Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial.

Background: We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian human immunodeficiency virus-infected patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of up to 2.5 years after initiating PSP, including 1-year follow-up after PSP discontinuation. Methods: The trial had 3 phases: (1) 12 months of PSP; (2) a 6-month PSP extension period if CD4 count was ≤200 cells/µL at month 12; and (3) 12-month follow-up after stopping PSP. The probability of relapse and risk factors were calculated using Kaplan-Meier methods and Cox regression analysis. Results: For the 74 patients included, final study outcomes were as follows: 39 (53%) relapse-free, 20 (27%) relapsed, 5 (7%) deaths, 10 (14%) lost to follow-up. The 2-year risk of relapse was 36.9% (95% confidence interval, 23.4%-55.0%) and was highest for those with a history of VL relapse and low baseline CD4 count. Forty-five patients were relapse-free and in follow-up at month 12 of PSP. This included 28 patients with month 12 CD4 counts >200 cells/µL, remaining relapse-free after PSP discontinuation. Among the 17 with month 12 CD4 count <200 cells/µL, 1 relapsed and 3 were lost during the PSP extension period. During 1-year post-PSP follow-up, 2 patients relapsed and 1 was lost to follow-up. No PSP-related serious adverse events were reported during the PSP-extension/post-PSP follow-up period. Conclusions: It seems safe to discontinue PSP at month 12 CD4 counts of >200 cells/µL. The management of those failing to reach this level remains to be defined. Clinical Trials Registration: NCT01360762.

The Risk and Predictors of Visceral Leishmaniasis Relapse in Human Immunodeficiency Virus-Coinfected Patients in Ethiopia: A Retrospective Cohort Study.

BACKGROUND: East Africa, where Leishmania donovani is prevalent, faces the highest burden world-wide of visceral leishmaniasis (VL) and human immunodeficiency virus (HIV) coinfection. However, data on the risk and predictors of VL relapse are scarce. Such information is vital to target medical follow-up and interventions to those at highest risk. METHODS: We conducted a retrospective cohort study at a Médecins Sans Frontières-supported health center in northwest Ethiopia. We included adult VL-HIV coinfected patients treated for VL and discharged cured between February 2008 and February 2013. The risk of relapse was calculated using Kaplan-Meier methods, and predictors were determined using Cox regression models. RESULTS: Of the 146 patients included, 140 (96%) were male and the median age was 31 years. At the index VL diagnosis, 110 (75%) had primary VL, 57 (40%) were on antiretroviral therapy (ART), and the median CD4 count was 149 cells/µL. The median follow-up time after cure was 11 months, during which 44 (30%) patients relapsed. The risk of relapse was 15% at 6 months, 26% at 12 months, and 35% at 24 months. Predictors of relapse were: not being on ART at VL diagnosis, ART not initiated during VL treatment, and high tissue parasite load (parasite grade 6+) at VL diagnosis. CONCLUSIONS: The risk of VL relapse in coinfected patients was high, particularly in those not on ART or presenting with a high tissue parasite load. These patients should be preferentially targeted for secondary prophylaxis and/or regular medical follow-up. Timely ART initiation in all coinfected patients is crucial.

Status of zoonotic disease research in refugees, asylum seekers and internally displaced people, globally: A scoping review of forty clinically important zoonotic pathogens.

