435–42)
Received 18 June 2007; accepted 19 June 2007;
electronically published 22 October 2007.
Reprints or correspondence: Dr. Franc ¸ois Chappuis, Travel
and Migration Medicine Unit, Geneva University Hospital, 24
rue Micheli-du-Crest, 1211 Geneva 14, Switzerland
(francois.chappuis@hcuge.ch).
Clinical Infectious Diseases 2007;45:1443–5
  2007 by the Infectious Diseases Society of America. All
rights reserved.
1058-4838/2007/4511-0007$15.00
DOI: 10.1086/522983
There is little doubt that human African
trypanosomiasis (HAT) would stand on
the podium of a most-neglected diseases
contest, despite the dishearteningly high
number of other candidates. The disease
is present solely in sub-Saharan Africa.
The vast majority of patients areverypoor
and live in remote rural areas of countries
recently or currently affected by deep so-
cial unrest, such as Angola, the Demo-
cratic Republic of Congo, the Republic of
Congo, Uganda, and Sudan. In these
countries,HATduetoTrypanosomabrucei
gambiense reached epidemic proportions
during the 1990s, following decades of de-
ﬁcient surveillance and control activities.
Fortunately, the improved political situa-
tion in some countries and the conjugated
efforts of national disease-control pro-
grams, nongovernmental organizations,
and the World Health Organization
(WHO) allowed the trend to be reversed.
Despitesomemajoruncertainties(e.g.,the
proportion of patients who are not cov-
ered by existing control and surveillance
programsisunknown),itisnowestimated
by the WHO that 50,000–70,000 cases of
T. brucei gambiense HAT occur annually
in Africa [1].
The disease is transmitted via the bite
of tsetse ﬂies (Glossina species). T. brucei
gambiense HAT is aslowlyevolvingdisease
(it progresses over months to years) that
leads to death in the absence of treatment.
After an initial stage during which the try-
panosomes remain conﬁned to the hem-
olymphaticsystem(ﬁrst-stagedisease),the
parasites invade the CNS, leading to the
various neuropsychiatric disorders, such
as confusion, convulsions, speech and
walking disturbances, sleep disturbances,
and lethargy, of the second (or menin-
goencephalitic) stage.
The diagnosis of HAT is cumbersome
and follows a 3-step approach: screening,
parasitological conﬁrmation (microscopic
examination of lymph node and blood
specimens), and staging (examination for
trypanosomes and for increased WBC
counts in the CSF). This staging step is
essential, because the means of treating
ﬁrst- and second-stage disease differ
widely. The treatment of ﬁrst-stage illness
relies on daily intramuscular injections of
pentamidinefor7–10days.Thistreatment
is relatively safe and practical, allowingfor
ambulatory treatment of patients. Pafur-
amidine maleate (DB289), given orallyfor
10 days, is being developed as an alter-
native to pentamidine that may facilitate
home-based treatment of patients with
ﬁrst-stage disease.
The treatment of second-stage illness is
much more problematic. It has relied on
arsenical derivatives sincethebeginningof
the 20th century; in particular,ithasrelied
on melarsoprol since 1949. Melarsoprol is
given by slow intravenous administration
in 3–4 series of 3–4 injections (with the
old schedules) or through 10 consecutive
injections (with the modern schedule).
With either schedule, 3%–6% patients die
during or after treatment of an encepha-
lopathic syndrome (severe cerebral edema
or bleeding).Otheradverseeffectscanalso
be life-threatening,includinglivertoxicity,
severe enterocolitis, and diffuse peripheral
neuropathy. The high toxicity of melar-
soprol has been repetitively reported for
decades. This may have induced a certain
sense of tolerance or resignation among
some, but certainly not among ﬁrst-line
caregivers who have to report patients’
deaths to relatives. Moreover, high failure
rates associated with melarsoprol have
been reported from several endemic foci
in Angola, the Democratic Republic of
Congo, Sudan, Central African Republic,
and Uganda [2].
Because the disease is fatal if left un-
treated, the use of melarsoprol was ac-
ceptable in the absence of safer alterna-
tives. This is no longer the case.
Eﬂornithine (diﬂuoro-methyl-ornithine),
an ornithine decarboxylase inhibitor, was1444 • CID 2007:45 (1 December) • CSE THEME ARTICLE
ﬁrst used to treat patients with HAT due
to T. brucei gambiense 120 years ago [3].
The recommended dosage of 400 mg/kg
divided in 6-hourly intravenous infusions
for 14 days was shown to be efﬁcient in
adults, but higher doses must be given in
