Comparison of Repeated Doses of Ivermectin Versus Ivermectin Plus Albendazole for the Treatment of Onchocerciasis: A Randomized, Open-label, Clinical Trial.

BACKGROUND: Improved treatment for onchocerciasis is needed to accelerate onchocerciasis elimination in Africa. Aiming to better exploit registered drugs, this study was undertaken to determine whether annual or semiannual treatment with ivermectin (IVM; 200 µg/kg) plus albendazole (ALB; 800 mg single dose) is superior to IVM alone. METHODS: This trial was performed in Ghana and included 272 participants with microfilariae (MF), who were randomly assigned to 4 treatment arms: (1) IVM annually at 0, 12, and 24 months; (2) IVM semiannually at 0, 6, 12, 18, and 24 months; (3) IVM+ALB annually; or (4) IVM+ALB semiannually. Microfiladermia was determined pretreatment and at 6, 18, and 36 months. The primary outcome was the proportion of fertile and viable female worms in onchocercomata excised at 36 months. RESULTS: Posttreatment nodule histology showed that 15/135 (11.1%), 22/155 (14.2%), 35/154 (22.7%), and 20/125 (16.0%) living female worms had normal embryogenesis in the IVM annual, IVM semiannual, IVM+ALB annual, and IVM+ALB semiannual groups, respectively (P = .1229). Proportions of dead worms also did not differ between the 4 groups (P = .9198). Proportions of patients without MF at 36 months (1 year after the last treatment) were 35/56 (63%) after annual IVM, 42/59 (71%) after semiannual IVM, 39/64 (61%) after annual IVM+ALB, and 43/53 (81%) after semiannual IVM+ALB. CONCLUSIONS: The combination treatment of IVM plus ALB was no better than IVM alone for sterilizing, killing adult worms, or achieving sustained MF clearance. However, semiannual treatment was superior to annual treatment for achieving sustained clearance of Onchocerca volvulus MF from the skin (P = .024). CLINICAL TRIALS REGISTRATION: ISRCTN50035143.

Orthopedic surgery in the developing world: workforce and operative volumes in Ghana compared to those in the United States.

BACKGROUND: Musculoskeletal disease is a growing burden in low- and middle-income countries (LMICs), yet little research exists to describe the problem. The purposes of this study were to characterize orthopedic surgery in an LMIC and compare the findings to those from a developed country. METHODS: The study location was the Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana. Orthopedic surgeon, resident, and postgraduate training program numbers were compared to analogous data from a developed nation, the United States. Annual surgical volumes were compared to those at a level I trauma center in the United States, the San Francisco General Hospital (SFGH). RESULTS: There were 24 surgeons in Ghana compared to 23,956 in the United States. There were 7 orthopedic residents and 1 residency program in Ghana versus 3,371 residents and 155 residencies in the United States. Annual case volume was 2,161 at KATH and 2,132 at SFGH. Trauma accounted for 95 % of operations at KATH compared to 65 % at SFGH. The proportion of surgeries devoted to severe fractures was 29 % at KATH compared to 12 % at SFGH. Infections comprised 15 % of procedures at KATH and 5 % at SFGH. CONCLUSIONS: Annual case volume at a referral hospital in an LMIC is equivalent to that of a level I trauma center in an industrialized country. Total case volume is similar, but the LMIC institution manages a disproportionately large number of trauma cases, severe fractures, and infections. There is a large burden of orthopedic disease in the developing nation, and there are too few providers and training programs to address these conditions.

An observational cohort study of the adoption of elastic stable intramedullary nailing for the treatment of pediatric femur fractures in Kumasi, Ghana.

BACKGROUND: In high- and middle-income countries, elastic stable intramedullary nailing (ESIN) is the commonest treatment of femur fractures in children 5-11 years of age. At Komfo Anokye Teaching hospital (KATH) in Kumasi, Ghana, prior to this study all pediatric femur fractures were treated with skin traction to union. This study was designed to report the early results and costs of the adoption of ESIN at KATH to provide data to other low- and middle-income sites considering adoption of this surgical technique. METHODS: An observational cohort study that included 84 pediatric patients ages 3-14 years presenting with closed femur fractures and treated with either skin traction or ESIN. Multivariate logistic regression was used to compare the rate of treatment success between treatment groups. RESULTS: Treatment success (coronal and sagittal angulation less than 10 ° and shortening less than 15 mm at osseous union) was achieved in 92 % of the ESIN group versus 67 % of the skin traction group (odds ratio for ESIN group 9.28 (1.6-54.7); p = 0.0138). Average length of stay was significantly lower in the ESIN group (p = 0.001), but charges to patients were higher in the ESIN group (p < 0.001) because of the high cost of implants. CONCLUSIONS: The initial experience of operative treatment of femoral shaft fractures in children using ESIN was positive, with improved rates of treatment success and no surgical complications. Because of the high cost of implants, direct costs of treatment remained higher with ESIN despite reductions in length of hospital stay.