BACKGROUND: At the end of 2022, there were over 108 million forcibly displaced people globally, including refugees, asylum seekers (AS) and internally displaced people (IDPs). Forced migration increases the risk of infectious disease transmission, and zoonotic pathogens account for 61% of emerging and re-emerging infectious diseases. Zoonoses create a high burden of disease and have the potential to cause large-scale outbreaks. This scoping review aimed to assess the state of research on a range of clinically relevant zoonotic pathogens in displaced populations in order to identify the gaps in literature and guide future research. METHODOLOGY / PRINCIPAL FINDINGS: Literature was systematically searched to identify original research related to 40 selected zoonotic pathogens of interest in refugees, AS and IDPs. We included only peer-reviewed original research in English, with no publication date restrictions. Demographic data, migration pathways, health factors, associated outbreaks, predictive factors and preventative measures were extracted and synthesized. We identified 4,295 articles, of which 347 were included; dates of publications ranged from 1937 to 2022. Refugees were the most common population investigated (75%). Migration pathways of displaced populations increased over time towards a more complex web, involving migration in dual directions. The most frequent pathogen investigated was Schistosoma spp. (n = 99 articles). Disease outbreaks were reported in 46 publications (13.3%), with viruses being the most commonly reported pathogen type. Limited access to hygiene/sanitation, crowding and refugee status were the most commonly discussed predictors of infection. Vaccination/prophylaxis drug administration, surveillance/screening and improved hygiene/sanitation were the most commonly discussed preventative measures. CONCLUSIONS / SIGNIFICANCE: The current research on zoonoses in displaced populations displays gaps in the spectrum of pathogens studied, as well as in the (sub)populations investigated. Future studies should be more inclusive of One Health approaches to adequately investigate the impact of zoonotic pathogens and identify transmission pathways as a basis for designing interventions for displaced populations.

Obstetric Outcomes of Eritrean Immigrants in Switzerland: A Comparative Study.

Objectives: This study aims to compare obstetric outcomes between Eritrean and Swiss women in Switzerland, focusing on instrumental or surgical interventions and analgesia use. Methods: The study included data from 45,412 Swiss and 1,132 Eritrean women who gave birth in Swiss hospitals (2019-2022). Mixed-effects logistic regression was used to assess the effect of nationality on mode of delivery and analgesia use and multinomial mixed-effects logistic regression to assess the effect of nationality on mode of delivery in women intended for spontaneous vaginal delivery. Results: Compared with Swiss, Eritrean women had a lower rate of primary C-section (Adj. OR 0.73, 95% CI [0.60, 0.89]) but a higher risk of initially planned vaginal deliveries ending in emergency C-section (RRR 1.31, 95% CI [1.05, 1.63]). Eritrean women were less likely to receive epidural analgesia (Adj. OR 0.53, 95% CI [0.45, 0.62]) and more likely to not receive any analgesia (Adj. OR 1.73, 95% CI [1.52, 1.96]). Conclusion: This study reveals disparities in obstetric care, notably in higher emergency C-section rates and lower analgesia use among Eritrean women. For promoting equitable healthcare practices deeper understanding of obstetrics decision-making is needed.

Navigating challenges: a socioecological analysis of sexual and reproductive health barriers among Eritrean refugee women in Ethiopia, using a key informant approach.

OBJECTIVES: The study aimed to explore the experiences and perceptions of healthcare providers (HCPs) regarding the sexual and reproductive health (SRH) challenges of Eritrean refugee women in Ethiopia. DESIGN: A qualitative exploratory design with the key informant approach. SETTING AND PARTICIPANTS: The study was conducted in the Afar regional state, North East, Ethiopia. The study participants were HCP responsible for providing SRH care for refugee women. RESULTS: Eritrean refugee women have worse health outcomes than the host population. The SRH needs were found to be hindered at multiple layers of socioecological model (SEM). High turnover and shortage of HCP, restrictive laws, language issues, cultural inconsistencies and gender inequalities were among the main barriers reported. Complex multistructural factors are needed to improve SRH needs of Eritrean refugee women. CONCLUSIONS: A complex set of issues spanning individual needs, social norms, community resources, healthcare limitations and structural mismatches create significant barriers to fulfilling the SRH needs of Eritrean refugee women in Ethiopia. Factors like limited awareness, cultural taboos, lack of safe spaces, inadequate healthcare facilities and restrictive policies all contribute to the severe limitations on SRH services available in refugee settings. The overlap in findings underscores the importance of developing multilevel interventions that are culturally sensitive to the needs of refugee women across all SEM levels. A bilateral collaboration between Refugees and Returnees Service (RRS) structures and the Asayta district healthcare system is critically important.

Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis.

