Doxycycline Leads to Sterility and Enhanced Killing of Female<i>Onchocerca volvulus</i>Worms in an Area With Persistent Microfilaridermia After Repeated Ivermectin Treatment: A Randomized, Placebo-Controlled, Double-Blind Trial

Debrah, Alexander Yaw; Specht, Sabine; Klarmann‐Schulz, Ute; Batsa, Linda; Mand, Sabine; Marfo-Debrekyei, Yeboah; Fimmers, Rolf; Dubben, Bettina; Kwarteng, Alexander; Osei-Atweneboana, Mike Y.; Boakye, Daniel; Ricchiuto, Arcangelo; Büttner, Marcelle; Adjei, Ohene; Mackenzie, Charles D.; Hoerauf, Achim

doi:10.1093/cid/civ363

Cited by 68 publications

(61 citation statements)

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“…65% of the female worms in the control group (ALB 3d) were Wolbachia -positive (Table 2), a level that is consistent with other endemic areas with lowered transmission and a higher proportion of older worms [10], possibly induced by MDA or as a result of intensified gold digging and thus pollution of the water breeding habitat of the vector [38]. In contrast, only 1.3% contained intact Wolbachia in the standard treatment group (DOX 4w).…”

Section: Resultssupporting

confidence: 78%

“…The number and type of AR were similar in the DOX 4w and DOX 3w group, therefore a longer treatment time does not alter AR. It is important to note that the range of AR after DOX is similar to that seen in a previous study [10], in which DOX was used in lower doses and was performed under blinded conditions. MIN associated AR were mainly dizziness, a common side effect of this drug.…”

Section: Resultssupporting

confidence: 70%

“…However, its benefits and costs are highly sensitive to systematic noncompliance and it may not always be feasible to implement biannual treatment, particularly in hard-to-reach populations [6, 7, 42]. In addition, given the problem of re-emergence of infections, suboptimal efficacy of IVM [10] and regions that are co-endemic for Loa loa , the development of new drugs or drug regimens is urgently needed to achieve the elimination of onchocerciasis. This would increase cost effectiveness by avoiding unnecessary treatments of uninfected individuals within the MDA schemes, especially in “end-game” scenarios or when switching from MDA to “test & treat” strategies.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Doxycycline, Minocycline, Doxycycline plus Albendazole and Albendazole Alone in Their Efficacy against Onchocerciasis in a Randomized, Open-Label, Pilot Trial

et al. 2017

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The search for new macrofilaricidal drugs against onchocerciasis that can be administered in shorter regimens than required for doxycycline (DOX, 200mg/d given for 4–6 weeks), identified minocycline (MIN) with superior efficacy to DOX. Further reduction in the treatment regimen may be achieved with co-administration with standard anti-filarial drugs. Therefore a randomized, open-label, pilot trial was carried out in an area in Ghana endemic for onchocerciasis, comprising 5 different regimens: the standard regimen DOX 200mg/d for 4 weeks (DOX 4w, N = 33), the experimental regimens MIN 200mg/d for 3 weeks (MIN 3w; N = 30), DOX 200mg/d for 3 weeks plus albendazole (ALB) 800mg/d for 3 days (DOX 3w + ALB 3d, N = 32), DOX 200mg/d for 3 weeks (DOX 3w, N = 31) and ALB 800mg for 3 days (ALB 3d, N = 30). Out of 158 randomized participants, 116 (74.4%) were present for the follow-up at 6 months of whom 99 participants (63.5%) followed the treatment per protocol and underwent surgery. Histological analysis of the adult worms in the extirpated nodules revealed absence of Wolbachia in 98.8% (DOX 4w), 81.4% (DOX 3w + ALB 3d), 72.7% (MIN 3w), 64.1% (DOX 3w) and 35.2% (ALB 3d) of the female worms. All 4 treatment regimens showed superiority to ALB 3d (p < 0.001, p < 0.001, p = 0.002, p = 0.008, respectively), which was confirmed by real-time PCR. Additionally, DOX 4w showed superiority to all other treatment arms. Furthermore DOX 4w and DOX 3w + ALB 3d showed a higher amount of female worms with degenerated embryogenesis compared to ALB 3d (p = 0.028, p = 0.042, respectively). These results confirm earlier studies that DOX 4w is sufficient for Wolbachia depletion and the desired parasitological effects. The data further suggest that there is an additive effect of ALB (3 days) on top of that of DOX alone, and that MIN shows a trend for stronger potency than DOX. These latter two results are preliminary and need confirmation in a fully randomized controlled phase 2 trial.Trial Registration: ClinicalTrials.gov #06010453

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Section: Resultssupporting

confidence: 78%

Section: Resultssupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Comparison of Doxycycline, Minocycline, Doxycycline plus Albendazole and Albendazole Alone in Their Efficacy against Onchocerciasis in a Randomized, Open-Label, Pilot Trial

et al. 2017

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“…Numerous clinical studies in onchocerciasis (or LF) have been conducted to examine the effect of different dose regimens of doxycycline, rifampicin and azithromycin (Hoerauf et al., 2001, Hoerauf et al., 2003, Debrah et al., 2006, Richards et al., 2007, Specht et al., 2008, Hoerauf et al., 2008a, Hoerauf et al., 2009, Turner et al., 2010, Debrah et al., 2015, Abegunde et al., 2016). To date, doxycycline has shown the highest efficacy.…”

