Doxycycline plus ivermectin versus ivermectin alone for treatment of patients with onchocerciasis

  • Review
  • Intervention

Authors


Abstract

Background

Onchocerciasis, also known as "river blindness," is a parasitic disease that is caused by infection from the filarial nematode (roundworm), Onchocerca volvulus. Nematodes are transmitted from person to person by blackflies of the Simulium genus, which usually breed in fast flowing streams and rivers. The disease is the second leading infectious cause of blindness in endemic areas.

Ivermectin (a microfilaricide) is widely distributed to endemic populations for prevention and treatment of onchocerciasis. Doxycycline, an antibiotic, targets Wolbachia organisms that are crucial to the survival of adult onchocerca (macrofilaricide). Combined treatment with both drugs is believed to cause direct microfilarial death by ivermectin and indirect macrofilarial death by doxycycline. Long-term reduction in the numbers of microfilaria in the skin and eyes and in the numbers of adult worms in the body has the potential to reduce the transmission and occurrence of onchocercal eye disease.

Objectives

The primary aim of this review was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocerciasis. The secondary aim was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocercal ocular lesions in communities co-endemic for onchocerciasis and Loa loa (loiasis) infection.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 7, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), PubMed (1948 to July 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to July 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 1 July 2014), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 July 2015.

Selection criteria

We included randomized controlled trials (RCTs) that had compared doxycycline plus ivermectin versus ivermectin alone. Participants with or without one or more characteristic signs of ocular onchocerciasis resided in communities where onchocerciasis was endemic.

Data collection and analysis

Two review authors independently assessed trial eligibility and extracted data. We used standard methodological procedures as expected by Cochrane.

Main results

We identified three RCTs including a total of 466 participants with a diagnosis of onchocerciasis. All trials compared doxycycline plus ivermectin versus ivermectin alone. One study investigated improvement in visual impairment at six-month follow-up; the other two studies measured microfilarial loads in skin snips to assess sustained effects of treatment at follow-up of 21 months or longer. The studies were conducted at various centers across three countries (Cameroon, Ghana, and Liberia). We judged all studies to be at overall high risk of bias because of inadequate randomization and lack of masking (one study), missing data (two studies), and selective outcome reporting (three studies).

Only one study measured visual outcomes. This study reported uncertainty about the difference in the proportion of participants with improvement in visual impairment at six-month follow-up for doxycycline plus ivermectin compared with ivermectin alone (risk ratio (RR) 1.06, 95% confidence interval (95% CI) 0.80 to 1.39; 240 participants; very low-quality evidence). No participant in either group showed improvement in optic atrophy, chorioretinitis, or sclerosing keratitis at six-month follow-up. More participants in the doxycycline plus ivermectin group than in the ivermectin alone group showed improvement in iridocyclitis (RR 1.24, 95% CI 0.69 to 2.22) and punctate keratitis (RR 1.43, 95% CI 1.02 to 2.00) at six-month follow-up; however, we graded these results as very low quality.

Two studies reported that a six-week course of doxycycline may result in Wolbachia depletion and macrofilaricidal and sterilizing activities in female Onchocerca worms; however, no analysis was possible because data were missing and incomplete (graded evidence as very low quality). Adverse events were reported in 16 of 135 (12%) participants in one of these studies and included itching, headaches, body pains, and vertigo; no difference between treatment groups was reported for any adverse event. The second study reported that one (1.3%) participant in the doxycycline plus ivermectin group had bloody diarrhea after treatment was initiated.

Authors' conclusions

Available evidence on the effectiveness of doxycycline plus ivermectin compared with ivermectin alone in preventing and treating onchocerciasis is unclear. Limited evidence of very low quality from two studies indicates that a six-week course of doxycycline followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult Onchocerca compared with ivermectin alone; however, effects on vision-related outcomes are uncertain. Future studies should consider the effectiveness of treatments in preventing visual acuity and visual field loss and their effects on anterior and posterior segment lesions, particularly chorioretinitis. These studies should report outcomes in a uniform and consistent manner at follow-up of three years or longer to allow detection of meaningful changes in vision-related outcomes.

Plain language summary

Doxycycline plus ivermectin for preventing and treating river blindness (onchocerciasis)

Review question

We reviewed the evidence on the effect of adding doxycycline to ivermectin, the usual treatment for people with river blindness (RB). RB also is known as onchocerciasis.

Background

RB is caused by an infection of worms. The worms are transmitted from person to person by a small biting fly, which breeds in fast flowing rivers and streams, mainly in West Africa. Both tiny (young) and large (adult) worms exist in the infected person. These worms cause severe itching and thickening of the skin. Only the tiny worms can enter the eyes. They can damage the eye, causing loss of vision.

RB is treated with ivermectin, which targets the tiny, young worms. It does not kill the large, adult worms. Adult worms need a certain type of bacteria (Wolbachia) to live. Doxycycline is an antibiotic. If doxycycline is able to kill this type of bacteria in the body, adult worms cannot live. The purpose of this review is to find out if combining the antibiotic doxycycline with ivermectin might provide additional benefit in preventing and treating RB.

Study characteristics

As of 15 July 2015, we identified three randomized controlled trials. A total of 466 people with RB participated in the three trials. The trials were conducted in Cameroon, Ghana, and Liberia. In the Cameroon and Ghana trials, people with RB took doxycycline or placebo (sugar pills) for four weeks or six weeks. One dose of ivermectin was then given four or six months later. People were then followed for two to three years. In the trial from Liberia, people with RB were divided into two groups. One group was given doxycycline for 6 weeks followed by a single dose of ivermectin. The other group was given ivermectin alone. Both Liberian groups were followed up for six months.

Key results

Evidence of the effect of adding doxycycline to the usual treatment of ivermectin for people with river blindness is unclear. Only one of the three trials looked at the vision of participants. This trial reported insufficient evidence to show a difference between treatment groups in the proportion of participants with visual improvement six months after the start of the study. Two trials showed reduced bacteria (Wolbachia) and fewer adult worms with combined doxycycline and ivermectin treatment than with ivermectin alone after about two years. However, new worms with the bacteria were found after treatment in one trial.

Two trials reported adverse treatment effects in some participants; both reported no differences between treatment groups. One study reported that adverse treatment effects, including itching, fever, headache, body pain, and vertigo, occurred in 12% of study participants. The other study reported that one (1.3%) person had bloody diarrhea after starting treatment with doxycycline plus ivermectin, which stopped when treatment was withdrawn.

Quality of the evidence

We judged the overall quality of the evidence as very low because of methodological issues noted in the trials.

Laienverständliche Zusammenfassung

Prävention und Behandlung von Flussblindheit (Onchozeriose) mit einer Kombination aus Doxyzyklin und Ivermectin

Fragestellung des Reviews

Wir untersuchten die Evidenz für eine Wirkung von Doxyzyklin als Behandlung von Flussblindheit, wenn dieses als Ergänzung zur üblichen Therapie mit Ivermectin verabreicht wird. Die Flusskrankheit wird auch als Onchozerkose bezeichnet.

Hintergrund

Flussblindheit wird durch eine Wurminfektion verursacht. Die Fadenwürmer werden durch eine kleine Stechmückenart von Mensch zu Mensch übertragen, deren Larven in schnell fließenden Gewässern aufwachsen und die insbesondere in Westafrika vorkommt. Im infizierten Menschen leben sowohl sehr kleine (junge) und große (ausgewachsene) Fadenwürmer. Diese Würmer verursachen starken Juckreiz und Verdickungen der Haut. Nur die kleinen Würmer können in die Augen eindringen. Sie können das Auge bis hin zum Sehverlust schädigen.

Flussblindheit wird mit Ivermectin behandelt, das die kleinen Jungwürmer (Filarien) abtötet. Es tötet jedoch nicht die großen, ausgewachsenen Würmer. Ausgewachsene Würmer benötigen zum Leben ein bestimmtes Bakterium (Wolbachia). Bei Doxyzyklin handelt es sich um ein Antibiotikum. Wenn Doxyzyklin diese Art von Bakterien im Körper abtöten kann, dann sterben die ausgewachsenen Würmer. Ziel dieses Reviews ist es herauszufinden, ob eine Kombination des Antibiotikums Doxyzyklin mit Ivermectin die Prävention und Behandlung von Flussblindheit weiter verbessern kann.

Studienmerkmale

Bis zum 15. Juli 2015 hatten wir drei randomisierte kontrollierte Studien gefunden. Insgesamt 466 an Flussblindheit erkrankte Menschen nahmen an den Studien teil, die in Kamerun, Ghana und Liberia durchgeführt wurden. In Kamerun und Ghana wurde Patienten mit Flussblindheit über vier bzw. sechs Wochen Doxyzyklin oder ein Plazebo (Zuckertablette) verabreicht. Vier bzw. sechs Monate später erhielten die Patienten eine Dosis Ivermectin. Diese Menschen wurde daraufhin zwei bis drei Jahre beobachtet. Bei der Studie in Liberia wurden die Patienten mit Flussblindheit in zwei Gruppen aufgeteilt. Eine Gruppe erhielt sechs Wochen lang Doxyzyklin und anschließend eine einzige Dosis Ivermectin. Die andere Gruppe bekam nur Ivermectin. Beide liberianischen Gruppen wurden über sechs Monate hinweg beobachtet.

Hauptergebnisse

Die Evidenz dafür, dass die zusätzliche Verabreichung von Doxyzyklin die übliche Behandlungsweise mit Ivermectin bei an Flussblindheit erkrankten Patienten beeinflusst, ist unklar. Nur eine der drei Studien untersuchte das Sehvermögen der Teilnehmer. Diese Studie ergab keinen ausreichenden wissenschaftlichen Beleg dafür, dass zwischen den behandelten Gruppen ein Unterschied hinsichtlich des Anteils an Teilnehmern bestand, deren Sehvermögen sich innerhalb von sechs Monaten ab Beginn der Studie verbessert hatte. Zwei Studien zeigten nach rund zwei Jahren eine geringere Bakterienzahl (Wolbachia) und weniger ausgewachsene Fadenwürmer bei einer Kombination aus Doxyzyklin und Ivermectin als bei einer Behandlung mit Ivermectin allein. In einer Studie wurden jedoch neue Würmer mit den Bakterien nach der Behandlung festgestellt.

Zwei Studien berichteten von unerwünschten Nebenwirkungen bei einigen Teilnehmern, wobei bei beiden kein Unterschied zwischen den Behandlungsgruppen festgestellt wurde. Eine Studie verzeichnete unerwünschte Nebenwirkungen einschließlich Juckreiz, Fieber, Kopf- und Körperschmerz sowie Schwindel bei 12% der Studienteilnehmer. Die andere Studie berichtete von einem Probanden (1,3%) mit blutigem Durchfall zu Beginn der Behandlung mit Doxyzyklin und Ivermectin. Bei Abbruch der Behandlung endeten diese Beschwerden.

Qualität der Evidenz

Aufgrund methodischer Probleme in den Studien beurteilten wir die Qualität der Evidenz als insgesamt sehr niedrig.

Anmerkungen zur Übersetzung

B. Bayerlein, freigegeben durch Cochrane Schweiz.

Laički sažetak

Kombinacija doksiciklina i ivermektina u odnosu na sami ivermektin za liječenje pacijenata s riječnom sljepoćom (onhocerkozom)

Istraživačko pitanje

U ovom Cochrane sustavnom pregledu analizirani su dokazi o učinku dodavanja doksiciklina ivermektinu, uobičajenoj terapiji za ljude s riječnom sljepoćom (engl., river blindness, RB). RB se također naziva onhocerkoza.

Dosadašnje spoznaje

RB je posljedica infekcije parazitom - crvom. Crvi se prenose s čovjeka na čovjeka preko muhe koja ujeda i koja se razmnožava u rijekama i potocima koje brzo teku, većinom u Zapadnoj Africi. I mali (mladi) i veliki (odrasli) crvi nalaze se u zaraženoj osobi. Uzrokuju jak svrbež i zadebljanje kože. Samo mali crvi mogu ući u oči. Mogu oštetiti oko i uzrokovati gubitak vida.

RB se liječi ivermektinom, koji napada male, mlade crve. Ne ubija one velike, odrasle. Odrasli crvi trebaju jednu vrstu bakterije (Wolbachia) da bi preživjeli. Doksiciklin je antibiotik. Ako doksiciklin može ubiti tu vrstu bakterije, odrasli crvi ne mogu preživjeti. Cilj ovog Cochrane sustavnog pregleda je otkriti donosi li kombinacija doksiciklina i ivermektina dodatnu korist u prevenciji I liječenju RB.

Obilježja studija

Do 15. srpnja 2015. provedena su tri randomizirana kontrolirana pokusa na tu temu. U ta tri klinička pokusa sudjelovalo je ukupno 466 ljudi s RB. Klinički pokusi su se provodili u Kamerunu, Gani i Liberiji. U kliničkim pokusima u Kamerunu i Gani, oboljeli od RB su primali doksiciklin ili placebo (tablete sa šećerom) četiri ili šest tjedana. Četiri ili šest mjeseci poslije dana je jedna doza ivermektina. Ljudi su bili praćeni kroz dvije do tri godine. U kliničkom pokusu u Liberiji, ljudi s RB su bili podijeljeni u dvije skupine. Jednoj skupini se davao doksiciklin šest tjedana u kombinaciji s jednom dozom ivermektina. Drugoj se skupini davao sam ivermektin. Obje skupine u Liberiji praćene su šest mjeseci.