BACKGROUND: Visceral leishmaniasis (VL) is a vector-borne disease that is deadly if left untreated. Understanding which factors have prognostic value may help to focus clinical management and reduce case fatality. However, information about prognostic factors is scattered and conflicting. We conducted a systematic review and meta-analysis to identify prognostic factors for mortality among VL patients in East Africa. METHODOLOGY/PRINCIPAL FINDINGS: The review protocol was registered in PROSPERO (CRD42016043112). We included studies published in English after 1970 describing VL patients treated in East African health facilities. To be included, studies had to report on associations between clinical or laboratory factors and mortality during admission or during VL treatment, with a minimal study size of ten patients. Conference abstracts and evaluations of genetic or immunological prognostic factors were excluded. We searched for studies in MEDLINE and four other databases in December 2018. To assess the risk of bias in observational studies and clinical trials, we used the Quality in Prognostic Studies (QUIPS) tool. We included 48 studies in the systematic review, describing 150,072 VL patients of whom 7,847 (5.2%) died. Twelve prognostic factors were evaluated in five or more studies and these results were submitted to meta-analysis producing one pooled crude odds ratio (OR) per prognostic factor. The following factors were strongly (OR>3) and significantly (P-value<0.05) associated with mortality: jaundice (OR = 8.27), HIV (OR = 4.60), tuberculosis (OR = 4.06), age >45 years (OR = 3.69), oedema (OR = 3.52), bleeding (OR = 3.37), and haemoglobin ≤6.5 g/dl (OR = 3.26). Factors significantly and moderately (OR between one and three) associated with death were severe malnutrition, long duration of illness, young age (<5 years), and large spleen size. CONCLUSIONS/SIGNIFICANCE: These prognostic factors can be identified by health professionals in resource-constrained settings. They should be considered as "core" prognostic factors in future studies that aim at improving the prognosis of VL patients.

Severe post-kala-azar dermal leishmaniasis successfully treated with miltefosine in an Ethiopian HIV patient.

Post-kala-azar dermal leishmaniasis (PKDL) is a neglected tropical disease characterized by a dermatosis which often appears after successful treatment of visceral leishmaniasis caused by Leishmania donovani. PKDL treatment options are few and have severe limitations. In East-Africa, the standard treatment of PKDL is with daily painful potentially toxic sodium stibogluconate injections, administered for a prolonged duration of 30-60 days. In the Indian subcontinent, PKDL is mainly treated with miltefosine, a safer orally administered drug. However, in East-Africa, there is very limited experience in the use of miltefosine for treatment of severe PKDL, with only one published case report. Here we report a severe PKDL case in an Ethiopian HIV patient successfully treated with oral miltefosine (100mg/day for 28 days). Miltefosine was efficacious, safe and well tolerated, suggesting that it can play an important role in the treatment of severe PKDL also in East-African patients. Further research is warranted.

Long term outcomes and prognostics of visceral leishmaniasis in HIV infected patients with use of pentamidine as secondary prophylaxis based on CD4 level: a prospective cohort study in Ethiopia.

BACKGROUND: The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited. METHODS: A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/µL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/µL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed. RESULTS: Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/µL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/µL who started pentamidine. Three patients with CD4 <200 cells/µL did not start pentamidine. Amongst those with CD4 ≥200 cells/µL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns. CONCLUSION: The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/µL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/µL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count.

The initial effectiveness of liposomal amphotericin B (AmBisome) and miltefosine combination for treatment of visceral leishmaniasis in HIV co-infected patients in Ethiopia: A retrospective cohort study.

