AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial.

BACKGROUND: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent. METHODS: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations. RESULTS: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm. CONCLUSIONS: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r).

Infectious Disease Risk and Vaccination in Northern Syria after 5 Years of Civil War: The MSF Experience.

INTRODUCTION: In 2015, following an influx of population into Kobanê in northern Syria, Médecins Sans Frontières (MSF) in collaboration with the Kobanê Health Administration (KHA) initiated primary healthcare activities. A vaccination coverage survey and vaccine-preventable disease (VPD) risk analysis were undertaken to clarify the VPD risk and vaccination needs. This was followed by a measles Supplementary Immunization Activity (SIA). We describe the methods and results used for this prioritisation activity around vaccination in Kobanê in 2015. METHODS: We implemented a pre-SIA survey in 135 randomly-selected households in Kobanê using a vaccination history questionnaire for all children <5 years. We conducted a VPD Risk Analysis using MSF 'Preventive Vaccination in Humanitarian Emergencies' guidance to prioritize antigens with the highest public health threat for mass vaccination activities. A Measles SIA was then implemented and followed by vaccine coverage survey in 282 randomly-selected households targeting children <5 years. RESULTS: The pre-SIA survey showed that 168/212 children (79.3%; 95%CI=72.7-84.6%) had received one vaccine or more in their lifetime. Forty-three children (20.3%; 95%CI: 15.1-26.6%) had received all vaccines due by their age; only one was <12 months old and this child had received all vaccinations outside of Syria. The VPD Risk Analysis prioritised measles, Haemophilus Influenza type B (Hib) and Pneumococcus vaccinations. In the measles SIA, 3410 children aged 6-59 months were vaccinated. The use of multiple small vaccination sites to reduce risks associated with crowds in this active conflict setting was noted as a lesson learnt. The post-SIA survey estimated 82% (95%CI: 76.9-85.9%; n=229/280) measles vaccination coverage in children 6-59 months. DISCUSSION: As a result of the conflict in Syria, the progressive collapse of the health care system in Kobanê has resulted in low vaccine coverage rates, particularly in younger age groups. The repeated displacements of the population, attacks on health institutions and exodus of healthcare workers, challenge the resumption of routine immunization in this conflict setting and limit the use of SIAs to ensure sustainable immunity to VPDs. We have shown that the risk for several VPDs in Kobanê remains high. CONCLUSION: We call on all health actors and the international community to work towards re-establishment of routine immunisation activities as a priority to ensure that children who have had no access to vaccination in the last five years are adequately protected for VPDs as soon as possible.

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.

Barriers and delays in tuberculosis diagnosis and treatment services: does gender matter?

Background. Tuberculosis (TB) remains a global public health problem with known gender-related disparities. We reviewed the quantitative evidence for gender-related differences in accessing TB services from symptom onset to treatment initiation. Methods. Following a systematic review process, we: searched 12 electronic databases; included quantitative studies assessing gender differences in accessing TB diagnostic and treatment services; abstracted data; and assessed study validity. We defined barriers and delays at the individual and provider/system levels using a conceptual framework of the TB care continuum and examined gender-related differences. Results. Among 13,448 articles, 137 were included: many assessed individual-level barriers (52%) and delays (42%), 76% surveyed persons presenting for care with diagnosed or suspected TB, 24% surveyed community members, and two-thirds were from African and Asian regions. Many studies reported no gender differences. Among studies reporting disparities, women faced greater barriers (financial: 64% versus 36%; physical: 100% versus 0%; stigma: 85% versus 15%; health literacy: 67% versus 33%; and provider-/system-level: 100% versus 0%) and longer delays (presentation to diagnosis: 45% versus 0%) than men. Conclusions. Many studies found no quantitative gender-related differences in barriers and delays limiting access to TB services. When differences were identified, women experienced greater barriers and longer delays than men.