children [4]. For almost 2 decades, pa-
tients with HAT had no access to eﬂor-
nithine because of high price or lack of
production. This unacceptable situation
fueled a strong advocacy campaign led by
Me ´decins Sans Frontie `res and other or-
ganizations in the late 1990s. Aventis
Pharma (now Sanoﬁ-Aventis) and the
WHO signed 2 consecutive 5-year agree-
ments in 2001 and 2006 that included ﬁ-
nancial support for control and research
programs and the donation of the key an-
titrypanosomal drugs (pentamidine, me-
larsoprol, and eﬂornithine). Eﬂornithine
has therefore been available in the ﬁeld
and widely used in control programs run
by nongovernmental organizations since
2001. In southern Sudan, 4222 patients
with second-stage HAT were treated with
eﬂornithine by Me ´decins Sans Frontie `res
and Malteser during the period 2001–
2006. In these settings, the treatment was
safe (in-hospital case-fatality rate, 1.1%)
and effective (relapse rate, !10%) (un-
published data). Two studies demon-
strated the signiﬁcantly lower rates of
death and severe adverseeffectswitheﬂor-
nithine, compared with melarsoprol, in
consecutive cohorts of Congolese and Su-
danese patients [5, 6]. Therefore, eﬂor-
nithine is the drug of choice for second-
stage T. brucei gambiense HAT. However,
it remains to be seen whether these good
results can be replicated in the more sim-
ple settings of government-run treatment
centers.
The introduction of eﬂornithine as
ﬁrst-line treatment to replace melarsoprol
for patients with second-stagediseasewho
are receiving treatment in hospitals or
health centersrunbynationalcontrolpro-
grams is progressing slowly. This slowness
is mainly associated with factors that are
inherent to the complex mode of eﬂor-
nithine administration, which involves
substantiallogisticconstraintsandindirect
costs (e.g., acquisition and transportofin-
fusion materials from the capital to the
ﬁeld), and the need for sufﬁcient and
trained human resources to assume ade-
quate round-the-clock nursing care.
Training workshops for regional nurses
have been organized by the WHO. Med-
ical kits containing all necessarydrugsand
infusion materials have beenpreparedand
will be available at no cost for national
control programs. These initiativesshould
facilitate—tosomeextent—widerﬁelduse
of eﬂornithine, but its complicated treat-
ment regimen (56 slow infusions admin-
istered over 14 days) will remain a chal-
lenge to its widespread implementation.
There is another concern with eﬂorni-
thine. Sooner or later, the widespread—
and, therefore, less controlled—use of
eﬂornithine as monotherapy is likely to
lead to parasite resistance, which would
have catastrophic consequences. It is thus
vital to protect the efﬁcacy of this drug by
using it in combination regimens, an ap-
proach that has been successful for nu-
merous infectious diseases, such as HIV
infection, tuberculosis, and malaria. The
most promising option today is the com-
bination of eﬂornithine with oral nifur-
timox, a nitrofuran compound registered
for treatment of American trypanosomi-
asis. Nifurtimox has shown some degree
of effectiveness against second-stage HAT,
but its use as monotherapy should be dis-
couraged, because most studies have re-
ported high treatment failure rates [7, 8].
Nifurtimox has also been used in com-
bination with melarsoprol but published
data are very limited. The melarsoprol-
nifurtimox combination was shown to be
associated with a lower risk of relapsethan
melarsoprol alone in one study [8], but
there are serious concerns about the safety
of this combination [9].
Preliminary data on eﬂornithine-nifur-
timox combination therapy originate
from 2 studies (an aborted 3-arm ran-
domized study and a case series) led by
Epicentre in northwesternUganda[9,10].
In total, 48 patients received 7 days of in-
travenous eﬂornithine (400 mg/kgperday
given in 4 infusions) and 10 days of oral
nifurtimox (15–20 mg/kg per day). The
treatment was well tolerated, with no re-
lapses observed during the 24-month fol-
low-up period. These promising results
led Epicentre, Me ´decins Sans Frontie `res,
and the Ministry of HealthoftheRepublic
of Congo to launch, in Nkayi, a random-
ized phase III study calledtheNifurtimox-
Eﬂornithine Clinical Trial (NECT), which
compared eﬂornithine-nifurtimox ther-
apy with the standard 14-day course of
eﬂornithine therapy. The total dose of
eﬂornithineintheeﬂornithine-nifurtimox
arm was the same as that used in the 2
preliminary studies, but the drug was ad-