BACKGROUND: North-west Ethiopia faces the highest burden world-wide of visceral leishmaniasis (VL) and HIV co-infection. VL-HIV co-infected patients have higher (initial) parasitological failure and relapse rates than HIV-negative VL patients. Whereas secondary prophylaxis reduces the relapse rate, parasitological failure rates remain high with the available antileishmanial drugs, especially when administered as monotherapy. We aimed to determine the initial effectiveness (parasitologically-confirmed cure) of a combination of liposomal amphotericin B (AmBisome) and miltefosine for treatment of VL in HIV co-infected patients. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a retrospective cohort study at a Médecins Sans Frontières-supported health center in north-west Ethiopia. We included VL-HIV co-infected adults, treated for VL between January 2011 and August 2014, with AmBisome infusion (30 mg/kg total dose) and miltefosine orally for 28 days (100 mg/day). Proportions of initial treatment outcome categories were calculated. Predictors of initial parasitological failure and of death were determined using multivariable logistic regression. Of the 173 patients included, 170 (98.3%) were male and the median age was 32 years. The proportion of patients with primary VL (48.0%) and relapse VL (52.0%) were similar. The majority had advanced HIV disease (n = 111; 73.5%) and were on antiretroviral therapy prior to VL diagnosis (n = 106; 64.2%). Initial cure rate was 83.8% (95% confidence interval [CI], 77.6-88.6); death rate 12.7% (95% CI, 8.5-18.5) and parasitological failure rate 3.5% (95% CI, 1.6-7.4). Tuberculosis co-infection at VL diagnosis was predictive of parasitological failure (adjusted odds ratio (aOR), 8.14; p = 0.02). Predictors of death were age >40 years (aOR, 5.10; p = 0.009), hemoglobin ≤6.5 g/dL (aOR, 5.20; p = 0.002) and primary VL (aOR, 8.33; p = 0.001). CONCLUSIONS/SIGNIFICANCE: Initial parasitological failure rates were very low with AmBisome and miltefosine combination therapy. This regimen seems a suitable treatment option. Knowledge of predictors of poor outcome may facilitate better management. These findings remain to be confirmed in clinical trials.

Does timing of antiretroviral treatment influence treatment outcomes of visceral leishmaniasis in Northwest Ethiopia?

Background: Visceral leishmaniasis (VL) patients with HIV co-infection should receive antiretroviral treatment (ART). However, the best timing for initiation of ART is not known. Among such individuals, we assessed the influence of ART timing on VL outcomes. Methods: A retrospective cohort study was conducted in Northwest Ethiopia among VL patients starting ART between 2008 and 2015. VL outcomes were assessed by the twelfth month of starting ART, within 4 weeks of VL diagnosis or thereafter. Results: Of 213 VL-HIV co-infected patients with ART initiation, 96 (45.1%) had moderate to severe malnutrition, 53 (24.9%) had active TB and 128 (60.1%) had hemoglobin levels under 9 g/dL. Eighty-nine (41.8%) were already on ART before VL diagnosis, 46 (21.6%) started ART within 4 weeks, and 78 (36.6%) thereafter. Definitive cure in those starting ART within 4 weeks 59% (95% CI 43-75%) and those starting thereafter 56% (95% CI 44-68%) was not significantly different. Those starting ART before primary VL had higher 12-months mortality compared to those starting later (RR 0.6; 95% CI 0.4-0.9; p=0.012). Conclusions: VL-HIV patients are severely ill and with serious additional comorbidities. Outcomes of HIV-VL management are unsatisfactory and early ART initiation was associated with higher mortality. Further research on the optimal timing of ART initiation, and ensuring earlier diagnosis of VL patients, with improved management of comorbidities are needed.

Development and external validation of a clinical prognostic score for death in visceral leishmaniasis patients in a high HIV co-infection burden area in Ethiopia.

BACKGROUND: In Ethiopia, case fatality rates among subgroups of visceral leishmaniasis (VL) patients are high. A clinical prognostic score for death in VL patients could contribute to optimal management and reduction of these case fatality rates. We aimed to identify predictors of death from VL, and to develop and externally validate a clinical prognostic score for death in VL patients, in a high HIV co-infection burden area in Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a retrospective cohort study in north west Ethiopia. Predictors with an adjusted likelihood ratio ≥1.5 or ≤0.67 were retained to calculate the predictor score. The derivation cohort consisted of 1686 VL patients treated at an upgraded health center and the external validation cohort consisted of 404 VL patients treated in hospital. There were 99 deaths in the derivation cohort and 53 deaths in the external validation cohort. The predictors of death were: age >40 years (score +1); HIV seropositive (score +1); HIV seronegative (score -1); hemoglobin ≤6.5 g/dl (score +1); bleeding (score +1); jaundice (score +1); edema (score +1); ascites (score +2) and tuberculosis (score +1). The total predictor score per patient ranged from -1 to +5. A score of -1, indicated a low risk of death (1.0%), a score of 0 an intermediate risk of death (3.8%) and a score of +1 to +5, a high risk of death (10.4-85.7%). The area under the receiver operating characteristic curve was 0.83 (95% confidence interval: 0.79-0.87) in derivation, and 0.78 (95% confidence interval: 0.72-0.83) in external validation. CONCLUSIONS/SIGNIFICANCE: The overall performance of the score was good. The score can enable the early detection of VL cases at high risk of death, which can inform operational, clinical management guidelines, and VL program management. Implementation of focused strategies could contribute to optimal management and reduction of the case fatality rates.