Ključni rezultati

Dokazi o učinku dodavanja doksiciklina uobičajenoj terapiji ivermektina ljudima s RB su nejasni. Samo je jedan od tri klinička pokusa analizirao vid ispitanika. Taj klinički pokus ne donosi dovoljno dokaza da bi pokazao razliku između ispitivane skupine u odnosu na udio ispitanika s vizualnim poboljšanjem šest mjeseci nakon početka kliničkog pokusa. Dva klinička pokusa su nakon otprilike dvije godine pokazala manji broj bakterija (Wolbachia) i odraslih crva uz kombinaciju doksiciklina i ivermektina nego uz sam ivermektin. Međutim, u jednom kliničkom pokusu su nakon liječenja ipak pronađeni novi crvi s bakterijama.

Dva klinička pokusa su pokazala štetne učinke terapije u nekim sudionicima. Oba su našla da nema razlike između skupina koje su primale terapiju. Jedna je studija pokazala da se štetni učinci liječenja, uključujući svrbež, temperaturu, glavobolju, tjelesnu bol i vrtoglavicu, pojavljuju u 12% ispitanika. U drugoj studiji je pokazano da je jedna osoba (1,3%) imala krvavi proljev nakon što je počela primati kombinaciju doksiciklina i ivermektina, koji je prestao kada je liječenje prekinuto.

Kvaliteta dokaza

Ukupna kvaliteta dokaza je ocjenjena jako niskom, zbog manjkave metodologije koja je korištena u kliničkim pokusima.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Ivan Stvorić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. aDowngraded for high risk of bias (-1) as studies were assessed at high risk of selection, performance, detection, and reporting biases.
    bDowngraded for uncertainty (-1) as the outcome was not reported or was not reported uniformly by all studies.
    cDowngraded for missing or incomplete data (-1) as determined when data for more than 35% of randomly assigned participants were not analyzed or reported.
    dDowngraded for imprecision (-1) as observed by a wide confidence interval.

Doxycycline plus ivermectin compared with ivermectin alone for onchocerciasis

Population: people residing in communities endemic for onchocerciasis

Setting: community-based

Intervention: doxycycline plus ivermectin

Comparison: ivermectin alone

OutcomesIllustrative comparative risks (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Ivermectin aloneDoxycycline plus ivermectin
Improvement in visual impairment at 6 months450 per 1000477 per 1000
(360 to 626)
RR 1.06
(0.80 to 1.39)
240 participants
(1 study)

⊕⊝⊝⊝

Very low a,b,c,d

Two studies did not report visual impairment as an outcome (Hoerauf 2008; Turner 2010)
Parasitological outcomesSee commentsSee comments  

⊕⊝⊝⊝

Very low a,b,c

Two studies reported Wolbachia depletion and macrofilaricidal and sterilizing activities in the doxycycline plus ivermectin groups compared with the ivermectin alone groups on the basis of skin snips at follow-up of 21 to 27 months (Hoerauf 2008; Turner 2010); however, no quantitative analysis was performed because of missing or incomplete data

Clinical outcomes:

improvement in optic atrophy, chorioretinitis, or sclerosing keratitis at 6 months

See commentsSee comments  

⊕⊝⊝⊝

Very low a,b,c

One study that assessed these outcomes reported that no participant in either treatment group experienced these outcomes by 6 months follow-up. Two studies did not report ocular clinical outcomes (Hoerauf 2008; Turner 2010)

Clinical outcomes:

improvement in iridocyclitis at 6 months

142 per 1000176 per 1000
(98 to 315)
RR 1.24
(0.69 to 2.22)
240 participants
(1)

⊕⊝⊝⊝

Very low a,b,c,d

Two studies did not report ocular clinical outcomes (Hoerauf 2008; Turner 2010)

Clinical outcomes:

improvement in punctate keratitis at 6 months

308 per 1000533 per 1000
(315 to 617)
RR 1.43
(1.02 to 2.00)
240 participants
(1)

⊕⊝⊝⊝

Very low a,b,c

Two studies did not report ocular clinical outcomes (Hoerauf 2008; Turner 2010)
Adverse eventsTwo studies reported adverse events. In Turner 2010, 8 participants in the doxycycline plus ivermectin group were reported to have had an adverse event at 6 weeks compared with 7 participants in the ivermectin group; 6 participants in the doxycycline plus ivermectin group were reported to have had a mild or moderate adverse reaction 48 hours following ivermectin treatment compared with 7 participants in the ivermectin group. In Hoerauf 2008, 1 participant in the doxycycline plus ivermectin group was reported to have had bloody diarrhea. Masud 2009 did not report adverse events
*The basis for the assumed risk (e.g. control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Onchocerciasis, also known as river blindness, is a parasitic disease caused by infection from the filarial nematode (roundworm), Onchocerca volvulus. Nematodes are transmitted from person to person by blackflies of the Simulium genus (WHO 2015a). Blackflies breed in fast flowing rivers; therefore infection typically affects people who live and work near such rivers. Embryonic worms (microfilariae) are obtained from an infected host when the blackfly takes a blood meal (Figure 1). The ingested microfilariae then mature into larvae in the thoracic cavity of the blackfly and are introduced into another human host when the blackfly takes another blood meal. Filarial larvae enter the human body and develop into adult worms (macrofilariae). The large adult female worms are contained within fibrous nodules or onchocercomas in subcutaneous or deeper tissues (Tamarozzi 2011). Millions of microfilariae are produced when adult worms mate within the human host. These microfilariae migrate throughout the skin, causing severe skin disease and itching, and eventually gain entry into the eye (WHO 2015a). The exact pathway by which microfilariae gain entry into the eye is not completely understood; however, putative routes of entry include posterior ciliary arteries, nerves that supply the eye, hematogenous spread, cerebrospinal fluid, orbital septum, and cheek ligaments.

Figure 1.

Diagram of the life cycle of Onchocerca volvulus. Public access image created by the Centers for Disease Control and Prevention (CDC), USA; http://www.cdc.gov/parasites/onchocerciasis/biology.html.

Epidemiology

The natural history of onchocercal infection is characterized by severe itching and chronic papular onchodermatitis, progressive skin depigmentation (leopard skin), impaired vision, and blindness, with eye lesions generally occurring in individuals between 30 and 45 years of age. Onchocercal eye lesions may occur more rapidly in individuals with severe infection and more commonly affect men who work outdoors, possibly as the result of more frequent occupational exposure and consequently higher microfilarial (mf) loads. Onchocercal eye disease has been associated with various factors, such as localization of nodules in the upper part of the body (Simonsen 2009), vector species (Baker 1986), microfilarial burdens (Little 2004), parasite strain (Zimmerman 1992), and, more recently, with a higher Wolbachia load in the more virulent savanna strain (Higazi 2005). However, the incidence of visual impairment and blindness has been dramatically reduced in areas in which onchocerciasis control programs have been implemented (Shibuya 2000).

Onchocerciasis is endemic in 37 countries worldwide, including 31 countries in Africa, 5 in South and Central America, and 1 in the Eastern Mediterranean (Yemen) (WHO 2015a). About 25 to 37 million people are infected globally, of whom 99% are in sub-Saharan Africa (CDC 2013; Hopkins 2012; WHO 2015a). The prevalence of infection in hyperendemic areas in sub-Saharan Africa is 20% or more (WHO 2015b). Blindness and visual impairment represent the most severe pathological outcomes of onchocerciasis, with estimates of 300,000 people blinded from infection and an additional 800,000 with some level of visual impairment as of 1993 (CDC 2013; WHO 1995). Onchocerciasis is the second most common cause of blindness resulting from infection in the world (WHO 2015b). Ocular pathology varies between geographical locations and is more common in savanna areas of West Africa and Central Africa and in Latin America (Boatin 2006) than in the Mediterranean (WHO 1995). In a hyperendemic area in Sierra Leone, complete blindness was found in 1.3%, visual impairment in 4.3%, and uniocular blindness in a further 3.4% of the population that could be assessed (Whitworth 1993). In this study, identified causes of visual impairment and blindness included cataract (48.8%), corneal opacity (17.8%), onchocerciasis (9.3%), glaucoma (4.6%), uveitis (3.8%), and other causes (6.9%) (Whitworth 1993). Community-based surveys undertaken in selected areas in West Africa show that in some localities, onchocerciasis has overtaken cataract as the leading cause of blindness (Schwartz 1997). However, a large quantity of the epidemiological data on onchocerciasis was collected before mass treatment programs were initiated to prevent and eliminate infection (Hopkins 2012).

Presentation and diagnosis

The most common ocular pathology involves the cornea, but other structures of the anterior and posterior segments can also be affected. Corneal pathology usually begins with "fluffy" or "snow-flake" opacities (punctate keratitis). These opacities occur as a reaction to dead microfilariae in the anterior stroma and resolve when the microfilariae are absorbed. A more serious reaction occurs when infection is prolonged and inflammation occurs in the posterior cornea (sclerosing keratitis). Areas of the cornea become hyperpigmented (white), and without treatment the entire cornea becomes permanently scarred. In the anterior chamber, dead microfilariae can cause uveitis with formation of synechiae, cataract, and glaucoma. Posterior segment lesions include atrophy of the retinal-pigment epithelium, chorioretinal scarring, subretinal fibrosis, and postneuritic optical atrophy (Enk 2006).

The most common method of diagnosing onchocerciasis involves skin snip, a procedure in which 1 to 2 mg shavings or biopsy specimens of the skin are taken from about six different areas of the body. The skin biopsy specimens are immersed in normal saline to draw out the larvae for visual confirmation of infection (CDC 2013). If larvae are not seen, diagnosis can be made via polymerase chain reaction (PCR) of the skin (CDC 2013). Skin nodules, when present, can be removed surgically and examined for adult worms to confirm infection. The condition also can be diagnosed by slit lamp examination of the anterior portion of the eye in individuals with visual evidence of onchocercal eye disease, such as microfilariae or lesions from infection. Antibody tests are available in some regions; however, antibody tests cannot distinguish between past and current infections. Therefore, antibody testing is useful for diagnosing onchocerciasis among visitors to endemic areas but has limited utility in people who live or have lived in an endemic area (CDC 2013).

Live microfilariae in the eye typically do not cause overt symptoms and may be seen during slit lamp examination of the cornea and the anterior chamber of the eyes of individuals in endemic areas. The death of microfilariae triggers a severe immune response, which, when left untreated, leads to inflammation, progressive eye disease, and blindness (Winthrop 2011). Local invasion of microfilariae into retinal tissue has been postulated as a mechanism for retinal damage (Burnham 1998). The following ocular lesions of onchocerciasis can lead to vision impairment and blindness: sclerosing keratitis, chorioretinitis, and optic nerve disease. Blindness also can result from iridocyclitis leading to secondary cataract or secondary glaucoma (Johnson 1998). The discovery of the Wolbachia bacterium, an endosymbiont within worms, has led to new insights about the pathogenesis of anterior eye disease. It is believed that the presence of Wolbachia and microfilariae in the front of the eye elicits the immune response that is associated with punctate keratitis, sclerosing keratitis, and iridocyclitis (Hise 2007; Saint Andre 2002). The pathogenesis of posterior eye disease, including chorioretinitis, optic neuritis, and subsequent optic atrophy, is less clear and cannot be explained solely by the presence of Wolbachia and microfilariae. On the basis of the observation of structural similarity between an Onchocerca volvulus antigen (Ov39) and a human retinal antigen (hr44), researchers have hypothesized that chorioretinal pathology is initiated by an autoimmune process caused by the presence of local microfilariae (Cooper 1996). Further, extension of chorioretinal lesions may occur even after infection has been treated (Cooper 1997).

Description of the intervention

Ivermectin, an antiparasitic medication, is the standard agent for prevention and treatment of individuals with onchocerciasis. Although ivermectin is effective in killing microfilariae and in temporarily inhibiting the reproductive process of adult worms, it is not directly effective in killing adult worms. Therefore, multiple treatments are needed over the long term to ensure that infection is controlled. People usually are treated with a 150 microgram dose at least once a year for 10 to 15 years. Ivermectin is known by the brand name Mectizan® (Merck & Co., Inc., White Station, NJ, USA). In 1987, Merck & Co., Inc., launched the Mectizan Donation Program and committed to donating the drug for all who need it for perpetuity (www.mectizan.org). In 1995, the African Programme for Onchocerciasis Control (APOC) was launched to distribute ivermectin within endemic communities (WHO 2015a). As of early 2012, more than 900 million treatments for ivermectin had been donated in 34 countries as part of mass drug administration programs (Mackenzie 2012). The aim of community prevention and treatment with ivermectin in Africa and other affected areas is to kill microfilariae in infected people, thus preventing spread of the disease to others (WHO 2015a).