ministered in 2 infusions per day only.
This decision was justiﬁed by the poten-
tially large beneﬁcial impact on feasibil-
ity—and, therefore, on ﬁeld application—
of a simpliﬁed treatment schedule that
does not require full-time presence of
qualiﬁed nurses (14 eﬂornithine infusions
were given over 7 days, as opposed to 56
infusions given over 14 days).
The NECT was designed as a random-
ized, open-label, noninferiority trial with
a sample size calculated at 280 patients.
This objective was not reached in Nkayi
becauseofalowenrollmentrate.Thepub-
lication of partial data in this issueofClin-
ical Infectious Diseasesmay raisesomecrit-
ical voices, but the researchers’ decision
must be interpreted in the light of the
atypical context of HAT and the urgent
needfordataontreatmentofsecond-stage
illness [11]. The authors are to be con-
gratulated for the excellent study design
and for the exceptionally high rate of fol-
low-up (95%), which highlights the ded-
ication of the research team in the ﬁeld.
Fifty-twoand51patientsweretreatedwith
eﬂornithine-nifurtimox and standard
eﬂornithine, respectively. Cure rates were
excellent (1 94%) in both arms. No HAT-
or treatment-related deaths occurred dur-
ing hospitalization or during follow-up in
the eﬂornithine-nifurtimox arm. The rate
of hematologic (in particular, severe neu-
tropenia) and neuropsychiatricadverseef-CSE THEME ARTICLE • CID 2007:45 (1 December) • 1445
fects appeared to be low in the eﬂorni-
thine-nifurtimox arm. As stated by the
authors, for the time being, none of these
ﬁndings should be considered as proof.
Since 2005, the NECT has become a
multiple-center trial, with a gradual ex-
tensionto5otherﬁeldsites(3intheDem-
ocratic Republic of Congo and 2 in
Uganda), under the coordination of the
DrugsforNeglectedDiseasesinitiativeand
WHO–Tropical Diseases Research, with
several other partners (Epicentre, Me ´de-
cins Sans Frontie `res, the SwissTropicalIn-
stitute, and the national HAT control pro-
grams of the Democratic Republic of
Congo and Uganda). The NECT is the
only ongoing clinical trialforsecond-stage
HAT, and thus, it provides the only per-
spectivetowardimprovedtreatmentinthe
next 5 to 10 years. Research and devel-
opment of new HAT drugs have been re-
vived—for instance, through the effortsof
the Drugs for Neglected Diseasesinitiative
and the University of North Carolinacon-
sortium—but no new drug candidate for
treatment of for second-stage illness has
reached clinicaldevelopment.Iftheprom-
ising results presentedbyPriottoetal.[11]
are conﬁrmed at the other study sites (the
deﬁnitive results of this multiple-center
study will not be available before mid-
2008), the eﬂornithine-nifurtimox com-
bination therapy should become the ﬁrst-
line treatment of choice for second-stage
T. brucei gambienseHAT.Inthemeantime,
standard eﬂornithine therapy should be
more widely used. Nifurtimox, used as
part of combination treatment, should al-
ready be available for compassionate use
in patients who experience relapse who,
otherwise, have nothing other than death
to face.
Acknowledgments
Potential conﬂicts of interest. F.C. is part of
the NECT scientiﬁc committee and a part-time
employee of the Medical Department of Me ´decins
Sans Frontie `res (Swiss section).
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Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clin Infect Dis

Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis

High-dose nifurtimox for arsenoresistant Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire. Trans R Soc Trop Med Hyg

Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bull World Health Organ

Nifurtimox plus eflornithine for late-stage Trypanosoma brucei gambiense sleeping sickness in Uganda: a case-series. PloS Neglected Dis

Organization. Human African trypanosomiasis (sleeping sickness): epidemiological update. Wkly Epidemiol Record

Shortcourse eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial. Bull World Health Organ

The phenomenon of treatment failures in human African Trypanosomiasis. Trop Med Int Health

Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda. PLoS Clin Trials

Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial. Trans R Soc Trop Med Hyg

Melarsoprol-Free Drug Combinations for Second-Stage Gambian Sleeping Sickness: The Way to Go.

Melarsoprol-Free Drug Combinations for Second-Stage Gambian Sleeping Sickness: The Way to Go.

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