A Comparison of the Effectiveness of Sodium Stibogluconate Monotherapy to Sodium Stibogluconate and Paromomycin Combination for the Treatment of Severe Post Kala Azar Dermal Leishmaniasis in South Sudan - A Retrospective Cohort Study.

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL) is a common dermatological complication following successful treatment of Visceral Leishmaniasis (VL) caused by Leishmania donovani. PKDL presents as macular, papular, nodular or mixed skin rash on sun-exposed body parts. Patients are not ill unless there are complications due to mucosal involvement or ulceration. As PKDL in East Africa is typically self-healing, and treatment is long and with significant adverse events, only severe and complicated cases are treated. Studies to determine optimal treatment of PKDL are rare and based on small cohorts. Since 1989, Médecins Sans Frontières is treating severe PKDL within VL treatment programmes in South Sudan. Treatment was initially with sodium stibogluconate (SSG) monotherapy and since 2002 with a combination of SSG and paromomycin (PM). SSG monotherapy (20 mg/kg/day for a minimum of 30 days) was provided in primary health units, and the combination of PM (15 mg sulphate/kg/day for 17 days) plus SSG (30 mg/kg/day for a minimum of 17 days) was provided in secondary health facilities. METHODOLOGY/PRINCIPAL FINDINGS: By retrospective analysis of routinely collected programme data we compared the effectiveness (outcome and treatment duration) of both regimens. Between 2002 and 2008, 422 patients with severe PKDL were treated; 343 received SSG and 79 SSG/PM combination. The cure rate was significantly better with combination treatment when compared to monotherapy (97% vs. 90%; odds ratio [OR], 7.6; p = 0.02), treatment duration was shorter (mean 34 days vs. 42 days; p = 0.005), and defaulter rate was lower (3% vs. 9%; OR, 0.3; p = 0.03). There was no significant difference in death rate (0% vs. 1%; p = 0.5). CONCLUSIONS/SIGNIFICANCE: We found that SSG/PM combination therapy resulted in more favourable outcomes than SSG monotherapy. An additional advantage is the lower cost of the combination therapy, due to the shorter treatment duration. A combination of SSG and PM is therefore a suitable option for the treatment of PKDL in East Africa.

Use of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in HIV Infected Patients, the First Twelve Months of a Prospective Cohort Study.

BACKGROUND: Visceral leishmaniasis (VL) has become an important opportunistic infection in persons with HIV-infection in VL-endemic areas. The co-infection leads to profound immunosuppression and high rate of annual VL recurrence. This study assessed the effectiveness, safety and feasibility of monthly pentamidine infusions to prevent recurrence of VL in HIV co-infected patients. METHODS: A single-arm, open-label trial was conducted at two leishmaniasis treatment centers in northwest Ethiopia. HIV-infected patients with a VL episode were included after parasitological cure. Monthly infusions of 4 mg/kg pentamidine-isethionate diluted in normal-saline were started for 12 months. All received antiretroviral therapy (ART). Time-to-relapse or death was the primary end point. RESULTS: Seventy-four patients were included. The probability of relapse-free survival at 6 months and at 12 months was 79% and 71% respectively. Renal failure, a possible drug-related serious adverse event, occurred in two patients with severe pneumonia. Forty-one patients completed the regimen taking at least 11 of the 12 doses. Main reasons to discontinue were: 15 relapsed, five died and seven became lost to follow-up. More patients failed among those with a CD4+cell count ≤ 50 cells/µl, 5/7 (71.4%) than those with counts above 200 cells/µl, 2/12 (16.7%), (p = 0.005). CONCLUSION: Pentamidine secondary prophylaxis led to a 29% failure rate within one year, much lower than reported in historical controls (50%-100%). Patients with low CD4+cell counts are at increased risk of relapse despite effective initial VL treatment, ART and secondary prophylaxis. VL should be detected and treated early enough in patients with HIV infection before profound immune deficiency installs.