An earlier Cochrane systematic review of randomized controlled trials (RCTs) evaluated the effects of ivermectin deployed during mass treatment programs in endemic areas (Ejere 2012). Although ivermectin was shown to reduce the number of microfilariae in skin and eyes and to decrease ocular pathology in the front of the eye, its effect on preventing visual impairment and blindness was not clear (Ejere 2012). The main evidence that mass treatment with ivermectin may be protective against visual field loss and optic nerve disease has been received from communities mesoendemic for the savanna strain of Onchocerca volvulus (Little 2004). In a cohort of about 300,000 people followed for 30 years, onchocerciasis as a cause of blindness dropped from 29.7% to 19.6% after treatment with ivermectin was initiated. However, evidence is lacking as to the effects of ivermectin in communities affected by the forest strain of Onchocerca volvulus in which people are co-infected with Loa loa. In these communities, treatment with ivermectin has been associated with a high incidence of adverse events due to a Mazzotti reaction - a complex response caused by the immune response to dead microfilariae in the body, characterized by fever, skin rash, tachycardia (rapid heart rate), swelling of lymph nodes, stomach pain, and inflammation of the front and back of the eye (Gardon 1997).

Doxycycline, an antibiotic, may be effective in killing and sterilizing adult Onchocerca volvulus (Hoerauf 2008). The standard dose of doxycycline is 100 mg daily for six weeks. However, a dosage of 200 mg for six weeks has been shown to provide the highest possible level of macrofilaricidal activity (Tamarozzi 2011). Although doxycycline can be used in regions in which various strains of Onchocerca volvulus are endemic and Loa loa is co-endemic, the duration of doxycycline treatment poses potential logistical problems associated with mass treatment and risk of poor compliance (Hoerauf 2009). Additionally, doxycycline is contraindicated in pregnant women and in children younger than eight years of age, further limiting its widespread use (Tamarozzi 2011). Moreover, the cost-effectiveness of widespread treatment with doxycycline and ivermectin is currently unknown.

How the intervention might work

Doxycycline targets Wolbachia organisms within worms. These organisms are thought to be crucial for the survival of adult Onchocerca worms. Doxycycline added to ivermectin therapy represents a complementary treatment approach for the control of onchocerciasis, whereby all stages of the life cycle of the worm can be targeted. This combined treatment is expected to cause direct microfilarial death by ivermectin and macrofilarial death by doxycycline. Long-term reduction in the numbers of microfilariae in the skin and eyes and in the numbers of adult worms in the body can reduce the transmission and occurrence of onchocercal eye disease.

Why it is important to do this review

Successful control of onchocercal infection with ivermectin has made it the standard treatment for onchocerciasis. However, as ivermectin does not directly target adult worms, multiple treatments over many years are needed to control infection because the average life span of the adult worm is about 14 years (Plaisier 1991).

Treatment with ivermectin raises three questions. First, does treatment with ivermectin prevent progressive posterior segment disease or long-term blindness from onchocercal eye disease? Second, does a Wolbachia-targeted antibiotic that causes macrofilarial death reduce the duration of suppressive therapy and exposure of microfilariae? Third, does a Wolbachia-targeted antibiotic prevent progressive anterior and posterior segment eye disease? The first question was addressed in a previous Cochrane systematic review (Ejere 2012).

Objectives

The primary aim of this review was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocerciasis. The secondary aim was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocercal ocular lesions in communities co-endemic for onchocerciasis and Loa loa (loiasis) infection.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include in this review only randomized controlled trials (RCTs), as specified in the published protocol (Abegunde 2014).

Types of participants

We included trials in which participants resided in communities endemic for onchocerciasis. We included studies of participants with skin (eg, itchiness, skin depigmentation) and ocular signs (eg, inflammation) of onchocerciasis that was diagnosed with positive skin snip for microfilariae, with presence of onchocercal nodules and characteristic ocular signs of onchocerciasis noted on slit lamp examination.

Types of interventions

We included trials comparing treatment with doxycyline plus ivermectin versus ivermectin alone. Treatment in the intervention arm was defined according to the recommended dose of doxycycline, 100 milligrams daily for six weeks, plus ivermectin, 150 micrograms per kilogram of body weight, taken orally as a single dose annually or semi annually, or as given in an individual study. Treatment in the control arm was defined as 150 micrograms of ivermectin per kilogram of body weight annually or semi annually, or as given in the study.

Types of outcome measures

Primary outcomes

Primary outcomes for this review when treatment effects were measured between study groups include the following.

  • Visual field: risk of visual field deterioration (unilateral or bilateral) during a follow-up period of one year. As visual field deterioration can be measured by different methods, such as Amsler charts and perimetry, we used the definitions provided by the included studies.

  • Visual acuity: risk of visual acuity loss (unilateral or bilateral) during a follow-up period of one year. We considered new visual acuity loss as any case of visual impairment; a loss of three or more lines of LogMAR (Bailey 1976), or equivalent, from baseline; or blindness, defined as deterioration of visual acuity with best correction in either eye to less than 20/200 during the study period.

Outcomes of this review are similar with those from a previous Cochrane systematic review of ivermectin (versus placebo) for onchocercal eye disease (Ejere 2012). We dealt with potential confounding factors in participants with onchocerciasis, such as concomitant glaucoma, vitamin A deficiency, age-related macular degeneration, and diabetic eye disease, by stratifying data when possible.

Secondary outcomes

Secondary outcomes of interest for this review include the following.

  • Parasitological: mean count of microfilariae or proportion of participants with a count of microfilariae greater than one in:

    • cornea;

    • anterior chamber; or

    • skin.

  • Clinical: proportion of participants with incident cases or progression of any of the following:

    • optic nerve disease;

    • chorioretinitis;

    • iridocyclitis;

    • sclerosing keratitis; or

    • punctate keratitis.

Adverse outcomes

Adverse outcomes, such as photosensitivity, liver enzyme abnormalities, diarrhea, rash, fever, arthralgia, or nausea and vomiting, were recorded as defined in the respective trials.

We recorded outcomes as measured by study investigators and considered them according to the unit of randomization in each study, which was the individual. As no cluster-randomized studies were included, we did not record secondary outcomes at the community level. We planned to obtain data on proportions of participants with early and advanced stages of the following lesions: keratitis, iridocyclitis, chorioretinitis, and optic nerve disease (ie, data on early and late keratitis were combined to achieve data on keratitis as an outcome); however, no such data were reported. We planned to obtain data for the proportion of participants with a skin snip microfilarial load count between one and four, and to compare the proportion of participants with a microfilarial load count above four versus the proportion of participants with a microfilarial load count of more than one, but these data were not reported in included studies. We examined secondary outcomes reported at one year and at two years when data were available. For this review, we did not plan to assess quality of life and economic data.

Search methods for identification of studies

Electronic searches

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 7, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), PubMed (1948 to July 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to July 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 1 July 2014), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 July 2015.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), PubMed (Appendix 4, LILACS (Appendix 5), mRCT (Appendix 6), ClinicalTrials.gov (Appendix 7) and the ICTRP (Appendix 8).

Searching other resources

We searched the reference lists of included studies to find additional studies and used the Web of Science to identify additional studies that had cited included studies (last searched 26 February 2015).

Data collection and analysis

Selection of studies

Two review authors independently assessed studies for inclusion in two steps. First, two review authors independently reviewed the titles and abstracts and assessed each record as "definitely relevant," "possibly relevant," or "definitely not relevant." We resolved discrepancies by discussion. Second, we obtained full-text reports for any record that referred to "possibly relevant" or "definitely relevant" studies; two review authors then independently reviewed all full-text reports against eligibility criteria for this review and classified each study as "include," "awaiting classification," or "exclude." We resolved discrepancies through discussion. We documented studies excluded after full-text assessment in the Characteristics of excluded studies table, along with reasons for exclusion. We did not contact study investigators to determine study eligibility during the selection process.

Data extraction and management

Two review authors independently extracted data using data extraction forms developed and piloted by the Cochrane Eyes and Vision Group (CEV). We extracted data relevant to study design, participant characteristics, risk of bias, and outcomes. We resolved discrepancies by consulting a third review author when necessary. We contacted study investigators to request additional information regarding unclear and unreported data for primary and secondary outcomes and allowed two weeks for feedback. One review author entered information into Cochrane's Review Manager software (RevMan 2014), and a second author verified the accuracy of data as entered.

Assessment of risk of bias in included studies

We assessed "Risk of bias" according to methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). Two review authors evaluated studies for the following domains: selection bias (sequence generation and allocation concealment before randomization), performance bias (masking of participants and study personnel), detection bias (masking of outcome assessors), attrition bias (incomplete outcome data), reporting bias (selective outcome reporting), and other sources of bias. Two review authors independently judged each included study to be at "low," "high," or "unclear" (information insufficient to assess) risk for each potential source of bias. We contacted study investigators to ask for additional information on issues that were unclear from the study reports. When the trial investigator did not respond within two weeks, we made judgments on the basis of available information. We resolved discrepancies through discussion.

Measures of treatment effect

We assessed measures of treatment effect according to the methods set out in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). For continuous outcomes, we planned to calculate mean differences (MDs) with 95% confidence intervals (CIs) for measurements. Continuous outcomes for this review included the primary outcome (mean change in visual acuity at one year from baseline) and some of the secondary outcomes (mean microfilariae count). For dichotomous outcomes, we calculated risk ratios (RRs) with 95% CIs. Dichotomous outcomes for this review included the proportion of participants with new visual field deterioration, the proportion of participants with new visual acuity loss, the proportion of participants with a microfilariae count greater than one, the proportion of participants with new or progression of keratitis, iridocyclitis, chorioretinitis, or optic nerve disease, and the proportion of participants with adverse events.

Unit of analysis issues

The unit of analysis in this review was the individual participant.

Dealing with missing data

We contacted the primary investigators of included studies to request details regarding study methods, outcome data, and other desired information that had not been reported or had been reported unclearly. We used available data included in the study reports when we received no response within two weeks. We did not impute data for the purposes of this review.

Assessment of heterogeneity

We assessed clinical heterogeneity by comparing participant characteristics, inclusion and exclusion criteria, interventions, primary and secondary outcomes, and assessed methodological heterogeneity by evaluating study design and risk of bias. When meta-analysis was appropriate, we planned to assess statistical heterogeneity by examining the I2 statistic, with I2 greater than 50% considered to indicate substantial statistical heterogeneity. The I2 statistic estimates the percentage of variability in effect estimates that is due to heterogeneity rather than to sampling error. We also planned to examine results of the Chi2 test for heterogeneity (with P value < 0.1 indicating heterogeneity) and the degree of overlap in CIs in effect estimates from included studies. We considered poor overlap of CIs to suggest heterogeneity among studies.

Assessment of reporting biases

We planned to assess selective outcome reporting by comparing outcomes reported in the included studies versus outcomes listed in the study protocols; however, protocols for the included studies were not available. Thus, we assessed studies for selective outcome reporting by comparing outcomes described in the methods section versus outcomes reported in the results section of the study report. We planned to assess publication bias by using a funnel plot when a sufficient number of studies (10 or more) were identified; an asymmetrical funnel plot may indicate reporting bias, although it also may indicate that effects of treatment are different among studies for other reasons.

Data synthesis

When substantial statistical heterogeneity (I2 > 50%) was detected and individual treatment estimates were discordant, we planned to refrain from combining studies in meta-analysis; instead we planned to present a narrative summary. When the I2 statistic and inspection of the forest plot did not suggest substantial heterogeneity, we planned to combine the results of included studies in a meta-analysis by using a random-effects model. We would use a fixed-effect model when fewer than three studies were included in a meta-analysis, and when no evidence suggested statistical, clinical, or methodological heterogeneity.

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analyses of participants with or without visual loss at the start of treatment, participants with or without corneal disease at the start of treatment, and participants co-endemic or not co-endemic for onchocerciasis and Loa loa infection, when sufficient data were available.

Sensitivity analysis

We planned to conduct a sensitivity analysis to determine the impact of unpublished studies, industry-funded studies, and studies at high risk of bias on incomplete outcome data or selective reporting. However, because insufficient data were provided by studies, we did not conduct the sensitivity analysis.

"Summary of findings"

We prepared a "Summary of findings" table that includes assumed risk and corresponding risk for relevant outcomes based on risk across control groups in the included studies. We graded the overall quality of evidence for each outcome using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) classification (GRADEpro 2015). We assessed the certainty of evidence for each outcome as "high," "moderate," "low," or "very low" according to the following criteria as described in Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011).

  • High risk of bias among included studies

  • Indirectness of evidence

  • Unexplained heterogeneity or inconsistency of results

  • Imprecision of results (ie, wide confidence intervals)

  • High probability of publication bias

Results

Description of studies

Results of the search

Searches of electronic databases were performed on 15 July 2015 and resulted in a total of 1336 unique records; 1285 records were identified through electronic searches of bibliographic databases, and 51 were identified from clinical trial registers (Figure 2). We identified and screened 90 additional records derived from manual searches. After screening 1426 total titles and abstracts, we excluded 1421 records and retrieved full-text reports for five potentially relevant records. Upon review of the five full-text reports, we excluded two studies and identified three eligible studies. We contacted investigators of two included studies for additional data via their email addresses as corresponding authors of reports (Hoerauf 2008; Masud 2009).

Figure 2.

Study flow diagram.

Included studies

We included three studies with a total of 466 participants with a diagnosis of onchocerciasis (Hoerauf 2008; Masud 2009; Turner 2010). We later learned from the study investigator that one study that we had initially included on the basis of the full-text report was not randomized, but rather was quasi-randomized (Masud 2009). Another study that we initially included on the basis of the full-text report had analyzed an additional 22 non-randomized participants with the randomized cohort for some outcomes; all non-randomized participants had Loa loa co-infection and were assigned to the combined doxycycline plus ivermectin group (Turner 2010). We decided to keep both studies in the review and to address the limitations of these studies as part of the bias assessment and grading of evidence.

