Macrofilaricidal activity after doxycycline only treatment of Onchocerca volvulus in an area of Loa loa co-endemicity: a randomized controlled trial.
BACKGROUND
The risk of severe adverse events following treatment of onchocerciasis with ivermectin in areas co-endemic with loiasis currently compromises the development of control programmes and the treatment of co-infected individuals. We therefore assessed whether doxycycline treatment could be used without subsequent ivermectin administration to effectively deliver sustained effects on Onchocerca volvulus microfilaridermia and adult viability. Furthermore we assessed the safety of doxycycline treatment prior to ivermectin administration in a subset of onchocerciasis individuals co-infected with low to moderate intensities of Loa loa microfilaraemia.


METHODS
A double-blind, randomized, field trial was conducted of 6 weeks of doxycycline (200 mg/day) alone, doxycycline in combination with ivermectin (150 microg/kg) at +4 months or placebo matching doxycycline + ivermectin at +4 months in 150 individuals infected with Onchocerca volvulus. A further 22 individuals infected with O. volvulus and low to moderate intensities of Loa loa infection were administered with a course of 6 weeks doxycycline with ivermectin at +4 months. Treatment efficacy was determined at 4, 12 and 21 months after the start of doxycycline treatment together with the frequency and severity of adverse events.


RESULTS
One hundred and four (60.5%) participants completed all treatment allocations and follow up assessments over the 21-month trial period. At 12 months, doxycycline/ivermectin treated individuals had lower levels of microfilaridermia and higher frequency of amicrofilaridermia compared with ivermectin or doxycycline only groups. At 21 months, microfilaridermia in doxycycline/ivermectin and doxycycline only groups was significantly reduced compared to the ivermectin only group. 89% of the doxycycline/ivermectin group and 67% of the doxycycline only group were amicrofilaridermic, compared with 21% in the ivermectin only group. O. volvulus from doxycycline groups were depleted of Wolbachia and all embryonic stages in utero. Notably, the viability of female adult worms was significantly reduced in doxycycline treated groups and the macrofilaricidal and sterilising activity was unaffected by the addition of ivermectin. Treatment with doxycycline was well tolerated and the incidence of adverse event to doxycycline or ivermectin did not significantly deviate between treatment groups.


CONCLUSIONS
A six-week course of doxycycline delivers macrofilaricidal and sterilizing activities, which is not dependent upon co-administration of ivermectin. Doxycycline is well tolerated in patients co-infected with moderate intensities of L. loa microfilariae. Therefore, further trials are warranted to assess the safety and efficacy of doxycycline-based interventions to treat onchocerciasis in individuals at risk of serious adverse reactions to standard treatments due to the co-occurrence of high intensities of L. loa parasitaemias. The development of an anti-wolbachial treatment regime compatible with MDA control programmes could offer an alternative to the control of onchocerciasis in areas of co-endemicity with loiasis and at risk of severe adverse reactions to ivermectin.


BACKGROUND
Controlled-Trials.com ISRCTN48118452.
Turner
Joseph D
JD
Filariasis Research Laboratory, Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Tendongfor
Nicholas
N
Esum
Mathias
M
Johnston
Kelly L
KL
Langley
R Stuart
RS
Ford
Louise
L
Faragher
Brian
B
Specht
Sabine
S
Mand
Sabine
S
Hoerauf
Achim
A
Enyong
Peter
P
Wanji
Samuel
S
Taylor
Mark J
MJ
D000293:Adolescent; D000328:Adult; D000818:Animals; D004311:Double-Blind Method; D004318:Doxycycline / Q000008:administration & dosage* / Q000009:adverse effects; D019353:Endemic Diseases; D005260:Female; D005369:Filaricides / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007559:Ivermectin / Q000008:administration & dosage / Q000009:adverse effects; D008118:Loiasis / Q000150:complications / Q000188:drug therapy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D017181:Onchocerca volvulus / Q000187:drug effects*; D009855:Onchocerciasis / Q000150:complications / Q000188:drug therapy*; D010919:Placebos / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
D005369:Filaricides; D010919:Placebos; D007559:Ivermectin; D004318:Doxycycline
Filaria J. 2003 Feb 7;2(1):2
12605722
Ann Trop Med Parasitol. 1980 Apr;74(2):189-97
7002073
Ann Trop Med Parasitol. 2004 Apr;98(3):231-49
15119969
J Infect Dis. 2002 Mar 15;185(6):805-11
11920298
Trop Med Int Health. 1996 Oct;1(5):581-9
8911442
Ann Trop Med Parasitol. 2008 Sep;102 Suppl 1:39-44
18718154
PLoS Med. 2006 Sep;3(9):e371
17002504
Trans R Soc Trop Med Hyg. 2005 Apr;99(4):279-89
15708387
Br J Ophthalmol. 1987 Feb;71(2):78-85
3548811
Mol Biochem Parasitol. 2008 Aug;160(2):123-8
18538871
Curr Opin Infect Dis. 2008 Dec;21(6):673-81
18978537
Mol Biochem Parasitol. 2004 May;135(1):57-67
15287587
Lancet. 2001 May 5;357(9266):1415-6
11356444
Parasit Vectors. 2009 Jan 21;2(1):7
19154624
Filaria J. 2005 Mar 23;4(1):1
15788103
Am J Trop Med Hyg. 2004 Aug;71(2):211-5
15306713
Exp Parasitol. 2004 Jul-Aug;107(3-4):145-56
15363940
Ann Trop Med Parasitol. 2004 Jun;98(4):359-70
15228717
Trop Med Parasitol. 1988 Mar;39(1):19-24
3291074
Lancet. 2000 Apr 8;355(9211):1242-3
10770311
Filaria J. 2005 Apr 07;4(1):2
15817124
Parasitol Res. 2009 Jan;104(2):437-47
18850111
J Infect Dis. 1993 Jul;168(1):202-6
8515109
Trans R Soc Trop Med Hyg. 2007 Aug;101(8):777-85
17531279
Ann Trop Med Parasitol. 2002 Oct;96(7):707-15
12537632
Lancet. 2002 Jul 20;360(9328):203-10
12133654
Microbes Infect. 2003 Apr;5(4):261-73
12706439
Lancet. 2007 Jun 16;369(9578):2021-2029
17574093
Filaria J. 2003 May 2;2(1):9
12816546
Parasit Vectors. 2009 Aug 27;2(1):39
19712455
Lancet. 2005 Jun 18-24;365(9477):2116-21
15964448
Expert Opin Drug Discov. 2007 Oct;2(s1):S41-52
23489032
Lancet. 2001 Dec 1;358(9296):1873-5
11741630
Med Microbiol Immunol. 2008 Sep;197(3):295-311
17999080
Filaria J. 2003 Oct 24;2 Suppl 1:S4
14975061
Filaria J. 2003 May 9;2(1):10
12801420
PLoS Negl Trop Dis. 2007 Aug 30;1(1):e72
17989786
PLoS Negl Trop Dis. 2009 Jul 21;3(7):e497
19621091