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