We provided detailed study characteristics in the Characteristics of included studies table.

Setting and participants

All three studies were conducted in West Africa: Ghana (Hoerauf 2008), Liberia (Masud 2009), and Cameroon (Turner 2010). All studies recruited participants normally residing in endemic onchocercal communities.

All three studies included participants who had infection with Onchocerca volvulus. Additionally, Masud 2009 required eligible participants to have had visual impairment due to onchocerciasis. More men than women were recruited (men: 65.7%, women: 34.3%). Ages of participants across studies ranged from 15 to 61 years. Data from 371 (79.6%) of 466 participants were available among the three studies during follow-up ranging from six to 27 months. Investigators of two studies reported sample size calculations (Hoerauf 2008; Turner 2010). Hoerauf 2008 calculated a sample size of 20 participants per treatment group for a power of 90% at a significance level of 0.001 to observe a significantly higher proportion of doxycycline-treated participants without skin microfilariae compared with participants treated with ivermectin alone, and allowing a 20% drop-out rate (25 participants for each arm to start). Turner 2010 reported a power of 80% for recruitment of 30 participants into each treatment group to allow for a drop-out rate of up to 15% over the follow-up period.

Interventions

All studies compared doxycycline plus ivermectin versus ivermectin alone in at least two treatment groups. All three studies used the same dose for ivermectin (single dose of 0.15 mg/kg); however, the timing of ivermectin administration and the dose and frequency of doxycycline varied among studies. In Hoerauf 2008, all participants received ivermectin after six months, and in Turner 2010, participants received ivermectin after four months. Masud 2009 did not report the timing of ivermectin administration.

Hoerauf 2008 was a three-arm trial that compared two durations of doxycycline treatment (four weeks and six weeks) in combination groups versus ivermectin alone. The duration of doxycycline treatment was six weeks in Masud 2009 and Turner 2010. The doxycycline dose was 200 mg/d in Hoerauf 2008 and Turner 2010, and Masud 2009 used 100 mg/d. Additionally, Turner 2010 included a doxycycline-only group (no ivermectin), which we excluded from our comparison of interventions.

Outcomes
Vision-related outcomes

One of the three included studies reported the number of participants with improvement in visual impairment at six-month follow-up (Masud 2009). The remaining studies did not report outcomes related to visual field or visual acuity.

Parasitological outcomes

Investigators from all studies reported that they took skin snips. Turner 2010 reported the median and the range of the number of microfilarial loads per skin snip at 12 months and 21 months after the start of treatment. Hoerauf 2008 reported this outcome at 20-month and 27-month follow-up. Skin snip data also were examined in Masud 2009, but only for select cases; the number of nodules was reported, but no further information was given. No study reported assessment of ocular microfilariae counts.

Clinical outcomes

Clinical outcomes, including optic atrophy, chorioretinitis, iridocyclitis, sclerosing keratitis, and punctate keratitis, were reported in Masud 2009 at six-month follow-up. Additionally, Masud 2009 reported perilimbal pigmentation and pannus outcomes. The remaining two studies did not provide data on these conditions.

Adverse outcomes

Two included studies reported occurrences of adverse events in participants (Hoerauf 2008; Turner 2010); no adverse event was reported in Masud 2009.

Excluded studies

We excluded two studies; both are comparative studies without randomization. We documented reasons for exclusion in the Characteristics of excluded studies table.

Risk of bias in included studies

We described "Risk of bias" assessments for individual studies in detail in the Characteristics of included studies tables and summarized them in Figure 3.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

All studies were reported as randomized; however, only two of the three studies used randomization methods sufficient to prevent bias (Hoerauf 2008; Turner 2010). We judged these two studies as being at low risk of selection bias for using adequate methods of sequence generation and allocation concealment before randomization. We judged Masud 2009 as being at high risk of selection bias after communication with the study investigator revealed that the study was quasi-randomized (investigators used participants' registration numbers to assign treatment).

Masking (performance bias and detection bias)

Two studies reported masking participants, study personnel, and outcome assessors (Hoerauf 2008; Turner 2010); therefore, we judged these studies as having low risk of performance bias and detection bias. We judged Masud 2009 as being at high risk of performance bias and detection bias because the study was conducted without masking.

Incomplete outcome data

We judged one study to be at low risk of attrition bias; Masud 2009 reported outcome data for all participants. We judged two studies to be at high risk of attrition bias because more than 35% of randomly assigned participants were excluded from the analysis (Hoerauf 2008; Turner 2010).

Selective reporting

We judged all three studies to be at high risk of reporting bias. The authors of Hoerauf 2008 reported deviations from the original protocol based on results from previous studies that they had conducted and indicated that some outcomes were not reported when no difference was found between groups. Selective reporting of data was indicated, as some measurements (eg, skin snips) were omitted or included for some treatment groups during follow-up. In Masud 2009, nodulectomies and skin snips were performed in selected cases, and these data were not reported. In Turner 2010, some outcome data were not reported separately for randomized and non-randomized participants.

Other potential sources of bias

We judged two studies to be at high risk for other sources of bias: Hoerauf 2008 reported baseline imbalances in microfilarial loads among treatment groups and indicated that treatments were donated by a pharmaceutical company, and Turner 2010 included data from a non-randomized subgroup of participants.

Effects of interventions

See: Summary of findings for the main comparison

We did not conduct any meta-analysis because we observed differences in design, outcomes, and follow-up time points among studies. All three studies compared doxycycline plus ivermectin versus ivermectin alone, with doxycycline given at doses of 100 mg/d (Masud 2009) and 200 mg/d (Hoerauf 2008; Turner 2010).

Vision-related outcomes

Only one study assessed any vision-related outcome (Masud 2009). At six-month follow-up, improvement in visual impairment was observed in 48% (57/120) of participants in the doxycycline plus ivermectin group compared with 45% (54/120) of participants in the ivermectin alone group (RR 1.06, 95% CI 0.80 to 1.39). No participants with visual deterioration were reported, which may imply that no participant developed worsening of visual impairment or blindness during the study. However, because study authors did not report their criteria for visual improvement or deterioration, we were not able to determine whether their definition met the criteria used for this review.

Hoerauf 2008 and Turner 2010 did not report vision-related outcome data.

We graded the certainty of evidence for vision-related outcomes as very low because of imprecision, high risk of bias among studies, and lack of reporting of this outcome by two studies.

Parasitological outcomes

Two studies reported parasitological outcomes by assessing microfilarial loads in skin snips (Hoerauf 2008; Turner 2010). No meta-analysis was performed for this outcome because of uncertainty regarding proportions resulting from large quantities of missing data (> 40% missing data in Hoerauf 2008 and 35% in Turner 2010), and because Turner 2010 reported only combined data for randomly assigned and non-randomly assigned participants.

In Hoerauf 2008, 60% (6/10) of participants in the four-week doxycycline plus ivermectin group, 15% (3/14) of participants in the six-week doxycycline plus ivermectin group, and 94% (17/18) of participants in the ivermectin alone group had skin microfilariae at 20 months; data were unknown for 34/76 (45%) randomly assigned participants. At 27-month follow-up, 50% (5/10) of participants in the four-week doxycycline plus ivermectin group, 70% (7/10) of participants in the six-week doxycycline plus ivermectin group, and 80% (12/15) of those in the ivermectin alone group had skin microfilariae; data were unknown for 41/76 (54%) randomly assigned participants.

Masud 2009 collected skin skips from a select group of participants but did not report parasitological outcomes.

We graded the certainty of evidence for parasitological outcomes as very low because large quantities of data were missing, risk of bias among studies was high, and reporting of this outcome was insufficient for analysis.

Clinical outcomes

Masud 2009 reported the proportion of participants in each group with improvement in ocular signs. At six-month follow-up, no participant in either treatment group showed improvement with respect to optic atrophy, chorioretinitis, or sclerosing keratitis. A total of 18% (21/120) of participants in the doxycycline plus ivermectin group compared with 14% (17/120) of participants in the ivermectin alone group showed improvement in iridocyclitis at six-month follow-up (RR 1.24, 95% CI 0.69 to 2.22). More participants in the doxycycline plus ivermectin group (44%; 53/120) than in the ivermectin alone group (31%; 37/120) showed improvement in punctate keratitis at six-month follow-up (RR 1.43, 95% CI 1.02 to 2.00).

Hoerauf 2008 and Turner 2010 did not report clinical outcomes in ocular signs.

We graded the certainty of evidence for clinical outcomes as very low because of imprecision, high risk of bias among studies, and lack of reporting of this outcome by two studies.

Adverse events

Two studies reported adverse events. Hoerauf 2008 reported bloody diarrhea in one participant in the four-week doxycycline group on day 3 of treatment. Treatment was stopped and the participant recovered quickly after treatment with metronidazole. Other side effects were not specified but were reported as mild and not lasting longer than three days, and researchers noted no differences between treatment groups in frequency of adverse events. One participant from the four-week doxycycline group died eight months after receiving doxycycline treatment; however, the cause of death was not confirmed. No other serious adverse events were reported. Turner 2010 reported adverse events in 15 randomly assigned participants during the six-week period of doxycycline or matching placebo. No significant differences were reported between the three treatment groups with respect to frequency of adverse events during six weeks of doxycycline treatment (doxycycline plus ivermectin: 6/52 (11.5%) versus doxycycline alone: 2/29 (6.9%) versus ivermectin alone: 7/54 (11.9%)). Adverse events were mild or moderate and consisted of itching, fever, headache, body pains, and vertigo. Forty-eight hours following ivermectin or placebo allocation, symptoms consistent with adverse reactions were observed in 13 participants (doxycycline plus ivermectin: 3/42 (7.1%) versus doxycycline alone: 3/25 (12.0%) versus ivermectin alone: 7/45 (15.6%)). Masud 2009 did not report adverse events.

Discussion

Summary of main results

This review presents the results of three studies with a total of 466 randomly assigned participants with a diagnosis of onchocerciasis. All studies compared the effects of doxycycline plus ivermectin treatment versus ivermectin alone; however, only one study evaluated vision-related or ocular clinical outcomes (Masud 2009). We planned to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocercal ocular lesions in communities co-endemic for onchocerciasis and Loa loa (loiasis) infection; however, none of the randomly assigned participants were eligible for this comparison.

No meta-analysis was possible because of differences among studies in outcome measures and follow-up times. Two studies investigated sustained effects of doxycycline plus ivermectin treatment versus ivermectin alone on microfilarial loads in skin snips and on depletion of Wolbachia within adult worms after follow-up of 12 to 20 months (Hoerauf 2008; Turner 2010); one study investigated effects of doxycycline plus ivermectin versus ivermectin alone on visual impairment and ocular signs of onchocerciasis at six-month follow-up (Masud 2009).

The three studies included in this review provided evidence suggesting that the effectiveness of doxycycline plus ivermectin in the treatment of individuals with onchocerciasis is highly uncertain. Improvement in visual impairment was uncertain when doxycycline plus ivermectin treatment was compared with ivermectin alone at six-month follow-up in one study (Masud 2009). Limited, very low-quality evidence from two studies indicate that a six-week course of doxycycline followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult onchocerca than are seen with ivermectin alone at up to 27-month follow-up (Hoerauf 2008; Turner 2010). Combination therapy with doxycycline plus ivermectin may be more effective than ivermectin alone for healing at early stages of onchocercal eye disease (punctuate keratitis); however, no clinical differences between groups were noted for other clinical signs (iridocyclitis, optic atrophy, chorioretinitis, and sclerosing keratitis). Two studies reported adverse events, such as bloody diarrhea, itching, fever, headache, body pains, and vertigo, in fewer than 13% of participants.

Overall completeness and applicability of evidence

Two of the studies included in this systematic review were not designed primarily to evaluate the effectiveness of doxycycline plus ivermectin in the treatment of patients with onchocercal eye disease (Hoerauf 2008; Turner 2010). Most important, the effect of combination therapy of doxycycline plus ivermectin in preventing visual loss, which is an outcome of primary importance to people suffering from river blindness, was not properly evaluated in any of the studies included in this systematic review. Clearly this effect presents a key question that remains unanswered.

Masud 2009 followed participants for only six months, which may not be a sufficient duration for adequate assessment of vision-related outcomes. On the other hand, Hoerauf 2008 and Turner 2010 followed participants longer (21 and 27 months, respectively) but lost more than 35% of randomly assigned participants. Therefore, data at follow-up of one year or longer were not available or complete for any included study.

All studies were conducted primarily in West Africa, and their generalizability to other settings is unknown. No data were provided for randomly assigned participants co-endemic for onchocerciasis and Loa loa infection.

Quality of the evidence

We graded the certainty of evidence for all outcomes as very low because of imprecision, high risk of bias among studies, and lack of reporting of many outcomes by the authors of included studies. These assessments limit the strength of the conclusions that can be drawn from this systematic review.

Potential biases in the review process

Potential bias may have been introduced because the choice of methods was influenced by prior knowledge of the results of included trials. However, we think this is unlikely, as we used standard Cochrane methods to minimize potential bias.

