Effect of a single dose of 8 mg moxidectin or 150 μg/kg ivermectin on O. volvulus skin microfilariae in a randomized trial: Differences between areas in the Democratic Republic of the Congo, Liberia and Ghana and impact of intensity of infection

Abstract

Background: Our study in CDTI-naïve areas in Nord Kivu and Ituri (Democratic Republic of the Congo, DRC), Lofa County (Liberia) and Nkwanta district (Ghana) showed that a single 8 mg moxidectin dose reduced skin microfilariae density (microfilariae/mg skin, SmfD) better and for longer than a single 150μg/kg ivermectin dose. We now analysed efficacy by study area and pre-treatment SmfD (intensity of infection, IoI).

Methodology/principal findings: Four and three IoI categories were defined for across-study and by-study area analyses, respectively. We used a general linear model to analyse SmfD 1, 6, 12 and 18 months post-treatment, a logistic model to determine the odds of undetectable SmfD from month 1 to month 6 (UD1-6), month 12 (UD1-12) and month 18 (UD1-18), and descriptive statistics to quantitate inter-interindividual response differences. Twelve months post-treatment, treatment differences (difference in adjusted geometric mean SmfD after moxidectin and ivermectin in percentage of the adjusted geometric mean SmfD after ivermectin treatment) were 92.9%, 90.1%, 86.8% and 84.5% in Nord Kivu, Ituri, Lofa and Nkwanta, and 74.1%, 84.2%, 90.0% and 95.4% for participants with SmfD 10-20, ≥20-<50, ≥50-<80, ≥80, respectively. Ivermectin's efficacy was lower in Ituri and Nkwanta than Nord Kivu and Lofa (p≤0.002) and moxidectin's efficacy lower in Nkwanta than Nord Kivu, Ituri and Lofa (p<0.006). Odds ratios for UD1-6, UD1-12 or UD1-18 after moxidectin versus ivermectin treatment exceeded 7.0. Suboptimal response (SmfD 12 months post-treatment >40% of pre-treatment SmfD) occurred in 0%, 0.3%, 1.6% and 3.9% of moxidectin and 12.1%, 23.7%, 10.8% and 28.0% of ivermectin treated participants in Nord Kivu, Ituri, Lofa and Nkwanta, respectively.

Conclusions/significance: The benefit of moxidectin vs ivermectin treatment increased with pre-treatment IoI. The possibility that parasite populations in different areas have different drug susceptibility without prior ivermectin selection pressure needs to be considered and further investigated.

Clinical trial registration: Registered on 14 November 2008 in Clinicaltrials.gov (ID: NCT00790998).

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: ACK and CMH are staff of WHO which funded the work of all co-authors on the study whose data are analysed here through its department UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). Author Safari L Masembe was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge.

Figures

Fig 1. Geometric mean (95% CI) SmfD before and after treatment by study area.

N Kivu Nord Kivu, N Ituri Nord Ituri, Lofa Lofa County, Nkwanta Nkwanta North district, N number treated (for number with follow up data at each time point, see Tables S5-S8 in S1 File).

Fig 2. Geometric mean (95% CI) SmfD by intensity of infection category across study areas.

SmfD skin microfilariae density, moxi moxidectin, IVM ivermectin, N number treated (for number with follow up data at each time point, see Table S4 in S1 File).

Fig 3. Geometric mean (95% CI) SmfD by intensity of infection category and study area.

Moxi: moxidectin, IVM: ivermectin, N: number treated (for number with follow up data at each time point, see Tables S4-S8 in S1 File), IoI intensity of infection: <20: 10-<20 mf/mg skin; 20–50: 20-<50 mf/mg skin, ≥50: ≥50 mf/mg skin pre-treatment.

Fig 4. Percentage of participants with undetectable SmfD by study area, pre-treatment SmfD and post-treatment time.

M1, M6, M12, M18: month 1, 6, 12 18 after treatment (for numbers treated see Fig 3, for numbers with follow up data at each time point, see Tables S4-S8 in S1 File).

Fig 5. Skin microfilariae levels pre-treatment, at month 1 and at month 6 among participants who had detectable levels 1 month after treatment.

SmfD: Skin microfilariae density, to allow displaying these data on a logarithmic scale, 1 was added to the SmfD values at Month 1 and 6.

Fig 6. Odds for undetectable SmfD from 1 to 6, 12 or 18 months by IoI across study areas.

SmfD skin microfilariae density, UD1-6, UD 1–12, UD 1–18 undetectable levels of SmfD at month 1 and 6, at month 1, 6 and 12, and at month 1, 6, 12 and 18, respectively (for number with follow up data at each relevant time point, see Table S11 in S1 File).

Fig 7. SmfD 1, 6, 12 and 18 month post-treatment in participants with ‘suboptimal microfilariae response’ to ivermectin as indicated by ≤80% reduction of skin microfilariae levels from pre-treatment to 1 month after treatment’. SmfD: skin microfilariae density.

Fig 8. Minimum SmfD for participants with detectable SmfD at all post-treatment evaluations.

Left: moxidectin treated participants, center: ivermectin treated participants from DRC, right: ivermectin treated participants from Lofa country and Nkwanta North, IVM ivermectin, Moxi moxidectin, SmfD Skin microfilariae density.

Fig 9. SmfD at Month 1, 6, 12 and 18 vs pre-treatment SmfD for the 10 moxidectin and 88 ivermectin treated participants with ‘suboptimal response’ participants with ‘suboptimal response’.

IVM ivermectin, Moxi moxidectin, SmfD Skin microfilariae density.