Predictors of quality of life, economic impact, and loss to follow-up after open tibial shaft fractures in Ghana.

Objectives: Open tibia fractures are associated with substantial morbidity and impact on quality of life. Despite increasing incidence in low-resource settings, most open tibia fracture research comes from high-resource settings. This study aimed to assess the impact of socioeconomic status on treatment modality and evaluate predictors of health-related quality of life following open tibia fractures in Ghana. Design: A single-center prospective observational study was conducted in Kumasi, Ghana, from May 2020 to April 2022. Adults with open tibial shaft fractures presenting within 2 weeks of injury were eligible. Demographics, comorbidities, socioeconomic factors, and hospital course were collected at enrollment. Follow-up was scheduled at 8, 12, 26, and 52 weeks. A telephone survey assessing reasons for loss to follow-up was initiated on enrollment completion. Results: A total of 180 patients were enrolled. Most patients were employed before injury (79.9%), had government insurance (67.2%), and were from rural areas (59.4%). Fracture classification was primarily Gustilo-Anderson type 3A (49.1%). No relationship between socioeconomic predictors and treatment modality was identified. The largest barriers to follow-up were preference for bonesetter treatment (63.1%), treatment cost (48.8%), and travel cost (29.8%). Of the lost to follow-up patients contacted, 67 (79.8%) reported receiving traditional bonesetter care. Reasons for seeking traditional bonesetter care included ease of access (83.6%), lower cost (77.6%), and familial influence (50.7%). Conclusion: No association was identified between socioeconomic predictors and choice of treatment. Bonesetter treatment plays a substantial role in the care of open tibia fractures in Ghana, largely because of ease of access and lower cost.

Training Traditional Bonesetters in Basic Principles of Fracture Treatment: A Proof of Concept in Ghana.

BACKGROUND: Our study assessed the effectiveness of a traditional bonesetter (TBS) educational program that was designed to increase knowledge, reduce complications, and promote the referral of patients to local hospitals by TBSs when necessary. METHODS: From April to December 2021, TBSs from the Northern Sector (the Northern, Savannah, and North East regions) and the Ashanti region of Ghana underwent a 4-day training course that had been designed to teach basic principles of fracture care with the use of local tools. We assessed the levels of knowledge of the TBSs both before and after training. The change in practice of the trained TBSs also was assessed at 6 months using a structured questionnaire and a checklist. RESULTS: In total, 157 TBSs were trained in 5 training sessions over a 9-month period. There was an improvement in knowledge in all of the modules of training, with an overall knowledge gain of 19.7% (from 67.2% to 86.9%). At 6 months of follow-up, the practices of TBSs that had most improved were record-keeping, hand hygiene, and patient rehabilitation. As a result of the referral system that was established by the training project, a total of 37 patients were referred to local hospitals in the 6 months following the training. CONCLUSIONS: Formal training for TBSs that was provided by a multidisciplinary team with use of a locally developed curriculum and tools was effective in improving the practice and outcomes of treatment by TBSs. There was marked knowledge retention by the trained TBSs at 6 months after training in fracture management. CLINICAL RELEVANCE: Education, training, and the establishment of referral pathways between TBSs and local hospitals could improve trauma care in Ghana.

Utility of an orthopaedic trauma registry in Ghana.

In most low- and middle-income countries, trauma registries are uncommon. Although institutional registries for all trauma patients are ideal, it can be more practical to institute departmental registries for specific subsets of patients. Komfo Anokye Teaching Hospital (KATH) has started a locally developed, self-funded orthopaedic trauma registry. We describe methods and experiences for data collection and examine patient and injury characteristics, data quality, and the utility of the registry. Of 961 individuals in the registry, 67.9% were males, and the median age was 40 years. Motor vehicle collision (23.3%) was the most frequent mechanism of injury. Lower extremity fractures were the most common injury (60.6%), and 43.9% of injuries were managed operatively. Data quality was reasonable with missingness under 10% for 13 of 14 key variables, with inconsistencies of dates of injury, admission, treatment, and discharge in 9.1% of cases. However, the type of operation was missing for 73.2% of operative cases. Despite these limitations, the registry has been used for quality improvement and to successfully advocate for resources to improve trauma care. The registry has been improved by adding more detailed outcome variables, creating a standardised codebook of categorical variables, and adding more fields to allow for multiple injuries. In conclusion, it is practical and sustainable to institute a locally developed, self-funded orthopaedic trauma registry in Ghana that provides data with reasonable quality. Such a registry can be used to advocate for more resources to care for injured patients adequately and for quality improvement. Funding: None declared.

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

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.

Efficacy of 5-week doxycycline treatment on adult Onchocerca volvulus.