Agreements and disagreements with other studies or reviews

A limited number of randomized and non-randomized studies have suggested that doxycycline (for four to six weeks) plus ivermectin is more effective than ivermectin alone with regard to macrofilaricidal activity and permanent sterilization of adult Onchocerca volvulus (Hoerauf 2003; Tamarozzi 2012; Wanji 2009). However, the findings of our review do not fully support the conclusions presented by authors of those studies. First, new Wolbachia-containing worms acquired after administration of doxycycline were detected in one study. This observation raises questions about how the drug can be used optimally within current public health campaigns based on mass drug administration in regions with high transmission and increased potential for re-infection. Second, the efficacy of doxycycline plus ivermectin for prevention and treatment of onchocercal eye lesions is unclear because the only study that examined this question had several methodological weaknesses. Furthermore, certain populations, such as pregnant women and children, have been excluded from trials studying the safety and efficacy of doxycycline plus ivermectin for prevention and treatment of onchocerciasis because doxycycline is contraindicated in pregnant women and in children younger than eight years of age. These restrictions have implications for widespread use in onchocerciasis control programs. Therefore, alternative drugs or combinations that are more effective and those that can be delivered via shorter regimens with fewer contraindications are needed. The A-WOL Consortium seeks to deliver optimized regimens of existing drugs for rapid deployment in restricted settings, and to identify alternative drugs and combinations that are effective within shorter time frames and that are safe for children and for pregnant women. We agree with the conclusions of the review authors in Taylor et al that doxycycline plus ivermectin can be used to complement existing mass drug administration strategies in ‘hot spot’ foci or residual populations in mass drug administration end-game scenarios, when test and treat strategies may be more cost-effective and deliverable than mass drug administration (Taylor 2014). However, discovery of new and safer anti-Wolbachia therapies remains the most promising strategy.

Authors' conclusions

Implications for practice

Evidence for the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocercal eye disease remains unclear. Limited, very low-quality evidence from two studies indicates that a six-week course of doxycycline followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult onchocerca compared with ivermectin alone; however, effects on vision-related outcomes have not been established.

Implications for research

The most important public health problems posed by onchocerciasis are blindness and visual impairment. Future studies should focus on the microfilaricidal and macrofilaricidal properties of doxycycline plus ivermectin, and should specifically consider their effectiveness in preventing loss of visual acuity and effects on visual fields and anterior and posterior segment lesions, particularly chorioretinitis. Future studies should include appropriate sample sizes, allowing sufficient power to detect important treatment differences with respect to preventing visual loss in onchocerciasis. These studies also should report parasitological, clinical, and visual outcomes in a uniform and consistent manner. The duration of these studies should be sufficiently long to permit detection of meaningful changes in visual acuity (≥ 3 years). Given that these studies would be conducted in rural communities, simple visual acuity tests, such as the illiterate E chart (Taylor 1978), could be used and outcome measures reported as "proportion of participants in each treatment group becoming visually impaired or blind during follow-up," in keeping with the definition of visual impairment provided by the World Health Organization in the International Statistical Classification of Diseases, Injuries, and Causes of Death, 10th revision (ICD-10), and based on “best-corrected” vision (ie, visual acuity attained with the best possible refractive correction) (WHO 2013). This method is proposed to ensure that the real impact of onchocerciasis on visual impairment or blindness is not underestimated. Retinal and optic nerve imaging and anterior segment photography could be used to objectively assess progression and regression of clinical signs and the incidence of new lesions. Regimen refinement studies aimed at optimizing regimens of existing anti-Wolbachia drugs in combination and at reducing time frames for delivery in restricted settings, such as regions co-endemic with Loa loa, should be conducted. Research to develop alternative treatments for high-risk subgroups that cannot take doxycycline, such as pregnant women and children, also should be undertaken.

Acknowledgements

We acknowledge:

  • Henry Ejere for performing previous work and providing assistance with developing the topic for this review;

  • Lori Rosman for devising and running the electronic search strategies;

  • Xuan Hui and Kristina Lindsley at CEV@US, and Anupa Shah, Managing Editor for CEV, for providing support and guidance during completion of this review; and

  • Robert Dellavalle, Clare Gilbert, and Barbara Hawkins for providing comments on this review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Onchocerciasis] explode all trees
#2 MeSH descriptor: [Onchocerca] explode all trees
#3 MeSH descriptor: [Microfilaria] explode all trees
#4 (Onchocerc* or Oncocerc*)
#5 (river near/2 blindness)
#6 Robles* disease or "O volvulus" or volvulosis or craw-craw or sowdah
#7 #1 or #2 or #4 or #5 or #6
#8 MeSH descriptor: [Ivermectin] explode all trees
#9 (Ivermec* or Ivermek* or Ivomec* or "Ablaze-IM" or "ABZ Plus" or "Albacos-IR" or "Albosym-IR" or Alvect or "Anthel-UP" or "Ariban Plus" or Ascapil or "Bandy Plus" or "Benrod-I" or Benzole or Cardomec or "Dermoper IV" or Dermopero or Detebencil or Diapec or Ectin or Ectover or "Elect-A" or Epimek or Eqvalan or Eqvalen or "Eris Plus" or "Getrid-I" or "Hymin Plus" or Ifact or Imectin or Ivecop or "Ivecop-AB" or Ivercid or "Ivercid-A" or Ivermin or Iversan or "Iver-Sol" or Iverstar or Ivertal or Iverx or Iverzole or Ivexterm or Ivor or Ivoral or Ivori or Kaonol or Kidi or Kilox or Leverctin or Macbi or Maikeding or Mectin or Mectizan or Mediderm or "MK 933" or MK933 or Networm or Oramec or Plurimec or Quamox or "Quanox Gotas" or Revectina or Sanifer or Securo or Simpiox or Sklice or Stromectol or Vermectil or Vermectin or Vermokill or Yvermil)
#10 70288-86-7
#11 #8 or #9 or #10
#12 MeSH descriptor: [Doxycycline] explode all trees
#13 (Abadox or Abraxil or "Acnedox-LB" or Actidox or Adoxa or "Ai Rui De An" or "Aknefug Doxy" or "Ak-Ramycin" or "Ak-Ratabs" or Aliudox or Alodox or "Alpha 6 Deoxyoxytetracycline" or "Alpha-6-Deoxyoxytetracycline" or Ambrodoxy or "Ambroxol AL comp" or "Ambroxol comp" or "Amdox-Puren" or Amermycin or Anfadox or "Antodox Apidox" or Apociclina or Apodoxin or Apodoxy or "Apo-Doxy" or Apprilon or Atridox or "Avidox-LB" or "Avidox-OZ" or "Avidox-SP" or Avidoxy or "Azudoxat-T" or Bactidox or "Bidox-DT" or Biocin or Biodoxi or Bioximicina or "BMY 28689" or BMY28689 or "BU 3839T" or "Chemedox-HT" or Ciclidoxan or Clifordin or Codox or Cyclodox)
#14 (Dedoxyn or Dentarec or Dobid or Docdoxyc or Docyl or "Doksiciklinas monohidratas" or Doksisiklin or Doksisykliini or Doksisykliinimonohydraatti or Doksycyklina or "Dom-Doxycycline" or Doranbax or Doryx or Dosyklin or Dotur or Doxacin or Doxakne or Doxat or Doxibiot or Doxiciclina or Doxiciklin or Doxicip or Doxicor or Doxilegrand or Doxilina or Doximed or Doxina or Doxipil or Doxitab or Doxithal or Doxitidin or Doxitin or "Dox-M DT" or "Dox-M ST" or "Dox-M TZ" or "Dox-M-A" or "Dox-M-OZ" or "Doxodin-TR" or Doxt or Doxy or "Doxy-1 L-DR Forte" or "Doxy-100" or Doxybene or Doxycap or Doxycin or Doxycline or Doxycyclin or Doxycycline or Doxycyclinum or "Doxycyklin monohydrate" or Doxycyklinmonohydrat or Doxyderma or Doxydoc or Doxyferm or Doxyguard or Doxyhexal or "Doxy-HP" or Doxylan or Doxyleb or Doxylin or "Doxylin-DT" or "Doxylin-TZ" or Doxylis or "Doxy-M" or Doxyman or Doxymerck or Doxymono or Doxymycin or "Doxy-N-Tablinen" or Doxypalu or Doxyprotect or "Doxyratio M" or Doxyremed or Doxyric or Doxysol or Doxystad or Doxytab or "Doxy-Tabs" or Doxytop or "Doxy-Wolff" or Dumoxin or Duradox or Duradoxal or "DX-24")
#15 (Efracea or Emdox or "Emdox-TZ" or Frakas or Geeox or Ginadox or "Glodox-LB" or Granudoxy or "GS-3065" or Hydramycin or Ibimycin or Idocyklin or Ivamycin or Jenacyclin or LAA or Lentomyk or Lupidox or Madoxy or "Martidox-M" or "M-Dox" or Microdox or Minicycline or Monodox or Morgidox or "Nab-DT" or Nee or Novadox or "Novo-Doxylin" or Novum or Nudoxy or NutriDox or Ocudox or Oracea or Oraxyl or Oraycea or Periosan or Periostat or "PHL-Doxycycline" or Plemex or "PMS-Doxycycline" or Pondoxcycline or Randoclin or Remycin or Sigadoxin or Supracyclin or Supracycline or Synvibra or "Tasmacyclin Akne" or Tetradox or Tolexine or Tremesal or Unidox or "Vibra Tabs" or Vibradox or Vibradoxin or Vibramicina or Vibramycin or Vibramycine or "Vibra-S" or Vibratab or "Vibra-Tabs" or Vibravenos or Vivradoxil or Xedocine)
#16 (564-25-0 or 17086-28-1)
#17 #12 or #13 or #14 or #15 or #16
#18 #11 or #17
#19 #7 and #18

Appendix 2. MEDLINE (Ovid) search strategy

1. Randomized Controlled Trial.pt.
2. Controlled Clinical Trial.pt.
3. (randomized or randomised).ab,ti.
4. placebo.ab,ti.
5. drug therapy.fs.
6. randomly.ab,ti.
7. trial.ab,ti.
8. groups.ab,ti.
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. exp animals/ not humans.sh.
11. 9 not 10
12. exp Onchocerciasis/
13. exp Onchocerca/
14. exp Microfilaria/
15. (Onchocerc* or Oncocerc*).tw.
16. (river adj2 blindness).tw.
17. (Robles* disease or "O volvulus" or volvulosis or craw-craw or sowdah).tw.
18. or/12-17
19. exp Ivermectin/
20. (Ivermec* or Ivermek* or Ivomec* or "Ablaze-IM" or "ABZ Plus" or "Albacos-IR" or "Albosym-IR" or Alvect or "Anthel-UP" or "Ariban Plus" or Ascapil or "Bandy Plus" or "Benrod-I" or Benzole or Cardomec or "Dermoper IV" or Dermopero or Detebencil or Diapec or Ectin or Ectover or "Elect-A" or Epimek or Eqvalan or Eqvalen or "Eris Plus" or "Getrid-I" or "Hymin Plus" or Ifact or Imectin or Ivecop or "Ivecop-AB" or Ivercid or "Ivercid-A" or Ivermin or Iversan or "Iver-Sol" or Iverstar or Ivertal or Iverx or Iverzole or Ivexterm or Ivor or Ivoral or Ivori or Kaonol or Kidi or Kilox or Leverctin or Macbi or Maikeding or Mectin or Mectizan or Mediderm or "MK 933" or MK933 or Networm or Oramec or Plurimec or Quamox or "Quanox Gotas" or Revectina or Sanifer or Securo or Simpiox or Sklice or Stromectol or Vermectil or Vermectin or Vermokill or Yvermil).tw.
21. 70288-86-7.rn.
22. or/19-21
23. exp Doxycycline/
24. (Abadox or Abraxil or "Acnedox-LB" or Actidox or Adoxa or "Ai Rui De An" or "Aknefug Doxy" or "Ak-Ramycin" or "Ak-Ratabs" or Aliudox or Alodox or "Alpha 6 Deoxyoxytetracycline" or "Alpha-6-Deoxyoxytetracycline" or Ambrodoxy or "Ambroxol AL comp" or "Ambroxol comp" or "Amdox-Puren" or Amermycin or Anfadox or "Antodox Apidox" or Apociclina or Apodoxin or Apodoxy or "Apo-Doxy" or Apprilon or Atridox or "Avidox-LB" or "Avidox-OZ" or "Avidox-SP" or Avidoxy or "Azudoxat-T" or Bactidox or "Bidox-DT" or Biocin or Biodoxi or Bioximicina or "BMY 28689" or BMY28689 or "BU 3839T" or "Chemedox-HT" or Ciclidoxan or Clifordin or Codox or Cyclodox).tw.
25. (Dedoxyn or Dentarec or Dobid or Docdoxyc or Docyl or "Doksiciklinas monohidratas" or Doksisiklin or Doksisykliini or Doksisykliinimonohydraatti or Doksycyklina or "Dom-Doxycycline" or Doranbax or Doryx or Dosyklin or Dotur or Doxacin or Doxakne or Doxat or Doxibiot or Doxiciclina or Doxiciklin or Doxicip or Doxicor or Doxilegrand or Doxilina or Doximed or Doxina or Doxipil or Doxitab or Doxithal or Doxitidin or Doxitin or "Dox-M DT" or "Dox-M ST" or "Dox-M TZ" or "Dox-M-A" or "Dox-M-OZ" or "Doxodin-TR" or Doxt or Doxy or "Doxy-1 L-DR Forte" or "Doxy-100" or Doxybene or Doxycap or Doxycin or Doxycline or Doxycyclin or Doxycycline or Doxycyclinum or "Doxycyklin monohydrate" or Doxycyklinmonohydrat or Doxyderma or Doxydoc or Doxyferm or Doxyguard or Doxyhexal or "Doxy-HP" or Doxylan or Doxyleb or Doxylin or "Doxylin-DT" or "Doxylin-TZ" or Doxylis or "Doxy-M" or Doxyman or Doxymerck or Doxymono or Doxymycin or "Doxy-N-Tablinen" or Doxypalu or Doxyprotect or "Doxyratio M" or Doxyremed or Doxyric or Doxysol or Doxystad or Doxytab or "Doxy-Tabs" or Doxytop or "Doxy-Wolff" or Dumoxin or Duradox or Duradoxal or "DX-24").tw.
26. (Efracea or Emdox or "Emdox-TZ" or Frakas or Geeox or Ginadox or "Glodox-LB" or Granudoxy or "GS-3065" or Hydramycin or Ibimycin or Idocyklin or Ivamycin or Jenacyclin or LAA or Lentomyk or Lupidox or Madoxy or "Martidox-M" or "M-Dox" or Microdox or Minicycline or Monodox or Morgidox or "Nab-DT" or Nee or Novadox or "Novo-Doxylin" or Novum or Nudoxy or NutriDox or Ocudox or Oracea or Oraxyl or Oraycea or Periosan or Periostat or "PHL-Doxycycline" or Plemex or "PMS-Doxycycline" or Pondoxcycline or Randoclin or Remycin or Sigadoxin or Supracyclin or Supracycline or Synvibra or "Tasmacyclin Akne" or Tetradox or Tolexine or Tremesal or Unidox or "Vibra Tabs" or Vibradox or Vibradoxin or Vibramicina or Vibramycin or Vibramycine or "Vibra-S" or Vibratab or "Vibra-Tabs" or Vibravenos or Vivradoxil or Xedocine).tw.
27. (564-25-0 or 17086-28-1).rn.
28. 23 or 24 or 25 or 26 or 27
29. 22 or 28
30. 11 and 18 and 29