Section: Research For New Drugs For Onchocerciasis Control and Eliminmentioning

confidence: 99%

Research for new drugs for elimination of onchocerciasis in Africa

Kuesel

2016

International Journal for Parasitology: Drugs and Drug Resistan

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Onchocerciasis is a parasitic, vector borne disease caused by the filarial nematode Onchocerca volvulus. More than 99% of the population at risk of infection live in Africa. Onchocerciasis control was initiated in West Africa in 1974 with vector control, later complemented by ivermectin mass drug administration and in the other African endemic countries in 1995 with annual community directed treatment with ivermectin (CDTI.) This has significantly reduced infection prevalence. Together with proof-of-concept for onchocerciasis elimination with annual CDTI from foci in Senegal and Mali, this has resulted in targeting onchocerciasis elimination in selected African countries by 2020 and in 80% of African countries by 2025. The challenges for meeting these targets include the number of endemic countries where conflict has delayed or interrupted control programmes, cross-border foci, potential emergence of parasite strains with low susceptibility to ivermectin and co-endemicity of loiasis, another parasitic vector borne disease, which slows down or prohibits CDTI implementation. Some of these challenges could be addressed with new drugs or drug combinations with a higher effect on Onchocerca volvulus than ivermectin. This paper reviews the path from discovery of new compounds to their qualification for large scale use and the support regulatory authorities provide for development of drugs for neglected tropical diseases. The status of research for new drugs or treatment regimens for onchocerciasis along the path to regulatory approval and qualification for large scale use is reviewed. This research includes new regimens and combinations of ivermectin and albendazole, antibiotics targeting the O. volvulus endosymbiont Wolbachia, flubendazole, moxidectin and emodepside and discovery of new compounds.

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“…As an alternative approach, endosymbiotic Wolbachia bacteria present in most human pathogenic filariae, including those causing onchocerciasis and lymphatic filariasis, can be targeted with antibiotics [10][11][12]. In human clinical trials doxycycline and rifampicin treatment have been shown to deplete Wolbachia, leading to the sterilization of female adult filariae of Onchocerca volvulus and Wuchereria bancrofti as well as to adult worm death [12][13][14][15]. Moreover, since Loa loa filariae do not possess endosymbiotic Wolbachia, drug-related serious adverse events in areas co-endemic for loiasis are unlikely to occur with Wolbachia-targeting drugs [9,16].…”

Section: Introductionmentioning

confidence: 99%

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis

Ehrens¹,

Lunde²,

Jacobs³

et al. 2020

PLoS Negl Trop Dis

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The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontisinfected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment.These results indicate that AN11251 is superior to doxycycline and comparable to highdose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.PLOS Neglected Tropical Diseases | https://doi.Onchocerciasis and lymphatic filariasis are human filarial tropical diseases, which can cause blindness and severe dermatitis (onchocerciasis) or lymphedema and hydrocele (lymphatic filariasis). Current strategies to eliminate these diseases include the mass drug administration (MDA) of drugs that target the progeny of the filariae, the microfilariae, and temporarily inhibit filarial embryogenesis and, therefore, the transmission of the disease. However, MDA has several limitations that delay the goal of elimination including the lack of a drug with a short term regimen and a potent macrofilaricidal effect. As an alternative approach, the antibiotic doxycycline has been proven to be effective in depleting Wolbachia endosymbionts from adult filariae, which then leads to permanent sterilization and death of the adult worms. Due to contraindications for doxycycline and prolonged treatment regimen of at least 4 weeks, there is an urgent need for new anti-filarial drugs with an improved safety profile and shorter regimens. The current study demonstrates that the boron-pleuromutilin derivative AN11251 provides an excellent in vivo anti-Wolbachia depletion in the Litomosoides sigmodontis filarial mouse model that is superior to doxycycline and comparable to rifampicin, allowing for regimens as short as 10-14 days. Combination with doxycycline for 7 da...

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Doxycycline Leads to Sterility and Enhanced Killing of FemaleOnchocerca volvulusWorms in an Area With Persistent Microfilaridermia After Repeated Ivermectin Treatment: A Randomized, Placebo-Controlled, Double-Blind Trial

Cited by 68 publications

References 31 publications

Comparison of Doxycycline, Minocycline, Doxycycline plus Albendazole and Albendazole Alone in Their Efficacy against Onchocerciasis in a Randomized, Open-Label, Pilot Trial

Comparison of Doxycycline, Minocycline, Doxycycline plus Albendazole and Albendazole Alone in Their Efficacy against Onchocerciasis in a Randomized, Open-Label, Pilot Trial

Research for new drugs for elimination of onchocerciasis in Africa

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis

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