The effects of 5-week doxycycline treatment on the depletion of Wolbachia endobacteria from Onchocerca volvulus, on the interruption of embryogenesis and on microfilariae production, and with regard to macrofilaricidal activity were studied. In 2003, in an endemic area in Ghana, 22 onchocerciasis patients received 100 mg/day doxycycline for 5 weeks. Two years after the start of the study, 20 treated and ten untreated patients were nodulectomized and skin microfilariae were counted. The onchocercomas were examined by immunohistology for the presence of Wolbachia, embryogenesis, and vitality of adult filariae. The latter two parameters were further assessed by alternating logistic regression analysis, taking into account the dependency of worms and nodules in patients. Doxycycline resulted in depletion of Wolbachia and in complete interruption of embryogenesis in all worms that were assumed to have been present during treatment. In the treated patients, only 51% of the female worms were alive, compared to 84% in the untreated patients, indicating a moderate but distinct macrofilaricidal activity of doxycycline at this dose. It is concluded that, in areas with ongoing transmission, doxycycline cannot replace regular ivermectin mass treatment because new infections would require repeated rounds of doxycycline. However, doxycycline can be used for the treatment of individuals outside transmission areas, in foci where ivermectin resistance may occur, and in countries where onchocerciasis and loiasis are co-endemic.

Effects of 6-week azithromycin treatment on the Wolbachia endobacteria of Onchocerca volvulus.

The effects of azithromycin treatment on the presence of Wolbachia endobacteria and on the embryogenesis and microfilariae production of Onchocerca volvulus were studied. In 2002, in an endemic area in Ghana, 37 onchocerciasis patients were treated for 6 weeks with azithromycin: 23 patients received 250 mg every day, and 14 took 1,200 mg once a week. After 6 and/or 12 months, all palpable worm nodules were extirpated from 31 treated and nine additional untreated patients, and the presence of Wolbachia and embryogenesis were assessed by immunohistology. In nodules taken 6 months after treatment with either dose and 12 months after 1,200 mg/week, the Wolbachia loads of the worms were not different from those of untreated worms. However, 12 months after the 250-mg/day azithromycin regimen, significantly less female worms (65% compared to 92% untreated ones) presented many Wolbachia, although the reduction was less pronounced than observed in other studies after treatment with doxycycline. Embryogenesis and microfilariae production were not reduced. It is concluded that azithromycin administered alone for 6 weeks at 250 mg/day or 1,200 mg/week is not suitable for treatment of human onchocerciasis. But daily azithromycin should be studied in combination with other drugs and with other doses.

Efficacy of 2- and 4-week rifampicin treatment on the Wolbachia of Onchocerca volvulus.

The microfilaricidal and temporarily sterilizing drug ivermectin is used for mass treatment of filarial infections. Filariae containing Wolbachia endobacteria can also be treated by the antibiotic doxycycline. The loss of Wolbachia results in sterilization of Onchocerca volvulus and macrofilaricidal effects. Besides doxycycline, other antibiotics may be effective in depleting Wolbachia. A preliminary study on the effects of rifampicin on the endobacteria, embryogenesis and microfilariae production of O. volvulus was carried out in the year 2000 in Ghana. Twenty-six onchocerciasis patients were treated for 2 or 4 weeks with 10 mg/kg/day rifampicin. From 17 treated and nine untreated patients, all palpable nodules were extirpated 1 or 18 months after the start of the study and examined for Wolbachia and embryogenesis using immunohistology. One and 18 months after rifampicin treatment, the proportion of Wolbachia-positive worms was significantly reduced compared to the untreated group. In patients treated 4 weeks with rifampicin, only 21% and 18% of living female filariae contained Wolbachia after 1 and 18 months, respectively, compared to 92% in the untreated patients. The reduction of Wolbachia after 2 weeks rifampicin was less but also significant. Embryogenesis and microfilariae production were reduced after 4 weeks rifampicin treatment, rendering rifampicin an antibiotic with anti-wolbachial efficacy in human onchocerciasis. This treatment is less efficient than treatment with 6 weeks doxycycline, but might be an alternative for cases that cannot be treated with doxycycline, e.g. children, or might be further developed for combination therapy.

Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study.

In a randomized, placebo-controlled trial in Ghana, 67 onchocerciasis patients received 200-mg/day doxycycline for 4-6 weeks, followed by ivermectin (IVM) after 6 months. After 6-27 months, efficacy was evaluated by onchocercoma histology, PCR and microfilariae determination. Administration of doxycycline resulted in endobacteria depletion and female worm sterilization. The 6-week treatment was macrofilaricidal, with >60% of the female worms found dead, despite the presence of new, Wolbachia-containing worms acquired after the administration of doxycycline. Doxycycline may be developed as second-line drug for onchocerciasis, to be administered in areas without transmission, in foci with IVM resistance and in areas with Loa co-infections.