Appendix 3. Embase.com search strategy

#1 'randomized controlled trial'/exp
#2 'randomization'/exp
#3 'double blind procedure'/exp
#4 'single blind procedure'/exp
#5 random*:ab,ti
#6 #1 OR #2 OR #3 OR #4 OR #5
#7 'animal'/exp OR 'animal experiment'/exp
#8 'human'/exp
#9 #7 AND #8
#10 #7 NOT #9
#11 #6 NOT #10
#12 'clinical trial'/exp
#13 (clin* NEAR/3 trial*):ab,ti
#14 ((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti
#15 'placebo'/exp
#16 placebo*:ab,ti
#17 random*:ab,ti
#18 'experimental design'/exp
#19 'crossover procedure'/exp
#20 'control group'/exp
#21 'latin square design'/exp
#22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
#23 #22 NOT #10
#24 #23 NOT #11
#25 'comparative study'/exp
#26 'evaluation'/exp
#27 'prospective study'/exp
#28 control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti
#29 #25 OR #26 OR #27 OR #28
#30 #29 NOT #10
#31 #30 NOT (#11 OR #23)
#32 #11 OR #24 OR #31
#33 'onchocerciasis'/exp
#34 'onchocerca'/exp
#35 'microfilaria'/exp
#36 'microfilaria (nematode larva)'/exp
#37 onchocerc*:ab,ti OR oncocerc*:ab,ti
#38 (river NEAR/2 blindness):ab,ti
#39 (robles* NEAR/1 disease):ab,ti OR 'o volvulus':ab,ti OR volvulosis:ab,ti OR 'craw craw':ab,ti OR sowdah:ab,ti
#40 #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39
#41 'ivermectin'/exp
#42 ivermec*:ab,ti OR ivermek*:ab,ti OR ivomec*:ab,ti OR 'ablaze-im':ab,ti OR 'abz plus':ab,ti OR 'albacos-ir':ab,ti OR 'albosym-ir':ab,ti OR alvect:ab,ti OR 'anthel-up':ab,ti OR 'ariban plus':ab,ti OR ascapil:ab,ti OR 'bandy plus':ab,ti OR 'benrod-i':ab,ti OR benzole:ab,ti OR cardomec:ab,ti OR 'dermoper iv':ab,ti OR dermopero:ab,ti OR detebencil:ab,ti OR diapec:ab,ti OR ectin:ab,ti OR ectover:ab,ti OR 'elect-a':ab,ti OR epimek:ab,ti OR eqvalan:ab,ti OR eqvalen:ab,ti OR 'eris plus':ab,ti OR 'getrid-i':ab,ti OR 'hymin plus':ab,ti OR ifact:ab,ti OR imectin:ab,ti OR ivecop:ab,ti OR 'ivecop-ab':ab,ti OR ivercid:ab,ti OR 'ivercid-a':ab,ti OR ivermin:ab,ti OR iversan:ab,ti OR 'iver-sol':ab,ti OR iverstar:ab,ti OR ivertal:ab,ti OR iverx:ab,ti OR iverzole:ab,ti OR ivexterm:ab,ti OR ivor:ab,ti OR ivoral:ab,ti OR ivori:ab,ti OR kaonol:ab,ti OR kidi:ab,ti OR kilox:ab,ti OR leverctin:ab,ti OR macbi:ab,ti OR maikeding:ab,ti OR mectin:ab,ti OR mectizan:ab,ti OR mediderm:ab,ti OR 'mk 933':ab,ti OR mk933:ab,ti OR networm:ab,ti OR oramec:ab,ti OR plurimec:ab,ti OR quamox:ab,ti OR 'quanox gotas':ab,ti OR revectina:ab,ti OR sanifer:ab,ti OR securo:ab,ti OR simpiox:ab,ti OR sklice:ab,ti OR stromectol:ab,ti OR vermectil:ab,ti OR vermectin:ab,ti OR vermokill:ab,ti OR yvermil:ab,ti
#43 '70288 86 7':rn
#44 #41 OR #42 OR #43
#45 'doxycycline'/exp
#46 abadox:ab,ti OR abraxil:ab,ti OR 'acnedox-lb':ab,ti OR actidox:ab,ti OR adoxa:ab,ti OR 'ai rui de an':ab,ti OR 'aknefug doxy':ab,ti OR 'ak-ramycin':ab,ti OR 'ak-ratabs':ab,ti OR aliudox:ab,ti OR alodox:ab,ti OR 'alpha 6 deoxyoxytetracycline':ab,ti OR 'alpha-6-deoxyoxytetracycline':ab,ti OR ambrodoxy:ab,ti OR 'ambroxol al comp':ab,ti OR 'ambroxol comp':ab,ti OR 'amdox-puren':ab,ti OR amermycin:ab,ti OR anfadox:ab,ti OR 'antodox apidox':ab,ti OR apociclina:ab,ti OR apodoxin:ab,ti OR apodoxy:ab,ti OR 'apo-doxy':ab,ti OR apprilon:ab,ti OR atridox:ab,ti OR 'avidox-lb':ab,ti OR 'avidox-oz':ab,ti OR 'avidox-sp':ab,ti OR avidoxy:ab,ti OR 'azudoxat-t':ab,ti OR bactidox:ab,ti OR 'bidox-dt':ab,ti OR biocin:ab,ti OR biodoxi:ab,ti OR bioximicina:ab,ti OR 'bmy 28689':ab,ti OR bmy28689:ab,ti OR 'bu 3839t':ab,ti OR 'chemedox-ht':ab,ti OR ciclidoxan:ab,ti OR clifordin:ab,ti OR codox:ab,ti OR cyclodox:ab,ti
#47 dedoxyn:ab,ti OR dentarec:ab,ti OR dobid:ab,ti OR docdoxyc:ab,ti OR docyl:ab,ti OR 'doksiciklinas monohidratas':ab,ti OR doksisiklin:ab,ti OR doksisykliini:ab,ti OR doksisykliinimonohydraatti:ab,ti OR doksycyklina:ab,ti OR 'dom-doxycycline':ab,ti OR doranbax:ab,ti OR doryx:ab,ti OR dosyklin:ab,ti OR dotur:ab,ti OR doxacin:ab,ti OR doxakne:ab,ti OR doxat:ab,ti OR doxibiot:ab,ti OR doxiciclina:ab,ti OR doxiciklin:ab,ti OR doxicip:ab,ti OR doxicor:ab,ti OR doxilegrand:ab,ti OR doxilina:ab,ti OR doximed:ab,ti OR doxina:ab,ti OR doxipil:ab,ti OR doxitab:ab,ti OR doxithal:ab,ti OR doxitidin:ab,ti OR doxitin:ab,ti OR 'dox-m dt':ab,ti OR 'dox-m st':ab,ti OR 'dox-m tz':ab,ti OR 'dox-m-a':ab,ti OR 'dox-m-oz':ab,ti OR 'doxodin-tr':ab,ti OR doxt:ab,ti OR doxy:ab,ti OR 'doxy-1 l-dr forte':ab,ti OR 'doxy-100':ab,ti OR doxybene:ab,ti OR doxycap:ab,ti OR doxycin:ab,ti OR doxycline:ab,ti OR doxycyclin:ab,ti OR doxycycline:ab,ti OR doxycyclinum:ab,ti OR 'doxycyklin monohydrate':ab,ti OR doxycyklinmonohydrat:ab,ti OR doxyderma:ab,ti OR doxydoc:ab,ti OR doxyferm:ab,ti OR doxyguard:ab,ti OR doxyhexal:ab,ti OR 'doxy-hp':ab,ti OR doxylan:ab,ti OR doxyleb:ab,ti OR doxylin:ab,ti OR 'doxylin-dt':ab,ti OR 'doxylin-tz':ab,ti OR doxylis:ab,ti OR 'doxy-m':ab,ti OR doxyman:ab,ti OR doxymerck:ab,ti OR doxymono:ab,ti OR doxymycin:ab,ti OR 'doxy-n-tablinen':ab,ti OR doxypalu:ab,ti OR doxyprotect:ab,ti OR 'doxyratio m':ab,ti OR doxyremed:ab,ti OR doxyric:ab,ti OR doxysol:ab,ti OR doxystad:ab,ti OR doxytab:ab,ti OR 'doxy-tabs':ab,ti OR doxytop:ab,ti OR 'doxy-wolff':ab,ti OR dumoxin:ab,ti OR duradox:ab,ti OR duradoxal:ab,ti OR 'dx-24':ab,ti
#48 efracea:ab,ti OR emdox:ab,ti OR 'emdox-tz':ab,ti OR frakas:ab,ti OR geeox:ab,ti OR ginadox:ab,ti OR 'glodox-lb':ab,ti OR granudoxy:ab,ti OR 'gs-3065':ab,ti OR hydramycin:ab,ti OR ibimycin:ab,ti OR idocyklin:ab,ti OR ivamycin:ab,ti OR jenacyclin:ab,ti OR laa:ab,ti OR lentomyk:ab,ti OR lupidox:ab,ti OR madoxy:ab,ti OR 'martidox-m':ab,ti OR 'm-dox':ab,ti OR microdox:ab,ti OR minicycline:ab,ti OR monodox:ab,ti OR morgidox:ab,ti OR 'nab-dt':ab,ti OR nee:ab,ti OR novadox:ab,ti OR 'novo-doxylin':ab,ti OR novum:ab,ti OR nudoxy:ab,ti OR nutridox:ab,ti OR ocudox:ab,ti OR oracea:ab,ti OR oraxyl:ab,ti OR oraycea:ab,ti OR periosan:ab,ti OR periostat:ab,ti OR 'phl-doxycycline':ab,ti OR plemex:ab,ti OR 'pms-doxycycline':ab,ti OR pondoxcycline:ab,ti OR randoclin:ab,ti OR remycin:ab,ti OR sigadoxin:ab,ti OR supracyclin:ab,ti OR supracycline:ab,ti OR synvibra:ab,ti OR 'tasmacyclin akne':ab,ti OR tetradox:ab,ti OR tolexine:ab,ti OR tremesal:ab,ti OR unidox:ab,ti OR 'vibra tabs':ab,ti OR vibradox:ab,ti OR vibradoxin:ab,ti OR vibramicina:ab,ti OR vibramycin:ab,ti OR vibramycine:ab,ti OR 'vibra-s':ab,ti OR vibratab:ab,ti OR 'vibra-tabs':ab,ti OR vibravenos:ab,ti OR vivradoxil:ab,ti OR xedocine:ab,ti
#49 '564 25 0':rn OR '17086 28 1':rn
#50 #45 OR #46 OR #47 OR #48 OR #49
#51 #44 OR #50
#52 #32 AND #40 AND #51

Appendix 4. PubMed search strategy

#1 ((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomised[tiab] OR randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT (animals[mh] NOT humans[mh])
#2 (Onchocerc*[tiab] OR oncocerc*[tiab]) NOT Medline[sb]
#3 (river[tiab] AND blindness[tiab]) NOT Medline[sb]
#4 (Robles* disease[tiab] OR "O volvulus"[tiab] OR volvulosis[tiab] OR craw-craw[tiab] OR sowdah[tiab]) NOT Medline[sb]
#5 #2 OR #3 OR #4
#6 (Ivermec*[tiab] OR Ivermek*[tiab] OR Ivomec*[tiab] OR "Ablaze-IM"[tiab] OR "ABZ Plus"[tiab] OR "Albacos-IR"[tiab] OR "Albosym-IR"[tiab] OR Alvect[tiab] OR "Anthel-UP"[tiab] OR "Ariban Plus"[tiab] OR Ascapil[tiab] OR "Bandy Plus"[tiab] OR "Benrod-I"[tiab] OR Benzole[tiab] OR Cardomec[tiab] OR "Dermoper IV"[tiab] OR Dermopero[tiab] OR Detebencil[tiab] OR Diapec[tiab] OR Ectin[tiab] OR Ectover[tiab] OR "Elect-A"[tiab] OR Epimek[tiab] OR Eqvalan[tiab] OR Eqvalen[tiab] OR "Eris Plus"[tiab] OR "Getrid-I"[tiab] OR "Hymin Plus"[tiab] OR Ifact[tiab] OR Imectin[tiab] OR Ivecop[tiab] OR "Ivecop-AB"[tiab] OR Ivercid[tiab] OR "Ivercid-A"[tiab] OR Ivermin[tiab] OR Iversan[tiab] OR "Iver-Sol"[tiab] OR Iverstar[tiab] OR Ivertal[tiab] OR Iverx[tiab] OR Iverzole[tiab] OR Ivexterm[tiab] OR Ivor[tiab] OR Ivoral[tiab] OR Ivori[tiab] OR Kaonol[tiab] OR Kidi[tiab] OR Kilox[tiab] OR Leverctin[tiab] OR Macbi[tiab] OR Maikeding[tiab] OR Mectin[tiab] OR Mectizan[tiab] OR Mediderm[tiab] OR "MK 933"[tiab] OR MK933[tiab] OR Networm[tiab] OR Oramec[tiab] OR Plurimec[tiab] OR Quamox[tiab] OR "Quanox Gotas"[tiab] OR Revectina[tiab] OR Sanifer[tiab] OR Securo[tiab] OR Simpiox[tiab] OR Sklice[tiab] OR Stromectol[tiab] OR Vermectil[tiab] OR Vermectin[tiab] OR Vermokill[tiab] OR Yvermil[tiab]) NOT Medline[sb]
#7 (Abadox[tiab] OR Abraxil[tiab] OR "Acnedox-LB"[tiab] OR Actidox[tiab] OR Adoxa[tiab] OR "Ai Rui De An"[tiab] OR "Aknefug Doxy"[tiab] OR "Ak-Ramycin"[tiab] OR "Ak-Ratabs"[tiab] OR Aliudox[tiab] OR Alodox[tiab] OR "Alpha 6 Deoxyoxytetracycline"[tiab] OR "Alpha-6-Deoxyoxytetracycline"[tiab] OR Ambrodoxy[tiab] OR "Ambroxol AL comp"[tiab] OR "Ambroxol comp"[tiab] OR "Amdox-Puren"[tiab] OR Amermycin[tiab] OR Anfadox[tiab] OR "Antodox Apidox"[tiab] OR Apociclina[tiab] OR Apodoxin[tiab] OR Apodoxy[tiab] OR "Apo-Doxy"[tiab] OR Apprilon[tiab] OR Atridox[tiab] OR "Avidox-LB"[tiab] OR "Avidox-OZ"[tiab] OR "Avidox-SP"[tiab] OR Avidoxy[tiab] OR "Azudoxat-T"[tiab] OR Bactidox[tiab] OR "Bidox-DT"[tiab] OR Biocin[tiab] OR Biodoxi[tiab] OR Bioximicina[tiab] OR "BMY 28689"[tiab] OR BMY28689[tiab] OR "BU 3839T"[tiab] OR "Chemedox-HT"[tiab] OR Ciclidoxan[tiab] OR Clifordin[tiab] OR Codox[tiab] OR Cyclodox[tiab]) NOT Medline[sb]
#8 (Dedoxyn[tiab] OR Dentarec[tiab] OR Dobid[tiab] OR Docdoxyc[tiab] OR Docyl[tiab] OR "Doksiciklinas monohidratas"[tiab] OR Doksisiklin[tiab] OR Doksisykliini[tiab] OR Doksisykliinimonohydraatti[tiab] OR Doksycyklina[tiab] OR "Dom-Doxycycline"[tiab] OR Doranbax[tiab] OR Doryx[tiab] OR Dosyklin[tiab] OR Dotur[tiab] OR Doxacin[tiab] OR Doxakne[tiab] OR Doxat[tiab] OR Doxibiot[tiab] OR Doxiciclina[tiab] OR Doxiciklin[tiab] OR Doxicip[tiab] OR Doxicor[tiab] OR Doxilegrand[tiab] OR Doxilina[tiab] OR Doximed[tiab] OR Doxina[tiab] OR Doxipil[tiab] OR Doxitab[tiab] OR Doxithal[tiab] OR Doxitidin[tiab] OR Doxitin[tiab] OR "Dox-M DT"[tiab] OR "Dox-M ST"[tiab] OR "Dox-M TZ"[tiab] OR "Dox-M-A"[tiab] OR "Dox-M-OZ"[tiab] OR "Doxodin-TR"[tiab] OR Doxt[tiab] OR Doxy[tiab] OR "Doxy-1 L-DR Forte"[tiab] OR "Doxy-100"[tiab] OR Doxybene[tiab] OR Doxycap[tiab] OR Doxycin[tiab] OR Doxycline[tiab] OR Doxycyclin[tiab] OR Doxycycline[tiab] OR Doxycyclinum[tiab] OR "Doxycyklin monohydrate"[tiab] OR Doxycyklinmonohydrat[tiab] OR Doxyderma[tiab] OR Doxydoc[tiab] OR Doxyferm[tiab] OR Doxyguard[tiab] OR Doxyhexal[tiab] OR "Doxy-HP"[tiab] OR Doxylan[tiab] OR Doxyleb[tiab] OR Doxylin[tiab] OR "Doxylin-DT"[tiab] OR "Doxylin-TZ"[tiab] OR Doxylis[tiab] OR "Doxy-M"[tiab] OR Doxyman[tiab] OR Doxymerck[tiab] OR Doxymono[tiab] OR Doxymycin[tiab] OR "Doxy-N-Tablinen"[tiab] OR Doxypalu[tiab] OR Doxyprotect[tiab] OR "Doxyratio M"[tiab] OR Doxyremed[tiab] OR Doxyric[tiab] OR Doxysol[tiab] OR Doxystad[tiab] OR Doxytab[tiab] OR "Doxy-Tabs"[tiab] OR Doxytop[tiab] OR "Doxy-Wolff"[tiab] OR Dumoxin[tiab] OR Duradox[tiab] OR Duradoxal[tiab] OR "DX-24"[tiab]) NOT Medline[sb]
#9 (Efracea[tiab] OR Emdox[tiab] OR "Emdox-TZ"[tiab] OR Frakas[tiab] OR Geeox[tiab] OR Ginadox[tiab] OR "Glodox-LB"[tiab] OR Granudoxy[tiab] OR "GS-3065"[tiab] OR Hydramycin[tiab] OR Ibimycin[tiab] OR Idocyklin[tiab] OR Ivamycin[tiab] OR Jenacyclin[tiab] OR LAA[tiab] OR Lentomyk[tiab] OR Lupidox[tiab] OR Madoxy[tiab] OR "Martidox-M"[tiab] OR "M-Dox"[tiab] OR Microdox[tiab] OR Minicycline[tiab] OR Monodox[tiab] OR Morgidox[tiab] OR "Nab-DT"[tiab] OR Nee[tiab] OR Novadox[tiab] OR "Novo-Doxylin"[tiab] OR Novum[tiab] OR Nudoxy[tiab] OR NutriDox[tiab] OR Ocudox[tiab] OR Oracea[tiab] OR Oraxyl[tiab] OR Oraycea[tiab] OR Periosan[tiab] OR Periostat[tiab] OR "PHL-Doxycycline"[tiab] OR Plemex[tiab] OR "PMS-Doxycycline"[tiab] OR Pondoxcycline[tiab] OR Randoclin[tiab] OR Remycin[tiab] OR Sigadoxin[tiab] OR Supracyclin[tiab] OR Supracycline[tiab] OR Synvibra[tiab] OR "Tasmacyclin Akne"[tiab] OR Tetradox[tiab] OR Tolexine[tiab] OR Tremesal[tiab] OR Unidox[tiab] OR "Vibra Tabs"[tiab] OR Vibradox[tiab] OR Vibradoxin[tiab] OR Vibramicina[tiab] OR Vibramycin[tiab] OR Vibramycine[tiab] OR "Vibra-S"[tiab] OR Vibratab[tiab] OR "Vibra-Tabs"[tiab] OR Vibravenos[tiab] OR Vivradoxil[tiab] OR Xedocine[tiab]) NOT Medline[sb]
#10 #7 OR #8 OR #9
#11 #6 OR #10
#12 #1 AND #5 AND #11

Appendix 5. LILACS search strategy

(Onchocerc$ OR Oncocerc$ OR MH:C03.335.508.700.750.361.699$ OR MH:C03.858.650$ OR MH:C17.800.838.775.690$ OR MH:C23.996.700$ OR MH:SP4.001.012.118.099$ OR MH:B01.050.500.500.294.700.750.700.300.510$ OR "river blindness" OR "Robles disease" OR "Robles' disease" OR "O volvulus" OR volvulosis OR "craw-craw" OR sowdah) AND (Ivermec$ OR Ivermek$ OR Ivomec$ OR MH:D02.540.505.330$ OR Doxycyclin$ OR Doxiciclin$ OR MH:D02.455.426.559.847.562.900.200$ OR MH:D04.615.562.900.200$)

Appendix 6. metaRegister of Controlled Trials search strategy

Onchocerciasis OR onchocerca OR onchocerciases OR onchocercosis OR river blindness OR robles' disease OR volvulosis OR Microfilaria

Appendix 7. ClinicalTrials.gov search strategy

Onchocerciasis OR Microfilaria

Appendix 8. ICTRP search strategy

Onchocerciasis OR onchocerca OR onchocerciases OR onchocercosis OR river blindness OR robles' disease OR volvulosis OR Microfilaria

Contributions of authors

Conceiving of the review: ATA, RMA, NJO.
Designing the review: ATA, RMA, NJO.
Co-ordinating the review: ATA.
Undertaking manual searches: ATA, RMA, NJO.
Screening search results: ATA, RMA, NJO.
Organizing retrieval of papers: ATA, RMA, NJO.
Screening retrieved papers against inclusion criteria: ATA, RMA, NJO.
Appraising risk of bias in included studies: ATA, RMA, NJO.
Abstracting data from papers: ATA, RMA, NJO.
Writing to authors of papers to ask for additional information: ATA, RMA, NJO.
Obtaining and screening data from unpublished studies: ATA, RMA, NJO.
Managing data for the review: ATA, RMA, NJO.
Entering data into RevMan: ATA, RMA, NJO.
Interpreting data: ATA, RMA, NJO.
Writing the review: ATA, RMA, NJO.
Performing previous work that served as the foundation of the current study: ATA, RMA, NJO.
Serving as guarantor for the review: ATA.

Declarations of interest

ATA: none known.
RMA: none known.
NJO: none known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Eye Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.

    Methodological support from the Cochrane Eyes and Vision US Project, cooperative agreement 1 U01 EY020522

  • National Institute of Health Research (NIHR), UK.

    • Richard Wormald, Co-ordinating Editor for the Cochrane Eyes and Vision (CEV), acknowledges financial support for his CEVG research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology

    • The NIHR also funds the CEV Editorial Base in London

    • The views expressed in this publication are those of the review authors and are not necessarily those of the NIHR, NHS or Department of Health

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Hoerauf 2008

Methods

Study design: parallel-group randomized controlled trial

Number randomly assigned: 76 total participants; 26 in the doxycycline 4 weeks plus ivermectin group, 25 in the doxycycline 6 weeks plus ivermectin group, and 25 in the ivermectin group

Exclusions after randomization: 9 total; 4 in the doxycycline 4 weeks plus ivermectin group, 3 in the doxycycline 6 weeks plus ivermectin group, and 2 in the ivermectin group

Losses to follow-up:

At 20 months: 31 total; 15 in the doxycycline 4 weeks plus ivermectin group, 9 in the doxycycline 6 weeks plus ivermectin group, and 7 in the ivermectin group

At 27 months: 48 total; 15 in the doxycycline 4 weeks plus ivermectin group, 17 in the doxycycline 6 weeks plus ivermectin group, and 16 in the ivermectin group

Number analyzed:

At 20 months: 36 total; 7 in the doxycycline 4 weeks plus ivermectin group, 13 in the doxycycline 6 weeks plus ivermectin group, and 16 in the ivermectin group

At 27 months: 19 total; 7 in the doxycycline 4 weeks plus ivermectin group, 5 in the doxycycline 6 weeks plus ivermectin group, and 7 in the ivermectin group

Unit of analysis: individual

Power calculation: “The sample size was calculated for the presence of mf in the patients’ skin. Applying Fisher’s exact test, the power calculation resulted in a sample size of 20 patients per treatment arm for a power of 90% at a significance level of 0.001, in order to observe a significantly higher proportion of doxycycline-treated patients without skin mf compared to placebo. Allowing a dropout rate of 20%, the calculation suggested starting treatment with 25 patients for each arm”

Participants

Country: Ghana

Mean age: total not provided; per group: 39 years (range 23 to 58) in the doxycycline 4 weeks plus ivermectin group, 41 years (range 19 to 59) in the doxycycline 6 weeks plus ivermectin group, and 39 years (range 20 to 61) in the ivermectin group

Gender: 51 (76.1%) men, 16 (23.9%) women; per group: 18 men, 4 women in the doxycycline 4 weeks plus ivermectin group; 18 men, 4 women in the doxycycline 6 weeks plus ivermectin group; and 15 men, 8 women in the ivermectin group

Inclusion criteria: “nodule carriers of both sexes, aged 18–62 years, with a body weight of more than 40 kg, in good health, and without any clinical condition requiring chronic medication”

Exclusion criteria: “palpation of less than two onchocercomas, abnormal hepatic and renal enzymes (AST [0–40 IU/l], ALT [0–45 IU/l], and creatinine [3–126 mol/l]), pregnancy, breast-feeding, intolerance to doxycycline, and alcohol or drug abuse”

Equivalence of baseline characteristics: no, “The mf loads of the 6-week doxycycline group were higher than those in the other two groups”

Interventions

Intervention 1: 200 mg/d doxycycline for 4 weeks, then placebo for 2 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months

Intervention 2: 200 mg/d doxycycline for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months

Intervention 3: placebo for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months

Length of follow-up:

Planned: 27 months
Actual: 27 months

Outcomes

Primary outcome, as defined in study report: "The primary outcome of this study was the assessment of sustained effects of doxycycline treatment on worm fertility and worm survival. Worm fertility was measured (1) by observation of the presence or absence of normal or degenerated embryos in female worms and of mf in the human nodule tissue using histology, and (2) by analysis of the presence and quantity of skin mf. Worm survival was measured as the proportion of living and dead worms detected by histology"

Secondary outcomes, as defined in study report: median and range of microfilarial loads for skin snips
Adverse events reported: yes

Intervals at which outcomes assessed: 6, 20, and 27 months

Subgroup analyses: none reported

Notes

Study period: September 2003 to November 2006

Trial registration: ISRCTN 71141922

Funding sources: “This study received major funding by the European Commission (ICA4-2002-10051). AYD received a PhD scholarship from the German Academic Exchange Service (DAAD). PWzer Inc., Karlsruhe, donated Vibramycin® capsules and matching placebos. Technical assistance by Daniel Tagoe, Kumasi, Ingeborg Albrecht, Frank Geisinger, Hamburg, and Karin Lemke, Bonn, is gratefully acknowledged”

Disclosures of interest: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk“The random allocation sequence was computer-generated by AH (StatView® version 4.5. for Macintosh)”
Allocation concealment (selection bias)Low risk“The random allocation sequence was implemented by packing tablet containers according to the consecutive running numbers to which the mode of treatment had been allocated and which had been assigned to the patients”
Masking of participants and personnel (performance bias)Low risk“Blinding was assured by the exclusion of persons involved in randomisation or tablet packaging in any clinical or laboratory assessments as described. At the beginning of the study and during drug treatment, all members of the team and the patients were blinded. Patients were blinded to group allocation. A few nodules were excised from patients with many onchocercomas at 6 months after the beginning of the study to confirm the depletion of Wolbachia. These patients had been selected by AH without giving information on treatment to other members of the team (only a list with patient identification numbers was provided)”
Masking of outcome assessment (detection bias)Low risk“All persons involved with the assessment of nodules and skin biopsies in the laboratory were kept blinded until the end of the analysis”
Incomplete outcome data (attrition bias)
All outcomes
High risk

At 20 months, 40 (52.6%) of 76 participants who were randomly assigned were excluded or lost to follow-up, and they were not included in the analysis

At 27 months, 57 (75.0%) of 76 participants who were randomly assigned were excluded or lost to follow-up, and they were not included in the analysis

Selective reporting (reporting bias)High risk

“New information based on the results of the studies that we had performed in 2000–2003 led to some deviations from the original study protocol”

“Since skin snipping without the prospect of nodulectomy would have led to reduced compliance at later follow-up times, we omitted mf analysis at 6 months in the 4-week doxycycline group”

“Since no difference between placebo and doxycycline was seen, we do not report this topic here”

“All patients who were available for follow-up underwent skin snipping regardless of their IVM uptake. However, IVM itself affects skin mf. Therefore, for the analysis of skin mf in Table 5, only patients who had taken IVM at 6 months were included. The data from patients without IVM were measured but were not considered, although inclusion of these patients did not alter the significance of the data (not shown)”

Other biasHigh risk

Difference at baseline: “The mf loads of the 6-week doxycycline group were higher than those in the other two groups”

Vibramycin and placebo capsules were donated by a pharmaceutical company

Masud 2009

Methods

Study design: parallel-group quasi-randomized controlled trial

Number randomized: 240 total participants; 120 in each group

Exclusions after randomization: none reported

Losses to follow up: none reported

Number analyzed: total 240, ivermectin 120; doxycycline + ivermectin 120

Unit of analysis: individual

Power calculation: not reported

Participants

Country: Liberia

Mean age: 34 years; per group not provided

Gender: 157 (65.4%) men, 83 (34.6%) women; per group not provided

Inclusion criteria: “history of exposure to blackfly in endemic area, symptoms of generalized and ocular itching, visual impairment associated with pannus/perilimbal pigmentation, punctuate/sclerosing keratitis, iridocyclitis, chorioretinitis and optic atrophy”; “lesions suggestive of onchodermatitis and subcutaneous nodules”

Exclusion criteria: “allergic conjunctivitis, history of measles and rubella, pregnant/breast-feeding women and children under 16 years of age”

Equivalence of baseline characteristics: not reported

Interventions

Intervention 1: 100 mg/d doxycycline for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin

Intervention 2: single dose of 0.15 mg/kg ivermectin

Length of follow-up: 6 months

Planned: 6 months
Actual: 6 months

Outcomes

Primary and secondary outcomes were not differentiated
Main outcomes, as reported in study: improvement in clinical symptoms (itching and visual impairment), improvement in ocular signs (perilimbal pigmentation, pannus, punctuate keratitis, sclerosing keratitis, iridocyclitis, chorioretinitis, and optic atrophy) and dermal signs (dermatitis and nodules)

Adverse events reported: none reported

Intervals at which outcomes assessed: 6 months

Subgroup analyses: none reported

Notes

Study period: March to December 2005

Trial registration: none reported

Funding sources: not reported

Disclosures of interest: “The authors indicate no financial conflict of interest involved in design and conduct of study, collection of data, analysis and interpretation of data, preparation of the manuscript and literature search, review of the manuscript, and final approval of the manuscript. This study was performed with the approval of the Ministry of Health of Liberia”

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskParticipants' registration numbers were used to assign treatments (email communication)
Allocation concealment (selection bias)High riskParticipants' registration numbers were used to assign treatments (email communication)
Masking of participants and personnel (performance bias)High risk“It was a prospective, randomized, comparative trial without blinding”
Masking of outcome assessment (detection bias)High risk“It was a prospective, randomized, comparative trial without blinding”
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data reported
Selective reporting (reporting bias)High riskNo study protocol available (email communication), but nodulectomies and skin snips were performed in selected cases, and these data were not reported
Other biasLow riskNone identified

Turner 2010

Methods

Study design: parallel-group randomized controlled trial

Number randomized: 150 total participants; 60 in the doxycycline plus ivermectin group, 60 in the ivermectin group, and 30 in the doxycycline group

Study design issues: an additional 22 participants co-infected with Loa loa were not randomly assigned, and all were assigned to the doxycycline plus ivermectin group. Some outcome data were not reported separately for randomized and non-randomized participants

Exclusions after randomization: none reported

Losses to follow up:

At 12 months: 55 total; 24 in the doxycycline plus ivermectin group, 23 in the ivermectin group, and 8 in the doxycycline group (plus an additional 6 participants with Loa loa)

At 21 months: 60 total; 28 in the doxycycline plus ivermectin group, 23 in the ivermectin group, and 9 in the doxycycline group (plus an additional 8 participants with Loa loa)

Number analyzed:

At 12 months: 95 total; 36 in the doxycycline plus ivermectin group, 37 in the ivermectin group, and 22 in the doxycycline group (plus an additional 16 participants with Loa loa)

At 21 months: 90 total; 32 in the doxycycline plus ivermectin group, 37 in the ivermectin group, and 21 in the doxycycline group (plus an additional 14 participants with Loa loa)

Unit of analysis: individual

Power calculation: at least 30 participants were recruited into each treatment group to allow for up to a 15% drop-out rate over the study period and a power of 80%

Participants

Country: Cameroon

Mean age: total not provided; per group: 35 years (range 15 to 50) in the doxycycline plus ivermectin group, 37 years (range 16 to 50) in the ivermectin group, and 35 years (range 15 to 50) in the doxycycline group

Gender: 51 (56.7%) men, 39 (43.3%) women; per group: 20 men, 12 women in the doxycycline plus ivermectin group; 18 men, 19 women in the ivermectin group; and 13 men, 8 women in the doxycycline group

Inclusion criteria: “adults of both sexes aged 15–60, with a minimum body weight of >/= 40 kg, in good health without any clinical condition requiring chronic medication”

Exclusion criteria: “an O. volvulus microfilarial load, 10 mf/mg, L. loa microfilarial load > 8000 mf/mL, hepatic and renal enzymes outside of normal ranges (AST [0–40 IU/l, ALT [0–45 IU/l] and creatinine [3–126 mmol/l]), pregnancy, lactation, intolerance to ivermectin, alcohol or drug abuse or anti-filarial therapy in the last 12 months”

Equivalence of baseline characteristics: yes

Interventions

Intervention 1: 200 mg/d doxycycline for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 4 months

Intervention 2: placebo for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 4 months

Intervention 3: 200 mg/d doxycycline for 6 weeks, followed by a single placebo after 4 months

Length of follow-up:

Planned: 21 months
Actual: 21 months

Outcomes

Primary and secondary outcomes were not differentiated
Main outcomes, as reported in study:

  • Number of mf present in skin snip biopsies taken at baseline, 4, 12 and 21 months after start of treatment

  • Clinical monitoring and assessment of adverse reactions during primary drug allocation (doxycycline) or secondary drug allocation (ivermectin) in patients singly infected with O. volvulus or co-infected with L. loa

Adverse events reported: yes

Intervals at which outcomes assessed: 4, 12, and 21 months

Subgroup analyses: the safety of doxycycline treatment before ivermectin administration in a subset of onchocerciasis individuals co-infected with low to moderate intensities of Loa loa microfilaraemia was assessed

Notes

Study period: 1 July 2003 to 31 March 2005

Trial registration: ISRCTN 48118452

Funding sources: “the European Commission (ICA4-2002-10051), the Wellcome Trust (Senior Fellowship award to MJT) and the Bill & Melinda Gates Foundation (A-WOL consortium award to the Liverpool School of Tropical Medicine). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript”

Disclosures of interest: “The authors have declared that no competing interests exist”

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk“Randomization for onchocerciasis was block stratified based on baseline microfilaridermia. All L. loa co-infected patients were assigned to doxycycline + ivermectin treatment”
Allocation concealment (selection bias)Low risk“Treatment allocation was assigned by randomized ID code (by JDT and MJT) and the course of treatment sealed in an envelope for allocation by the field team and district field officers”
Masking of participants and personnel (performance bias)Low risk

“All study personnel and participants were blinded to the doxycycline and placebo treatment assignment for the duration of the study”

“Placebo tablets for assessment of ivermectin adverse events were not supplied in time for treatment allocation and so unmarked lactose tablets of similar size, shape and colour were used as an alternative. The ivermectin and dummy pills were assigned to individuals in sealed unmarked envelopes before being handed over to district health officers for drug delivery and these together with individuals responsible for the clinical assessment of adverse events were not involved in any subsequent analysis”

Masking of outcome assessment (detection bias)Low risk“All study personnel and participants were blinded to the doxycycline and placebo treatment assignment for the duration of the study”
Incomplete outcome data (attrition bias)
All outcomes
High risk

Although “no significant differences in the drop-out patterns over the follow-up period between the three treatment groups” was reported, more than one-third of participants were not included in the final analyses

At 12 months, 55 (36.7%) of 150 participants who were randomly assigned were excluded or lost to follow-up, and they were not included in the analysis

At 21 months, 60 (40.0%) of 150 participants who were randomly assigned were excluded or lost to follow-up, and they were not included in the analysis

Selective reporting (reporting bias)High riskProtocol was not available for assessment of selective outcome reporting; however, some outcome data were not reported separately for randomly assigned and non-randomly assigned participants
Other biasHigh risk22 participants co-infected with L. loa were not randomly assigned; all were assigned to the combination group

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Hoerauf 2003Not a randomized controlled trial: an interventional comparative case series
Tamarozzi 2012Not a randomized controlled trial: a cohort study

Ancillary